Preventive Dermatology

Preventive Dermatology

Robert A. Norman (Ed.)

Preventive Dermatology

Dr. Robert A. Norman 8002 Gunn Highway Tampa, Florida, 33626 USA

ISBN: 978-1-84996-020-5     e-ISBN: 978-1-84996-021-2 DOI: 10.1007/978-1-84996-021-2 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2010920241 © Springer-Verlag London Limited 2010 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Foreword

In his latest book, Dr. Robert A. Norman introduces us to the intriguing concept of preventive dermatology. Although dermatologists have long been patient advocates and have stressed vigorously on the importance of sun avoidance and protection, there is still much more that we can do to prevent disease. Dr. Norman and his skilled coterie of collaborators discuss two distinct types of prevention in dermatology: the prevention of skin diseases and the prevention of systemic disorders, some with only very indirect connections to the skin. The first is fairly well known to dermatologists; the second is truly an emerging concept of great importance. Educational efforts to prevent or at least control skin disease may range from the proper use of sunscreens to weight loss in psoriatic patients, the avoidance of trigger factors in rosacea, proper skin care in atopic dermatitis, or adoption of a low-fat diet to decrease the incidence of actinic keratosis and nonmelanoma skin cancer. Another good example is the use of vaccines to protect against diseases such as herpes zoster and genital HPV infection in females. This book, however, looks beyond the prevention of skin diseases to suggest that dermatologists view their patients through a more holistic lens. This means treating the entire patient not just the skin. Thus Dr. Norman suggests that we be more proactive in addressing health issues such as obesity, smoking, stress management, and nutrition. Consider, for example, the psoriatic patient, whose disease must now be treated as a systemic disorder predisposing to the very serious risks of the metabolic triad. As dermatologists, we deal with numerous chronic diseases, seeing some patients repeatedly over many years. This longitudinal interaction offers an excellent platform for the practice of preventive dermatology. Read and enjoy this book. It could make you a better dermatologist. Professor and Chairman Department of Dermatology Baylor College of Medicine

John E. Wolf, Jr., MD

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Preface

This is the first book fully dedicated to prevention in dermatology. It seems almost counterintuitive to take on this task, because so much of what we do in dermatology is based on repair and restructuring of skin maladies. But with the shortage of dermatology providers and the shift to cosmetics and procedures, it is urgent to make sure our patients are given a fair chance to succeed in the fast-changing world of modern health care. Although we are specialists in skin care, we are health care providers first, and should treat our patients with a holistic and caring approach that includes prevention. We live in a world between expectation and reality – and our goal as providers is to help ourselves and our patients anticipate problems and provide solutions. A smoker may have expectations of invincibility. Like many of you, I have succeeded most often in getting the person to quit by appealing to the vanity of the smoker by pointing out the accumulated wrinkles if he or she persists. If that method works, it is a success! Time’s arrow only moves in one direction – forward – and chronological aging takes a toll on all of us, especially visible on the most recognizable features of our facial skin. A rising tide of boomers are arriving daily at the shores of older age and demanding more help, including prevention of skin problems. Much can be done to prevent the disfiguring effects brought on by the abuse of sun, nicotine and alcohol, excess weight, mobility and exercise difficulties, dysfunctional nutrition, improper hygiene, lack of immunizations, poor reading and comprehension skills, inadequate cosmetic repair, and many other problems. Preventive dermatology focuses on ways we can minimize skin problems, and maximize and enjoy the time we have been given. We have highly effective sunscreens, a plethora of information about skin care on the internet, and more prevention and treatment modalities than ever before. But even the most informed patients need guidance, and that is why you need the information included in this book. I hope you share this information with your colleagues and patients, and this first book on prevention in dermatology is a springboard for many more books, ideas, and discussions to improve the quality of our lives. Tampa, FL 2010

Dr. Robert A. Norman

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Acknowledgment

Thanks to all my patients, friends and family, professors, chapter authors, and to the great people at Springer, including Grant Weston, Balasaraswathi Jayakumar, Barbara Lopez-Lucio, and others, who helped give birth to this book. Dr. Robert A. Norman

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Contents

Part I  Prevention — an Overview   1 Stress, Relaxation, and General Well-Being . . . . . . . . . . . . . . . . . . . . . . Nana Smith and Francisco A. Tausk

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  2 Smoking, Obesity/Nutrition, Sun, and the Skin . . . . . . . . . . . . . . . . . . . Robert A. Norman and Max Rappaport

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  3 Raising Awareness on the Health Literacy Epidemic . . . . . . . . . . . . . . Michelle C. Duhaney

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  4 Domestic Violence, Abuse, and Neglect: Indicators for Dermatology . . Jina P. Lewallen and Susan R. Adams

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  5 Working with Other Healthcare Providers . . . . . . . . . . . . . . . . . . . . . . Jina P. Lewallen, Carolyn Lazaro Tuturro, and Angelo Turturro

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  6 The Future of Dermatological Therapy and Preventive Dermatology . . . Robert A. Norman

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Part II  Common Problems and Treatment in Dermatological Prevention   7 Prevention of Drug Reactions and Allergies in Dermatology . . . . . . . . Lisa C. Hutchison and Oumitana Kajkenova

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  8 Xerosis and Stasis Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Margaret E. M. Kirkup

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  9 Photoprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Camile L. Hexsel and Henry W. Lim

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10 Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Panoglotis Mitropoulos and Robert A. Norman

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11 Occupational Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Athena Theodosatos and Robert Haight

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12 Diagnosis and Prevention of Bullous Diseases . . . . . . . . . . . . . . . . . . . . 115 Supriya Venugopal and Dedee F. Murrell 13 Diagnosis and Prevention of Atopic Eczema . . . . . . . . . . . . . . . . . . . . . 137 Stefan Wöhrl 14 Prevention of Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Gwynn Coatney and Robert A. Norman 15 Sports Dermatology: Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Brian B. Adams 16 Prevention of Cosmetic Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Zoe Diana Draelos 17 Nutrition, Vitamins, and Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Evangeline B. Handog and Trisha C. Crisostomo Part III  Sexually Transmitted Diseases, Viral Diseases, and Vaccines 18 Vaccines for Viral Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 Ivan D. Camacho and Brian Berman 19 Prevention of Sexually Transmitted Diseases from Office to Globe . . . 211 Kim K. Dernovsek 20 Current Vaccinations in Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Kamaldeep Singh and Robert A. Norman Part IV  Wounds, Surgery, and Dermatological Prevention 21 Prevention of Skin Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Dirk M. Elston 22 Wound Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Cynthia A. Fleck 23 Prevention of Surgical Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 Michael R. Hinckley 24 Prevention of Keloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Hillary E. Baldwin Appendix 1 Patient Handouts: Preventive Dermatology Topics ��������������� 293 Robert A. Norman and Lana H. McKinley Appendix 2 Skin Performance Assessment Questionnaire������������������������� 303 Robert A. Norman Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

Contents

Contributors

Brian B. Adams , MD, MPH  Department of Dermatology, University of Cincinnati, Cincinnati, OH, USA Susan R. Adams, BA, MSW (LCSW ACADC CCDP-D, QMRP)  Department of Health Science (Addiction Studies), University of Central Arkansas, Conway, AR, USA Hillary E. Baldwin, MD  Department of Dermatology, SUNY – Brooklyn, Brooklyn, NY, USA Brian Berman, MD, PhD  Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA Ivan D. Camacho, MD  Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, FL, USA Gwynn E. Coatney, DO  Department of Family Medicine, University of Medicine and Dentistry of New Jersey, Stratford, NJ, USA Trisha C. Crisostomo, MD  Section of Dermatology, Research Institute for Tropical Medicine, Muntinlupa City, Philippines Kim K. Dernovsek, MD  Department of Dermatology and Family Medicine, University of Colorado Health Sciences Center, Pueblo, CO, USA Zoe Diana Draelos, MD  Department of Dermatology, Duke University School of Medicine, 2444 North Main Street, High Point, Durham, North Carolina NC 27262 Michelle C. Duhaney, DO  Department of Family Medicine, Broward General Medical Centre, Fort Lauderdale, FL, USA Dirk M. Elston, MD  Department of Dermatology, Geisinger Medical Center, Danville, PA, USA Cynthia A. Fleck, MBA, BSN, RN, ET/WOCN, CWS, DNC, CFCN  The American Academy of Wound Management (AAWM), Past President, The Association for the Advancement of Wound Care (AAWC), Past Director, Medline Industries, Inc., Vice President, Clinical Marketing, St. Louis, MO, USA Robert Haight, MD, MS, PH  Consultant Sarasota, Private Practice Sarasoda Florida, FL, USA

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Evangeline B. Handog, MD, FPDS  Department of Dermatology, Asian Hospital and Medical Center, Filinvest Corporate City, Mutinlupa, Alabang, Philippines Camile L. Hexsel, MD  Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA Michael R. Hinckley, MD  Department of Dermatology, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA Lisa C. Hutchison, PharmD, MPH  Department of Pharmacy Practice, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA Oumitana Kajkenova, MD  Department of Geriatrics, Thomas and Lyon Longevity Clinic, University of Arkansas for Medical Sciences, Little Rock, AR, USA Margaret E. M. Kirkup, MBChB, MRCP  Department of Dermatology, Weston General Hospital, Weston-super-Mare, Avon, UK Jina P. Lewallen, LCSW, MA  Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA Henry W. Lim, MD  Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA Lana H. McKinley, BS, MS IV  College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale-Davie, FL, USA Panoglotis Mitropoulos, DO  Camp Long Troop Medical Clinic, South Korea Dedee F. Murrell, MA (Cambridge) BMBCh (Oxford) FAAD (USA) MD (UNSW)  Department of Dermatology, St. George Hospital, University of NSW Medical School, Sydney, Australia Robert A. Norman, DO, MPH  Nova Southeastern University, Ft. Lauderdale, Florida and Private Practice, Tampa, FL, USA Max J. Rappaport, BA  Ist Year Medical Student LECOM Bradenton, Florida Kamaldeep Singh, DO  Internal Medicine Resident, Stony Brook University Hospital, Stony Brook, NY, USA Nana Smith, MD  Department of Dermatology, University of Rochester, Rochester, NY, USA Francisco A. Tausk, MD  Department of Dermatology and Psychiatry, University of Rochester, Rochester, NY, USA Athena Theodosatos, DO, MPH  Department of Family Medicine, Florida Hospital, Winter Park, FL, USA Angelo Turturro, PhD, DADT  Graduate Gerontology Program, School of Social Work, University of Arkansas at Little Rock, Little Rock, AR, USA

Contributors

Contributors

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Carolyn Lazaro Turturro, PhD, CHES  Graduate Gerontology Program, School of Social Work, University of Arkansas at Little Rock, Little Rock, AR, USA Supriya Venugopal, BSc (Med) MBBS (UNSW)  Department of Dermatology, St. George Hospital, University of NSW Medical School, Sydney, Australia Stefan Wöhrl, MD, MSc  Department of Dermatology, Division of Immunology, Allergy and Infections Diseases (DIAID), Medical University of Vienna, Vienna, Austria

Part Prevention — An Overview

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Stress, Relaxation, and General Well-Being Nana Smith and Francisco A. Tausk

Your pain is the breaking of the shell that encloses your understanding. … It is the bitter potion by which the physician within you heals your sick self. Therefore trust the physician, and drink his remedy in silence and tranquility… From The Prophet, Khalil Gibran

We instinctively understand that, in general, stress is an uncomfortable and deleterious physical and emotional state. However, it is often difficult to recognize and control. In dermatology, stress can be both a consequence and an instigator of disease. This chapter will explore (1) definitions of stress, (2) the interplay between stress and the skin, and (3) various stressreducing modalities.

1.1 Stress Stress encompasses a myriad of emotional and physical triggers which have a taxing effect on our bodies. Stress can be acute or chronic. As humans, we are well adapted to acute stress. Imagine the changes in our predecessors’ heart rate and blood flow in response to the proximity of a predator. However, it could be argued that the concept of chronic stress is a creation of the modern world. Our ability to adapt to chronic stress is not necessarily innate and requires a much more creative and active approach. Stress can be considered as a disruption of balance which triggers various adaptive responses. Hans Selye,

N. Smith (*) Department of Dermatology, University of Rochester, Rochester, NY, USA e-mail: [email protected]

a 1930s endocrinologist, coined the term stress and defined it in terms of the General Adaptation Syndrome. Throughout his career he performed various experiments which showed that animals respond to stress in three stages. In the General Adaption Syndrome, the first stage is alarm. The physiology of this stage is wellunderstood and represents an acute response to stress. The sympathetic nervous system is activated, releasing catecholamines (CA) such as epinephrine and norepinepharine. This is the fight-or-flight response which causes blood to flow toward large muscular groups and away from the gastrointestinal system, the skin, and other organs. Walter Cannon, who in the 1920s first coined the term “fight or flight”1 described the responses of the sympathetic nervous system and adrenal gland to environmental stressors.2 The hypothalamic-pituitary-adrenal (HPA) axis is also stimulated, which releases hormones such as cortisol. Resistance is the second stage. Here the body’s coping resources are gradually diminished. In the final, exhaustion stage, the resources are depleted and the subject is unable to maintain homeostasis. Interestingly, the fight-or-flight response may now briefly reappear. However, with continued stressors, the adrenal gland and the immune system are sufficiently taxed and illnesses begin to manifest. This is analogous to a state of chronic stress. The term allostasis refers to the balance between stressors and coping mechanisms; it is the ability to  adapt to maintain balance and stability. This is a  slightly different framework for stress than that defined by Seyle.3 Allostasis is different from

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_1, © Springer-Verlag London Limited 2010

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There is a complex interplay between stressors, the central nervous system, the endocrine system, immune function, and the skin. The HPA axis is stimulated by signals which are processed in the hypothalamus and the brain stem (locus ceruleus [LC]). In response to

these stressors, the hypothalamus secretes corticotrophin-releasing hormone (CRH). From the hypothalamus, CRH-containing neurons communicate with the brain stem and spinal cord. CRH release further activates the HPA axis by causing the release of peptides from the pituitary. The peptides, such as adrenocorticotropic hormone (ACTH), enkephalins, and endorphins, are produced by the differential cleavage of pro-opiomelanocortin (POMC). ACTH induces release of glucocorticoids (GC) such as cortisol from the adrenal cortex. Activation of the noradrenergic pathways by CRH-containing neurons results in secretion of norpeinephrine (NE) by the sympathetic nervous system and release of NE and epinephrine (EPI) from the adrenal medulla. These are called CA. The activation of the sympathetic nervous system and the adrenal cortex and the subsequent release of hormones and neurotransmitters have significant effects on the immune system (Fig. 1.1). In general, Th1-derived cytokines (IFN-a, IL-2) are considered proinflammatory whereas Th2-derived cytokines (IL-4, IL-5, IL-10) are considered antiinflammatory. Both GCs and CAs have the ability to create a shift toward the Th2 pathway by up-regulating Th2-cytokine production and also by suppressing APC production of IL-12 and Th1 cytokine synthesis5 (Fig. 1.1). APC-derived IL-12 is one of the main inducers of Th1 cytokine synthesis.6 Therefore, chronic stress is essentially immunosuppressive. Furthermore, immune challenges such as bacterial infections can result in the release of bacterial lipopolysaccharides

Fig.  1.1  The hypothalamic-pituitary-adrenal (HPA) axis and immunity. The identification of an external perceived stressor by the brain results in the activation of the paraventricular nucleus of the hypothalamus and the closely interconnected locus coeruleus. CRF is secreted from the hypothalamus and transported through the portal circulation to the pituitary, where it induces the release of ACTH from the anterior pituitary into the general circulation. The effect of this molecule results in the secretion of glucocorticosteroids and to a lesser extent CA from the adrenal gland. Cortisol will act as a negative feedback on the hypothalamus, inhibiting the release of CRF. The cells of the locus coeruleus have a rich neuronal connection with the PVN, and activate the sympathetic system which results in the secretion of epinephrine and nor-epinephrin. Both the cathecholamines and cortisol have a potent effect on the immune system. They modulate antigen presenting cells and macrophages inhibiting their activity and the production of IL-12 and IL-18, and they mediate the differentiation of naïve T helper cells towards the TH2 constellation, in detriment of the development of TH1 mediated immu-

nity. This results in tilting the balance towards humoral immunity by increasing the production of IL-4, IL-5, and IL-13, which activate B-cells, mast cells, and eosinophils, increasing the allergic inflammatory response. The chronic dampening of cellmediated immunity could result in an impaired ability to confront effectively the development of infectious or tumoral insults. On the other hand, internal stressors are exemplified here by bacterial infections. The released bacterial lipopolysaccharides (LPS) bind to toll-like receptors on macrophages, and through NFkB induce the production of IL-1 and IL-6. These cytokines are able to cross the blood–brain barrier and reach the hypothalamus, where they stimulate the secretion of CRF, initiating the activation of the HPA axis. In this manner, infections have the potential to shift the immune balance favoring the humoral TH2 mediated response. Diseases that involve this arm of the immune system such as autoimmune or allergic diseases would deteriorate during the presence of stressors of the internal as well as external kind. Stimulation (straight arrows). Inhibition (broken arrows). Reproduced with permission from Harth et al104

homeostasis in that homeostasis is concerned with minute-to-minute regulation of bodily functions in a very narrow range whereas in allostasis the range is much wider. McEwen views the consequences of chronic stress as a type of allostatic load which can build up and lead to disease. In the ideal situation, a person is presented with a stressor, the body compensates by initiating certain stress responses, and when the stressor is gone, the stress response is shut off. In this situation, there is little allostatic load. Conditions in which allostatic load can build up include frequent stressor over time, lack of adaptation to stressors (decreased response to stressors over time), inability to shut down a stress response, and inadequate initial response which leads to compensations by other stress responses.4 Acute and chronic stresses have different effects on our bodies. The effects are seen in the cardiovascular and endocrine/metabolic systems, the brain, and the immune system.

1.2 Stress, Immune Function, and the Skin

1  Stress, Relaxation, and General Well-Being

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(LPS) which induces the nuclear factor (NF) kb mediated secretion of IL-1 and IL-6. These cytokines are responsible for fatigue, somnolence, and fever. These cytokines (IL-1, IL-6) stimulate the hypothalamic stress response in a positive feedback loop (Fig. 1.1). One main mechanism for the ability of GCs to ­suppress APCs is by inhibiting the costimulatory molecules

necessary for T cell activation. GCs also decrease the ability of neutrophils to find sites of inflammation (decreased chemotaxis) and to attach to vascular endothelium and extravasate into the tissue. The skin itself is a major source of central neuroendocrine stress mediators and has fully active peripheral equivalents of central stress responses systems. For

STRESS

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Inflammation

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example, skin cells produce a variety of neuropeptides, hormones, and neurotransmitters which have been implicated in modulating immune function in the skin, communicating with the hypothalamus, and playing a role in the development of skin diseases. The brain can affect inflammatory conditions in the skin but stimuli received by the skin can also influence the immune, endocrine, and nervous systems.7 Stress decreases wound-healing capacities. KiecoltGlaser et al found that in normal, healthy dental ­students, the time to heal a mucosal wound was approximately 3 days slower at the time of examination.8 They also showed that married couples with hostile interactions had impaired wound healing compared to happier couples. These findings may be explained by the effects of stress on matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs).9, 10 Tausk et  al investigated the effects of stress in mice induced by the smell of fox urine (a natural predator). Mice exposed to stress showed delayed wound healing compared to control mice (unpublished data). As most dermatologists have witnessed from their patients, skin disease is often worsened or initiated by stressful situations. Patients even associate conditions that have not been described in the literature as being stress-associated with increased stress in their lives. The stressor need not be emotional in nature; we are well aware of dermatologic conditions associated with recent illness, a type of physical stress. Emotional stressors have been associated with the development or worsening of a variety of dermatologic diseases including acne, vitiligo, alopecia areata, lichen planus, seborrheic dermatitis, telogen effluvium, herpes simplex infections, pemphigus, urticaria, psoriasis, angioedema atopic dermatitis, hyperhidrosis, neurotic excoriations, warts, cysts, and more.11–18 Stress has been reported to both precede the onset of psoriasis19 and to trigger flares.20, 21 The observation that led to further study of psoriasis and stress involved psoriasis patients who have undergone physical trauma. In some cases, where there was traumatic disconnection of sensory nerves, the psoriatic skin in the innervated areas resolved. When the fibers regenerated and sensitivity returned, the psoriatic plaques returned. It was hypothesized that local neuropeptides where responsible for the persistence of psoriatic plaques. It was later discovered that not only do psoriatic plaques have different content of neuropeptides such as SP (substance P), VIP (vasoactive intestinal

N. Smith and F. A. Tausk

peptide), CGRP(calcitonin gene-related protein), and NGF (nerve growth factor) but the density of nerve fibers in the plaques is elevated.22–25 Increased levels of NGF causes T cell and keratinocyte proliferation, mast cell degranulation, and memory T cell chemotaxis, which are all features seen in psoriasis.26–28 The HPA axis in psoriasis patients also exhibits an insufficient production of cortisol in the face of experimental stressors.29, 30 In atopic dermatitis, stress can also worsen the existing disease and stimulate flares.31, 32 In experimental studies, stress has been found to interfere with the barrier function of the skin.33 When the straum corneum is unable to recover from transepidermal water loss, the barrier is disrupted, inviting various infectious agents and allergens to initiate a disease flare.34 Another explanation for the connection between stress and atopic dermatitis is that, much as in psoriasis, patients with this disease have an insufficient HPA axis response to stress.35–37 Interestingly, the circulating leukocytes in patients with atopic dermatitis have a higher number of GC receptors than control patients. Therefore, and perhaps in compensation for a blunted HPA response, when immune cells are exposed to even a small amount of cortisol produced by stress they are hyperactive along the cortisol-induced Th2 pathway.38 This is detrimental, as IL-4 and IL-10 activate mast cells, eosinophils, and IgE production which further worsens atopic dermatitis. The worsening of atopic dermatitis in the face of stress may also be, in part, caused by the effects of epinephrine.39 Episodes of urticaria, especially adrenergic urticaria, have been associated with stressful events. Again, the cortisol-induced upregulation of Th2 cytokines, leading to the activation and degranulation of mast cells could explain this phenomenon40 as well as the fact that mast cell CRH receptors41 are upregulated under stress. Stress also plays a role in infections of the skin including those bacterial, viral, and fungal in nature.42–46 In rats, stressed by restraining them, HSV is reactivated in the dorsal root ganglion. Epidemiologic studies have found that in humans it is chronic, not necessarily acute stress which is associated with more frequent outbreaks.46,47 Various stress-reducing techniques have been shown to reduce outbreak frequency.48 In both human and animal studies, stress has been linked to malignancy, perhaps by suppressing lymphocyte and especially natural killer (NK) cell activity.49–62

1  Stress, Relaxation, and General Well-Being

Parker et al reported findings linking stress to skin cancer in mice.63 Two groups of mice were exposed to UV light; one group was stressed by the smell of a predator and the other group was not. The stressed group developed squamous cell carcinomas (SCCs) significantly earlier than the nonstressed group (SCC at week 8 vs. week 21, p < 0.05). This observation was confirmed by another group.64 Stress-reducing interventions have shown a survival benefit for patients with malignancies.65 For example, patients with metastatic melanoma had an increased 6-year survival rate when a stressreducing and psychological intervention was made.66 Again, this may be linked to altered NK function under stressful situations.67 In other studies, the cytotoxic function of the lymphocytes in older adults and in immunocompetent medical students was altered by chronic stress; relaxation training increased this cytotoxic function.68, 69 Other mice models have shown that chronic stress suppresses lymphocyte proliferation, increases metastases risk and growth of the primary tumor.70–72

1.3 Epidemiology Use of various stress-reducing modalities for skin disease is common among dermatologic patients throughout the world.73 A study performed in Leeds and South Wales in the United Kingdom investigated the use of complementary and alternative medicine (CAM) among patients presenting to an outpatient dermatology clinic. Three hundred and two completed questionnaires in Leeds and 415 in South Wales revealed that about 20% of Leeds patients and 5% of South Wales patients used aromatherapy. Faith or spiritual healing was used in about 10% in each group. Hypnotherapy was used in approximately 10% of Leeds patients and 5% of South Wales patients. Massage was used by around 15% of Leeds patients.74 Researchers elsewhere conducted 109 face-to-face interviews of patients referred to contact dermatitis clinic and found that aromatherapy was used by 18%.75 A German study conducted a validated questionnaire in 1,288 patients; 73 patients with atopic dermatitis under conventional therapy and 59 patients under alternative-medical therapy. In the alternative therapy group 65% used autogenic training and 43% used relaxation procedures for their skin disease. The

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numbers were 29 and 13% respectively for the conventional group.76 A study of 198 patients from the dermatology clinic at Show Chwan Memorial Hosp in Changhua City, Taiwan found that aromatherapy (4.6%), Qi-gong/Tai-Chi/yoga (r%), religion (1.5%), and meditation/hypnosis (0.5%) were used.77 A selfadministered questionnaire from 70 patients with atopic dermatitis referred to the university clinic at Oregon Health and Science University revealed that hypnosis (10.3%), massage (10.3%), and biofeedback (3.4%) were commonly used.78

1.4 Stress-Reducing Modalities In the realm of CAM, it is the mind–body interventions that have the most obvious implications for stress reduction. Use of mind–body interventions by the general American public is common (though not necessarily among dermatology patients). In 2002, mind–body techniques, including relaxation, meditation, guided imagery, biofeedback, and hypnosis were used by about 17% of the adult US population. Prayer was used by 45% of the population for health reasons.79 These modalities have shown their use in a variety of conditions: from coronary artery disease80 and pain control81, 82 to managing the symptoms of cancer and the side effects of its treatment.83–85 There are a multitude of case reports, case series, and some clinical trials suggesting that various mind– body interventions are useful in dermatologic conditions. The findings which relate to dermatology will be presented at the end of each of the following sections where appropriate. We will now look more closely into various stress-reducing techniques which may be helpful for people with skin disease.

1.4.1 Yoga Yoga is a spiritual practice which incorporates physical activity (breathing exercises and poses or postures) and meditation to create a connection between the mind and body.86 It has been used in India for over 5,000 years as a system of healing and a framework for how to live one’s life and obtain spiritual enlightenment. In the West, however, it grew popular as a form

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of exercise. Yoga was first introduced to the American society in the late nineteenth century by Swami Vivekananda. He believed that India had an abundance of spiritual wealth and that yoga could help those in Western societies to achieve spiritual well-being. Most yoga classes consist of a combination of physical exercises, breathing exercises, chanting, and meditation. Yoga may improve resistance to psychological stress, decrease feelings of bodily self-objectification, and promote a feeling of wholeness, balance, and wellbeing.86, 87 According to a survey by the National Center for CAM, yoga was the fifth most commonly used CAM therapy (2.8%) in the United States during 2002.79 It is thought by its practitioners to prevent specific diseases by keeping “energy meridians” open and “life energy” (Prana) freely flowing. Yoga is usually performed in group classes. Sessions are conducted at least once a week and for approximately 45  min. Yoga has been used to lower blood pressure, reduce stress, and improve coordination, flexibility, concentration, sleep, and digestion. It has also been used as supplementary therapy for such diverse conditions as cancer, diabetes, asthma, AIDS, and irritable bowel syndrome.88 There are many different styles of yoga; each has a particular emphasis. Hatha is a term that can encompass many of the physical types of yoga. It is slow-paced and gentle and is a good introduction to the basic yoga poses. Vinyasa, which means breath-synchronized movement, is a more vigorous style in which various poses (sun salutations) are connected to certain breathing techniques. Ashtanga, or power yoga is not recommended for beginning students. This is an intense, fast-paced style in which the poses are sequentially performed leading to a fluid movement from one pose to the other. Iyengar yoga is focused on bodily alignment and is interested in the details of each posture. The poses are typically held much longer than in other styles and props such as blankets, blocks, and straps are also used. This is a good style for beginners. Bikram yoga or hot yoga is practiced in a 95–100°room, which creates a saunalike effect that is thought to be cleansing and good for the muscles. Anusara combines an emphasis on alignment with the belief that there is intrinsic goodness in all beings. These classes are good for students of differing abilities and are very calming. Kundalini is an energizing form of yoga which is aimed at freeing “dormant spiritual energy” at the base of the spine and

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allowing it to move upwards. Jivamukti yoga is athletic, physically challenging but highly meditative. The focus is on fitness. Integral yoga is a gentle Hatha style which follows the teachings of Sri Swami Sachidananda, who came to the United States in the 1960s. It is aimed at helping people integrate yoga’s teachings into everyday life. Sivananda is a traditional, more lifestyle approach to yoga. The class structure is rigid and is based on five principles: proper exercise, proper breathing, proper relaxation, proper diet (vegetarian), and positive thinking and meditation. Kripalu yoga is focused on healing. It is great for beginning students and teaches inner focus and meditation, focus on alignment, breath, and presence of consciousness. Integrative yoga was designed for medical and mainstream wellness settings (hospitals and rehab). It involves gentle postures, guided imagery, and breathing techniques for treating specific health issues. It emphasizes holistic healing.

1.4.2 Deep Breathing Deep breathing is the act of breathing deep into your lungs by expanding your diaphragm rather than breathing shallowly by expanding your rib cage. It is also called diaphragmatic breathing, abdominal breathing, or belly breathing. When you breathe deeply your abdominal wall expands rather contracts. It is often used for hyperventilation and anxiety. To perform diaphragmatic breathing one should sit or lie wearing loose comfortable clothing. One hand is placed on the chest and one on the abdomen. Inhale through the nose or pursed lips. During inhalation, the abdomen should expand or press outward, the chest should not. Slowly exhale through pursed lips and then rest and repeat. The inhalation and exhalation times should be about equal. This method of stress reduction may be difficult for people with diaphragmatic dysfunction from various respiratory or neuromuscular conditions.

1.4.3  Tai Chi Tai chi originated in China as a martial art. Over time, people also began to use it for health purposes. Tai chi  incorporates a series of exercises that mimic the

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movements of certain animals with concepts of flexibility and meditation. The body moves slowly and gently, while the person is breathing deeply and meditating. Tai Chi practitioners believe that tai chi helps the flow of “vital energy” called qi. One can practice alone or in a group. Many movements are named for animals or birds, such as “White Crane Spreads Its Wings.” The simplest styles of tai chi incorporate 13 movements into a routine, but more complex routine can be learned. The entire body is always in motion as one movement flows into another. The upper body is kept upright and it is important to concentrate and not be distracted. Breathing should be deep, relaxed, and focused. People practice tai chi for a variety of health purposes including pain control, stress reduction, insomnia, enhancing coordination, flexibility and balance, and overall wellbeing. Tai chi is practiced by many people in China, even in hospitals and clinics. It is especially beneficial for the elderly.

1.4.4 Progressive Relaxation Progressive muscle relaxation was developed by an American physician Edmund Jacobson in the early 1920s as a stress reduction technique. It remains popular with modern physical therapists. The goal is to reduce anxiety and the effects of stress of the musculature. Jacobson found that the technique is also effective against ulcers, insomnia, and hypertension. Progressive relaxation is similar to autogenic training which is a form of self-hypnosis. The technique involves progressively tensing and then relaxing every consciously controlled muscle group until the entire body is relaxed; the sequence usually goes from head to foot. It is best done lying down on the floor or a bed.

1.4.5 Aromatherapy Aromatherapy is the use of plant-derived essential oils as a form of supportive care to improve quality of life and reduce stress and anxiety. Fragrant oils have been used for health purposes for thousands of years and in a variety of cultures. Essential oils (or volatile oils) are derived from various parts of the plant (leaves, bark, peel) and are usually extracted using alcohol.

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They are very concentrated. Aromatherapy likely works through smell receptors in the nose communicating with the brain’s limbic system and altering mood and emotions. The volatile oils are either inhaled by using a diffuser, or applied topically (usually in a diluted form) as part of a massage, poultice, or bath. Aromatherapy may improve quality of life in patients with cancer with regard to reducing side effects such as nausea, anxiety, and insomnia. Safety testing on essential oils shows few side effects when they are used as directed. Some essential oils have been approved as ingredients in food and are classified as GRAS (generally recognized as safe) by the US Food and Drug Administration. However, allergic contact or irritant dermatitis may occur in aromatherapists or in patients using aromatherapy, especially with long periods of skin contact. Photosensitivity may develop when citrus or other oils are applied to the skin before sun exposure. Lavender and tea tree oils have been found to have hormone-like effects similar to estrogen and also block or decrease the effect of androgens. Applying lavender and tea tree oils to the skin over a long period of time has been linked to gynecomastia in prepubescent boys. Essential oils with aldehyde or phenols structures especially cause an irritant dermatitis. Oils with ketone derivatives can cause neurotoxicity in epileptics, pregnant women, and babies. Sassafras oil and calamus oil have been shown to be carcinogenic.89, 90 Stevensen reviewed the dermatologic applications of various essential oils. Some of the antiseptic oils were geranium, petitgrain, winter savory, and tea tree oil. Juniper berry has anti-inflammatory properties whereas frankincense is an immunostimulant. French lavender is useful for burns, cajeput for genital herpes, and chamomile and lavender are good for stress reduction.89 Bensouilah also reviewed the use of aromatherapy in psoriatic patients to reduce disease severity and symptoms and to increase quality of life. Several antiinflammatory oils were listed which may be helpful in psoriasis including achillea millefolium, borage oil, evening primrose oil, sweet  almond oil, jojoba wax, tamanu oil (for the scalp especially), calendula, and avocado oil.90 When mice with experimental contact hypersensitivity were exposed to terpinyl acetate (which has a herbal lavender woody smell) and valerian oil in the presence of stress, the contact hypersensitivity worsened. The theory is that if stress is immunosuppressive,

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which would mute a contact dermatitis, stress reduction (via pleasant scents) would attenuate some of this immunosuppression and a more florid skin response would be seen. Valerian oil was also found to downregulate stressinduced plasma corticosterone levels in the mice.91 Another study in mice suggested that the smell of ­tuberose, lemon, oakmoss, and labdanum reduces some of  the immunologic effects of high-pressure-induced stress.92 Finally, in human volunteers, the smell of ­lavender and rosemary decreased saliva cortisol and increased free radical scavenging activity.93 A randomized controlled double blind trial of aromatherapy for alopecia areata was performed in 86 patients in an outpatient setting. Patients were randomized to massaged thyme, rosemary, lavender, and cedarwood oil mixed in carrier oils (jojoba and grapeseed) vs. the carrier oils alone. These oils were massaged onto the scalp daily for 7 months and results were evaluated at 3 and 7 months in terms of dermotologist-evaluated photographs and computer analysis of severity. Forty-four percent of patients in the aromatherapy group vs. 15% of patients in the control group showed improvement at the end of the trial (p > 0.008).94

1.4.6 Massage Massage therapy refers to a group of practices and techniques involving pressing, rubbing, and manipulation of the muscles and other soft tissues of the body. Most often the hands and fingers are used but forearms, elbows, feet, hot stones, and other tools are sometimes used. Some examples are Swedish massage, deep tissue massage, and shiatsu massage. A 2002 national survey on Americans’ use of CAM (published in 2004) found that 5% of the 31,000 participants had used massage therapy in the preceding 12 months, and 9.3% had ever used it.79 People use massage for a variety of reasons including pain relief, rehabilitation, stress reduction, and general well-being. Patients with a deep vein thrombosis, bleeding disorders or on anticoagulation, peripheral vascular disease, osteoporosis or recent fracture, tumors, open or healing wounds, neuropathy, or myopathies should consult their physician before receiving massage. In addition to providing stress reduction, massage may be beneficial in certain dermatologic conditions

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for other reasons. For example, emollients may be more effectively applied by massage in patients with atopic dermatitis, psoriasis, other dermatitic conditions, and icthiosis. Massage is often used as an adjuvant to compression stockings in lymphadema clinics. There is some theoretic suggestion that massage may help prevent fibrosis which may be useful in combination with conventional therapies for morphea and other fibrotic disorders. In general, touching the skin of our patients communicates lack of repulsion and judgment which is incredibly important in conditions like psoriasis which cause profound feelings of stigma and alienation.

1.4.7 Mindfulness Meditation Meditation refers to a group of techniques, the goal of which is to enhance health and wellness through the quiet focusing attention and maintenance of an open mind. Most time meditation involves a specific posture. People who practice meditation can often increase relaxation, calmness, and mental balance and enhance coping. Research using functional magnetic resonance imaging (fMRI) suggests that the areas of the brain involved in paying attention and in the control of the autonomic nervous system are stimulated during meditation. A large national survey on Americans’ use of CAM, found that nearly 8% of the participants had used meditation specifically for health reasons during the year before the survey.79 Mindfulness meditation has its origins in Buddhism. The concept is that one is  fully present during the meditation process; this involves being “mindful” or aware of thoughts, emotions, and physical feelings (including breath), whatever they may be. Gaston et  al performed a randomized, controlled trial to evaluate the efficacy of meditation as an adjunctive treatment for scalp psoriasis. For 20 weeks, 24 subjects were randomly allocated to one of four groups:  meditation, meditation and imagery, waiting list for treatment, and a treatment-free control. Eighteen ­subjects completed the trial. The meditation group did home meditation for 30 min daily. Subjects were allowed to continue their conventional psoriasis medications. The investigators used a blinded clinical severity score consisting of thickness, erythema, and scale and surface area. Using a Spearman’s coefficient, the  group was measuring the relationship over time

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between psoriasis and stress. The investigators found a significant difference between meditation vs. the control groups for treatment of psoriasis (r > 0.30, p < 0.01), with no impact of imagery. The clinical assessment also strongly supported this finding.95 Kabat, Zinn, et al performed a controlled trial with two independent randomization steps: randomization into ultraviolet B (UVB) vs. psoralen and ultraviolet A (PUVA) cohorts and randomization into use of a mindfulness-based stress reduction audiotape during light therapy vs. no audiotape. Patients received either UVB or PUVA therapy 3 times weekly until their psoriasis cleared or they dropped out of the study. During their light therapy, half of the subjects listened to tapes that encouraged being mindful of breathing, of body sensation, of ambient sounds, thoughts, and feelings and encouraged visualization of UV light slowing down the division of skin cells. The other half (control) received light therapy in silence. Thirty-seven subjects with moderate to severe psoriasis participated in the study. Their rate of psoriatic lesion clearing was assessed on four occasions in three independent ways: directly by unblinded clinic nurses, directly by blinded physicians, and indirectly via lesion photographs by blinded physicians. Time to first response, time to turning point, and time to halfway clearing were measured. In the UVB group there was a significantly shorter time to turning  point and time to halfway clearing compared to ­controls (p > 0.005, 0.002, respectively). In the PUVA group there was no significant difference between groups. Using Cox-proportional hazards regression models which adjust for confounding factors such as years with psoriasis and initial psychological state, estimated response time-to-clearance curves were constructed. These estimated curves showed a significantly shorter time-to-clearance between mindfulness tape and no mindfulness tape groups.96

1.4.8 Biofeedback Biofeedback is a procedure which provides the subject with feedback about certain bodily functions with the assistance of certain instruments. It provides a sort of mirror for various types of biological information. One is connected to a machine that monitors heart beat, muscle tone, skin temperature or resistance, and electric potential of the brain (EEG) for instance. The

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subject receives information about the activity level of those functions in the form of visual or auditory signals. The goal is to consciously control these functions to reach a desired state (i.e., reduced skin temperature in psoriasis). The most common forms of biofeedback are galvanic skin response, electromyographic biofeedback, thermal biofeedback, and electroencephalographic rhythm biofeedback. The electromyographic biofeedback (which measures variations in muscle electric potential) is best for anxiety states. Two phases are usually performed. There is a relaxation phase in which the practitioner gathers information about the patient’s life experiences, difficulties relaxing, and various images, thoughts, or sensations. The technical phase is when the therapist takes measurements and helps the patient overcome obstacles to relaxation. Usually 10–20 sessions are needed, with 1–2/week. Patients are encouraged to practice at home for 20 min a day using elementary portable instruments. The goal is that control of the function becomes automatic such that the subject can reproduce it in stressful situations.97 The most reasonable application in dermatology would be for neurodermatitis and related disorders (tricotillomania) and for pruritis. Keinan et al treated 32 subjects in a 3-month randomized, double-blind, controlled trial in which subjects were divided into three groups. One group was trained to do biofeedback and relaxation techniques, one relaxation only and the third group received no treatment. Efficacy was evaluated by a six-point symptom severity scale which ranged from no symptoms to very severe symptoms and by a symptom improvement scale, a nine-point scale ranging from complete remission to extreme worsening. No significant changes in symptom severity scale or symptom improvement scale were found.98 Biofeedback has also been reported to have efficacy in hyperhydrosis and Raynaud’s disease.

1.4.9 Autogenic Training Autogenic training is a form of self-hypnosis and relaxation which is usually used for stress control. Stewart and Thomas treated 18 adults with extensive atopic dermatitis with hypnotherapy, relaxation, and  stress management. During the hypnotherapy patients received direct suggestions for nonscratching behavior, skin

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comfort and coolness, and ego strengthening. Patients also received instructions on self-hypnosis. In this nonrandomized controlled clinical trial, significant reductions in itching, scratching, sleep disturbance, and tension were found compared to the control group. Use of topical steroids decreased by 60% at 16 weeks.99

1.4.10 Hypnosis Hypnosis was initially described in the late eighteenth century by Franz Anton Mesmer and was further developed by Milton Erickson in modern times. It is an altered state of consciousness in which the suggestions from someone else, the environment, or from oneself, allow the imagination to create a vivid reality. People innately have different levels of suggestiveness; in other words, people who are highly suggestible are more likely to benefit from hypnosis. It is difficult to predict a person’s level of suggestiveness. Many case reports of dermatologic conditions responding to hypnosis have been published.95 These include clearing of congenital ichthiosiform erythroderma of Brocq, erythromelalgia, herpes simplex, acne excoriee, alopecia areata, trichotillomania, neurodermatitis, furuncles, rosacea, vitiligo, and others. There have been case series of the efficacy of hypnosis for urticaria. Nonrandomized controlled trials exist for atopic dermatitis and, for verruca vulgaris, psoriasis and relaxation during procedures, there have been randomized controlled trials. Controlled studies using direct suggestion in hypnosis (DSIH) for warts show success rates between 27 and 55%. Children respond especially well.100 Tausk and Whitmore used hypnosis to treat psoriasis in a randomized, controlled, single-blind, 3-month study. Eleven patients with mild-to-moderate stable psoriasis were randomized to one of two groups: hypnosis with active suggestion or neutral hypnosis. In the active treatment, group subjects were asked to image the conventional therapy which they believed to be most effective for their psoriasis. Only subjects who were identified as being highly or moderately suggestible were included in the study. Subjects were treated with weekly hypnosis sessions for 3 months according to the treatment group; then the investigator was unblinded and both groups received active suggestion hypnosis for 3 more months. Psoriasis severity was assessed using

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the Psoriasis Area and Severity Index (PASI) and was performed by a different, blinded investigator. Results showed that highly suggestible individuals vs. moderately suggestible individuals had a significant improvement in psoriasis severity (p < 0.05).101

1.4.11 QI Gong/Reiki/Healing Touch Energy medicine is a CAM modality that deals with energy fields of two types: veritable and putative. The veritable energies are those that can be measured; they use vibrations, electromagnetic forces, visible light, and monochromatic radiation (i.e., LASER) for example. Putative energy cannot be measured. CAM modalities which claim to alter this subtle, immeasurable energy are reiki, qi gong, and healing touch. Qi gong is practiced commonly in clinics and hospitals of China. It is a branch of traditional Chinese medicine which is aimed at restoring balance and the free flow of qi or life energy. Reiki is a similar practice that originated in Japan. Therapeutic touch is perhaps the Western equivalent of the prior two modalities. All three involve movement of the practitioner’s hands over the patient’s body to sense and ultimately manipulate energy throughout the body. The evidence for these modalities is mixed and sparse. However, to the extent that they reduce stress, reiki, qi gong, and healing touch may be useful in dermatology patients.

1.4.12 Prayer Particularly devastating dermatologic conditions have the potential to alter our patients’ sense of spiritual well-being. Sometimes a sense of spirituality may allow a patient to better cope with a particular condition or diagnosis, other times patients feel a sense of divine punishment from their skin condition. It is important to know the role that spirituality plays in our patients’ lives, to the extent that we can support any positive attributes it may add to conventional management. If the patient obtains emotional support from his/her spirituality it would be appropriate to encourage patients to speak with a chaplain, clergy member, or spiritual leader regarding the condition. Dermatologists, and

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any physician, should respectfully support the patient’s use of spirituality to cope with their disease. If one feels comfortable, it is appropriate to both pray for and with patients when they are facing difficult times or decisions.102 In an Austrian study, 215 patients with melanoma were interviewed about their interests in CAM and reasons for pursuing this. More than half had an interest in nonconventional therapies. Interested subjects had a more active coping style, a tendency toward religiousness, and need to search for personal meaning in their disease than noninterested subjects. They also believed that they were receiving less emotional support from their physicians than the other group and expressed interest in getting more of such support.103

1.5 Conclusion As dermatologists, we have no less of an obligation to practice in the context of a bio-psycho-social model than other physicians. We should make it a habit to ask our patients about their stress levels and to what extent it contributes to their skin disease. It is also important to have practical advice to offer patients in terms of stress reduction techniques. To the extent of our control, the office setting and the personal experiences patients encounter in the clinic should be relaxing and promoting of the healing process. Also, in order to effective carry out our responsibilities as physicians, each of us should frequently monitor and control the stress in our own lives so that optimal care of our patients is not compromised.

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14 26. Raychaudhuri SP, Jiang WY, Farber EM. Psoriatic keratinocytes express high levels of nerve growth factor. Acta Derm Venereol. 1998;78(2):84–86 27. Raychaudhuri SP, Jiang WY, Smoller BR, Farber EM. Nerve growth factor and its receptor system in psoriasis. Br J Dermatol. 2000;143(1):198–200 28. Richards HL, Ray DW, Kirby B, et al Response of the hypothalamic-pituitary-adrenal axis to psychological stress in  patients with psoriasis. Br J Dermatol. 2005;153(6): 1114–1120 29. Schmid-Ott GJR, Jaëger B, et  al Stress induced endocrine and immunological changes in psoriasis patients and healthy controls. Psychother Psychosom. 1998;67:37–42 30. Langan SM, Bourke JF, Silcocks P, Williams HC. An exploratory prospective observational study of environmental factors exacerbating atopic eczema in children. Br J Dermatol. 2006;154(5):979–980 31. Faulstich ME, Williamson DA, Duchmann EG, et  al Psy­ chophysiological analysis of atopic dermatitis. J Psychosom Res. 1985;29(4):415–417 32. Altemus M, Rao B, Dhabhar FS, et al Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol. 2001;117(2):309–317 33. Zane L. Psychoneuroendocrinimmunodermatology: pathophysiological mechanisms of stress in cutaneous disease. In: Koo JYM, Lee CS, eds. Psychocutaneous Medicine. New York: Marcel Dekker; 2003:65–95 34. Buske-Kirschbaum A, Jobst S, Psych D, et  al Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis. Psychosom Med. 1997;59(4):419–426 35. Buske-Kirschbaum A, Geiben A, Hollig H, et  al Altered responsiveness of the hypothalamus-pituitary-adrenal axis and the sympathetic adrenomedullary system to stress in patients with atopic dermatitis. J Clin Endocrinol Metab. 2002;87(9):4245–4251 36. Rupprecht M, Rupprecht R, Kornhuber J, et al Elevated glucocorticoid receptor concentrations before and after glucocorticoid therapy in peripheral mononuclear leukocytes of patients with atopic dermatitis. Dermatologica. 1991;183:100–105 37. Schmid-Ott G, Jaeger B, Meyer S, et al Different expression of cytokine and membrane molecules by circulating lymphocytes on acute mental stress in patients with atopic dermatitis in comparison with healthy controls. J Allergy Clin Immunol. 2001;108:455–462 38. Delgado M, Fernandez-Alphonso MS, Fuentes A. Effect of adrenaline and glucocorticoids on monocyte cAMP-specific phospodiesterase (PDE4) in a monocyte cell line. Arch Dermatol Res. 2002;294:190–197 39. Theoharides TC, Donelan JM, Papadopoulou N, et al Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmacol Sci. 2004;25(11):563–568 40. Papadopoulou N, Kalogeromitros D, Staurianeas NG, et al Corticotropin-releasing hormone receptor-1 and histidine decarboxylase expression in chronic urticaria. J Invest Dermatol. 2005;125(5):952–955 41. Biondi M, Zannino LG. Psychological stress, neuroimmunomodulation, and susceptibility to infectious diseases in animals and man: a review. Psychother Psychosom. 1997;66 (1):3–26 42. Bailey MT, Engler H, Sheridan JF. Stress induces the translocation of cutaneous and gastrointestinal microflora to

N. Smith and F. A. Tausk s­ econdary lymphoid organs of C57BL/6 mice. J Neuroimmunol. 2006;171(1–2):29–37 43. Rojas IG, Padgett DA, Sheridan JF, Marucha PT. Stressinduced susceptibility to bacterial infection during cutaneous wound healing. Brain Behav Immun. 2002;16(1):74–84 44. Buske-Kirschbaum A, Geiben A, Wermke C, et  al Pre­ liminary evidence for Herpes labialis recurrence following experimentally induced disgust. Psychother Psychosom. 2001;70(2):86–91 45. Cohen S, Frank E, Doyle WJ, et al Types of stressors that increase susceptibility to the common cold in healthy adults [see comments]. Health Psychol. 1998;17(3):214–223 46. Cohen S, Tyrrell DA, Smith AP. Psychological stress and susceptibility to the common cold [see comments]. N Engl J Med. 1991;325(9):606–612 47. VanderPlate C, Kerrick G. Stress reduction treatment of severe recurrent genital herpes virus. Biofeedback Self Regul. 1985;10(2):181–188 48. Yang EV, Glaser R. Stress-induced immunomodulation: implications for tumorigenesis. Brain Behav Immun. 2003;17 (suppl 1):S37–S40 49. Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol. 2004;5(10): 617–625 50. Reiche EM, Morimoto HK, Nunes SM. Stress and depression-induced immune dysfunction: implications for the development and progression of cancer. Int Rev Psychiatr. 2005;17(6):515–527 51. Lillberg K, Verkasalo PK, Kaprio J, et al Stressful life events and risk of breast cancer in 10, 808 women: a cohort study. Am J Epidemiol. 2003;157(5):415–423 52. Riley V. Psychoneuroendocrine influences on immunocompetence and neoplasia. Science. 1981;212(4499):1100–1109 53. Wu W, Yamaura T, Murakami K, et al Social isolation stress enhanced liver metastasis of murine colon 26–L5 carcinoma cells by suppressing immune responses in mice. Life Sci. 2000;66(19):1827–1838 54. Ramirez AJ, Craig TK, Watson JP, et al Stress and relapse of breast cancer [see comments]. BMJ. 1989;298(6669):291–293 55. Havlik RJ, Vukasin AP, Ariyan S. The impact of stress on the clinical presentation of melanoma. Plast Reconstr Surg. 1992;90(1):57–61; discussion 2-4 56. Reynolds P, Kaplan GA. Social connections and risk for cancer: prospective evidence from the Alameda County Study. Behav Med. 1990;16(3):101–110 57. Jacobs JR, Bovasso GB. Early and chronic stress and their relation to breast cancer [In Process Citation]. Psychol Med. 2000;30(3):669–678 58. Grossarth-Maticek R, Eysenck HJ, Boyle GJ, et  al Interaction of psychosocial and physical risk factors in the causation of mammary cancer, and its prevention through psychological methods of treatment. J Clin Psychol. 2000;56(1): 33–50 59. Laudenslager ML, Ryan SM, Drugan RC, et al Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation. Science. 1983;221 (4610):568–570 60. Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G. Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer. 1999;80(6):880–888

1  Stress, Relaxation, and General Well-Being 61. Ben-Eliyahu S. The promotion of tumor metastasis by surgery and stress: immunological basis and implications for  psychoneuroimmunology. Brain Behav Immun. 2003; 17(suppl 1):S27–S36 62. Parker J, Klein SL, McClintock MK, et  al Chronic stress accelerates ultraviolet-induced cutaneous carcinogenesis. J Am Acad Dermatol. 2004;51(6):919–922 63. Saul AN, Oberyszyn TM, Daugherty C, et al Chronic stress and susceptibility to skin cancer. J Natl Cancer Inst. 2005; 97(23):1760–1767 64. Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer [see comments]. Lancet. 1989;2(8668): 888–891 65. Fawzy FI, Fawzy NW, Hyun CS, et al Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Arch Gen Psychiatr. 1993;50(9):681–689 66. Herberman RB, Ortaldo JR. Natural killer cells: their roles in defenses against disease. Science. 1981;214:24–30 67. Kiecolt-Glaser JK, Garner W, Speicher C, et al Psychosocial modifiers of immunocompetence in medical students. Psy­ chosom Med. 1984;46(1):7–14 68. Glaser R, Rice J, Speicher CE, et al Stress depresses interferon production by leukocytes concomitant with a decrease in natural killer cell activity. Behav Neurosci. 1986;100(5): 675–678 69. Riley V. Psychoneuroendocrine Influences on immunocompetence and neoplasia. Science. 1981;212:1100–1109 70. Wu W. Social isolation stress enhanced liver metastasis of murine colon 26–L5 carcinoma cells by suppressing immune responses in mice. Life Sci. 2000;66:1827–1838 71. Laudenslager ML. Coping and immunosuppression: inescapable but not escapable shock supresses lymphocyte proliferation. Science. 1983;221:568–570 72. Ernst E. The use of complementary therapies by dermatological patients: a systematic review. Br J Dermatol. 2000; 142:857–861 73. Baron SE, Goodwin RG, Nicolau N, et  al Use of complementary medicine among outpatients with dermatologic conditions within Yorkshire and South Wales, United Kingdom. J Am Acad Dermatol. 2005;52:589–594 74. Nicolaou N, Johnston GA. The use of complementary medicine by patients referred to a contact dermatitis clinic. Contact Derm. 2004;51:30–33 75. Augustin M, Zschocke I, Buhrke U. Attitudes and prior experience with respect to alternative medicine among dermatological patients: the Freiburg questionaire on attitudes to naturopathy (FAN). Res Complement Med. 1999;6 (suppl 2): 26–29 76. Chen Yu-Fu, Chang JS. Complementary and alternative medicine use among patients attending a hospital dermatology clinic in Taiwan. Int J Dermatol. 2003;42:616–621 77. Simpson EL, Basco M, Hanifin J. Cross-sectional survey of complementary and alternative medicine use in patients with atopic dermatitis. Am J Contact Derm. 2003;14:144–147 78. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Comple­ mentary and alternative medicine use among adults: United States, 2002. CDC Advance Data Report #343. 2004 79. Rutledge JC, Hyson DA, Garduno D, et al Lifestyle modification program in management of patients with coronary

15 artery disease: the clinical experience in a tertiary care hospital. J Cardiopulm Rehabil. 1999;19(4):226–234 80. Luskin FM, Newell KA, Griffith M, et al A review of mind/ body therapies in the treatment of musculoskeletal disorders with implications for the elderly. Altern Ther Health Med. 2000;6(2):46–56 81. Astin JA, Shapiro SL, Eisenberg DM, et al Mind-body medicine: state of the science, implications for practice. J Am Board Fam Pract. 2003;16(2):131–147 82. Mundy EA, DuHamel KN, Montgomery GH. The efficacy of behavioral interventions for cancer treatment-related side effects. Sem Clin Neuropsychiatr. 2003;8(4):253–275 83. Irwin MR, Pike JL, Cole JC, et  al Effects of a behavioral intervention, Tai Chi Chih, on varicella-zoster virus specific immunity and health functioning in older adults. Psychos­ omatic Med. 2003;65(5):824–830 84. Kiecolt-Glaser JK, Marucha PT, Atkinson C, et al Hypnosis as a modulator of cellular immune dysregulation during acute stress. J Consult Clin Psychol. 2001;69(4):674–682 85. yoga.about.com Yoga and Your Health, by Ann Pizer; 2008 Accessed 12.1.08 86. Cancer.gov. Pain control: Support for People with Cancer; 2008 Accessed 25.1.08 87. Deutsch J, Anderson E. Complementary Thera­pies for Phys­ ical Therapy: A Clinical Decision-Making Approach. Chap­ ter 8: Therapeutic Aspects of Yoga. St. Louis, MO: Saunders/ Elsevier; 2008 88. Stevensen CJ. Aromatherapy in dermatology. Clin Dermatol. 1998;16:689–694 89. Bensouilah J. Psoriasis and aromatherapy. Int J Aromatherap. 2003;13:2–8 90. Hosoi J, Tanida M, Tsuchiya T. Mitigation of stress-induced suppression of contact hypersensitivity by odorant inhalation. Br J Dermatol. 2001;145:716–719 91. Fujiwara R, Komori T, Noda Y, et al Effects of a long-term inhalation of fragrances on the stress-induced immunosuppression in mice. Neuroimmunomodulation. 1998;5(6): 318–322 92. Atsumi T, Tonosaki K. Smelling lavender and rosemary increases free radical scavenging activity and decreases cortisol level in saliva. Psychiatr Res. 2007;150:89–96 93. Hay I, Jamieson M, Ormerod AD. Randomized trial of aromatherapy: successful treatment for alopecia areata. Arch Dermatol. 1998;134:1349–1352 94. Gaston L, Crombez J, Lassonde M, et al Psychological stress and psoriasis: experimental and prospective correlational studies. Acta Derm Venereol (Stockh). 1991;156:37–43 95. Kabat-Zinn J, Wheeler E, Light T, et al Influence of a mindfullness meditation-based stress reduction intervention on rates of skin clearing in patients with moderate to severe psoriasis undergoing phototherapy (UVB) and photochemotherapy (PUVA). Psychosomatic Med. 1998;60:625–632 96. Sarti MG. Biofeedback in dermatology. Clin Dermatol. 1998;16:711–714 97. Keinan G, Segal A, Gal U, Brenner S. Stress management for psoriasis patients: the effectiveness of biofeedback and relaxation techniques. Stress Med. 1995;11(1):235–241 98. Schenefelt PD. Complementary psychocutaneous therapies in dermatology. Dermatol Clin. 2005;23:723–734 99. Bellini MA. Hypnosis in dermatology. Clin Dermatol. 1998; 16:725–726

16 100. Tausk FA, Whitmore E. A pilot study of hypnosis in the treatment of patients with psoriasis. Psychother Psychosom. 1998;68:221–225 101. Thomsen RJ. Spirituality in medical practice. Arch Derm. 1998;134:1443–1446 102. Sollner W, Zingg-Schir M, Rumpold G, Fritsch P. Attitude toward alternative therapy, compliance with standard

N. Smith and F. A. Tausk t­reatment, and need for emotional support in patients with melanoma. Arch Derm. 1997;133:316–321 103. Branzzini B, Ghersetich I, Hercogava J, Lotti T. The neuroimmuno-cutaneous-endocrine network: relationship bet­ ween mind and skin. Dermatol Ther. 2003;16:123–131 104. Harth W, Gieler U, Kusnir D, Tausk FA. Clinical Management of Psychodermatology. Heidelberg: Springer; 2009

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Smoking, Obesity/Nutrition, Sun, and the Skin Robert A. Norman and Max Rappaport

It is well-known that costs for medical problems associated with smoking, obesity, malnutrition, and sun damage are very high, making it extremely important to push the notion of prevention in all of these cases. Between 1995 and 1999, it has been estimated that the United States spent $157 billion in healthcare costs.1 The costs associated with medical costs in the United States attributed to inactivity alone are around $75 billion.2 Many medical issues are preventable, which an uninformed person may not realize. But information on the risks of smoking, obesity, or tanning is welldocumented and readily available. Still today there are around 1.25 billion smokers who will die an average of 7 years earlier than their nonsmoking counterparts.3 About 30% of people worldwide are considered to be obese and the numbers have been increasing dramatically ever since the 1980s.4, 5 Every year according to the World Health Organization (WHO),6 sun damage causes 60,000 premature deaths and the loss of 1.5 million disability-adjusted life years (DALYs); in addition almost 30 million Americans tan indoors every year.7 Health risks associated with these three highrisk factors have become common knowledge in many countries. Yet doctors see patients seeking healthcare related to damage done by one or more of these risks time and time again. The most difficult and expensive approach will always be to treat the complications related to a risky behavior after an accumulation of damage, thus – as with anything else in life – preventing a problem before it occurs is always the best option.

R. A. Norman (*) Nova Southeastern University, Ft. Lauderdale, Florida and Private Practice, Tampa, FL, USA e-mail: [email protected]

All three of these risky behaviors are preventable. Positive behavioral changes, even after damage, can be extremely beneficial to a person’s future health.

2.1 Smoking The dangers of smoking cigarettes have become wellknown; though the damage to the skin has been less studied. The smoke released from burning cigarettes at temperatures of 830–900°C contains some 5,000 chemicals. Many of these are hydrophobic agents that can diffuse through many cell membranes, reaching to the far ends of the body’s precious organs, including the skin.3, 8 Many of the dangerous chemicals are in the form of free radicals and oxidants, which can cause the malfunction of many biological functions and create cell damage. Smoking has been shown to increase many symptoms associated with aging: altered hormone production, reduced fertility, cancer, cardiovascular and respiratory disease, and diseases of the lung, esophagus, pharynx, larynx, stomach, pancreas, bladder, uterine, cervix, and skin.3, 8–10 Smoking causes premature aging of the skin by affecting the color, tone, and wrinkling. Smoking can also increase the risk for developing psoriasis, melanoma, squamous cell carcinomas on lips and oral mucosa, acne, and hair loss. Smoking also causes poor wound healing due to reduction of oxygen and nutrients to the skin.9,11–14 Many of the mechanisms that can explain these findings are complex and inexact. Premature skin aging may be caused in part by the same mechanisms which seem to cause the entire body’s aging process.15 The premature death of smokers follows similar old-age-related illnesses of nonsmokers such as osteoporosis, cancers, macular

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_2, © Springer-Verlag London Limited 2010

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degeneration, and cardiovascular diseases.12 The acceleration of aging in smokers may be caused in part by actual damage to the body or from destruction of chemicals needed to prevent aging in the body by causing molecular malfunctioning, leading to an increase in tumor development and a reduction in wound healing.3 Another theory on the causation of premature wrinkling of the skin may be increased elastosis in the skin. It has been found that the amount of wrinkling is directly related with the amount and duration of cigarettes smoked. The mechanism by which wrinkling occurs on the skin may be the same as the mechanism by which collagen and elastin in the lungs are damaged. Lastly, there is an idea that the skin damage is caused by extended exposure to intense heat while smoking.12 Smoking also affects the levels of antioxidants in the body, accounting for premature aging. Many of the chemicals in the cigarette smoke cause damage that has been shown to decrease cutaneous blood flow and immune responses in the blood and decrease the level of vitamin C, vitamin E, circulating levels of nitrous oxide, and plasma concentrations, while increasing lipid peroxidation.8 Health damage and premature deaths caused by smoking are in a large part preventable. An emphasis on preventing new smokers is important because quitting can be a difficult process. Every year almost 15 million smokers attempt to quit smoking in the United States, with around one million in specific cessation programs.13 This very small proportion of the actual smokers shows how difficult quitting can be. While people hear from everyone around them, including the media, that smoking is bad for their health, a healthcare provider must always push further intervention. Talking to parents of pediatric patients and directly to pediatric patients as early as possible is the primary role of the physician. Increasing education in schools about the dangers of smoking can also be a powerful tool to reduce new smoking behavior. It has been shown that health education programs using negative images to discourage smoking is more effective than positive images.16 Actual, real-life, positive role modeling by older students, parents, and teachers may be just as effective. While young smokers imagine the typical smoker as smart, good-looking, and considerate, nonsmokers perceive smokers as dull, childish, and confused. Reinforcement of the nonsmokers’ beliefs is important by positive role modeling.16 For youths who have already begun smoking, knowledge

R. A. Norman and M. Rappaport

that smoking may increase the rate of facial aging may increase their likeliness of quitting.13 Informing young smokers of the positive health benefits of quitting may be a powerful tool. It is known, for example, that the risk of psoriasis decreases with every year of smoking cessation and becomes insignificant 20 years after a smoker has quit.13

2.2 Obesity and Nutrition Obesity is another preventable disorder that, if gone untreated, can lead to a number of medical complications including orthopedic and metabolic problems, disrupted sleep, weakened immune system, impaired mobility, increased blood pressure, and hypertension. Psychosocial consequences include low self-esteem and depression. Long-term consequences include cardiovascular disease, insulin resistance, type 2 diabetes, hyperlipidemia, gall bladder disease, osteoarthritis, and certain cancers. When looking at prevention, it is important to note that obese children tend to grow into obese adults.4 Skin complications related to obesity include5,17,18: • • • • • • • • • • • • • • • • • • • • • • •

Acanthosis nigricans Acrochordons Keratosis pilaris Hyperandrogenism and hirsutism Striae distensae Adiposis dolorosa and fat redistribution Lymphedema Chronic venous insufficiency Plantar hyperkeratosis Cellulitis Hidradenitis suppurativa Psoriasis Insulin resistance syndrome Tophaceous gout Changes in cutaneous sensation and temperature regulation Foot pain Candidiasis Intertigo Candida folliculosis Erythrasma Tinea cruris Folliculitis Necrotizing fasciitis

2  Smoking, Obesity/Nutrition, Sun, and the Skin

• Gas gangrene • Leg ulcerations • Plantar hyperkeratosis Skin disorders attributed to malnutrition include scurvy, pellagra, ariboflavinosis, vitamin A deficiency, phrynoderma, and kwashiorkor.19, 20 Treatment of obese patients can also lead to a number of complications including difficulty in treating wounds and abnormal medicine dosages.5 Obesity prevention and nutritional education to the youth must be a powerful tool in the fight to prevent more obese adults. There are a number of factors that may be affecting the increased prevalence in obesity both in adults and in children. The list includes the individual’s genetic makeup including psychological tendencies; the individual family’s eating habits and amount of active behaviors while at school, school food, availability of vending machines, and cheap and readily available high-calorie, low-nutrition foods including fast foods. While many factors such as genetics and societal may not be readily changed, prevention will always be easier than treatment. Treating at-risk overweight kids before they become obese is extremely important. Care must be taken in school-based obesity prevention programs to prevent stigmatizing overweight children or pushing already underweight children further in that dangerous direction.4 Prevention programs must promote exercise, how to eat healthily, and the dangers associated with becoming obese. The most effective prevention plans must be effective, sustainable, and not harm the participants. Extreme low-calorie diets (<700 daily calories) with a lack of fruits, vegetables, fish, and eggs can lead to a deficiency in many essential vitamins and cause malnutrition disorders, such as phrynoderma, usually found in undeveloped nations. If detected early, diets rich in the missing vitamins and nutrients can be implemented to prevent these disorders.20 Positive role modeling and education must be used by all those who teach or influence children from the earliest age possible, of the dangers and risks of not taking care of their bodies.

2.3 Sun Damage Many societies today value the appearance of a dark, rich tan, causing many people to expose themselves to high levels of ultraviolet radiation (UVR) without

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the necessary and available protection to prevent illnesses associated with sun damage. Many factors affect the level of UVR a person can receive yearly, from distal factors such as ozone levels, cloud cover, latitude, season, and lower atmospheric pollution, to proximal factors such as sun-seeking, sun-protecting behaviors, genetic skin pigmentation, and cultural dress and behaviors.6 UVR damage can suppress cellmediated immunity in the body, have an adverse affect on the eyes and skin, and increase the risk of cancer. Absence of UVR can produce an insufficiency of vitamin D, increasing the risk of other complications including rickets, osteomalacia, osteoporosis, and tuberculosis.21 The skin is especially susceptible to damage from the sun; it is the first organ of the body to come in contact with UVR rays and covers the entire surface of the body. Specific damage to the skin caused by sun damage include malignant melanoma, cancer of the lip, squamous cell carcinoma, basal cell carcinoma, sunburn, photo-aging (wrinkles), psoriasis, and other photodermatoses such as solar urticaria, photoallergic contact dermatitis, actinic prurigo, polymorphic light eruption, and hydroa vacciniforme.21 Any skin damage caused by the sun is almost entirely preventable. For proper protection sunscreen with reapplications is necessary; wearing hats and long-sleeve shirts when in the sun is also recommended. Be aware of your risk category; people with lighter skin tend to burn more easily. People who spend their work days out-of-doors should be aware of the risks and take similar precautions. A general risk that should be addressed by the physician is the fact that intentional sun damage to gain a tan, even if using sunscreen, is a risk for all the same skin damages caused by sun damage without sunscreen. Knowledge on the damages caused by the sun is well-known and yet ignored by too many of today’s youth and adults.

2.4 Synergy of Risk and Integrating Prevention It is clear that smoking, exposure to UVR rays, obesity, and poor nutrition can lead to a number or dermatological issues that are entirely preventable. It has been noted that persons who participate in one type of

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risky behavior are more likely to participate in others. Therefore, it is necessary to consider that a combination of risk factors may be synergistic in nature, thus accelerating damage by just one risk factor. When looking at prevention, education in all of these risk factors must be addressed in part and as a whole. Positive role modeling by older peers, teachers, parents, and even physicians is extremely important in the battle of prevention. It has been noted that the more ambiguous a prevention plan is and the larger the number of possible options it offers, the more it is perceived with skepticism about its effectiveness and the more it is met with inaction.22 Another tool in fighting the three risks simultaneously is directing education at those in the process of smoking cessation, as persons trying to change one aspect of their life may be more inclined to change other aspects of their life at the same time.23 Finally, it is clear that action taken must be aimed at the younger populations to further educate persons on the risks associated with risky behaviors and the ease of preventing the harmful and deadly effects of smoking, malnutrition, obesity, and sun damage.

References   1. World Health Organization. World No Tobacco Day 2004. Tobacco and Poverty: A Vicious Circle. http://www.emro.who. int/tfi/wntd2004/Kit-Part1.htm; 2008 Accessed 29.12.08   2. World Health Organization. Physical Activity. http://www. who.int/dietphysicalactivity/publications/facts/pa/en/; 2008 Accessed 29.12.08   3. Bernhard D, Moser C, Aleksandar Backovic A, Wick G. Cigarette smoke – an aging accelerator? Exp Gerontol. 2007; 42:160–165   4. Doak CM, Visscher TLS, Renders CM, Seidell JC. The prevention of overweight and obesity in children and adolescents: a review of interventions and programmes. Obes Rev. 2006;7:111–136   5. Scheinfeld NS. Obesity and dermatology. Clin Dermatol. 2004;22:303–309   6. Lucas R, Prüss-Üstün A, World Health Organization, et al Solar ultraviolet eadiation: global burden of disease from

R. A. Norman and M. Rappaport solar ultraviolet radiation. Environmental Burden of Disease Series, No. 13. http://www.who.int/uv/publications/solaradgbd/ en/index.html; 2008 Accessed 28.12.08   7. Jung K, Seifert M, Herrling T, Fuchs J. UV-generated free radicals (FR) in the skin: their prevention by sunscreens and their induction by self-tanning agents. Spectrochim Acta Part A Mol Biomol Spectrosc. 2008;69(5):1423–1428. Epub 2007   8. Nicita-Mauro V, Lo Balbo C, Mento A, et al Smoking, aging and the centenarians. Exp Gerontol. 2008;43(2):95–101   9. Merimsky O, Inbar M. Cigarette smoking and skin cancer. Clin Dermatol. 1998;16:585–588 10. Shulman A, Wolf R. Cigarette smoking, hormonal changes, and the skin. Clin Dermatol. 1998;16:595–598 11. Morita A. Tobacco smoke causes premature skin aging. J Dermatol Sci. 2007;48:169–175 12. Boyd AS, Stasko T, Lloyd E, et  al Cigarette smoking– associated elastotic changes in the skin. J Am Acad Dermatol. 1999;41:23–26 13. Setty AR, Curhan G, Choi HK. Smoking and the risk of psoriasis in women: Nurses’ Health Study II. Am J Med. 2007; 120:953–959 14. Odenbro A, Gillgren P, Bellocco R, et al The risk for cutaneous malignant melanoma, melanoma in situ and intraocular malignant melanoma in relation to tobacco use and body mass index. Br J Dermatol. 2007;156:99–105 15. Demierre MF, Brooks D, Koh HK, Geller AC. Public knowledge, awareness, and perceptions of the association between skin aging and smoking. J Am Acad Dermatol. 1999; 41(1): 27–30 16. Piko BF, Bak J, Gibbons FX. Prototype perception and smoking: are negative or positive social images more important in adolescence? Addict Behav. 2007;32:1728–1732 17. Hidalgo LG. Dermatological complications of obesity. Am J Clin Dermatol. 2002;3(7):497–506 18. Yosipovitch G, DeVore A, Dawn A. Obesity and the skin: skin physiology and skin manifestations of obesity. J Am Acad Dermatol. 2007;56:901–916 19. Lee BY, Hogan DJ, Ursine S, et al Personal observation of skin disorders in malnutrition. Clin Dermatol. 2006;24:222–227 20. Di Stefani AD, Orlandi A, Chimenti S, Bianchi L. Phryn­ oderma: a cutaneous sign of an inadequate diet. CMAJ. 2007;177(8):855–856 21. World Health Organization: WHO Annexes: Annex 1. www. who.int/entity/uv/health/solaruvradann1.pdf; 2008 Accessed 28.12.08 22. Han PKJ, Moser RP, Klein WMP. Perceived ambiguity about cancer prevention recommendations: associations with cancer-related perceptions and behaviours in a U.S. population survey. Health Expect. 2007;10:321–336 23. Simmons VN, Vidrine JI, Brandon TH. Smoking cessation counseling as a teachable moment for skin cancer prevention: pilot studies. Am J Health Behav. 2008;32(2):137–145

3

Raising Awareness on the Health Literacy Epidemic Michelle C. Duhaney

Low health literacy is common in the United States of the twenty-first century. The ability to process and under­ stand basic health information and function appropriately in today’s healthcare environment requires basic reading and mathematical skills.1, 2 These basic skills are often taken for granted by patients with adequate health literacy. It is likely that most physicians will encounter on a daily basis patients who cannot read or spell, which is a barrier to accurate medical diagnosis and optimal treatment.3 The magnitude of the association between inadequate health literacy and mortality has captured the attention of many. The nature of this problem is complex and effectively addressing it is important to America’s well-being.4 In a study of elderly patients enrolling in a Medicare-managed care plan, inadequate health literacy independently predicted all-cause mortality and death due to cardiovascular events. This study concluded that the crude mortality rate for patients with inadequate health literacy was relatively high at 39.4%.5 In an era that has seen breakthrough drug regimens and life-saving treatments the effect of low health literacy on the mortality rate is alarming.2, 5 Health literacy is therefore gaining momentum among researchers. Research over the last 15 years has attempted to assess the nature and scope of health literacy and the impact that low health literacy has on the delivery of quality healthcare in the United States3, 4 Several studies have shown that patients with inadequate health literacy have decreased knowledge and understanding about diseases, especially chronic

M. C. Duhaney Department of Family Medicine, Broward General Medical Centre, Fort Lauderdale, FL, USA e-mail: [email protected]

diseases such as diabetes and hypertension.5, 6 Patients with inadequate health literacy also have decreased medication adherence, increased involvement in risky health behaviors, and a poor understanding of preventive health measures.6, 7 Low health literacy impacts more than the mortality rate; patients with inadequate health literacy have increased rates of hospitalization. If not appropriately addressed, America’s healthcare costs will continue to rise.6 Many researchers have documented the relationship between health literacy of adults in the United States and adverse health outcomes. A limited number of studies have been done, however, to assess the link between parental/caregiver health literacy and the health outcome of our nation’s children.5 In the few studies that have been documented, low parental health literacy has been linked to behaviors that negatively impact a child’s health.5 A patient’s level of education, age, race, ethnicity, and culture also impact the outcome of healthcare, contribute to patient compliance, and even affect healthcare costs.1, 8 It is not surprising, therefore, that by improving literacy, health outcomes will also improve. Many cognitive assessment tools are now available to measure health literacy. These tools assess a patient’s recognition of medical terms and ability to interpret written health materials.1 Since approximately 90 million adults have fair-to-poor literacy and 21–23% of adults read at the lowest reading level, other interventions such as educational videotapes or DVDs and color-coded medication schedules may improve the delivery of healthcare.1, 9 America has realized that quality healthcare relies on effective communication between patients and involving members of the healthcare team. Although attempts have been made to increase health literacy and in turn improve patients’ understanding through effective communication, the scope is not broad enough and certainly the pace is not

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_3, © Springer-Verlag London Limited 2010

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fast enough to make the progress that is necessary.4, 10 Awareness of this epidemic must be further increased and more research should be done.11

3.1 Introduction Health literacy has been defined “as the degree to which individuals have the capacity to obtain, process and understand basic health information and services needed to make appropriate health decisions.”12 The American Medical Association (AMA) expanded on the definition and defined health literacy “as a constellation of skills” which includes the ability to do basic reading and perform basic numerical tasks.1 A patient’s inability to perform these basic tasks acts as a barrier to accurate medical diagnosis and optimal treatment. This inadequacy of health literacy contributes to a weak healthcare system in the United States. Patients become noncompliant, chronic diseases become more difficult to control, and healthcare costs continue to rise.1 A significant proportion of adults in the United States are impacted by this epidemic. According to a report from the Institute of Medicine (IOM), almost 50% of Americans have difficulty understanding basic printed health information.1, 7 The 2003 national assessment of adult literacy (NAAL) revealed that approximately 90 million American adults have fair-to-poor literacy.1, 12 Effective patient–physician communication is therefore the key element to accurate medical diagnosis and optimal treatment. It is recommended that physicians elicit patient comprehension of disease processes.13 Effective communication will lead to improved patient satisfaction and medication adherence and subsequently improved health outcome.11, 13, 14 Physicians also need to be cognizant that health literacy is compounded by a patient’s age, race and ethnicity, culture, language spoken, and historical experiences with racial and ethnic disparities that have led to mistrust of the heathcare system.1, 15

3.2 Epidemiology In today’s society, the patients with the greatest ­healthcare needs may have the least ability to perform basic reading and mathematical tasks.11 A recent

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government study estimated that over 89 million American adults have limited health literacy.1 A systematic review estimated that 21–23% of adults read at the lowest reading level which is approximately fifth grade or lower.1 Inadequate health literacy in America is surprisingly common. A 2003 survey categorized US health literacy rates into four groups: proficient (11%), intermediate (53%), basic (22%), and below basic (14%).16 Health literacy becomes more complicated in elderly patients and in patients whose primary language is not English. Elderly patients may have a limited ability to read information pertinent to their health because of declining cognitive and sensory function.1, 17 In fact, the majority of patients older than 60 years have inadequate literacy.1 The ability to read and comprehend prescription bottles, appointment slips, and other essential health-related materials is decreased in the elderly.1, 15 Approximately 80% of the elderly in the United States have a limited ability in filling out forms, such as those requested in physician waiting rooms.1 A survey of patients at two US public hospitals revealed that 35% of English-speaking patients and 62% of Spanish-speaking patients had fair-to-poor health literacy.1,9 A majority of these patients may avoid seeking medical attention because they are in denial or because they are embarrassed.1 Limited health literacy has been linked to delayed medical diagnosis.6,18 Once a diagnosis is made, physicians may encounter patients who have a difficulty understanding their medical condition and the need for using preventive health measures.6,18 Adherence to medical instructions and self-management skills may also become problematic.6 Not only is there an association between low health literacy and morbidity, but low health literacy has been linked to an increase in the mortality rate. A 5-year prospective study of 2,500 adults with the average age of 75.6 was analyzed. After adjusting for demographic and socioeconomic status (SES), comorbid conditions and patient-health-related behaviors, there was a twofold increase in the mortality rate.18 In another prospective study, the crude mortality rate for patients with inadequate health literacy was 39.4%. The rates for the participants with marginal and adequate health literacy were 28.7 and 18.9% respectively.5 The NAAL survey estimated that 14% of adults in the United States have below basic level of prose literacy, the ability to use “printed and written information to function in society, to achieve one’s goals,

3  Raising Awareness on the Health Literacy Epidemic

and to develop one’s knowledge and potential.”9 Document literacy is the ability to read and comprehend documents such as drug or food labels.9 Twelve percent of adult patients are estimated to have below basic document literacy.9 Many patients are unable to understand prescription labels. Although 71% with inadequate health literacy correctly said “Take two tablets by mouth twice daily,” only 35% could demonstrate this instruction in a study done to assess patient comprehension.19 Another report found that 24–58% of patients did not understand directions to take a medication on an empty stomach.19 The NAAL survey also showed that 22% of adults are estimated to have below basic quantitative literacy. Quantitative literacy is defined as the ability to perform quantitative or mathematical tasks. Patients with inadequate quantitative literacy may be able to add up all the numbers on a bank slip, but they cannot, for example, compare ticket prices for some events.9 The elderly are more likely to have chronic and multiple medical comorbid conditions. These patients may have a difficult time with health literacy because of decreased sensory and cognitive function and as a result may have a difficult time controlling their chronic and comorbid conditions.1,17 On the basis of NAAL, it was analyzed that the patients over the age of 64 with below basic prose literacy, basic document literacy, and basic quantitative literacy accounted for 23, 27, and 34% respectively.9

3.3 Health Literacy Assessment Tools During the past decade, the magnitude of the health literacy epidemic in America and the effect it has had on health outcome and mortality has received considerable attention. Patients with inadequate health literacy have a complex array of difficulties which influence diagnosis and disease management.6, 11 It remains unclear whether screening patients for health literacy improves health outcome. A common mistake is to rely on patients’ own assessment of their level of health literacy. The majority of patients who have inadequate health literacy will say that they know more than they really do and overstate their reading competence.1 Patients with low literacy often are too embarrassed to admit that they do not understand and therefore refuse to ask their physician to explain or

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repeat relevant information regarding their health.1 Many have told no one about their handicap including their spouses and family members. Although the evidence is insufficient to conclude that screening improves patient–physician communication and subsequently morbidity and mortality, many types of standardized literacy assessment tools are now available.1, 5 They measure the health literacy and assess a patient’s recognition of healthcare terms. They also assess a patient’s ability to interpret written health materials.1 The rapid estimate of adult literacy in medicine (REALM) and test of functional health literacy in adults (TOFHLA) were developed specifically to measure patients’ health literacy.7 Although both the REALM and TOFHLA are valid and easily administered, the REALM is the most commonly used tool.7 Since its introduction in 1991 the REALM has been identified as the quickest of the two, taking less than 5 min to complete and can easily be administered by a nurse or other members of the medical staff.1 The REALM is a word recognition test. It is comprised of 66 medical terms that are arranged in order of increasing complexity.7 During the administration of this test patients are asked to read down the list and pronounce as many words as they can. The examiner uses standard dictionary pronunciation as the scoring standard and assigns a score based on the number of words pronounced correctly.7 One point is given for each word that is correctly pronounced. Scores therefore vary from 0 to 66. A score of 0 indicates that none of the words were pronounced correctly and a score of 66 indicates that all the words were pronounced correctly.7 The scores are then matched to a grade equivalent. A score of 0–18 would be equivalent to third grade or less, 19–44 would be equivalent to fourth to sixth grade, 45–60 would be equivalent to seventh to eighth grade and 61–66 would be equivalent to high school.1,7 The TOFHLA is also available for use by healthcare professionals and is available in both Spanish and English. Although the TOFHLA provides a more thorough assessment of a patient’s ability to comprehend, it is less practical for today’s use and it is more time-consuming.1 It takes approximately 22 min to administer.7 There is a short form of TOFHLA called the S-TOFHLA that takes approximately 7 min.7 In a well-written report, the validity of a new and rapid literacy assessment instrument was discussed. The newest vital sign (NVS) was introduced in 2005

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with the intention of addressing the speed and accuracy of health literacy assessment.12 NVS is now available in both English and Spanish and uses the TOFHLA as the reference standard.20 NVS was developed from a series of scenarios that were created by a panel of health literacy experts. The candidate scenarios included instructions from a prescription for headache medicine, a consent form for coronary angiography, instructions for self-care and management of heart failure, an ice cream nutrition label, and instructions for an asthma medication that included a tapering steroid dose.12 Patients were asked to read these healthrelated scenarios and then demonstrate their ability to use the information by answering certain questions about each scenario.20 Since one has to be able to do basic reading and perform basic mathematical tasks in order to survive in today’s healthcare environment, some of the scenarios did involve both reading and mathematical concepts.1,12, 20 The scenario that best determined the literacy level was the one with the ice cream nutrition label.12 The average completion time for the English version was 2.9 min. The Spanish version took on average more time to complete.12 In detecting marginal health literacy, NVS may be more sensitive than TOFHLA. The specificity of NVS is similar to or better than other screening tools such as the widely used CAGE questionnaires to detect alcohol abuse and the screening methods to detect arthritis.20 Like REALM and TOFHLA, NVS has its limitations. The Spanish version was not as good as the English version.20 The primary care practices that were involved in the study did not fully represent all primary care practices. They were selected because they had a high percentage of Spanish-speaking patients. Among these Spanish-speaking patients the percentage of males was relatively small.20 Despite these limitations the NVS has advantages over the REALM and TOFHLA. In the future, studies should examine the validity of NVS in both primary and nonprimary care setting and whether raising a physician’s awareness to the issue of health literacy results in better health outcome.20 During the last 15 years, research has shown that patients with inadequate health literacy often have a poorer understanding of their medical diagnosis and are less likely to utilize disease management techniques. These patients tend to underuse health promoting and disease prevention programs and often engage themselves in risky health behaviors.7 The number of

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patients that are affected is alarming. On the basis of these findings, more research should concentrate on improving screening methods. Physicians should also pay special attention to informal behavioral cues that may help detect low health literacy. Patients with inadequate health literacy often attempt to identify their medications by looking at the pill instead of the medication label. Other behavioral cues include frequent misspelling or turning in incomplete medical forms.12 Making excuses and mimicking others may also be signs suggestive of inadequate health literacy.1

3.4 The Nature of this Epidemic The magnitude and the consequence of low health literacy are of concern to many, especially when one considers the effect it has had on morbidity and mortality. Many researchers describe low literacy as a silent epidemic.9 The problems are numerous and complex and for that reason health literacy has been receiving considerable attention. Patients with inadequate health literacy have a difficult time using the healthcare system. These patients may refuse to keep doctor’s appointments because they may not be able to register for health insurance or even follow simple driving directions. Once these patients arrive at the office they may not be able to complete medical forms because they cannot read or follow simple instructions and once that appointment is over they may not know when to follow up.1 Physicians should be alert for this problem because most patients are too embarrassed to admit that they have a literacy issue. Patients with inadequate health literacy are less likely to participate in health promotion and disease prevention programs. They have a poor understanding of disease-preventive measures such as pap smears, mammography, and colonoscopy. Not only do these patients have less basic health knowledge and worse self-management skills, but they are more likely to be hospitalized.1,6 Even after adjusting for other factors associated with increased risk for hospitalization, studies conclude that patients with inadequate health literacy are more likely to be hospitalized.12 Patients with inadequate health literacy have 29–52% higher hospitalization rates.5 One study showed that adult males with inadequate health literacy would commonly present with advanced stage prostate cancer. It was suggested that those with

3  Raising Awareness on the Health Literacy Epidemic

inadequate health literacy delayed seeking medical attention and presented in the very late stages of the disease.12 Other diseases like diabetes and hypertension require a patient to be health literate in order to be adequately controlled. Diabetes and hypertension are chronic diseases that require the patient to be educated to avoid adverse health outcomes.14 Patients with hypertension may need to understand how to take multiple medications. The intricacies involved with selfmanagement of diabetes often get ignored in a patient with inadequate health literacy. Patients with inadequate reading and mathematical skills often have a difficult time monitoring home glucose levels and administering insulin.14 In an observational study of 408 patients with type 2 diabetes, inadequate literacy was associated with poor glycemic control and an increase in the rate of diabetic retinopathy.21 In another study of over 500 patients hospitalized for diabetes, only 50% of patients with inadequate literacy knew the symptoms of hypoglycemia compared to 94% with adequate literacy.14 Ninety-two percent of patients with hypertension who had adequate literacy knew that a blood pressure reading of 160/100  mmHg was high while only 55% of patients with low health literacy were able to evaluate this reading.14

3.5 Education and Health Literacy A patient’s level of education plays a vital role in their understanding that lifestyle and behavioral modifications are required when managing diseases. Especially when managing diabetes and hypertension, health literacy must be up to par to achieve adequate control and to prevent adverse outcomes such as death.14 Most health-related materials are written at the tenth grade level or higher. The majority of adults have a difficult time comprehending these health-related materials since most adults read between the eighth and ninth grade level.1 Patients with poor reading and poor mathematical skills may have a difficult time reading food labels and calculating calories. Health literacy is thus associated with diet and medication adherence. In a report of 2,659 predominantly poor patients at two public hospitals, up to 58% of patients did not understand the direction to take a medication on an empty stomach.14 Proper medication administration is crucial to adequate disease management. Physicians need to

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elicit their patients’ understanding. Evidence clearly links patient–physician communication to patient adherence and health outcome. Patients in general recall or comprehend as little as half of what physicians convey.13 This is even lower in a patient with inadequate literacy. In a study that used direct observation to measure the extent to which primary care physicians assess patient recall and comprehension during diabetic patient encounters, it was found that these physicians rarely assessed recall or comprehension of new concepts.13 This reflects a missed opportunity to improve and enhance patient compliance and ultimately improve disease management.13 There is clear evidence that improving a patient’s comprehension of a disease improves medication adherence and disease outcome. Ensuring recall and comprehension becomes especially important in our diabetic and hypertensive patients since they must cope with the complex nature of their disease and the intricacies of self-management.13

3.6 Age and Health Literacy The impact of age on clinical care is important. As age increases, so do the deficits in literacy.1 Elderly patients may have a difficult time reading and compre­ hending information regarding their health because of an increased time since formal education. Decreased cognitive and sensory function also compounds this problem of health literacy. The majority of patients older than 60 years have low health literacy. Eighty percent have a difficult time filling out forms such as insurance forms and the ones they have to complete in physician waiting rooms.1 To determine the ­prevalence of low functional health literacy among Medicare enrollees, a cross-sectional survey of new enrollees in health plans of a national managed care organization was done.6,17 After adjusting for years of school completed and cognitive impairment, a patient’s reading ability was seen to decline with  age.17 Approximately 30% of English-speaking patients and 50% of Spanish-speaking patients had low or marginal health literacy.17 The study concluded that elderly managed care enrollees may not be able to function appropriately in a health-care setting. Low health literacy may impair their understanding and thus limit their ability to care for themselves and their

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medical problems.17 Higher total medical and emergency costs are associated with low health literacy in the elderly. Patients tend to avoid outpatient doctors’ offices because they are embarrassed about their inability to fill out paperwork. They may find emergency rooms easier to use because information is taken and forms filled out by others.9 Elderly patients with low health literacy and high prevalence of chronic conditions may have increased levels of depression.22 Investigators also sought to determine whether older adults with inadequate health literacy were more likely to report depressive symptoms.22 Overall, 13% of the respondents were classified as being depressed.22 Although some patients with inadequate health literacy are unaware of their handicap; others feel significant shame and decreased worth.1,22 One study found that among those patients who admitted that they had a reading problem, the majority did not disclose this information to their spouse or family22; 19% of subjects had never even disclosed their inability to read to their healthcare provider.22 Such embarrassment may lead to social isolation. It is possible that these feelings of embarrassment and shame could lead to a higher prevalence of depression. In fact, individuals in the study who had less social support had significantly higher odds of being depressed.22 Data generally suggest that the higher the level of education a person attains the fewer depressed symptoms they will have. Some studies propose that this may be due to a greater financial success, improved lifestyle behaviors, and improved problemsolving capacity.22 The investigators also sought to determine whether the potential relationship between health literacy and depression may be mediated by health status. Some literature suggests that there is a strong predictive power of health status on depression.22 Especially among the elderly, there may be higher rates of depression because of low health literacy coupled with a high prevalence of chronic conditions.22 Even after controlling for other factors, it was found that individuals who were inactive and exercised less than twice a week were twice as likely to have symptoms of depression.22 In the cross-sectional survey, patients with low health literacy were more likely to report that they were depressed than those patients with adequate health literacy. This was mostly explained by their worse health status. This relationship between depression and poor health status ­suggests the need to research ways to improve patients’ health.

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Patients may need to be referred for social support to help with their ­depression and exercise programs to increase exercise ­tolerance and compliance.22

3.7 Parental Health Literacy and Pediatric Health Health literacy is now gaining momentum among researchers. Many studies have been done to assess the relationship between adult health literacy and health outcomes. A limited number of studies have been done to evaluate the association between parental literacy and a child’s health outcome. In the few studies that have been done, low parental health literacy has been linked to behaviors that have a negative impact on children’s health.12 The REALM was utilized in a study of 600 pregnant women. After controlling for age, race, marital status, living with a smoker, and current smoking status, the study concluded that pregnant women with inadequate health literacy had significantly less knowledge about the negative effects that smoking had on their babies’ health.12 In fact, 66% of the pregnant women with at least a ninth grade level of education were more concerned about the effects of smoking and their babies’ health as compared to only 37% of women who had a third grade level of education or lower.12 The issue of not initiating breastfeeding and how this may affect a baby’s health were also studied. A study done by Kaufman and coworkers on primarily low SES mothers showed that those women with at least a ninth grade education were more likely to breastfeed for at least 2 months. This was estimated to be 54% as compared to 23% of parents with a seventh or eighth grade level of education.12 All parents are required to receive information on childhood immunization. One study found that this information is written above the tenth grade level of reading. In fact, a study of documents available through the American Academy of Pediatrics found that the reading levels of asthma management plans ranged from eighth grade to twelfth grade.12 Most adults in the United States read at the eighth grade level and below.1 One study assessed asthma care measures in children who presented for care in an outpatient clinic and found that children of parents with low health literacy were more likely to have emergency department visits and had more

3  Raising Awareness on the Health Literacy Epidemic

hospita­lizations.12 Screening for parents/caregivers is not easy. Most physicians do not screen parents due to time constraints and they may also lack the knowledge on how to intervene when they discover that a parent has inadequate health literacy.12

3.8 Childhood and Adolescent Health Literacy There may be a link between child and adolescent health literacy and their own health outcome. Only a limited number of studies have been done to assess this possible link.12 One study was done on 3,000 students in Australia that found an association between adolescent literacy level and substance use, namely tobacco.12 The same study concluded that there is a link between the health literacy of adolescent boys and alcohol misuse.12 A study done of over 350 US children concluded that there is a link between low literacy and carrying weapons and participating in fights at school.12 Recently a study was done to assess the link between child health literacy, parent health literacy and childhood obesity. Adjustments were made for the children’s age, gender, insurance, eating-self efficacy, exercise self efficacy, exercise activity, grade in school and reported reading level and the parents’ primary language spoken at home and body mass index.12 After adjusting these confounders it was found that low child health literacy as opposed to low parent health literacy had an association with body mass index Z-scores.12 Although research is limited, some studies have concluded that a child’s health is impacted not only by parental/caregiver health literacy but also by the health literacy of the child. It is unclear whether screening children and adolescent for health literacy is necessary. In December 2006, a screening tool called the REALM-Teen was developed to assess health literacy in the adolescent population.12 The REALM-Teen is a word recognition test intended for grades 6 through 12. It allows physicians to recognize adolescent patients that read health-related information below their grade-reading level.12 This screening tool takes no more than 5 min to administer. Similar to the other screening tools used to assess health literacy in adults, the REALMTeen has its limitations as it is only available in English.12

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3.9 Culture, Race, Ethnicity, and Health Literacy Health literacy is significantly impacting the delivery of healthcare in America. Not only does a patient’s age, level of education, language spoken affect the delivery of healthcare, but sociocultural factors, race, and ethnicity also impact the healthcare system.1, 8, 23 Culture, race, and ethnicity influence a patient’s belief and health practices.12, 23 It is essential that healthcare providers deliver care that is sensitive to the needs of patients from different cultures, race, and ethnicity.8, 23 Achieving cultural competence is a multifaceted project.8 There has been growing interest in preparing healthcare providers to care for patients with different cultural backgrounds.8 Despite this interest, only a few studies have been done to examine efforts to educate healthcare providers in cross-cultural care.8, 23 By 2015, it is estimated that over 50% of patients that will be seeking primary care will be of the racial and ethnic minorities.8 Cultural differences between patients and healthcare providers influence communication, patients’ adherence, and health outcome.23 Certain patients may be viewed as having inadequate health literacy because they have beliefs and practices that are not understood by healthcare professionals. These misunderstandings can lead to negative health outcomes. The role of mistrust in the healthcare system by racial and ethnic minorities is also an important aspect in medical care. African Americans especially carry with them the continuing legacy of the Tuskegee Syphilis Study that contributes to mistrust in the healthcare system.8, 24, 25 A physician’s full understanding of this historical experience is necessary in achieving optimal patient–physician encounter.8 The Society of General Internal Medicine Health Disparities Task Force made recommendations to address the racial and ethnic health. The Task Force recommends examining and understanding patients’ attitudes such as mistrust. It was also recommended that the correct skills are needed to effectively communicate across cultures, languages, and literacy levels.

3.10 Health Literacy and Mortality Patients with inadequate health literacy face enormous obstacles. During the last 15 years researchers have shown that there is some association between inadequate

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health literacy and poor understanding of chronic diseases, poor self-management skills and underuse of health promoting/disease prevention programs.5, 7 Unfortunately, patients with inadequate health literacy are at an increased risk for adverse health outcomes including death. One study reported that among community-dwelling adults aged 70–79 years, there was an association between the performance on the REALM and mortality. Worse performance during this screening was associated with higher mortality rates.5 A prospective cohort study was performed on 3,260 medicare-managed care enrollees in the four previously mentioned US metropolitan areas of Cleveland, Houston, Tampa, and the Ft. Lauderdale/ Miami area.5 This prospective cohort study was designed to determine if there is a relationship between health literacy and mortality and whether low health literacy independently predicts overall and cause-specific mortality.5 Health literacy is essential for managing health conditions.1, 12 It is a cornerstone for patient safety in twenty-first-century America. In the study, the participants were of the age 65 years and older. Race/ethnicity, level of education, chronic health conditions, physical and mental health were some of the areas that were assessed. The patients involved in the cohort study were also asked to complete the short form of the TOFHLA, the S-TOFHLA.5 The S-TOFHLA included two reading passages and four mathematical questions to assess the participants’ ability to read and perform numerical tasks. Among the 3,260 participants the number of participants with adequate literacy, marginal literacy, and inadequate literacy were 2,094, 366, and 800 respectively.5 According to the results of this prospective cohort study, elderly patients with poor health literacy have higher incidence of all cause mortality and cardiovascular death.5 A participant’s health literacy was determined or measured by reading fluency which according to the authors “was a more powerful variable than education for examining the association between SES and health.” The study analyzed differences in mortality during a 6-year period. The National Death Index was used to identify the deaths through 2003.5 Of the 3,260 participants, a total of 815 participants died during an average follow-up period of 67.8 months.5 For those participants with inadequate health literacy, the crude mortality rate was 39.4% compared with 28.7% in those participants with marginal health literacy. Participants with adequate health literacy had the lowest crude mortality rate of 18.9%.5 Cardiovascular disease was the cause of death in 11.7% of participants;

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which accounts for a total of 380 participants. Those participants with inadequate health literacy had higher rates of mortality secondary to cardiovascular disease (19.3%) as compared to those with marginal health literacy and adequate health literacy whose rates were 16.7 and 7.9% respectively.5 Although the crude cancer mortality rates were higher in patients with inadequate literacy, multivariate analyses had similar rates. The authors have therefore concluded that “participants with inadequate health literacy had higher risk-adjusted rates of cardiovascular death but not death due to cancer.” The authors explored several possible explanations for the association between health literacy and mortality. Smoking, alcohol use, and physical activity were examined to determine if these behaviors could explain the higher mortality rate among those with inadequate health literacy. Health behaviors were found to be only weakly predictive of mortality.5 This was also the case when the authors explored the association between the amount of years a participant completed in school and the rate of mortality. In bivariate analyses, years of school completed had a weak association with mortality. In multivariate analyses, the amount of years of school completed did not significantly predict mortality. Since many individuals progress through the school system without meeting desired requirements, the authors also concluded that the number of years completed in school is not a true measure of educational accomplishment.5 For the elderly, the number of years completed in school does not capture or account for lifelong learning or age-related declines in reading fluency.12 For this reason, the authors concluded that fluency was a more powerful variable than education. Inadequate health literacy is associated with poor self-management of chronic diseases such as diabetes and hypertension.1, 6 Medication adherence also becomes affected. To function appropriately in today’s healthcare system, patients need to be able to perform numerical tasks. HIV-positive patients, for example, must be able to follow dosing instructions to properly manage their disease. Use of health promoting/disease prevention measures such as cancer screening and immunization are lower among those with inadequate health literacy.5 One study done on patients aged 50 years and older concluded that patients with inadequate health literacy were less knowledgeable about colorectal cancer screening.26 The authors of the July 23rd issue concluded that the association between

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health literacy and adverse outcomes such as death is probably secondary to the cumulative effect of multiple causes.5 Countless numbers of patients are at risk in today’s healthcare system because they do not ­possess adequate health literacy. Inadequate health ­literacy correlates with decreased knowledge about diseases, decreased medication adherence, increased involvement in risky health behaviors, and a poorer understanding of preventive health measures. Patients with inadequate health literacy are therefore at an increased risk for adverse health outcomes. The adverse health outcome that is most concerning is untimely death, since in most cases, death could be avoided if patients had adequate knowledge about diseases and diagnoses were not delayed. As a result, improvements in communication and possibly improvements in screening will more than likely be necessary to reduce the association between health literacy and mortality.12, 20 According to Baker et al, “To achieve this goal, we must further elucidate the causal pathways linking health literacy and adverse health outcomes and use this information to design more comprehensive and effective interventions.”5

3.11 Addressing Health Literacy Inadequate health literacy is surprisingly common in the United States. People of all ages, races, ethnicities, cultures, and education levels are challenged by this problem. During the past decade, the consequence that poor health literacy has had, America’s healthcare system has been receiving considerable attention. Many will agree that achieving a health-literate America is a multifaceted project. The AMA became the first national medical organization to adopt a policy that recognizes that there is a causal pathway to how inadequate health literacy negatively affects medical diagnosis and treatment.12 The AMA’s Council on Scientific Affairs, through an Ad-Hoc Committee on Health Literacy, published a report in 1999.1, 12 The report adopted five statements. It was identified in the first statement that limited health literacy is a barrier to medical diagnosis and effective treatment.12 The remaining statements recommended increasing public awareness, promoting the education of the medical community, supporting assessment of health literacy, and encouraging research on health literacy.1, 12 The

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joint commission on accreditation of healthcare organizations (JCAHO) added health literacy benchmarks for hospitals to achieve. JCAHO mandated that hospitals and other health organizations assess patients’ knowledge and provide instructions that patients can easily understand.14 The IOM convened a Committee on Health Literacy. Composed of experts from a wide range of academic disciplines, this committee was created to define the nature and scope of the problem, to identify any obstacles to solving this problem, to assess all the approaches that have been attempted and to identify goals for health literacy and suggest approaches to reach these goals.4, 10 In 2004, the IOM issued a well-written 345-page report, Health literacy: a prescription to end confusion. In the words of the IOM report, “efforts to improve quality, reduce cost, and reduce disparities cannot succeed without simultaneous improvements in health literacy.”10 The first finding of the Health Literacy Committee was that health literacy is “based on the interaction of the individuals’ skills with health contexts . . . the healthcare system, the education system and broad social and cultural factors at home, at work and in the community.”10 The healthcare system does not carry sole responsibility for creating a health-literate America. The responsibility must be shared among several sectors in today’s society. In the IOM health literacy report recommendations were made to increase both Federal and non-federal funds for research.10 Future research should focus on improving the health literacy screening methods. Research should also focus on techniques to improve health education.11 It was also recommended that in order to fulfill accreditation requirements, schools should implement National Health Education standards and funds should be increased to achieve these standards.10 Professional schools should also incorporate health literacy into their curricula. Private and public healthcare systems should get involved and help to identify ways to improve health literacy in America. Accreditation bodies such as JCAHO should incorporate health literacy assessment in data collection and healthcare information systems.10 In the report by the JCAHO titled “What did the doctor say?”: Improving health literacy to protect patient safety it was identified that inadequate health literacy complicates the communication process between healthcare workers and patients.27 Effective patient–physician communication has a direct link to improved understanding of diseases, increased

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medication adherence, and subsequently improved health outcomes. Sociocultural factors complicate the communication process between healthcare providers and patients. During an encounter, three cultures come into play; the culture of the patient, the culture of the physician, and the culture of medicine. America is now in an era where technology is producing numerous breakthrough drug regimens and life-saving treatments.2 Patients who have a difficult time with health literacy miss out on the lifesaving interventions and generally have worse health outcomes. The Joint Commission encourages accredited organizations to ensure patients’ understanding by providing information both written and oral in a way that they can understand.2 Many physicians rely on written health information that are often written at a grade level above most patients’ understanding.1 More than half the written medical information has a readability level at the tenth grade level or higher.12 In order to facilitate patient understanding, written healthcare materials should be short and simple.1, 12 In a randomized controlled trial the effectiveness of using a low literacy educational handout in increasing pneumococcal vaccine rates was demonstrated.1 Patients who received this one page instruction sheet written for fifth grade level were 4 times more likely to discuss the vaccine with their physician.1, 12 It is recommended that materials should be written at the fourth through eighth grade level for the general public to comprehend. The National Institute of Health convened a Plain Language Coordinating Committee that proposed that written materials should be in “plain language.” Plain language was defined as “clear writing that tells the reader exactly what the reader needs to know without unnecessary words or expressions.”12 Educational videotapes, pictorial illustrations, and simplified brochures may also improve understanding.9,12 Oral communication is another strategy that has been proposed. Healthcare providers should avoid using medical jargon and should speak slowly when providing verbal health related information.1,12 Speaking slowly may prove more beneficial to the elderly since they have a relative decline in cognitive and sensory function. Determining whether or not a patient understands what was said or what was provided in a written form is also very important in a patient–physician encounter. To assess a patient’s understanding, physicians should have patients

M. C. Duhaney

repeat in their own words what was said.1 This method is called the “teach back” strategy.1 To facilitate full comprehension, a combination of methods such as oral and written may prove beneficial. To improve communication some patients may benefit from group sessions. In fact, research has demonstrated that group sessions improve communication and subsequently improve behavioral and health outcomes.12 Patients with inadequate health literacy often feel embarrassed and by offering this method of communication some patients may find it easier to discuss their health issues. It is essential to deliver care that is sensitive to different races/ethnicities. Culture plays a vital role in shaping an individual’s health beliefs and practices. By utilizing educational programs that take into consideration cultural preferences, patients may become more involved and learning will be facilitated.12 A number of studies have been done to prove the effectiveness of the individualized approach to patient education. At this point in time there is no general consensus that the individualized approach is more effective in improving communication. A one-to-one counseling program was designed for pregnant African American and Hispanic women from WIC (women, infants, and children) who had limited health literacy and smoked.12 Smoking cessation materials were also provided. Women that were randomized were more likely to quit smoking at the 9-month follow-up session.12 The relapse rate was also relatively low for ex-smokers.12 Parents have a very strong influence on the health of their children because they are responsible for managing health conditions and at the same time preventing adverse health outcomes. Studies that have addressed improving the understanding of adults with low health literacy also have implications that are important for the pediatric population.12 All parents are required to receive immunization schedules and vaccine information at well-child visits. Since these documents are written at an eleventh grade reading level this poses a threat to those with limited health literacy.12 In 2005 the American Academy of Pediatrics formed a Health Literacy Project Advisory Committee to address the issue of health literacy as it relates to the pediatric population.12 As mentioned earlier, approximately 50% of American adults are unable to understand printed healthcare materials.1 A brief screening test may prove beneficial in identifying the parents that have inadequate health literacy. Adolescent

3  Raising Awareness on the Health Literacy Epidemic

health literacy assessment is also of importance to many researchers. The REALM-Teen allows physicians to assess health literacy in children that are in grades 6 through 12.12 One disadvantage of the REALM-Teen is that it is only available in English. It is essential that healthcare workers deliver care that is sensitive to the needs of patients that are from different races/ethnicities and cultures. The authors of a well-written article titled Viewpoint: cultural competence and the African American experience with healthcare in the February 2007 issue of Academic Medicine proposed that awareness of historical information of different ethnicities and race may improve communication.8 The authors identified key influences such as slavery and the Tuskegee syphilis study that have led to African American patients’ mistrust in the healthcare system.8 Patients with inadequate health literacy may have delayed diagnosis of medical conditions because they do not seek medical attention in the early stages of their disease. This could certainly be secondary to some cultural practices that involve the use of home remedies, mistrust in today’s healthcare system, or simply because patients have poor understanding about their health.1, 8 Whether patients have inadequate health literacy that is compounded by mistrust in America’s healthcare system or not, the authors proposed increasing awareness through cultural education as a method of improving communication in a clinical setting.8 The Joint Commission also recognizes that addressing culture and even language is essential to quality healthcare.2 In 2006, the Joint Commission implemented standards that required the documentation of patients’ language and communication need by accredited organizations.2 At some point in most people’s lives, healthcare decisions must be made because they are faced with medical conditions that require medical intervention. Patients with diabetes, for example, need their blood sugars to be properly managed to avoid adverse health outcomes. Widespread improvements in patients’ understanding will likely be a necessity if there is to be a reduction in the association between health literacy and adverse health outcomes such as death.5 Interventions that extend beyond the patient physician encounter should also be addressed.28 Considering that today’s healthcare system has placed a myriad of demands on patients, researchers have proposed multidisciplinary support teams and outreach activities.28 Recently, management strategies

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for chronic diseases were developed for those patients with inadequate health literacy.28 These strategies which included education and follow-up methods for patients with diseases such as diabetes and heart failure appear to be effective.28 In a pilot survey study that assessed the knowledge of colorectal cancer screening in patients 50 years and older, it was found that patients with limited health literacy were less likely to be knowledgeable about the screening method.26 A different approach for improving the education of patients with inadequate health literacy was studied.12 In a randomized control trial, healthcare providers were trained on screening guidelines for colorectal cancer and on methods to improve communication with patients with limited health literacy.12 Two thousand VA patients were involved in this trial and were provided with information on colorectal screening via video and a simple and clear pictogram brochure.12 The trial concluded that patients with inadequate health literacy (health literacy level less than the ninth grade) had an increased likelihood in completing colorectal screening test.12 Although further studies are recommended on assessing provider training methods, this method may prove beneficial at improving patient understanding and health outcomes.

3.12 Conclusion The future of America’s healthcare system depends on ingenuity and the commitment of necessary resources to improve patient–physician communication and subsequently improve patients’ health outcomes. Accepting the fact that health literacy is an issue in the United States is a crucial first step. Healthcare workers need to be more cognizant of the issues associated with inadequate health literacy as they impact patients’ morbidity and mortality and America’s healthcare costs. Becoming aware of these issues of health literacy as they relate to the patient, to healthcare, and society will enable better planning of care.27 After accepting that approximately 90 million adults have fair to poor literacy and that 21–23% of adults read at the lowest reading level, the next crucial step is identifying patients with these deficits.1 No simple method of identifying patients with inadequate health literacy exists and this is complicated by the fact that most are hesitant to disclose their limitations because they are

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too embarrassed.1, 29 Simply asking a patient for his or her highest level of education attained is not an accurate assessment of the patient’s health literacy.12 One study found a difference of 4.8 grade levels between educational attainment and the actual level the patients read.12 During the last 15 years, research has focused on several screening methods. Most physicians do not utilize these screening instruments because of time constraints. Others may lack the knowledge on how to address the issue of inadequate health literacy when they indentify a patient with this deficit.12 During the past decade, the magnitude of inadequate health literacy and consequences it has had on America’s healthcare system have been receiving attention. Although research is now gaining momentum the pace is not fast enough and the scope is not broad enough.10 The time is now to reach a resolution. We are certainly in an era where there are drug regimens and technology that can save patients’ lives. There should be no reason, therefore, that countless numbers of patients have poor health outcomes and are dying from health conditions that can be cured or at least treated. One study concluded that the crude mortality rate of patients with inadequate health literacy was highest at almost 40% relative to those participants with marginal and adequate health literacy which were 28.7 and 18.9% respectively.5 Patients with inadequate health literacy have a vast array of communication difficulties and therefore are less likely to effectively self-manage diseases or utilize preventive services.1,6,14 Physicians need to be aware of certain behaviors that are suggestive of inadequate literacy skills such as frequently missing appointments, noncompliance with medication, incompletely filling out forms, misspellings, need for assistance, and mimicking others.1,12 Physicians also need to evaluate themselves on their own literacy and identify areas that need improvement. One area that must be improved is the understanding of different cultures and ethnicities. Effective communication across different cultures and ethnicities is directly linked to improved patient satisfaction and increased adherence.23 Adverse health outcomes that may be associated with inappropriate treatment of chronic diseases such as diabetes and hypertension can be avoided if there is effective communication between patients and physicians. Both direct and indirect causal pathways that link inadequate health literacy to adverse health outcomes must be further explored and this information should be used to design interventions.5

M. C. Duhaney

Pediatric health is dependent on the health literacy of parents/caregivers. By addressing the communication between parents/caregivers and physicians, adverse health outcomes that affect children may be avoided. The American Academy of pediatrics in 2005 formed a committee to address issues of inadequate health literacy and how it relates to the pediatric population.12 In the well-written article Health literacy and pediatric health by Yin, MD et  al the American academy of pediatrics health literacy project advisory committee was introduced.12 The article stated that this committee is in the process of developing an agenda to address the challenges that parents with inadequate health literacy may face and how this affects the health of America’s children.12 Among the projects proposed by the committee were parent handouts in English and Spanish and health literacy guidebook for pediatricians. Although the committee is developing an agenda to address the impact of low literacy and the pediatric population there is limited research on this topic.12 The 2004 IOM report suggested that the healthcare system should not be solely responsible for addressing health literacy in America but instead other areas of society such as the education system should play a vital role. Direct involvement of patients should also be encouraged. In developing educational materials, a patient’s direct involvement may empower him or her to, for example, avoid risky behaviors, use preventive services, and subsequently improve his or her own health.30 Future research should explore the usefulness of screening and address the improvements in educational techniques. Certainly, the increased cost associated with inadequate health literacy needs effective intervention.11 Now is the time to make this happen. The issues associated with this health literacy epidemic should not be ignored. Awareness must be increased to effectively achieve a health-literate America.

References   1. Keenan J, Safeer R. Health literacy: the gap between physicians and patients. Am Fam Phys. 2005;72:463–468   2. Murphy–Knoll L. Low health literacy puts patients at risk. J Nurs Care Qual. 2007;22:205–209   3. Anon. Health literacy. Report of council on scientific affairs. JAMA. 1999;281:552

3  Raising Awareness on the Health Literacy Epidemic   4. Kindig DA, Nielsen-Bohlman L, Panzer AM. Health literacy: a prescription to end confusion. N Engl J Med. 2005; 352:947–948   5. Baker DW, Gazmararian JA, et al Health literacy and mortality among elderly persons. Arch Intern Med. 2007; 167: 1503–1509   6. Baker DW, Gazmararian JA, Wolf MS. Health literacy and functional health status among older adults. Arch Intern Med. 2005;165:1946–1952   7. Wallace L. Patients’ health literacy skills: the missing demographic variable in primary care research. Ann Fam Med. 2006;4:85–86   8. Eiser AR, Ellis G. Viewpoint: cultural competence and the African American experience with health care: the case for specific content in cross–cultural education. Acad Med. 2007;82(2):176–183   9. Marcus EN. The silent epidemic – the health effects of illiteracy. N Engl J Med. 2006;355:339–341 10. Kindig DA, Parker RM. Beyond the institute of medicine health literacy report: are the recommendations being taken seriously. J Gen Intern Med. 2006;21(8):891–892 11. Kellerman R, Rudd R, et al Health literacy: report of the council on scientific affairs. Ad Hoc Committee on Health Literacy for the Council on Scientific Affairs, American Medical Association. JAMA. 1999;282:525–527 12. Dreyer BP, Forbis SG, Yin HS. Health literacy and pediatric health. Curr Probl Pediatr Adolesc Health Care. 2007;37: 258–286 13. Bindman AB, Castro C, Schillinger D, et al Physician communication with diabetic patients who have low health literacy. Arch Intern Med. 2003;163:83–90 14. Baker DW, Nurss JR, et al Relationship of functional health literacy to patients’ knowledge of their chronic disease. A study of patients with hypertension and diabetes. Arch Intern Med. 1998;158:166–172 15. Betancourt JR, Bowles J, et al Recommendations for teaching about racial and ethnic disparities in health and health care. Ann intern Med. 2007;147(9):654–665 16. Baer J, Kutner REF, Greenberg E. National assessment of Adult Literacy (NAAL). A first look at the literacy of America’s adults in 21st century. Available at: ; 2009 Accessed 16.04.09

33 17. Baker DW, Gazmararian JA, Fehrenbach SN, et  al Health literacy among medicare enrollees in a managed care organization. JAMA. 1999;281:545–551 18. Satterfield S, Sudore RL, Yaffe K, et al Limited Literacy and mortality in the elderly: the health, aging and body composition study. J Gen Intern Med. 2006;21:806 19. Bass PF, Davis TC, Wolf MS, et al Literacy and misunderstanding prescription drug labels. Ann Intern Med. 2006; 145:887 20. Weiss BD, Mays MZ, Martz W, et al Quick assessment of literacy in primary care: the newest vital sign. Ann Fam Med. 2005;3:514–522 21. Grumbach K, Piette J, Schillinger D, et  al Association of health literacy with diabetes outcomes. JAMA. 2002;288:475 22. Baker D, Blazer DG, Gazmararian J, et  al A multivariate analysis of factors associated with depression. Evaluating the role of health literacy as a potential contributor. Arch Intern Med. 2000;160:3307–3314 23. Flores G. Culture and the patient–physician relationship: achieving cultural competency in health care. J Pediatr. 2000;136:14 24. Thomas SB, Quinn SC. Public health then and now. The Tuskegee Syphilis Study, 1932 to 1972: implications for HIV education and AIDS risk education programs in black community. Am J Public Health. 1991;81:1498–1504 25. White RM. Misinformation and misbeliefs in the Tuskegee Study of Untreated Syphilis fuel mistrust in the health care system. J Natl Med Assoc. 2005;97:1566–1573 26. Brownlee CD, McCoy TP, Miller DP, et  al The effect of health literacy on knowledge and receipt of colorectal cancer screening: a survey study. BMC Fam Pract. 2007;8:16 27. Ross J. Health literacy and its influence on patient safety. J Peri Anes Nurs. 2007;22:220–222 28. Bennett L, Davis TC, Wolf MS, et al Literacy, self efficacy, and HIV medication adherence. Patient Educ Couns. 2007; 65:253–260 29. Parikh NS, Parker RM, Nurss JR, et  al Shame and health literacy: the unspoken connection. Patient Educ Couns. 1996;27:33–39 30. Comings JP, Rudd RE. Learner developed materials: an empowering product. Health Educ Q. 1994;21:313–327

4

Domestic Violence, Abuse, and Neglect: Indicators for Dermatology Jina P. Lewallen and Susan R. Adams

4.1 Introduction This chapter will discuss the prevalence of domestic violence and abuse and/or neglect of patients and the dermatologic indicators for assessment, diagnosis, and treatment. This chapter includes the following: • A definition and view of domestic violence, abuse, and/or neglect • Review of current literature to include national and global statistics that demonstrate the prevalence of these issues • Mandated reporting laws and process • Assessment and diagnosis for the dermatologist • Multidisciplinary approach in treatment • Case studies • Follow-up issues

4.2 Definitions We need to begin with a definition of domestic violence, abuse (physical and sexual), and neglect. To understand sexual abuse and domestic violence, we must first agree on what these are. The United States Centers for Disease Control and Prevention1 defines domestic violence as: Actual or threatened physical or sexual violence, or psychological/emotional abuse by a spouse, ex-spouse, boyfriend/girlfriend, ex-boyfriend/ex-girlfriend, or date. Some of the common terms that are used to describe intimate

J. P. Lewallen (*) Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA e-mail: [email protected]

partner violence are domestic abuse, spouse abuse, domestic violence, courtship violence, battering, marital rape and date rape.

Domestic violence is a pattern of abusive and threatening behaviors that may include physical, emotional, economic, and sexual violence as well as intimidation, isolation, and coercion. The purpose of domestic violence is to establish and exert power and control over another; men most often use it against their intimate partners, such as current or former spouses, girlfriends, or dating partners. While other forms of violence within the family are also serious, this chapter will address the unique characteristics of violence against women in their intimate relationships. Domestic violence is a behavior that is learned through observation and reinforcement in both the family and society. It is not caused by genetics or illness. Domestic violence is repeated because it works. Domestic violence allows the perpetrator to gain control of the victim through fear and intimidation. Gaining the victim’s compliance, even temporarily, reinforces the perpetrator’s use of these tactics of control. More importantly, however, the perpetrator’s abusive behavior is reinforced by the socially sanctioned belief that men have the right to control women in relationships and the right to use force to ensure that control.2 Sexual abuse refers to any sexual activity perpetrated against another person, against their will or without consent. Child sexual abuse is defined as sexual violation of a child who cannot give consent. In the United States and several countries, medical and social service professionals, along with law enforcement and the clergy, are mandated by law to report any suspected abuse or neglect to law officers. After the report is made, a follow-up to determine abuse or neglect is made, usually within 24–72  h. Failure to report by professionals can result in loss of

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_4, © Springer-Verlag London Limited 2010

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J. P. Lewallen and S. R. Adams

licensure or privilege to work in that profession. Dermatologists fall within this category. Practitioners should also be aware of the importance of informed consent when treating patients. It is crucial in the development of trust in creating the therapeutic alliance. Informed consent in relation to abuse cases includes an understanding between patient and practitioner regarding the role of mandated reporting. This should be in addition to standard disclosure and understanding statements related to treatment options and risks. Other types of violence perpetrated against women and children can be seen in child and elder abuse. There are a smaller percentage of men who are victims of domestic abuse and the number of male children is significant in cases of sexual abuse.

4.3 Common Characteristics of Victims Victims may share common characteristics regardless of age or sex. They are often overwhelmed by feelings of helplessness and dependency. Presentation of anxiety or anger, along with multiple physical complaints, may be present during the diagnostic interview. Victims may feel responsible for the abuse or neglect and will often provided detailed explanations for the perpetrators actions. Typically, symptoms of depression and low self-esteem will also be a factor. In addition to the injuries sustained, emotional trauma and damage persists long after physical health is restored. It is common for children and adults to “try harder” to prevent future attacks. Understanding the futility of this mission is difficult for victims to comprehend.

4.3.1 Children Federal legislation provides a foundation for the states by identifying a minimum set of acts or behaviors that define child abuse and neglect. The federal child abuse prevention and treatment act (CAPTA),3 as amended by the Keeping Children and Families Safe Act of 2003 defines child abuse and neglect as, at minimum: Any recent act or failure to act on the part of a parent or caretaker which results in death, serious physical or emotional harm, sexual abuse or exploitation; or An act or failure to act which presents an imminent risk of serious harm.

This definition of child abuse and neglect refers specifically to parents and other caregivers. A “child” under this definition generally means a person who is under the age of 18 or who is not an emancipated minor. Children with special needs are at a higher risk of abuse or neglect. Many times children will wear the history of their trauma including scars, physical abnormalities, or disabilities. Head injury is a major cause of death and permanent disability for children under the age of two; therefore, special attention should be given to internal ear and eye exams. Bones and joints are manipulated to assess for tenderness and range of motion. Addressing eating patterns, sleeping patterns, problems swallowing, and mastery of age-appropriate tasks are also areas for assessment.

4.3.2 Elder Abuse and Domestic Violence Elder domestic abuse is a pattern of violence started earlier in life that has persisted in later years. It may also begin in later life due to strains of retirement, disability, or illness that comes in aging years. Like domestic violence in early years, the perpetrators are usually male. Elder sexual abuse is any nonconsensual contact with an older person. This includes fondling, oral, anal, vaginal sex, pornography, and other sexual acts meant to demean, injure, or mental or emotionally trauma as a result of contact. Physical abuse is any physical contact that results in injury, pain, or impairment. This includes hitting, kicking, biting, and inappropriate restraint of an elderly person. Psychological abuse and financial abuse are also of importance and should be noted. According to the national incident study on elder abuse: • Female elders are abused at a higher rate than males, after accounting for their larger proportion in the aging population. • Our oldest elders (80 years and over) are abused and neglected at 2–3 times their proportion of the elderly population. • In almost 90% of the elder abuse and neglect incidents with a known perpetrator, the perpetrator is a family member, and two-thirds of the perpetrators are adult children or spouses.

4  Domestic Violence, Abuse, and Neglect: Indicators for Dermatology

4.3.3 Warning Signs It is important for every healthcare provider to be aware of and act on signs and symptoms of abuse while creating a safe environment for the elderly person to report without fear of continued mistreatment from family and/or caregivers. The National Elder Abuse Incidence Study4 prepared for the administration for children and families and the administration on aging in the US Department of Health and Human Services gives the signs and symptoms shown in Table 4.1 to assist healthcare professionals in what to look for when investigating possible abuse of children and elderly persons.

4.4 Mandatory Reporting Victims of domestic abuse or sexual abuse need immediate medical care. In the United States, healthcare providers are mandated by state laws to report suspected abuse or neglect of any patient they treat. According to the child welfare information gateway,5 all states, the District of Columbia, the Commonwealth of Puerto Rico, and the US territories of American Samoa, Guam, the Northern Mariana Islands, and the Virgin Islands have statutes identifying mandatory reporters of child maltreatment. A mandatory reporter is a person who is required by law to make a report of child maltreatment under specific circumstances. Approxi­ mately 48 states, the District of Columbia, Puerto Rico, and the territories have designated individuals, typically by professional group, who are mandated by law to report child maltreatment. Individuals typically designated as mandatory reporters have frequent contact with children. Such individuals may include: • • • • • • • •

Physicians Social workers School personnel Healthcare workers Mental health professionals Childcare providers Medical examiners or coroners Law enforcement officers

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result in fines, penalties, and loss of licensure to practice. Check with your local authority. Reporting is mandatory whenever a healthcare professional suspects domestic violence, abuse, or neglect, whether or not it is proven. Some professionals are very sensitive about reporting suspected abuse for fear of misreporting or repercussions over unproved reports. However, the law protects mandatory reporters from prosecution if the report is not proven. It is important to remember that you must report and failure to do so can affect your practice in the future.

4.5 Common Characteristics of Abusers Along with an awareness of possible victims, practitioners should also be cognizant of possible perpetrators as well. It is not unusual for the abuser to bring the victim to medical appointments and to insist on being part of the interview. Persons who abuse lack control over aggressive impulses that lead to explosive behavior. The offenders will often explain their behavior as a form of “discipline” and necessary. Emotional immaturity is a common problem, as is the inability to process situations in an appropriate manner. Narcissism is also a common characteristic that leads to difficulty in engaging and maintaining adult relationships. This egocentric view interferes with the abusers’ ability to recognize the needs of others. They may also view their potential victims as objects responsible for meeting their needs. Persons who abuse have a tendency to be suspicious of everyone with whom they are in contact. On some level, there is recognition that their behavior is abnormal in relation to society’s expectations and they fear exposure. There are no obvious signs of mental illness, substance abuse, or related symptoms that can easily establish the identity of an offender, so it is important to be aware of indicators in order to obtain additional information about your patients and their situations.

4.6 Role of Healthcare Provider

The same applies for all ages of suspected abuse or  The role of the healthcare provider in detecting and neglect victims. Each state determines who is a man- preventing abuse begins with the first look or assessdated reporter. Failure to report, in many states, can ment of the patient. For dermatology, assessment of

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J. P. Lewallen and S. R. Adams

Table 4.1  Warning signs of abuse and neglect in children and the elderly General   Frequent unexplained crying   Unexplained fear of or suspicion of particular person(s) in the home   Bruises, black eyes, welts, lacerations, and rope marks   Bone fractures, broken bones, and skull fractures   Open wounds, cuts, punctures, untreated injuries, and injuries in various stages of healing   Stains, dislocations, and internal injuries/bleeding   Broken eyeglasses/frames   Physical signs of being subjected to punishment and signs of being restrained   Laboratory findings of medication overdose or underutilization of prescribed drugs   An elder’s report of being hit, slapped, kicked, or mistreated   An elder’s sudden change in behavior   A caregiver’s refusal to allow visitors to see an elder alone Sexual abuse   Bruises around the breasts or genital area   Unexplained venereal disease or genital infections   Unexplained vaginal or anal bleeding   Torn, stained, or bloody underclothing   An elder’s report of being sexually assaulted or raped Emotional and psychological abuse   Emotional upset or agitation   Extreme withdrawal and noncommunication or nonresponsiveness   An elder’s report of being verbally or emotionally mistreated Neglect   Dehydration, malnutrition, untreated bedsores, and poor personal hygiene   Unattended or untreated health problems   Hazardous or unsafe living conditions (e.g., improper wiring, no heat or no running water)   Unsanitary or unclean living conditions (e.g., dirt, fleas, lice on person, soiled bedding, fecal/urine smell, inadequate clothing)   An elder’s report of being neglected Abandonment   The desertion of an elder at a hospital, nursing facility, or other similar institution   The desertion of an elder at a shopping center or other public location   An elder’s own report of being abandoned Self-neglect   Dehydration, malnutrition, untreated or improperly attended medical conditions, and poor personal hygiene   Hazardous or unsafe living conditions (e.g., improper wiring, no indoor plumbing, no heat, or no running water)   Unsanitary or unclean living quarters (e.g., animal/insect infestation, no functioning toilet, fecal/urine smell)   Inappropriate and/or inadequate clothing, lack of necessary medical aids (e.g., eyeglasses, hearing aid, dentures)   Grossly inadequate housing or homelessness

4  Domestic Violence, Abuse, and Neglect: Indicators for Dermatology

bruises, cuts, and abrasions can be relevant in the diagnosis of a skin disease or condition, or of suspected abuse. There are many skin conditions that mimic signs of abuse and will be discussed later in the chapter. One of the most difficult problems caused by these family dynamics is treatment noncompliance. As noted, offenders may be very suspicious of any medical professional attempting to engage the victim. They may discourage the patient from keeping return appointments or refuse to allow private interviews with the victim. They may have multiple caregivers in order to avoid arousing suspicion.

4.6.1 Patient Interviews When working with patients, interviews should be nonthreatening and nonjudgmental. It is easy to become part of the abusive system rather than a possible haven. Beginning the interview by asking general, nonthreatening questions will help the client feel more at ease. Making basic inquires into patients needs will indicate the willingness to listen and open the doorway to more detailed communication. Some victims will have a desire to discuss the situation quickly while others may choose to be more cautious in their revelations. Once rapport has been established, it will be necessary to address the injuries and their possible origins. Patients will need to know they will have some form of protection if abuse is revealed to the physician. Accurate referral information should be maintained in the office. When evaluating patients for possible abuse, there are several factors that should be noted in developing an assessment6 including • Nonverbal communication between patient and caregiver, partner, or parent • Verbal communication between patient and caregiver, partner, or parent • Body language of all persons involved • Balance of communication between patient and practitioner and caregiver, partner, or parent • Dominant or submissive behavior of patient and caregiver, partner, or parent • Effectual responses to interview material • Ability to answer questions directly vs. subject changes and evasive, tangential, or irrelevant answers • Comfort levels of individuals during interview

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Practitioners must fully understand the implications of abuse and mandated reporting and be competent to safeguard the patient if abuse is suspected.

4.7 Statistics on Abuse, Neglect, and Violence Although men can be victims of domestic violence, abuse, or neglect, reports indicate that while males have a higher incident of abuse as children, as adults they are rarely a reported victim. Many potential male victims do not report for various reasons. Some men feel they could have prevented the abuse; others victimized by another male, fear to reveal intimate details of their sexual orientation. In the elderly, men may fail to report because they are not cognitively aware that they have been mistreated. In this case, professionals should take extra care in assessing for potential abuse. The same holds true for any elderly or mentally disabled person. Up to 44% of American women have experienced some type of domestic violence during their lives, either as a witness or as a victim.7, 8 The prevalence of violence, abuse, and neglect for women and children is not limited to the United States. Globally, that number is even higher; one out of three women reported being beaten, raped, or abused emotionally or economically during her lifetime.9 Many of the women reported witnessing or being a victim of abuse as children. Outcomes for women and children victims are many10: • More than three women are murdered every day by husbands or boyfriends as a result of domestic violence. • One in five high school females report being abused sexually or physically by a dating partner. • Half of the men who abuse their wives also abuse their children. • Three in four 18-year-old women reported rape or physical assault by a dating partner, cohabitating partner, or spouse; corroborating police reports that showed reported attacks by an acquaintance were higher than assault by a stranger. Globally, domestic violence is dependent on definition of cultural norms and laws. Many countries do not have laws or enforce laws that deal with domestic

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violence as they find it culturally acceptable. Some of these practices are seen in the statistics for global violence. Global statistics vary, but indicate prevalence for abuse through sex and human trafficking, increased rates of HIV and AIDS in women and children, murder, genital mutilation, and an increase in hospitalizations for women and children as the result of domestic, physical, or sexual violence.11 In healthcare practice, cultural norms must be considered in assessment and treatment of suspected abuse. While many countries agree on the definition of domestic violence, sexual abuse, and neglect, some practice violence as part of their culture. An example of this can be seen in the practice of female genital mutilation (FGM), a cultural practice many would consider physical or sexual abuse of female children.12 Each year at least two million girls face the risk of genital mutilation, most of who are between 2 and 8 years old. About 85–114 million females worldwide have mutilated genitalia. Most of these females reside in Africa. They encounter pain, trauma, and often, physical complications (e.g., bleeding, infections, and death). FGM consists of clitoridectomy (partial or total removal of the clitoris and/or the labia minora) or infibulation (total removal of the clitoris, partial or total removal of the labia minora, and incisions in the labia majora). FGM is a cultural, not religious, tradition which is used to prepare girls for womanhood. Muslims, Christians, some animists, and one Jewish sect practice FGM, but none of these religions require FGM. It is used to perpetuate women’s second-class status. FGM enhances the sexual pleasure of men while genitally mutilated women sense little or no sexual pleasure. This denial of sexual pleasure can have psychological effects on women. These women therefore become sexual objects and reproductive vehicles for men. The FGM practitioners vary by area and include traditional birth attendants, female laypeople, physicians and other trained health personnel, and women leaders. African women created the Inter-African Committee Against Traditional Practices Affecting the Health of Women and Children in 1984, which serves as the basis for global action against FGM. African immigrants in developed countries have taken the practice of FGM with them. Women in these countries have brought FGM to the fore and are pressing for laws against it. Protection from physical and sexual abuse, such as FGM, is a child’s right. Information on prevalence,

J. P. Lewallen and S. R. Adams

physical, and psychological effects, and religious requirements are needed to take action against FGM. Legal remedies include international action and national law. Each country’s mass communication systems and popular culture should be engaged in spreading information about FGM and in generating discussions on FGM. In the United States, FMG is considered child abuse and is reportable to legal and social services agencies. A report13 that surveyed and analyzed doctors’ reporting records found that one-third of the surveyed doctors did not keep a record on domestic violence reported by patients, nor did they report much support, advice, or resources to those who did report being a victim. Only 10% of doctors in the survey reported giving any information on where patients could seek assistance. A third reported that they were not confident about counseling patients who reported domestic abuse. This report demonstrates the need for physicians and other healthcare professionals to get training and be aware of mandated reporting laws. Many healthcare settings have diverse populations. Patients come from different racial, ethnic, or cultural backgrounds and practitioners need to be aware of cultural norms or differences. In many cultures, traditional treatments are used before seeking professional medical treatments. Health­ care practitioners should be knowledgeable about certain cultural practices as they can also resemble indicators of abuse. When assessing patients for diagnoses, the practitioner may observe what looks like abuse indicators, so a complete history of the patient, including cultural norms, is indicated. Some examples that apply to dermatology can be seen in therapeutic burning (moxibustion), cupping, coin rubbing, and pinching. Moxibustion, or therapeutic burning, is a folk remedy used in Southwest Asia and parts of Africa. Dot and patterned burns on the abdominal area, arms, and legs are thought to correlate to the internal energy channels on the skin. In Korean culture, moxibustion is used to correct the disharmony in the body due to illness. The yin and the yang are rebalanced and the patient is considered healed. Cupping is a very common folk treatment. A piece of cotton or material is set afire in the bottom of a glass or cup and the open mouth of the vessel is quickly placed on the patient’s back. The heat and suction produces a bruise or welt and sometimes a burn. The procedure may be repeated up and down the back of the patient. The cupped areas are believed to draw out

4  Domestic Violence, Abuse, and Neglect: Indicators for Dermatology

fever and illness. Many people who go for cupping treatments believe it will eliminate toxins through breathing and through the skin. It is believed that cupping draws out any illness in the body, leaving the patient healthier overall. Coin rubbing or coining is another common folk remedy for releasing illness or fever from the body. In the traditional technique, a coin is dipped in oil or mentholated cream and rubbed across the skin to produce welts or burns. This practice is believed to restore balance in the sick patient by withdrawing illness. In addition to cupping and coining, many Asian cultures and medicinal practices include pinching. The treatment involves pinching the neck, bridge of the nose, and other areas of the skin where the illness is believed to originate. The pinching is severe enough to cause dermabrasion or bruising to the skin. This practice is believed to draw out the bad force or illness and restores body balance. Other mimickers of abuse include dermatological conditions unrelated to previous folk treatments. Dermatitis as a result of irritants, seborrheic dermatitis, pinworms, and scabies can be misdiagnosed by general practitioners. Referral to dermatology specialists is warranted. Other skin conditions that may mimic abuse warrant a closer evaluation by the practitioner. There are many incidents where skin conditions may mimic abuse14: • • • • • • • • • •

Genital warts Pigmented vulvar hamartomas Darier’s disease Lichen sclerosus Crohn’s disease Localized varicella or zoster infection Pseudoverrucous papules Hemangiomas Urethral prolapse Allergic contact dermatitis

4.8 Assessment and Diagnoses for Dermatology In assessing the patient for suspected abuse or neglect, the dermatologist needs to conduct a thorough examination of the patient, keep accurate documentation, obtain photographs, and ensure the patient’s safety during the process.

41

For bruising, True petechiae and purpura, infections, group A streptococcal infections, Lichen sclerosus, vascular malformities, phytophotodermatitis. Mongolian spots, urticaria/angioedema, pernio to folk medicine remedies such as “cupping” and Cao gio or coin rubbing, both used to “draw out fever and disease.” For mimicking burns: impetigo, diaper dermatitis, pernio, chemical burns from over-the-counter treatments such as analgesic balm, sunburn can be observed as inflicted burns and reported as abuse. In cases as a result of abuse, team care is absolute in diagnosing, treating, reporting, and follow-up for the victim. Team care needs to include healthcare providers, social services, legal authorities to ensure the safety of the patient, especially in abuse cases involving minors or elderly who are most often vulnerable.

4.9 Prevalence A broad view and understanding of the prevalence of domestic violence, abuse, and neglect can be found in Bureau of Justice statistics15 (Table  4.2). On average since 2001, for nonfatal intimate partner violence, about one-third of female and male victims reported that they were physically attacked (Table  4.3) while two-thirds said that they were threatened with attack, including threats with a weapon and threats to kill (Table 4.4). Half of the females suffered an injury from their victimization. Forty-four percent suffered minor injuries while 5% were seriously injured; 3% were raped or sexually assaulted (Table  4.5). More than one-third of the male victims were injured: 36% with minor injuries and 4% with major injuries (Table 4.6). Less than one-fifth of victims reporting an injury sought treatment following the injury (Table 4.7).

Table 4.2  Average annual percent of threats, attempted attacks, and physical attacks in nonfatal intimate partner victimization, 2001–2005 Type of violence Percent of victims of intimate partner violence Female Male Attempt or threat

67.2

66.3

Physically attacked

32.8

33.7

100

100

42

J. P. Lewallen and S. R. Adams

Table 4.3  Average annual percent of attacks, by type, in nonfatal intimate partner violent crime, 2001–2005 Type of attack Percent of victims of nonfatal intimate partner violence who were attacked Female Male Raped

7.2

0.8a

Sexual assault

1.9

0.9

Attacked with firearm

0.5a

–

Attacked with knife

2.5

8a

Hit by thrown object

2.1

4.5a

Attacked with other weapon

0.8a

1.8a

Hit, slapped, knocked down

62.7

62.2

Table  4.5  Average annual number and percent of injuries sustained by female victims as a result of nonfatal intimate partner violence, 2001–2005 Intimate partner victim Average annual Number Percent

Grabbed, held, tripped 54.9 26 a Based on ten or fewer sample cases “–” Information is not provided because the small number of cases is insufficient for reliable estimates Table 4.4  Average annual percent of threats, by type and gender, in nonfatal intimate partner violence crime, 2001–2005 Type of threat Percent of victims of nonfatal intimate partner violence, 2001–2005 Female Male Threatened to kill

26.9

15.1a

Threatened to rape

0.5a

–

Threatened with harm

59.3

55.3

Threatened with a weapon

17.6

22.9

Threw object at victim

7.5

7.4a

Followed/surrounded victim

5.9

1.8

510,970

100

Not injured

248,805

48.7

Injured

262,170

51.3

Serious injury

25,710

5

Gunshot wound

595

0.1a

Knife wounds

4,940

1a

Internal injuries

3,440

0.7a

Broken bones

12,155

2.4

Knocked unconscious

3,730

0.7a

Other serious injuries

855

0.2a

Rape/sexual assault without additional injuries

13,350

2.6

Minor injuries only

222,670

43.6

Injuries unknown 435 0.1a Based on ten or fewer sample cases Note: total may not add to 100% due to rounding

a

Table  4.6  Average annual number and percent of injuries sustained by male victims as a result of nonfatal intimate partner violence, 2001–2005 Average annual Number Percent

a

Tried to hit, slap, or knock 14.1 12.6 down victim a Based on ten or fewer sample cases “–” Information is not provided because the small number of cases is insufficient for reliable estimates Note: detail may not add to total because victims may have reported more than one type of threat

Total

a

Total intimate partner victims

104,820

100

Not injured

61,285

58.5

Injured

43,540

41.5

Serious injury

4,335

4.1a

Minor injuries only

38,050

36.3

Rape/sexual assault without other injuries

580

0.6a

Injuries unknown 570 0.5a Based on ten or fewer sample cases Note: detail may not add to totals due to rounding

a

4.9.1 Costs of Violence-Related Injury in America The costs of assessing, diagnosing, and treating domestic abuse are high. According to the Centers for Disease Control and Prevention16: • Americans suffer 16,800 homicides and 2.2 million medically treated injuries due to interpersonal

v­ iolence annually, at a cost of $37 billion ($33 billion in productivity losses, $4 billion in medical treatment). • The cost of self-inflicted injuries (suicide and attempted suicide) is $33 billion annually ($32 billion in productivity losses, $1 billion in medical costs).

4  Domestic Violence, Abuse, and Neglect: Indicators for Dermatology Table 4.7  Average annual percent of medical treatment sought as a result of nonfatal intimate partner violence, by gender, 2001–2005 Average annual (%) Female Male

43

4.10 Identification and Assessment of the Patient

• People aged 15–44 years comprise 44% of the population, but account for nearly 75% of injuries and 83% of costs due to interpersonal violence.

In healthcare settings, many victims of domestic, physical, or sexual abuse present themselves for other medical issues or with unexplained or poorly explained injuries. Some patients present with chronic pain complaints, some with bruising, scratches, or burns that are not consistent with accidental injury. Patients who are victims of abuse may cover their common sites of injury such as arms, neck, breasts, chest, and abdomen with clothing, many times inappropriate for the weather. An example of this can be seen in patients coming in with turtleneck or long-sleeved shirts in summer. Hats, gloves, and scarves are also commonly used. In assessing for physical injuries in the healthcare setting it is important to make the patient feel safe. Patients are often reluctant to report abuse or violence for fear of retribution from abuser, separation from abuser, and uncertainty of belief from the provider assessing them and to uncertainty of what will happen to them if they report. This is prevalent in domestic violence as the perpetrator of the abuse is a spouse who has isolated their partner from family and friends and made her dependent on him for economic and emotional support.

4.9.2 Result of Violence-Related Injury17

4.10.1 Universal Guidelines

• The average cost per homicide was $1.3 million in lost productivity and $4,906 in medical costs. • The average cost per case for a nonfatal assault resulting in hospitalization was $57,209 in lost productivity and $24,353 in medical costs. • The average cost per case of suicide is $1 million lost productivity and $2,596 in medical costs. • The average cost for a nonfatal self-inflicted injury was $9,726 in lost productivity and $7,234 in medical costs. • Economic costs provide, at best, an incomplete measure of the toll of violence. Victims of violence are more likely to experience a broad range of mental and physical health problems not reflected in these estimates from posttraumatic stress disorder to depression, cardiovascular disease, and diabetes.

These guidelines are globally recognized as a complete assessment for diagnosis and charting procedures for evidence for mandated reporting.18

Not injured

48.7

58.5

Injured

51.3

41.5

Injured, not treated

32.8

27.9

Treated for injury

18.5

13.1

At scene or home

8.3

9.8

Doctor’s office or clinic

1.3

0.6a

Hospital

8.7

2.8a

Not admitted

8.4

2.8a

Admitted

0.3

–

Other locale

0.2

–

Don’t know – 0.5a Based on ten or fewer sample cases “–” Information is not provided because the small number of cases was insufficient for reliable estimates Note: detail may not add to totals due to rounding a

4.10.1.1 Physical Examination All healthcare providers should implement routine physical exam techniques that ensure accurate medical diagnosis: • Central distribution of injury: face, neck, throat, chest, abdomen, genitals • Bilateral distribution of injury to multiple areas • Contusions, lacerations, abrasions, human bites, or no evidence of physical trauma despite subjective complaint by patient/victim

44

J. P. Lewallen and S. R. Adams

• Delay between onset of injury and presentation for treatment • Multiple injuries in various stages of healing • Extent or type of injury inconsistent with patient’s explanation • Evidence of alcohol or drug abuse • Evidence of rape • Repeated chronic injuries • Chronic pain, psychogenic pain, or pain due to diffuse trauma without visible evidence • Documentation of pertinent negative findings should address all subjective complaints for which there is no physical evidence • With the patient’s permission, photographs should be obtained of visible injuries Any assessment for domestic violence should be included as part of psychosocial and mental health assessments. The stress of domestic violence may aggravate psychiatric disorders. Mental health disorders can be exacerbated by domestic violence, sexual abuse, or neglect. Some mental health reactions can be observed and assessed in the patient as: • • • • • •

Suicidal thoughts and attempts Depression Feelings of helplessness Substance abuse Posttraumatic stress disorder Psychoses

In addition, healthcare providers should be especially alert to injuries and indicators during pregnancy including: • Injuries, particularly to the breasts, abdomen, and genital area • Substance abuse, poor nutrition, depression, and late or sporadic access to prenatal care • “Spontaneous” abortions, miscarriages, and premature labor • Rapid heartbeat, asthma, and reported inability to sleep 4.10.1.2 Charting Healthcare providers should make a complete, legible record/chart of their findings. The reporting form is no substitute for complete documentation in the medical record. This chart should include:

• A detailed description of patient injuries: type, extent, age, location, and the use of a body chart when applicable (see resources at the end of the chapter) • Photographs of patient injuries. The patient should be informed that the photographs are to be used as possible evidence and give permission. • The maintenance of physical evidence. Forensic nurses and technicians collect physical evidence, and social services are available for emotional assessment and support during the process of examination. • The inclusion of relevant past medical history: history of falls, “accident prone” injuries; social history: overly concerned partner; history of substance abuse (including alcohol) by patient or partner; and sexual history: history of sexually transmitted diseases or rape • All charts should include comments by the healthcare providers as to whether the explanation offered for the injury adequately explains the injury. • The patient’s own words, with the use of quotation marks, should be entered into the chart in the chief complaint and history of present illness section(s) describing the abusive event. • Name of investigating officer and any action taken if the police were called. • Document every detail, even seemingly trivial ones, such as torn clothing, smeared make-up, broken fingernails, scratches, and bruises. • Include names of all personnel who examined or talked with the patient about the injuries or abuse in the record. All personnel who attend the patient should have collaborating notes in the chart.

4.10.1.3 Admissibility of Records Note that records are admissible as evidence if: • They were made during the “regular course of business” • They were made in accordance with routinely followed procedures • They were stored properly and access to them is limited to staff only Even if a patient later decides that s/he does not want to pursue legal remedies, a case can still be proven by introducing the statements s/he made to people in the past about what happened. Include anything that might

4  Domestic Violence, Abuse, and Neglect: Indicators for Dermatology

allow you to remember the patient’s attitude, face, and experience at a later date.

4.11 Clinical Assessments and Diagnosis for the Dermatologist In the healthcare setting, domestic violence, sexual abuse/neglect of children and elderly is diagnosed in the initial healthcare visit. Dermatology is viewed as a team member in assessment and diagnosis of abuse or neglect and is often times called upon to confirm a report by the primary care practitioner. While primary practitioners, geriatricians, pediatricians, and family practitioners are all trained in abuse and neglect, it is often the dermatologist who makes the definitive diagnosis with skin injuries, rashes, and other indicators of abuse.

4.12 Multidiciplinary Approach In domestic violence, abuse, and or neglect, best ­outcomes are reported by using a multidisciplinary approach. In building a case for domestic violence and abuse/neglect, a multidisciplinary report offers the whole picture for events occurred to the patient, and provides a timeline for outcomes from initial contact with healthcare systems through treatment and followup. The identification of suspected domestic violence, abuse or neglect, multidisciplinary teams, including dermatology, is often the best determiner of abuse.

45

Persons who have been victimized through domestic violence, abuse, or neglect often require medical care and healthcare providers are most often the initial point of contact.

References   1. United States Center for Disease Control, 2000   2. Anne L. Ganley, Susan Schechter. Domestic Violence: A National Curriculum for Family Preservation Practitioners. 1995:17–18   3. Federal Child Abuse Prevention and Treatment Act (CAPTA) [(42 U.S.C.A. §5106g)], as amended by the Keeping Children and Families Safe Act of 2003   4. National Elder Abuse Incidence Study (Final Report, Sept. 1998) prepared for The Administration for Children and Families and The Administration on Aging in The U.S. Department of Health and Human Services   5. Welfare Information Gateway, 2005   6. Mental Health Psychiatric Nursing   7. Family Violence Prevention Fund   8. American Journal of Preventative Medicine, June 2004   9. UN Commission of the Status of Women, 2/28/00 10. Statistics reviewed from the Bureau of Justice: Crime and Victim Summary (2000–2002) report 11. World Health Organization report on Gender Based Violence 12. Toubia N. New York, New York, Women, Ink, 1993. 48 p 13. Forbes.com issue: December 2005 14. Dermatology, Chapter 105, skin signs of Physical Abuse (McGraw Hill, Access Medicine website 15. Bureau of Justice statistics 16. Centers for Disease Control 17. Corso PS, Mercy JA, Simon TR, et al Medical costs and productivity losses due to interpersonal violence and selfdirected violence. Am J Prev Med. 2007;32(6):474–482 18. Family Violence Prevention Fund and Educational programs Manual for health Care Professionals

5

Working with Other Healthcare Providers Jina P. Lewallen, Carolyn Lazaro Tuturro, and Angelo Turturro

5.1 Introduction In the treatment of dermatological problems, the multior interdisciplinary approach encourages each discipline to bring its own training, skills, and experience to the problem-solving and treatment options for complete care of the patient. Each member of the team has a professional interest in their patient, while working in a team environment encourages each member to bring their own skills, experience, and perspective to the table. This also gives each member the flexibility to develop a care plan that meets all of the patients needs, medical and nonmedical. The team approach can be used for problem solving and for exchange of information and ideas in caring of the patient for best outcomes. This integrated approach to medical care, although it may appear to be a product of significant recent changes in medicine (or a result of a more social approach to medicine pioneered in the 1960s), is actually much older. Working together with other professional providers for patient care was first formalized in 1905 at Massachusetts General Hospital where there was a consideration of the whole patient and the relationship between illness and social conditions in treatment.18 How a multidisciplinary approach works can be illustrated by considering a scenario in the pathway of care for the patient. The patient goes to his/her primary care physician (PCP), who refers the patient

J. P. Lewallen (*) Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA e-mail: [email protected]

to a dermatologist. The communication between these two medical professionals is a vital link to the overall care of the patient. Nursing staff, lab staff, and scheduling staff are all needed to efficiently guide the patient through the healthcare pathway. Social work staff may assist in coordinating care through resources and referrals, especially for continuance of care at home. Psychiatrists, occupational therapists, and physical therapists may be called on for collaborative and collateral consultations and parallel treatments. All of these professionals on the team play an integral part in total patient care. This is especially important for dermatological care since the skin is an external organ and what afflicts the skin is often seen by other people. Their reactions can be almost as significant to the patient as the problem itself. Multidisciplinary and/or interdisciplinary work has proven to be most effective when team members: • Have common goals for healthcare outcomes. • Have professional and personal commitment to care. • Have clarification of their role on the team. • Have the support and respect of other team members for their contributions to the team. • Have good communication among the team members. • Have an environment that promotes these factors. For teaching and training, multidisciplinary/interdisciplinary teams give students a collaborative experience and view of healthcare delivery that enhances their own discipline. Students from all areas of healthcare education programs gain collaborative and extensive knowledge and skills from each member while learning about team/group process.

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_5, © Springer-Verlag London Limited 2010

47

48

J. P. Lewallen et al.

5.2 The Scope and Extent of Multidisciplinary Efforts 5.2.1 Scope of Multidisciplinary Efforts Clark et  al4 report that the joint commission on the accreditation of healthcare organizations (JCAHO) requires evidence of disciplines working collaboratively as part of its accreditation process in hospitals, nursing homes, and clinics. Bringing together different disciplines encourages an exchange of knowledge and ideas which are applied to the care of the patient. While each discipline shares basic knowledge and values (ethics) on patient care, each discipline also brings its unique contribution to the care and treatment of the patient from its perspective field. The need for interdisciplinary, multidisciplinary teamwork has been recognized most commonly in the field of geriatrics. This may be because of the multifocal aspects of the diseases of aging and the tendency of aging to integrate these factors over the lifetime of the patient. Some of the other areas of medical care, besides dermatology, where multidisciplinary approaches are commonplace include: • • • • •

Pediatrics Emergency medicine Oncology Ophthalmology, ENT Orthopedics

5.2.2 Multidisciplinary Efforts in Dermatological Care For dermatological care, some of the professions and roles that collaborate with the dermatologist include • Nursing staff, who provide triage, basic medical assessment, and disease-specific care for patients • Laboratory staff, who conduct general medical tests and diagnostics but especially dermatological­disease-specific analyses and assessments for patient treatment (some that require special training) • Pharmacy staff, who provide drug education and support for the patient • Social workers, psychologists, and psychiatrists, who help with nonmedical concerns and issues for

the patient during treatment by the dermatologist to address the complex issues of self-image, social response, and support for the consequences of dermal disease (e.g., psoriasis) • Genetic counseling staff, who provide genetic testing to confirm dermatological conditions that are inherited or can be passed on to further generations, for advice and support • Health educators, who keep patients informed about their particular dermatological conditions and treatments and, along with social services, provide support for total care • Obstetrics and gynecology, who work with dermatology on issues of skin disorders for pregnant women and as partners in total care of the patient One consideration that should not be overlooked is that the list of disciplines involved need not be static as the patient’s condition evolves, or even the same for different dermatological problems. A key aspect of the multidisciplinary approach is that different disciplines are called in as needed.

5.2.3 Challenges for Multidisciplinary Efforts The challenges of working in multidisciplinary care teams are universal in working in any team setting. These are varied, but include: • Determining who will be in charge of the team. In dermatological settings, it can be the dermatologist, or the PCP, or (more problematically) both as equally in charge. Patients usually need to identify with a leader who can answer questions and provide a connection between specialties during assessment and treatment. • Clinical protocols, which can take varied pathways from general medical protocol to more specific protocol, depending on the patient’s need or medical condition. The team needs to prioritize protocol for treatment and identify who will take charge of each procedure. • Challenges that arise when two or more team members cannot agree on treatment protocol. As we know, there are varied ways to apply caring and treatment options. It is necessary that the team members agree on assessment, diagnosis, and treatment with the best outcomes for the patient as the ­common

5  Working with Other Healthcare Providers

goal. When challenges arise, the team should have consensus on which is the first or the best treatment protocol for the patient. This is a special area of concern since, if this is not done, treatments by different members can be at cross-purposes with no clear way to assess whether they are working or not. • Each team member brings their own experience, level of education, and expertise which may or may not be on the same level as other team members. Team members have the opportunity to share this knowledge and experience with other team members to enrich the experience and to achieve a more level arena in which to work. • Each discipline has its own language and philosophy of practice, so consideration for each must be addressed and an agreed on language/philosophy needs to be adopted for best patient outcomes.

5.3 Creating and Maintaining a Multidisciplinary Team 5.3.1 Creating a Team Creating a multidisciplinary team is bringing team members from different disciplines together with shared goals and responsibilities to the patient. Team members must be able to communicate ideas and solutions openly. All members should share responsibilities, and accountability to the care of each patient. They must be willing to respect and collaborate with each team members for the best outcomes in patient care. They must also be committed to the process of team caring. Core members of the team must all possess basic knowledge in medical care and services for the dermatology patient. The doctor, nurse, pharmacist, lab, social services professionals must all be able to communicate their roles on the team and be able to present team decision for care to the patient and families or caregivers. Team members must meet on a regular basis during the patient’s assessment and treatment phases so they can monitor the patient’s progress or address any issues or concerns that arise during treatment. Each team member should be responsible for their particular piece of treatment and be able to present findings, address concerns, and add to the general knowledge and experience of the team.

49 Multidisciplinary Team for Total Patient Care

Pharmacy

Primary Care Dermatology

Laboratory Patient

Nursing

Oncology

Social Services Health Education

Fig. 5.1  A model of the structure of a team

Team members should share the lead throughout the treatment process, depending on the need of the patient during that phase of treatment in which one member has expertise. An example of this would be for a designated person to speak with the pharmacist about medication concerns, or the surgeon, if surgical intervention is part of the treatment process (Fig. 5.1). According to the multidisciplinary team approach, the patient will have a continuum of care throughout diagnoses and treatment: The full continuum of care includes prevention, patient and family education, screening, staging and work-up, initial and subsequent treatment, follow-up, palliative and hospice care, and psychosocial services.1

With any discipline, it is important that the philosophy of treating the whole patient is in the forefront of any process. With multidisciplinary care, this may insure that the whole patient will get the continuum of care from all aspects, including medical, social, and psychological viewpoints. Including the patient and family in the team will enhance the understanding and treatment outcomes as they will be part of the process, able to access education and knowledge about their diagnosis and treatment.

5.3.2 Maintaining a Team When a team is created it is part of a continuing commitment to multidisciplinary care to include a need for training and maintaining communication. There is a

50

growing consensus for the need of improved communication and collaboration among healthcare providers. Clark3 found that obstacles to effective teamwork were reported to be turf/territoriality, conflict/communication, team process, and organizational constraints with the major participant goal stated to be better collaboration at work.

J. P. Lewallen et al.

5.4 Special Conditions for Various Patient Groups Multidisciplinary work with various patient groups calls on each team to customize their approach.

5.4.1 Pediatric Patients 5.3.2.1 Training The development and evaluation of a teamwork model using a blend of theory and practical experience has been found to be important to the development of effective interdisciplinary strategies of patient care.5 A training program for an interdisciplinary team might include topics focused on leadership, conflict/ communication challenges, and the relationship of teamwork with quality improvement for best patient outcomes. As an example, Clark3 developed a leadership module that included a review of the different types of leadership styles and ways to cultivate leaders. The participants of the module discussed their observation of leadership and ways to promote leadership within healthcare teams. Teams were encouraged to gather data to evaluate both the effectiveness of the teamwork education and practice to avert backtracking to discipline- and department-specific methods when faced with financial and institutional stress. The relationship of quality improvement and teams was also presented with participants breaking-out into small groups to discuss their own experiences.3

5.3.2.2 Communication Open and clear communication in multidisciplinary teams may be challenging but it is essential. Poor communication among a team of medical specialists and between family members and providers can adversely affect patient care and quality of life.16 Patients should not have to answer the same questions over and over again to different providers. A good 20-min meeting with the family, focusing on that family and their concerns, can make admission smoother.16 The quality of communication among a medical team has been linked to patient and family well-being in acute care settings.2

Pediatric patients will almost always be unable to be part of the assessment and treatment plan. Parents or caregivers will usually need to assume the responsibility as a team member to advocate for their children the best course of treatment. A special case is the occurrence of skin conditions and disorders that may appear to be normal consequences of childhood activity (like bruises and scrapes) or may be indicators or abuse or neglect. When skin conditions are present, the dermatologist can assess and detect signs of abuse and neglect vs. accidental injury, benign skin symptoms, and other skin disorders that can mimic abuse. This is particularly important as PCPs, nursing staff, social workers, therapists, and other team members may not have the expertise to differentiate between skin disorders that can mimic abuse and abuse. This makes the inclusion of the parent as a team member a complex issue. On the one hand, the report of the dermatologist can remove the suspicion of abuse and lead to better support for the patient’s parent in the team context. On the other hand, the team can be interfered with by the presence of a suspected abuser. It is important to resolve this issue before bringing the potential problem into the team. The high price to be paid when not making this determination may be the effective exclusion of the patient’s advocate from the team.

5.4.2 Gerontological Patients Many issues similar to those that arise in pediatric patients also come up in older patients, especially when the patient is incapacitated by forms of dementia. In the elderly, skin is oftentimes bruised or scratched, due to thinning skin and use of anticoagulants given to elderly for prevention of heart attack, stroke, or deep vein thrombosis (DVT). When there is

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a question of differentiation of diagnosis between abuse, neglect, and the by-product of medication, thin skin, or accidental injury, a dermatologist should be part of the diagnosis team. Working with other healthcare professionals can bring accurate assessments and diagnoses and enable the team to work collaboratively in treatment options or report findings as mandated by law for abuse or neglect. A different series of issues in elderly patients are those related to the multifocal origin of problems. There is rarely, if ever, one thing wrong in the elderly. Instead there is often a constellation of events that may be involved. Leg ulcers may arise from a poor circulation, but lack of exercise (as a result of osteoarthritis), nutritional problems (from suppressed ingestion as a result of depression), and various other problems may influence disease progress. Attempts to address one problem can often set off a series of new ones. For instance, using antibiotics to fight infections often results in diarrhea. Diarrhea, in patients receiving diuretics, can easily result in hypokalemia, even in the presence of prescribed potassium. Older patients are more “fragile,” i.e., with fewer reserves, so can fall into problems sooner. Considering the total patient – the hallmark of multidisciplinary efforts – becomes necessary unless the patient is to bounce from one problem to another.

5.4.3 Psychiatric Patients These patients present with some of the same problems as children in that there are questions about who adequately represents the patient’s interest on the multidisciplinary team as well as the same issues about abuse that arise in children and the elderly. However, the special needs of the psychiatric patients have stimulated interest in a new area termed psychodermatology. Focused on the boundary between psychiatry and dermatology, psychodermatology is concerned with conditions that involve an interaction between the mind and the skin.11 Management of psychodermatologic disorders requires assessment and treatment, not only of the skin manifestation but of the psychosocial factors that may be associated with or exacerbate the condition. Koo and Lebwohl divide psychodermatologic disorders into three broad areas. The first consists of

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patients with primary psychiatric disorders. These patients may present with delusions of parasitosis where they believe erroneously that they are infested with some type of organism. Other examples of primary psychiatric disorders include neurotic or psychologic excoriations, where patients self-inflict scratch marks with their own fingernails, and factitial dermatitis, where other instruments besides fingernails are used to damage skin.11 Careful psychiatric diagnosis and treatment is of utmost important in this type of disorder and the inclusion of a psychiatrist on the multidisciplinary team is essential. The second area includes secondary psychiatric disorders. These disorders may accompany skin conditions simply because of their visibility to other people. Conditions such as cystic acne, alopecia areata, psoriasis, hemangiomas, and Kaposi’s sarcoma may be cause for psychological and social distress.11 As cited in Koo and Lebwohl,11 Love12 reports that persons with skin disorders may encounter discrimination and have difficulty obtaining employment, and Ginsburg and Link6 notes that discrimination occurs particularly when their skin disorder appears contagious. The multidisciplinary team is the perfect place to approach these problems in a holistic context, combining education, referral, counseling, and perhaps adding a legal member to the team. In addition, patients with emotional distress may be helped by the team by referral to a mental health professional or dermatological support group.11 The third area, and by far the most common of the psychodermatologic disorders seen in the clinic are those that can be termed psychophysiologic disorders.11 Although discussed in context of specific disorders below, the common thread of these disorders is that these skin conditions that may be exacerbated by emotional stress. Examples include: acne, eczema, psoriasis, atopic and seborrheic dermatitis, alopecia areata, and uticaria (hives). When these skin conditions are recalcitrant to dermatologic treatment, psychosocial or occupational stress may be contributing to the disorder and warrant further investigation.11 The treatment of chronic dermatoses may be difficult without addressing stress as an exacerbating factor. The multidisciplinary team should include members to address these areas. Stress management or relaxation techniques and exercise may be beneficial, but some issues may require counseling or therapy, antianxiety medication, or psychiatric referral.11

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5.4.4 Other Patients Other patients that are especially served by multidisciplinary efforts include those with language difficulties, those with problems in accessing medical care, and the under- and uninsured. The nonmedical aspects of multidisciplinary teams may be more crucial than the medical aspects in some cases.

5.5 Special Conditions: Various Dermatological Disorders Just as various special patient populations can influence the actions and composition of multidisciplinary groups, so can the need to address specific dermatological problems.

5.5.1 Wound Healing Chronic wounds that are resistant to treatment add an additional risk to the patient and negatively influence their quality of life.7 Lower extremity ulcers related to venous insufficiency are the most common type of chronic ulcer in the United States, followed by diabetic ulcers of the foot, and pressure ulcers on any body part.13 Pain, infection, sepsis, and amputation are often associated with these ulcers. Problem wounds had traditionally been treated by different medical specialties and healthcare workers, but over the last 20 years multidisciplinary wound healing centers have been developed in the United States as well as other countries.7 A central clinic that uses the multidisciplinary approach to wound care can provide better patient care through more focused and efficient physician–patient encounters, a larger stock of products, and easy collaboration among specialties.13 Mostrow13 described the process of developing a multidisciplinary wound clinic using the four Ps: people, places, products, and protocols. The specialties and their perspective that Mostrow13 described include: • Dermatologist: provides medical care of ulcers with emphasis on skin care, biopsies potential malignancies, vasculitis, and infections.

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• Vascular surgeon: evaluates patients with impaired circulation for possible intervention. • Plastic surgeon: provides special expertise in flaps and grafts, surgical debridements. • Orthopedic surgeon: often addresses neuropathic foot ulcers, offloading pressure of ulcer and assessment of vascular supply. • Podiatrist: provides general foot care with expertise in nails, debridement, and footwear issues. • Nurse practitioner: runs clinic and maintains patient contact throughout week. • Other nurses: provide patient care and education especially in relation to dressing and compression. Gottrup et al7 tested the hypothesis whether “an independent, multidisciplinary wound healing center in an accepted national expert function of wound healing is the optimal way to improve prophylaxis and treatment of patients with problem wounds.” The results of the study, conducted with 23,802 patients with varying types of wounds and 1,014 patients inpatient, showed that the use of multidisciplinary teams led to improvement in healing rates and a reduction in major amputations as well as a decrease in the number of admits to the wound center. Specifically for leg ulceration often caused by chronic venous leg insufficiency (CVI), health behaviors such as cigarette smoking and exercise are asso­ ciated with circulation disorders that can influence the prognosis of CVI.8 Heinen et  al9 worked with a multidisciplinary project team to develop a health promotion program for patients with venous ulcers that supported adherence with compression therapy and positive lifestyle changes. The program coached patients toward adherence with compression therapy and pain management as well as leg and foot care, and targeted lifestyle behaviors of exercise, smoking, nutrition, and weight management (Heinen 2006).9 The authors advocated development of lifestyle approaches for other patients as well.

5.5.2 Melanoma The incidence of melanoma has risen rapidly over the past several decades. Melanoma represents the fifth most common type of cancer yet is one of the leading cancers accounting for average years of life lost per person. Often, several disciplines are needed simultaneously

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to optimally diagnose and treat patients with melanoma. Work-up, treatment, and follow-up recommendations may differ by physicians and healthcare providers in separate specialty settings, leading to inconsistencies in patient management and care.10 Specialty of the primary provider and their practice patterns have been found to influence the treatment options offered to patients with melanoma, which in turn may influence patient outcomes.17 Evidence also suggests that multidisciplinary programs that coordinate providers and centralize care may increase patient access to comprehensive melanoma care.17 An example of addressing melanoma in a multidisciplinary context is provided by Johnson et  al10 The model used was devised by the University of Michigan multidisciplinary melanoma clinic (MDMC). The process begins with the patient who has a diagnosis of melanoma. The patient goes through the process of care from the multidisciplinary view. The process is documented as:10 • • • • •

• • •

Intake Direct contact via nursing staff Clerical for information packets and appointment Clinic visit, to include dermatology, surgery, social work, physical therapy, occupational therapy, etc. Case conference with the multidisciplinary team to assess and review plan of treatment (patient is assigned to relevant specialties with the team) Specialty visits, treatments Conference with multidisciplinary team and family for updates/changes in treatment Documentation management

Each patient is to be treated as “family” with each multidisciplinary member contributing their knowledge and expertise in a “turf-less” environment, dedicated to total care for the patient. Johnson et al10 found that multidisciplinary melanoma care centers can optimize care of patients with melanoma and can be the most efficient plan of treatment.

5.5.3 Atopic Dermatitis Atopic dermatitis (AD), or atopic eczema, is a common chronic, skin disorder noted by dry, itchy skin that is easily irritated. AD is the most common relapsing

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skin disorder in infants and children.15 The scratching and rubbing of the itchy skin which can cause further irritation and inflammation to the skin is known as the “itchscratch” cycle. Although stress or other emotions do not cause AD, emotions may exacerbate the “itch-scratch” cycle.15 It has long been recognized that treatment of AD patients has better outcomes with multidisciplinary care, especially in patients with moderate-to-severe disease.14 The multidisciplinary team should include the PCP, nurses, nurse practitioners, physician assistants, patient advocates, social workers, and health education professionals.14 Patient education is of special significance with emphasis on trigger avoidance, specific skin care recommendations, and follow-up. It is also important to be clear and explicit about the use of topical medications because incorrect use of these medications is one of the primary reasons for poor treatment outcomes.15 This is a condition where the team effort becomes a learning experience for the whole team. This is because the topical medications used are quickly evolving and what works best is currently still being worked out. Coordinated multidisciplinary care, especially using nurse practitioners, has been successful, and results in improved care and improved satisfaction for patients, families, and healthcare providers alike.15

5.6 Case Study The following case study is instructive about the multidisciplinary approach in a dermatological case.

5.6.1 Patient History Mr. P. is an 80-year-old white male coming in with a red, scaly spot on the right side of his neck. He is seen by PCP in local hospital clinic setting. The PCP reports to Mr. P. that the spot appears to be an irritation and gives Mr. P. a prescription for steroidal cream, to be applied twice daily. Mr. P. returns 6 months later to report the red, scaly spot has grown and has become very itchy. The PCP reports that this is most likely a fungal infection and prescribes an antifungal ointment, twice daily.

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Mr. P. sees a new PCP at a local senior health clinic and reports the spot on his neck is not getting any better. He also reports the past year’s treatment with steroid and antifungal with no resolution. By this time, the spot has increased in size and remains red and inflamed. The senior health practitioner refers Mr. P. to a local dermatology clinic where he was diagnosed with squamous cell carcinoma and had surgical intervention (MONS) to remove the spot. The follow-up below is a result of this intervention. Mr. P. was referred to the local university hospital system by the senior health clinic to review and assess Mr. P.

5.6.2 Continuation of Care of Patient Mr. P. Mr. P. was referred to dermatology for suspected CA after squamous cell carcinoma ED and C (removed with electrodesiccation and cutterage) from face previously. Mr. P. is an 80-year-old white male who is a new patient. with history of squamous cell carcinoma ED and C from right jawline by local dermatologist, Dr. M. The patient also has history of actinic keratoses and would like to establish dermatologic care here. He denies any pain, burning, numbness, stinging, or pruritus to his recent skin cancer scars. He does have a few scaly areas to the face that are occasionally tender.

5.6.3 Physical Examination Mr. P. is a well-developed, well-nourished white male in no acute distress. He is the primary caregiver for his 80-year-old wife who has multi-infarct dementia.

J. P. Lewallen et al.

stuck-on papules consistent with seborrheic keratoses. The remainder of the exam is unremarkable.

5.6.4 Assessment and Plan 1. Actinic keratoses are treated with cryosurgery for the destruction primarily to the patient’s central face, on the cheeks and nose as well as arms and hands. He was given EFUDEX® to apply primarily to his forehead and scalp for the next 3 weeks, with a specific recommendation to apply it to treat the helices of his ears. Education was given on the use of EFUDEX® as well as the side effects of this medication. 2. History of squamous cell carcinoma to the right jawline, no evidence of recurrence at this time. 3. Seborrheic keratoses, benign. Will see in clinic in 3 months. He was seen with Dr. M. (the dermatologist) with the attending physician Dr. D.

5.6.5 Dermatological Clinical Staff Call Patient’s daughter phoned stating that her father had developed a strong reaction to EFUDEX® and would like us to call patient. Patient states he has used EFUDEX® for 20 days and his face is very red and scabs “oozing” with swelling. Patient was given a Desonide by Dr. E. (an attending on call) and told to apply it to the red areas. Per Dr. M.’s review of the case, patient is to continue the Desonide to the red areas and apply Vaseline® or Aquaphor® to the areas that are crusty and oozing. Patient verbalized his understanding. He was also referred to senior health clinic.

5.6.3.1 Integumentary Scalp, face, neck, back, chest, abdomen, and bilateral upper extremities are examined. He has numerous illdefined, scaly, erythematous papules primarily to the scalp, forehead, and the sides of his face consistent with actinic keratoses. He has a well-healed scar to the right jawline which shows no evidence of recurrence. He has a few ill-defined scaly, erythematous papules to the forearms and hands as well. He has scattered hyperpigmented

5.6.6 Senior Health Clinic Note (Next Day) Patient was seen in Senior Health Clinic as a walk-in due to his concern about swelling and possible infection. History of presenting illness: 80-year-old white male here today for concern about EFUDEX® treatment and redness and swelling to the face. He had been to dermatology a month ago and has been using EFUDEX®

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to the face for treatment of actinic keratoses. Today, he is observed having pus and drainage to the face and he is concerned about infection. He denies any fever. He states swelling is better today, but pus and drainage worse. Denies any other systemic complaints.

5.6.7 Medications KEFLEX® 500 mg caps (cephalexin) take one tablet 2 times daily

5.6.8 Dermatological Clinic Follow-Up Mr. P. was followed up with dermatology about 2 months later with face much better and EFUDEX® and Desonide completed.

5.6.9 Multidisciplinary Assessment Mr. P. was seen in two separate clinics, with multiple team members including • His PCP who gave the first referral • Dermatology for assessment and treatment of actinic keratoses and seborrheic keratoses and history of squamous cell carcinoma • Pharmacy which addressed medication education and information on how to use medicine and their side effects (of obvious importance in this case) • Laboratory to review skin samples for diagnosis of squamous cell carcinoma and evaluate and monitor general health status • Nursing staff for dermatology to take calls and review information and give advice as per doctor on treatment concerns • Advanced practical nurse for intervention and concern for infection after treatment with other medications • Social work for case management and support during care (again a special need in this case because much of the problem appears to have arisen from treatment) All of these team members worked in coordination for Mr. P.’s best outcome.

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5.7 Conclusion Although generally useful, it is evident that for special patients, such as children, the elderly, and psychiatric patients, their special needs strongly support the use of multidisciplinary teams in the efficient resolution of their dermatological disorders. Also for a series of common dermatological orders, it is clear that stress, exercise, patient education, and a holistic approach to the patient is useful to improving the outcome of their treatment, sometimes dramatically. As the interface with the outside world, skin has an important role to play in how an individual feels about him/herself and how he/she relates to their social context. As such, it is not that much of a surprise that a comprehensive approach, bringing together expertise in the many areas that contribute to these complex outer and inner images, is more successful in addressing the problems that dermatological disorders bring than approaches that simply treat the skin problem like it had no effect on the life of the patient. Although multidisciplinary teams can be a complicated and cumbersome process at times, the nature of dermatological disorders is also complicated, with their effects on quality of life of equal or more concern to patients than the strictly medical problem itself.

References   1. Anon. The American Federation of Clinical Oncologic Societies access to quality cancer care: consensus statement. J Clin Oncol. 1998;164:1628–1630   2. Boyle DK, Miller PA, Forbes-Thompson SA. Communi­ cations and end-of-life care in the intensive care unit: patient, family, and clinician outcomes. Crit Care Nurs Q. 2005; 28(4):302–316   3. Clark PG. Evaluating an interdisciplinary team training institute in geriatrics: implications for teaching teamwork theory and practice. Educ Gerontol. 2002;28:511–528   4. Clark PG, Leinhaus MM, Filinson R. Developing and evaluating an interdisciplinary team training program: lessons taught and lessons learned. Educ Gerontol. 2002;28:491–510   5. Clark PG, Puxty J, Ross LG. Evaluating an interdisciplinary geriatric education and training institute: what can be learned by studying processes and outcomes? Educ Gerontol. 1997;23(7):725–744   6. Ginsburg IH, Link BG. Psychosocial consequences of rejection and stigma feelings in psoriasis patients. Int J Dermatol. 1993;32:587–591

56   7. Gottrup F, Holstein P, Jorgensen B, Lohmann M, Karlsmar T. A new concept of a multidisciplinary wound healing center and a national expert function of wound healing. Arch Surg. 2001;136:765–772   8. Heinen MM, van Achterberg T, op Reimer WS, et al Venous leg ulcer patients: a review of the literature on lifestyle and pain-related interventions. J Clin Nurs. 2004;13(3): 355–366   9. Heinen MM, Bartholomew LK, Wensing M, Kerkhof P, Achterberg T. Supporting adherence and healthy lifestyles in leg ulcer patients: Systematic development of the lively legs program for dermatology outpatient clinics. Patient Education and Counseling. 2006;61:279–291 10. Johnson TM, Chang A, Redman B, et  al Management of melanoma with a multidisciplinary melanoma clinic model. J Am Acad Dermatol. 2000;42:820–826 11. Koo J, Lebwohl A. Psychodermatology: the mind and skin connection. Am Fam Physician. 2001;64:1873

J. P. Lewallen et al. 12. Love B, Byrne C, Roberts J, Browne G, Brown B. Adult ­psychosocial adjustment following childhood injury: the effect of disfigurement. J Burn Care Rehabil. 1987;8:280–285 13. Mostrow EN. Wound healing: a multidisciplinary approach for dermatologists. Dermatol Clin. 2003;21:371–387 14. Nichol NH, Boguniewicz M. Successful strategies in atopic dermatitis management. Dermatol Nurs. 2008;suppl:3–19 15. Nicol NH. Multidisciplinary teams are critical in the care of atopic dermatitis patients. Medscape Dermatol. 2005;6(2) @2005 Medscape 12/20/2005 16. Penson RT, Kyriakou H, Zuckerman D, Chabner BA, Lynch TJ Jr. Teams: communication in multidisciplinary care. Oncologist. 2006;11:520–526 17. Stitzenberg KB, Thomas NE, Ollila DW. Influence of provider and practice characteristics on melanoma care. Am J Surg. 2007;193:206–212 18. Tanaka M. Multidisciplinary team approach for elderly patients. Geriatr Gerontol Int. 2003;3:69–72

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The Future of Dermatological Therapy and Preventive Dermatology Robert A. Norman

I generally start off any of my writing in response to questions I ask myself. And I asked myself many questions when I pondered the future of the skin and prevention of skin disease. Upon reflecting on the needs of my patients and others, dozens of possibilities arose from the myriad images, smells, touch, and sounds that have filled my head from patient interactions over the years. Although I began my inquiry with the more utilitarian potential of future skin developments, I also realized, given the enormous influence of esthetics among Homo sapiens, that the future progression will also include the “skin as entertainment” arena. What about the skin as a vehicle for delivery of other drugs besides creams and ointments? How about providing a built-in protection for those with a heightened need for sun protection, such as those unfortunate souls with the dramatic disease xeroderma pigmentosa? Or even a safeguard for the mild, fair-haired, red-eyed lass? What if one could change skin colors based on mood? I knew of many patients with frustrating blush disorders that had wished their state of mind was not so readily visible on their hot red skin. However, others may want a change in color, such as a military person who is trying to hide from an approaching enemy. And of course there will be those who suffer a certain ennui from their current display of tattoos, and an everchanging tableaux would offer an extensive realm of show and tell. What will the future of dermatology be like? What will be the new detection options? What will be the new treatment options? What will be the new educational

R. A. Norman Nova Southeastern University, Ft. Lauderdale, Florida and Private Practice, Tampa, FL, USA e-mail: [email protected]

and patient teaching options? How will ethics and patient selection be challenged? How will integrative therapies and cosmetic surgeries evolve? Skin diseases can be expensive and time-consuming and affect self-esteem, personal relationships, and careers. They also have health implications – predisposing individuals to infection, scarring, and other diseases. As immunosuppressive and laser research are still in their infancies, the future of these fields appears boundless with new therapies constantly in development. Obviously, the continuous appearance of new treatments necessitates the regular update and revision of a physician’s standard practice methods. Dermatological concerns are among the most common consults physicians and pharmacists get if you consider hair, skin, and nails. Therapy in dermatology, particularly in the treatment of psoriasis and eczema, is changing significantly as new approaches to therapy reach the market and already-marketed products find new uses. As a result of the increased understanding of the molecular mechanisms of skin diseases, dozens of drugs are in phase II or III trials. The “survivors” in this arduous contest will reach the market in the near future.

6.1 The Genetic Century What will be other new treatment options for diseases such as xeroderma pigmentosum? The disease, characterized by defective DNA repair, with young bearers of this autosomal recessive condition having severe solar damage and skin cancers, pigmented dry skin, and eye abnormalities, have fought an uphill battle for many years. Incorporating bacterial repair enzyme T4 endonuclease V (T4N5) into a liposomal delivery vehicle and applying it to the skin results in markedly decreased

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_6, © Springer-Verlag London Limited 2010

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skin damage. With the virtual completion of the Human Genome Project mapping of 30,000 genes, genomic maps will be available to guide the efforts to determine the genetic basis of disease. We will be able to determine response to treatment and chart a person’s prognosis with greater efficiency. The twenty-first century will be the “genetic century” as we discover how the mutations bring on skin disease and the multiple mechanisms surrounding their expression. With specific diseases such as melanoma, hope is on the horizon to replace traditional chemotherapy. Pills such as BAY 43-9006 (Sorafenib), which should reach the market within 3 years, are a new generation of “targeted” therapies that are transforming the treatment of horrible diseases such as melanoma. The pill attacks the underlying molecular mechanism and will allow cancers to be treated as a chronic disease such as high blood pressure, diabetes, or depression. Specifically, the new cancer drug attacks malignant tumors by blocking a chain reaction inside the cancer cells that allows them to multiply and attract blood vessels for growth.

6.2 New Skin The skin is a marvel. In the best circumstances, it heals itself if broken down, repairing and restoring its former integrity. It is dour in sorrow, radiates warmth in love, and shines in tranquillity. The skin is an organ in and of itself, with its own personality, temperament, and particular eccentricities. Its crucial body-covering role is becoming increasingly recognized, as well as the time it can use an outside boost. With almost every trauma, it rebounds, but in burn victims who have lost more than 40% of their skin surface, a temporary cover by a meshwork of donor human skin or grafts is needed. In the future, more lasting and durable skin substitutes will be needed. Likely candidates will include artificial matrices to grow skin from stem cells taken from the foreskin or umbilical cord of newborn infants. Others will use epidermal cells on an artificial dermis. Other options are appearing, such as a three-dimensional matrix composed of a combination of human skin cells and biodegradable polymers. The bilayered matrix acts as both a foundation and environment on which the dermal cells grow and shape. The porous underlayer allows the ingrowth of human dermal cells

R. A. Norman

and the outer layer, entirely synthetic, is designed as a barrier against infection, water loss, and ultraviolet light. The human dermal cells taken from neonatal foreskin are seeded and adhere onto the polymer matrix and allowed to incubate for several weeks. The cells multiply and organize themselves into functioning tissue and can be applied to replace damaged skin. Chemically bonding collagen taken from animal tendons with glycosaminoglycan (GAG) molecules from animal cartilage to create a simple model of the extracellular matrix also may provide a new dermis.

6.3 Teaching, Detection, Therapy, and the Modern Era What will be the new educational options in dermatology? I discussed this with Ben Barankin, MD. He stated: We will have virtual learning on the Internet with personalized medical histories and genetic tracking. As more physicians become computer and Internet savvy, and as the resources on the Internet improve, a physician will be able to sit down with the patient and their laptop to show other people with the same condition on dermatology atlas websites, as well as to recommend patient support groups, and other good resources of information. Also, physicians will be able to take pictures of the patient, and to show them what their potential scar will look like following the procedure, for those concerned with their scar appearance. The new computer systems will integrate digital photography, touch screens, voice recognition, downloads to pharmacies and HMO’s to streamline the patient interactions.There will certainly be therapeutic options for those with genetic diseases. This will include most probably oral forms of medication that dermatologists and medical geneticists will collaborate on in terms of development and provision to patients. There will be further developments in the treatment of skin cancers using creams, and children will be vaccinated against a multitude of wart virus strains so as to prevent their development. As far as detection, there will be computers and robots that will do full-body scans on a semi-annual basis and be able to compare changes in moles or other concerning external and internal developments. Physicians will be there to verify these findings, biopsy as necessary, and initiate treatment.

New devices to detect skin cancer and other skin maladies include image analysis and computer-assisted diagnosis, multispectral imaging and automated diagnosis, confocal laser microscopy, optical coherence tomography, ultrasound, magnetic resonance imaging,

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spectrophotometric intracutaneous analysis, and artificial neural networks. Continuous research and refinement will allow improvements in detection and treatment. Teledermatology (computer-assisted, long-distance transmission of dermatological cases) will allow detection and therapeutic suggestions to areas where handson dermatology is limited. Dr. Joe Kvedar of Harvard Medical School writes, “characterized as time-and place-independent care delivery, the exploding global computing network infrastructure (Internet) offers the opportunity for delivery of care anytime, anywhere. This care delivery method will enable dermatologists to offer services in a place-independent fashion and may interrupt current referral networks.”1 Tania J. Phillips, MD, Professor of Dermatology at the Boston University School of Medicine, stated: I think teledermatology will play an increasing role, physician extenders will be increasingly used, and instruments such as the dermatoscope and other in vivo imaging techniques will be used. Treatments such as the immune response modifier molecules and biologics will be increasingly used for different indications. Hopefully for wound patients there will be new, affordable cell based therapies available. For education and teaching I think that the internet and computer based learning will supplant many of our traditional methods, as they are already doing!

What else is coming up over the horizon? Long-lasting fillers that will more permanently repair defects and make changes are being studied. The future of these skin enhancers should include a plethora of exciting new products and techniques. Face transplants have been done; a radical procedure intended for patients with severe disfigurement. Although doctors in the past have successfully reattached faces to patients after accidents, transferring facial tissue and blood vessels from a cadaver to a new patient may become more common. Although the transplant also brings a lifetime dependence on expensive immunosuppressant drugs to block rejection of the new tissue, the operation could offer an improved future for those who suffer severe burns, cancer, or gunshot wounds. Of course, the procedure raises major moral, ethical, and psychological issues.2 At the Georgia institute of technology, researchers have developed micro-thin implantable films that release medication according to changes in temperature. The device will allow patients to forgo daily injections and pills including insulin, hormone therapy,

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chemotherapy, biologics for psoriasis and other dermatological diseases, and other treatments.3 Hair growth and transplantation will be safer and the individual, artificial-appearing hair plugs will be a historical reference. New and more individualized hair growth drugs will become available. Cloning of individual hair cells will allow an unlimited source of replacement hair. Mike Morgan, MD, provided his reflections on the “brave new world of dermatology” and changes to be expected in diagnosis: In the near term of the next 20 years the dermatopathologist will continue to assume the primary responsibility of diagnosis although there will be changes in who reports the diagnosis and how it is accomplished. Increasing fiscal pressures exerted by third party payers and Medicare debt will force the application of technologies such as telepathology, that were initially intended for improving medical care access, to be subverted under the pretext of cheaper medical care. Familiarity with this concept by managed-care executives and its passive approval by dermatologists will eventuate in diagnosis performed by anonymous pathologists in offshore locations as has been recently witnessed in the radiologic field. Domestically, these technologies and the applied mantra of “economies of scale” could serve as a rationalization for ­centralization and a monopoly of diagnostic services by ­well-connected individuals or singular corporate entities. Ongoing scientific discoveries and the application of nascent technologies will however eventually lead to wholesale changes in the diagnosis and management of cutaneous disorders. The dermatologist of the late twenty-first century will assume a greater degree of responsibility for diagnosis. Armed with hand-held spectrophotometric and chemical detection devices the vast majority of cutaneous neoplasms will not only be accurately identified but risk assessed in situ. Characteristic light diffraction spectra will differentially fingerprint the types of cutaneous malignancy and the application of light or sound emitting devices will precisely gauge the depth of tumor penetration. Chemical detecting devices programmed to recognize subtle changes in the metabolic by-products of cancerous cells will complement the light-emitting devices. Similarly, these devices will be relied upon to assess the extent of residual disease. Computerized algorithms that reconcile the measured variables of epidermal thickness, vascular density and depth of inflammatory infiltrate with preprogrammed archetypes will also permit the assessment and identification of many dermatoses. Such advances will undoubtedly change the role of and importance of dermatopathology in the equation of dermatologic care. As they would be relegated to the arbitration of equivocal cases or sought in the assessment of confounding data or following incomplete response to therapy.

From an ethical standpoint, Internet-based “virtual details” on new products will become more common.

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Hopefully, less bias in prescribing based on personal influence from pharmaceutical companies and more objective, evidence-based data and research findings will result. Virtual details will help us to make our own decisions and not be influenced as much by the “drug reps” that wish us to sway our prescription-writing choices toward their products.4 The future of integrative therapies in dermatology, in particular preventive medicine, botanicals including antioxidants, hypnosis, and behavioral modification will allow new detection and treatment options. Based on research in integrative medicine, new educational and patient teaching options will be utilized in dermatology. Future scientific discoveries may demonstrate humoral connections for many dermatologic diseases that we have long suspected to be autoimmune. Through a mixture of good clinical observation and dumb luck, we will make more connections. However, we must still discover whether these are an epiphenomena or actually a factor in disease formation. We may soon look at the age of dermatological surgery for skin cancers with a healthy nostalgia when immune therapies and ­vaccines replace the need for these difficult, ­time-consuming surgeries. What about the future detective? We may have skin detective agencies utilizing bacteriological forensic techniques, pointing to individuals at the scene of a crime. Perhaps the characteristic microflora of a criminal suspect could be just as important to the detective as a fingerprint or other genetic markers. If an individual’s microflora, established shortly after birth, remains comparatively constant throughout life, a microbial sampling of room dust, saliva, and so on, might reveal groups of identifiable organisms which would match the pattern of a suspect. The particular manner of acquisition of the many different phage-types of bacteria from mother, hospital, and early contacts could differentiate two suspects who would support different organisms. By

R. A. Norman

sophisticated phage-typing methods, bacteria could be called to give evidence in court. The creation of a biochip that can be implanted into the skin of people to transmit their personal and medical information will be fodder for legal and scientific inquiry. Perhaps the old adage about “what you don’t see can’t hurt you” applies. The huge majority or those critters that live on the skin are invisible and earn our indifference. And when it does bother us, at least we have treatments. As far as I know, we are the only species to have dermatologists, and nail salons, and beauty parlors, and a myriad of other sources to rid our body of real or perceived ailments. I am forever humbled, for along with my fellow soldiers who fight these ever-lasting skin diseases, I know we can never win the battle. However, when I think about the thousands of patients I treat with skin problems every year, I hope to provide solace from the onslaught of our own invaders. I’m glad I can provide a little help along the way and I’m looking forward to the future and what more we can offer. Thanks to Mike Morgan, MD; Lisa Hutchinson, PharmD, MPH; Ben Barankin, MD; David Elpern, MD; and Tania Phillips, MD in the preparation of this chapter.

References   1. Watson AJ, Bergman H, Kvedar JC. Teledermatology. eMedicine from WebMD. Updated 27 Feb 2007. ; 2009 Accessed 8.03.09   2. BBC News. “Woman has first face transplant.” Available at: ; 2009 Accessed 8.03.09   3. Heat-controlled Drug Implants Offer Hope for Future. Available at: ; 2009 Accessed 8.03.09   4. Norman R. The Woman Who Lost Her Skin and Other Dermatological Tales. New York: Routledge; 2004

Part Common Problems and Treatment in Dermatological Prevention

II

7

Prevention of Drug Reactions and Allergies in Dermatology Lisa C. Hutchison and Oumitana Kajkenova

7.1 Introduction Adverse drug reactions are defined as noxious or unintended responses to a drug used in standard doses for the purpose of prophylaxis, diagnosis, or treatment.8 Many side effects to a medication are recognized and accepted as part of the risk/benefit evaluation in determining whether or not it is indicated in a particular patient. For example, diarrhea is a recognized adverse drug reaction associated with the use of erythromycin in 7% of patients.33 However, it is not an intended response when the drug is used to cure an infection, yet we recognize it as a frequent consequence of oral erythromycin use and are willing to accept this risk in order to achieve the benefit. Cutaneous drug reactions are one of the most recognized and common types of adverse drug reactions.35 When asked whether they have allergies or adverse drug reactions, most patients initially report on medications which caused them to have a skin rash with past use. Because most skin rashes develop within 1 week of starting a new medication, this association is reasonable. However, many medications may cause cutaneous reactions after several weeks of therapy and require additional detective work to assess the likelihood of association with a medication. Also, medications cause skin changes that are not immunologic in their mechanism and develop over an extended period of time. Finally, some cutaneous drug reactions may occur in the patient in particular circumstances only

L. C. Hutchison (*) Department of Pharmacy Practice, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA e-mail: [email protected]

because the patient has an increased risk because of specific time-limited factors. Later use of the same medication may not cause a reaction if the risk factors have resolved. A focus on prevention of adverse drug reactions has recently gained national prominence. Because treating adverse drug events (which include adverse drug reactions) has been estimated to cost $77 billion in the ambulatory patient population of the United States, prevention of cutaneous drug reactions is not only a preferred patient outcome, it is also a preferred economic outcome.19 It is imperative for the clinician to be aware of the common cutaneous drug reactions, medications most frequently associated with these reactions and methods to diminish their occurrence and/or severity.

7.1.1 Frequency of Cutaneous Drug Reactions To identify if one has been successful in reducing the frequency of adverse cutaneous drug reactions, one must first know how often they occur. Several prospective studies have focused upon hospitalized patients and found allergic drug-induced cutaneous reactions to occur in up to 6% of hospitalized patients. A wide variability is seen due to differences in study design, particularly when studies rely upon spontaneous reporting, chart review, or patient recall for information. Table 7.1 provides information from epidemiologic studies on cutaneous drug reactions. The frequency of cutaneous drug reactions is also related to the relative usage of specific medications that are more likely to cause allergic or other types of skin reactions. In particular, the use of antibiotics in the penicillin family is associated with a higher rate of

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_7, © Springer-Verlag London Limited 2010

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L. C. Hutchison and O. Kajkenova

Table 7.1  Epidemiologic studies of cutaneous drug reactions Study Rate (%) Comment Bigby7

2.2

Seven-year prospective study in Boston

Hunziker et al18

2.7

Twenty-year prospective study in Switzerland

Naldi et al24

0.01

Spontaneous reporting over 2 years in Italy

Van der Linden et al36

0.36

Retrospective evaluation of medical records over 18 months in The Netherlands

Rademaker et al26

6

Prospective 6 month survey in the hospital setting in New Zealand

cutaneous drug reactions. One study compared the rate of drugs received by at least 1,000 patients reported in nine studies and reported amoxicillin and ampicillin to cause cutaneous drug reactions at a rate of 1.2–8%. Sulfonamides, including co-trimoxazole had a rate of 2.5–3.7% and the rate for cefaclor was 4.8%.5 Amiodarone will cause a slate blue skin discoloration in 4–9% of patients treated with the drug.39 Risk factors have been identified for some allergic cutaneous drug reactions. Infection with human immunodeficiency virus or infectious mononucleosis increases the risk for cutaneous drug reactions. Therefore, an individual who received amoxicillin while infected with mononucleosis may develop a rash; but given the same antibiotic years later, this individual has no reaction. Female sex and either very young age or very old age are inconsistently reported as risk factors.

7.1.2 Serious and Life-Threatening Cutaneous Drug Reactions Considering that cutaneous drug reactions are the most common type of adverse drug reaction, it is fortunate that they cause serious or life-threatening reactions at a much lower rate. Depending upon the definition of “serious,” most reviews place the incidence of serious cutaneous drug reactions in the range of 1/1,000– 1/100,000 patients treated whether studied in adults or children.20, 32 Cutaneous skin reactions considered serious are those which cause skin damage or affect multiple organs. In a 6-month prospective study of

hospitalized patients with cutaneous drug reactions, 34% were considered serious because they prompted hospitalization, prolonged hospitalization, or were life-threatening. Only 2% were considered life-threatening, but no deaths were reported.13

7.1.3 Preventability of Cutaneous Drug Reactions For adverse drug reactions in general, studies indicate that 28–57% of those that occur in hospitalized patients are preventable or avoidable.4,9 However, the preventability rate for cutaneous drug reactions is likely much lower. Many occur upon first exposure to a medication or provide no warning when they occur with a subsequent exposure. Only one study reports assessment of preventability based upon consensus between a dermatologist and a pharmacologist upon retrospective review of the patient records. In this study they determined that 15% of serious cutaneous drug reactions were preventable but did not elucidate beyond providing this rate.13 This study was limited to allergic cutaneous drug reactions. When one considers the full spectrum of cutaneous drug reactions that includes pharmacologic reactions and cumulative reactions, preventability rates are probably much higher.

7.2 Classification of Adverse Cutaneous Drug Reactions Adverse drug events, including cutaneous drug reactions, are classified into one of four types.2 Type A reactions are those that can be anticipated from the pharmacologic properties of the medication. These are expected exaggerations of known pharmacologic effects, may occur at normal doses, and display a dosedependency. They are nonimmunologic in nature. Few cutaneous drug reactions fall into this category. Type B reactions are usually unexpected reactions, most of which are immune-mediated. Many cutaneous drug reactions fall into this category including urticaria, petechiae, morbilliform reactions, Stevens–Johnson syndrome, and toxic epidermal necrolysis. Type C reactions are associated with cumulative doses of medications over extended periods of time. These are rare

7  Prevention of Drug Reactions and Allergies in Dermatology

for cutaneous drug reactions but include skin discolorations from extended doses of carotenoids or amiodarone. Finally, Type D reactions are delayed effects such as teratogenesis or carcinogenesis and are also rare for cutaneous drug reactions.

7.2.1 Gell-Coombs Classification of Hypersensitivity Reactions Because the majority of cutaneous drug reactions fall into Type B reactions, it is helpful to further subdivide this category. The Gell-Coombs classification divides immunologically mediated reactions according to pathogenesis.25, 27 This is helpful for investigating the cause of a cutaneous drug reaction or for researchers to find common links. However, one must realize that the Gell-Coombs classification tries to pigeon-hole reactions which may have several mechanisms underlying their development. Nevertheless, the Gell-Coombs classification system remains widely accepted. Type 1 reactions are immediate reactions that are mediated through IgE immunoglobulins. IgE binds to mast cells causing them to release histamine and other inflammatory mediators. Urticaria, angioedema, pruritis, and anaphylaxis are examples of this type of immune reaction. These reactions occur within minutes to hours after exposure to a medication. Gell-Coombs Type 2 reactions result from the drug combining with cytotoxic antibodies to cause cell lysis. Examples include druginduced pemphigus and petechia resulting from druginduced thrombocytopenic purpura. Gell-Coombs Type 3 reactions are medicated by IgG or IgM immunoglobulins which form immune complexes. These immune complexes are deposited in the basement membrane of small blood vessels and activate complement causing vasculitis or serum sickness. Finally, Gell-Coombs Type 4 reactions are cell-mediated immune reactions causing morbilliform exanthematous rashes, fixed drug eruptions, lichenoid eruptions, Stevens– Johnson syndrome, and toxic epidermal necrolysis.

7.2.2 Clinical Classification Cutaneous drug reactions may or may not be immunologic in origin and even if they are immunologic in

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origin, the immunologic classifications do not always clearly follow the clinical picture. For these reasons, a separate classification system based upon the clinical presentation is useful in the discussion of prevention and management.28

7.2.2.1 Exanthematous Reactions Exanthematous reactions are the most common type of cutaneous drug reaction and can be morbilliform or maculopapular. Eruptions usually start on the trunk, spread peripherally, and may be pruritic. With the first exposure to the culprit drug, the patient will produce the reaction in 7–14 days, but with rechallenge the rash occurs more rapidly. Any medication may cause this type of cutaneous drug reaction, but it is most closely associated with the penicillins, sulfonamides, antiepileptic drugs, and nonnucleoside transcriptase inhibitors. Patients with infectious mononucleosis or human immunodeficiency virus have an increased risk of developing exanthematous reactions when treated with a penicillin or sulfonamide.

7.2.2.2 Urticaria and Angioedema Urticaria is the second most frequent cutaneous drug reaction.34 Pruritic red wheals of various sizes develop within minutes to hours after exposure to the medication, and occur rapidly upon rechallenge, although intentional rechallenges are rarely attempted. Angioedema may affect only limited parts of the face or neck and is nonpruritic. It may last from 2 h to 5 days. Penicillins and cephalosporins are most commonly associated with urticarial reactions but also consider nonsteroidal antiinflammatory drugs, phenytoin and carbamazepine as culprits. Angioedema is seen with angiotensin converting enzyme inhibitors.

7.2.2.3 Fixed Drug Eruptions Fixed drug eruptions are well-delineated lesions dusky red to violet in color that may appear anywhere on the body, primarily the torso, limbs, lips or genitalia. One peculiar feature of fixed drug eruptions is that they will recur in exactly the same location on the body when a patient is rechallenged with the same medication.

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Fixed drug eruptions may be confused with macular– papular eruptions, so their reported frequency is likely underestimated. Many drugs can cause fixed drug eruptions including sulfonamides, ciprofloxacin, nonsteroidal anti-inflammatory drugs, phenytoin and pseudoephedrine.

7.2.2.4 Drug-Induced Erythema Multiforme, Stevens–Johnson Syndrome, and Toxic Epidermal Necrolysis Erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis are considered severe and life-threatening drug reactions.20 As such, they require early recognition and discontinuation of all possible offending agents without delay to avoid serious outcomes. Systemic symptoms such as fever, lymphadenopathy, eosinophilia, sore throat, and cough may accompany the skin lesions. Some believe these entities to fit into a continuum with erythema multiforme being self-limited and benign with lesions occurring symmetrically on the extremities and sometimes on the oral mucosa; Stevens-Johnson syndrome always involves at least two mucosal lesions but also includes lesions on multiple organs (eyes, mouth, genitalia, and skin). Detachment of skin occurs over less than 10% of the body surface area in Stevens-Johnson syndrome as compared to toxic epidermal necrolysis, where over 30% of the body surface area may slough off. Patients with toxic epidermal necrolysis must be treated similarly to burn victims with so much skin surface affected. Causative agents most often identified are phenytoin, carbamazepine, sulfonamides, barbiturates, allopurinol, minocycline, aminopenicillins, and nonsteroidal antiinflammatory agents.20 The importance of discontinuing all potentially responsible medications cannot be overemphasized. Mortality in one study was 11% for patients who had prompt discontinuation of causative agents compared to 27% when drug withdrawal occurred later.15

7.2.3 Associated Nondermatologic Symptoms Cutaneous reactions must include assessment of associated systemic symptoms along with any skin eruptions.

L. C. Hutchison and O. Kajkenova

When systemic symptoms occur, the cutaneous drug reaction is considered to be more serious than when symptoms are limited to the skin and skin structure. Systemic symptoms may be minor or major. Minor symptoms include fever, malaise, and arthralgias. Major symptoms include pharyngitis and lymphadenopathy. Laboratory evidence of a major reaction may be seen such as lymphocytosis, eosinophilia, elevated liver function tests, proteinuria, and renal impairment.20

7.3 General Prevention Principles Luckily most cutaneous drug reactions are self-limiting once the offending agent is discontinued. However, the most basic prevention principle is to avoid using a medication if it is not indicated. Elderly patients in particular seem to be at risk for overprescribing of medication and with each additional drug, the risk of an adverse drug event rises, including the risk for cutaneous drug reactions.2 Specific medications have associated recommendations for prevention of cutaneous reactions when the drug is required for therapeutic benefit. These recommendations involve the choice of agent, choice of patient dose, duration of therapy, administration techniques, and monitoring requirements.

7.4 Specific Medications Associated with Cutaneous Reactions The following discussion provides examples of each type of adverse drug reaction. Type A or pharmacologic adverse reactions are seen with corticosteroids. These are dose-related reactions and can be predicted with long-term use of high dose and high potency corticosteroids. Type B or immunologic adverse cutaneous reactions are seen with anticonvulsants and with tumor necrosis factor alpha inhibitors. However, as our understanding of the mechanisms of reactions increase, our ability to predict who is at greater risk for these reactions to anticonvulsant agents has also grown. Type C or cumulative toxicity is seen with amiodarone skin discoloration. Finally, Type D or delayed effect toxicity is a theoretical risk with topical calcineurin

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inhibitors which are currently under scrutiny to determine what risk of carcinogenesis they may carry.

7.4.1 Corticosteroids Both systemic and topical corticosteroids are linked with cutaneous adverse reactions. Long-term use of oral corticosteroids has been implicated in development of localized or disseminated infection caused by grampositive bacteria of the genus Nocardia. Cutaneous involvement can manifest as ulceration, cellulitis or subcutaneous abscess.3 Lipodystrophy was the most frequent adverse event reported during the 3-months use of high dose of prednisone. It has also been considered the most distressing by the patients and was most frequent in women and younger patients. Other skin disorders including hirsutism, spontaneous bruising, and altered wound healing were noted by 46% of patients and were more frequent among women.12 Topical corticosteroids cause a multitude of cutaneous adverse effects which were first noted after introduction of higher-potency topical steroids like fludrocortisone.16 Topical steroids have been classified into very potent, potent, moderately potent, and mild categories. The most common skin change is atrophy. Atrophic skin is described as increased in transparency with increased bruising, tearing, and fragility; the term “cigarette paper consistency” has been used. Telangectasias, striae, and ulcerations may also occur.31 Topical corticosteroids suppress cell proliferation, reduce collagen synthesis, reduce the thickness of the epidermis and stratum corneum, decrease keratinocyte size, and reduce the number of fibroblasts. Figure 7.1 depicts marked thinning of the skin due to steroidinduced atrophy. Topical steroids have also been associated with causing acne, rosacea, altered pigmentation, and photosensitization. These reactions occur more commonly with higher potency steroids. Contact sensitization has been reported with a prevalence of 0.2–6%; however, it is more often associated with lower potency nonfluorinated corticosteroids such as hydrocortisone and budesonide.16 Cutaneous adverse effects, particularly skin atrophy, from topical corticosteroids can be prevented by following several measures.6 First, use the least-potent corticosteroid possible for the least amount of time to

Fig. 7.1  Steroid-induced skin atrophy. Photo courtesy of Charles Goldberg

obtain therapeutic benefit. If very high potency topical corticosteroids are necessary, consider application only once daily or alternate treatment with nonsteroid therapies. Avoidance of occlusive dressings over the topical corticosteroid will reduce absorption. Use of creams instead of ointments over face, groin, axillae, genital, and perineal areas is recommended because absorption is higher over these sensitive areas. In addition, increased absorption is anticipated over ulcerated or atrophic skin.

7.4.2 Topical Calcineurin Inhibitors Pimecrolimus cream and tacrolimus ointment have provided a welcome addition to the pharmacological armamentarium against atopic dermatitis. These agents reduce the proliferation of T cells and resultant levels of inflammatory cytokines. The United States Food and Drug Administration has required manufacturers to add a black-box warning and medication guide for patients which communicate that the long-term safety of these agents has not been established and malignancy is a creditable risk with their long-term use.36 Development of T-cell lymphoma is the primary concern. However, adverse event surveillance in clinical trials and postmarketing has not found a higher rate of malignancies in users of pimecrolimus or tacrolimus. Pharmacokinetic studies indicate that topical application of calcineurin inhibitors results in negligible amounts of systemic absorption. This holds true for

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children with large percentage of body surface area treated with the medications.23 It is unlikely that topical calcineurin inhibitors will found to increase the risk for lymphoma, although continued surveillance is warranted.

7.4.3 Anticonvulsants For many years the anticonvulsants have been tagged with a high frequency of cutaneous reactions, ranging from simple rashes to toxic epidermal necrolysis. Over the decades our understanding of the mechanism by which these reactions occur has grown. Better understanding of the mechanism of cutaneous reactions has led to recommendations for therapy which help to prevent these reactions from occurring. The rash which occurs secondary to anticonvulsant medications is tied to a generalized hypersensitivity reaction that includes fever, lymph node enlargement, and often hepatitis along with mucosal blisters and erythematous skin eruptions.21 Some investigators have called this syndrome DRESS (drug reactions with eosinophilia and systemic signs).14 Anticonvulsants are particularly associated with this reaction as it is attributed to an arene oxide metabolite from the aromatic structure of many anticonvulsants. In particular phenobarbital, phenytoin, carbamazepine, and lamotrigine are frequently identified as causative agents.21,29 The risk for anticonvulsant cutaneous drug reactions ranges from 1 to 10/10,000.22, 30 These aromatic lipid-soluble drugs are usually oxidized through the cytochrome P450 system into active and inactive metabolites. However, a percentage of the metabolism is routed to form reactive arene oxide metabolites. The percentage which undergoes this pathway of metabolism is generally small, however, if other pathways are inhibited or defective, a higher percentage of the reactive metabolite will be produced, increasing the risk for cutaneous skin reactions.21, 29 Recently, the United States Food and Drug Adminis­ tration informed healthcare professionals that dangerous or fatal skin reactions (i.e., Stevens–Johnson syndrome and toxic epidermal necrolysis), can be caused by carbamazepine therapy and are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B1502.37 This allele occurs almost exclusively in patients with ancestry

L. C. Hutchison and O. Kajkenova

across broad areas of Asia, including South Asian Indians. Patients from these areas should be screened for the HLA-B1502 allele before starting treatment with carbamazepine. If these individuals test positive, carbamazepine should not be started unless the expected benefit clearly outweighs the increased risk of serious skin reactions. However, the reactions generally occur within 2–6 weeks of beginning therapy.22,30 Patients who have been taking carbamazepine for more than few months without developing skin reactions are at low risk of these events ever developing from carbamazepine. This same mechanism and risk is seen with phenytoin and phenobarbital and cross-reactivity is between 40 and 70%.21 Therefore, other anticonvulsants such as topiramate, levetiracetam, or gabapentin should be used rather than anticonvulsants with aromatic structures. Lamotrigine has also been associated with severe cutaneous reactions, and it is metabolized in the same manner as carbamazepine.17 Therefore, it likely has the same increased incidence in Asian populations. Recommendations to reduce the risk for rash with lamotrigine are to initiate therapy at 25  mg daily for 2 weeks, then increase to 50  mg daily for 2 weeks. Thereafter, doses may be increased by 50–100  mg every week. Other anticonvulsant medications may affect these recommendations because they are potent inducers and inhibitors of the cytochrome P450 system. Lamotrigine increases the levels of the epoxide metabolite of carbamazepine, increasing the risk for toxicity. Other anticonvulsants reduce plasma levels of lamotrigine, requiring higher doses to achieve therapeutic effects.

7.4.4 Tumor Necrosis Factor Alpha Inhibitors Tumor necrosis factor-alpha inhibitors, such as etanercept (Enbrel), adalimunab (Humira), infliximab (Remicade), and thalidomide have been used in the treatment of autoimmune and lymphoproliferative diseases. Injection site reactions are common but usually minor problems. Incidence in a 6-month study of etanercept was 37%. Urticaria can develop as a part of acute infusion reactions. Current strategies for prevention of acute infusion reactions include premedication

7  Prevention of Drug Reactions and Allergies in Dermatology

with diphenhydramine and acetaminophen 90  min prior to infusion, or use of loratadine for 5 days prior to the infusion. Reactions can also be managed by reducing the rate of infusion. Other adverse cutaneous effects were reported: • Interstitial granulomatous dermatitis which developed within 1–3 months and in some patients a year later after drug initiation10 • Leucoclastic vasculitis, lichenoid eruption, discoid lupus erythematous-like eruption, acute folliculitis, and necrotizing fasciitis7, 11

7.4.5 Amiodarone Amiodarone is an antiarrhythmic agent used for atrial fibrillation, ventricular tachycardia, and several other electrical cardiac disturbances. It has a unique profile of adverse events, causing corneal micro deposits, photosensitivity, thyroid disorders, hepatotoxicity, and pulmonary fibrosis.39 Unique to amiodarone is the risk for a blue-gray skin discoloration reported to occur in 4–9% of patients treated with the medication. One hypothesis attributed this hyperpigmentation to dermal lipofuscinosis. Macrophages were thought to accumulate lipofuscin in granular sacs and this activity was thought to be related to sunlight because hyperpigmentation occurs primarily on light-exposed areas of skin. Other researchers note that amiodarone and metabolite concentrations in skin with the blue-gray discoloration have been reported to be 10 times higher than concentrations in nonpigmented skin. One case report of amiodarone associated blue-gray hyperpigmentation showed no lipofuscin pigments leaving the authors to conclude that drug and metabolite deposits in the photo-exposed skin was the primary mechanism of the reaction.1 Prevention of the blue-gray hyperpigmentation is related to reducing exposure to the medication. The lowest effective dose should be used for the shortest possible time. Case reports of this cutaneous adverse effect occur after an average of 20 months of treatment. Reversal occurs years after discontinuation of the drug. A cumulative dose of at least 160 g of amiodarone is required for the reaction to occur which is commonly achieved within 3 years of initiation of therapy at an average dose of 200 mg daily.

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7.5 Conclusion Adverse cutaneous drug reactions are common, but most are not severe or life-threatening. The most effective means for prevention of these reactions is to reduce medication exposure by discontinuing medications that are not indicated, using the lowest effective dose and limiting the duration of therapy.

References   1. Ammoury A, Michaud S, et  al Photodistribution of bluegray hyperpigmentation after amiodarone treatment: molecular characterization of amiodarone in the skin. Arch Dermatol. 2008;144(1):92–96   2. Atkin PA, Veitch PC, et  al The epidemiology of serious adverse drug reactions among the elderly. Drugs Aging. 1999;14(2):141–152   3. Baldi BG, Santana AN, et  al Pulmonary and cutaneous nocardiosis in a patient treated with corticosteroids. J Bras Pneumol. 2006;32(6):592–595   4. Bates DW, Leape LL, et al Incidence and preventability of adverse drug events in hospitalized adults. J Gen Intern Med. 1993;8(6):289–294   5. Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol. 2001;137(6):765–770   6. Brazzini B, Pimpinelli N. New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Am J Clin Dermatol. 2002;3(1):47–58   7. Chan AT, Cleeve V, et  al Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J. 2002;78(915):47–48   8. Cousins DD. Medication Use: A Systems Approach to Reducing Errors. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 1998   9. Cullen DJ, Bates DW, et al The incident reporting system does not detect adverse drug events: a problem for quality improvement. Jt Comm J Qual Improv. 1995;21(10):541–548 10. Deng A, Harvey V, et al Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alpha inhibitors. Arch Dermatol. 2006;142(2):198–202 11. Devos SA, Van Den Bossche N, et al Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy. Dermatology. 2003;206(4):388–390 12. Fardet L, Flahault A, et  al Corticosteroid-induced clinical adverse events: frequency, risk factors and patient’s opinion. Br J Dermatol. 2007;157(1):142–148 13. Fiszenson-Albala F, Auzerie V, et al A 6-month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol. 2003;149(5):1018–1022 14. Gaig P, Garcia-Ortega P, et al Drug neosensitization during anticonvulsant hypersensitivity syndrome. J Investig Allergol Clin Immunol. 2006;16(5):321–326 15. Garcia-Doval I, LeCleach L, et al Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136(3):323–327

70 16. Hengge UR, Ruzicka T, et al Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54(1):1-15; quiz 16–18 17. Hilas O, Charneski L. Lamotrigine-induced StevensJohnson syndrome. Am J Health Syst Pharm. 2007;64(3): 273–275 18. Hunziker T, Kunzi UP, et  al Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey. Allergy. 1997;52(4):388–393 19. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med. 1995; 155(18):1949–1956 20. Knowles SR, Shear NH. Recognition and management of severe cutaneous drug reactions. Dermatol Clin. 2007; 25(2):245–253, viii 21. Krauss G. Current understanding of delayed anticonvulsant hypersensitivity reactions. Epilepsy Curr. 2006;6(2):33–37 22. Mockenhaupt M, Messenheimer J, et  al Risk of StevensJohnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64(7):1134–1138 23. Munzenberger PJ, Montejo JM. Safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Pharmaco­ therapy. 2007;27(7):1020–1028 24. Naldi L, Conforti A, et al Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol. 1999;48(6):839–846 25. Posadas SJ, Pichler WJ. Delayed drug hypersensitivity reactions – new concepts. Clin Exp Allergy. 2007;37(7):989–999 26. Rademaker M, Oakley A, Duffill MB. Cutaneous adverse drug reactions in a hospital setting. N Z Med J. 1995; 108(999):165–166 27. Rajan TV. The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation. Trends Immunol. 2003; 24(7):376–379 28. Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003;68(9):1781–1790

L. C. Hutchison and O. Kajkenova 29. Roychowdhury S, Svensson CK. Mechanisms of druginduced delayed-type hypersensitivity reactions in the skin. Aaps J. 2005;7(4):E834–E846 30. Rzany B, Correia O, et al Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet. 1999;353(9171):2190–2194 31. Schoepe S, Schacke H, et al Glucocorticoid therapy-induced skin atrophy. Exp Dermatol. 2006;15(6):406–420 32. Segal A, Doherty K, et  al Cutaneous reactions to drugs in children. Pediatrics. 2007;120(4):e1082–e1096 33. Semla TP, Beizer JL, et  al Geriatric Dosage Handbook. Hudson, OH: Lexi-Comp; 2006. 34. Shipley D, Ormerod AD. Drug-induced urticaria. Recognition and treatment. Am J Clin Dermatol. 2001;2(3): 151–158 35. Svensson C, EW C, et  al Cutaneous drug reactions. Pharmacol Rev. 2000;53(3):357–379 36. U.S. Food and Drug Administration, (March 10, 2005). FDA Public Health Advisory Elidel (Pimecrolimus) Cream and Protopic (Tacrolimus) Ointment. Retrieved 21 December 2009, from http://www.fda.gov/Drugs/ DrugSafety/PublicHealthAdvisories/ucm051760.htm 37. U.S. Food and Drug Administration, (December 12, 2007). Information for Healthcare Professionals: Dangerous or Even Fatal Skin Reactions - Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, and generics). Retrieved 21 Dec­ember 2009, from http://www.fda.gov/Drugs/DrugSafety/Postmarket DrugSafetyInformationforPatientsandProviders/ucm124718. htm 38. van der Linden PD, van der Lei J, et  al Skin reactions to antibacterial agents in general practice. J Clin Epidemiol. 1998;51(8):703–708 39. Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA. 2007; 298(11):1312–1322

8

Xerosis and Stasis Dermatitis Margaret E. M. Kirkup

8.1 Introduction Dry skin and stasis dermatitis are common conditions of senescence although they can occur at any age given the predisposing constitutional or environmental factors. In this chapter, I will attempt to describe the differences between dry and normal skin and the influences which can contribute to dryness with emphasis on those which are reversible before a clinical problem develops. In addition, I shall discuss the nature of and preventative measures possible in stasis dermatitis. Knowledge of the microstructure of the epidermis, particularly the stratum corneum, is important in understanding how dry skin occurs and the efficacy of the preventative measures which are available. Stasis dermatitis, a common condition of the lower limb, is due to failure of the tissue drainage mechanisms. The result is abnormality of appearance of the skin including discoloration, followed by inflammation. Ultimately fibrosis and ulceration can occur. Prevention of dry skin requires avoiding contact with irritant substances, attention to the environment of the skin, and regular application of moisturizing and emollient agents. Prevention of stasis dermatitis requires avoidance of pooling of blood and tissue fluids in the lower limbs by exercise, weight control, and prompt and continuous treatment of vein and lymphatic disease. Also required is prevention of localized xerosis with its loss of skin-barrier function that leaves the limbs vulnerable to dermatitis.

M. E. M. Kirkup Department of Dermatology, Weston General Hospital, Weston-super-Mare, Avon, UK e-mail: [email protected]

The fact that there is no universally accepted definition of dry skin has hampered research in this area. It may be perceived as cosmetic rather than pathological by some physicians. Indeed there is a spectrum of severity from a few dry patches on the face to a generalized pruritic condition. Dry skin can be severe and symptomatic, involving a detrimental effect on quality of life. Left untreated, it may be major reason for itching, especially in the elderly. Dry skin can be constitutional or hereditary. It can be acquired by poor skin care or contact with irritants, including friction and exposure. It can also be a component sign of skin disease such as atopic eczema or associated with systemic diseases, including renal failure, thyroid disease, and malignancies. The term xerosis (Greek xeros > dry) is frequently used interchangeably with “dry skin.” Dry skin is considered here to mean skin which is free of dermatological disease but which feels dry and rough to the touch. The surface appears to lack the normal, smooth, slightly oily feel and can appear to be covered in white powdery flakes. In established cases, the skin has a mosaic-like appearance sometimes described as “crazy paving” or eczema craquelé (Fig.  8.1). Such skin will often be described as feeling “tight” and will lack elasticity. It can and often does itch. It has a tendency to worsen in winter but can also be exacerbated by sun exposure. Dry skin is vulnerable to damage from friction, shearing forces, and trauma. This can lead to development of fissures, which heal poorly. Dry skin shows increased penetration by substances, rendering it more susceptible to development of irritant contact dermatitis.1 Chronic stasis dermatitis has several synonyms, including gravitational eczema, venous stasis eczema, and varicose eczema. The onset is gradual after many months or years of venous hypertension or lymphedema, signs of which may be relatively subtle clinically when

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_8, © Springer-Verlag London Limited 2010

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8.2 Xerosis 8.2.1 Pathogenesis of Xerosis

Fig. 8.1  Eczema Craquelé on the thighs

the skin changes begin to appear. Failure of drainage of the skin and subcutaneous tissue of the leg due to inadequacy of the venous or lymphatic systems leads to malnourishment of those tissues and poor oxygenation of the cells. However, the mechanism of development of dermatitis is unclear. The epidermal changes are speculated to be secondary to alterations in the function of the dermal blood vessels.2 Signs of chronic venous stasis disease include edema, varicosities of the veins due to failure of the valves in the superficial venous system or perforating veins and variable skin changes. There is extravasation of blood into the skin which is clinically seen as hemosiderin staining (Fig.  8.2). Dryness and erythema are common features.

Fig. 8.2  Venous stasis disease showing early ulceration, xerosis, and hemosiderin staining

The major component of the skin which is altered when dryness occurs is the epidermis, principally the stratum corneum. Stratum corneum consists of the terminally differentiated keratinocytes known as corneocytes. Corneo­cytes are flattened in shape compared to the keratinocytes in the deeper layers of the epidermis. They have no nucleus and consist of a cell envelope surrounding a compacted mass of keratin and amorphous matrix. Part of this intracellular matrix is a complex mixture of compounds described as the natural moisturizing factor, the function of which seems to be to retain water in the stratum corneum. The corneocytes are arranged rather like a brick wall, the mortar of which consists mainly of a bilayer of lipid. The effect of this layer is to waterproof the skin, preventing evaporation and waterlogging, yet allow diffusion of hydrophilic materials. The cells of the epidermis are held together by desmosomes. In the stratum corneum the corresponding structures, the corneodesmosomes, break down naturally allowing the spent cells to be shed imperceptibly. Water is necessary for the activity of the enzymes involved in this process. In xerotic skin there is failure of the corneocytes to be shed in the normal way. The corneodesmosomes do not break down at the normal rate and the cells are shed in clumps, perceived macroscopically as scale and roughness (Fig. 8.3). The rough, dry appearance and feeling is due to this dysfunctional

Fig. 8.3  Very dry skin in an elderly lady

8  Xerosis and Stasis Dermatitis

desquamation but also due to increased evaporation of water and reduction in intercellular lipid. Dry skin cannot perform all of its functions. Being in direct contact with the external environment, the epidermis is particularly vulnerable to physical and chemical influences. Dry skin has reduced barrier function, which renders it more vulnerable to these environmental influences. This loss of function is in part due to the reduced levels of lipid and in part due to the dehydration of the cellular component, allowing the skin to fissure and permitting entry of chemical substances and microbiological invaders. In most cases, it is likely that a combination of genetic predisposition and environmental influences are involved. Individual thresholds for barrier function breakdown are very variable. Contributing environmental factors are • • • • • • •

Cold Heat Wind Low humidity Ultraviolet radiation Soaps, detergents, and other cleaning products Friction

Systemic medication may contribute to dry skin. For example, diuretics which are very widely used may have a dehydrating effect on the skin and retinoids have an effect on keratinization with a dose-related drying effect. Measuring skin dryness is essential in experimental work but is of no practical use in a clinical setting. Among the measures commonly used are electrical impedance, which is an indicator of the water content by its ability to conduct electricity, and transepidermal water loss (TEWL), an indicator of the protective skin barrier function.

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legs and is of increased prevalence with increasing age. Institutionalized elderly people are at particular risk due to the conditions of low humidity and high environmental temperatures often to be found in care homes and hospitals. Prevalence rates of 29–58% are reported in nursing home patients.6, 7 It is more difficult to perform epidemiological studies in noninstitutionalized people and studies in unselected populations are sparse. Epidemiological studies of skin do not always include xerosis as a pathological condition. However, there is a high prevalence of xerosis reported in several studies of patients attending dermatology facilities.8, 9 While women are more likely than men to complain of dry skin, inflamed dry skin known as asteatotic eczema is more common in men.10, 11 Outdoor workers are at risk because of exposure to the effect of temperature extremes, UV radiation, and wind. Definition of dry skin and cultural values make it difficult to compare populations. There is some evidence that immigrant men from East Asia, the Middle East, and North Africa are more aware of dry skin than other groups following migration to a Western community.12

8.2.3 Prevention of Xerosis Prevention of dry skin and treatment of established cases follow the same principles. These are avoidance of aggravating factors, manipulation of the micro-environment of the skin surface, and application of topical agents to enhance or support the functions of the stratum corneum. There is limited evidence of benefit from systemic pharmaceutical agents.

8.2.3.1 Manipulation of the External Environment of the Skin

8.2.2 Epidemiology of Xerosis Studies reveal that xerosis is one of the most common abnormalities of older skin.3, 4 Some evidence suggests that females are more likely to describe their skin as dry at all ages5 and dry skin was found to be more common in females than males in study of noninstitutionalized older individuals.3 Clinically recognizable xerosis is most common on the face and lower

The environment needs to be manipulated to avoid the skin being exposed to extremes of temperature. Suitable clothing should be worn to protection against wind, rain, and sunlight. Use of sun-protective topical agents may help in two ways, both by preventing UV radiation damage to the DNA of the skin cells and by having a moisturizing effect. Clothing is being developed which is made from very fine, smooth fibers which may have a place in primary prevention

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of xerosis. Measures should be taken to increase the humidity of the local environment. This may require reduction in ambient temperature or adjustment of the time exposed to air conditioning or central heating. Some additional increase in moisture in the air may be gained by placing open containers of water around the home or workplace. Indoor plants may also help.

8.2.3.2 Personal Care Since indoor bathrooms became commonplace in the twentieth century, there has been a tendency toward frequent showering and bathing. Millions are spent every year on advertising soaps, shower and bath gels, and shampoos. We are encouraged to believe that we should be sweet-smelling at all times and over-washing may be a factor in development of xerosis. Water, soap, and detergent skin-washing liquids are generally the most common irritants applied to the skin. In my experience, many people with dry, itchy skin find the application of water gives temporary relief and reduces the feeling of dryness. They may need considerable persuasion to convince them to reduce excess contact with water that, in the long term, is damaging their skin. There is a huge industry involved in developing and marketing skin cleansing products. A study of commonly used soaps and cleansers in Mexico showed that the majority of washing agents were irritants as assessed by a 5-day patch test technique.13 Soaps, soap-free cleansers, shampoos, shower and bath gels and creams may be described as “moisturizing” but as a general rule contain surfactants which strip the natural lipid from the stratum corneum, contributing to dryness. Reducing washing frequency and use of soap-substitutes goes a long way toward preventing xerosis.

8.2.3.3 Topical Agents Almost any moisturizer or emollient can be used as a soap-substitute or applied directly to the skin. Emollients are skin softeners, reducing the feeling of roughness; moisturizers also add water to the epidermis, improving its function. In practice, they can be used interchangeably in most cases and the terms are

M. E. M. Kirkup

often used as synonyms. Instruction needs to be given in how to use these products. While they can be added to very hot water and whipped into a suspension or emulsion, allowing use as a liquid skin cleanser, it is equally effective to use these products by applying them directly to the skin. Gentle removal with sponge or flannel in the bath or shower is cleansing and leaves a pleasant layer of the product on the skin. The water must not be very hot or cold. Moisturizers and emollient preparations containing antimicrobial agents may be helpful on a short-term basis where scratching or other skin trauma increases the risk of infection. Bath oils and liquid emollients added to the bath water, form a film on the surface of the water. Some of this will cling to the skin on leaving the bath giving additional benefit. Emollients and moisturizers can cause the surface of the bath to be slippery and extra care is required to avoid falls, particularly in children and the elderly. After bathing, the skin should be gently patted dry with a soft towel to avoid frictional trauma and a further layer of emollient or moisturizer applied. Ideally this should be done before the skin is quite dry. Emollient or moisturizer should be reapplied throughout the day to protect from the environment and prevent development of signs of dryness. The frequency of application will depend partly on the severity of the xerosis or tendency to dryness but should be at least twice daily. Social circumstances and clothing may well have an influence on what is practical.

8.2.3.4 Moisturizing As well as spending vast sums of money on production and advertising of skin cleansers, the cosmetics and toiletries industries are investing heavily in developing and advertising moisturizers. While those at risk from genetic and environmental factors are well-advised to be liberal with applications of moisturizing agents, what is the evidence that regular moisturizing actually prevents dryness in those at low risk? There is good evidence that regular moisturizing reduces the incidence of irritant dermatitis in those at risk and prevents recurrence of the dry skin, suggesting that primary prevention would also be effective.14 Moisturizing has been shown to have a significantly protective effect against detergents in healthy volunteers.15

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8.2.4 Choice of Moisturizer and Soap-Substitute The range of moisturizers available is vast and includes lotions (solutions, suspensions or emulsions of lipid and water) creams (emulsions of water in oil or oil in water), ointments (with hydrophilic or hydrophobic bases), pastes (solids suspended in a base), and gels.16 The ideal emollient might be a simple preparation, such as soft white paraffin, which softens the skin and provides a waterproof film, preventing contact with irritants and preventing evaporation of water from the stratum corneum. However, it is not always cosmetically acceptable to use and can stain clothing and make skin surface slippery, reducing grip. A balance has to be struck between cosmesis and effectiveness. The best topical agent is the one which the individual will actually use and it may take some time to find the best one for each individual. Compromise between effectiveness and cosmetic acceptability may be necessary. When xerosis is established, it can take many weeks of persistence with a good moisturizing regimen before normal skin barrier function is restored. Secondary prevention in the form of continued moisturizing and avoidance of irritants is wise.

Moisturizers and emollient ingredients vary. While the best combination for any given patient may be found by trial and error, it can be useful for healthcare professionals to have some knowledge of the constituents of these products. Ideally, the chosen preparation should include a humectant, which retains or attracts water, and a grease or lipid to act as a waterproof barrier, preventing evaporation of water and protecting the skin from the influences of an adverse environment. Examples of humectants are lactic acid, glycerol, and urea. Some products also contain physiological lipids, which may improve the differentiation of the epidermis and may help reform the lipid bilayer.17 Additional ingredients such as ammonium lactate may improve the efficacy by keratolysis, thus normalizing desquamation. The risk of skin irritation and development of contact allergy is reduced by careful selection of products to avoid irritant and allergenic ingredients. It may also be necessary to select different products for different areas of the body and for different times of day; a heavier, greasier product may be more acceptable at night than before dressing for the day. A compromise product is better than none. Ingredients used in emollient and moisturizer manufacture are shown in Table  8.1. Most commercial products will also contain preservatives, perfumes, and emulsifying agents and some contain coloring materials.

Table 8.1  Ingredients commonly used in emollients and moisturizers Ingredient Example

Primary function

Water

–

Adds moisture

Fats and oils

Liquid paraffin, petrolatum

Prevents evaporation

Physiological lipid

Cholesterol, ceramides

Prevent evaporation and may play a role in restoration of function of the stratum corneum

Humectant

Glycerol, lactic acid, urea

Restore water content of stratum corneum

Antioxidants

Tocopherols, gallates

Inhibit oxidation

Keratolytics

Ammonium lactate

Enhance lysis of corneodesmosomes

Preservative (antimicrobial)

Parabens, alcohol

Reduce microbial growth in opened container

Emulsifying agent

Stearic acid, palmitic acid, sodium lauryl sulfate

Collect at interface of two phases to promote emulsification

Perfumes Color

Increase acceptability of the product –

Increase acceptability of the product

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8.2.5 Adverse Effects of Moisturizing Serious reactions are rare but allergic contact dermatitis to contents of these products can occur. Irritant dermatitis is more common with frequent and prolonged use of preparations containing potential irritants such as sodium lauryl sulfate. Humectants such as urea and lactic acid are associated with causing a subjective sensation in some individuals.16

M. E. M. Kirkup

deep, painful, and slow to heal. The thick layer itself can cause difficulty with walking and shoe-fitting. Paring away the build-up of thick skin may give temporary relief but the skin responds by rebuilding the thick stratum corneum unless measures are taken to alter the local environment of the feet. Application of emollients will soften the hyperkeratotic skin and improve comfort while helping reduce further build-up. Particular care is needed in those with diabetes and peripheral ischemia. 8.2.6.3 Flexures

8.2.6 Specific Body Areas Some areas of the body may require special attention. Among these are hands, feet, and flexures.

8.2.6.1 Hands Those in occupations which involve frequent unavoidable exposure to water, such as domestic cleaners, catering workers, healthcare workers, hairdressers, and bar staff will need additional advice on protection of the hands. Dry skin is the precursor to irritant hand eczema. It is always best to place a barrier between the skin and the water where possible. Gloves form a better barrier than topical agents. Gloves need to be appropriate to the task and may not be easily accepted. Powdered latex must be avoided to reduce the risk of latex allergy. Hand washing with an emollient is acceptable in most settings but liberal and frequent application of emollients or moisturizers after washing or other exposure to water is also vital. Wearing gloves in cold and wet weather will also help prevent drying of the skin. Cotton gloves can be useful to wear after liberal application of topical agents.

Body flexures are vulnerable areas because the epidermis tends to be thin with a thin stratum corneum and because the skin folds can trap topical agents and irritants if not adequately cleansed. Build-up of sweat, retained cleaning agents and other applications such as talcum powder can contribute to the development of irritation.

8.2.7 Occupational Factors In the workplace and in domestic cleaning, it is essential to avoid direct contact of the skin and irritants. Water is an irritant, especially if contact is prolonged. Protective gloves are widely available. The gloves chosen need to be appropriate for the task. Nonpowdered latex should be avoided as it increases the risk of sensitization to latex. It is the duty of the employer to ensure that appropriate gloves and other protective clothing are available but it is the duty of the employee to make sure that they use them. Training may be required. Regulations exist to protect the workforce against extremes of temperature. Control of humidity is less well-regulated.

8.2.6.2 Feet The skin on the soles of the feet is thick, mainly due to hyperkeratosis of the stratum corneum, maximal on weight-bearing areas. While this is likely to be a physiological response it is more pronounced with advancing age and with obesity and is exacerbated by frictional stresses including ill-fitting footwear. This thick epidermal layer tends to desiccate and crack especially in middle age and beyond, leading to fissures which can be

8.3 Stasis Dermatitis 8.3.1 Introduction Stasis dermatitis affects the lower legs bilaterally, often beginning insidiously on the shin or “gaiter” area above the ankles. It is believed to be due to stasis of tissue fluids but is an under-researched condition. The stasis

8  Xerosis and Stasis Dermatitis

may not be clinically overt when the skin changes present. Reduced efficacy of the activity of the drainage mechanisms of the lower limbs results in inflammation and gross changes of appearance of the skin. Etiology can be multifactorial; lymphatic or venous obstruction or insufficiency may be implicated. Lymphatic drainage can be overwhelmed and impaired by systemic disease of the cardiovascular, renal or hepatic systems and by obstruction to the drainage by lymphatic involvement in malignancy or obesity. Local damage to the lymphatics can occur after deep venous thrombosis (DVT), repeated attacks of cellulitis, or as a result of trauma. Congenital lymphatic insufficiency can be symptomless until adult life. Venous disease may be overt as in DVT or varicose veins but can occur insidiously in immobility and advancing age when lymphatic insufficiency is likely to be worsened by venous stasis. Obesity compounds the problem whatever primary cause is involved due to increased hydrostatic pressure, which can overcome the capacity to drain the interstitial tissues. Flow may also become retrograde when the limbs are dependent and immobile.

8.3.2 Pathogenesis of Stasis Dermatitis The pathogenesis of stasis dermatitis has not been fully elucidated. Poorly drained skin demonstrates changes microscopically before clinical problems present. The lymphatics are dilated, dermal blood vessel walls thicken and passage of fluid and cells in either direction becomes impaired. The inflammatory process leading to stasis dermatitis seems to involve white blood cells sequestration in postcapillary venules which increases cell adhesion leading to leucocyte activation in the superficial dermal microvasculature.2 This process becomes self-perpetuating. Left untreated the process leads to fibrosis and ultimately ulceration. Extravasated blood cells cannot reenter the circulation and are broken down slowly in situ leading to hemosiderin staining (Fig.  8.2). The skin becomes xerotic and inflammation ensues. Dry skin may itch and scratching may be the final straw in developing signs of dermatitis. However, itch is not a prominent clinical feature in many cases. The “gaiter” area just above the ankles seems to be the most vulnerable site and this is the most common site for development of ulceration if stasis problems are not addressed.

77 Table 8.2  Ankle Brachial Pressure Index (ABPI) Measure blood pressure in brachial artery as normal Apply blood pressure cuff to lower limb and inflate Use handheld Doppler probe over the posterior tibial artery and dorsalis pedis artery in turn to measure systolic ABPI = systolic pressure at ankle divided by the systolic pressure at brachial artery. For example, with blood pressure of 170/80 and post tibial pressure of 150, the ABPI = 0.88

8.3.3 Epidemiology of Stasis Dermatitis There is a slight female preponderance in this condition. Females have increased risk factors for the conditions which predispose to the development of the underlying stasis. Frequency increases with advancing age. It is estimated that 2–5% of the adult population of the United States shows changes associated with venous insufficiency.

8.3.4 Predisposing Factors to Stasis Dermatitis Factors predisposing to stasis dermatitis are: • • • • • • • • • • • • •

Obesity Cardiac failure Immobility Renal failure Advancing age Hepatic failure Xerosis Hypothyroidism Venous disease Hypoalbuminemia Lymphatic obstruction Malignancy Smoking

8.3.5 Prevention of Stasis Dermatitis Primary prevention of stasis dermatitis requires correction of the condition of tissue fluid stasis, reducing pressure on the venous or lymphatic return. This restores the

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physiological state of tissues toward normal. Depending on the underlying predisposition, it may not be possible to completely correct the problem. Leg elevation, exercise of the lower leg musculature, compression hosiery, and prevention of xerosis, as outlined above, all have a part to play. 8.3.5.1 Leg Elevation Dependency of the lower limb causes the drainage systems to be under conditions of increased hydrostatic pressure. Simple elevation of the legs when at rest will relieve this pressure. This can be achieved by recumbence with raising of the foot end of the bed. There are many comfortable chairs available which include the facility to raise the feet at least level with the hips.

M. E. M. Kirkup Table  8.3  Classification of compression hosiery in various countries UK France Germany USA (mmHg) (mmHg) (mmHg) (mmHg) Class 1

14–17

10–15

18–21

15–30

Class 2

18–24

15–20

23–32

30–40

Class 3

25–35

20–36

34–46

40+

>36

>49

Class 4

The calf muscles act as a pump, aiding venous and lymphatic return. Simple exercises to increase the activity of these muscles are a useful adjunct to management and help prevent the condition. Exercises can be performed while sitting or recumbent.18 ,19

The higher the class of garment, the lower is the likelihood of compliance. There is some evidence that there is little difference in reduction of edema between classes I and II in preulcer states.20 Therefore, to optimize compliance, class I compression may be sufficient for prevention. As few as 21% of those prescribed compression for venous disease use the compression on a daily basis.21 The more compressive the garment, the more difficult it is to put on, the higher grades requiring considerable dexterity and strength. The physical act of putting on compression hosiery can be extremely difficult or impossible for those who have impaired joint mobility, flexibility, weakness, or cognitive dysfunction. Many suppliers can provide aids to assist but there is no substitute for having someone to help.

8.3.5.3 Compression

8.3.5.4 Emollients

Where it is not possible to restore the drainage to normal, external support in the form of compression hosiery or bandaging will encourage fluid into the deep venous or lymphatic system and reduce the tissue fluid pressure in the skin. Compression must not be introduced if it will compromise the arterial supply of the limb or if there is any infection present. It is essential to palpate the limb pulses and observe for signs of ischemia. If there is doubt, Doppler studies of the pressure in the peripheral arteries give an indication of suitability for compression but it may be necessary to formally investigate for arterial disease surgeon before proceeding. A useful rule of thumb is not to introduce compression if the ankle brachial pressure index (ABPI) is greater than 0.8. The method of measuring ABPI is shown in Table 8.2. There are many suppliers of compression hosiery and many different methods of classification of the degree of support provided by the products. Compression hosiery classifications vary from country to country. Examples of the systems in use are shown in Table 8.3.

Emollient therapy as outlined above is the most appropriate topical therapy for reducing the appearance of stasis dermatitis. Xerosis is an important part of the pathophysiology of the condition. Application is easier if there is someone to help as the lower legs can be out of reach of many obese, elderly, ill people. Application is best done by smoothing the agent on in the direction of hair growth to avoid occlusion of follicles.

8.3.5.2 Exercise

8.3.5.5 Pharmaceutical Interventions There is unconfirmed evidence that oral flavonoids, which are botanical antioxidants, are venotropic and can help reverse venous stasis disease.22 Other pharmaceutical agents such as the angiogenesis inhibitor calcium dobesilate and xanthine derivative pentoxyfyline may have a role in management of established stasis dermatitis but their place in prevention is untested.23, 24

8  Xerosis and Stasis Dermatitis

References   1. Smith HR, Rowson M, Basketter DA, McFadden JP. Intraindividual variation of irritant threshold and relationship to transepidermal water loss measurement of skin irritation. Contact Derm. 2004;51:26–29   2. Cheatle TR, Scott HJ, Scurr JH, et al White cells, venous blood flow and venous ulcers. Br J Dermatol. 1991;125:288–290   3. Beauregard S, Gilchrest BA. A survey of skin problem and skin care regimens in the elderly. Arch Dermatol. 1987;123: 1638–1643   4. Weisman K, Krakauer R, Wanscher B. Prevalence of skin disease in old age. Acta Derm Venereol. 1980;60:352–353   5. Jemec GBE, Serup J. Scaling, dry skin and gender. Acta Derm Venereol. 1992;177:26–28   6. Norman RA. Xerosis and pruritus in elderly patients, part 1. Ostomy Wound Manage. 2006;52:12–14   7. Smith DR, Atkinson R, Tang S, Yamagata Z. A survey of skin disease among patients in an Australian nursing home. J Epidemiol. 2002;12:336–340   8. Thaiisuttikul Y. Pruritic skin diseases in the elderly. J Dermatol. 1998;25:153–157   9. McFadden N, Hande KO. A survey of elderly new patients at a dermatology outpatient clinic. Acta Derm Venereol. 1989;69:260–262 10. Anderson C. Asteatotic eczema. E medicine, emedicine. com; 2006 11. Fritsch PO, Reider N. Other eczematous disorders. In: Bolognia JL, Jorizzo JL, Rapini R, eds. Dermatology. Philadelphia: Mosby; 2003:218 12. Dalgard F, Holm JO, Svensson A, et  al Self reported skin morbidity and ethnicity: a population based study in a Western community. BMC Dermatol. 2006;7:4

79 13. Baranda L, Gonzalez-Amaro R, Torres-Alvarez B, et  al Correlation between pH and irritant effect of cleansers marketed for dry skin. Int J Dermatol. 2002;41:494–499 14. Simion FA, Abrutyn ES, Draelos Z. Ability of moisturisers to reduce dry skin and irritation and to prevent their return. J Cosmet Sci. 2005;56:427–444 15. Ramsing DW, Agner T. Preventive and therapeutic effects of a moisturizer. Acta Derm Venereol. 1997;77:335–337 16. Loden M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol. 2003;4:771–788 17. Proksch E, Lachapelle J-M. The management of dry skin with topical emollients – recent perspectives. J Dtsch Dermatol Ges. 2005;3:768–774 18. Hansson C. Optimal treatment of venous (stasis) ulcers in elderly patients. Drugs Aging. 1994;5:323–334 19. Padberg FT Jr, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufficiency: a randomized trial. J Vasc Surg. 2004;39:79–87 20. Gniadecka M, Karlsmark T, Bertram A. Removal of dermal oedema with class I and II compression stockings in patients with lipodermatosclerosis. J Am Acad Dermatol. 1998;39:966–970 21. Raju S, Hollis K, Neglen P. Use of compression stockings in chronic venous disease: patient compliance and efficacy. Ann Vasc Surg. 2007;21:790–795 22. Katsenis K. Micronized purified flavonoid fraction (MPFF): a review of its pharmacological effects, therapeutic efficacy and benefits in the management of chronic venous insufficiency. Curr Vasc Pharmacol. 2005;3:1–9 23. Ciapponi A, Laffaire E, Roque M. Calcium dobesilate for chronic venous insufficiency: a systematic review. Angiology. 2004;55:147–154 24. Pascarella L, Schoenbein GW, Bergan JJ. Microcirculation and venous ulceration: a review. Ann Vasc Surg. 2005;19:921–927

9

Photoprotection Camile L. Hexsel and Henry W. Lim

Author contributions: Dr. Lim and Dr. Hexsel have participated in the conception and design, drafting and critical revision of the chapter for important intellectual content. Conflict of interest: Dr. Lim is a consultant for La Roche-Posay, Orfagen, Johnson and Johnson, and Dow Pharmaceuticals; and he has received research grant support from Johnson and Johnson. Dr. Hexsel has no conflicts of interest to declare.

9.1 Cutaneous Effects of Ultraviolet Radiation Ultraviolet (UV) radiation consists of UVC (270–290 nanometers [nm]), ultraviolet B (UVB) (290–320 nm) and ultraviolet A (UVA), which is further classified into UVA1 (340–400  nm) and UVA2 (320–340  nm). UVC radiation does not reach the surface of the earth as it is filtered by the ozone layer. On the surface of the earth, there is 20 times more UVA than UVB. Cutaneous effects of UV radiation can be divided into acute and chronic. Acute effects include erythema, edema, blisters, and immediate and delayed pigment darkening followed by tanning or neomelanogenesis, acanthosis, and dermal thickening. Exposure to UV can also induce immunosuppression, vitamin D synthesis, and development of photodermatoses. Erythema and edema are primarily induced by UVB, start at 3–4 h after UVB exposure, and peak at

C. L. Hexsel (*) Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA e-mail: [email protected]

8–24 h. They last 24–48 h or longer in light-skinned individuals. Delayed tanning or neomelanogenesis peaks at 72 h after UV radiation. UVB-induced delayed tanning requires a preceding erythemal response and has a sun protection factor (SPF) of 3. In contrast to UVB, UVA-induced erythema peaks at 1–2  h after exposure and subsides gradually over 24–72 h. Because of the longer wavelength of UVA, it takes 1,000-fold more fluence (dose) to induce erythema by UVA compared to UVB. UVA also induces immediate and delayed pigment darkening followed by tanning. Immediate pigment darkening (IPD) occurs within seconds after UVA and visible light irradiation, and resolves in 2 h; it is due to photo-oxidation of preexisting melanin.1 Persistent pigment darkening (PPD) is also a result of a photo-oxidation and redistribution of preexisting melanin; PPD persists from 2 to 24 h after irradiation.1, 2 UVA-induced delayed tanning, which is secondary to neomelanogenesis, appears usually 3 days after exposure.1 Chronic effects of UV radiation include photoaging and the development of actinic keratosis, basal cell carcinoma, and squamous cell carcimona.1, 3, 4 Melanoma has been associated with intermittent intense acute sun exposure and history of sunburns. The specific wavelengths associated with melanoma have not completely been identified; therefore, although sunburns are associated with an increased risk of melanoma, the specific wavelengths of UV responsible for sunburn may not be the same wavelengths responsible for the development of melanoma.3 Although solar radiation comprises a broad range of wavelengths, several eye disorders are related to UV, visible and infra-red radiation. Examples of acute opthalmological effects include photokeratitis (welder’s flash or snow blindness) from UVC and UVB radiation; solar retinitis (blue light retinitis or eclipse blindness)

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_9, © Springer-Verlag London Limited 2010

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from unprotected exposure to intense sunlight; retinal photochemical burn from short-wavelength visible light (blue–violet light); retinal thermal damage from longer wavelengths and short pulses of intense visible light. Long-term effects of UV radiation associated with longterm exposure to sunlight include age-related macular degeneration, cataracts, pterygium, and pinguecula.5

C. L. Hexsel and H. W. Lim Table 9.1  Recommendations for photoprotection Seek shade during peak hours of UV radiation (between 10 AM and 4 PM or when a person’s shadow is shorter than their height) Use sunscreens with broad spectrum UVB and UVA coverage with minimum sun protection factor (SPF) 15, preferably 30 First apply sunscreen 15–30 min before sun exposure followed by another application 15–30 min later

9.2 General Photoprotection Recommendations and Their Rationales

Reapply sunscreen at least every 2 h and after swimming, perspiring, and towel drying

Cutaneous effects of UV radiation can be effectively prevented with the use of multiple photoprotection measures. UV radiation is more intense between 10 AM and 4 PM.1 Approximately 20–30% of total UV radiation reaches the earth between 11 AM and 1 PM, and 75% between 9 AM and 3 PM. Maximal irradiance occurs in the summer months, although seasonal variation in UV radiation decreases with latitude. Furthermore, there is an increase of about 3% in UV reaching the surface per degree decrease in latitude. Because of the wide range of geographical, latitude, and time zone distribution,6 the “shadow rule” has been proposed as a simple way to determine the peak hours of UV radiation. During peak hours of UV radiation, a person’s shadow is shorter than their height, while during off-peak hours, it is longer.4, 6 Therefore, the first recommendation in photoprotection is: seek shade during peak hours of UV radiation (between 10 AM and 4 PM)1 or when one’s shadow is shorter than one’s height (Table 9.1).4, 6 An effective and widely used photoprotection method is sunscreen. Discussion of the sunscreen actives available will be discussed in detail in this chapter. Correct use, appropriate amounts, and reapplication frequency are important factors for the effectiveness of sunscreens. Studies have shown that most of those who use sunscreens apply them inadequately. Concentrations of sunscreen used by consumers (0.5–1  mg/cm2), compared to that used in testing (2 mg/cm2) is the reason that in-use SPF frequently is only 20–50% of the labeled SPF value.1, 6 To achieve a 2  mg/cm2 concentration, the average adult should apply approximately 35 mL evenly, which is the equivalent of a full 1-ounce shot glass. Sunscreen should be applied 15–30  min before going out in the sun,

In children younger than 6 months of age, use physical measures for photoprotection (shade, clothing, hat). If absolutely necessary, use sunscreen limited only on exposed areas and infrequently

In addition to sunscreen, use other physical barriers such as shade, a wide-brimmed hat, tightly woven or specifically designed protective clothing

If you are at risk for vitamin D deficiency, take a minimum of 800–1,000 IU of vitamin D supplementation If planning multiday sun exposure, use higher SPFs

followed by a second application 15–30 min after sun exposure.1 The second application can provide up to 3 times increase in photoprotection, thus compensating for improper first application. Sweating, swimming, and towel drying can considerably decrease the efficacy of sunscreens1; towel drying can remove up to 85% of a product.4 With swimming and sweating, even the most water-resistant product requires a more frequent application than every 2 h. Therefore, the second recommendation in photoprotection is: use sunscreens with broad-spectrum UVB and UVA coverage and a minimum SPF 15, preferably 30. Sunscreen should be reapplied at least every 2 h and after swimming, perspiring, and towel drying. Sunscreen should be first applied 15–30  min before sun exposure followed by another application 15–30 min later (Table 9.1). As will be outlined in more detail below, sunscreens do not provide complete protection to the whole spectrum of UV radiation. Therefore, in addition to sunscreens, other physical barriers, such as shade, a wide-brimmed hat, tightly woven or specifically designed protective clothing, and sunglasses are an integral part of photoprotection strategy. Because of the higher skin-surface-to-body-weight ratio, and because the metabolism and excretion of absorbed substances are not completely developed in children under 6 months of age, it is recommended that

9  Photoprotection

for children younger than 6 months of age, photoprotection be achieved by physical measures (shade, clothing, hat). If absolutely necessary, limited and infrequent use of sunscreen on exposed areas may be done.1 The 1999 sunscreen monograph recommends that physicians be consulted for the use of sunscreen in this age group.7 Vitamin D oral supplementation is practical and inexpensive. Therefore, oral vitamin D supplementation is recommended for individuals at risk for vitamin D deficiency. These individuals at risk of vitamin D deficiency include those living in northern latitudes (above 35°), elderly, housebound, and darker-skinned individuals. Intake of vitamin D should be 400–800 IU/day depending on the age, for individuals at low risk for vitamin D deficiency; the recommended intake of vitamin D for high-risk individuals is 800–1,000 IU/ day or up to 50,000  IU of vitamin D per month (Table 9.1).4 Other factors should be considered for effective photoprotection. Multiday exposure affects the sensitivity to the sun since erythema peaks at 8–24 h of sun exposure. Therefore, higher SPFs are recommended for multiday sun exposure.1 Various surfaces cause significant reflection of UV radiation. Snow reflects 30–80% of absorbed radiation, sand 15–30%, water less than 5%, and most ground surfaces less than 10%. UV radiation can penetrate through water to a depth of 60  cm. Although complete cloud cover reduces surface UV radiation by approximately 50%, light scattered cloud cover has minimal impact on surface UV radiation.8

9.2.1 Sunscreens Organic sunscreens, previously called chemical sunscreens, act by absorbing UV radiation in the UVB and/or UVA spectra. Inorganic filters, previously called physical sunscreens, act by either reflecting or absorbing UV radiation, depending on the particle size.1 Sunscreens have been shown to prevent both acute and most chronic effects of UV radiation.3,  9, 10 In the United States, the Food and Drug Adminis­ tration (FDA) regulates sunscreens as over-the-counter drugs. The most recent version of the final FDA sunscreen monograph was issued in 1999 with a list of 16 approved sunscreen drugs (Table 9.2), approved maximum concentration, testing procedures, and

83 Table 9.2  Sunscreen drugs listed in the 1999 FDA sunscreen monographa Inorganic sunscreen drugs Titanium dioxide Zinc oxide Organic sunscreen drugs UVB Para-aminobenzoic acid (PABA) Padimate O Octinoxate Cinoxate Octisalate Homosalate Trolamine salycilate Octocrylene Ensulizole UVA Oxybenzone Sulisobenzone Dioxybenzone Avobenzone Meradimate FDA Food and Drug Administration; UVB ultraviolet B; UVA ultraviolet A a All listed as United States adapted name (USAN)

labeling requirements.1,7 A proposed amendment to the 1999 monograph was published in August, 2007.2 There are two different methods available for application of FDA approval for sunscreen drugs: the new drug application (NDA), and the time and extent application (TEA). To be considered for TEA approval, the FDA requires submission of the data acquired from at least 5 years of over-the-counter marketing of the product in the same country outside the United States.11 Various broad-spectrum sunscreen products containing ecamsule (terephtalydene dicamphor sulfonic acid, Mexoryl SX™) were recently approved by the FDA, the first one in July 2006.12 Ecamsule is not listed among the approved sunscreen drugs since ecamsulecontaining products were approved as final products rather than individual UV sunscreen drugs by the NDA process.

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9.2.2 Organic UVB Filters

9.2.3 Organic UVA Filters

SPF is the ratio of the dose of UV radiation (290–400 nm) needed to produce one minimal erythema dose (MED) on sunscreen-protected skin (2 mg/cm2 of product) over the dose needed to produce one MED on unprotected skin.1, 3 Therefore, SPF is a reflection of predominantly the erythemogenic effect of UVB, and to a lesser extend, UVA2. A proposed amendment to the 1999 monograph was published by the FDA on 27 Aug 2007.2 Key propositions comprise a new grading system for UVB and UVA protection, a cap of the SPF at 50+, and several recommendations in directions of use and labeling, including the requisite of a sun alert statement warning. In the 2007 amendment, the FDA suggests modifying the acronym “SPF” from “SPF” to “UVB sunburn protection factor” to better differentiate the biologic effects of UVB and UVA. Furthermore, a grading system for UVB sunburn protection factor was proposed based on the following four categories: low UVB sunburn protection (SPF 2 £ 15), medium UVB sunburn protection (SPF 15 £ 30), high UVB sunburn protection (SPF 30–50), highest UVB sunburn protection (SPF over 50). The FDA is of the opinion that there are no current data reporting the accuracy and reproducibility of SPF values over 50. Thus, the FDA proposes that manufacturers label their products with the specific SPF values up to, but no greater than 50; those products with SPF>50 would be labeled as 50+. Products would need to have SPF of 60 to obtain a SPF50+.2 FDA-approved UVB sunscreen drugs are listed in Table 9.2. Several important points regarding UVB filters listed in Table 9.2 need to be made. Octinoxate (ethylhexyl methoxicinnamate, Parsol MCX™) is the most widely used UVB sunscreen drug in the United States. Octinoxate has maximum peak absorption at 311 nm but it is less potent and photostable than Padimate O, and hence, requires additional photostable UVB drugs, or stabilizers, to achieve a high SPF value. Octisalate (ethyl hexyl salicylate), homosalate (homomenthyl salicilate), and octocrylene (2-ethylhexyl-2-cyano-3, 3-diphenylacrylate) are photostable; they are often combined with other sunscreen drugs to enhance the photostability of the final product.

The 2007 proposed amendment to the FDA sunscreen monograph presents a new grading system of the level of UVA protection, comprising a four-star rating system that ranges from low, medium, high, to highest UVA protection (Table 9.3). The rating system is based on both in vivo and in vitro testing procedures. The PPD test is proposed by the FDA as the standard method of in vivo UVA testing. UVA protection factor is subsequently determined by the ratio of the minimal pigmentation dose in sunscreen-protected skin to the minimal pigmentation dose in unprotected skin, evaluated between 3 and 24 h after the irradiation.2 Since UVA2 is the portion of UVA mostly represented in the PPD testing,13 the FDA proposed an in vitro testing that provides a measure of UVA1 protection, specifically, the ratio of UVA1 absorbance to total UV (290–400 nm) absorbance. When discordances between in  vitro and in  vivo test results occur, the final rating will be the lowest rating determined by either of these two methods. For example, a product with an in vivo UVA-PF of 15 and an in  vitro UVA1/UV ratio of 8 would be rated as a three-star product. FDA-approved organic UVA sunscreen drugs are listed in Table  9.2. The FDA recently approved sunscreen products containing ecamsule (terephtalydene dicamphor sulfonic acid, Mexoryl SX™). There are at least five ecamsule-containing sunscreen products in the US market. Oxybenzone (benzophenone-3, Bp-3), is a photostable UVB and UVA2 filter; it is the most common cause of photoallergic contact dermatitis from UV Table  9.3  Grading system of the level of UVA protection recommended by the FDA in the 2007 proposed amendment of the 1999 sunscreen monograph Star UVA-PF UVA1/UV Rating None

<2

<0.2

No UVA protection

*

2 to <4

0.2–0.39

Low

**

4 to <8

0.4–0.69

Medium

***

8 to <12

0.7–0.95

High

**** >12 >0.95 Highest UVA ultraviolet A; FDA Food and Drug Administration; UV ultraviolet; UVA-PF ultraviolet A protection factor

9  Photoprotection

filters.1 Avobenzone (butyl methoxydibenzoylmethane, Parsol 1789™) is the best UVA1 sunscreen drug available in the United States; however, it is photolabile and must be combined with photostable UVB sunscreen drugs; in some products, nonultraviolet-filter stabilizers, such as diethylhexyl 2,6-naphtalate, are also used.1 Other broad-spectrum and intrinsically photostable UVB and UVA sunscreen actives, currently unavailable in the United States, include silatriazole (drometriazole trisiloxane, Mexoryl XL™), bisoctrizole (methylene-bisbenzotriazoyl tetramethylbutylphenol, Tinosorb M™), and bemotrizinol (anizotriazine, bis-ethylhexyloxyphenol methoxyphenol triazine, Tinosorb S™)11; the last two are undergoing the FDA TEA approval process.1, 11

9.2.4 Inorganic Filters Inorganic sunscreen drugs are photostable; they photoprotect by reflecting or absorbing UV radiation, depending on the particle size. They are less efficient UV absorbers than organic UV filters. Thick coating is required to achieve satisfactory degree of reflection. Reducing the particle size considerably improves cosmetic acceptability, but also results in less scattering of visible light and shifts the protection toward shorter wavelengths and toward absorbency function. Opaque inorganic sunscreen actives may protect against visible light-induced photosensitivity. Microfine zinc oxide is a photostable sunscreen drug that protects from the UVB to the UVA1 range. Microfine titanium dioxide is a photostable sunscreen drug that is conversely more protective in the UVB and UVA2 range. Titanium dioxide has a higher refractive index and is therefore whiter, despite a smaller particle size.1, 3

9.2.5 Contact, Photocontact, and Phototoxic Reactions to Sunscreen Considering the widespread use of sunscreens, irritant and allergic contact, photocontact allergic and phototoxic reactions to sunscreen are rare. Currently oxybenzone is the most common contact photoallergen, replacing para-aminobenzoic acid (PABA), which is

85

not as frequently used anymore. The UVB filters ­methylbenziledene ­camphor, octinoxate and ensulizole, padimate O, and UVA filters avobenzone and sulizobenzone may only rarely induce contact allergic and photoallergic reactions.1, 3

9.2.6 Controversies on Sunscreens 9.2.6.1 Compensation Hypothesis The compensation hypothesis postulates that the use of high SPF sunscreen may encourage longer exposure to UV radiation, resulting in higher exposure to UVA radiation. Therefore, sunscreens could theoretically increase skin cancer susceptibility, especially melanoma.6 However, a systematic review by Dennis et al.14 that examined 18 heterogeneous case control studies published from 1966 to 2003 found no association between melanoma and sunscreen use.3, 14 9.2.6.2 Hormonal Effects In vitro, Schlumpf et  al.15 demonstrated an increased MCF-7 breast cancer cell proliferation after exposure to five different UVB filters. In vivo, they also demonstrated a dose dependent increase in uterine weight of immature Long-Evans rats after oral administration of two UVB filters, enzacamene and octinoxate. In addition, a dose-dependent increase in uterine weight in immature hairless rats after dermal administration of enzacamene was reported.15 Another study from the same group by Ma et al. reported the in vitro antiandrogenic activity of the sunscreen drugs oxybenzone and homosalate in the human breast carcinoma cell line MDA-kb2.16 Nakagawa and Suzuki reported the estrogenic effect of some hydroxylated intermediates of sulizobenzone in human breast cancer cells in vitro.17 It should be noted that the doses of sunscreen drug products used were unrealistically high compared to human exposure scenarios.1 Furthermore, a study by Janjua et al.18reported no effects on reproductive hormone levels in 32 volunteers after topical application of oxybenzone, octinoxate, and enzacamene, daily for 5 days.18 The scientific committee of cosmetic products and nonfood products, a European Committee based in Belgium, stated that the relative estrogenic

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potencies of UV sunscreen products were about one million less than estradiol, the positive control substance used in these studies.1 Therefore, while the reported estrogenic effect of UV sunscreen actives is still not completely clear, it most likely has no biologic relevance in otherwise healthy human subjects.

9.2.7 Other Topical, Oral, and Dietary Photoprotection Agents These agents are listed in Table 9.4. Selected ones are discussed below. UVB can induce immunosuppression by generating damage to DNA, directly via the formation of cyclobutane pyrimidine dimers (CPD), or indirectly, via reactive oxygen species formation. Photolyase, a DNA repair enzyme has been shown to decrease the number of UVB-induced dimers by 40–45% in human skin when applied immediately after UVB exposure1 and therefore, prevents immunosuppression, erythema, and sunburn formation.19 T4 endonuclease V is a bacterial DNA excision repair enzyme that repairs CPD in DNA. Its liposome form used as topical treatment was shown to remove dimers in DNA in the epidermis of animals and human beings, and nearly completely prevented UV-induced upregulation of IL-10 and tumor necrosis factor-alpha messenger RNAs. Application of T4 endonuclease V immediately after UV exposure partially protects against sunburn cell formation, local suppression of contact hypersensitivity, and suppression of delayed-type hypersensitivity and has minimal or no effect on UV-induced skin edema.1 Topical application of T4 endonuclease V for 1 year lowered the rate of development of actinic keratoses and basal cell carcinomas in patients with xeroderma pigmentosum.1, 19 UV irradiation generates short DNA fragments during the course of excision repair process. One small single-stranded DNA fragment, thymidine dinucleotide, has been extensively studied. Thymidine dinucleotides mimic cellular responses to UV radiation including increased DNA repair, reversible cell growth arrest, tumor necrosis factor-alpha expression and secretion, induction of IL-10 expression, and enhanced melanogenesis. Some of these effects are mediated through activation of p53 and increased messenger RNA levels for the responsible proteins. In human

C. L. Hexsel and H. W. Lim

fibroblasts, pretreatment with thymidine dinucleotide enhances activation of p53 and p53-upregulated proteins. Therefore, thymidine dinucletides may play a role in photoprotection. Antioxidants agents have been administered both orally and topically for photoprotection. Topical antioxidants are inefficient UV filters and have low SPF; therefore, they are commonly used in combination with sunscreens to enhance their efficacy. They are less potent than sunscreens in preventing sunburn. The limitations of topical antioxidants are the requirement of compliance with application, difficulties with diffusion into the epidermis, instability, and dose or concentration-dependent effectiveness. Commonly used antioxidants in sunscreen products include vitamin E and vitamin C. Topical application of calcitriol (1,25-dihydroxyvitamin D3, 1,25 hydroxyvitamin D), the active form of vitamin D, has been reported to inhibit UVB-induced sunburn cell formation in mice skin by inducing the expression of metallothionein,1,20 a sulhydryl-rich protein that acts as a potent radical scavenger. Green tea, consumed regularly by two-thirds of the world’s population, contains four main polyphenolic compounds, (-)-epicatechin (EC), (-)-epicatechin gallate (ECG), (-)-epigallotechin (EGC), and (-)-epigallotechin-3-gallate (EGCG). EGCG is considered the main polyphenol responsible for the antioxidant effects.21 Green tea polyphenols have absorption maximum at 273 nm, in the UVC range. These compounds exhibit anti-inflammatory activity, causing inhibition of UV radiation-induced skin erythema, edema, depletion of the epidermal antioxidant defense system, induction of epidermal cycloxygenase and ornithine decarboxylase enzyme activities, immunosuppression, a decrease in the number of sunburn cells, downregulation of UVB-induced production of IL 10, increased production of IL12, suppression of contact hypersensitivity,21 and inhibition of phosphorilation of MAPKs and NF-kB pathways.1 Effects on photocarcinogenesis include a decrease tumor burden, inhibition on the formation and size of malignant and nonmalignant tumors and regression of these tumors in mice with established tumors, enhanced UVB-induced increases in epidermal wild type p53, p21 and apoptotic sunburn. EGCG has also been reported to inhibit UV-induced lipid peroxidation, to restore UV-induced decrease in glutathione levels, to prevent CPD formation, to reduce prostaglandin metabolites, particularly prostaglandin

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Table 9.4  Photoprotective agents other than sunscreens Agent Photoprotective properties T4 endonuclease V, Photolyase

Repair of cyclobutane pyrimidine dimer

Source Bacterial DNA excision enzyme

Thymidine dinucleotide Enhancement of melanogenesis, increase of DNA repair

Synthetic

Alpha tocopherol (vitamin E)

Reduction of erythema, sunburn cell formation, chronic UVB-induced photodamage, photocarcinogenesis. Reduction in epidermal Langerhans cell density and contact hypersensitivity

Plants and vegetables, dietary supplements

L-ascorbic acid (vitamin C)

Reduction of erythema, sunburn cell formation, UVB-induced immunosuppression and contact hypersensitivity

Plants and vegetables, dietary supplements

Carotenoids

Protective against squamous cell carcinoma, visible light-induced retinal damage and aged-related macular degeneration, reduction in photosensitivity in patients with erythropoietic protoporphyria

Plants and vegetables, dietary supplements

Calcitriol (1,25-dihydroxyvitamin D3)

Induction of metallothionein (scavenger of free radicals). Induction of p53 protein expression, improved survival of keratinocytes post-UV radiation, reduction in nitric oxide products, sunburn cells, cyclobutane pyrimidine dimers (CPD) formation

Synthesized in kidneys after diet and sun exposure

Zinc

Antioxidant, reduction in sunburn cell formation, UVA1-induced early and delayed apoptosis of fibroblasts

Diet and dietary supplements

2-Furildioxime

Iron chelator, reduction of erythema, sunburn cell formation, acanthosis, infiltration of inflammatory cells

Synthetic

Polyphenolic compounds

Antioxidant

Green tea

Caffeine

Enhancement of apoptosis, reduction in the formation of nonmalignant and malignant tumors and photodamage

Plant

Caffeic acid and ferulic acid

Antioxidant and radial scavenging

Plants and vegetables

Genistein

Protection against UV-induced inflammation and immunosuppression, UV-induced carcinogenesis, photoaging, contact hypersensitivity

Soybean, Greek oregano, Greek sage, ginko biloba extract

Equol

Protection against UV-induced inflammation and immunosuppression, UV-induced carcinogenesis by induction of metallothionein

Red clover

Flavonoid cocoa

Protection against UV-induced inflammation, skin thickening, and epidermal water loss

Diet

Pomegranate extract

Inhibits the phosphorilation of NF-kB and MAPK pathways, reduces UV-induced inflammation, hyperplasia, hydrogen peroxide and CPD formation

Fruit extract

Cistus

Free radical scavenging and inhibition of lipid peroxidation

Mediterranean shrubs

Plant xyloglucans

Prevention of UVB-induced systemic immunosuppression

Tamarind seeds

Aloe plant poly/ oligosaccharide

Suppression of delayed-type and contact hypersensitivity

Aloe barbadensis

Polypodium leucotomos

Antioxidant and antiinflammation

Plant extract

Omega-3 polyunsaturated fatty acid

Decrease of sunburn cell formation, inflammation, UVA provocation response

Fish oil

N-acetylcysteine (NAC) Increase of glutathione level (endogenous antioxidant)

Synthetic

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E2, which plays a major role in skin tumor promotion. Effects of green tea polyphenols in photoaging include the inhibition of UVB-induced expression of matrix metalloproteinases and reduction of UVB-induced collagen cross-linking.1 The plant extract Polypodium leucotomos does not have significant absorption in either UVB or UVA range. In humans and animal models, the plant extract Polypodium leucotomos exhibits antioxidant and anti-inflammatory properties.1 Other proposed effects include prevention of UV-induced photoisomerization of trans-urocanic acid,22 suppression of the production of nitric oxide and induction of TNF alpha expression,23 and prevention of UV-induced apoptosis in human keratinocytes and fibroblasts.24 After topical and oral administration, Polypodium leucotomos was reported to increase the UV dose required for IPD, MED, minimal melanogenic dose and minimal phototoxic dose. In humans, oral and topical administration of Polypodium leucotomos was shown to be photoprotective against psoralenUVA-induced phototoxic reaction and pigmentary and histological changes. Fish oil, which is rich in omega-3 polyunsaturated fatty acid, has been shown to decrease UVB-induced sunburn cell formation and inflammation and reduce UVA provocation response. Due to the latter properties, it has been used for patients with polymorphous light eruption; however, relatively large amount of fish oil needs to be ingested for such effect; therefore it is not widely used for the management of this condition. N-acetylcysteine (NAC) is an agent that increases the levels of the endogenous antioxidant glutathione. Topical application of NAC before UVB exposure can protect against immunosuppression in mice. The mechanism of action is unclear. NAC has also been reported to have antioxidant properties against UVA cytotoxicity in human fibroblasts.1

9.2.8 Shade The sun protection provided by shade varies with diurnal variation of the angle of the sun and the amount of area or density of coverage provided.1, 6 Shade alone reduces solar irradiation by 50–95% and is, therefore, an important adjuvant of other photoprotective measures.3

C. L. Hexsel and H. W. Lim

9.2.9 Clothing Clothing is an essential part of photoprotection not only for the general population, but also and especially for particular groups of the population such as children, employees exposed to artificial sources of UV radiation, and those working outdoors and performing outdoor recreational activities and hobbies4, 25 photosensitive patients,25 and patients with risk factors for skin cancer. UV protection factor (UPF) is the measurement of UV photoprotection of fabrics. UPF is measured in vitro with a spectrophotometer that determines the transmission of UVA and UVB through fabrics. This in vitro method was reported to be accurate and reproducible, particularly for samples with UPF below 50,1 and appears to be the most suitable method for the evaluation of UPF.3 Recent advances in clothing photoprotection have included specifically designed clothing with UPF, and the development of regulation standards of photoprotection by clothing, the first one being the Australian/ New Zealand standard issued in July 1996. Subsequently, other standards have been developed, such as the United Kingdom, the European and the United States. These standards usually address the minimum UPF and the minimum recommended body coverage for photoprotection (e.g., trunk, upper arms).25 Several factors affect the UPF of fabrics, and should be taken into account when using clothing as a photoprotection method. These include the construction and the color of fabrics, hydration, washing and wearing, chemical treatments, stretching, and distance of the fabric from the skin.1, 25 Clothing with tightly woven fibers (wool and synthetic materials such as polyester) and thick fibers have higher UPF than loosely woven (cotton, linen, acetate, and rayon) and thin fabrics. Typical summer cotton T-shirts provide UPF of five to nine, and when wet, the UPF decreases to only three to four. Denim provides UPF of 1,700. When wet, changes in the UPF are variable due to scattering and absorption properties of the fabrics. In general, hydration results in a decline in the UPF because the presence of water in the interstices of the fabrics enhances UV transmission. Conversely, the UPF frequently increases when the textile becomes wet in fabrics made of viscose or silk, or those that have been treated with broad-spectrum UV absorbers.1

9  Photoprotection

Washing shrinks and reduces the gaps between fibers. UPF is also affected by chemical treatment of the fabrics with optical brightening agents and UV absorbers. Optical brightening agents are compounds which that absorb the energy and fluoresce at the visible light range, leading to reduced UV transmission and the appearance of being bright.1 White fabrics with an optical whitening agent have slightly higher UPF than other pale-colored fabrics.25 Dark-colored fabrics have greater UPF and visible light absorption than light-colored fabrics.1 The laundry additive containing UV absorber Tinosorb FD has been shown to result in significantly increased UPF than fabrics exposed to regular washing. The UPF decreases considerably when fabrics are stretched. Unstretched Lycra (DuPont, Wilmington, Del) may block 100% of UV radiation; on the other hand, the UPF may decrease to two when stretched. Another factor that affects the UPF of fabrics is the distance of the fabric from the skin. The closer to the skin, the lesser the photoprotection the fabric provides because the smaller the distance is between the fabric and the skin, the lesser the diffusion of the UV beam reaching the skin.1

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cosmetic film on the skin surface lasts up to 4 h after application; ­subsequent decrease in photoprotective property is due to migration into the dermatoglyphs and accumulation in the follicular ostia. The loss in photoprotective property could occur in a shorter period as a result of perspiration, tearing, sebum production, and accidental removal. Thus, reapplication at least every 2  h is recommended for patients who rely on their facial foundation engaging in outdoor activities.1

9.2.12 Sunless Tanning Agents Dihydroxy acetone, the active ingredient of sunless tanning preparations have an SPF of two, and has photoprotective properties against UVA and the low end of visible light for approximately 5–6 days.1, 3 It acts by an oxidative effect that changes skin color to orange– brown; the color binds chemically to the stratum corneum and does not interfere with normal skin function.1 Dihydroxy acetone may provide some protection against UVA and visible light induced photodermatosis.26

9.2.10 Hats 9.2.13 Sunglasses Hats can provide protection not only to the face and neck, but are highly recommended for scalp protection of individuals with alopecia or thin or short hairs.6 Photoprotection of hats depends on the brim width, material, and weaving. A wide-brimmed hat (>7.5 cm) has SPF 7 for nose, three for cheek, five for neck, and two for chin. Medium-brimmed hats (2.5–7.5 cm) provide SPF 3 for nose, two for cheek and neck, and none for chin, whereas narrow-brimmed hats provide SPF 1.5 for nose, and little protection for chin and neck.1

9.2.11 Makeup Foundations containing UV filters with high SPF are of great value and recommended for daily photoprotection. Foundation makeup without sunscreen provides SPF 3–4 due to its pigment content. This photoprotective property and ability to create an even

Sunglasses should reduce glare and provide protection against UV radiation. UV radiation is recognized to be potentially hazardous to the structure of the eyes, predominantly the cornea, lens, and retina. The cornea absorbs wavelengths below 295  nm, the crystalline lens between 295 and 400 nm and the retina between 400 and 1,400 nm; thus visible and infrared light are transmitted to the retina. Sunglasses standards have been developed to ensure quality, performance, and adequate protection to consumers. Australia, Europe, and the United States have all developed standards. While the Australian and European standards are mandatory, the United States standard is voluntary and not followed by all manufacturers. Sunglasses have been classified in three categories: cosmetic (which provide minimal UV protection), general purpose (which reduce the glare of bright light) and special purpose sunglasses (which are indicated for specific activities such as skiing and going to the

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beach). Furthermore, polarizing lenses reduce glare but do not add UV-blocking properties. For general purpose sunglasses, the United States standard (ANZI Z80.3) requires less than 1% of the wavelengths below 310 nm to be transmitted. For ideal photoprotection, sunglasses should wrap around the eyes maximizing eye and eyelid protection, since a significant amount of UV can reach unprotected eyes. For added photoprotection, a widebrimmed hat is recommended to reduce the level of radiation reaching the eyes. Extensive and dark-tinted sunglasses can cause pupillary dilatation and increase lid opening, thus resulting in increased UV exposure to the lens of the eye. Clear glasses absorb the vast majority of UVB radiation but no UVA radiation, thus, for UVA protection a plastic film containing zinc, chrome, nickel or other metals with broad spectrum UV coverage is recommended. There is no regulation regarding lens color; in spite of this, the effect of the color should not interfere with the ability to see color-coded signals, especially red and green traffic signals. Neutral gray and amber brown are two popular colors that allow color discrimination. Only visible light, not UV radiation, is required for human vision. Therefore the ideal sunglasses should substantially reduce UV to cornea and lens, including that from lateral directions. Additional retinal protection can be accomplished with lenses that reduce the transmission of short-wavelength violet/ blue light since this portion of visible light is considered to be hazardous to the retina.

9.2.14 Window Glass In daily activity, considerable time is spent indoors and in vehicles. Contemporary residential and commercial architectural design increasingly incorporates more and larger window areas. Nonetheless, exposure to UV radiation through architectural window glass and automobile glass is generally unappreciated. Recent developments in the glass industry have resulted in window glass that provides broad UV protection without the historically associated loss of visible light transmission. Factors affecting the UV protective properties of glass are glass type, glass color, interleave between glass and glass coating. In contrast, thickness of glass has limited effect on the properties of visible light and UV transmission.

C. L. Hexsel and H. W. Lim

Window glasses can have a single pane of glass (monolithic glass); however, this type of glass was largely replaced by insulating glass units, which comprise two or more panes of glass separated by a perimeter spacer to keep the glasses apart and sealed with curable adhesive material to hold the pieces together. While standard glass filters out UVB but not UVA, visible light, and infrared radiation, several types of glass are now available commercially in which the use of additional filters for UVA and infrared radiation are incorporated. The interlayer is virtually invisible. It can filter 99% of UV (up to 380 nm). It also reduces the transmission of sound. Laminated glass is widely used in automobiles, airports, museums, schools, sound studios, and large public spaces.

9.2.15 Automobile Glass For safety reasons, all car windshields are made of laminated glass, which is produced by binding two pieces of glass together with a plastic interlayer; if broken, glass fragments will adhere to the interlayer rather than fall free. Laminated glass blocks the vast portion of UVA radiation. On the other hand, rear and side windows are usually made from nonlaminated glass that transmits a significant amount of UVA. Yet, it is possible to add tints to rear and side windows to reduce the transmission of UVA radiation, visible and infrared light resulting in reduced unwanted heat gain and minimizing the fading of the interior components. Photosensitive patients are advised to choose vehicles with complete laminated window glass packages or to apply a plastic film to nonlaminated rear and side windows. Nevertheless, this does not substitute general photoprotection measures such as sunscreen and protective clothing use.5

9.3 Summary Effective photoprotection measures should be undertaken by all individuals to prevent transitory and permanent harmful effects of UV radiation. If possible, sun exposure should be avoided during peak hours of UV radiation (between 10 AM and 4 PM1 or when one’s shadow is shorter than one’s height).4, 6 Since

9  Photoprotection

often sun avoidance during those hours is not possible or practical, other effective photoprotection measures should be undertaken. Sunscreens with broad spectrum UVB and UVA coverage of minimum SPF 15, preferably 30, should be correctly applied at least every 2 h and after swimming, perspiring, and towel drying. To account for frequent inadequacy of application, sunscreen should be first applied 15–30  min before sun exposure followed by another application 15–30 min later. Sunscreens do not completely block all UV radiation, especially UVA. The use of physical barriers in addition to sunscreen, such as shade, a wide-brimmed hat, tightly woven or specifically designed protective clothing, sunglasses and window glass is an essential adjunctive method of photoprotection to sunscreen. Children younger than 6 months of age should be photoprotected mainly by physical measures. Oral vitamin D supplementation is recommended for individuals at risk for vitamin D deficiency.1

References   1. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Dermatol. 2005;52:937-958; quiz 959–962   2. Food and Drug Administration. 21 CFR Parts 347 and 352. Sunscreen drug products for over-the-counter human use: proposed amendment of final monograph; proposed rule. Federal Register 2007;72:49070–49122   3. Lautenschlager S, Wulf HC, Pittelkow MR. Photoprotection. Lancet. 2007;370:528-537   4. Palm MD, O’Donoghue MN. Update on photoprotection. Dermatol Ther. 2007;20:360–376   5. Tuchinda C, Srivannaboon S, Lim HW. Photoprotection by window glass, automobile glass, and sunglasses. J Am Acad Dermatol. 2006;54:845–854   6. Eide MJ, Weinstock MA. Public health challenges in sun protection. Dermatol Clin. 2006;24:119–124   7. Food and Drug Administration. Sunscreen drug products for over–the-counter human use; final monograph. Food and Drug Administration, HHS. Final rule. Federal Register 1999;64: 27666–27693   8. Rai R, Srinivas CR. Photoprotection. Indian J Dermatol Venereol Leprol. 2007;73:73–79   9. Green A, Williams G, Neale R, et al Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet. 1999;354:723–729 10. van der Pols JC, Williams GM, Pandeya N, et al Prolonged prevention of squamous cell carcinoma of the skin by ­regular

91 sunscreen use. Cancer Epidemiol Biomark Prev. 2006;15: 2546–2548 11. Tuchinda C, Lim HW, Osterwalder U, Rougier A. Novel emerging sunscreen technologies. Dermatol Clin. 2006;24: 105–117 12. The FDA approves new over-the-counter sunscreen. FDA consumer 2006;40:4 13. Bissonnette R, Allas S, Moyal D, Provost N. Comparison of UVA protection afforded by high sun protection factor sunscreens. J Am Acad Dermatol. 2000;43:1036–1038 14. Dennis LK, Beane Freeman LE, VanBeek MJ. Sunscreen use and the risk for melanoma: a quantitative review. Ann Intern Med. 2003;139:966–978 15. Schlumpf M, Cotton B, Conscience M, et  al In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect. 2001;109:239–244 16. Ma R, Cotton B, Lichtensteiger W, Schlumpf M. UV filters with antagonistic action at androgen receptors in the MDA-kb2 cell transcriptional-activation assay. Toxicol Sci. 2003;74:43–50 17. Nakagawa Y, Suzuki T. Metabolism of 2-hydroxy-4-methoxybenzophenone in isolated rat hepatocytes and xenoestrogenic effects of its metabolites on MCF-7 human breast cancer cells. Chem Biol Interact. 2002;139:115–128 18. Janjua NR, Mogensen B, Andersson AM, et  al Systemic absorption of the sunscreens benzophenone-3, octyl-methoxycinnamate, and 3-(4-methyl-benzylidene) camphor after whole-body topical application and reproductive hormone levels in humans. J Invest Dermatol. 2004;123:57–61 19. Verschooten L, Claerhout S, Van Laethem A, et al New strategies of photoprotection. Photochem Photobiol. 2006;82: 1016–1023 20. Lee J, Youn JI. The photoprotective effect of 1, 25-dihydroxyvitamin D3 on ultraviolet light B-induced damage in keratinocyte and its mechanism of action. J Dermatol Sci. 1998;18:11–18 21. Afaq F, Mukhtar H. Botanical antioxidants in the prevention of photocarcinogenesis and photoaging. Exp Dermatol. 2006;15:678–684 22. Capote R, Alonso-Lebrero JL, Garcia F, et  al Polypodium leucotomos extract inhibits trans-urocanic acid photoisomerization and photodecomposition. J Photochem Photobiol. 2006;82:173–179 23. Janczyk A, Garcia-Lopez MA, Fernandez-Penas P, et al A Polypodium leucotomos extract inhibits solar-simulated radiation-induced TNF-alpha and iNOS expression, transcriptional activation and apoptosis. Exp Dermatol. 2007; 16:823–829 24. Alonso-Lebrero JL, Dominguez-Jimenez C, Tejedor R, et al Photoprotective properties of a hydrophilic extract of the fern Polypodium leucotomos on human skin cells. J Photochem Photobiol. 2003;70:31–37 25. Gies P. Photoprotection by clothing. Photodermatol Photo­ immunol Photomed. 2007;23:264–274 26. Deleo V. Sunscreen use in photodermatoses. Dermatol Clin. 2006;24:27–33

10

Biologics Panoglotis Mitropoulos and Robert A. Norman

Modern advances in our understanding of immunologic processes, along with discoveries in disease pathophysiology, have led to the development of innovative therapeutic tools. In several fields of medicine, biologic response modifiers, selective immunoregulatory drugs, or simply biologics are now being used in the treatment of conditions for which either no other effective therapies exist or the existing therapies provide substandard therapeutic results. Biologic agents comprise a variety of medicinal products already in use, such as vaccines, human cells and tissues, recombinant therapeutic proteins, allergenic products, blood components, and human gene therapy products. The term biologics, however, is more commonly used to describe a class of medications produced by means of biological processes involving recombinant DNA technology. These are immunoregulators and bioengineered proteins, such as fusion proteins, chimeric or fully humanized monoclonal antibodies, or recombinant cytokines that directly interfere with the pathological effects of T cells.

10.1 Indications Currently, the only US Food and Drug Administrationapproved indication of biologics in dermatology is for the treatment of psoriasis (Table 10.1).1–5 Nonetheless, the treatment potential of these medications has led to their off-label use for several other conditions in dermatology. Some of these include

P. Mitropoulos (*) Camp Long Troop Medical Clinic, South Korea e-mail: [email protected]

pemphigus vulgaris, paraneoplastic pemphigus, epidermolysis bullosa acquisita, primary cutaneous B-cell lymphoma, dermatomyositis, atopic dermatitis, chronic urticaria, sarcoidosis, granuloma annulare, Sweet’s syndrome, lupus erythematosus, and several other granulomatous, autoimmune, inflammatory, and neutrophilic dermatoses.1 For psoriasis, biologics do not constitute first-line treatment. Biologic therapy should be reserved for moderate-to-severe plaque psoriasis, and in cases where traditional treatments do not appear to be adequate or are contraindicated. Current initial therapies for psoriasis include topical agents (corticosteroids, coal tar, anthralins, vitamin A and D derivatives) and systemic agents (methotrexate, cyclosporine, retinoids) as well as phototherapy. Biologic therapy may be reasonable for patients who fall in two or more of the following categories: • Age ³18 year old • Chronic (³6 months) moderate/severe plaque psoriasis • Psoriasis-area severity index (PASI) score of ten or more (or body surface area (BSA) of 10% or greater if PASI score not applicable), and a dermatology quality life index (DQLI) of less than ten • Inadequate response or intolerance to standard therapy • Higher than average risk of developing clinically important drug-related toxicity with the standard treatments • Significant coexistent unrelated morbidity (i.e., unstable congestive heart failure [CHF], liver disease) which precludes the use of systemic agents like cyclosporine or methotrexate • Disease requiring repeated inpatient management for control

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_10, © Springer-Verlag London Limited 2010

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Table 10.1  Currently FDA approved biologics for treatment of psoriasis and psoriatic arthritsis1–5 Name Type Principal mechanism of action

FDA approval

Alefacept (Amevive®)

Fusion protein/Immunoglobulin G1 (IgG1)

T-cell depletory

Psoriasis

Etarnecept (Enbrel®)

Fusion protein/Soluble tumor necrosis factor-alpha (TNF-a) receptor

TNF-a antagonist

Psoriasis, psoriatic arthritis

Infliximab (Remicade®)

Chimeric monoclonal antibody

TNF-a antagonist

Psoriasis, psoriatic arthritis

Adalimumab (Humira®)

Fully humanized monoclonal antibody

TNF-a antagonist

Psoriasis, psoriatic arthritis

Ustekinumab (Stelara)

Chimeric monoclonal antibody

Human monoclonal antibody targets the activity of cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23)

Psoriasis, psoriatic arthritis

• Patient not receiving any immunosuppressive medications except those used for the treatment of psoriasis • Presence of psoriatic arthritis

Table  10.2  Administration and dosing of biologics for the treatment of psoriasis Drug Route of Recommended administration dosage Alefacept (Amevive®)

Intramuscular or Intravenous

IV: 7 5 mg bolus once a week for 12 weeks

10.2 Dosage and Administration There are two methods of administration for the biologic agents currently used in dermatology (Table 10.2), subcutaneous (SC) or intravenous (IV). Since these medications are composed of relatively large molecules, parenteral administration, rather than oral, ensures better absorption and bioavailability. Following appropriate education and demonstration from their physician, patients may choose to self-inject themselves at home subcutaneously according to their recommended dosing regimen. Intravenous administration should be completed at a clinic or other medical environment under the supervision of a physician.

10.3 Side Effects The side effects of biologic medications vary. The most frequently reported event with all biologics is skin irritation at the site of injection. Other common adverse reactions may include flu-like symptoms, headache, dizziness, chills, low-grade fever, nausea,

IM: 15 mg injection once a week for 12 weeks

Etarnecept (Enbrel®)

Subcutaneous (SC)

Twice a week 50 mg injection for 3 months; then once a week for maintenance

Infliximab (Remicade®)

Intravenous

Initially: Infusion (over 2–3 h) 5 mg/kg on weeks 0, 2, and 6; then one infusion every 8 weeks for maintenance

Adalimumab (Humira®)

SC

Initial dose of 80 mg; then 40 mg once bi-weekly starting a week after initial dose

Ustekinumab (Stelara)

SC

45 mg (for pts < 200 lbs) at week 0, 4 & q 12 weeks 90 mg (for pts > 200) at week 0, 4 & q 12 weeks

asthenia, myalgia, or arthralgia. Typically, these symptoms are mild and transient. They are most likely to occur after the first two initial treatments and generally do not recur with subsequent doses.

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Overall, biologics are well-tolerated and contrary to the conventional systemic antipsoriatic agents (methotrexate, cyclosporine) they have a limited organ-toxicity profile. Biologics are being used successfully in patients with renal insufficiency or hepatic dysfunction; when indicated they may be preferable to the aforementioned traditional systemic psoriasis treatments. The most serious side effects of biologic therapy are related to their immunosuppressive and immunoregulatory properties.

10.3.1 Infections There is an increased risk of reactivation of latent infections or emergence of new infections associated with tumor necrosing factor (TNF)-a (alpha) inhibition. All the biologics currently used in dermatology contribute to immunosuppression via their depleting or modulation effect on B cells, T-cells, cytokines, or other molecules of the body’s immune mechanism. Upon infection, TNF-a (alpha) plays a key role in the recruitment of defense cells to the site of infection, and in the formation and maintenance of granulomas. Tuberculosis (TB) and other serious opportunistic infections, including histoplasmosis, listeriosis, aspergillosis, toxoplasmosis, coccidioidomycosis, candidiasis, cutaneous Nocardia, and pneumocystosis, have been reported in both clinical research and postmarking surveillance settings.6–8 Physicians must be cautious when prescribing biologics to patients who reside in geographical areas where the aforementioned diseases may be endemic. Additionally, the risk for opportunistic infections increases further more in patients who are receiving one or more immunosuppressant agents, or are HIV positive.

10.3.2 Neurological Disease Development or worsening of nervous system disorders, including demyelinating diseases such as multiple sclerosis, transverse myelitis, seizures, Parkinson’s disease, and optic neuritis, has been documented in patients who were receiving treatment with biologics.8,9 It is suggested that biologic agents be withheld

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from patients who have a history of, or a first degree relative with, a demyelinating disease.

10.3.3 Cardiovascular Disease Higher incidence of mortality and hospitalization for worsening heart failure has been documented in patients with moderate-to-severe CHF (New York Heart Association classes III or IV) who were being treated with TNF-a (alpha) antagonists and, specifically, infliximab, and etarnecept.3,8 Caution should be used when using TNF inhibitors in patients with unstable cardiac dysfunction.

10.3.4 Hepatitis/Hepatic Dysfunction Several clinical studies have demonstrated evidence of hepatic enzymes elevation with use of all of the biologic medications.6,10 These abnormalities are thought to be confounded by comorbid conditions and concomitant use of medications, as nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, or cyclosporine have also been associated with hepatic dysfunction. Autoimmune hepatitis and liver damage is a rare but increasingly recognized serious complication of treatment with the TNF-a (alpha) blocking agent, infliximab. It is noteworthy that a number of cases of liver failure resulting in liver transplantation or death have been reported in patients receiving infliximab.11–13 Signs of severe hepatic reaction may include jaundice, cholestasis, and marked elevation (more than 5 times the upper limit of normal) in liver enzymes. The rest of the biologic medications used in the treatment of psoriasis have more favorable hepatic dysfunction profile which mainly involves a mild increase in liver enzymes. Some reports are emerging regarding fulminant hepatic failure in patients with chronic hepatitis B virus (HBV) infection. HBV reactivation has been reported very rarely in patients with chronic hepatitis B infection receiving a biologic medication.3, 8, 14 This is why serologic screening for viral hepatitis (HBV and hepatitis C virus) is recommended prior to initiation of therapy with biologics. For patients who are

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hepatitis B surface antigen (HBsAg)-positive, prophylaxis with lamivudine or other antiviral agent should be considered. Roux and colleagues evaluated the safety of TNF inhibitors in patients with concurrent chronic viral hepatitis.15 Their retrospective study demonstrated that TNF inhibitors can be given safely in patients with chronic hepatitis B who were receiving lamivudine, and no changes were seen in their serum aminotransferase levels.

10.3.5 Occurrence of Autoantibodies and Autoimmunity The development of antibodies (human antichimeric antibodies, antinuclear antibodies, antidouble stranded DNA antibodies, anticardiolipin, antiphospholipid antibodies) and autoimmune disorders has been associated with TNF-a (alpha) antagonism treatment.7 TNF-a (alpha) instigates its immunosuppressive effect by regulating antigen-presenting cell functions and apoptosis of potentially autoreactive T cells. Therefore, antagonizing TNF and its suppressive effects may lead to the development or unmasking of autoimmune diseases. There are reports of lupus-associated antibodies occurring after administration of biologics.7 Patients may develop positivity for antinuclear antibodies (ANAs), antihistone, and anti-DNA. However, no evidence exists that patients who develop new autoantibodies are at significantly increased risk of developing lupus-like syndrome or lupus erythematosus.6, 7, 16 Although progressive reduction in ANA titers takes place after discontinuation of treatment the majority of patients will remain ANA-positive.17 Furthermore, formation of antibodies against the biologic drug itself is an emerging issue. Autoantibodies formation and autoimmunity appears to be more commonly associated with infliximab therapy, than treatment with etarnecept, and only limited reports exist for adalimumab.7,11,13 Whether these antibodies attenuate the efficacy of the treatment or whether they have no measurable effect on the activity of the agent has yet to be determined.

10.3.6 Blood Disorders Rare reports of patients developing pancytopenia and aplastic anemia on infliximab and etarnecept have been

P. Mitropoulos and R. A. Norman

described. Leucopenia and thrombocytopenia, although not common, are recognized side effects of TNFblocking therapy.3,18 The exact mechanism of cytopenias as a result of TNF-block therapy is still unclear.

10.3.7 Malignancy The risk for developing malignancies (non-Hodgkin lymphoma, melanoma, and nonmelanoma skin cancer) while under therapy with biologic medications has been investigated. However, no compelling evidence exists that biologics are directly related to an increase in the rate of malignancies.3,19 Specifically, in patients with psoriasis, no clear findings identify whether lymphoma risk is associated with disease severity, treatment, other unidentified factors, or a combination of factors.20 Patients who have been exposed to more than 1,000 J cumulative dosage of psoralen and UVA (PUVA) (more than 200 treatments) may be at increased risk for cutaneous malignancies.21 The risk is greatest for squamous cell carcinomas, but melanoma is not excluded. Nonmelanoma skin cancer is not an absolute contraindication to biologic therapy. Nevertheless, because these patients represent a particular, high-risk group, caution is warranted when considering biologics. The known excess of malignancies in immunosuppressed populations, and the known immunosuppressive effects of the biologic agents do, however, provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to confirm a clear association. Meanwhile, current practice recommendation should probably not go any further than awareness that certain malignancies have been associated with biologics, and alertness for any suspicious symptoms should be maintained.

10.3.8 Anaphylaxis/Allergic Reactions Formation of antibodies against the biologic drug itself has been reported. More specifically, antibodies against infliximab have been associated with immediate as  well as delayed hypersensitivity reactions.7,8,22 Symptoms may range from mild urticaria and pruritus to more severe anaphylaxis, hypotension, and shock. A

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reaction may develop during or within 2  h of infliximab infusion, and it is most likely to occur during the first and second infusion. Reinstitution of infliximab after a prolonged period without treatment (more than 16 weeks) can cause a delayed hypersensitivity or serum-like sickness reaction. Symptoms of delayed reaction may include muscle or joint pain with fever or rash, itching, swelling of the hands, lips or face, difficulty swallowing, nettle-type rash, sore throat, and headache. There has been promising success in decreasing the risk of infusion reactions with daily low dose of corticosteroids.22,23 In addition, diphenhydramine 25–50 mg IV 1.5 h prior to infusion is commonly practiced. All patients receiving infliximab infusions must be medically observed for 1–2  h following the infusion in case a reaction develops. Individuals who are sensitive to latex should be careful not to handle the rubber cover in the single prefilled autoinjectors of adalimumab (Humira) and etarnecept (Enbrel).4,24

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examination and detailed personal and family medical history should be an essential part of all patient encounters. Even for a patient with a “clean bill of health,” the physician should offer the option of treatment with biologics to those patients who they feel will be compliant with the dosing schedule and with follow-up visits, and will comprehend how to self-assess and report the onset of signs or symptoms that may signal the onset of an adverse event.

10.4.1 Treatment Exclusion Criteria Biologics are generally not indicated for patients who meet one or more of the following criteria: • • • • • •

10.3.9 Pregnancy/Breast-Feeding All the biologic medications currently in use in dermatology are pregnancy category B (no human studies conducted, but no adverse effects have been noted in animal studies). An exception to this is efalizumab which has been labeled category C (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans). Since no human data is available, initiation of biologic therapy should be avoided in women who are pregnant, planning for pregnancy, or currently breast-feeding. For women of reproductive age, efficient contraception methods should be suggested and implemented prior to therapy.

10.4 Treatment Risk Reduction Strategies Not all patients are suitable candidates for treatment with a biologic agent. Appropriate patient selection is key in order to achieve treatment success and avert potential unfavorable outcomes. A thorough physical

• • • •

Active TB Moderate to severe CHF History of demyelinating disease or optic neuritis Hepatitis B or C positivity HIV positivity Active infections (i.e., chronic leg ulcers, persistent or recurring chest infections, indwelling urinary catheter) Septic arthritis or sepsis of prosthetic joint within last 12 months Pregnancy, planning to become pregnant, or currently breast-feeding Premalignant states Patients who have had extensive immunosuppressant therapy or prolonged PUVA treatment

10.4.2 Baseline Screening Tests Specific, guidelines regarding objective screening and monitoring prior to and during treatment with biologics have not been established. In accordance with good clinical practice, baseline and follow-up laboratory tests and imaging studies ought to be offered to all patients when considering therapy with a biologic agent. Initial laboratory testing and subsequent monitoring should be determined on an individual basis according to patient, region of practice, and medication to be utilized. The United States FDA only mandates TB testing prior to initiating treatment with adalimumab and

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infliximab. However, because of the increased risk of granulomatous disease with all immunoregulatory medications it is prudent to offer TB screening (tuberculin purified protein derivative [PPD] and/or a chest X-ray) to all patients who are being considered for treatment. Table 10.3 lists the current FDA-mandated laboratory and imaging testing according to biologic agent. A number of patients may already be receiving medications for the same or different medical condition. A psoriasis patient may already be on an immunosuppressant medication, such as methotrexate. In this case, if biologic therapy is considered, a stricter monitoring strategy may be implemented. The recommended baseline studies shown in Table  10.3 may be used as a guideline. Ultimately, it should be each patient’s medical history, family history, social history, physical examination, and individualized risk assessment that directs the appropriate screening and monitoring.

10.4.3 Periodic Monitoring Close, routine follow-up physical examination and laboratory testing, although not FDA-mandated, are reasonable in order to evaluate the safety of the biologic drug the patient is receiving along with its therapeutic efficacy.

10.4.3.1 Physical Examination Patient health status should be monitored regularly and any changes or pertinent positives in the review of systems need to be identified and addressed promptly, with special attention to: • Symptoms and signs of infection • Symptoms and signs of CHF • Symptoms and signs of demyelinating disease

10.4.3.2 Laboratory Tests Many patients do well and feel fine while on biologics and may not see the need for frequent follow-up visits and tests. Regular reevaluation, however, is strongly recommended as biologics are not benign medications. Monthly evaluations are prudent during the initial months of treatment. If the progression of treatment is satisfactory then patient and physician may agree to decrease frequency of follow-up to every 3 months and, subsequently, to every 6 months. At a minimum, monitoring tests should include: • Complete blood count (CBC) • Liver function tests (LFT) • Renal function tests (RFT)

Table 10.3  Guidelines for screening and monitoring studies according to biologic agent Drug FDA required Recommended (non-FDA-mandated) baseline screening Alefacept (Amevive®)

Baseline CD4 level; monitor biweekly. Withhold treatment for at least 1 month if CD4 < 250 cells/mL

PPD/Chest X-ray, complete blood count (CBC) with differential, liver function tests (LFT), renal function tests (RFT), b-hcg, HIV

Etarnecept (Enbrel®)

None mandated

PPD/Chest X-ray, RFT, LFT, Hepatitis B and C serology, b-hcg, HIV

Infliximab (Remicade®)

PPD and/or Chest X-ray for latent TB screening

CBC, RFT, LFT, Hepatitis B and C serology, b-hcg, HIV

Adalimumab (Humira®)

PPD and/or Chest X-ray for latent TB screening

CBC, RFT, LFT, Hepatitis B and C serology, b-hcg, HIV

Ustekinumab (Stelara)

PPD and/or Chest X-ray for latent TB screening

CBC, RFT, LFT, Hepatitis B and C serology, b-hcg, HIV

Recommended (non-FDA-mandated) periodic monitoring CBC, LFT, RFT, and clinical evaluation every 6 months

CBC, LFT, RFT, and clinical evaluation every 6 months

10  Biologics

10.4.4 Tuberculosis Risk Before initiating biologic therapy, all patients must have their TB risk assessed.25 This should include a history of any prior TB infection and treatment, BCG (bacillus Calmette Guérin) vaccination, a thorough clinical examination, and a chest X-ray. The chest X-ray needs to be taken as close as possible to the planned start date of the biologic therapy.25 A PPD test is advised. However, one should keep in mind that the accuracy and reliability of the tuberculin skin test is significantly affected by immunosuppressive therapy. If the patient is currently on immunosuppressive medications, such as methotrexate or cyclosporine, the PPD test should be regarded as unreliable. The same holds true for patients who have stopped immunosuppressive therapy for a period of less than 3 months from the test. Referral to a pulmonologist or TB specialist is warranted for individuals with a positive PPD, abnormal chest X-ray, or history of TB infection.25 If the patient is found to have active TB infection or have had inadequate treatment of past infection, then appropriate TB treatment should be commenced. Initiating biologic therapy in this case is contraindicated. If the patient is found to have had adequate treatment of a previous TB infection, then biologic therapy may be initiated. However, a repeat chest X-ray 3 month after the initiation of therapy should be acquired to help rule out TB reoccurrence.25 For patients with normal chest X-ray, negative PPD (less than 5  mm induration), and no history of TB, therapy with biologic medications may be initiated.

10.4.5 Vaccinations Seasonal influenza vaccine is not mandated but recommended and commonly administered to patients who are being treated with biologics. The exception to this is the intranasal FluMist vaccine which is a live, attenuated influenza virus vaccination product and its administration to patients who are on immunosuppressants, including biologics, is contraindicated.5 Several other live, attenuated vaccines currently licensed for use and distribution in several countries, including the United States are also contraindicated in patients who are receiving biologic therapy. These include:

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• • • • • • • •

Measles, mumps, and rubella (MMR) BCG Poliomyelitis (oral Sabin vaccine) Yellow fever Typhoid (oral) Varicella (Varivax) Zoster (Zostavax) Smallpox (Vaccinia)

If for any reason a patient requires a live vaccination while on therapy with a biologic agent, it would be prudent that therapy be stopped at least 2 weeks prior to immunization and, ideally, not be resumed until at least 4 weeks after.

10.4.6 Withdrawal of Therapy As with any medication, treatment should be promptly withdrawn in the event of an adverse event. According to the circumstances, withdrawal may be temporary or permanent. Table 10.4 lists some of the reasons therapy with a biologic medication should be interrupted: • If a patient develops lupus-like symptoms, blood tests for antinuclear antibodies and antidoublestranded DNA antibodies should be repeated before considering any further treatment. • If disease response is unsatisfactory after 3–6 months of treatment, switching to a different biologic agent may be appropriate. Failure of one agent to produce results does not equate failure of the medication class as a whole.26 • A high index of suspicion for infection should be kept at all times and appropriate screening should be undertaken if required. Table 10.4  Indications for withdrawal of biologic therapy Permanent withdrawal Temporary withdrawal of of treatment treatment Malignancy Severe drug-related toxicity Drug-associated allergic reaction

Pregnancy

Neurological symptoms

Need for surgical procedure

Congestive heart failure (CHF)

Severe intercurrent infection

Lupus-like symptoms

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• Patient should be educated to promptly report any neurologic events including visual changes. • Therapy should be discontinued 2–4 weeks prior to any major surgical procedure and not resume until at least 4 weeks after. • Effective contraception in women of reproductive age and avoidance of breast-feeding while on biologics is warranted.

10.5 Combination Therapy/ Concomitant Medications Hepatotoxicity and nephrotoxicity have been associated with the most commonly used systemic psoriasis treatment agents, methotrexate and cyclosporine. Combining these traditional agents with biologic therapy may achieve not only improved therapeutic efficacy but also a decrease in the risk of end organ toxicity. The concern of combination therapy leading to increased immunosuppression and its consequences has been addressed. However, there are a number of case reports in literature of successful use of biologic agents concurrently with methotrexate. Additionally, phototherapy is generally considered safe to implement concomitantly with biologic agents. To date, no long-term clinical studies on quantifying risks and benefits of combination therapy exist, and therefore combination therapy should only be cautiously recommended. As our knowledge and experience with this class of medication increases, the intricacies and potential of combination therapy will continue to be refined.

10.6 Pediatrics Treatment of psoriasis in children is challenging. Trials of biologic agents for managing psoriasis in children are being conducted but information is currently limited and the long-term safety profile still being evaluated. To date, none of the biologics in use in dermatology are FDA-approved for treating psoriasis in individuals less than 18 years of age. Etarnecept has been approved for treatment of juvenile rheumatoid arthritis (JRA) for children as young as 4 years of age. Both psoriasis and rheumatoid arthritis share

P. Mitropoulos and R. A. Norman

similarities in their pathogenesis at the molecular level. The fact that a biologic agent has succeeded in studies and gained approval for use in children with JRA foreshadows potential future approval for the use of these agents in children with psoriasis and/or psoriatic arthritis.

10.7 Elderly The elderly (65 years of age or older) take more medications (prescription and nonprescription) than any other age group. The risk of side effects and drug–drug interaction increases proportionally with the number of medications. Additionally, the more medications a patient is asked to take the higher the risk of nonadherence. One should also keep in mind that as the body ages the pharmacokinetics and pharmacodynamics of drugs are also altered. However, there are no studies to date that indicate any differences in the safety or efficacy of biologic agents between older and younger patients. Certain additional practical considerations should be implemented prior to initiating biologic therapy to treat psoriasis in an older individual: • Obtain complete medication history that includes prescription, nonprescription, and herbs. Patient should be instructed to bring medications in at every visit. • Discontinue any medications if the benefit is marginal or if a nonpharmacologic alternative exists. • Be sure the patient understands how to take the medication. If necessary write and provide clear instructions for the patient and anyone who is assisting in treatment. • Be sure the patient understands the potential risks and side effects of each drug taken. • In-home support and supervision should be encouraged. • Because of the increased risk of infections in the  elderly a higher suspicion index should be maintained. • Consider the cost of the drug. Safe medication use in the elderly requires vigilance and awareness from everyone involved in the patient’s treatment. Everyone should be alert for any subtle changes that may signal a potential adverse event. It is especially important to keep track of all maintenance drugs and ensure they are taken properly. The patient must

10  Biologics

u­ nderstand and feel comfortable in directing all medical questions and concerns promptly to their physician.

References   1. Alexis AF, Strober BE. Off-label dermatologic uses of antiTNF-a therapies. J Cutan Med Surg. 2005;9:296–302   2. Biogen Inc. Amevive (alefacept), package insert. 2008   3. Desai SB, Furst DE. Problems encountered during antitumour necrosis factor therapy. Best Pract Res Clin Rheumatol. 2006;20(4):757–790   4. Immunex Corporation. Enbrel (etarnecept), package insert. 2008   5. National Psoriasis Foundation. Flu vaccines warranted for psoriasis patients. 2004. At: www.psoriasis.org; 2008 Accessed 15.01.08   6. Jackson Mark J. TNF-a inhibitors. Dermatol Ther. 2007; 20(4):251–264   7. Rott S, Mrowietz U. Recent developments in the use of biologics in psoriasis and autoimmune disorders. The role of antibodies. BMJ. 2005;330:716–720   8. Tandon VR, Mahajan A, Khajuria V, Kapoor V. Biologics and challenges ahead for the physician. Indian Acad Clin Med. 2006;7(4):334–343   9. Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurological events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis. Arthritis Rheum. 2001;44:1977–1983 10. Suissa S, Ernst P, Hudson M, et al Newer disease modifying antirheumatic drugs and the risk of serious hepatic adverse events in patients with rheumatoid arthritis. Am J Med. 2004;117(2):87–92 11. Centocor. Remicade (infliximab), package insert. 2007 12. Tobon GJ, Cañas C, Jaller JJ, et  al Serious liver disease induced by infliximab. Clin Rheumatol. 2007;26(4):578–581 13. United States Food and Drug Administration. Safety alerts for drugs, biologics medical devices, and dietary supplements. Remicade (infliximab). Washington, DC: FDA, 2004. At: http://www.fda.gov/medwatch/SAFETY/2004/safety04. htm#Remicade2; 2008 Accessed 2.02.08

101 14. Thiele DL. Is anti-TNF therapy safe in patients with rheumatic disease who also have concurrent B or C chronic hepatitis? Nat Clin Pract Rheumatol. 2007;3:130–131 15. Roux CH, Brocq O, Breuil V, et  al Safety of anti-TNF-a therapy in rheumatoid arthritis and spondylarthropathies with concurrent B or C chronic hepatitis. Rheumatology. 2006;45(10):1294–1297 16. Eriksson C, Engstrand S, Sunddqvist KG, RantapaaDahlqvist S. Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF alpha. Ann Rheum Dis. 2005;64:403–407 17. Vermeire S, Noman M, Van Assche G, et al Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn’s disease: a prospective cohort study. Gastroenterology. 2003;125(1):32–39 18. Pathare SK, Heycock C, Hamilton J. TNFa blocker-induced thrombocytopenia. Rheumatology. 2006;45(10):1313–1314 19. Wolfe F, Michaud K. The effect of methotrexate and ­anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19, 562 patients during 89, 710 person-years of observation. Arthritis Rheum. 2007;56: 1433–1439 20. Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol. 2003;139(11):1425–1429 21. Lindelöf B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer: a large-scale epidemiological study. Lancet. 1991;338 (8759):91–93 22. Baert F, De Vos M, Louis M, et al. Immunogenicity of infliximab: how to handle the problem? Acta Gastroenterol Belg. 2007;70(2):163–170 23. Augustsson J, Eksborg S, Ernestam S, et al Low-dose glucocorticoid therapy decreases risk for treatment-limiting infusion reaction to infliximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2007;66:1462–1466 24. Abbot Laboratories. Humira (adalimumab), package insert. 2008 25. Ledingham J, Wilkinson C, Deighton C. British thoracic society (BTS) recommendations for assessing risk and managing tuberculosis in patients due to start anti-TNF-a treatments. Rheumatology. 2005;44(10):1205–1206 26. Menter A, Hamilton TK, Toth DP, et al Transitioning patients from efalizumab to alternate psoriasis therapies: findings from an open-label, multicenter, Phase IIIb study. Int J Dermatol. 2007;46(6):637–648

Occupational Dermatology

11

Athena Theodosatos and Robert Haight

11.1 Introduction Occupational medicine specializes in treating patients with injuries and illnesses from exposures in the workplace. People often encounter very harsh environments in the workplace. Although today’s workplace in general is considerably tamer than that of the past, skin problems remain a serious issue.1 The bureau of labor statistics (BLS) calculates the frequency of work-related injuries and illnesses for private industry. According to BLS, skin diseases accounted for 15.6% of the nonfatal illnesses in private industry in 2004.2 This is hardly insignificant. Many occupational medicine physicians rarely see skin disorders. This might be because occupational skin problems are from specific exposures which are associated with specific industries. These industries do not have a uniform geographic distribution.2

friction, electricity, and ionizing radiation can, under some circumstances, be occupational. Water can even cause skin lesions under the right conditions. Toxins and infectious agents are found in some workplaces. The classic occupational skin diseases were chloracne and chrome ulcers. Those diseases are rare in the developed world today. Less acute skin lesions such as hyperpigmentation, leukoderma, alopecia, and lichenification can be occupational.1–3 Other dermatoses are the major differential to consider when evaluating occupational skin disorders. Any nondermatologist who deals with occupational skin lesions must be able to differentiate them from dermatitis and the other common nonwork-related diagnoses. This means that the physician needs to be able recognize and understand them.

11.2.1 Relevant History 11.2 Diagnosis Occupational dermatology includes a broad spectrum of disorders but the majority are acute and chronic contact dermatitis. The most commonly cited are irritant contact dermatitis and allergic contact dermatitis. Since sunlight can be an occupational exposure, skin disorders caused by the sun can therefore be considered work-related for some jobs. Likewise, skin injuries from other physical agents like hot, cold, pressure, A. Theodosatos (*) Department of Family Medicine, Florida Hospital, Winter Park, FL, USA e-mail: [email protected]

Occupational skin disorders require a detailed history of the skin findings and a work history. The basic questions to consider when evaluating an occupational skin disorder include: • What does the patient do for a living? • How long has the patient been doing this job? (the position) • What is the patient exposed to at work? (Chemicals? Physical agents?) • What personal protective equipment does the patient use at work? • Has there been any change to any of the processes at work? • Do other people at work have similar skin conditions? • What is the patient exposed to outside of work?

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_11, © Springer-Verlag London Limited 2010

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• Has the patient had a work-related skin disorder in the past? • Has the patient had any exposure-related skin disorders? • Does the patient have any nonwork-related skin disorders? • Does the patient have any chronic medical conditions? • Does the patient have any allergies or a history of atopy? • Does the patient take any medications? Material safety data sheet (MSDS) is a brief description of a chemicals physical properties and health effects.1, 2 Data that should be included are: chemical identity; hazardous ingredients; physical and chemical characteristics; fire and exposure hazard data; reactivity data; health hazards; precautions for safe handling and use; and control measures. Although the Hazardous Communication Standard (29 CFR 1910.1200) requires employers to have an MSDS on all of the chemicals to which workers might be exposed, they may be little help to the medical professional except for providing the names of the chemicals to which an employee was exposed.1–3

11.3 Worker’s Compensation Each state has a different worker’s compensation system. Each of these systems has so many idiosyncrasies that dealing with them has become a major part of the practice of occupational medicine. Not surprisingly, the willingness of other specialists to deal with these systems is related to how the reimbursement compares to that of other payers and how difficult the rules are to deal with.4 Part of the extra awkwardness of a worker’s compensation system comes from the extra dimension of work-relatedness. Causation is a topic that is unique to occupational medicine. To thrive in the realm of occupational medicine, specialists need to have some understanding of causation.4

11.3.1 Assessing Causation Causation is often a matter of major contention. The worker’s compensation system is a compromise. As with most compromises, neither party is satisfied. The employers and the insurance companies would prefer that an injury not be labeled as work-related. The injured

A. Theodosatos and R. Haight

worker has an interest in an occupational etiology. Often, not only is payment for the injury on the line but disability compensation is at stake. This is many times more than enough money to inspire litigation. Highly contested cases might require an independent medical examination (IME). In IMEs, the physician is approached as a consultant to answer specific questions. Causation is a very common question. If a dermatologist or another specialist wants to get some of IME business, the ability to discuss causation intelligently becomes important.4 In particular, hand dermatitis and nail disorders require careful evaluation since many of them may be workrelated or nonwork-related.5 Contact dermatitis is the most common occupational skin disorder.3 Mathias suggested that the presence of four of seven criteria favor an occupational dermatitis4: 1. Is the clinical appearance consistent with contact dermatitis? 2. Are there workplace exposures to potential cutaneous irritants or allergens? 3. Is the anatomic distribution of dermatitis consistent with cutaneous exposure in relation to job task? 4. Is the temporal relationship between exposure and onset consistent with contact dermatitis? 5. Are nonoccupational exposures excluded as probable causes? 6. Does dermatitis improve away from work exposure to the suspected irritant or allergen? 7. Do patch or provocation test identify a probable causal agent? Mathias also suggested that a preexisting dermatitis can probably be said to be aggravated if new dermatitis has occurred on a skin surface that was not previously affected or the dermatitis has become more severe in an area that was already affected by the preexisting dermatitis. If an aggravation has developed, the above seven criteria can be used to determine if the aggravation is due to a superimposed occupational dermatitis.4

11.3.2 Determination of Impairment When a worker’s compensation patient reaches the point of maximum medical improvement, the physician determines the degree of permanent impairment. The level of impairment is a frequent point of contention

11  Occupational Dermatology

because it affects the amount of compensation. The American Medical Association publishes the Guides to the Evaluation of Permanent Impairment to help to standardize the determination of impairment ratings. A number of states have developed their own guides to calculating impairment ratings.1,4 There is a chapter that provides criteria for rating permanent impairment due to skin disorders. There are five classes of impairment due to skin disease with impairment ratings ranging from 0 to 95%. The class of impairment is determined by whether the signs and symptoms are present intermittently or constantly, if there is limitation of the activities of daily living, and if they require intermittent or constant treatment.6

11.4 Phototoxic Reactions and Photoallergic Reactions A phototoxic reaction occurs when a chemical forms free radicals by reacting with ultraviolet light. Classically, phototoxic reactions occur in workers that are exposed to tars. Photoallergic reactions occur when an allergen is produced from an interaction of a chemical with light. Photosensitivity can refer to phototoxic or photoallergic responses. Either form of photosensitivity requires that both the chemical and the proper wavelength of light are present. These reactions can occur following topical exposure or an internal dose.7

11.5 Occupational Acne Folliculitis is an inflammation of the hair follicles. It may be caused by irritants or infections. The folliculitis is seen in the areas that are exposed to the irritant chemical. Acne is most commonly seen with exposures to oils and tars.1, 3 Chloracne is a specific folliculitis caused by halogenated aromatic hydrocarbons,1 most often polychlorinated biphenyls (PCBs). Small, straw-colored cysts typically occur on the sides of the forehead, around the lateral aspects of the eyelids, and behind the ears. The neck, groin, chest, back, and buttocks may also be involved. The nose is rarely involved. While an ordinary folliculitis normally resolves in a week or less, chloracne may persist for decades.1 This is not surprising because the serum half-life of highly chlorinated PCBs is 15 years.1

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11.6 Pigment Changes Some authors differentiate occupational vitiligo from leukoderma. Both are acquired depigmentation disorders with selective destruction of melanocytes. A number of chemicals are implicated in occupational vitiligo from leukoderma. The major difference is that contact vitiligo may spread beyond the areas of contact while leukoderma remains confined to the areas of contact.8 Hypopigmentation can be a nonspecific consequence of contact dermatitis or burns. Hyperpigmentation is caused by an increase in melanin production. This most often occurs with coal tar pitch, psoralens, heavy metals, and ionizing and nonionizing radiation.8

11.7 Occupational Skin Cancers Occupational exposures are seldom considered for skin cancers. It is estimated that occupational exposures account for 2% or less of cancers.9 Cancer may be caused by occupational exposure to chemical carcinogens such as polycyclic aromatic hydrocarbons or radiation from exposure to the sun or X-rays. Skin cancers can also arise from scarring of burns acquired in the workplace.10 Carcinogens to be considered in the indoor air include: tobacco smoke, radon, and pollutants from cooking and heating.9

11.8 Occupational Skin Infections Worker can be exposed to a number of organisms that can result in a skin infection. The organisms can often be predicted based on the occupation and the exposure (Table 11.1).1, 3

11.9 Skin Notations The absorption of chemicals through the skin depends on a number of factors. These include: solute concentration, exposure time, the amount of skin surface exposed, the anatomical site of the exposed skin, and the hydrophobicity of the chemical.1

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Table 11.1  Occupational exposures and infectious agents Exposure Infectious agent Any skin trauma

Staphylococcus, Streptococcus

Fresh- or saltwater fish, crustacea, poultry

Erysipelothrix rhusiopathiae (gram-positive rod)

Wet work

Candida

Soil, foliage

Sporotrichosis

Fish tanks

Mycobacterium marinum

Healthcare

Scabies

Healthcare (puncture)

Herpes simplex

Sheep, goats

Orf

11.10 Specific Industries and Exposures Since solar radiation can be an occupational exposure, photoaging, skin cancer, phototoxic, and photoallergic reactions can be attributed to occupational skin disease.7 Segmental vibration can result in Raynaud’s phenomenon. Chromium (VI) is a powerful skin irritant. Although rarely seen today in the developed world, exposure can cause painful ulcers known as chrome holes.1, 3, 7

11.11 Occupational Dermatitis About 15% of all workplace injuries are due to dermatoses.11 It is therefore an important area of medicine for physicians and healthcare workers. Morbidity associated with these occupational exposures is significantly high in the working population and the cost of care is continually rising. The ultimate goal should be to enable healthcare workers to be able to assess risk factors and develop interventions that will reduce jobrelated skin injury and disease.11 Occupational contact dermatitis is an inflammatory skin condition that can develop with exposure to various agents in the workplace. The two most common forms are irritant and allergic contact dermatitis.12 It is important to differentiate between the two forms because, although treatment may be the same, diagnosis and prevention strategies differ. Irritant dermatitis is a cutaneous inflammatory reaction that results from a direct cytotoxic effect of a chemical or physical

agent. Allergic contact dermatitis is an acquired sensitivity to different substances that produce inflammatory reactions in those who have been previously sensitized to the allergen.12, 13 Approximately 80% of the cases of contact dermatitis have been shown to be due to chemical irritants and about 20% have been shown to be due to allergic reactions.11 Some new data suggest that allergic contact dermatitis may actually be more prevalent than irritant dermatitis.13 The 5-year study indicated an under-diagnosis of allergic dermatitis based on the under-utilization of patch testing. Comparison studies in other countries showed higher rates of diagnosis of allergic contact dermatitis in multiple studies. Results suggest the need for a wider array of allergens to be used in patch testing and also encourage a stronger emphasis on performing patch testing.13 The importance of proper patch testing and patience needed by the physician and patient in order to diagnosis the correct condition is also underscored.13

11.11.1 Causes The skin initially becomes red and may burn or itch when it comes in contact with an irritating or sensitizing substance. After the initial contact cutaneous erythema sets in, small vesicles and papules can develop. Later scales and crusts form. The most commonly affected areas are the hands and forearms. Although the most commonly affected areas are the exposed regions of the body, if the offending agent is a chemical, it has the ability to soak through the clothing and affect the normally unexposed areas such as the chest, back, and upper thighs. If the causative agent does not remain in contact with the skin, the rash will disappear. Sometimes it may take a few weeks or longer for complete resolution of the skin reaction. One factor that significantly increases the time it takes for the dermatitis to resolve is prolonged length of exposure. Prolonged or chronic exposure leads to hyperpigmentation, fissure formation, and often, secondary infections. Other factors that increase resolution time include increased age, due to the altered skin response that occurs as our skin ages, and pigmentation; darker skin burning more easily than lighter. Genetic predisposition and environmental factors such as extremes in temperature may also lead to lengthy recovery times.11–13

11  Occupational Dermatology

Women have been noted to be more likely to develop occupational hand dermatitis than men. This may be due to occupations that many women have that increase their risk for exposure to irritating chemicals and other substances. An example may be kitchen work and other household cleaning jobs that women tend to do more than men.14, 15 The presence of atopic dermatitis or allergic contact dermatitis has been associated with more severe outcomes. Lower socioeconomic status has been postulated as a possible risk factor for development of occupational contact dermatitis.15 Prolonged sick leave and frequent change of jobs are common in individuals with a chronic job-related skin dermatosis.16 Almost any substance has the ability to cause a skin reaction; the most frequently encountered ones will be mentioned here. Irritant dermatitis is most often encountered with use of scented soaps and detergents, other cleaning agents, and many food varieties. Allergic contact dermatitis is often caused by plants, dyes, rubber additives, nickel, and plastic resins. Certain occupations may increase risk of exposure and development of contact dermatitis. Agriculture and manufacturing jobs have been shown by the BLS to be the highest affected occupations.2 Construction workers have a substantial risk of developing irritant or allergic dermatitis. Within construction, tile workers and terrazzo workers have a strikingly high incidence of occupational skin disease.11, 12 Hairdressers also have a highrisk of developing hand dermatitis; 50% have been shown to develop it within the first 3 years of beginning work.17 Massage therapists are at increased risk of developing hand dermatitis, mainly due to the use of aromatherapy products in massage oils. Their patients are also at increased risk for occupational dermatitis from the sensitizing effects of massage oils.18 An uncommon but interesting cause of occupational dermatosis has been documented in some hairdressers and dog groomers.19 In these cases, the affected individuals developed an inflammatory response to penetration of hair fragments into the interdigital spaces of the hands. The affected individuals had a recurrence of erythema, papules, and draining pustules in the interdigital web spaces and went on to require foreign body removal of the hairs. Eventually, they were diagnosed with trichogranuloma, also known as a pilonidal sinus. Antibiotics are generally resistant in this condition, therefore prevention is key. The use of gloves and prompt removal of any embedded hairs is encouraged. This condition, although rare, is important to be aware

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of because multiple sinuses can form leading to fistula formation and further morbidity.19 The food industry is a known source of exposure to various agents responsible for dermatological problems. The seafood processing centers have been reported to be a cause of dermatitis in up to 78% of workers in a study done in South Africa. The study reveals a major cause for contact dermatitis development to be unprotected skin exposure, due to the lack of protective equipment.20 The majority of seafood industry related skin conditions were found to be due to particular irritants such as spices, onions, garlic, and vinegar.20 Antimicrobial allergy from plastic gloves is a rare cause of allergic contact dermatitis. It has been reported that some people have had hand dermatitis developing after using gloves that were manufactured with benzisothiazolinone, which is a biocide used in the manufacture of disposable polyvinyl chloride (PVC) gloves. It may benefit patients to have patch testing done with benzisothiazolinone if they experience a skin reaction after using PVC gloves.21 Latex allergies have been increasing drastically in the United States. Latex is a known contributor to morbidity and mortality in the hospital and the only way to improve the adverse reactions associated with latex is education of the causes, signs and symptoms, and prevention measures. Avoidance is the only way to prevent allergic reactivation but proper diagnosis via patch testing and serological assays are also very important in making sure the proper diagnosis was made.22 Latex gloves are the primary barrier used in healthcare settings for protection against infection. Natural latex is produced from the Havea brasiliensis tree.23 A coagulation process occurs after the liquid is collected from the tree and mixed with other chemicals. The demand for latex gloves has been growing, resulting in less refined production procedures. Latex allergies may occur from a delayed hypersensitivity or an immediate hypersensitivity reaction. If symptoms develop within 30 min, the reaction is immediate and skin findings such as erythema and vesicle formation develop. This reaction is due to the proteins in the latex. Experts believe that the change in the manufacturing process that increased the natural rubber latex proteins has been a huge factor in the development of allergic reactions.22, 23 Other contributing factors include better awareness and universal precautions leading to increased glove use.

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The most severe, immediate allergic reaction to natural rubber latex proteins is an IgE-mediated (type 1) hypersensitivity.24, 25 Once sensitization occurs the next exposure will lead to a more serious reaction. Despite the increased recognition of latex rubber allergies, powder-free gloves and patient education has led to a decrease in the number of latex allergies overall.26

11.11.2 Patch Testing The patch test can help to identify the offending agent in a patient with contact dermatitis. The role of a suspected material as an inciting agent can be supported by the observation of an inflammatory response after it is applied to an unaffected area of skin. The patch test is performed by applying solids, liquids, or powders to the back under metallic disks or in a hydrogel suspension.27 The procedures are standardized in respect to the concentration of antigen, type of vehicle, character of the vehicle, and the testing and interpretation procedure. The Finn chamber test uses aluminum cups, which are affixed with polyacrylate adhesive tape.28 The True test uses strips of tape with measured amounts of antigen in hydrophilic gel film on 9 × 9 mm patches.29 Standardized concentrations of chemicals are applied to the back in vertical rows and covered with hypoallergenic tape. The patch test remains in place for 48 h. In occupational medicine it is important to determine what materials will be informative based on the history and physical examination. The patch test should never be performed with unknown exposure chemicals that the employee might bring with him. Simply using a standard panel may not provide the necessary information. For instance, in a study where the number of antigens was increased to 49, an additional 12.4% of the patients were defined as allergic.1,27–29 In occupational medicine, the potential for a fruitless result is increased by the fact that there are more exposures that may not be recognized by the primary care physician. If done correctly, the patch test can distinguish an irritant from an allergen. This is an issue because many allergens are also irritants. To do this it is important to use a concentration of the agent that will usually only cause a reaction in sensitized patients. The assumption is that patients who are allergic will react against the agent at a concentration below that at which an irritant

A. Theodosatos and R. Haight

reaction will be observed. Using the proper dilution and understanding the mechanisms of the reactions is the key.27 The exposed area is examined at the time that the test is removed and again 24–72 h later. The reactions are quantified: a weak positive reaction (+) is defined by erythema, infiltration, and discrete papules. A strong positive reaction (++) is defined by erythema, infiltration, papules, and discrete vesicles. An extreme positive reaction (+++) is defined by coalescing vesicles or bullae. A patient that has an extreme reaction will be capable of reacting to a lower concentration of antigen than a patient with a 1+ reaction. Interpreting the skin reactions is a skill which must be developed through experience. If the intensity of the reaction increases between 24 and 48 h, this supports an allergic reaction; a decrease of intensity favors an irritant reaction.27–29

11.11.2.1 TRUE Test The 24 antigen patches used in the TRUE test are listed in Table  11.2.27 Wood alcohol is found in cosmetics, soaps, and topical medications. Potassium dichromate may cause a reaction in patients who are allergic to cement, tanned leather, welding fumes, cutting oils, antirust paints, or other industrial chemicals. Colophony is a resin that is found in cosmetics, adhesives, and industrial and household products. Parabens are used as preservatives in a number of topical preparations. Balsam of Peru is found in cosmetics, topical medications, and foods. Ethylenediamine dihydrochloride may cause a reaction in patients who are allergic to topical medications, eye drops, anticorrosive agents, or industrial solvents. Cobalt is found in cement, metal plated objects, and paints. The p-tert-butylphenol formaldehyde resin reacts in patients who are allergic to waterproof glues, bonded leather, construction materials, paper, or fabrics. Epoxy resins are found in two-part adhesives, surface coatings, and paints. The carba mix may react in individuals who are allergic to rubber products, leather glues, pesticides, vinyl soaps, or disinfectants. Patients that are allergic to preservatives in cosmetics, skin products, polishes, or cleaners may react to quaterium-15. Patients that are allergic to rubber products, adhesives, flea sprays or powders, or film emulsion may react to mercaptobenzothiazole.

11  Occupational Dermatology Table 11.2  Antigen patches used in the true test Nickel sulphate

109 Table 11.3  Rule of nines Body area

Total body surface area (%)

Wood alcohol

Each upper limb

9

Neomycin sulphate

Each lower limb

18

Potassium dichromate

Anterior and posterior trunk

18 anterior, 18 posterior

Caine mix

Head and neck

9

Fragrance mix

Perineum and genitalia

1

Colophony Paraben mix Negative control Balsam of Peru Ethylenediamine dihyrochloride Cobalt dichloride p-tert-Butylphenol formaldehyde resin Epoxy resin Carba mix Black rubber mix Cl+Me- Isothiazolinone Quaternium-15 Mercaptobenzenzothiazole p-Phenylenediamine Formaldehyde Mercapto mix

each side of the patient’s upper back approximately 5  cm from the midline. Cleaning with potential irritants is unnecessary and may interfere with the test. The test is removed 48 h later. The reactions are interpreted at 72–96 h after the application of the test. The reactions are interpreted as shown in Table 11.3. The more positive the test the more likely is that it represents a true allergic reaction. The patient should be instructed to return if a late reaction occurs 4–5 days after the application. This is most often seen with p-phenylenediamine.1,27–29 Application of the test during an extensive ongoing dermatitis may intensify the reaction. The application to a previously affected site may result in a false positive. A false positive may also result from hyperirritable skin. False negatives may result from inadequate contact between the allergen and the skin or corticosteroid use.27

Thimerosol Thiuram mix

Workers that are allergic to dyed textiles, printing ink, or photo developer may react to p-phenylenediamine. Formaldehyde is found in fabric finishes, plastics, synthetic resins, glues, textiles, and a number of construction materials. The negative control is an uncoated polyester patch. The manufacturer claims that this panel accounts for 80% of the cases of allergic contact dermatitis.1,27–29 Dehydrated forms of these standardized antigens are incorporated into hydrophilic gels and attached to waterproof backings. There is no allergen preparation required on the part of the physician. The patches are simply placed on the patient’s back where perspiration will dehydrate the antigen. The antigens are supplied in two panels. The panels are applied to healthy hairless skin that is free of any dermatological lesions on

11.11.2.2 Finn Chamber The Finn chamber test uses (8 or 12 mm) aluminum or polypropylene (8, 12, or 18) coated chambers. The chambers must be filled by the clinician. Like the TRUE test the Finn test is applied to the upper back and utilizes an occlusive method. The makers of the Finn test recommend cleaning the skin with alcohol if necessary. The test is removed in 1–2 days. A ringshaped depression at the time of removal verifies that there was adequate occlusion. The test is read 20 min after the chambers are removed and 3–7 days after application. The patient should avoid vigorous activity or shower while the test is in place.28 The Finn chamber offers a choice in antigens but requires more work from the physician. Since the antigen concentration (depending on the selection of the examiner) may be less standardized, there is more of

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an opportunity for an irritant reaction to cause confusion. Drying of the filter paper may result in a false negative. Using the causative agent in an insufficient strength will also result in a false negative test. False positives may be observed due to the aluminum.28 Patch testing will not be helpful if the causative agent is omitted. An allergic reaction pattern along with the right indicates an allergic contact dermatitis. In contrast, an irritant reaction does not add significant support to an irritant contact reaction. The patch test is the only technique available to demonstrate that an allergen causes an allergic contact dermatitis. As with any test the patch test must be considered in the context of the patient’s history and physical examination.27–29

11.11.3 Prevention and Treatment of Occupational Dermatitis The use of gloves has been a significant factor in the reduction of hand dermatitis, but improper glove use has led to more severe dermatitis due to the repeated exposure to chemicals and or irritating substances.30 These findings show a need to make sure that proper glove use is taught and encouraged in the workplace. There are a variety of mechanisms that can lead to glove failure. When gloves are used more than once the chance to be exposed to the contaminated exterior of the glove is increased.31 Permeation of small amounts of certain chemicals through the glove occurs if the glove is worn longer than the breakthrough time, which is the minimum time needed for a particular chemical to diffuse through the glove. Penetration through a glove occurs when an opening or hole develops in the glove.30, 31 Altered skin pH has also been shown to play a role in the development of dermatitis.32 Gloves have the ability to maintain skin pH and therefore reduce dermatitis. Gloves should be changed frequently and examined for defects often to minimize the chance of contamination and development of hand dermatitis.30–33 There are many ways to intervene and treat patients with occupational dermatitis. Some of the most common treatments are barrier creams and moisturizers.33 Other treatments are more effective for moderate-tosevere dermatitis, including topical steroid creams. Eventually, nonsteroidal creams should be used because they do not cause thinning of the skin.31,–33

A. Theodosatos and R. Haight

11.12 Burns Although we have improved strategies to decrease morbidity and mortality in burn patients, skin care is often neglected. Reports show that there are over two million burn injuries each year in the United States. They result from direct or indirect transfer of heat to the body and they are encountered in a variety of workplaces. Prompt treatment is important to avoid infections and long-term sequlae.34 The location, type, and classification of a burn help determine the aggressiveness needed in its treatment. Acute treatment with wound debridement helps decrease the risk for hypertrophic scar formation and allows donor sites to be found if a skin graft is needed.35 Burned skin is fragile and very susceptible to sunburn. Without appropriate postburn care, skin breakdown occurs. Pruritus, caused by the destruction of the sebaceous glands, is a symptom of healing burns. These glands are destroyed most commonly in full-thickness burns but can be seen in some partial-thickness burns. Treatment of pruritus is generally accomplished with emollient creams and short-term antihistamine use.34–36 Scar formation is hastened and cosmetic outcomes improved when tretinoin creams, topical steroids and hydroquinones are used. The treatment time varies but usually lasts for several months. Proper patient education and involvement of multiple healthcare professionals in treatment and follow-up yield the best results.35

11.12.1 Chemical Burns in the Workplace Industrial exposures are a frequent cause of chemical burns. Cleaning products and agricultural products are also common offending agents resulting in many chemical burns. These burns account for 2.1–6.5% of admissions to burn units. The cutaneous manifestations of chemical burns include necrosis at the site of injury with surrounding erythema and blistering. The greater the depth of the chemical burn, the more persistent the necrosis is. Chemical agents that can lead to systemic complications include various acids, oxidizing agents, protoplasmic poisons, and vesicants.37–39 Acids and alkalis cause injury to the body by different mechanisms. Most acids denature proteins when they come in contact with the skin and produce a coagulative necrosis. Hydrofluoric (HF) acids are different

11  Occupational Dermatology

in that they produce a liquefactive type of necrosis, like alkalis. Chemicals that cause liquefactive necrosis may result in more extensive burns because they are able to extend further and deeper into the skin. The process leading to liquefactive necrosis starts with denaturation of proteins and saponification of fats.35–39 History and physical exam should not only focus on the history obtained by the affected person. The physician examining the patient should try and obtain the container that the substance was in and also contact poison control. The mode of exposure is also very important, in addition to the duration of exposure. Once airway, breathing, and circulation are maintained, special attention must be made to keep burned patients from becoming hypothermic. Further injury prevention is also important; therefore removal of contaminated clothing and attention to the area of affected skin is necessary.40, 41 Oral burns may lead to contractures of the oropharynx. These burns typically result from caustic lye ingestion. Initial oral and gastrointestinal symptoms are erythema, swelling, and pain. Later progression to drooling, stridor, and airway obstruction may develop. Ocular exposures need immediate decontamination followed by a thorough ophthalmologic evaluation. Decontamination with irrigation should be continued until the pH of the eye is returned to normal (pH 7–8). Ophthalmologic evaluation should also include fluorescein staining to check for corneal abrasions. Slit lamp examination can be helpful in evaluating the anterior chamber of the eye, following the ocular irrigation and examination.34, 39 Cutaneous burn depth and size should be carefully documented. First degree burns are superficial and present as erythematous areas with intact sensation. Second degree burns are deeper involving varying levels of the dermis. They can form blisters although sensation is still intact. Third degree burns are known as full-thickness burns, as they involve all layers of the dermis. They appear swollen, dry, mottled, and white and they do not elicit any sensation. Fourth degree burns go deeper into the muscle or bone.34, 36 Burn severity is determined by the depth and total body surface area involved. Total body surface area is estimated using the rule of nines (Table  11.3). This rule estimates a percentage of the body involved by each body part. HF acid has many applications and is a common cause for severe chemical injury. It can be found in

111

plastics, pesticides, fertilizers, high octane fuels, and heavy duty household cleaners. There are two forms: anhydrous HF and aqueous HF. The anhydrous form is stronger and more deadly than the aqueous form, but the majority of HF burns are due to the aqueous form. These burns manifest as pain, erythema, blister formation, and finally tissue destruction. Since this acid is mostly found in household cleaners the affected site is usually the fingertips. HF causes injury by first penetrating the epidermis and then lipophilic fluoride ions. Finally, it goes into the cells where it binds calcium and magnesium. When this occurs, necrosis of soft tissue begins and pain develops from the immobilization of calcium.39 Phenol is a weak organic acid with a variety of uses in medicine. It is used frequently for facial peels and topical and injectable anesthetics. It damages the skin through corrosive effects, which cause the skin the slough. Skin exams may reveal partial-thickness burns, although full-thickness burns are also common. Phenol is rapidly absorbed and systemic symptoms are a major concern. Systemic findings include: premature ventricular contractions, tachycardia, hypotension, central nervous system (CNS) depression, and finally respiratory failure.41 Chromic acid burns produce localized coagulative necrosis and sometimes gastrointestinal, renal, and CNS complications. When chromium is absorbed it produces a hexavalent form that can be absorbed by red blood cells and bind hemoglobin, impairing its oxygen-carrying capacity. Formic acid is also used in industry and it produces a localized chemical burn similar to one caused by chromic acid. One major systemic effect is acidosis, which develops when formic acid interferes with cellular respiration. Complex acidosis increases proximal tubule reabsorption, decreasing formic acid excretion. Other systemic findings are hypotension, hematuria, hemoglobinuria, renal failure, and end organ damage.34–38 Alkali agents are also common causes of chemical burns. Some frequently encountered alkali agents include: anhydrous ammonia, cement burns and airbag injuries.42 Anhydrous ammonia is a colorless gas found in cleaning products used in the home. These burns may appear grayish-yellow in appearance in partialthickness burns and leathery and white in full-thickness burns. Cement burns are encountered in the lower extremities of some construction workers.37 These burns develop from calcium oxide penetration, causing

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a liquefactive type of necrosis. The skin is damaged from abrasions due to the coarse consistency of cement. Airbag injuries are associated with the release of sodium azide and sodium hydroxide.42 It has been estimated that skin injuries account for approximately 8% of all injuries from airbag deployment. White phosphorus can cause corrosive damage to the skin by a chemical and thermal combined burn. This oxidizing agent is used in weaponry, some fertilizers, and fireworks. Immediate removal of this chemical from the skin is important to prevent the progression to systemic effects, such as liver and kidney damage.38 Sulfur mustard is a blistering agent, used in the past in warfare. This chemical has the ability to cause the skin to blister after an asymptomatic period. This blistering effect mostly involves the intertriginous areas, although it does spread easily. They may coalesce and form larger bulla. Systemic effects are also observed, therefore prompt treatment is important. Betadine is an antiseptic containing water, iodine, and polyvinyl pyrrolidine. It has the ability to cause burns especially on areas of the skin that are not dried properly. Dependent areas of the body are most commonly affected. Other skin cleansing agents must be used with caution, especially in babies and the elderly.43 Table 11.4 lists some common burn-causing chemical agents, their uses, and medical treatment. Laboratory studies can be useful in burns that are known to cause systemic effects and in burns involving mild-to-moderate amounts of skin. The common

systemic effects that occur vary by the type of chemical involved. Fluid and electrolyte monitoring may be necessary to identify patients needing closer monitoring in the hospital. Initial management of any burn patient requires removal of the offending agent. Next, contaminated clothes should be removed and affected areas of the skin should be irrigated. Earlier irrigation has been shown to limit burn depth and also decrease the duration of time spent in the hospital. Fluid resuscitation is important in chemical burns because these burns tend to be deeper in the tissue than other types of burns. Irrigation dilutes the chemical and removes unreacted chemicals from the skin. Burn treatment also includes pain management, physical therapy, and occupational therapy. Sometimes skin grafting may be needed along with cosmetic reconstruction. Some studies have shown that certain biological dressings can be used effectively in second degree burns. For example, xenoderm can lead to a reduction in dressing times, reduce hospital stay, and decrease the formation of scars.34, 44 Burn patients who receive the earliest care have been shown to have the best clinical outcomes. In order to be able to treat a burn patient appropriately early on, healthcare providers need to be have a clear clinical picture of the different types and causes of burns, especially in the workplace. This can be accomplished by setting up burn education and prevention measures, especially in high-risk jobs.34, 44

Table 11.4  Chemical agents, their uses, and medical management Chemical agent Uses

Medical management

Hydrofluoric (HF) acid

Fertilizers, pesticides, dyes, plastics, and household cleaners

Irrigation, ammonium compounds (to inactivate free fluoride ions), calcium gluconate gels (neutralization), and sometimes debridement

Phenol, carbolic acid, hydoxybenzene

Sewage treatment, topical and systemic anesthetics, chemical face peels

Irrigation, polyethylene glycol (PEG)

Chromic acid

Dye production

Irrigation, phosphate buffers, thiosulfate soaks, EDTA

Formic acid

Descaling agent, rubber processor

Irrigation, IVF hydration, bicarbonate therapy, folic acid, dialysis (severe)

Cement

Construction products

Irrigation, dry lime, soap and water

White phosphorus

Weaponry, manufacture of insecticides and fertilizers, fireworks

Irrigation, wet compresses, and surgical debridement

11  Occupational Dermatology

References   1. Rom WM. Environmental and Occupational Medicine. 3rd ed. Philadelphia: Lippincott-Raven; 1998   2. US Department of Labor, US Bureau of Labor Statistics. Occupational Injuries and Illnesses: counts, rates, and characteristics, 2004. Bulletin 2584. 2006   3. Emmett EA. Occupational dermatitosis. In: Fitzpatrick TB, Eisen AZ, Wolf K, et  al eds. Dermatology in General Medicine. 3rd ed. New York: McGraw-Hill; 1987   4. Mathias CGT. Contact dermatitis and workers’ compensation: criteria for establishing occupational causation and aggravation. J Am Acad Derm. 1989;20(5):842–848   5. Dhir H. Hand dermatitis and nail disorders of the workplace. Clin Occup Environ Med. 2006;5(2):381–396   6. Cocchiarella L, Anderson GBJ. Guides to the Evaluation of Permanent Impairment. 5th ed. Chicago: American Medical Association; 2000   7. Pharda V, Gruber F, Kastelan M, et al Occupational skin diseases caused by solar radiation. Coll Antropol. 2007;31(1): 87–90   8. Boissy RE, Manga P. On the etiology of contact/occupational vitiligo. Pigment Cell Res. 2004;17(3):208–214   9. Boffetta P. Epidemiology of environmental and occupational cancer. Oncogene. 2004;23(38):6392–6403 10. Gawkrodger DJ. Occupational skin cancer. Occup Med. 2004;54(7):458–463 11. McCall BP, Horwitz IB, Feldman SR, Balkrishnan R. Incidence rates, costs, severity, and work-related factors of occupational dermatitis-A workers compensation analysis of Oregon 1990–1997. Arch Dermatol. 2005;141:713–718 12. Rietschel RL. Occupational contact dermatitis. Lancet. 1997;349:1093–1095 13. Kucenic MJ, Belsito DV. Occupational allergic contact dermatitis is more prevalent than irritant contact dermatitis: a 5 year study. J Am Acad Dermatol. 2002;46:695–699 14. Robinson JK, Ramos-e-Siliva M. Women’s dermatologic diseases, health care delivery, and socioeconomic barriers. Arch Dermatol. 2006;142:362–364 15. Cvetkovski RS, Zachariae R, et al Prognosis of occupational hand eczema. Arch Dermatol. 2006;142:305–311 16. Olsen J, Mathiesen L, et al Relation between diagnoses on severity, sick leave and loss of job among patients with occupational hand eczema. Br J Dermatol. 2004;152:93–98 17. Worth A, Arshad SH, Sheikh A. Occupational dermatitis in a hairdresser. Br Med J. 2007;335:399 18. Crawford GH, Katz KA, Ellis E, James WD. Use of aromatherapy products and increased risk of hand dermatitis in massage therapists. Arch Dermatol. 2004;140:991–996 19. Vaccaro M, Guarneri F, Barbuzza O, et al A prickly pair. Am J Med. 2007;120:1026–1027 20. Jeebhay MF, Lopata AL, Robins TG. Seafood processing in South Africa: a study of working practices, occupational health services and allergic problems in the industry. Occup Med. 2000;50:406–413 21. Aalton-Korte K, Alanko K, et al Antimicrobial allergy from polyvinyl chloride gloves. Arch Dermatol Oct. 2006;142: 1326–1330

113 22. Wilkinson SM, Beck MH. Allergic contact dermatitis from latex rubber. Br J Dermatol. 1996;134:910–914 23. Sinha A, Harrison PV. Latex glove allergy among hospital employees: a study in the north-west of England. Occup Med. 1998;48:405–410 24. Woods JA, Lambert S, Thomas AE, et  al Natural rubber latex allergy: spectrum, diagnostic approach, and therapy. J Emerg Med. 1997;15:71–85 25. Bock M, Schmidt A, et al Occupational skin disease in the construction industry. Br J Derm. 2003;149:1165–1171 26. Henning A, et al Primary prevention of natural rubber latex allergy in the German health care system through education and intervention. J Allergy Clin Immunol. 2002;110: 318–323 27. True Test Physician’s Reference Manual. At: www.truetest. com; 2009 Accessed 17.02.09 28. Finn Chamber on Scanpor. At: www.epitest.fi; 2009 Accessed 17.02.09 29. Marks JG, Belsito DV, DeLeo VA, et al Clinical and laboratory studies: North American contact dermatitis group patch test for the determination of delayed- type hypersensitivity to topical allergens. J Am Ac Derm. 1998;38(6):911–918 30. Saary J, et al A systematic review of contact dermatitis treatment and prevention. J Am Acad Dermatol. 2005;53: 843–855 31. Soonyou K, Lauren S, et al Role of protective gloves in the causation and treatment of occupational irritant contact dermatitis. J Am Acad Dermatol. 2006;55:891–896 32. Mirza R, et al A randomized, controlled, double blind study of the effect of wearing coated pH 5.5 latex gloves compared with standard powder free latex gloves on skin pH, transepidermal water loss and skin irritation. Contact Derm. 2006; 55:20–25 33. Wigger-Alberti W, Elsner P. Prevention of irritant contact dermatitis-new aspects. Immunol Allergy Clin N Am. 1997; 17:443–450 34. Monafo WW. Initial management of burns. N Engl J Med. 1996;335(21):1581–1586 35. Ho WS, Chan HH, Ying SY, et al Skin care in burn patients: a team approach. Burns. 2001;27:489–491 36. Kales SN, Christiani DC. Acute chemical emergencies. N Engl J Med. 2004;350(8):800–808 37. Spoo J, Elsner P. Cement burns: a review 1960–2000. Contact Derm. 2001;45(2):68–71 38. Chou TD, Lee TW, Chen SL, et al The management of white phosphorus burns. Burns. 2001;27(5):492–497 39. Hatzifotis M, Williams A, Muller M, et al Hydrofluoric acid burns. Burns. 2004;30(2):156–159 40. Browne TD. The treatment of hydrofluoric acid burns. Occup Med. 1974;24:80–89 41. Horch R, Spilker G, Stark GB. Phenol burns and intoxications. Burns. 1994;20(1):45–50 42. Corazza M, Bacilieri S, Morandi P. Airbag dermatitis. Contact Derm. 2000;42(6):367–368 43. Maenthaisong R, Chaiyakunapruk N, et  al The efficacy of aloe vera used for burn wound healing: A systematic review. Burns. 2007;33:713–718 44. Cox RD. Burns, Chemical. At www.emedicine.com; 2008 Accessed 15.05.08. Chemical burns

Diagnosis and Prevention of Bullous Diseases

12

Supriya S. Venugopal and Dedee F. Murrell

12.1 Introduction Bullous diseases may be broadly divided into the inherited, autoimmune, and infectious types. This chapter will deal with each in turn: how to diagnose and how to, where possible, prevent these from occurring or worsening.

12.2 Inherited Bullous Diseases 12.2.1 Epidermolysis Bullosa Epidermolysis bullosa is a blistering disease occurring at birth or shortly after birth, characterized by the tendency to develop blisters spontaneously or after sustaining minimal trauma. There are many different types of epidermolysis bullosa. The three main inherited subtypes (Table 12.1), classified according to the level at which skin cleavage occurs, include: • Epidermolysis bullosa simplex (EBS) • Junctional epidermolysis bullosa (JEB) • Dystrophic epidermolysis bullosa (DEB) EBS is characterized by intradermal skin cleavage above the basement membrane at the level of the keratinocytes. In JEB, blister formation occurs at the level of

D. F. Murrell (*) Department of Dermatology, St. George Hospital, University of NSW Medical School, Sydney, Australia e-mail: [email protected]

the lamina lucida, and DEB is characterized by blister formation in the sublamina densa.65 The classification of EB has been upgraded67 and at the time of writing this chapter the terminology was being further revised and upgraded to include some additional syndromes.68 EBS is a blistering disorder affecting the basal layer of the epidermis. Most cases are caused by mutations in the genes encoding keratin 5 (K5) and keratin 14 (K14) and are characterized by cytolysis within the basal layer of the epidermis.163 Patients with the Dowling-Meara type of EB simplex (EBS-DM) can have severe blistering at birth, but this tends to markedly improve as the patient grows older and by early adulthood, patients rarely develop blisters.135 Additional features are hyperkeratosis of the palms and soles, and herpetiform grouping of blisters.36 In EBS-DM, some of the keratin filaments are organized into dense, circumscribed clumps that sometimes connect with either hemidesmosomes or desmosomes.12 Transmission electron microscopy (TEM) is highly specific for the diagnosis of the EBS-DM, though it has variable sensitivity.104, 213 There are multiple important considerations with respect to the ultrastructural findings in autosomal recessive EBS (R-EBS) and autosomal recessive EBS associated with muscular dystrophy (EBS-MD). In R-EBS, there may be an ablation of K14 expression and also a lack of visible keratin filaments in basal but not suprabasal keratinocytes.112, 214 Autosomal recessive EBS is associated with the following findings: a lack of integration of keratin filaments with hemidesmosomes, neuro­muscular disease, and mutation of the plectin gene.64, 147 JEB is an autosomal recessive disorder characterized by blisters that develop within the lamina lucida. Clinical manifestations aid in subtype classification in particular, generalized (Herlitz, H-JEB) type, which is

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Table 12.1  The major EB types, subtypes, and the associated targeted proteins (Fine et al 2008) Major EB type Major EB Targeted proteins subtypes Epidermolysis bullosa simplex (EBS)

Suprabasal Basal

Plakophilin-1 Desmoplakin Keratins 5 and 14; plectin; a6b4 integrins

Junctional epidermolysis bullosa (JEB)

JEB-Herlitz JEB-other

Lam332 Lam 332; Col XVII; a6b4 integrins

Dystrophic epidermolysis bullosa (DEB)

Dominant Recessive

Collagen VII Collagen VII

Kindler syndrome

–

Kindlin 1

lethal, and a generalized but less severe (non-Herlitz, nH-JEB) type.68 H-JEB is caused by mutations in one of the three genes encoding the anchoring filament components of laminin 5, now referred to as Lam332 (LAMA3, LAMB3, and LAMC2).137 nH-JEB is caused by less deleterious mutations in the aforementioned genes or mutations in the gene that encodes type XVII collagen or BP180, known as COL17A1.111,136,137 Classical sites of involvement include the buttocks, mouth, back of the scalp, and periungual areas.52 Absent or dystrophic nails, enamel hypoplasia, laryngeal edema or stenosis, profound growth retardation, anemia, and the presence of exuberant granulation tissue, particularly on the trunk and on periorificial and periungual sites, are also features. Epidermolysis bullosa, usually but not necessarily in the lamina lucida, associated with pyloric atresia (EB-PA), manifests with neonatal blistering and gastric anomalies. EB-PA is known to be caused by mutations in the hemidesmosomal genes ITGA6 and ITGB4, encoding the alpha6 and beta4 integrin polypeptides, respectively.157 Herlitz JEB skin demonstrates a split at the dermal– epidermal junction with minimal dermal inflammation (Fig.  12.1). Immunofluorescence mapping (IFM) and electron microscopy (EM) studies confirm the level of cleavage to be through the lamina lucida. Hemidesmosomes may be significantly reduced, small, and lacking normal subbasal plates.189 More severely affected patients may display absence or marked reduction in density of the subbasal dense plate along the ­dermoepidermal junction. In addition, a reduction in hermidesmosome count is associated with a rudimentary

Fig. 12.1  H-JEB with groin involvement exacerbated by nappies

or embryonic-appearing ultrastructure. Severely affected individuals are associated with either the absence of hemidesmosomes or have reduced numbers of hemidesmosomes lacking subbasal dense plates.66 Laminin 5 is a glycoprotein comprising three subunits: alpha 3, beta 3, and gamma 2. These subunit chains are encoded by the following genes: LAMA3 (localized to chromosome 18q),15 LAMB3 (at 1q32), and LAMC2 (at 1q25–31),194 respectively. These have been proposed as candidate genes in Herlitz disease. Studies have demonstrated that mutations in any one of these three genes may be associated with the Herlitz ­phenotype.1, 116, 165 Mutations in LAMB3 have also been shown to underlie non-Herlitz JEB,136, 137 and recently mutations in the genes encoding (b)4 integrin and the 180-kDa bullous pemphigoid (BP) antigens have also been demonstrated (Fig. 12.2).136, 137, 195

Fig. 12.2  Grouped blistering and postinflammatory change in EBS-DM

12  Diagnosis and Prevention of Bullous Diseases

DEB may be inherited in an autosomal dominant (DDEB) and an autosomal recessive manner (RDEB). Mutations in the type VII collagen gene (COL7A1) gene result in both RDEB and DDEB.47 RDEB is further subclassified into: • • • • • •

RDEB-GS: Generalized Severe type RDEB-nGS: Generalized non severe type Inversa RDEB Centripetal RDEB Pruriginosa RDEB Pretibial RDEB

The generalized severe type (RDEB-GS) is characterized by generalized lesions and scarring of the hands and feet, leading to fusion of the digits pseudosyndactyly and severe mucosal involvement. The milder RDEB-nGS type can be localized or generalized, in contrast with RDEB-GS is associated with very mild or no pseudo-syndactyly, and less frequent extra-cutaneous involvement (Fig. 12.3).67 The precise diagnosis of EB is crucial for molecular diagnosis and is the key for prevention using prenatal diagnosis. There are three main modalities for the diagnosis of EB. These include: • Transmission electron microscopy (TEM) • Immunofluorescence antigenic mapping • Genetic studies Ultrastructural examination demonstrates the level of skin cleavage, allowing discrimination of epidermolytic, junctional, and dermolytic types of EB. Immunofluorescence

Fig.  12.3  Gastrostomy in RDEB-HS to prevent malnutrition, osteoporosis. Protective nonstick dressing to prevent blistering

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antigenic mapping (IFM) is a convenient and rapid method for classification and involves the localization of previously defined components within certain ultrastructural regions of the dermoepidermal junction. TEM allows direct visualization and quantification of specific ultrastructural features. TEM was first used as a diagnostic tool in EB in the early 1960s by Pearson154, 155 which allowed for the first accurate method of distinguishing between the various types of EB. Further developments and refinement of TEM methods have allowed for the diagnosis of further subclassification in the major types of EB. TEM may help establish a definitive diagnosis not only of major variants of EB, but also of main subtypes.11 TEM is performed on tissue that is stained with uranyl acetate, lead citrate, and osmium tetroxide. The tissue is visualized under EM with a specific focus on the level of skin cleavage present. TEM also allows measurement of the number of keratin tonofilaments, hemi­ desmosones, subbasal dense plates, and anchoring fibrils.154,155 Alternative methods to the diagnosis of EB include IFM, first described by Hintner et al98 IFM has been aided by the discovery of several individual basement membrane zone (BMZ) antibodies. IFM is a powerful diagnostic tool for EB when combined with immunohistochemical mapping of these BMZ monoclonal antibodies. IFM determines the precise level of skin cleavage of a specimen by determining the site of binding by a series of antibodies directed to these BMZ antigens, with known ultrastructural binding sites.63 There are many reasons for favoring the use of IFM compared with TEM in modern dermatological practice in the diagnosis of EB. Yiasemides et  al213 concluded that TEM and IFM were appropriate first-line techniques of choice in the diagnosis of EB. The study concluded that despite the lack of statistical significance, IFM consistently had higher sensitivity, specificity, and predictive values in the diagnosis of all three subtypes of EB compared with TEM. There are also several other reasons to favor the use of IFM as opposed to TEM. TEM requires a long training period and sample preparation is more laborious, often taking days to weeks to complete. As a result of skills shortage, TEM is not readily available in all hospitals and laboratories. In addition, interpretation of the skin biopsy using TEM may lead to greater mistakes in diagnosis. This is due to the relatively small area of the specimen sample

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that is visualized, which may result in the blister being missed. This may also result in the overestimation or underestimation of the number of fibrils and other structural components in EB. At high magnifications, artifactual spaces may be misinterpreted for cleavage sites. Other diagnostic misinterpretations include reporting nonspecific dense bundles of keratin filaments as clumped tonofilaments (i.e., resulting in the diagnosis of EBS-DM).213 Due to the variance in the ultrastructural findings in the various subsets of EB, TEM faces difficulties in the accurate diagnosis of the various different subgroups in EB. This is perhaps one of the main reasons why TEM appears to be less accurate in subset diagnosis of EB compared with IFM. Morphometric analysis in JEB demonstrates marked desmosomal heterogeneity.190 In more severe recessive generalized DEB cases, morphometric analysis has shown a total absence of anchoring fibrils.35 Immunohistochemical staining of collagen IV in formalin fixed and paraffin-embedded samples followed by examination under a light microscope is a more rapid alternative to TEM. EBS variants are diagnosed by the presence of collagen IV staining at the floor of the blister. The positive staining in the roof of the blister establishes the diagnosis of dystrophic variants of EB. The present technique identifies collagen IV within the lamina densa and subsequently does not allow differentiation between EB simplex and junctional EB.23

12.2.1.1 Prevention of EB Prenatal genetic diagnosis (PND) has most frequently been performed for the following subtypes of EB, as they are the most severe59–61,138,180: • Recessive dystrophic EB - generalized severe • Herlitz junctional EB • Junctional EB associated with congenital pyloric atresia However, in some countries there are differing ethical paradigms which have allowed PND for “milder” forms of EB, since these may not be perceived to be “mild” by the patients themselves or their carers. These include non-Herlitz JEB141 and dominant dystrophic EB118 and disorders in the EB umbrella, skin fragility ectodermal dysplasia and Kindler syndrome.59–61, 68

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Prenatal diagnosis for EB was initially done by examination of a fetal skin biopsy with EM and/or immunohistochemistry.55, 56, 91, 92, 171 In the 1990s, the genes responsible for respective EB subtypes and the family-specific mutations were identified, as mentioned above. This led to the feasibility of DNA-based PND using fetal DNA extracted from amniocentesis at 12–15 weeks initially and later from chorionic villous sampling at about 10 weeks. Direct assessment of previously identified pathogenic mutations or the use of indirect linkage markers have been the methods used for the majority of DNA-based PND in RDEB.180 Mutational analysis of the type VII collagen gene, COLA1 or haplotype analysis using a number of welldescribed informative polymorphisms within or flanking COL7A1, if the mutation(s) has/have not been identified are some of the assesment methods used.138 Fetal skin biopsy has several disadvantages and has been superseded by molecular diagnosis. A fetal skin biopsy can only be obtained later in gestation, usually 16 weeks or more, and is associated with a relatively high rate of miscarriage.66 Mutation detection using fetal amniocytes or chorionic villous sampling can be performed earlier and as they are less invasive and have lower risks of miscarriage. However, fetal skin biopsy remains an option in those rare cases in which mutations cannot be identified and linked markers are not available to be used for prenatal diagnosis. Very few obstetricians have experience with fetal skin biopsies, however. Prenatal diagnosis can be greater than 98% accurate and is highly beneficial in pregnancy screening for mutations or informative markers.158 Analyzing the sequence traces with the aid of computer software, rather than by hand, is mandatory nowadays to reduce human errors. Analysis of fetal skin biopsies and DNA-based prenatal tests allow the diagnosis of an affected fetus to be made once pregnancy is established, and can result in considerable emotional and physical distress for the parents contemplating the prospect of termination.59–61 Preimplantation genetic diagnosis (PGD) is a technique involving a single cell biopsy from the six-to-ten cell blastomere stage of the fertilized embryo proceeded by DNA mutational analysis.86 Less DNA is needed if genome wide markers are used.59–61 Diseasefree embryos are then implanted into the uterus, thereby avoiding any pregnancy termination procedures usually associated with conventional PND methods.

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Mothers who decide to give birth to a baby known to have EB or at high-risk of EB can prevent some of the blistering associated with birth trauma in these infants by undergoing a planned Caesarian section rather than a normal vaginal delivery.

12.3 Autoimmune Bullous Diseases Autoimmune bullous diseases are associated with autoimmunity against structural components which maintain cell–cell and cell-matrix adhesion in the skin and mucous membranes.139 They include those where the skin blisters at the BMZ (BP, herpes gestationis, mucous membrane pemphigoid [MMP], linear IgA dermatosis [LAD], epidermolysis bullosa acquisita [EBA], bullous lupus and dermatitis herpetiformis [DH]) and those where the skin blisters within the epidermis (pemphigus vulgaris [PV], pemphigus foliaceus [PF] and other subtypes of pemphigus88). Due to the considerable overlap in the clinical presentation of these conditions, diagnosis of autoimmune bullous skin conditions can be challenging. Detection of tissue-bound and circulating serum autoantibodies and characterization of their molecular specificity is an important modality for diagnosis. In the past decade, there have been several advances in diagnostic modalities for autoimmune bullous skin conditions.

12.3.1 Pemphigus Pemphigus is a word derived from the Greek work “pemphix” meaning bubble or blister and is a ­life-threatening autoimmune blistering disease, characterized by intraepithelial blister formation.95, 96, 102, 124 Circulating autoantibodies directed against intercellular adhesion struc­tures result in the loss of adhesion between the keratinocytes.5, 17 The incidence of pemphigus is approximately 1 in 100,000 people.186 The variants of pemphigus are determined according to the level of intraepidermal split formation. There are five main variants of pemphigus. These include PV, PF, pemphigus erythematosus, drug-induced pemphigus, and paraneoplastic pemphigus (PNP). The hallmark of pemphigus is acantholysis, an intradermal split formation due to the loss of adhesion

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between epidermal keratinocytes. This may result in the development of the Tzanck phenomenon (the rounding of single epidermal cells due to the loss of cell–cell attachment). Inflammatory cell infiltrates of the involved skin are generally absent. PF and PV are usually characterized by suprabasilar loss of adhesion leaving a single layer of basal keratinocytes attached to the dermoepidermal basement membrane (tombstone pattern). PF is associated with a superficial split formation in the subcorneal layer. Tissue-bound IgG or IgA in a characteristic netlike intercellular distribution pattern within the epidermis, commonly associated with precipitation of C3 is ­demonstrated on direct immunofluorescence microscopy. Indirect immunofluorescence microscopy, the gold standard in pemphigus, reveals the presence of serum autoantibodies against desmosomal antigens. Pemphigus sera show a characteristic netlike intercellular staining of IgG with human skin as a substrate. Other substrates such as monkey esophagus, guinea pig esophagus, or rat bladder epithelium may be used in the diagnosis of PNP.110 Immunoserological tests such as enzyme-linked immunosorbent assay (ELISA) confirm the diagnosis of pemphigus and results can be used to determine disease activity. The development and commercial use of ELISA has provided higher sensitivity and specificity in making the diagnosis of pemphigus subtypes.105 ELISA alone is insufficient to diagnose the condition. Immunoserological tests can provide valuable information on the clinical course of pemphigus, and can also be used as a diagnostic and prognostic indicator in the management of pemphigus. Desmoglein 35,7 and desmoglein 137,57 are the targets for autoantibodies in PV and PF, respectively. In active PV, immunoblot analysis with recombinant Dsg3 demonstrated that anti-Dsg3 of the IgG4, IgA, and IgE subtypes predominate; however, chronic remittent PV is characterized by IgG1 and IgG4 autoantibodies.22,88,120,185 PV is the most common variant of pemphigus with an incidence of 0.1–0.5 per 100,000 population, and higher among Jewish patients.3 The diagnosis of PV is made using four major criteria. These consist of: • • • •

Clinical findings Light microscopic findings Direct immunofluorescence findings Indirect immunofluorescence findings95, 143

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Fig. 12.4  Erosions and crusting of the scalp in a patient with pemphigus vulgaris (PV)

PV is the most common subtype of pemphigus (Fig. 12.4). It is a potentially life-threatening autoimmune vesiculobullous disorder characterized by nonscarring, fragile vesicles and bullae involving the mucosae with varying cutaneous involvement. PV usually presents in adults and can affect anywhere in the body but predominantly affects the buccal and labial mucosa. This condition is characterized by Nikolsky’s sign: the application of slight pressure on the blisters resulting in their spread to neighboring areas. Histo­ logical studies of PV lesions usually demonstrate acantholysis in the suprabasilar part of the epidermis. Typical findings include IgG and/or C3 binding to the intracellular cement substance (ICS) in the mid-lower or entire epidermis of perilesional skin or mucosa on DIF.2,125,176,177 PV is associated with autoantibodies to 130-kDa glycoprotein Dsg3 and secondary development of antibodies to 160-kDa glycoprotein Dsg1 antigens, when the skin is involved.186 Acetylcholine receptors on keratinocytes have also been reported as a possible further target antigen in PV.82,181,196 PF generally has a benign clinical course and most frequently presents on the scalp, face, and upper trunk and is characterized by erythema, scaling, and crusting lesions and spares the mucus membranes.186 An endemic version of PF, fogo selvagem (FS), is endemic to an Indian reservation in Brazil. The cause of this may be environmental and in particular may be due to saliva components of insects which may initiate the spread of the disease; the exact cause is not known but

S. S. Venugopal and D. F. Murrell

as it has also been reported in unrelated people moving in to the reservation, not just those from the indigenous population there, it suggests an environmental agent.49 Penicillamine is also a known causative agent in PF.26 Other drugs and environmental agents/chemicals may be associated with triggering PV. Exposure to pesticides and occupational exposure to metal vapor were associated with an increased risk of pemphigus.31 Brenner et  al32 discussed the importance of various exogenic factors in triggering pemphigus including drugs, particularly those containing thiol and phenol groups, calcium channel blockers, ultraviolet radiation, burns, X-rays, neoplasms, nutritional factors, emotional stress, hormones and pregnancy, viruses and vaccinations. There are a number of cases in which exposure to viral disease, in particular herpes simplex, Epstein Barr virus, cytomegalovirus or human herpes viruses, have been associated with PV or PF. Pemphigus erythematosus or Senear-Usher syndrome is a localized variant of PF. It is characterized by the presence of a malar erythema, similar to the rash of lupus erythematosus, also extending to sunexposed areas of the scalp, face, and upper trunk.186 Histological and immunopathological studies confirm the diagnosis of PF. Histopathological examination of PF lesions show subcorneal acantholytic bullae. Binding of IgG and/or C3 to the ICS in the upper stratum malphigii is demonstrated on (DIF) studies of perilesional skin.176 PNP, a rare autoimmune bullous disease related to underlying neoplasia, is characterized by severe, painful mucosal erosions and polymorphous skin lesions.10 PNP occurs in patients with underlying malignancies such as non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and thymoma.8 PNP is associated with autoantibodies to Dsg1, desmoglein3 (Dsg3) and plakins, a characteristic that differentiates this from the other variants of pemphigus.41 Histopathologic hallmarks include acantholysis and interface dermatitis or keratinocyte necrosis.100 PNP is characterized by the development of autoantibodies directed against multiple antigens, predominantly of the plakin family of intermediate filament-associated proteins and the desmogleins of the cadherin family in desmosomes.6,24,89,164 PV is strongly associated with the human leukocyte antigen (HLA) serotypes HLA-DR4 and HLA-DR6.188 Ahmed et  al4 reported low levels of autoantibody in 48% of healthy relatives of PV patients, and the inheritance of antibody positivity was linked to the DR4 and

12  Diagnosis and Prevention of Bullous Diseases

DR6 haplotype. Greater than 95% of PV patients possess one or both of these haplotypes.191 However, population studies report the differing prevalence of alleles in various ethnic groups and concluded that in the nonJewish population, eight alleles were positively associated and one allele was negatively associated with PV.123 The two candidate alleles, most likely to contribute to disease susceptibility in the non-Jewish population, included DRB1*0402 and DQB1*0503. DRB1*0402 was determined to be the sole allele likely to confer susceptibility to PV in Ashkenazi Jewish patients. The global knowledge of PV is quickly advancing; however, there is a dearth of multicenter trials focused on effective strategies for the treatment of pemphigus and multiplicity of outcome measures used.133 In 2005, the International Pemphigus Definitions Group proposed a consensus statement which provided clear definitions of pemphigus. The consensus statement on disease endpoints and therapeutic response for pemphigus142 divides pemphigus disease activity into the following categories: 1. Early endpoints (a)  Baseline (b)  Control of disease activity (c)  End of consolidation phase 2. Late end points (a)  Complete remission off therapy (b)  Complete remission on therapy −− Minimal therapy −− Minimal adjuvant therapy −− Partial remission off therapy −− Partial remission on minimal therapy 3. Relapse/flare 4. Treatment failure Early endpoints provide a useful clinical indicator for clinicians regarding the commencement of differing treatment regimes. The baseline is classified as the day that the treating practitioner initiates treatment. Control of disease activity is defined as the time at which there is cessation of new lesions in conjunction with the healing of preexisting lesions. In the majority of cases the expected time period in this stage is weeks. The end of the consolidation phase is the time period in which no new lesions have developed over a minimum period of 2 weeks. This phase is also characterized by the healing of most lesions, and most medical practitioners would consider the weaning of steroids.

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Late endpoints of disease activity may be reached with or without therapy. Complete remission off therapy is characterized by the absence of new lesions over a 2-month period post cessation of therapy. Minimal therapy constitutes treatment with less than or equal to, 10 mg/day of prednisone or the equivalent and/or the use of minimal adjuvant therapy for a duration of at least 2 months. Minimal adjuvant therapy comprises half the dose required to be defined as treatment failure. Partial remission off therapy is classified as development of lesions post cessation of treatment that heal within 1 week without treatment. The patient must be off systemic therapy for 2 months to be classified in this category. Patients may suffer a partial remission on minimal therapy when they develop new lesions that heal within a week whilst receiving minimal therapy. Topical steroids also constitute minimal therapy. A relapse/flare is defined by the development of three or more new lesions which persist without healing for greater than a week or by the extension of preexisting established lesions. Treatment failure results when there is no change in disease activity despite treatment on therapeutic doses of systemic steroids and other agents whose doses and durations were agreed by international consensus.142

12.3.2 Neonatal Pemphigus and Prevention Neonatal PV is an autoimmune disease secondary to transplacental transferrance of IgG antibodies.51 The first neonatal PV case was reported in 1975 after a woman with PV gave birth to a newborn who exhibited a positive direct immunofluorescence staining to epidermal acantholytic cells in a Tzanck preparation.175 Pemphigus antibodies have been detected in fetal cardiac blood83 and cord blood199 in other stillborns. Pregnancy may precipitate PV or aggravate PV which has been in remission. The timing of conception should probably be targeted to a period of clinical remission, with low IF titers and the choice and dosage of maternal medications should take into account possible fetal effects.174 Patients with PV tend to develop their skin lesions during the first or second trimester or immediately postpartum.113 The improvement of PV during the third trimester may be due to rising endogenous

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corticosteroid production by the chorion and consequent immunosuppression.200 Transplacental transmission of maternally derived intercellular substance reactive IgG antibodies to the fetus, may result in clinical manifestation of PV in the neonate. This is supported by findings of circulating pemphigus antibodies in fetal plasma and its deposition in fetal skin, having the characteristic skin lesions of PV.199 The serum titer of pemphigus antibodies does not appear to influence neonatal outcome and there is no definite correlation between severity of the maternal disease and the neonatal outcome.94 The treatment of choice is oral corticosteroids and plasmapheresis should be reserved for severe cases resistant to high dose corticosteroid therapy. Because of the significant risk of fetal loss, regular fetal monitoring, along with ultrasonography, is recommended.94 Vaginal delivery is the method of choice. Although local trauma sustained during a natural delivery can extend and impair recovery, Caesarean sections are generally discouraged because both the disease process and corticosteroid therapy can impair wound healing. Breast-feeding is not contraindicated but local lesions can occur and there is the theoretical possibility of passive transfer of PV IgG antibodies from mother to baby.80 There are several case reports of the cutaneous side effects of penicillamine, in particular PF, and is also implicated in patients with rheumatoid arthritis and systemic sclerosis.202 Reports of pemphigoid are less common. Mashiah and Brenner134 have reported various environmental and pharmacological aetiological factors in pemphigus. The acronym PEMPHIGUS was proposed to summarize these factors: PEsticides, Malignancy, Pharmaceuticals, Hormones, Infectious agents, Gastro­ nomy, Ultraviolet radiation, and Stress.33 Drugs reported to induce pemphigus are divided into three main groups according to their chemical structure: • Drugs containing a sulfhydryl radical, thiol drugs, including penicillamine, captopril, gold sodium thiomalate, penicillin, and piroxicam, and others. • Phenol drugs, containing phenolic compounds, including rifampicin, levodopa, aspirin, heroin, and others. • Nonthiol nonphenol drugs, including some of the calcium channel blockers, angiotensin converting

S. S. Venugopal and D. F. Murrell

enzyme inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs), in addition to dipyrone, and glibenclamide.29,33,81 Also recently reported has been the triggering of localized pemphigus by imiquimod used to treat nonmelanoma skin cancer.40,129 Garden materials and pesticides are an important cause of contact pemphigus.27 Infectious diseases and immunizations have been implicated in inducing or exacerbating pemphigus, including viruses of the Herpetoviridae family.32 Certain foods have also been purported to induce or trigger pemphigus, in particular foods containing an allium, phenol, thiol, or urshiol group.28,193 Several studies point to the possible contribution of emotional stress as a precipitating factor in pemphigus,25,31 and pemphigus has long been considered a photosensitive disease.109 Acantholysis in pemphigus may be due to the induction of interleukin-1a and tumor necrosis factor-a release by keratinocytes resulting in the regulation and synthesis of complement and proteases like plasminogen activator.34, 87 PV is uncommon in neonates and children and is a disease predominantly of the third to sixth decades of life.152 PV in neonates is caused by maternal autoimmune disease with transplacental transmission of IgG antibodies.44,166,197 It is controversial whether therapy with corticosteroids, azathioprine, or plasmapheresis in affected pregnant women is of benefit to the neonate.174 In adults with PV, autoantibodies to Dsg 3 lead to mucosal blistering, whereas blistering of the skin is usually caused by autoantibodies to Dsg 1.9 In contrast to the skin of adults, antibodies to Dsg 3 may induce blisters in the skin of neonates.170 There are several reported cases of neonatal PV. Neonatal PV is generally associated with a good prognosis and is due to transplacental transmission of IgG autoantibodies.44, 166 In addition, the autoantibodies to Dsg 3 predominantly belong to the IgG4 subclass.152 The pathogenic process leading to blistering in adults with PV is autoantibodies to Dsg3, whereas in neonates it is associated with autoantibodies to Dsg1.9 This is because the IgG4 anti-Dsg1 antibodies can cross the placenta and therefore the manifestation is in the skin rather than mucous membranes. In PV, maternal autoantibody titers appear to correlate well with disease activity in the newborn and mother. This is in

12  Diagnosis and Prevention of Bullous Diseases

contrast to the correlation in those with FS.48 Alvarez et al169 reported that this entity shares similar clinical and immunopathological features with the nonendemic form of PF seen in the rest of the world. The majority of the mothers with FS showed moderately low titers of PF autoantibodies and the babies’ cord sera showed low titers or no autoantibodies. Therefore, it was concluded that the placenta may function as an “in-vivo immunoadsorbent” of pathogenic antibodies. However, Avalos-Diaz et al14 demonstrated the reproduction of clinical, histological, and immunological features of PF in neonatal mice after intraperitoneal injection of anti-Dsg1 autoantibodies from the cord blood of a baby with PF. The exact mechanism of neonatal protection in PF is unknown. There are several proposed theories for the absence of clinical disease in the newborn with mothers with PF. Wu et  al211 demonstrated that protection against blisters induced by PF antibodies is provided by desmoglein 3 expression in the superficial epidermis in neonates. Hence in the rare cases of neonatal PF, the infants may lack the normal neonatal expression of desmoglein 3 in the upper epidermis, or the mothers may produce antidesmoglein 3 antibodies. Ishii et al106 reported a patient with PF in whom PV subsequently developed. This case suggests that mothers who deliver infants with bullous pathology may have undergone an antigenic shift and may be producing antidesmoglein 3 antibodies as well.

12.3.3 Bullous Pemphigoid BP was first described by Lever in 1953 as a subepidermal blistering disease. Its immunohistological features include dermal–epidermal junction separation, an inflammatory cell infiltrate in the upper dermis, and BMZ-bound autoantibodies.124 These autoantibodies show a linear staining at the dermal–epidermal junction, activate complement, and recognize two major hemidesmosomal antigens, BP230 (BPAG1) and BP180 (BPAG2 or type XVII collagen).130 BP typically affects the elderly, with most cases occurring in patients greater than 60 years of age. Its incidence is approximately 6.1–7/million in European countries.41, 187 BP is the most common autoimmune blistering disease and typically presents with lesions on the trunk, proximal extremities, and flexural surfaces,

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and involves the oral mucosa in 20% of cases.41 There is ongoing research into the possibility that BP is associated with increased incidence of digestive tract, bladder and lung malignancies. However these associations may be age related rather than directly due to BP. Other autoimmune disorders such as rheumatoid arthritis, Hashimoto’s thyroiditis, dermatomyositis, lupus erythematosus, and autoimmune thrombocytopenia have been described.96 There are several clinical variants of BP and these include:187 • • • • • • • •

Erythematous and oedematous BP Vesicular BP Localized BP Seborrheic pemphigoid Vegetating BP Dyshidrosiform pemphigoid Nodular BP Cicatricial pemphigoid (mucus membrane pemphi­ goid) • Localized scarring pemphigoid • Disseminated scarring pemphigoid • Herpes gestationis (pemphigoid gestationis) The gold standard for diagnosis is direct immunoelectron microscopy and ELISA assays for BP 230 and BP 180, but these two tests are not routinely available in many countries. More recently, ELISA assays for BP 230 and BP 180 with bacterially derived recombinant proteins have been developed, which have been shown in recent studies to increase the sensitivity in diagnosing BP. Light microscopy is useful in initial classification; however in the early stages of the disease or in atypical cases of BP, this technique is not diagnostic. The findings on light microscopy include subepidermal blister formation with a dermal inflammatory infiltrate predominantly composed of neutrophils and eosinophils. In the early phases of BP, subepidermal clefts and eosinophilic spongiosis are present.124 DIF demonstrates the deposition of IgG and C3 at the BMZ.54 BP may be differentiated by the separation of skin layers at the dermoepidermoid junction using salt split skin, where autoantibodies bind to the upper portion of the split, as they are binding within the hemidesmosome and lamina lucida.41 Indirect immunoflourescence (IIF) is used to detect autoantibody titers and is a useful diagnostic technique for the diagnosis and evaluation of disease activity in BP. The major pathogenic epitope is the noncollagenous

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extracellular domain (NC 16A) of the 180-kDa transmembrane hemidesmosomal protein (BPAG2). The extracellular portion of BP antigen 180 contains 15 collagenous and 16 noncollagenous domains containing different antigenic sites recognized by autoantibodies from several blistering diseases including BP, MMP, and linear immunoglobulin a disease.217 IIF studies are positive for circulating IgG antibodies in 60–80% of patients and the antibodies bind to the epidermal side of saline separated normal human skin.96 Several studies have reported that the circulating antibody titers detected by IIF are not a reliable indicator of disease activity. Moreover, it is reported that IIF titers of BP patients’ sera mainly reflect the amount of circulating anti-BPAG1 antibodies rather than of the pathogenic anti-BPAG2 antibodies.153 Autoantibodies to BP antigen 180 and BP antigen 230 are detected in the sera using immunoblot and immunoprecipitation studies in 60–100% of cases.96 IIF is sufficient for the serological diagnosis of BP in most cases however in cases that are negative on IIF, immunoblot studies may reveal circulating antibodies, particularly to BPAg2.77 Recently, the measurement of circulating pathogenic antibodies in BP patients has been commercially possible using an ELISA kit using the NC16A domain recombinant protein (BP180 ELISA kit).192 concluded that the ELISA index measured by this commercially available kit correlated better with disease activity than the IIF titers, and may be a useful tool to evaluate the disease activity and to assess the effectiveness of the treatment of BP. The combination of BP230 ELISA and BP180 ELISA is a highly sensitive method for the diagnosis of BP.215 A recent study by Sitaru et  al184 investigated the ELISA system using NC16A tetramers instead of monomers, and found it to be a sensitive and specific tool for the diagnosis and monitoring of BP and PG. The sensitivity and specificity of the new antitetrameric NC16A ELISA were 89.9 and 97.8% respectively. The study also concluded that the levels of circulating autoantibodies against BP180 paralleled disease activity in the pemphigoid patients. Alternatively, BP may be diagnosed by investigation of the blister fluid. Although the blister fluid is not a more sensitive substrate than serum, obtaining the fluid involves a less traumatic procedure than venepuncture, making it particularly applicable to children and elderly patients. This may be a useful adjunct method for detecting BMZ antibody titer, subclass, and complement fixing activity in BP.216

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12.3.3.1 Prevention of Bullous Pemphigoid In 1970, drug-induced BP was first reported secondary to salicylazosulfapyridine in an 11-year-old child.16 The association between drugs and BP is being increasingly reported in the literature including frusemide, penicillins, sulfasalazine, and ibuprofen.178 Shachar et  al178 postulated that nonimmunological mechanisms involve splitting at the dermoepidermal junction in drug-induced BP, independent of autoantibodies or other immune factors. Immunological mechanisms are generally of two types. Firstly, the drug produces an antigenic stimulus or, secondly, the drug has a direct regulatory effect on the immune system and results in immune dysregulation and autoantibody production. Calcium channel blockers may result in drug induced BP. Brenner et al concluded that drug induced BP may be as a result of induced alterations in calcium concentrations.30 The study found that normal human skin explants cultured in the presence of nifedipine at different concentrations resulted in intraepithelial splitting (pemphigus type) which showed cell–cell dyshesion among the keratinocytes and subepithelial splitting (pemphigoid type) displaying dermoepidermal cleft formation. The study also concluded that the type of pathological change was donor-specific and not concentration-related.30 This study has not been reproduced elsewhere, however. Several case reports have been published linking penicillamine as a causative factor for BP.127,131,202 There is strong evidence to suggest that drug-induced pemphigoid reverses with cessation of the offending medications and hence clinicians must be vigilant when drug-induced pemphigoid is suspected.

12.3.4 Pemphigoid Gestationis Pemphigoid gestationis, previously referred to as herpes gestationis, is a pregnancy-associated nonviral autoimmune subepidermal blistering disease. It is not related to herpes virus infections; the old term herpes gestationis rather describes the occurrence of herpetiform lesions as part of the clinical picture of this condition.58, 179 Gestational pemphigoid is also known as “herpes gestationis” or “pemphigoid gestationis.” It typically occurs during the second or third trimesters

12  Diagnosis and Prevention of Bullous Diseases

of pregnancy and resolves after delivery. It clinically presents with urticarial plaques, which develop into tense vesicles in the periumbilical area. The lesions may generalize and typically reappear in subsequent pregnancies. This condition is immunologically identical to BP. Linear deposition of C3 and, less frequently, of immunoglobulin G along the cutaneous BMZ, detected on direct immunofluorescence microscopy are immunopathological hallmarks of pemphigoid gestationis.179 Indirect complement fixation immunofluorescence identifies circulating immunoglobulin G autoantibodies, termed herpes gestationis factor and is identified in the sera of the majority of pemphigoid gestationis patients. Deposition of immunoreactants to the upper portion of the lamina lucida, directly beneath the plasma membrane of basal keratinocytes is evident on immunoelectronmicroscopy.179 The 16th noncollagenous A domain of BP antigen 180 is the major target of autoantibodies in pemphigoid gestationis.43,79,128,182 The antigenic sites are clustered within the membraneproximal portion of this domain.43,128,182,183 ELISA using recombinant BP antigen 180 is a sensitive tool for the detection and monitoring of levels of autoantibodies in pemphigoid gestationis.183 Gestational pemphigoid may be rarely associated with a choriocarcinoma, hydatiform mole, or premature birth. It is clinically important to differentiate PG from polymorphic urticarial plaques of pregnancy (PUPPP). Both conditions have similar presentations and have differing fetal and maternal prognostic implications. Powell et al162 found NC16a ELISA as highly sensitive and highly specific in differentiating PG from PUPPP, and a valuable tool in the serodiagnosis of PG.

12.3.5 Mucous Membrane Pemphigoid MMP, formerly known as cicatricial pemphigoid, is a heterogeneous group of autoimmune subepidermal blistering diseases associated most commonly with autoantibodies to BP 180 and less frequently with those to laminin 5 or type VII collagen. In addition, a few cases have been described with autoantibodies to the b4 subunit of a6b4 integrin.126 MMP is an autoimmune bullous disease that primarily affects mucous membranes leading to a scarring phenotype. This is in contrast to BP where healing

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predominantly occurs without scarring. Patients can be classified as low or high risk. Low-risk patients have lesions which are limited to the oral mucosa and skin. High-risk patients have involvement of other mucosal surfaces resulting in significant morbidity. MMP patients produce autoantibodies to two recognized components of the dermoepidermal BMZ: BP180 and laminin 5 (Lam332).18 IgG reactivity to Lam332 of the MMP and BP sera was not significantly associated with IgG reactivity against other autoantigens of the BMZ, such as BP180 or BP230. Thus, the established Lam332 ELISA may be a valuable novel diagnostic and prognostic parameter for MMP.18

12.3.6 Epidermolysis Bullosa Acquisita EBA is an acquired bullous disease characterized by immunoglobulin G (IgG) autoantibodies that react with type VII collagen in the anchoring fibrils, resulting in bullae formation at the dermoepidermal junction.210 The autoantibodies specifically bind to the 145-kDa amino-terminal domain (NC1).122,208 EBA is a rare disease with an incidence of 0.17–0.26/million people in Western Europe and usually presents in the fourth to fifth decades of life, but has been reported in childhood.20,84,218 Roenigk et al172 was the first to set the initial diagnostic criteria for EBA. The etiology of EBA is unknown; however an autoimmune pathogenesis is postulated.209,210 Bullous systemic lupus erythematosus (SLE) compared with EBA also display autoantibodies against type VII collagen.73 The association of EBA and bullous SLE with HLA major histocompatibility (MHC) class II cell surface antigen, HLA-DR2 further supports the autoimmune hypothesis for EBA (Fig. 12.5).74,96 There are two main phenotypes. These include the classic noninflammatory mechanobullous type and the inflammatory type. Patients with the classic noninflammatory mechanobullous type have marked skin fragility with blisters and erosions at trauma sites. Healing results in scarring and milia. The inflammatory type71 can be difficult to differentiate from BP, cicatricial pemphigoid, and chronic bullous dermatosis of childhood.151 Previous studies have reported that at least 50% of patients with EBA show a BP-like clinical presentation and 10% of patients with the clinical presentation of BP may actually have EBA.72

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VII collagen. This study also showed that passive transfer of EBA autoantibodies directed against the CMP subdomain into mice are pathogenic and recommended that further fine mapping of the pathogenic epitope to a smaller region with the 227 AA CMP subdomain may also facilitate the development of effective peptide therapy for EBA.

12.3.7 Dermatitis Herpetiformis

Fig. 12.5  Milia and atrophic scarring on the dorsal fingers in classical epidermolysis bullosa acquisita (EBA). Sites exposed to chronic trauma have most of the blistering

On direct and indirect immunofluorescence testing, linear IgG and C3 deposits on the basement membrane are found in both BP and EBA.62 Dermal–epidermal separation with sodium chloride or suction can be a useful technique demonstrating IgG deposits at the DEJ, but immunoblotting confirms the diagnosis.103,115 Direct immunoelectron microscopy is the gold standard of diagnosis and demonstrates IgG deposits either within or below the lamina densa of the BMZ.41 Blisters in EBA and bullous systemic lupus erythematosus (BSLE) are due to defective adhesion of the lamina densa subregion of the epithelial basement membrane to the underlying dermis. Previous studies of a small number of EBA patients show recognition by autoantibodies of proteolytic fragments containing the 145-kDa noncollagenous domain of type VII collagen. Interference with the adhesion function of type VII collagen may occur due to antibodies binding to fibronectin homology regions within the 145-kDa noncollagenous domain and contribute to lamina densadermal dysadhesion in epidermolysis bullous acquisita and bullous SLE.75 Lapiere et  al identified four major immunodominant epitopes localized within the amino-terminal, noncollagenous (NC-1) domain in patients with EBA. Sera from patients with bullous SLE (BSLE) revealed a similar pattern of epitopes to EBA, suggesting that the same epitopes could serve as autoantigens in both blistering conditions. Chen et  al42 recently described that the pathogenic antibodies in EBA have been shown to bind to the cartilage matrix domain (CMP) of type

DH is a relatively rare skin disorder with an estimated incidence of 1:10,000 in the United Kingdom and typically presents in patients in their third or fourth decades. In Anglo-Saxon and Scandinavian populations the prevalence is between 10 and 39 per 100,000. DH is much less common in blacks and Asians. Men are slightly more likely to be affected than females with a ratio of approximately 3:2.46 The typical lesions in DH include intensely pruritic eruptions of erythematous papules or vesicles distributed symmetrically along extensor surfaces. The areas most commonly affected are the extensor surfaces of the elbows and knees, and the buttocks and scalp. The diagnosis of DH is based on clinical presentation, biopsy for hematoxylin and eosin, and direct immunofluorescence.198 Definitive diagnosis of DH depends on the direct immunofluorescence finding of granular or fibrillar IgA deposits along the BMZ.161 In DH, dermal papillary edema and neutrophil infiltration are seen. A biopsy of an intact vescicle demonstrates a subepidermal blister with neutrophils. The hallmark finding on direct immunofluorescence testing in DH is granular deposition of IgA in the dermal papillae of perilesional skin.70,146,220 DH typically has a chronic course with exacerbations and remissions. DH can be associated with a gluten-sensitive enteropathy which is identical to Celiac disease (CD). Most affected patients are asymptomatic however may develop steatorrhea, abnormal D-xylose absorption, or anemia caused by iron or folate deficiency.114 Two-thirds of patients have a small intestinal enteropathy with villous atrophy as seen in CD. However, the remaining third also show evidence of gluten sensitivity in the intestine. Gluten challenge in these patients results in villous atrophy. The initial treatment of the rash is gluten withdrawal in combination with one of the following three drugs: dapsone, sulphapyridine, or

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sulphamethoxypyridazine.69 Despite DH being a skin manifestation of CD, many patients with DH may not complain of gastrointestinal symptoms.146 Patients with DH have a high incidence of autoimmune disorders including thyroid disease, pernicious anemia, and insulin-dependent diabetes, and should be screened for these conditions on a yearly basis. There is also an increased incidence of lymphoma.69 DH patients can suffer from both B-Cell and T-cell lymphomas. Hervonen et  al97 concluded that patients adhering to a strict gluten-free diet had a reduced incidence of lymphoma. DH must be considered as a differential diagnosis for patients with a diagnosis of eczema, unresponsive to treatment. Eczema generally presents in early childhood, characterized by intraepidermal vesicles and bullae at sites of spongiosis.19,159 Screening for DH can be performed by testing for tissue transglutaminase antibodies or antiendomysial antibodies (AEmA).38,156 However, the gold standard is a skin biopsy for routine histologic examination and direct immunofluorescence.76 In summary, key findings that can confirm a diagnosis of DH include: clinical findings, DIF detection of typical junctional IgA deposits, and positive serum tests for coeliac disease. Any two of these three findings are consistent with DH.21 Adherence to a strict gluten-free diet requiring avoidance of foods containing wheat, rye, or barley can prevent outbreaks of DH.69

12.3.8 Linear IgA Dermatosis LAD, an acquired subepidermal blistering skin disease, presents with vesicular or bullous skin lesions, often with herpetiform arrangement, and is associated with intense burning and pruritus. It can be differentiated from DH and BP by the linear deposits of IgA in the BMZ. The disease is not associated with a glutensensitive enteropathy. Histopathological findings include subepidermal blisters and intrapapillary microabscesses. There are two clinical phenotypes reported: adult and childhood LAD (chronic bullous dermatosis of childhood). Childhood LAD usually remits in 64% of subjects by the age of 6–8 years.50 The adult type of LAD predominantly presents in the fourth decade or later, has a slight female predisposition, and a remission rate of 48%.204

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LAD is caused by the presence of IgA autoantibodies against different dermoepidermal antigens and is characterized by a homogeneous linear band of IgA deposition along the BMZ.167 Frequently recognized antigens are a 180-kDa protein, presumably BP antigen II, a 120-kDa, and a 97-kDa molecule, related proteins associated with breakdown products of collagen type XVII.219, 221 The following antigenic proteins are also reported: BP230,78 collagen VII90, 209 and antigens of molecular weights of 100, 110–120, 145, 160–180, 200, 220, 230, 255, and 285 kDa.53, 205, 212 LAD1 and LADB97, BP 230, LAD 285, and collagen VII are the target antigens.99,132 EM studies have shown that serum from patients with LAD binds to the lamina lucida as well as the sublamina densa regions.107 IgA autoantibodies also bind to the NC16 transmembrane epitope as well as the COL15 and Ecto 2 epitopes, located at the carboxyl terminus of the ectodomain in BP 180.219,41 The gold standard for diagnosis of LAD is direct immunofluorescence showing linear deposits of IgA along the BMZ.39

12.3.8.1 Prevention Collier et al45 stated that there were no contraindications to pregnancy in patients with LAD, and recommended that therapy be reduced or ceased whenever possible during pregnancy, with particular emphasis on counseling regarding the possibility of relapse post partum. Medications reported to induce LAD include amiodarone, ampicillin, captopril, cefamandole, cyclosporine, diclofenac, glibenclamide, interferon-[gamma], interleukin 2, lithium, penicillin G, phenytoin, piroxicam, somatostatin, sulfamethoxazole/trimethoprim, and vigabatrin.117, 160 Up to two-thirds of LAD cases may be drug-induced, and vancomycin is the offending drug in approximately half of the drug-induced LAD cases.160 Vancomycin-induced LAD (VILAD) has a heterogeneous clinical presentation. It may be difficult to differentiate VILAD from other common blistering disorders, such as BP or DH.121 VILAD can present with targetoid erythema multiforme-like lesions, papules, vesicles, and bullae, predominantly located on the extremities (90%) and trunk (77%).144 Histological findings in VILAD include subepidermal bullae with a predominately neutrophilic infiltrate and basal cell vacuolization and these features distinguish it from other blistering conditions such as PF or

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PV.144 Clinical differentials for VILAD include ­erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis. VILAD can be distinguished morphologically from these conditions by the absence of interface changes and keratinocyte necrosis.140, 148 Perilesional skin biopsy DIF in VILAD reveals strong linear deposition of IgA along the BMZ, whereas BP is characterized by a linear IgG deposition along the BMZ. VILAD cannot be differentiated from idiopathic LAD, but the differing clinical course of these diseases suggests differing pathogenesis.144 Sponta­ neous remission post vancomycin withdrawal has been observed in previously reported cases of VILAD. Based on available evidence, autoantibody mediated bullae formation is postulated as the pathogenesis of VILAD.121,168,206

12.3.9 Other Drug-Induced Bullous Diseases 12.3.9.1 Toxic Epidermal Necrolysis Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening, bullous cutaneous diseases generally considered as immune-mediated reactions to drugs resulting in severe cutaneous adverse reactions (SCAR), characterized by epidermal necrosis, extensive detachment of the epidermis, erosions of mucous membranes, and severe constitutional symptoms.85 The majority of TEN cases are related to chemicals systemically administered as drug therapy. The drugs implicated in most series were antibacterial sulfonamides, anticonvulsants, allopurinol, pyrazolone derivatives, and, less frequently, other NSAIDs.93 The SCAR study included 245 patients with TEN and SJS in Europe and confirmed the responsibility of the “classical culprit” drugs: antibacterial sulfonamides (cotrimoxazole); aromatic anticonvulsants (phenobarbital, phenytoin, carbamazepine); some antibiotics (aminopenicillins, quinolines, cephalosporins); some NSAIDs (tenoxicam, piroxicam), chlormezanone, and allopurinol.173 Most of these drugs are therapeutic and may not be avoided, as the overall risk of SCAR is low. However, if there are early signs of SCAR, then these drugs are the likeliest causes and should be ceased. They should then be avoided completely in future, as

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these are potentially life-threatening drug reactions. Wearing a medicalert bracelet with the name of the culprit is worthwhile as a preventative to being given the SCAR-inducing drug again.

12.4 Infective Causes Herpes simplex virus (HSV), also known as Human Herpes virus, has two strains: HSV1 and HSV2 and typically causes blisters in the skin, mucus membranes or the genitals. HSV becomes latent after the primary infection in the cell bodies of the nerves in the area of the primary infection. Transmission of the virus occurs with contact of carriers with active HSV. The vectors for HSV transmission include saliva, semen, vaginal fluid, and shed skin from active lesions. Herpes may also be transmitted to an infant during childbirth, which may result in aseptic meningitis. HSV1 may be prevented by simple measures such as not kissing when active lesions are present, and HSV2 can be prevented by barrier contraception and avoidance of sex when the blisters are active; however viral shedding may occur even without blisters. Erythema multiforme (EM) is a disease of multiple etiologies and often recurs. It results in a polymorphic eruption caused by exposure to medication or various infections, in particular HSV.13,119 The most common predisposing factor for EM is HSV. Other causes include mycoplasma and fungal disease. The medications predisposing to EM, outlined in the SCAR study, include: antibacterial sulfonamides, anticonvulsants (phenobarbital, phenytoin, carbamazepine, and valproic acid), oxicam NSAIDs, chlormezanone, allopurinol, and acetaminophen in countries other than France, imidazole antifungal agents, corticosteroids for systemic use, aminopenicillins, cephalosporins, quinolones, and tetracyclines.173 Differences in case selection in terms of subsets of EM studied may have partly resulted in wide variations in the detection of HSV DNA (36–75%) by polymerase chain reaction (PCR) in EM.145 Kokuba et  al119 state that HSV associated erythema multiforme pathology includes a delayed-type hypersensitivity component and is mechanistically distinct from drug-induced erythema multiforme. Diagnostic tests for HSV-induced erythema multiforme include serum hematology and biochemistry tests, blood and

12  Diagnosis and Prevention of Bullous Diseases

vesicle cultures, punch biopsy for histological examination, and PCR. Oral acyclovir is used to suppress erythema multiforme associated with HSV. EM is not prevented if oral acyclovir is administered after a herpes simplex recurrence is evident, and it is of no value after erythema multiforme has occurred. There is some question whether prevention of erythema multiforme may be achieved with continuous topical treatment with acyclovir to sites affected by recurrent herpes.101 Herpes zoster (HZ), commonly known as shingles, is a disease caused by the varicella zoster virus (VZV) and is characterized by a painful, vesicular skin rash. The virus may remain dormant in the nerve cell bodies and trigger latent infections, typically in a dermatomal distribution. It particularly affects immunocomprised patients, resulting in significant morbidity. Clinical findings are often sufficient to diagnose HZ. Atypical presentations may be confirmed on viral culture, direct immunoflourescence assay or PCR. Laboratory techniques can be particularly helpful when differentiating between VZV and zosteriform herpes simplex.201 Oxman et al150 found that use of the zoster vaccine, live attenuated Oka/Merck VZV vaccine, reduced the incidence of postherpetic neuralgia by 66% and HZ by 51%, and concluded that the vaccine markedly reduced the morbidity and postherpetic neuralgia associated with HZ in patients older than 60. Also, the treatment of HZ with oral acyclovir can reduce residual pain after 6 months in almost 50% of immunocompetent adults.108 Wood et  al207 found that acyclovir reduced zoster-related pain duration and prevalence by half. Combined acyclovir and prednisone therapy can improve quality of life in relatively healthy patients older than 50 years of age with localized HZ.203 Orf virus is an exanthemous disease caused by a parapox virus predominantly affecting sheep and goats. Orf is a zoonotic disease and may be transmitted to humans via direct contact from the infected animals. Infection in humans results in a self-limiting and benign course in immunocompetent individuals resulting in purulent papules with localized symptoms. Prevention of the Orf virus can be achieved by using gloves and good personal hygiene, particularly when working with infected animals.149 Acknowledgment  The authors would like to thank Ms. Kezia Gaitskell of Oxford University Medical School for proofreading of this manuscript.

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S. S. Venugopal and D. F. Murrell 175. Ruocco V, Rossi A, Astarita C, et al A congenital acantholytic bullous eruption in the newborn infant of a pemphigus mother. Ital Gen Rev Dermatol. 1975;12:169–174 176. Scott JE, Ahmed AR. The blistering diseases. Med Clin North Am. 1998;82:1239–1283 177. Scully C. A review of mucocutaneous disorders affecting the mouth and lips. Ann Acad Med Singap. 1999;28: 704–707 178. Shachar E, Bialy-Golan A, Srebrnik A, Brenner S. “Twostep” drug-induced bullous pemphigoid. Int J Dermatol. 1998;37(12):938–939 179. Shimanovich I, Bröcker EB, Zillikens D. Pemphigoid gestationis: new insights into the pathogenesis lead to novel diagnostic tools. Br J Obstet Gynaecol. 2002;109: 970–976 180. Shimizu H, Suzumori L. Prenatal diagnosis as a test for genodermatoses: its past, present and future. J Dermatol Sci. 1999;19:1–8 181. Sison-Fonacier L, Bystryn JC. Heterogeneity of pemphigus vulgaris antigens. Arch Dermatol. 1987;123:1507–1510 182. Sitaru C, Powell J, Shimanovich I, et al Pemphigoid gestationis: maternal sera recognise epitopes restricted to the N-terminal portion of the extracellular domain of BP180 not present on its shed ectodomain. Br J Dermatol. 2003; 149:420–422 183. Sitaru C, Powell J, Messer G, Brocker EB, Wojnarowska F, Zillikens D. Immunoblotting and enzyme-linked immunosorbent assay for the diagnosis of pemphigoid gestationis. Obstet Gynecol. 2004;103(4):757–763 184. Sitaru C, Dahnrich C, Probst C, et al Enzyme-linked immunosorbent assay using multimers of the 16th non-collagenous domain of the BP180 antigen for sensitive and specific detection of pemphigoid autoantibodies. Exp Dermatol. 2007;16(9):770–777 185. Späth S, Riechers R, Borradori L, Zillikens D, Bdinger L, Hertl M. Detection of autoantibodies of various subclasses (IgG1, IgG4, IgA, IgE) against desmoglein 3 in patients with acute onset and chronic pemphigus vulgaris. Br J Dermatol. 2001;144:1183–1188 186. Stanley JR. Pemphigus. In: Freedberg IM, ed. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York: McGraw Hill; 1999:654–666 187. Stanley JR. Bullous pemphigoid. In: Freedberg IM, ed. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York: McGraw Hill; 1999:574–580 188. Szafer F, Brautbar C, Tzfoni E, et al Detection of diseasespecific restriction fragment length polymorphisms in pemphigus vulgaris linked to the DQw1 and DQw3 alleles of the HLA-D region. Proc Natl Acad Sci USA. 1987;84: 6542 189. Tidman M, Eady RA. Hemidesmosomes heterogeneity in junctional epidermolysis bullosa revealed by morphometric analysis. J Invest Dermatol. 1986;86:51–56 190. Tidman M, Eady RA. Diagnosis and diagnostic techniques. In: Wojnarowska F, Briggaman RA, eds. Management of Blistering Diseases. London: Chapman and Hall; 1990 191. Todd JA, Acha-Orbea H, Bell JI, et al A molecular basis for MHC class II–associated autoimmunity. Science. 1988; 240:1003 192. Tsuji-Abe Y, Akiyama M, Yamanaka Y, Kikuchi T, SatoMatsumura KC, Shimizu H. Correlation of clinical severity

12  Diagnosis and Prevention of Bullous Diseases and ELISA indices for the NC16A domain of BP180 measured using BP180 ELISA kit in bullous pemphigoid. J Dermatol Sci. 2005;37(3):145–149 193. Tur E, Brenner S. Diet and pemphigus. In pursuit of exogenous factors in pemphigus and fogo selvagem. Arch Dermatol. 1998;134:1406–1410 194. Vailley J, Szepetowski P, Pedeutour F, et al The genes for nicein/kalinin 125kDa and 100kDa subunits, candidates for junctional epidermolysis bullosa, map to chromosome 1q32 and 1q25–q31. Genomics. 1994;21:286–288 195. Vidal F, Aberdam D, Miquel C, et al Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet. 1995;10:229–234 196. Vu TN, Lee TX, Ndoye A, et al The pathophysiological significance of nondesmoglein targets of pemphigus autoimmunity. Development of antibodies against keratinocyte cholinergic receptors in patients with pemphigus vulgaris and pemphigus foliaceus. Arch Dermatol. 1998;134(8): 971–980 197. Waananukul S, Pongprasit P. Childhood pemphigus. Int J Dermatol. 1999;38:29–35 198. Warren SJ, Cockerell CJ. Characterization of a subgroup of patients with dermatitis herpetiformis with nonclassical histologic features. Am J Dermatopathol. 2002;24(4): 305–308 199. Wasserstrum N, Laros RK Jr. Transplacental transmission of pemphigus. JAMA. 1983;249(11):1480–1482 200. Weinberg ED. Pregnancy-associated depression of cellmediated immunity. Rev Infect Dis. 1984;6:814–831 201. Weinberg JM. Herpes zoster: epidemiology, natural history, and common complications. J Am Acad Dermatol. 2007;57 (6):130–135 202. Weller R, White MI. Bullous pemphigoid and penicillamine. Clin Exp Dermatol. 1996;21(2):121–122 203. Whitley RJ, Weiss H, Gnann JW Jr, et al Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann Intern Med. 1996;125(5): 376–383 204. Wojnarowska F, Marsden RA, Bhogal B, Black MM. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol. 1988;19:792–805 205. Wojnarowska F, Whitehead P, Leigh IM, Bhogal BS, Black MM. Identification of the target antigen in chronic bullous disease of childhood and linear IgA disease of adults. Br J Dermatol. 1991;124:157–162 206. Wojnarowska F, Allen J, Collier P. Linear IgA disease: a heterogenous disease. Dermatology. 1994;189:52–56 207. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo controlled trials. Clin Infect Dis. 1996;22:341–347

135 208. Woodley DT. Epidermolysis bullosa acquista. Prog Dermatol. 1988;22:1 209. Woodley DT, Briggaman RA, O’Keefe EJ, Inman AO, Queen LL, Gammon WR. Identification of the skin basement-membrane autoantigen in epidermolysis bullosa acquisita. N Engl J Med. 1984;310:1007–1013 210. Woodley DT, Burgeson RE, Lunstrum G, et al Epidermolysis bullosa acquisita antigen is globular carboxyl terminus of type VII procollagen. J Clin Invest. 1988;81:683–687 211. Wu H, Wang ZH, Yan A, et al Protection against pemphigus foliaceus by desmoglein 3 in neonates. N Engl J Med. 2000;343:31–35 212. Yamane Y, Sato H, Higashi K, Yaoita H. Linear immunoglobulin A (IgA) bullous dermatosis of childhood: identification of the target antigens and study of the cellular sources. Br J Dermatol. 1996;135:785–790 213. Yiasemedes E, Walton J, Marr P, Villaneuva EV, Murrell DF. A comparative study between transmission electron microscopy and immunofluorescence mapping in the diagnosis of epidermolysis bullosa. Am J Dermatopathol. 2006;28(5):387–394 214. Yiasemides E, Trisnowati N, Su J, Dang NN, Klingberg S, Marr P, Chow CW, Orchard D, Varigos G, Murrell DF: Clinical heterogeneity in recessive epidermolysis bullosa due to mutations in the keratin 14 gene, KRT14. Clin Exp Dermatol. Nov 2008; 33(6):689–97 215. Yoshida M, Hamada T, Amagai M, et  al Enzyme-linked immunosorbent assay using bacterial recombinant proteins of human BP230 as a diagnostic tool for bullous pemphigoid. J Dermatol Sci. 2006;41(1):21–30 216. Zhou S, Wakelin SH, Allen J, Wojnarowska F. Blister fluid for the diagnosis of subepidermal immunobullous diseases: a comparative study of basement membrane zone autoantibodies detected in blister fluid and serum. Br J Dermatol. 1998;139(1):27–32 217. Zillikens D. Acquired skin disease of hemidesmosomes. J Dermatol Sci. 1999;20:134–154 218. Zillikens D, Wever S, Roth A, Hashimoto T, Brocker EB. Incidence of autoimmune subepidermal blistering dermatosis in a region of central Germany. Arch Dermatol. 1995; 131:957–958 219. Zillikens D, Herzele K, Georgi M, et al Autoantibodies in a subgroup of patients with linear IgA disease react with the  NC16A domain of BP180. J Invest Dermatol. 1999; 113:947–953 220. Zone JJ. Skin manifestations of celiac disease. Gastroen­ terology. 2005;128:S87–S91 221. Zone JJ, Taylor TB, Meyer LJ, Petersen MJ. The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAG 2. J Invest Dermatol. 1998;110: 207–210

Diagnosis and Prevention of Atopic Eczema

13

Stefan Wöhrl

13.1 Introduction Atopic eczema (AE) is a chronic, highly prevalent, inflammatory skin disease with a characteristic phenotype and distribution pattern. A variety of terms have been created to describe this characteristic phenotype. The historic terms “neurodermitis” and “neurodermatitis”1 were replaced later by the term “atopic dermatitis” and finally “AE.”2 The term AE will be used in this chapter because it is the proposed term in the World Allergy Organization (WAO) guideline of 2004.2 AE often occurs together with allergic rhinoconjunctivitis and bronchial asthma. These three entities are referred to as “atopic diseases” or “allergic diseases.” The atopic diseases have the highest levels of incidence in the first decades of life.3 Typically, AE is the earliest symptom in the life of infants, then continues to allergic rhinoconjunctivitis and, finally, ends with allergic bronchial asthma. The term “atopic march” was coined for this natural course of the disease complex.4 Over the past decades, the prevalence of AE has steadily increased to affect now about 1 out of 10 young children and 2 out of 100 adults in the Western societies.5 A large worldwide study with more than 50 participating countries showed that the increase of atopic diseases has become less steep in recent years but is still on the rise.5 How can this be

S. Wöhrl Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases (DIAID), Medical University of Vienna, Vienna, Austria e-mail: [email protected]

explained? Although it has been observed for a long time that the predisposition for atopic diseases is highly inherited,6 human genes cannot have changed within the past century and other factors have to be involved. “Western lifestyle” has often been accused as one of the causes of the “allergy epidemic.”7 The “hygiene hypothesis” postulates that the neonatal immune system needs microbial and parasitic infection for full maturation and that the much-too-clean environment of childhood nowadays shifts the immune system from tolerance toward allergy to environmental allergens.8 Although attractive, this theory has been challenged lately.9 Others speculated that modern housing conditions lead to increased allergen exposition and that this contributes to higher rates of sensitization to indoor allergens such as storage and house dust mites in 33% or to cat dander in 13% of the patients suffering from AE when compared with nonatopic controls (25 and 4%, respec­ tively).10 So, environmental conditions have changed. Both abnormal immunologic response to harmless allergens and inadequate epidermal barrier function lead to the development of AE; “Western lifestyle,” for example, directly changed environmental factors affecting the skin. The frequency of daily personal washing has increased dramatically in the past decades. The average use of water for this purpose increased from 11 L in 1961 to 51 L in 1997.11 Using soap and other detergents during washing aggravates the situation and has also increased. The use of soap and personal wash detergents in the UK increased from £76 million in 1981 to £453 million (inflation adjusted) in 2001 while the population remained nearly stable.12

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_13, © Springer-Verlag London Limited 2010

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13.2 Pathophysiology 13.2.1 Skin Physiology The skin is the largest organ and serves as a barrier between the interior and the exterior world. It protects the body from desiccation and from xenobiotics. The epidermal barrier function has been visualized as a “brick wall” with the corneocytes – the flattened keratinocytes of the upper epidermis – serving as the bricks and the lipid lamellae as cement13 (Fig. 13.1).12, 14 The lipid lamellae are secreted by the corneocytes and are composed mainly of ceramides, cholesterol, fatty acids, and cholesterol esters.15 These substances form the socalled “cornified envelope” and surround the corneocytes. The main function of the lipid lamellae is the prevention of water loss. The integrity of these lamellae can be reduced by washing the skin with mild detergents, e.g., soaps. Other important structures are the corneodesmosomes, modified desmosomes of the Stratum corneum. They lock the corneocytes together. Corneodesmosomes provide the Str. corneum with the strength to resist against shearing forces.12 These structures can be visualized as iron rods (Fig. 13.1). Upon normal epidermal turnover, the corneodesmosomes are cleaved in the upper corneal layer by endogenous serine proteases such as the Str. corneum chymotryptic enzyme to facilitate epidermal shedding. A fine balance has to be kept for maintaining epidermal homeostasis. Exaggerated corneodesmolysis by endogenous or Staphylococci and house dust mite enzymes leads to epidermal thinning and decreased barrier function, decelerated endogenous cleavage to squamation.

Cork et  al.12 speculate that skin thickness is an important key to explain the mystique behind the predilection sites of AE. The eyelids are reported to have the lowest skin thickness, followed by genitals, flexural forearm and the posterior auricular region.12 The thickness of the elbow flexures is unknown but the ones of the palms and soles are the thickest. Skin thickness is also associated with percutaneous penetration of topically applied drugs like corticosteroids. Neonatal skin is not fully mature in respect of barrier function and percutaneous penetration is elevated in compare with adult skin.16

13.2.2 Genetics There is a strong genetic background for all kinds of atopic diseases. Until recently, the focus has been on the immunologic side. In 1999, Taïeb14 hypothesized that genes involved in the epidermal barrier function might also play an important role in the etiology of AE. In a very important study, Palmer et al.17 showed that two loss-of-function deletions in the gene encoding for filaggrin are associated with a high risk for suffering from AE. Around 49% of the European population are heterozygous carriers for this allele.18 Interestingly, carriers of the mutated allele are not only at higher risk for AE but also for bronchial asthma. A recent metaanalysis of nine studies on filaggrin mutations in AE pinned the odds ratio for carriers down to four when compared with noncarriers.18 Also other factors contribute to the reduced barrier function of atopic skin; for example, the normal Corneocyte Lipid lamella Corneodesmosome

Stratum corneum

Fig. 13.1  The “brick wall” model of the upper epidermis, modified after Taïeb14 and Cork et al12: in this model, the corneocytes – the flattened keratinocytes of the upper epidermis – are visualized as bricks and the lipid lamella, almost a synonym for the “cornified envelope,” as cement. The main function of the lipid lamella is to waterproof the epidermis. The corneodesmosomes are visualized as iron rods that provide resistance to shearing forces

13  Diagnosis and Prevention of Atopic Eczema

un-inflamed skin of AE patients contains less ceramide and sphingosine than that of nonatopic controls.15

13.2.3 Immunology and Allergy 13.2.3.1 Immunology Although the breakdown of the skin barrier is an important aspect in the initiation phase of AE, there has been the long-term clinical observation that using potent immunosuppression (e.g., cyclosporine) stops skin inflammation and leads to long-term remission. The immunologic response to antigens in atopic patients differs from nonatopic controls. Atopics have a pronounced immunological response of Th2 cells to external antigens with a characteristic cytokine profile, namely interleukin-4 (IL-4), IL-5, IL-9, and IL-13. IL-4 differentiates naïve T-helper 0 cells (Th0) into Th21 and together with IL-13 promotes isotype-switching of B-cells to IgE production.19 IL-4 upregulates Fce [epsilon] receptor I expression on dendritic cells facilitating allergen uptake in dendritic cells and allergen presentation to other immunologic cell types. Finally, it suppresses the production of Th1-type cytokines like IFN-g (gamma) and IL-12.20 IL-5 attracts and stimulates the growth of eosinophils. These are the reasons for the elevated serum IgE levels and the eosinophilia in differential blood counts from patients suffering from atopic diseases. Interestingly, AE lesions are biphasic in nature. Th2 cytokines predominate in acute AE lesions, whereas the Th1 cytokines IFN-g (gamma) and IL-12 outweigh in chronic eczema.21 Regulatory T-cells are key players in self-tolerance and tolerance to environmental antigens such as allergens. Their upregulation is a key feature of regaining tolerance to allergens with specific immunotherapy.22 Verhagen et  al.23 showed that regulatory T-cells are missing in AE skin lesions.

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of up to 2 years and may cause skin rashes in around 35% of pediatric AE patients.24 Milk protein, hen’s egg, soy, wheat, peanut, tree nut, fish, and shellfish are the most important food allergens. Among them, milk is the predominant allergen in infants. The prognosis for food allergy in young children is good. Eighty percent will outgrow their symptoms by their fifth birthday with the exception of peanut allergy, which persists in 80% of the patients.24 Three-and-a-half to 4% of adult Americans have specific IgE to food allergens.24 Contrasting AE as the main manifestation of food allergy in young children, food-allergic adults tend to suffer from other type-1 allergic manifestations like urticaria, angioedema, gastrointestinal symptoms, or anaphylaxis. Sensitization to aeroallergens like birch, grass, and ragweed pollen as well as house dust mite and cat dander comes into fore from the age of 2 years and above. The degree of sensitization to house dust, mite, and fungal allergens was shown to correlate with symptom severity in AE patients.25 Patients with a primary sensitization to pollen aeroallergens may cross-react to the same allergenic components in food laying the base for typical syndromes (e.g., the “oral allergy syndrome” to apples and tree nuts in birch-pollen–allergic patients or the “mugwort-celery-spice” syndrome in patients sensitized to profilins).26 A subset of severely affected AE patients has specific IgE against the superoxide manganese dismutase, an inducible human stress enzyme. It is one of several described self-antigens that were termed “atopy related autoantigens.”20 Patients with high levels of self-IgEautoantibodies suffer from a more severe disease than those without and belong to the subgroup with an onset in early childhood.27 The human superoxide manganese dismutase cross-reacts with that from the skin-colonizing yeast Malassezia sympodialis. A high colonization with Malassezia sympodialis was described as an important trigger for AE.28

13.2.4 Disease-Aggravating Factors 13.2.4.1 Stress and Itch

13.2.3.2 Allergy Sensitization with specific IgE to food and aeroallergens is an important contributor to symptom severity in atopic patients. Food is the major allergen in infants

Patients with AE suffer from chronic itch that typically intensifies periodically. Scratch marks are a frequent clinical sign of severely affected patients. Pruritus has several pathophysiological dimensions:

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• The central “neurogenic” itch is generated in the central nervous system in response to circulating pruritogens as in cholestasis or in response to intraspinal morphines.29 • “Psychogenic” itch is also produced in the central nervous system and aggravated by emotional stress.20 The immune system of patients with AE reacts to psychological stress with a higher elevation of IL-4, IL-5, and CLA+, a T cell activation marker, than healthy controls.30 This means that psychological stress influences an atopic immune system in a more pronounced way than a healthy one. • The peripheral “pruritoreceptive itch” is generated in inflamed skin.29 Itch is mediated by sensory peripheral nerves. Sensory peripheral nerves can be activated by histamine type 1, 2, and 3 receptors as well as by Substance P. Mast cells are an important booster of pruritus by releasing histamine but also other mediators such as tryptase and mast cell chymase.31 Their number is increased in lesional as well as nonlesional skin of atopic patients.32 Dermal contacts between mast cells and peripheral nerve fibers as well as the number of nerval fibers themselves are increased in atopic skin.33 The latter can be (partly) explained by elevated levels of the nerve-growth promoting neurotrophins in the serum of patients with AE.34 IL-31 is a recently described cytokine. Its overexpression in transgenic mice leads to severe pruritus and AE-like dermatitis.35 IL-31 expression is increased in the epidermis of atopic patients when compared with healthy controls.36 Interestingly, the IL-31 serum levels do not differ between both patients groups.

13.2.4.2 Superinfection with Staphylococci and Herpes Virus Exacerbations of AE are often accompanied by infection with Staphylococcus aureus.37 The bacterium S. aureus is not part of the normal skin flora and only 36% of healthy nonatopic children are colonized in their nostrils, the natural reservoir.38 In contrast, more than 90% of inflammatory and 76% of noninflammatory AE skin lesions are colonized with S. aureus.39 S.  aureus produces several enterotoxins that can serve as superantigens.40 A subset of AE patients also produces mea­ surable specific IgE against these superantigens.41 S. aureus produces ceramidase, further aggravating the

S. Wöhrl

lack of ceramides in atopic skin (see Sect.  13.2.1). Also, staphylococcal enterotoxin leads to rapid upregulation of the pruritogenic IL-31 in atopic patients aggravating their itch sensation42 (see Sect. 13.2.4.1). Also, innate immunity is reduced in AE patients. Human skin expresses antibacterial peptides that inhibit bacterial growth of Staphylococci, so-called cathelicidins and b (beta)-defensins. It was shown that the production of both peptides is reduced in lesional as well as nonlesional skin of AE patients.43 Cathelicidins also provide resistance to viral infection. AE patients with a very low epidermal cathelicidin activity are prone to recurrent, severe infections with herpes viruses, the socalled “eczema herpeticum.”44

13.3 Diagnosis of Atopic Eczema 13.3.1 Clinical Presentation The case presentation of AE is age-dependent. While infants typically suffer from facial eczema and a cradle cap – an eczema of the scalp – toddlers and adolescents tend to suffer from flexural eczema as cardinal symptoms. Eyelid eczema is another characteristic presentation in 21% of young adults.45 Other typical variants are neck and hand eczema as well as the socalled “atopic winter feet.” More clinical features of AE in adults are listed Table 13.1.46 The clinical spectrum of AE is very broad, ranging from very mild variants presenting as fingertip eczema (“pulpitis sicca”) to a generalized erythromatous rash.47 In difficult cases, scratch marks can be observed as a sign of the severe pruritus.

13.3.2 Diagnostic Criteria According to the 2004 WAO definition, “atopic dermatitis” should be referred to as “AE.”2 The term AE should stay restricted to patients with elevated total IgE of >150  kU/L and sensitization to aero- and/or food-allergens proved either by skin tests or by measuring specific serum IgE. According to current data, 80% of adult AE patients are monosensitized to at least one allergen and should be classified as AE.20 Formerly, this type of AE was called “extrinsic atopic dermatitis.”1 The other 20% of patients can be classified as

13  Diagnosis and Prevention of Atopic Eczema Table 13.1  Diagnostic features of AE according to Hanifin and Rajka46 Major criteria: 3 of 4 present

Pruritus Typical morphology and distribution of skin lesions Chronic or chronically relapsing dermatitis Personal or family history of atopy

Minor criteria: 3 of 23 present

Xerosis Ichthyosis/palmar hyperlinearity/keratosis pilaris Immediate (type I) skin test reactivity Elevated serum IgE Early age of onset Tendency toward cutaneous infections/impaired cell-mediated immunity Tendency toward nonspecific hand or foot dermatitis Nipple eczema Cheilitis Recurrent conjunctivitis Dennie-Morgan infraorbital fold Keratoconus Anterior subcapsular cataracts Orbital darkening Facial pallor/erythema Pityriasis alba Anterior neck folds Itch when sweating Intolerance to wool and lipid solvents Perifollicular accentuation Food intolerance Course influenced by environmental/emotional factors White dermographism/delayed blanch

suffering from “nonatopic eczema,”2 formerly known as “intrinsic atopic dermatitis.”1 It remains to be seen whether this classification will find acceptance in the dermatologic community. Currently, there are no definitive criteria for the diagnosis of AE. In 1980, Hanifin and Rajka46 were the first to set up rules for the definition of AE. They based their definition on extensive dermatological criteria. Three out of four main and 3 out of 28 minor criteria must be fulfilled for the diagnosis of AE (Table 13.1).46 The UK working party developed much simpler criteria

141 Table 13.2  Diagnostic criteria for diagnosing AE according to the UK working party48 Major criterion: 1 of 1 present

Itchy skin condition in the preceding 12 months

Minor criteria: 3 of 5 present

Onset <2 years History of flexural involvement History of a generally dry skin Personal history of other atopic disease or atopic disease in first degree relatives when age of patient <4 years Visible dermatitis as per photographic protocol

depending on the presence of just one main and three out of five minor criteria (Table 13.2).48 Although the approach of the UK criteria is much simpler, both ways of defining AE show good agreement on comparison.49 Hence, for daily practice, use of the UK criteria seems to be sufficient and is recommended by the British National Institute for Health and Clinical Excellence (NICE) guidelines on the management of AE in children of up to 12 years.50

13.3.3 Allergologic Workup The allergologic workup should begin with a careful dermatological examination. Several clinical scoring systems have been published for objectivation (e.g.,  SCORAD – score atopic dermatitis [1993]). A careful history-taking should give special regard to a family history for atopic diseases, to a worsening of the eczema after exposure to certain foods, to exposure to environmental allergens such as pets or job related allergens, and to hints of other atopic diseases such as bronchial asthma. The performance of skin prick tests and/or the measurement of specific IgE should be performed to assess the sensitization to type-1 environmental and food allergens as well as the measurement of total serum IgE. Under special circumstances, skin prick tests with fresh food may be performed as “prick to prick tests.” A lung function must be performed whenever bronchial asthma is suspected. In daily practice, the clinical relevance of sensitization to foods often remains unresolved. Food challenge

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is the gold standard for the confirmation of the clinical relevance of the sensitization in the patient. It can be performed open label or, in severe cases, as double blind, placebo-controlled, food challenge. The atopy patch test (APT) is derived from the patch test performed for assessing contact dermatitis with type-4 allergens. It was developed with the aim to make oral food challenges superfluous. In an APT, a type-1 allergen is tested either in the form of a commercial extract or as fresh food (e.g., milk) in Finn chambers (Epitest Ltd Oy, Tuusula, Finland) on either the back or the lateral upper arm. The current European guideline recommends using preferably fresh food whenever possible.51 The sensitivity of APTs with fresh food is higher.52 While the specificity of the APT is good, the sensitivity is low, so that its value in daily practice is still a matter of debate.53 Alternative medicine is quite popular among AE patients.54 Some methods of questionable validity are offered by health professionals and nonprofessionals alike. Some of them can cause considerable harm to patients, especially if they are leading to wrong recommendations (e.g., unnecessary elimination diets). The measurement of serum IgG levels to food allergens is one such method. Its clinical value has not yet been demonstrated and should therefore not be performed in AE patients.55

13.3.4 Differential Diagnoses The most important differential diagnoses to AE are other variants of eczema. In adults, irritant eczema often occurs in combination with AE, such as nummular and dyshidrotic (pompholyx) eczema. Palmoplantar psoriasis must be differentiated from AE in patients with exclusive eczema of the palms and soles. Chronic eczema can lead to type-4 sensitization and contact allergy that should be considered as a differential diagnosis.56 Scabies infection must be considered, especially if other family members are also affected. In newborns with a cradle cap, seborrheic dermatitis is an important differential diagnosis. Cutaneous T cell lymphomas should be considered in elderly patients with very chronic eczematous lesions, in particular when they are reappearing at the same sites after several courses of topical corticosteroid treatment.

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Genetic disorders must be considered in young patients as they can mimic AE. Ichthyosis vulgaris is the most common keratinization disorder. One in 250 UK school children is affected. Patients present with dry skin, flexural ichthyosis, and palmar hyperlamellosis. Interestingly, they carry the same mutations in the filaggrin gene that put patients at risk for AE.57 Netherton syndrome is a rare congenital syndrome characterized by ichthyosiform erythroderma, hair shaft abnormalities, and atopic diathesis. It could be linked to a defect in the SPINK5 gene, a serine protease.58 The recently described IPEX syndrome is caused by a very rare mutation of the FoxP3 gene that is essential for a normal function of regulatory T cells. As a consequence, these patients lack the toleranceinducing regulatory T-cells. The phenotype is characterized by an eczematous rash, the early onset of multiple autoendocrinopathies such as type-1 diabetes and highly elevated IgE levels.59 In patients with eosinophilia and elevated serum IgE levels, parasite infections should be considered as a differential.

13.4 Prevention 13.4.1 Primary Prevention (“Fighting the Cause”) Primary prevention strategies are meant for those who are not yet affected. This can be achieved either by avoiding known risks or by promoting “health-sustaining” conditions. In the context of preventing AE, the main strategy has been to avoid exposure to potent allergens (e.g., cat as a major indoor allergen and milk as a prominent food allergen)3 as well as other known risk factors such as cigarette smoke.60 The most direct approach of dietary allergen avoidance is breast-feeding. European61 and American62 guidelines recommend 4–6 months of exclusive breast-feeding in children at risk (with a first degree relative suffering from an allergic disease). If breast-feeding is not possible, the same guidelines recommend using hydrolyzed cow’s milk formulas. There is only little evidence that delaying the introduction of complementary foods beyond the age of 6 months prevents the occurring of atopic disease.62 Elimination diets impose significant harm to small infants

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by withholding essential dietary nutrients. A thorough allergologic work-up is a “must” before recommending elimination diets to parents and food-challenges are needed in cases of doubt. Beyond the age of 3, food allergy is generally outgrown and elimination diets are usually not needed in adolescent or adult AE.63, 64 Dietary restrictions in pregnancy to protect the fetus and for the lactating mother had never been recommended in the European guidelines61 and, due to the lack of evidence, have also been abandoned in the 2008 American guidelines.62 The situation is more complex for nonfood allergens. While the avoidance of cats seem to reduce the arising of allergic asthma,65, 66 primary prevention from house dust mite exposure does not prevent the arising of allergy because children living at high altitudes – where there are practically no house dust mites – develop allergies in the same way as those in the lowlands.67 The second aspect of primary prevention, promoting “health-sustaining conditions,” does not seem to be met by what is called the Western lifestyle.68 Children growing up under more natural anthroposophical lifestyle (e.g., avoidance of vaccination and conventional medication, consumption of more traditional food) within Western societies have a lower prevalence of AE and allergic asthma than controls.69 Another protective factor is early attendance at daycare facilities which has been attributed as a surrogate marker for more episodes of viral infections.3 Growing up among livestock farming is an even stronger preventive environment.72 The change of living conditions when migrating from a country with a low prevalence of allergies to a highly developed country with a high prevalence of allergies increases the risk of atopic diseases.70 De-worming of Gabonese school children led to a higher skin prick test-reactivity to house dust mites.71 These observations have been placed in the context of the “hygiene hypothesis”; resulting in another active intervention approach. Children with a high colonization of commensal and hardly pathogenic germs such as Lactobacilli, Bifidobacteria and Mycobacteria have a low rate of atopic diseases. Alimentation with the addition of these bacteria in the form of “probiotics” led to a reduction of allergic asthma, rhinoconjunctivitis73, 74 and AE.75 However, most of these data come from one group and could not be reproduced sufficiently elsewhere. It is possible that components of “probiotics” such as CpG motifs will be safer, better defined, and have stronger effects in the near future.

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For a prevention of allergic sensitization, preventive allergen vaccinations in nonsensitized infants were proposed before a sensitization occurs, in analogy to preventive vaccination for viral diseases.76 Valenta’s group demonstrated that they could induce allergy-protecting “blocking IgG” antibodies with a genetically modified birch protein that was unable to induce the potentially “anaphylactogenic IgE” antibodies.77 They argue that a preventive allergy vaccination to the most common type-1 allergens could be useful to prevent allergies in all newborns. However, type-1 allergy causes significant morbidity but hardly any mortality. Hence, the necessity to prevent type-1 allergy has a much lower clinical priority than the prevention of potentially life-threatening viral infectious like measles. Currently, the medical community is judging the benefit–risk ratio of a broad allergy vaccination in not-yet allergic infants as an unfavorable one. Maybe this will change sometime in the future. In contrast to the very clear recommendations concerning breast-feeding and using hydrolyzed cow’s milk formulas, all other data on primary prevention strategies are much less clear and the evidence was not validated high enough to include any of these possible intervention methods into the joint American/European PRACTALL guidelines.63, 64

13.4.2 Secondary Prevention (“Preventing Disease Progression”) Only a few possibilities have been tested to stop disease progression in already sensitized individuals. It was shown convincingly that specific immunotherapy (allergy shots) can stop disease progression, reduce the morbidity of allergic asthma and rhinoconjunctivitis, and reduce the acquisition of new allergies.78, 79 Sublingual immunotherapy seems to work in the same way although it has a weaker effect. In contrast, patients with AE did not benefit from specific immunotherapy and, until recently, specific immunotherapy was not recommended in patients with AE. Two recent studies came up showing a reduction of AE-severity after treating eczema patients sensitized to house dust mite with specific immunotherapy.80, 81 For patients suffering from AE and concomitant allergic rhinoconjunctivitis and/or asthma, the situation is clear. They should undergo specific immunotherapy

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for their rhinoconjunctivitis and/or asthma but must be informed that the effect of the specific immunotherapy on AE is yet not clear. For patients with AE and a sensitization to house dust mite and no other atopic diseases more data are needed before specific immunotherapy can be recommended unequivocally.

13.4.3 Tertiary Prevention (“Preventing Complications and Permanent Disabilities”) The treatment of patients with chronic AE is challenging. A stepwise approach depending on the symptom severity was developed by a joint American/European initiative endorsing members of the American Academy of Immunology (AAAI) and the European Academy of Allergy and Immunology (EAACI) called PRACTALL for “practical allergy” (Fig. 13.2).63, 64 13.4.3.1 Topical Therapy Skin Care

Step 1

Fig. 13.2  Stepwise management of patients with atopic eczema (AE) according to the joint American/European PRACTALL guidelines63,64

Step 2

Intensity of disease

Step 3

Step 4

Dry skin is a prominent feature of AE. Hence, the regular use of emollients 2 times a day is the basic treatment for AE patients.50, 56 Emollients should be

applied continuously even if the patient is currently in remission for the prevention of relapses.63, 64 Addition of low concentrations of urea (up to 4%) can increase the rehydrating effect. “Topical emollients are preferentially applied directly after a bath or shower, when the skin is still slightly humid, after gentle drying.”56 Skin hydration can be ameliorated by using bath oils. Hot water, especially showering, and swimming in water with high chlorine concentrations worsens the xerosis in the same way as alcohol used for disinfection. The lack of ceramides is an important factor in the increased transepidermal water loss of atopic skin. New emollients with physiological ceramide concentration (e.g., Atopiclair®, Sinclair) have shown some promising effect by increasing the rehydrating effect in patients with mild-to-moderate AE.82 Detergents such as the ones used in soaps should be replaced by synthetic wash syndets (synthetic detergents) with a neutral or mild acidic pH 6.0–5.5.63, 64 Dry skin is prone to micro-fissures, easing the entry of bacteria. Wet dressings can help in treating severely affected lesions.47 Rough clothing or wool is known to cause irritation and should be avoided.63, 64 Activities leading to increased perspiration like some sports can exacerbate AE. Cigarette smoke is another known irritant. Further hints for counseling AE patients on the avoidance of nonspecific irritants can be found in Table 13.3.56

Recalcitrant, Severe AE Systemic therapy e.g. cyclosporine, phototherapy

Moderate to Severe AE * Mid-high potency TCS and/or TCI

Mild to Moderate AE Low to mind potency TCS and/or TCI

*

Dry Skin only Basic treatment: skin hydration, emollients, avoidance of irritants, identification and avoidance of specific triggers

AE = atopic eczema, TCI = topical calcineurin inhibitor, TCS = topical corticosteroid,* = > 2 years

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Table 13.3  List for counseling AE patients56 Clothing: avoid skin contact with irritating fibers (wool, large-fiber textiles); do not use tight and too warm clothing to avoid excessive sweating Tobacco: avoid exposure Cool temperature in the bedroom; avoid too many bed covers Increase emollient use with cold weather Vaccines: normal schedule in noninvolved skin, including egg-allergic patients Sun exposure: no specific restriction. Usually helpful because of improvement of epidermal barrier. Encourage summer holidays at high altitude or at beach resorts Physical exercise, sports: no restriction. If sweating induces flares of AE, progressive adaptation to exercise. Shower and emollients after swimming pool Allergy: Food allergens Maintain breast-feeding until 4–6 months if possible or use hydrolyzed formula and delay introduction of solid foods until the seventh month. Avoid foods possibly containing peanut (marked “vegetal fat”). Otherwise normal diet, unless an allergy workup has proven the need to exclude a specific food Indoor aeroallergens House dust mites Use adequate ventilation of housing. Keep the rooms well-aerated even in winter Avoid wall-to-wall carpeting Remove dust with a wet sponge Avoid soft toys in bed (cot), except washable ones Wash bedsheets at a temperature higher than 55°C every 10 days Use bed and pillow encasings Furred pets Advise to avoid preventively; if allergy is demonstrated, be firm on avoidance measures

Topical Corticosteroids Although nearly all published guidelines consider topical corticosteroids (TCS) as the first-line treatment for AE, there is a lack of literature demonstrating the efficacy of this recommendation.83 TCS are grouped according to their potency, which should be known to their prescribers56: group I: mild; group II: moderate; group III and IV: potent to very potent. Because side effects of TCS such as striae, telangiectasias, or atrophy are directly related to their strength, very potent TCS should only be used for a very short time and not on the face or intertriginous areas.47 Systemic resorption of TCS has to be kept in mind in children of less than 2 years and in patients with severe flares. Using TCS twice a day does not improve efficacy over a once-a-day regimen.84 Interestingly, the type of corticosteroid used does not seem to be of much importance in terms of efficacy.83 TCS are the treatment of

choice for acute flares.83 Once control over the current flare has been reached, some authors proposed that a twice-weekly application on skin sites prone to relapse can help to maintain long-term control.85 Recently, the term “proactive therapy” has been introduced for this preventive treatment concept and studies were performed with some corticosteroids and the topical calcineurin inhibitor tacrolimus.86

Topical Calcineurin Inhibitors In the United States and Europe, pimecrolimus (Elidel®, Novartis) cream (1%) and tacrolimus (Protopic®, Astellas) ointment (0.03%) are approved for the treatment of AE in children of more than 2 years and of adults. Tacrolimus ointment (0.1%) is only approved for use in adults.63, 64 Both drugs have shown their efficacy in numerous studies.83 The clinical potency of

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tacrolimus is comparable with a TCS of intermediate activity87 while pimecrolimus is less active.88 The most observed side effect of both is a transient, mild, burning sensation on the application site.56 Since the United States Food and Drug Adminis­ tration (FDA) issued a “black box warning” on March tenth 2005 concerning the safety of the topical calcineurin inhibitors because of a lack of long-term safety data,89 these valuable alternatives to TCS have been labeled as second-line therapy and their use is not recommended in infants younger than the age of 2. Many clinicians found the FDA warning overcautious and statements on the safety have been issued in response to the warning by multiple scientific societies. For example, the American Academy of Dermatology (AAD) states that “topical calcineurin inhibitors remain available for patients with atopic dermatitis.”90 Recent literature published after the FDA warning indicates that the overall safety profile of both drugs is still excellent even after longterm use.91,92

13.4.3.2 UV Light Therapy The treatment of AE with UV light is a well-established standard second-line therapy.63, 64 A combination with TCS for the treatment of acute flares is possible. All treatment regimens have been used: broadband UVB (280–320 nm), narrow-band UVB (311–313 nm), UVA (320–400 nm), UVA1 (340–400 nm), PUVA, and Balneo-PUVA.56 Erythema and inflammation are limiting to this method. Due to the unknown long-term safety profile, phototherapy should be restricted to patients of 12 years and above.63, 64

13.4.3.3 Antimicrobial Therapy As already mentioned above (see Sect. 13.2.4.2), the atopic skin tends to be over-colonized by microbes like Staphylococci and some fungi.

Topical The use of “intelligent clothing” consisting of silvercoated fabrics and specially coated silk textiles with antimicrobial have shown some promising effect in

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preliminary studies.93 The PRACTALL guidelines recommend the use of chlorhexidine or triclosan to reduce the microbial load.63, 64 The use of topical antibiotics like erythromycin and fusidic acid has increased the abundance of resistant Staphylococci. Therefore, topical antibiotic therapy should not be extended over more than 2 weeks.63, 64

Systemic Severe exacerbations with widespread bacterial infection need a systemic antibiotic therapy. Usually, oral therapy with penicillinase-resistant penicillins or first or second generation cephalosporins for 7–10 days is sufficient. Clindamycin and fusidic acid are alternatives. Acute eczema herpeticum is a dermatological emergency and hospitalization should be considered. Neck stiffness is a clue to meningeal involvement and lumbar puncture should be performed to exclude herpes meningitis. Acute eczema herpeticum should be treated with intravenous acyclovir.94 For AE patients with recurrent eczema herpeticum a continuous suppression therapy with acyclovir or valacyclovir can reduce the frequency of episodes and should be recommended to these patients.94 Fungal infection is often found in patients with severe AE. However, it is yet not clear whether systemic antimycotic treatment reduces symptom severity and is not recommended.63, 64

13.4.3.4 Dietary Restrictions As mentioned above (allergy), dietary restrictions in children should only be recommended when food allergy has been proven by meaningful methods (see Sect. 13.3.3). Hints on counseling patients with proven allergies are found in Table 13.3.56

13.4.3.5 Antipruritic Treatment Topical polidocanol at 1%, although known as a weak contact sensitizer, can be added to emollients and has a mild antipruritic effect. The pruritus of AE patients typically exacerbates at night. Hence, sleeplessness is a common problem. The treatment of choice is adjuvant sedation with first-generation antihistamines that

13  Diagnosis and Prevention of Atopic Eczema

are capable of crossing the blood–brain barrier and sedating central arousal functions mediated by histamine.50 Typical drugs are diphenhydramine and hydroxycine.95 Both drugs are available for children and in liquid form. Doxepin is a tricyclic antidepressant with a pronounced antagonistic effect on histamine receptors. It is a strong sedating drug and another option for treating sleep disturbances. It is used at a dose of 10 mg for pediatric and 25 mg for adult AE patients.95 Melatonin has also been suggested for mild cases.95

13.4.3.6 Systemic Immunosuppression Cyclosporine Cyclosporine A is a calcineurin inhibitor functioning in the same way as the topical immunomodulators. Treatment with cyclosporine leads to a reduction of the T-cell activating IL-2 and IFN-g (gamma) cytokines. In fact, it is a very potent drug for the treatment of AE and its clinical effectiveness has been demonstrated in numerous studies for children and adults with an excellent level of evidence.96 It is a registered therapy for the treatment of AE and is recommended as first option for patients with AE refractory to conventional treatment.97 The treatment can either be based on short-term high dose (3–5  mg/kg body weight) or on long-term low dose (2.5 mg/kg body weight) regimens.63, 64 The narrow therapeutic index and the known side effects such as renal toxicity or elevation of the blood pressure limit this therapy to severe cases. Malignancies have been reported after high-dose, long-term treatment in transplant patients. A recent review on the long-term safety data of dermatologic patients revealed a higher risk for the development of basal cell carcinoma but not of other tumors.98 The authors conclude that due to the overall beneficial benefit–risk ratio, cyclosporine can still be used at the lower dermatologic doses of 3–5 mg/kg body weight.98

Azathioprine Azathioprine at 1–3 mg/kg body weight has some tradition as off-label therapy for recalcitrant AE.56 The onset of action is rather slow. Myelosuppression, hepatotoxicity, and induction of skin malignancies, among

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others, are relevant side effects. Azathioprine is metabolized by the thiopurine methyltransferase. Around 11.5% of the population have a reduced or no activity in this enzyme caused mostly by three mutations.99 Since this enzyme deficiency causes most toxicities, enzymatic or genetic testing must be performed before starting this therapy.99

Other Immunosuppression Different other immunosuppressive modalities have been tried for the treatment AE: mycophenolate mofetil at 2  g/day has a better security profile than azathioprine but larger randomized trials are still missing.56 Systemic corticosteroids are usually avoided because of the pronounced rebound effect in AE patients. Although a short-term course during an acute flare might be useful in some cases, a long-term treatment should be avoided especially in children due to the problematic side-effect profile (osteoporosis, growth retardation, diabetes, cataracts). The so-called biologicals that have been so valuable for the treatment of psoriasis have been disappointing when tried anecdotally in AE and currently have no place in the treatment of atopic skin.100

13.4.3.7 Nonpharmacological Intervention Strategies The goal of patient education is for patients to accept their diagnosis of AE, to increase their knowledge of the disease, and to reduce doctor shopping. Hints for counseling AE patients are found in Table 13.3.56 Other guidelines from the UK regarding counseling of AE patients are available online.101 One excellently designed German study showed that an educational intervention (6 weekly standardized group sessions led by a multidisciplinary team consisting of dermatologists or pediatricians, psychologists, and dieticians who had undergone 40 h of special training) resulted in a reduction of objective eczema as well as subjective severity indexes when compared with a nonintervention control group.102 One American guideline covers recommendations on psychological approaches,83 while such are lacking in other guidelines.50, 56, 63, 64 Behavior modification techniques and relaxation techniques showed some

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benefit in reducing scratching, although the data are contradictive.103 A recent Cochrane review104 concludes that the level of evidence for the effectiveness for educational and psychological interventions in AE is low due to the small number and the inferior design of existing studies except for the one German study mentioned above.102

References   1. Novak N, Bieber T, et  al Immune mechanisms leading to atopic dermatitis. J Allergy Clin Immunol. 2003;112(6 suppl):S128–S139   2. Johansson SG, Bieber T, et  al Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832–836   3. Hamelmann E, Beyer K, et al Primary prevention of allergy: avoiding risk or providing protection? Clin Exp Allergy. 2008;38(2):233–245   4. Illi S, von Mutius E, et al The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol. 2004;113(5):925–931   5. Asher MI, Montefort S, et al Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys. Lancet. 2006; 368(9537):733–743   6. Van Eerdewegh P, Little RD, et  al Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002;418(6896):426–430   7. Prescott SL. Allergy: the price we pay for cleaner living? Ann Allergy Asthma Immunol. 2003;90(6 suppl 3):64–70   8. Liu AH. Hygiene theory and allergy and asthma prevention. Paediatr Perinat Epidemiol. 2007;21(suppl 3):2–7   9. Ring J, Krämer U, et al A critical approach to the hygiene hypothesis. Clin Exp Allergy Rev. 2004;4(suppl 2):40–44 10. Jovanovic S, Felder-Kennel A, et  al Exposition und Sensibilisierung gegenüber Milben- und Katzenallergenen bei Kindern in Baden-Württemberg. Gesundheitswesen. 2003;65(7):457–463 11. Cork M, Murphy R, et  al The rising prevalence of atopic eczema and environmental trauma to the skin. Dermatol Pract. 2002;10(3):22–26 12. Cork MJ, Robinson DA, et al New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol. 2006;118(1):3–21 13. Elias PM. Epidermal lipids, barrier function, and desquamation. J Invest Dermatol. 1983;80 suppl:44s–49s 14. Taïeb A. Hypothesis: from epidermal barrier dysfunction to atopic disorders. Contact Derm. 1999;41(4):177–180 15. Holleran WM, Takagi Y, et  al Epidermal sphingolipids: metabolism, function, and roles in skin disorders. FEBS Lett. 2006;580(23):5456–5466 16. Chiou YB, Blume-Peytavi U. Stratum corneum maturation. Skin Pharmacol Physiol. 2004;17(2):57–66

S. Wöhrl 17. Palmer CN, Irvine AD, et al Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38(4):441–446 18. Baurecht H, Irvine AD, et al Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. J Allergy Clin Immunol. 2007;120:1406–1412 19. Lebman DA, Coffman RL. Interleukin 4 causes isotype switching to IgE in T cell-stimulated clonal B cell cultures. J Exp Med. 1988;168(3):853–862 20. Maintz L, Novak N. Getting more and more complex: the pathophysiology of atopic eczema. Eur J Dermatol. 2007; 17(4):267–283 21. Hamid Q, Boguniewicz M, et al Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest. 1994;94(2):870–876 22. Larché M, Akdis CA, et al Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol. 2006;6(10):761–771 23. Verhagen J, Akdis M, et  al Absence of T-regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol. 2006;117(1):176–183 24. Sampson HA. Update on food allergy. J Allergy Clin Immunol. 2004;113(5):805–819; quiz 820 25. Scalabrin DM, Bavbek S, et al Use of specific IgE in assessing the relevance of fungal and dust mite allergens to atopic dermatitis: a comparison with asthmatic and nonasthmatic control subjects. J Allergy Clin Immunol. 1999; 104(6):1273–1279 26. Werfel T, Ballmer-Weber B, et al Eczematous reactions to food in atopic eczema: position paper of the EAACI and GA²LEN. Allergy. 2007;62(7):723–728 27. Mothes N, Niggemann B, et al The cradle of IgE autoreactivity in atopic eczema lies in early infancy. J Allergy Clin Immunol. 2005;116(3):706–709 28. Scheynius A, Johansson C, et al Atopic eczema/dermatitis syndrome and Malassezia. Int Arch Allergy Immunol. 2002; 127(3):161–169 29. Greaves MW. Recent advances in pathophysiology and current management of itch. Ann Acad Med Singap. 2007;36(9): 788–792 30. Schmid-Ott G, Jaeger B, et  al Different expression of cytokine and membrane molecules by circulating lymphocytes on acute mental stress in patients with atopic dermatitis in comparison with healthy controls. J Allergy Clin Immunol. 2001;108(3):455–462 31. Rukwied R, Lischetzki G, et  al Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study. Br J Dermatol. 2000;142(6): 1114–1120 32. Badertscher K, Bronnimann M, et al Mast cell chymase is increased in chronic atopic dermatitis but not in psoriasis. Arch Dermatol Res. 2005;296(10):503–506 33. Järvikallio A, Harvima IT, et al Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch Dermatol Res. 2003;295(1):2–7 34. Raap U, Werfel T, et al Circulating levels of brain-derived neurotrophic factor correlate with disease severity in the intrinsic type of atopic dermatitis. Allergy. 2006;61(12): 1416–1418 35. Dillon SR, Sprecher C, et al Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004;5(7):752–760

13  Diagnosis and Prevention of Atopic Eczema 36. Bilsborough J, Leung DY, et al IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol. 2006;117(2):418–425 37. Abeck D, Mempel M. Kutane Staphylococcus aureus Besiedelung des atopischen Ekzems. Hautarzt. 1998;49(12): 902–906 38. Bogaert D, van Belkum A, et al Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. Lancet. 2004;363(9424):1871–1872 39. Leyden JJ, Marples RR, et al Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol. 1974;90(5): 525–530 40. Novak N, Bieber T. Pathogenese des atopischen Ekzems. JDDG J Ger Soc Dermatol. 2005;3(12):994–1005 41. Bunikowski R, Mielke M, et al Prevalence and role of serum IgE antibodies to the Staphylococcus aureus-derived superantigens SEA and SEB in children with atopic dermatitis. J Allergy Clin Immunol. 1999;103(1 Pt 1):119–124 42. Sonkoly E, Muller A, et al IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117(2):411–417 43. Ong PY, Ohtake T, et al Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347(15):1151–1160 44. Howell MD, Wollenberg A, et  al Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117(4):836–841 45. Schudel P, Wüthrich B. Klinische Verlaufsbeobachtungen bei Neurodermitis atopica nach dem Kleinkindesalter. Eine katamnestische Untersuchung anhand von 121 Fällen. H±G Zeitschrift für Hautkrankheiten. 1985;60(6):479–486 46. Hanifin J, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh). 1980;92 suppl:44s–47s. 47. Leung DY, Bieber T. Atopic dermatitis. Lancet. 2003; 361(9352):151–160 48. Williams HC, Burney PG, et al The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131(3):383–396 49. Jøhnke H, Vach W, et al A comparison between criteria for diagnosing atopic eczema in infants. Br J Dermatol. 2005; 153(2):352–358 50. Lewis-Jones S, Mugglestone MA. Management of atopic eczema in children aged up to 12 years: summary of NICE guidance. Bmj. 2007;335(7632):1263–1264 51. Turjanmaa K, Darsow U, et  al EAACI/GA²LEN position paper: present status of the atopy patch test. Allergy. 2006;61(12):1377–1384 52. Berni Canani R, Ruotolo S, et al Diagnostic accuracy of the atopy patch test in children with food allergy-related gastrointestinal symptoms. Allergy. 2007;62(7):738–743 53. Mehl A, Rolinck-Werninghaus C, et al The atopy patch test in the diagnostic workup of suspected food-related symptoms in children. J Allergy Clin Immunol. 2006; 118(4): 923–929 54. Niggemann B, Gruber C. Unproven diagnostic procedures in IgE-mediated allergic diseases. Allergy. 2004;59(8): 806–808 55. Stapel SO, Asero R, et al Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI task force report. Allergy. 2008;63(7):793–796

149 56. Darsow U, Lübbe J, et  al Position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol. 2005;19(3):286–295 57. Smith FJ, Irvine AD, et al Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38(3):337–342 58. Lin SP, Huang SY, et al Netherton syndrome: mutation analysis of two Taiwanese families. Arch Dermatol Res. 2007;299(3):145–150 59. Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120(4):744–750 60. Lannerö E, Wickman M, et  al Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE). Respir Res. 2006;7:3 61. Muraro A, Dreborg S, et  al Dietary prevention of allergic diseases in infants and small children. Part III: critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol. 2004;15(4):291–307 62. Greer FR, Sicherer SH, et al Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121(1):183–191 63. Akdis CA, Akdis M, et al Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. J Allergy Clin Immunol. 2006;118(1):152–169 64. Akdis CA, Akdis M, et al Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy. 2006;61(8):969–987 65. Lowe LA, Woodcock A, et al Lung function at age 3 years: effect of pet ownership and exposure to indoor allergens. Arch Pediatr Adolesc Med. 2004;158(10):996–1001 66. Svanes C, Zock JP, et  al Do asthma and allergy influence subsequent pet keeping? An analysis of childhood and adulthood. J Allergy Clin Immunol. 2006;118(3):691–698 67. Sporik R, Ingram JM, et al Association of asthma with serum IgE and skin test reactivity to allergens among children living at high altitude. Tickling the dragon’s breath. Am J Respir Crit Care Med. 1995;151(5):1388–1392 68. von Mutius E, Weiland SK, et  al Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany. Lancet. 1998;351(9106):862–866 69. Flöistrup H, Swartz J, et al Allergic disease and sensitization in Steiner school children. J Allergy Clin Immunol. 2006;117(1):59–66 70. Ventura MT, Munno G, et al Allergy, asthma and markers of infections among Albanian migrants to Southern Italy. Allergy. 2004;59(6):632–636 71. van den Biggelaar AH, Rodrigues LC, et al Long-term treatment of intestinal helminths increases mite skin-test reactivity in Gabonese schoolchildren. J Infect Dis. 2004;189(5): 892–900 72. Flood JM, Weinstock HS, et  al Neurosyphilis during the AIDS epidemic, San Francisco, 1985–1992. J Infect Dis. 1998;177(4):931–940

150 73. Kalliomaki M, Salminen S, et al Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet. 2001;357(9262):1076–1079 74. Kalliomaki M, Salminen S, et al Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebocontrolled trial. Lancet. 2003;361(9372):1869–1871 75. Kalliomaki M, Salminen S, et al Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119(4):1019–1021 76. Niederberger V, Valenta R. Molecular approaches for new vaccines against allergy. Expert Rev Vaccines. 2006;5(1):103–110 77. Niederberger V, Horak F, et al Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci USA. 2004;101(suppl 2): 14677–14682 78. Niggemann B, Jacobsen L, et al Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy. 2006;61(7):855–859 79. Jacobsen L, Niggemann B, et al Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007;62(8): 943–948 80. Bussmann C, Maintz L, et  al Clinical improvement and immunological changes in atopic dermatitis patients undergoing subcutaneous immunotherapy with a house dust mite allergoid: a pilot study. Clin Exp Allergy. 2007;37(9): 1277–1285 81. Werfel T, Breuer K, et  al Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose-response study. Allergy. 2006;61(2):202–205 82. Abramovits W, Boguniewicz M. A multicenter, randomized, vehicle-controlled clinical study to examine the efficacy and safety of MAS063DP (Atopiclair) in the management of mild to moderate atopic dermatitis in adults. J Drugs Dermatol. 2006;5(3):236–244 83. Hanifin JM, Cooper KD, et al Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association “Administrative Regulations for Evidence-Based Clinical Practice Guidelines”. J Am Acad Dermatol. 2004;50(3):391–404   84. Hoare C, Li Wan Po A, et al Systematic review of treatments for atopic eczema. Health Technol Assess. 2000;4(37):1–191   85. Van Der Meer JB, Glazenburg EJ, et al The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate. The Netherlands Adult Atopic Dermatitis Study Group. Br J Dermatol. 1999;140(6): 1114–1121   86. Wollenberg A, Bieber T. Proactive therapy of atopic dermatitis – an emerging concept. Allergy. 2009;64(2):276–278   87. Ashcroft DM, Dimmock P, et al Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BMJ. 2005;330(7490):516

S. Wöhrl   88. Luger T, Van Leent EJ, et al SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol. 2001;144(4):788–794   89. Thaçi D, Salgo R. The topical calcineurin inhibitor pimecrolimus in atopic dermatitis: a safety update. Acta Dermatovenerol Alp Panonica Adriat. 2007;16(2):58, 60–62   90. Berger TG, Duvic M, et al The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force. J Am Acad Dermatol. 2006;54(5):818–823   91. Remitz A, Harper J, et al Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. Acta Derm Venereol. 2007;87(1):54–61   92. Ring J, Abraham A, et  al Control of atopic eczema with pimecrolimus cream 1% under daily practice conditions: results of a >2000 patient study. J Eur Acad Dermatol Venereol. 2008;22(2):195–203   93. Ricci G, Patrizi A, et al Use of textiles in atopic dermatitis: care of atopic dermatitis. Curr Probl Dermatol. 2006;33:127–143   94. Rerinck HC, Kamann S, et  al Eczema herpeticum: Pathogenese und Therapie. Hautarzt. 2006;57(7):586–591   95. Kelsay K. Management of sleep disturbance associated with atopic dermatitis. J Allergy Clin Immunol. 2006;118(1): 198–201   96. Schmitt J, Schmitt N, et al Cyclosporin in the treatment of patients with atopic eczema – a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2007;21(5): 606–619   97. Schmitt J, Schakel K, et  al Systemic treatment of severe atopic eczema: a systematic review. Acta Derm Venereol. 2007;87(2):100–111   98. Behnam SM, Behnam SE, et  al Review of cyclosporine immunosuppressive safety data in dermatology patients after two decades of use. J Drugs Dermatol. 2005;4(2): 189–194   99. Wise M, Callen JP. Azathioprine: a guide for the management of dermatology patients. Dermatol Ther. 2007; 20(4):206–215 100. Heymann WR. Antipsoriatic biologic agents for the treatment of atopic dermatitis. J Am Acad Dermatol. 2007;56(5): 854–855 101. National Institute for Health and Clinical Excellence. NICE guidance. At: ; 2009 Accessed 04.04.09 102. Staab D, Diepgen TL, et al Age related, structured educational programmes for the management of atopic dermatitis in children and adolescents: multicentre, randomised controlled trial. BMJ. 2006;332(7547):933–938 103. Chida Y, Steptoe A, et al The effects of psychological intervention on atopic dermatitis. A systematic review and meta-analysis. Int Arch Allergy Immunol. 2007;144(1):1–9 104. Ersser SJ, Latter S, et  al Psychological and educational interventions for atopic eczema in children. Cochrane Database Syst Rev. 2007;(3):CD004054

Prevention of Psoriasis

14

Gwynn Coatney and Robert A. Norman

14.1 Introduction Psoriasis is one of the most common skin diseases and it affects millions of people all over the world. It is usually chronic in nature with onset and flare-ups being unpredictable. The disease course ranges from mild forms consisting of annoying symptomatology of itchy dry skin and unsightly scaling plaques to extreme cases that can induce disfigurement, prolonged suffering, and systemic manifestations such as arthritis and even an increased mortality. Psoriasis is very costly to treat and treatment itself can be a very time-consuming commitment. Some of the newest treatments can cost up to $25,000 a year and most treatments involve months of intensive treatment regimens.13 In general, psoriasis is a major cause of social and physical discomfort that can also become a serious burden financially for patients affected by this inflammatory disease. Due to the widespread affliction and the severe nature of psoriasis special attention should be focused on preventing the disease.

14.1.1 Pathogenesis Psoriasis is an immune-mediated inflammatory disorder, in which epithelial cells have an increased production and turnover rate. Normal skin takes almost a month to cycle from newly formed keratinocytes (from

G. Coatney (*) Department of Family Medicine, University of Medicine and Dentistry of New Jersey, Stratford, NJ, USA e-mail: [email protected]

stem cells of the innermost or basal layer) upwards to the most superficial layer of the epidermis, the stratum corneum. In psoriasis this process is much faster, taking only 3–5 days to complete the cycle. The hyperproliferation of these cells is caused by an inflammatory response in the immune system. It is still unclear what causes this response in psoriasis, but it is known that the immune system erroneously activates T cells. T cells then activate inflammatory mediators, or cytokines like tumor necrosis factor-alpha (TNF-a), to trigger the increased proliferation of the epithelial cells.11, 24

14.1.2 Prevalence/Incidence Current estimates show that 2–3% of the world population is affected by psoriasis. Up to seven million people in the United States have this common cutaneous disease. It is also estimated that 150,000–200,000 new cases are diagnosed each year in the US. Psoriasis equally affects the male and female genders. There is a lower incidence of psoriasis seen in people with darker skin – Africans, Asians, and Inuits, and the disease is very rarely seen in North and South American Indians.11, 17, 24

14.1.3 Onset The peak age of onset of psoriasis usually occurs in people in their third decade of life, but it can present anywhere from the neonatal period to people in their 70s. When the disease presents early in life it is more likely to develop into a more severe form and become chronic in nature.24

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_14, © Springer-Verlag London Limited 2010

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14.1.4 Severity/Types/Distribution There are two major classifications of psoriasis, psoriasis vulgaris and pustular psoriasis (Table 14.1). Psoriasis vulgaris includes the acute guttate, chronic plaque, inverse and palmoplantar subtypes. Characteristically, these different types range from eruptive and inflammatory lesions to chronic and lichenified. Guttate psoriasis is seen in about 2% of all psoriasis cases and consists of small erythematous lesions that appear acutely. This subtype of psoriasis vulgaris can spontaneously resolve without treatment. Guttate psoriasis has a generalized distribution with the majority of lesions appearing on the trunk. A common presentation of guttate psoriasis occurs after an infection like streptococcal pharyngitis. The lesions appear diffusely on the skin, much like an exanthem-type rash. Plaque psoriasis is usually chronic in nature and is the most common type of psoriasis. Clinically, this subtype exhibits the classic lesions that most people associate with psoriasis. They are sharply demarcated, salmon pink to erythematous in color and have a loose silvery white scale. Lesions are classically concentrated on the elbows, knees, over the sacrum, on the scalp, and on the palms and soles of the hands and feet. The face and neck are rarely involved. These plaques are generally bilateral and symmetric. Inverse type of psoriasis chronically affects the skin-fold areas of the body including the groin region, under the breasts, and the axillae. These areas are moist, giving the psoriatic plaques a different appearance than seen in the classic presentation. The thick, scaly plaques are replaced with bright red and fissured lesions. The plaques of the palmoplantar type of psoriasis are distributed only on the palms and soles and usually demonstrate more hyperkeratotic and scaling type lesions.8

Pustular psoriasis has two subtypes, palmoplantar and generalized acute pustular psoriasis. Cases of pustular psoriasis are much less frequently seen than the psoriasis vulgaris types. Palmoplantar psoriasis usually appears later in life and has a higher incidence females, a ratio of almost 4:1. Palmoplantar pustulosis is a chronic condition where pustules in different stages of evolution and healing appear in groups only on the palms and soles of the hands and feet. Relapse and recurrence of the disorder is common. Generalized acute pustular psoriasis can be a dermatologic emergency. In this subtype the skin becomes diffusely erythematous and pustules appear in clusters within hours of initial onset. This condition is usually accompanied by fever, malaise and generalized weakness. About 10% of those diagnosed with psoriasis are also diagnosed with psoriatic arthritis. The age of onset for psoriatic arthritis is 10–15 years later in life, averaging in the mid-30s. Psoriatic arthritis is most often found in the hands and feet, resulting in “sausage” digits, but can also affect larger joints. Finger and toenails are involved in 25% of psoriatic cases in general, and have a high correlation with psoriatic arthritis. Clinically the nail may include pitting, hyperpigmented spots under the nail plate and hyperkeratotic changes of the nail itself. 11, 24

14.1.5 Genetics Immunological factors contribute to the pathophysiology of psoriasis, but it is unknown whether psoriasis is caused by an immune system dysfunction or by genetic defects found in keratinocytes of the epidermis.1 Many studies suggest that there is a genetic predisposition for psoriasis. The Lomholt study conducted on the Faroe Islands of Denmark found that 91% of those

Table 14.1  Types of psoriasis Psoriasis vulgaris subtypes

Pustular subtypes

Subtypes

Acute guttate

Chronic plaque

Inverse

Palmo-plantar

Generalized acute pustular

Palmo-plantar

Onset/duration

Acute

Chronic

Sub-acute to chronic

Chronic

Acute

Chronic

Distribution pattern

Diffuse, but mainly on the trunk

Bilateral, symmetric, elbows, knees, scalp, sacrum

In skin folds, under breast, groin, axillae

Palms of hands, soles of feet

Generalized and diffuse

Palms and soles

Characteristics

Erythematous, small, round-oval in shape

Salmon pink with a silvery scale, thick, sharply demarcated

Bright red, fissured

Scaly-crusted, thick

Base is erythematous with overlying clusters of pustules

Pustules are arranged in groups in different stages of healing

14  Prevention of Psoriasis

questioned with psoriasis had at least one first- or ­second-degree relative who were also inflicted with the disease.18, 23 Over 5,000 study subjects with psoriasis had family members also affected by the disease in a study done by Farber and Nall.4, 23 A study by Kavli showed that the prevalence of psoriasis increases with the number of relatives with the same disease.14, 23 Twin studies have been performed revealing that the heritability of psoriasis was estimated to be as high as 60–90%.2, 23 When one parent has psoriasis 8% of the offspring will develop the disease. When both parents have psoriasis 41% of their children will also have the disease. Psoriasis is inherited as a polygenic trait in which disease types, severity, and degree of skin involvement depends on several different alleles found on different genes. The human leukocyte antigen (HLA) types most frequently associated with psoriasis are HLA-B13, -B17, Bw57, and Cw6. Nearly half the patients with psoriatic arthritis will have HLA-B27, which is most commonly associated with ankylosing spondylitis.24

14.2 Risk Factors/Triggers Most triggers for psoriasis are immunologic in nature. Physical trauma like harsh rubbing of the epidermis or scratching can elicit the lesions, known as Koebner’s phenomenon. Infections have been known to precipitate outbreaks of psoriasis. For example, the first lesion of psoriasis can show up after a streptococcal infection. This is most often seen in the guttate type of psoriasis, and in children. Stress is an important risk factor causing flares in up to 40% of adults and children. In the Farber and Nall study one-third of the 5,600 psoriasis patients studied reported that stress or worry induced new areas of affected skin.4, 23 Certain types of drugs have been associated with the onset and exacerbation of psoriasis. The most studied include beta blockers, calcium channel blockers, lithium, NSAIDs, and antimalarial medications. Smoking cigarettes and drinking alcohol have a strong correlation with psoriasis. Combining the results of two studies performed in Germany, current smokers have a higher prevalence rate of psoriasis, when compared to those who have quit smoking or who have never smoked. The results indicating positive histories of both smoking and psoriasis were 3.8 vs. 2.7 and

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2.8% respectively. One of these studies also showed that participants that drank more than 20 g of alcohol a day had a prevalence of psoriasis of 4.7%.23 More specifically, 4.8% of the participants who drank a daily beer also had psoriasis, and of those who admitted to drinking at least three glasses of wine a week 6.4% also had the disease. The dermatology clinics of the University of Utah enrolled patients in the Utah Psoriasis Initiative (UPI), which studied the impact of smoking and obesity on psoriasis. Of the patients studied 37% admitted being current smokers. The prevalence of smoking in the UPI was higher than the general Utah population, which is 13%. It was also higher than in the nonpsoriatic population of Utah of which 25% are smokers.9 In the two separate research pursuits of Naldi and Kavli evidence was found that lack of a balanced diet or being deficient in certain vitamins and minerals are risk factors for psoriasis. Proper nutrition in general is important for a person’s overall health and maintenance of immune system function. People who have a low consumption of fruit and vegetables, especially carrots, tomatoes or Beta carotene are more likely to have psoriasis.20, 14

14.2.1 Disease Associations There are many diseases associated with psoriasis. Some of the more common disorders include hypertension, cardiovascular diseases, obesity, inflammatory bowel disorders, depression, and cancer.15, 16 Those who are overweight and obese or who have an increased body mass index (BMI) have been shown to have a higher incidence of psoriasis.20 Looking again at the UPI, the percentage of patients that were obese and had psoriasis was double the number compared to the general Utah population that was obese and without psoriasis. This study found that the majority of their participants were of normal weight at the time of onset or diagnosis of psoriasis and transitioned into being obese. This suggests that obesity is not a risk factor for psoriasis, but a result of the disease.9 There is a strong relationship between Crohn’s disease and psoriasis. This may be due to a common factor between inflammatory bowel disease and psoriasis; they both have increased levels of the inflammatory cytokine, tumor necrosis factor-a.19

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Multiple television ads portray people with psoriasis and their embarrassment about their skin’s appearance. Over the years many writers and poets have written about the disease and how it has a negative effect on their lives. It has long been known that psoriasis has a link to psychosocial disorders and decreased self-esteem.22 An Italian study done in 2006 sent questionnaires to patients who were diagnosed with psoriasis. The goal of this study was to assess the degree of depressive symptomatology in psoriasis patients. A total of 2,391 people participated and it was found that 62% of those polled admitted to symptoms of depression.3 A retrospective survey has shown the correlation of psoriasis and cancer. The percentage of subjects of this study with no cancer history was 3.3% compared with 9.4% of the participants who had a positive cancer history. These results were obtained after controlling age, gender, and alcohol or tobacco use. Many studies have concluded that patients with psoriasis are at an increased risk for developing a specific type of cancer, lymphoma.23, 5 Patients with psoriasis have an increased morbidity and mortality rate. A cohort study done by Dr. Gelfand and his colleagues used the United Kingdom’s general practice research database (GPRD) to follow patients with psoriasis over a 15-year period. They compared three groups of patients. The first included over 130,000 patients with mild psoriasis, the second group was comprised of almost 4,000 patients with severe psoriasis, and the third group was considered the control group, patients not diagnosed with psoriasis. This last group included 5 times as many patients as the first two groups combined. To differentiate between mild and severe psoriasis the researchers classified the mild group as patients that had the diagnosis of psoriasis, but had no history of systemic therapy. Conversely the severe group was classified as patients with the diagnosis of psoriasis and also with history of being treated with systemic therapy. One objective of this study was to determine whether psoriasis is an independent risk factor for myocardial infarction (MI). Adjustments were made to the study regarding major cardiovascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, age, sex, smoking history, family history of MI, BMI, or previous personal history of MI. The incidence of MI for the control group and the mild psoriasis group was about 2%. The incidence of MI in the severe psoriasis group was 2.9%. Relative risk was also measured according to age. For a 30-year-old

G. Coatney and R. A. Norman

patient the relative risk for MI is 1.29 for mild psoriasis and 3.10 for severe psoriasis. The relative risk for MI in a 60-year-old is 1.08 for mild and 1.36 for severe psoriasis. This same study found that the group of patients with severe psoriasis had a death rate almost double of the control group. This ratio even persisted after controlling other comorbidities linked to mortality from the equation, including smoking status, BMI, heart disease, AIDs, cancer, renal disease, and others. An interesting observation showed that there was no significant difference when comparing the death rate of the group with mild psoriasis to the group without psoriasis. On average, patients with severe psoriasis died 3–4 years earlier than patients not diagnosed with and treated for the severe form of the disease.6, 7

14.3 Treatments Psoriasis is a chronic and recurrent disease that requires appropriate care and often includes systematic treatment.12 A recent survey from the National Psoriasis Foundation polled 1,657 participants diagnosed with severe or moderate psoriasis to assess their level of treatment. This study found that almost 40% of those surveyed are currently receiving no treatment at all for their condition. In opposition, one quarter of those questioned with severe psoriasis were receiving either systemic therapy or phototherapy and 35% are being treated with only topical therapy (Table 14.2).10, 21

14.3.1 Topicals One of the longest treatments in use is Anthralin, a synthetic form of chrysarobin, which is a chemical compound found in the bark of the Araroba tree of South America. It can be a good treatment choice for the plaque type of psoriasis. Dovonex is a synthetic form of vitamin D3 which treats psoriasis by decreasing the rate of keratinocyte proliferation. It does not treat the inflammation aspect of the disease but it decreases the surface area of the lesions and helps in removing the scale. A scalp solution of Dovonex is also available. Recommendations say to apply the solution at night and wear a shower cap to bed. The solution can then be washed out in the

14  Prevention of Psoriasis Table 14.2  Overview of treatments Treatment Examples

155

Treatment for

Use in conjunction with

Common side effects

Topicals

Anthralin, Dovonex, Taclonex, Tazorac

Mild-to-moderate plaque psoriasis, scalp

Topical steroids, phototherapy or oral medications used to treat psoriasis

Anthralin can stain the skin, Dovonex, Taclonex, and Tazorac can cause skin irritation

Phototherapy

UVB treatment, PUVA treatment with Psoralen

Mild-to-moderate plaque psoriasis, vitiligo

May be used together or alternate with topicals, orals, or biologics, but avoid with Taclonex and Tazorac

Redness/sunburn, irritated skin, blistering. Psoralen can cause nausea

Oral systemics

Cyclosporine, Soriatane, Methotrexate

Moderate-to-severe psoriasis, Cyclosporine is good to treat nail involvement, Methotrexate can also treat psoriatic arthritis

Topical medications like Dovonex

Possibility of organ damage, most commonly the kidneys or liver

Biologics

Amevive, Enbrel, Humira, Remicade

Moderate to severe plaque psoriasis, those who did not clear with other treatments. Enbrel, Humira and Remicade can also be used to treat psoriatic arthritis

Can be used alternatively with phototherapy and oral medications like Methotrexate

Nausea, itching, chills, sore throat, dizziness, injection site irritation, headache, cough

morning. This cream or ointment has been shown to be safe and effective when used in combination with topical steroids and systemic treatments to combat more severe cases of psoriasis. Dovonex has also been shown to increase the effectiveness of phototherapy treatments when applied after the UV ray treatment. Another topical treatment option is Taclonex, which is a combination of the same active ingredient found in Dovonex and a steroid. There is also a formulation that can be used on the scalp. Tazorac is a topical therapy used for plaque psoriasis. It is a topical retinoid, or vitamin A derivative. Tazorac comes in two forms, gel and cream and each has two strengths, 0.05 and 0.1%. The gel is clear and fast-drying and the cream has a moisturizer that makes it a good choice for patients with drier, more sensitive skin. Both formulations work to slow the rapid proliferation of the epithelial cells. Tazorac can be combined with steroids to promote faster clearing time and can also reduce skin irritation and redness. Combining Tazorac with phototherapy has also been shown to get better results than using either treatment alone.

Topical steroids can be a great aid in the treatment of psoriasis. They can be used in combination with most other topical treatments but are not effective when used alone. They can help achieve the goal of clearing the psoriasis lesions at a faster rate. Their antiinflammatory capabilities help reduce side effects of the medications, including irritation, itching, and redness. For resistant psoriasis plaques intralesional injections of steroids may be a good option.21

14.3.2 Systemic Therapy Systemic therapy for psoriasis is usually reserved for moderate-to-severe psoriasis or for patients who have failed to become clear with topical or phototherapy treatment. Cyclosporine, or Neoral, is an immune-suppressant. Its mechanism of action works to inhibit T cells. It is taken every day in either pill or liquid form. Good ­outcomes have been achieved when combining

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Cyclosporine and Dovonex topical therapy. By using both medications the dosage of Cyclosporine can be lowered and thus decreases potential side effects caused by high doses or chronic use of Cyclosporine. The only oral retinoid approved for the treatment of psoriasis is called Soriatane. It is a synthetic form of vitamin A. Soriatane is a good treatment for the plaque, guttate, pustular and palmoplantar types of psoriasis. Oral retinoids like Soriatane result in clearer skin by modifying how keratinocytes multiply and the rate at which they divide and shed. Soriatane is taken once daily in pill form. It can be used in combination with Dovonex and has had great results when used in conjunction with phototherapy. Methotrexate is another common oral systemic medication used to treat psoriasis. It is a medication that has been used to treat cancer since the 1950s and 20 years later was approved to treat psoriasis. Methotrexate is effective in treating psoriasis because the medication decreases epithelial cell growth. Unlike Cyclosporine and Soriatane, Methotrexate can also be used to treat psoriatic arthritis. Methotrexate is administered once a week either in pill or liquid form, or by injection. After the clearance of psoriasis lesions is obtained the dosage is tapered. Some patients may require a maintenance dose to prevent relapse.21

and turnover of epithelial cells. Amevive and Raptiva are FDA-approved for the treatment of moderate-tosevere plaque psoriasis in adults, but not psoriatic arthritis. Patients receiving Amevive receive an intramuscular shot at their doctor’s office weekly for at least 12 weeks. If the goal of 75% clearance is not achieved a second 12 week course can be instituted. Raptiva can be selfinjected by patients on a weekly basis. The mechanism of action for Enbrel, Humira and Remicade consists of blocking TNF-a and interrupting the inflammatory cycle of psoriasis and psoriatic arthritis. Patients using Enbrel give themselves a subcutaneous injection once or twice weekly, those using Humira also inject subcutaneously, but only every other week. Remicade is given in a doctor’s office and the treatment includes three separate 2-h infusions during the first 6 weeks of treatment. Every 8 weeks following another infusion is given. Enbrel, Humira, and Remicade are currently approved to treat moderate-tosevere plaque psoriasis and psoriatic arthritis in adults. They are also being used to treat rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis. Remicade is also approved for the treatment of Crohn’s disease and ulcerative colitis. In the future Enbrel may be approved to treat psoriasis in children as well as adults.21

14.3.3 Biologics

14.3.4 Phototherapy

Biologics are the newest treatments for psoriasis and psoriatic arthritis. The name for this group of medications is fitting, because these formulations are derived from human or animal proteins, not chemicals or synthetic compounds. Biologics are different from other psoriasis treatments because they are designed to work in the immune system; their goal is to block the disease in the early developmental stages. Biologics do this by targeting the overactive immune cells in the body. Some concentrate on T cells by preventing their activation or by stopping their migration in the immune response. Other biologic treatments bind to TNF-a and prevent it from initiating the proliferation of keratinocytes. Amevive and Raptiva are two of the biologic preparations that work by blocking the activation of T cells, thereby decreasing inflammation and halting the immune response before TNF-a cells can cause rapid growth

Natural sunlight contains ultraviolet light bands A–C. Most ultraviolet light is absorbed by the earth’s atmosphere, with mostly UVA reaching the earth’s surface. UVB light can be beneficial to our skin in small doses by initiating vitamin D synthesis. Too much UVB exposure can be harmful by causing sunburn in human skin. UV treatments are being used in a controlled setting at dermatology offices to treat dermatologic conditions such as psoriasis and vitiligo. Many offices have stand-up units that emit the artificial rays and some have smaller handheld devices to treat localized areas. Exposure time starts at a few seconds and can be increased to 25 or 30  min increments. Phototherapy treatments are usually scheduled 3 times a week. Treatment times depend on the patient’s skin type and the skin’s ability to respond to the treatment and are gradually increased as the treatment progresses until clearing of the psoriasis lesions is achieved.

14  Prevention of Psoriasis

UVB phototherapy can be useful in treating psoriasis when supplied at a set length on a regular schedule. Broadband UVB treatment uses a wider range of UV wavelengths and the narrowband type of treatment uses a more specific range to treat psoriasis. Narrowband UVB has been shown to clear psoriasis faster and can achieve the treatment goal with less exposure time and with fewer treatments than broadband UVB. Unlike PUVA treatment, UVB can be used on adults as well as children. PUVA is a type of phototherapy treatment that combines Psoralen and ultraviolet light A. Psoralen is a light-sensitizing medication and represents the “P” in the acronym. It comes in a pill form and a topical form. UVA is ineffective to treat psoriasis by itself, but when combined with Psoralen in PUVA therapy it can clear up to 85% of patients. PUVA works by slowing down the increased cell production. This treatment has most patients cleared by 25 treatments and has a good chance of inducing remissions. PUVA is a good treatment for moderate to severe cases.21

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family history of psoriasis or a current diagnosis should quit smoking. According to studies, people who use tobacco are much more likely to develop psoriasis. Smoking has also been linked to making psoriasis outbreaks more severe and symptoms last longer.9

14.4.2 Diet Multiple studies have shown that psoriasis can actually cause nutritional deficiencies in protein, iron, and folate. It has also been noted that gaining weight can cause flares or can worsen symptoms or psoriasis. Therefore, a low-fat diet with high protein content and green leafy vegetables can help prevent psoriasis flares. Eliminating or limiting caffeinated beverages and foods with high gluten content may reduce outbreaks.20, 21

14.4.3 Side Effects of Treatments 14.4 Prevention 14.4.1 Avoid Risk Factors/Triggers Patients diagnosed with psoriasis or with a family history of the disease should avoid certain risk factors. Cold or dry climates can worsen symptoms and increase the severity of psoriasis. Avoid scratching and picking at the skin. Epidermal injuries or mechanical trauma such as cuts or scratches of the skin can invoke Koebner’s phenomenon. In this event, psoriasis lesions appear on the skin at sites of induced trauma. Although it may sound almost impossible, psoriasis patients should be encouraged to avoid stress and anxiety. They may wish to consider learning meditation techniques, yoga, or participate in regular exercise in order to reduce stress and anxiety. Infections can induce types of psoriasis or flares. Regular office visits and antibiotic treatment when indicated can reduce occurrences. Certain medications can also trigger psoriasis; therefore these medications should be avoided if possible. Potential patients should consult a physician before beginning any new medications that may induce psoriasis. Alcohol should be limited to two drinks a day for a man or one drink for a woman. People with a

Anthralin cream can stain surrounding unaffected skin and hair a brownish color. To prevent this adverse effect rub this medication only on areas of psoriasis and wipe excess cream away. Occlusive dressings should be used to prevent stains on clothing or bed linens. Patients with light hair should use caution if using Anthralin to treat scalp psoriasis because of the staining quality of the medication. Dovonex has no major side effects when used correctly. The most common adverse reaction is skin irritation. To prevent this Dovonex can be mixed with petroleum jelly in increasing potencies until the skin becomes adjusted to the medication. As with any topical steroid Taclonex should only be applied to any area of the skin for up to 4 weeks. It should also be omitted from use in the axillae, groin area, or face as there is increased sensitivity in those areas. The overuse of this medication can cause atrophy of the epidermis. Increased sun exposure should be limited when using this medication; therefore, no phototherapy treatment should be instituted to avoid unwanted side effects. The most common side effect from using Tazorac is skin irritation. The best way to prevent this effect is to spot test the medication on a small area of skin

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before using on all the affected areas. Tazorac can make your skin more susceptible to sunburn. To avoid the adverse effects of using the medication in the sun the patients should be instructed to wear sunscreen or protective clothing when sun exposure is expected. Another option would be to wear the cream at night and wash it off in the morning before spending a day out in the sun. Topical steroids can be great assets when treating psoriasis but those using topical steroids should be advised of the many possible adverse effects. The steroid strength should be chosen carefully by the treating physician, using low strengths on the face and groin, and the most potent on thick skin like elbows and knees. Overuse of steroids can cause skin to thin or change pigmentation. Topical steroids have also been known to induce acne. Psoriasis lesions may even become worse if steroid treatment suddenly ceases. It is recommended to slowly taper steroids when planning to discontinue use. Topical steroids, especially the more potent types should be avoided around the eyes. Cataracts and glaucoma can present after prolonged steroid exposure to the eyelids and skin around the orbit. Intralesional injections have few side effects if used sparingly and only on a few resistant lesions. Be careful not to inject the same area repeatedly which could lead to skin atrophy at the injection site and can even result in divots in the skin. To prevent these effects the treatment regimen involving steroids should be explained to patients. Patients should have regular visits to their dermatologist in order to closely monitor the frequency and duration of steroid use.21

14.4.4 Systemic Therapy: Oral Medications Patients that are immunocompromised (HIV, history of malignancy, current radiation treatment, etc.), or those with hypertension or renal disease should not take Cyclosporine. To prevent side effects seen with Cyclosporine patients should be encouraged to have their blood pressure and kidney functions closely monitored while taking this medication. Before starting patients on this medication physicians should obtain a detailed list of medications and supplements the patient is taking as there are many cross-reactions

G. Coatney and R. A. Norman

with Cyclosporine. Patients should also avoid eating grapefruit or drinking grapefruit juice, because it decreases the excretion of the drug leading to increased levels of Cyclosporine in the blood. Conversely St. John’s wort can decrease Cyclosporine levels in the blood so it should also be avoided. A good medical history and exam should be obtained before starting a patient on Methotrexate. To prevent side effects the patient should have no history or current illness including blood disorders, anemia, peptic ulcers, any significant liver or kidney abnormalities, or excessive alcohol use. A close calculation of the total dosage amount should be recorded each time the patient has a doctor’s visit. Once the cumulative dose exceeds 1.5 g there is an increased risk for irreversible liver damage. NSAIDs and medications containing sulfa should be avoided in patients taking Methotrexate to prevent harmful side effects. Common side effects in Cyclosporine and Soriatane include bleeding or sensitive gums, changes in lipid levels in the blood, hair loss or excessive hair growth, and joint and muscle pains to name a few. These adverse reactions disappear when the medication dosages are lowered or stopped all together. Soriatane and Methotrexate are known teratogenic drugs. They should be avoided at all costs in pregnant women or those who may become pregnant to prevent birth defects in the developing fetus. Women of childbearing age can prevent the chance of harmful side effects to the fetus by getting regular pregnancy tests and remaining on two types of contraceptives during ­treatment. Cyclosporine is usually contraindicated in ­pregnant or breast-feeding women, but in cases of ­pustular psoriasis where the patient’s life is threatened Cyclosporine may be the treatment of choice compared to the other options of Soriatane and Methotrexate.21

14.4.5 Prevention of Biologics Side Effects All of the biologics are administered by injection. Irritation, pain, and inflammation at the site of injection are common side effects but these reactions have been proven to decrease after the initial dose. Other common side effects include sore throat, cough, nausea, headache, dizziness, and abdominal pain. To prevent patients

14  Prevention of Psoriasis

from discontinuing treatment on their own due to adverse effects educate them on these potential side effects and how they will most likely decrease and cease if continuing to use the medication as directed. Biologics are still relatively new treatments for psoriasis. Long-term side effects are still being evaluated. Because Amevive decreases the body’s immune response, people with a history of malignancy, recurrent infections, or in an immunocompromised state (HIV) should not use this medication. Amevive decreases the amount of T cells in the body, even though patients with psoriasis have an increased amount of T cells some patients can exhibit lymphopenia. Weekly CBCs should be drawn to monitor white blood cell counts to prevent levels from dropping to dangerously low levels. Patients with any active infection or history of recurrent infections should not use Enbrel, Humira, or Remicade. Those who have a history of multiple sclerosis or congestive heart failure should also not use these medications. A PPD skin test should be performed on patients before initiating treatment to rule out latent tuberculosis.21

14.4.6 Prevention of Phototherapy Adverse Effects Prevention of UVB treatment side effects is simple. Before UV exposure, apply sunscreen to the areas that are free of psoriasis lesions. Patients should also avoid UV exposure in sensitive areas such as the groin and face and neck. As there are many prescription and over-the-counter medications that increase UV sensitivity patients should provide a detailed list of all medications and supplements they take on a regular basis to their dermatologist. Many UVB and PUVA therapy patients experience remission of their disease, but some patients may need to continue with a maintenance regimen to prevent relapse of psoriasis. The maintenance regimen could be once a week to once a month depending on how severe the case of psoriasis. Oral Psoralen can cause nausea, pruritus, and erythema. To prevent these side effects patients should consider drinking ginger ale or eating at the same time the pill is taken for the nausea, and take a mild

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antihistamine to alleviate itching. If the adverse effects are unbearable the switch to topical Psoralen should be considered. Patients that have participated in more than 150 phototherapy treatments are at an increased risk for sun-induced keratoses and nonmelanoma skin cancers. These patients should have an annual fullbody exam, even after phototherapy has stopped, performed by a dermatologist to catch and treat any precancerous lesions. To prevent cataracts and any other eye problems, UVA-blocking sunglasses should be worn for at least 12  h after taking Psoralen when going out in the sun. To help avoid risks associated with increased UVA exposure the number of treatments should be kept to a minimum. This can be achieved by combining phototherapy with other treatments. Anthralin or topical steroids can be added to treat persistent lesions. Dovonex can also be used in combination with UVA therapy, but needs to be applied after phototherapy because UVA can inactivate this medication.21

14.5 Conclusion There is no cure for psoriasis but there are many ways to prevent the initial onset or exacerbations of the disease. Health education is an important aspect of psoriatic prevention and treatment. Patients should be informed about risk factors associated with psoriasis and about potential side effects associated with specific treatments. As stated earlier, psoriasis has a genetic link, and therefore may be unpreventable for some people. Those who have a family history of the disorder should pay special attention to their health in general, and to the health of their skin in particular in order to prevent initial psoriasis outbreaks or flares of previous incidents of the disease. For patients already suffering from the disease the treatment goal is to prevent exacerbations and flares to achieve the longest possible remission. Since the severity of ­psoriasis varies so much from case to case it is ­imperative to monitor it as closely as possible by maintaining regular appointments with primary care physicians or dermatologists. If prevention of the initial onset of psoriasis or preventing exacerbations of the disease is achieved a greater quality of life can be maintained.

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References   1. Atochina O, Harn D. Prevention of psoriasis-like lesions development in fsn/fsn mice by helminth glycans. Exp Dermatol. 2006;15:461–468   2. Elder J, Nair R, Guo S, et al The genetics of psoriasis. Arch Dermatol. 1994;130:216–224   3. Esposito M, Saraceno R, Giunta A, et al An Italian study on psoriasis and depression. Dermatology. 2006;212:123–127   4. Farber E, Nall M. The natural history of psoriasis in 5,600 patients. Dermatologica. 1974;148:1–18   5. Gelfand JM, Berlin J, Van Voorhees A, et  al Lymphoma rates are low but increased in patients with psoriasis. Arch Dermatol. 2003;139:1425–1429   6. Gelfand JM, Neimann AL, Shin DB, et al Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296: 1735–1741   7. Gelfand JM, Troxel AB, Lewis JD, et al The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007;143(12):1493–1499   8. Glade CP, Van Erp PEJ, Werner-Schlenzka H, et al A clinical flow cytometric model to study remission and relapse in psoriasis. Acta Derm Venereol. 1998;78:180–185   9. Herron MD, Hinckley M, Hoffman MS, et al Impact of obesity and smoking on psoriasis presentation and management. Arch Dermatol. 2005;141:1527–1534 10. Horn EJ, Fox KM, Patel V, et al Are patients with psoriasis undertreated? Results of National Psoriasis Foundation survey. J Am Acad Dermatol. 2007;57:957–962 11. James WD, Berger TG, Elston DM. Andrews’ diseases of the skin. Clinical dermatology. Philadelphia: Saunders Elsevier; 2006 12. Jankowiak B, Krajewska-Kulak E, Van Damme-Ostapowicz K, et al The need for health education among patients with psoriasis. Dermatol Nurs. 2004;16:439–441

G. Coatney and R. A. Norman 13. Javitz H, Ward M, Farber E, et al The direct cost of care for psoriasis and psoriatic arthritis in the United States. J Am Acad Dermatol. 2002;46:850–860 14. Kavli G, Forde O, Arnesen E, et al Psoriasis: familial predisposition and environmental factors. Br Med J. 1985; 291: 999–1000 15. Kimball AB, Gladman D, Gelfand JM, et al National psoriasis foundation clinical consensus on psoriasis comorbidities and recommendations for screening. J Am Acad Dermatol. 2008;58:1031–1042 16. Kimball AB, Robinson D Jr, Wu Y, et al Cardiovascular disease and risk factors among psoriasis patients in two US healthcare databases, 2001–2002. Dermatology. 2008;217: 27–37 17. Lindegard B. Diseases associated with psoriasis in a general population of 159, 200 middle-aged, urban, native Swedes. Dermatologica. 1986;172:298–304 18. Lumholt G. Psoriasis: Prevalence, Spontaneous Course and Genetics- A Census study on the Prevalence of Skin Disease on the Faroer Islands. Copenhagen: GEC, GAD; 1963 19. Najarian DJ, Gottlieb AB. Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol. 2003;48: 805–821 20. Naldi L, Patrazzini F, Peli L, et al Dietary factors and the risk of psoriasis: results of and Italian case-control study. Br J Dermatol. 1996;134:101–106 21. National Psoriasis Foundation, Psoriasis Overview and Treatment, November 2008. URL 22. Rapp SR, Feldman SR, Exum ML, et al Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41:401–407 23. Schafer T. Epidemiology of psoriasis. Dermatology. 2006; 212:327–337 24. Wolff K, Johnson RA, Suurmond D. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. New York: McGraw-Hill; 2005

Sports Dermatology: Prevention

15

Brian B. Adams

The four main categories of skin conditions that afflict the athlete include infections, trauma, inflammation, and encounters with the environment. Knowledge of the etiology of cutaneous skin problems of athletes helps the clinician best formulate a prevention plan. Most of the skin ailments that sideline athletes can be prevented through proper disqualification, appropriate use of equipment, and selective use of pharmacologic agents.

15.1 Infections The four main types of infections that affect the athlete are bacteria, fungi, viruses, and parasites. In general, parasitic infestations play a relatively small role in sports dermatology. However, all contact athletes need screening before practice and competition to ensure that infestations with lice and scabies do not cause epidemics.

15.1.1 General Prevention Techniques Some athletes are particularly susceptible to infections because of intense and prolonged skin-to-skin contact and trauma, inherent to athletic activity, which disturbs the normal epidermal barrier and allows for microorganism penetration. Sweating provides an B. B. Adams Department of Dermatology, University of Cincinnati, Cincinnati, OH, USA e-mail: [email protected]

ideal microenvironment (warm and moist) for microorganism growth. Finally, athletes transmit infections among team competitors through sharing equipment (Table 15.1). Basic prevention principles for athletes include modifying these risk factors (Table  15.2). No athlete should share towels, pads (shoulder, knee, elbow), helmets, hats, gloves, sweatbands, clothing, footwear, or razors. Athletic trainers should also be careful to ensure that they do not cross-contaminate any communal source. For example, once a trainer dips a tongue depressor into a jar of gel and applies it to an athlete, that depressor must be discarded. Any subsequent applicator that gets dipped into that container must be clean though not necessarily sterile. Athletes should always consider placing a barrier between their skin and the athletic environment. During practice and competition (if allowed) athletes who anticipate prolonged and intense skin-to-skin contact with competitors should wear synthetic moisture-wicking clothing to cover exposed areas. Loose-fitting clothing made of this fabric keeps the athletes cool and their skin dry while creating a physical barrier between themselves and potentially infectious competitors. Athletes should also wear synthetic moisture-wicking socks at all times. The feet of athletes become warm and moist as a result of their athletic activity and experience occlusion by athletic footwear, which further exacerbates the risk of infection of tinea pedis (Table 15.3).1 Athletes should never go barefoot on the locker room or shower floors. Poolside is equally infectious and athletes should always wear sandals in these situations. One group of investigators cultured dermatophytes each time they examined the pool and locker room floors every other week for a year.2 Additionally, once experiencing a traumatic break in their skin, the athlete should carefully bandage the area.

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_15, © Springer-Verlag London Limited 2010

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Table  15.1  Evidence for transmission of Staphylococcus by fomites Equipment type Epidemic study Level of evidence

Table  15.2  Prevention techniques to avoid skin infection epidemics Frequent, if not daily, skin checks by athletes and trainers

Fencing sensor wires

MMWR, 2003

+

Daily showers immediately after practices or competition

Whirlpools

Kazakova

+

Routine antibacterial soap use in the showers

Begier

+++

Frequent hand washing by trainers and affected athletes

Bartlett

+++

Seidenfeld

–

Universal availability of alcohol-based, waterless, soap cleansers

Lindenmayer

–

Weights

Kazakova

+

Sharing towels

Kazakova

+

Begier

–

Seidenfeld

–

Sosin

–

Use of protective gloves when using weight-lifting equipment

Lindenmayer

–

Universal sandal usage in the locker room and showers

Begier

–

Seidenfeld

–

Sosin

–

Lindenmayer

–

Tape sharing

Seidenfeld

–

Elbow pad use

Sosin

+++

Synthetic moisture-wicking socks

Seidenfeld

++

Immediate showers after sporting activity

Bartlett

+++

Sosin

+++

Sandals or other footwear while in shower and locker room or pool deck

Bartlett

+++

Sharing equipment

Athletic tape use

Skin lubricants use Bartlett +++ “–” no statistical association “+” suggested link “++” increased risk but not statistically significant “+++” statistically significant increased risk From Adams.1 With permission from Springer Science and Business Media LLC

Appropriate cleansing remains a cornerstone of infection control among sports teams. Immediately after practice or competition, athletes should shower with antibacterial soap. Athletes and trainers should liberally and frequently use soapless cleansers with moisturizers while in the training room. It is vital that athletic trainers use these cleansers between caring for separate athletes. Salient and judicious placement of these cleansers in the training room help ensures its use.

Regular laundering of equipment and clothing Mandatory no sharing policy for equipment and personal items Required personal towels Meticulous covering of all wounds

Periodic formal education for the athletes, coaches, and trainers From Adams.1 With permission from Springer Science and Business Media LLC Table  15.3  Preventative measures for tinea pedis and tinea ungium

Thorough feet washing Regular cleaning of shower, locker room, and pool floors Daily application of antifungal cream to feet From Adams.1 With permission from Springer Science and Business Media LLC

Athletes, coaches, and trainers must together ensure timely diagnosis and prompt therapy of skin infections; daily skin examinations of athletes who experience intense skin-to-skin contact are mandatory. Often, a medley of clinicians care for athletes on the high school level and coordination of care can be difficult. One study demonstrated the untoward effects of having wrestlers return to wrestling before their communicable skin disease was adequately treated.3 This study demonstrated that a series of wrestlers were incorrectly diagnosed and treated for herpes gladiatorum when in fact they actually had impetigo (70%), tinea corporis gladiatorum (10%), and eczema (10%). Eighty percent

15  Sports Dermatology: Prevention

of these sidelined wrestlers returned to wrestling without proper treatment for their bacterial and fungal eruptions and 10% (eczema) of the benched athletes had no infection at all.3 Specific National Collegiate Athletic Association (NCAA) guidelines exist that assist clinicians in the disposition of infected athletes. Adherence to these guidelines can prevent epidemics.

15.1.2 Specific Prevention Techniques While these general methods significantly decrease the incidence of skin infections in athletes, specific recommendations exist for each unique condition. Herpes simplex virus causes two different types of skin conditions in athletes. First, in outdoor athletes, the ultraviolet rays (both direct and reflected) can activate herpes labialis. One double-blind placebo controlled study of skiers demonstrated that 71% of those using placebo lip balm developed herpes labialis; no skiers assigned to use sunscreen on their lips developed herpes labialis.4 Another study demonstrated that skiers that took valacyclovir 400  mg twice daily starting 12 h before skiing experienced significantly fewer outbreaks of herpes labialis.5 Herpes simplex virus (specifically HSV-1) also causes epidemics in wrestlers (Fig. 15.1). To address these epidemics, one research team examined the

Fig. 15.1  Herpes gladiatorum of the ear (From Adams.1 With permission from Springer Science and Business Media LLC)

163

effectiveness of season-long pharmacological prophylaxis.6 This double-blind placebo controlled study had four distinct groups. The first section represented wrestlers whose initial herpes lesion occurred more than 2 years prior; half of these individuals took placebo and half took 500 mg of valacyclovir. None of the athletes who took valacyclovir in this section developed herpes while 33% of the wrestlers who took placebo developed herpes. The second section represented athletes who had first had a history of herpes less than 2 years prior to the start of the study. The athletes who took valacyclovir developed herpes 21% of the time whereas 33% of those athletes who had placebo developed herpes. Though differences among groups do not exist upon close statistical analysis, season-long prophylaxis with 1 g of valacyclovir seems prudent and allows maximal athletic participation. Methicillin resistant Staphylococcus aureus (MRSA) has caused many epidemics in athletes at many ability levels. Athletes with positive skin cultures for MRSA need to also have their nares swabbed for culture. Mupirocin 2% applied twice daily to the nares for 1 week significantly decreases nasal carriage. This process should be repeated twice per year to decrease the athlete’s staphylococcal carriage.1 In repeated cutaneous disease, clinicians should also consider the perianal, groin, and axillae regions as possible sites of staphylococcal colonization. The same mupirocin 2% application process for the nares works also for the perianal, groin, and axillae areas. As athletes spend time in the whirlpool while rehabbing an injury, they risk developing hot tub folliculitis caused by Pseudomonas. Whirlpools must be cleaned routinely and adequately chlorinated to prevent hot tub folliculitis. The free chlorine level should be at least 0.6  mg/L and the pH kept between 7.2 and 7.8. Unfortunately, adequate chlorination does not ensure bacteria-free water. In 16% of Pseudomonas folliculitis epidemics, unfortunately, the chlorination has been adequate.7,8 Pools with Pseudomonas necessitate a hyperchlorination with 5 mg/L for 3 days.9 Other bacterial infections that occur in athletes such as erythrasma (groin and axillae) and pitted keratolysis (feet) propagate in warm and moist microenvironments (Fig. 15.2). Wearing synthetic moisture-wicking undergarments and socks prevent those infections. Some of these types of socks also possess antimicrobial properties. Athletes predisposed to pitted keratolysis may find it helpful to apply aluminum chloride (which is

164

B. B. Adams Table 15.4  Prevention of friction bullae Category Method

Fig. 15.2  Pitted keratolysis

quite drying) to the soles and interdigitally before exercising. Tinea corporis gladiatorum, caused by Trichophyton tonsurans, causes frequent epidemics among wrestling teams. Teams and their staff frequently clean the mats before and after practice, though only one study has ever documented dermatophyte presence on the mats.10 Two studies have examined pharmacological prevention of tinea corporis gladiatorum. Itraconazole (400 mg every other week), in an open-label prospective trial, decreased the incidence from 27 to 0%.11 A subsequent randomized placebo controlled study of 100 mg of weekly fluconazole significantly decreased the incidence of tinea corporis gladiatorum.12 As a complication of their skin becoming warm and sweaty, athletes also frequently develop tinea versicolor. Prevention of this condition thwarts the persistent discoloration (either hyperpigmentation or hypopigmentation) of the skin that occurs subsequently. Once per week, athletes can apply selenium sulfide 2.5% to the predisposed areas and wash off after 15 min.1 While no direct evidence-based medicine exists to support this specific recommendation, athletes with recurrent tinea pedis should indefinitely apply topical antifungal agents to their soles and interdigital regions on the weekends. This recommendation relates in part to one study that revealed a decrease in the prevalence of tinea pedis from 21.5 to 6.9% over 3 years after bathers used an antifungal powder upon leaving the pool.13 Athletes, with recurrent tinea pedis, should consider obtaining new shoes; one study documented dermatophytes in 15% of shoes kept in storage for 1–4 weeks.14

Equipment

Gloves

Shoes

Adequately sized toebox Nonslip insoles Supple shoes Unique lacing techniques

Socks

Double-layered Padded Synthetic moisture-wicking

Topical agents

Aluminum chloride Drying powders Micronized wax and silicone powder

Petroleum jelly Tissue adhesives From Adams.1 With permission from Springer Science and Business Media LLC

15.2 Trauma While skin infections can sideline athletes and disrupt team activities, trauma causes the most common cutaneous ailments in athletes. Friction between the athlete’s skin and athletic equipment results in bullae and occasionally erosions. Depending on location, these physical disruptions in the skin may result in significant decrease in athletic ability secondary to pain. The primary risk factors for the development of bullae include ill-fitted equipment, moisture, heat, and prolonged activity. Athletes typically experience friction on their hands, feet, groin, shoulders, face, and nipples. Several approaches assuage friction bullae production (Table 15.4). First and foremost, athletes need to wear properly fitted footwear. Shoes that are too small or too large can result in bullae. Special lacing techniques can ameliorate bullae on the feet by preventing slippage in shoes that are too large (Fig. 15.3). Slipresistant shoe insoles also help prevent bullae by not allowing the toes to slam into the toe box. Brand new shoes need to be gradually included into the exercise regimen. Wearing new shoes for a prolonged period during intense activity can lead to bullae. Athletes should also wear synthetic moisture-wicking clothing (including socks); decreasing the degree of wet clothing and equipment decreases the incidence of bullae. Before the development of frank bullae, athletes experience warmth in the skin on the affected area. Some socks have extra padding in these “hot

15  Sports Dermatology: Prevention

165

Fig. 15.3  (a) Rather than lacing across to the opposite hole, lace the shoestring through the hole on the same side. (b) Through each of the loops made by the lacing procedure in (a), lace across to the opposite side. (c) Finally pull up, out, and tight. This snug-

gly stabilizes the heel and ankle for athletic participation (From Adams.1 With permission from Springer Science and Business Media LLC)

spots” to decrease bulla formation while other socks lack seams that can contribute to bulla genesis. Athletes can also decrease friction by wearing two layers of synthetic moisture-wicking clothing. Athletes whose hands come in contact with implements also can acquire bullae on their hands; gloves serve to decrease the amount of friction. Athletes can also apply topical antiperspirants to these “hot spots” to decrease moisture. In addition, lubricants applied to these hot spots decrease the coefficient of friction between the skin and the equipment. These lubricants include cosmetically elegant vehicles but also cheaper alternatives such as a petroleum jelly. There remains one caveat to the use of these occlusive agents. In the short term, the coefficient of friction is reduced but after about 3  h the occlusive nature of these agents results in a decrease in transepidermal water loss and supersaturation of the epidermis. This excess local moisture thus increases the chance of bullae formation. Commercially available tissue adhesives also serve to decrease the degree of friction experienced by the epidermis.

Athletes’ skin that chronically experience these frictional forces develops calluses. These callosities occur in anatomic locations that relate to specific athletic activities (Table  15.5) and help prevent future bullae. The same methods that prevent bullae acutely prevent calluses in the long term. Other frictional forces result not in bullae but in painful erosions. Common locations for these eruptions include the nipples (runners) and thighs (cyclists). Prevention of these erosions requires a multifaceted approach. First, athletes should apply a barrier between the “hot spots” and the clothing. Petroleum jelly and multiple commercially available substances decrease the coefficient of friction thus preventing epidermal breakdown. Synthetic moisture wicking clothing (including undergarments) also decrease friction by adding a layer that will, instead of the skin, experience the shearing forces and by wicking away moisture from the skin. Without additional moisture, the epidermis is less likely to develop erosions. Runners may also purchase patches to apply over their nipples to decrease friction.

166 Table 15.5  Sport-specific callosities Sport

B. B. Adams

Location

Etiology

Archery

Fourth fingertip

Bowstring hand

Baseball

Palms

Batting

First finger

Pitching

Billiards

Nondominant, palmar aspect thumb and first finger; dorsal aspect second finger

Holding the cue

Bowling (no holes)

Throwing hand, third and fourth fingers

Throwing ball

With holes

Throwing hand, second, third, and fourth lateral fingers

Throwing ball

Canoeing/crew/kayaking/rowing

Palms (depends on oar type)

Rowing

Cycling

Ischial tuberosities

Peddling

Dance

Distal toes

Dancing ballet

Equestrian

Fingers and palms

Holding on to reins

Fishing

Thumb and opposite first finger

Reeling in fish

Golf

Dominant hand, first finger and opposite palm, and opposite third finger

Swinging club

Gymnastics

Palms

Horse, parallel bar, rings

In-line skating

Legs

Pushing off while skating

Karate/judo

Lateral sides of hands and heels

Blows, chops, kicks

Tennis (badminton, racquetball, squash)

Dominant palm and thumb

Swinging racquet

Track and field (discus)

Throwing hand, all palmar aspects of fingers except thumb Throwing discus

Shot put

Hypothenar eminence

Throwing shot

Distance runners

Heel (“runner’s bump”)

Running

Weightlifters Palms, web spaces between thumb and first fingers From Adams.1 With permission from Springer Science and Business Media LLC

Fig. 15.4  Like cyclists and surfers, skaters wearing tight-fitting skates may develop athletes’ nodules such as seen here on the medial aspect of the foot

Lifting

These shearing forces when experienced on the sole of the foot can cause talon noire. Black heel (or talon noire) may appear clinically similar to malignant melanoma. Heel cups may help prevent talon noire. Surfer’s and cyclist’s nodules represent another sports-related traumatic skin condition (Fig.  15.4). Surfer’s nodules occur on the knees and feet; protective padding on these areas prevent the nodules. Interestingly, cold-water surfers develop surfer’s nodules more frequently than surfers in warm water. While paddling out to catch waves in cold water, surfers rest on their board only on their knees and feet; this intense focal pressure results in nodular formation. Warm water surfers can lie prone on their board and thus distribute their weight equally. Cold-water surfers can decrease the incidence of surfer’s nodules by wearing wet suits that permit them to lie prone on the board in

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167

Fig.  15.5  A tight-fitting figure skate resulted in this athlete’s toenail abnormality

cold water.1 Cyclists develop morphologically similar nodules in sacrococcygeal area. Properly fitted and padded seats, along with padded biking shorts, decrease the incidence of cyclist’s nodules.1 Athlete’s toenail occurs in myriad athletes (Fig.  15.5). To prevent these nail changes, athletes need to cut their nails straight across so that the pressure of the toe box distributes equally across the nail. The shoe’s toe box must allow adequate room. Unique lacing techniques ensure that the most distal toenails do not slam into the toe box. Combined forces (heat, moisture, and friction) create acne mechanica in athletes (Fig.  15.6 and Table 15.6). The focus of prevention for acne mechanica aims to decrease all three factors on the skin. Athletes must shower immediately after practicing or competing. The use of mildly abrasive soaps may also decrease the incidence of acne mechanica. Athletes can also use keratolytic agents to prevent acne mechanica. Synthetic moisture-wicking clothing keeps the skin cool and dry and decreases friction. Athletes can use fragments of this type of clothing to form a barrier beneath chinstraps, knee pads, and elbow pads.

15.3 Inflammation Both allergic and irritant contact dermatitis occur in athletes; their equipment and environment can cause eruptions (Fig. 15.7 and Table 15.7). Topical medication and equipment alternatives allow sensitized

Fig.  15.6  Acne mechanica (From Adams.1 With permission from Springer Science and Business Media LLC)

athletes (allergic contact dermatitis) to compete and practice without incident. If no equipment alternatives exist, athletes should apply tape, coban wrap, tissue adhesive, petroleum jelly, or another barrier between the offending equipment and the skin. Athletes sensitized to poison ivy, poison oak, and poison sumac can apply bentoquatam (commercially available as IvyBlock) to their skin to prevent allergic reactions; these athletes need to apply this medication at least 15 min before going outdoors and reapply every 4 h.1 Irritant contact dermatitis results from a direct toxic irritation of the skin with some agent in the environment; an athlete’s own immune system plays little initial role in the pathogenesis (unlike allergic contact dermatitis). Athletes decrease their risk for irritant contact dermatitis by placing a barrier between their skin and the environmental irritant. Such barriers include waterproof gloves, wet suits, petroleum jelly, and clothing to decrease the amount of exposed skin.

168

B. B. Adams

Table 15.6  The location and cause of acne mechanica depending on sport Sport Acne location Etiology Dancers

Trunk

Beneath tight leotard

Football

Chin

Chin straps

Shoulders

Shoulder pads

Upper inner arm

Shoulder pad straps

Forehead, cheeks

Helmet

Golfers

Lower lateral back Golf bag while carrying it

Hockey

Chin

Chin straps

Shoulders

Shoulder pads

Upper inner arm

Shoulder pad straps

Forehead, cheeks

Helmet

Shot putters

Neck

Shot put before launch

Tennis

Back

Heavy warm clothes

Weightlifters

Upper back

Plastic/vinyl bench cover

Upper central chest

Weight bar

Wrestlers

Chin, neck periHeadgear auricular Elbows, knees Elbow and kneepads From Adams.1 With permission from Springer Science and Business Media LLC

Several types of urticaria occur in athletes. Athletes can prevent cholinergic urticaria with antihistamines; also a gradual increase in athletic intensity may result in habituation that allows the athlete to participate without bouts of urticaria. Cold-urticaria-susceptible athletes should wear cold weather synthetic moisturewicking clothing; using several layers of such clothing maximizes heat retention. Some authors have suggested that cyproheptadine hydrochloride best prevents cold urticaria.15 Athletes with solar urticaria need to apply broadband blocking water-resistant sunscreen frequently. The use of sun-protective athletic clothing and broad-brimmed hats also helps prevent solar urticaria. Athletes with severe recalcitrant solar urticaria may require antimalarial agents or desensitization with ultraviolet radiation. Inert oily substances applied to the exposed skin in sensitized athletes, prevents the exceedingly rare condition, aquagenic urticaria. Some athletes develop exercise-induced anaphylaxis. A study of 278 athletes reported that over threequarters of those affected identified running as a trigger of their disease.16 Several factors exacerbate exerciseinduced anaphylaxis including extreme temperatures, eating before exercise, and ingesting NSAIDS (nonsteroidal anti-inflammatory drugs), aspirin, and B-lactam antibiotics (Table 15.8). Some of the notable foodstuffs that trigger exercise-induced anaphylaxis include barley, beans, broccoli, cheese, chicken, eggs, garlic, grapes, lettuce, peaches, peanuts, rye, shellfish, tomatoes, and wheat.17 By avoiding these triggers, athletes can mitigate outbreaks. Ketotifen appears to ­prevent exercise-induced anaphylaxis-related angioedema18 and cromolyn mitigates the exercise-induced anaphylaxis-related respiratory-related symptoms.19 The symptoms of exercise-induced anaphylaxis do not occur consistently during each athletic activity; however, athletes with this disorder should never exercise alone.

15.4 Environmental Encounters Fig.  15.7  Note the linear pattern characteristic of poison ivy. Also note the black dots in several of the lesions. These dots represent oxidized uroshiol, the protein responsible for poison ivy

Some irritants will wash away if too much time has not elapsed.

Environmental conditions also put athletes at risk to develop several other dermatologic conditions. Athletes practice and compete during the peak hours of ultraviolet exposure (10 am to 4 pm). Several studies note an excessive exposure among athletes (Table  15.9). For instance, in the Tour de Suisse, the cyclists experienced

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169

Table 15.7  The etiologies of the various sports-related types of irritant contact dermatitis Category Sport Designation Irritant Playing field

Mountaineering Soccer Swimming

Canyoning hands Cement burns Pool dermatitis

Forces of nature (rocks, water, wind) Calcium oxide Halogenated compounds in pool water

Athletes’ implements

Basketball Hockey Injured athletes Board surfers

Basketball pebble fingers Hockey dermatitis Pack dermatitis Surf rider’s dermatitis

Pebbled nicked ball Fiberglass Ammonium nitrate Mixed (board, salt, sand)

Athletes themselves

Baseball Baseball pitcher’s friction dermatitis Swimming Swimmer’s shoulder From Adams.1 With permission from Springer Science and Business Media LLC Table  15.8  Critical history questions to ask the athlete with suspected exercise-induced angioedema/anaphylaxis Do you experience EIA flares more frequently when you... Exercise in very cold or very hot conditions? Eat certain foods before exercising? Take aspirin, ibuprofen (or other NSAIDS), or antibiotics before exercising? From Adams.1 With permission from Springer Science and Business Media LLC Table 15.9  Sports for which studies have specifically illustrated reasons for increased ultraviolet damage Sports Reasons for increased ultraviolet damage Triathalon, cycling, baseball, softball, golf

Gross exposure to severe level of UV rays

Skiing, soccer, runners

Failure to apply sunscreen

Outdoor athletes

High wind

Outdoor athletes

High temperatures

Outdoor athletes

Sweating

Skiing, snowboarding, Reflectance of UV rays swimming From Adams.1 With permission from Springer Science and Business Media LLC

Questionable coarse clothing Hair stubble

up to 17 times their MED (the minimal UV dose to barely cause the skin to be pink).20 Another study revealed that athletes’ sweat reduces, by 40%, the amount of ultraviolet exposure required for sunburn.21 Outdoor winter athletes and beach athletes must also endure significant reflectance of the ultraviolet rays. Avoidance of ultraviolet exposure prevents not only the acute effects of the sun (sunburn, bullae, sun poisoning) but also the long-term effects (premature aging, wrinkles, sun spots) and skin cancer (Table  15.10). When possible, athletes should avoid practicing during the peak hours of ultraviolet radiation. Athletes should wear water-resistant SPF 30+ sunscreen and reapply frequently with sweating and water exposure. Unfortunately, athletes – despite their obvious increased risk – do not often use sunscreen. In one study, 85% of 200 collegiate athletes never used sunscreen. Only 6% of these collegiate athletes used sunscreen at least 3 of 7 days of the week.22 This same study identified one of the major barriers to athletes’ use of sunscreen as the lack of access to it. By making sunscreen readily available in the training rooms of high schools, Table  15.11  Factors influencing the protection factor of an athlete’s clothing Variable of fabric Effect on protection factor Nylon, wool, silk

Relatively increases

Avoid, if possible the sun between 10 am and 3 pm

Cotton, rayon, linen

Relatively decreases

Apply SPF 30 sunscreen one half hour before practicing in outdoor sports

Dark color

Increases

UV absorbers added

Increases

Increasing wetness

Decreases

Table 15.10  Smart sun safety tips for athletes

Reapply sunscreen often while sweating or swimming Wear hats Wear sun-protective clothing From Adams.1 With permission from Springer Science and Business Media LLC

Increasing numbers of Increases washes From Adams.1 With permission from Springer Science and Business Media LLC

170

colleges, and professional venues, medical providers can increase the likelihood of athletes’ sunscreen use. In addition to sunscreen, athletes should wear hats and sun-protective clothing. Broad-brimmed hats do not allow athletes to forego sunscreen use on their face, however, as sand and snow (two common sporting activity venues), reflect a great deal of ultraviolet radiation. Experts assign the term UPF to describe the relative ultraviolet-protective value of clothing. Several factors of athletic clothing influence ultraviolet protection (Table  15.11). Nylon, silk, and wool possess higher sun-protective factors than do other fabric types. Darker-colored clothes block more ultraviolet rays as do tighter weave fabrics (though they will be hotter). The initial launderings of athletic clothing improve its sun-protection ability. However, in general when an athlete’s clothing becomes wet (either through sweating or from the environment) the sun protection ability of the clothing decreases.1 On the opposite spectrum from the sun and warmth, frostbite and chilblains can occur in winter sport athletes. To prevent these cold-weather-related ailments, athletes can layer synthetic moisture-wicking clothing; outerwear should be waterproof. Winter athletes should avoid wearing metal jewelry as it conducts heat. Commercially available warming packets can be placed in gloves or shoes. As they practice and compete, athletes also must endure insect (bees, flies, wasps, yellow jackets, hornets) attacks. Several methods assuage the attack of these insects. First, athletes should avoid wearing bright colors. Scented products and shiny jewelry also attract insects. Second, most arthropod pests have a specific time of day that they prevail; avoidance of this time helps prevent arthropod stings. Products containing 20% (or greater) DEET deter insect bites. Longsleeved synthetic moisture-wicking clothing keeps the athlete cool but also protected from insect bites. Athletes should also wear sandals in grass to prevent stepping on one of these insects. Some insects are social insects and release a pheromone if destroyed; this pheromone incites all nearby yellow jackets, for instance, to swarm around the destroyed insect. All sporting venues should remove trash receptacles from areas of athlete congregation to prevent stings.1 Insults from insects are not all that athletes must endure; aquatic athletes who frequent areas where sea urchins and starfish are prevalent should wear protective boots. Swimmers who use chlorinated pools,

B. B. Adams

instead of the ocean may develop a condition termed green hair. Green hair occurs in light haired aquatic athletes exposed to water rich in copper. To prevent green hair, these athletes should shampoo immediately after water exposure; shampooing with copper chelating shampoos also deters the production of green hair.1

15.5 Summary Knowledge of the etiology of cutaneous skin problems of athletes reviewed here helps the clinician best formulate a prevention plan. Most of the skin ailments that sideline athletes can be prevented by following the guidelines included in this chapter.

References   1. Adams BB. Sports Dermatology. New York: Springer; 2006   2. Detandt M, Nolard N. Dermatophytes and swimming pools: seasonal fluctuations. Mycoses. 1988;31:495–500   3. Dworkin MS, Shoemaker PC, Spitters C, et al Endemic spread of herpes simplex virus type I among adolescent wrestlers and their coaches. Pediatr Infect Dis J. 1999;18:1108–1109   4. Rooney JF, Bryson Y, Mannix ML, et al Prevention of ultraviolet-light induced herpes labialis by sunscreen. Lancet. 1991;338:1419–1422   5. Spruance SL, Hamill ML, Hoge WS, et al Valacyclovir prevents reactivation of herpes simplex labialis in skiers. JAMA. 1988;269:1597–1599   6. Anderson BJ. The effectiveness of valacyclovir in preventing reactivation of herpes gladiatorum in wrestlers. Clin J Sport Med. 1999;9:86–90   7. Fox AB, Hambrick GW. Recreationally associated Pseudomonas aeruginosa folliculitis. Arch Dermatol. 1984;120:1304–1307   8. Spitalny KC, Voot RL, Witherell LE. National survey on outbreaks associated with whirlpool spas. Am J Public Health. 1984;74:725–726   9. Thomas P, Moore M, Bell E, et al Pseudomonas dermatitis associated with a swimming pool. JAMA. 1985;253:1156–1159 10. El Fari M, Graser Y, Presber W, et al An epidemic of tinea corporis caused by Trichophyton tonsurans among children (wrestlers) in Germany. Mycoses. 2000;43:191–196 11. Hazen PG, Weil ML. Itraconazole in the prevention and management of dermatophytosis in competitive wrestlers. J Am Acad Dermatol. 1997;36:481–482 12. Kohl TD, Martin DC, Nemeth R, et al Fluconazole for the prevention and treatment of tinea gladiatorum. Pediatr Infect Dis J. 2000;19:717–722 13. Gentles JC, Evans EGV, Jones GR. Control of tinea pedis in a swimming bath. Br Med J. 1974;2:577–580

15  Sports Dermatology: Prevention 14. Ajello L, Getz ME. Recovery of dermatophytes from shoes and shower stalls. J Invest Dermatol. 1954;22:17–24 15. Briner WW. Physical allergies and exercise. Sport Med. 1993;15:365–373 16. Shaddick NA, Liang MH, Partridge AJ, et al The natural history of exercise induced anaphylaxis: survey results from a 10-year follow-up study. J Allergy Clin Immunol. 1999;104:123–127 17. Adams ES. Identifying and controlling metabolic skin disorders. Phys Sportsmed. 2004;32:29–40 18. Nichols AW. Exercise-induced anaphylaxis and urticaria. Clin Sports Med. 1992;11:303–312

171 19. Adams BB. Exercise-induced anaphylaxis in a marathon runner. Int J Dermatol. 2002;41:394–396 20. Moehrle M, Heinrich L, Schmid A, et al Extreme UV exposure of professional cyclists during selected outdoor activities. Photodermatol Photoimmunol Photomed. 2000;201: 44–45 21. Moehrle M, Koehle W, Dietz K, et al Reduction of minimal erythema dose by sweating. Photodermatol Photoimmunol Photomed. 2000;16:260–262 22. Hamant E, Adams BB. Sunscreen use among collegiate athletes. J Am Acad Dermatol. 2005;53:237–241

Prevention of Cosmetic Problems

16

Zoe Diana Draelos

Cosmetic problems can be prevented through proper diagnosis and the use of carefully selected products. These products typically fall in the over-the-counter (OTC) realm and can be classified as true cosmetics or OTC drugs. Products that are considered cosmetics include moisturizers, lip balms, and shaving preparations while OTC drugs include sunscreens and antiperspirants. This chapter examines the use of these products in the prevention of cosmetic-related skin disease including facial eczema, eyelid dermatitis, cheilitis, postinflammatory hyperpigmentation, hyperhidrosis, and acne. These are common cosmetic problems that can be exacerbated or alleviated based on the dermatologist’s ability to correctly recommend prescription and complimentary nonprescription therapies.

16.1 Facial Eczema The face is the most complex area of the entire body because more products are designed for facial use than any other. The face contains sebaceous, eccrine, and apocrine glands, as well as keratinized and transitional skin. The face is also characterized by numerous follicular structures in the form of pigmented terminal hairs in the eyebrows, eyelashes, and male beard combined with white fine downy vellus hairs over the rest of the face. These follicular structures are the transition between the skin on the surface of the face and the follicular ostia associated with the follicle and sebaceous

Z. D. Draelos  Department of Dermatology, Duke University School of Medicine, 2444 North Main Street, High Point, Durham, North Carolina NC 27262 e-mail: [email protected]

glands. This skin cannot be reached by traditional cosmetics and skin care products, but irritant or allergic reactions that occur at the skin surface can impact this follicular lining. Thus, moisturizer and cleanser formulations for the face must be hypoallergenic, noncomedogenic, and nonacnegenic, since the face is capable of all these reaction patterns.

16.1.1 Facial Moisturizers Facial moisturizers are the most important cosmetic in the prevention of facial eczema. These moisturizers attempt to mimic the effect of sebum and the intercellular lipids composed of sphingolipids, free sterols, and free fatty acids. They intend to provide an environment allowing healing of the stratum corneum barrier by replacement of the corneocytes and the intercellular lipids. Yet, the moisturizing substances must not occlude the sweat ducts, or miliaria will result; must not produce irritation at the follicular ostia, or an acneiform eruption will result; and must not initiate comedonal formation. Moisturizers are used to heal barrier-damaged skin by minimizing transepidermal water loss (TEWL) and creating an environment optimal for healing. There are three categories of substances that can be combined to enhance the water content of the skin, which include occlusives, humectants, and hydrocolloids (Table 16.1). Occlusives are oily substances that retard TEWL by placing an oil slick over the skin surface, while humectants are substances that attract water to the skin, not from the environment, unless the ambient humidity is 70%, but rather from the inner layers of the skin. Humectants draw water from the viable dermis into the viable epidermis and then from the nonviable epidermis

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_16, © Springer-Verlag London Limited 2010

173

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Z. D. Draelos

Table 16.1  Facial moisturizer categories Moisturizer category Ingredients

Skin effect

Occlusive

Petrolatum, mineral oil, cetyl alcohol, dimethicone, cyclomethicone, soybean oil, lanolin, shea butter, cocoa butter, sesame oil, borage oil, all vegetable oils

Prevent water evaporation from skin, smooth desquamating corneocytes, place protective film over nerve endings to alleviate itch, add skin shine

Humectant

Glycerin, hyaluronic acid, sodium PCA, sorbitol, propylene glycol, vitamins, gelatin

Act as a sponge to hold water within the skin enabling hydration

Hydrocolloid

Proteins, hyaluronic acid, colloidal oatmeal

Create a physical barrier to water evaporation from the skin

into the stratum corneum. Lastly, hydrocolloids are physically large substances, which cover the skin, thus retarding TEWL. The best moisturizers to prevent facial eczema combine occlusive and humectant ingredients to combine the benefit of both categories. For example, a well-formulated moisturizer might contain petrolatum, mineral oil, and dimethicone as occlusive agents. Petrolatum is the synthetic substance most like the natural intercellular lipids, but too high a concentration will yield a sticky, greasy ointment. The aesthetics of petrolatum can be improved by adding dimethicone, also able to occlude water loss, but allowing a reduction in the petrolatum concentration and a thinner, more acceptable formulation. Mineral oil is not quite as greasy as petrolatum, but still an excellent barrier repair agent that further improves the ability of the moisturizer to spread, yielding enhanced aesthetics. The addition of glycerin to the formulation will allow water attraction to the xerotic facial skin from the dermis, speeding hydration. It is through the careful combination of these ingredients that facial moisturizers can be constructed to prevent and heal facial eczema.

16.1.2 Facial Cleansers The second most important cosmetics for the prevention of facial eczema are cleansers. Facial hygiene is an important concern; however, the cleanser must normalize the biofilm without damaging the stratum corneum skin barrier. The biofilm is the thin layer of sebum, eccrine sweat, apocrine sweat, skin care products, cosmetics, medications, environmental dirt, bacteria, and fungus that is present on the facial skin surface. Thus, a cleanser must remove sebum, p. acnes, other bacteria,

Malassezia, other fungi, and Demodex to maintain the health of the facial skin. Good facial hygiene is a careful balance between maintaining a healthy biofilm while preserving the integrity of the barrier by leaving the intercellular lipids intact and preventing facial eczema. This can be challenging because cleansers cannot accurately differentiate between sebum and intercellular lipids. It is further challenged by the everchanging sebum production of the facial glands, which varies by both age and climate, and the different bacteria with which the body comes in contact. Cleansers for the face must be selected to maintain hygiene while preserving the intercellular lipids, which form the skin barrier. The three major chemical categories of cleansers are soaps, syndets, and combars, which can be placed on a variety of cleansing implements from the hands to a washcloth to a disposable face cloth (Table 16.2). True soap is a specific type of cleanser with an alkaline pH of 9–10 created by chemically reacting a fat and an alkali to create a fatty acid salt with detergent properties. Soap efficiently removes both sebum and intercellular lipids making it an excellent general facial cleanser, but a poor choice for dry, sensitive facial skin. Milder cleansing for normal to dry facial skin is found in the syndet cleansers, which contain sodium cocoyl isethionate formulated at a neutral pH of 5.5–7. This more neutral pH removes fewer intercellular lipids, making it a cleanser suitable for the prevention of facial xerotic eczema. If the patient has extremely dry facial skin or tendencies toward eczematous skin conditions, a moisturizing liquid cleanser that leaves behind a thin layer of petrolatum, dimethicone, or vegetable oils should be selected for prevention of disease recurrence. Finally, extremely dry sensitive skin should be cleansed with a lipid-free cleanser, based on sodium laurel lauryl sulfate, for facial eczema prevention.

16  Prevention of Cosmetic Problems Table 16.2  Cleanser categories Cleanser category

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Formulation

Appropriate patient selection

Soap (Ivory, P &G; pure and natural, Jergens)

Fatty acid salt, pH 9–10

Normal-to-oily skin, general cleansing

Syndet (Dove, Unilever; Olay Bar, P & G)

Synthetic detergent (sodium cocoyl isethionate), pH 5.5–7

Normal-to-dry skin, general cleansing

Combar (Dial, Dial Corporation; Irish Spring, Coast, ColgatePalmolive)

Soap and syndet combined, pH 7–9

Triclosan antibacterial useful in patient with wound infection, bacterial colonization, or body odor

Moisturizing body wash (Olay Ribbons, P & G; Dove Nutrium, Unilever)

Synthetic detergent combined with petrolatum, dimethicone, and/or vegetable oils

Extremely dry skin, similar to conditioning shampoo, leaves behind a thin film of occlusive moisturizers to minimize skin scaling and roughness

Lipid-free cleanser (Cetaphil, Galderma; Aquanil, Person and Covey; CeraVe Cleanser, Coria)

Sodium laurel sulfate with cetyl alcohol and stearyl alcohol

Dry, sensitive skin

16.2 Eyelid Dermatitis The most sensitive skin on the entire body is located on the eyelids. The eyelid skin moves constantly as the eyes open and close, thus it must possess unique mechanical properties. It must be thin enough for rapid movement yet strong enough to protect the tender eye tissues. Eyelid tissue shows the state of health and age of an individual more rapidly than any other skin of the body. When others comment on a tired appearance, they are usually assessing the appearance of the eyes and the eyelid tissue. When others comment on a sickly appearance, they are also assessing the appearance of the eyes and the eyelid tissue. The eyelid skin appears to age quickly resulting in the presence of redundant upper eyelid tissue and lower eyelid bags. The redundant upper eyelid tissue is due to loss of facial fat, cumulative collagen loss in the eyelid skin from UV exposure, and the effect of gravity pulling down the upper eyelid skin. Lower eyelid bags are also due to the effect UV damage and gravity, but edema or swelling may also contribute. This edema may be due to retained body fluids or the release of histamine from inhaled allergens. All of these factors contribute to the complexity of the eyelid skin. The eyelids are the thinnest skin on the body; hence the eyelids are the most common site for irritant contact dermatitis and allergic contact dermatitis, either from products that are directly applied to the eyelids or

from products transferred to the eyelids by the hands. The eyelid skin also has a paucity of sebaceous glands, making it a common area of skin dryness. While there are no hairs on the eyelids themselves, the eyelashes form an interesting transition between the keratinized eyelid skin and the cartilage of the tarsal plate giving structure to the edge of the eyelid. Tearing from the eye impacts the skin of the eyelid, since wetting and drying of the eyelid tissues can predispose to dermatitis. The eyelids are also a common source of symptoms induced by allergies. These symptoms can be itching, stinging, and/or burning. Most persons with these symptoms respond by vigorously rubbing the eyelids. This can cause mechanical damage to the eyelid skin from minor trauma resulting in sloughing of portions of the protective stratum corneum to major trauma resulting in small tears in the skin. Most of the skin on the body responds by thickening when rubbed. Eyelid skin will also thicken, but this predisposes to decreased functioning and worsening of the symptoms.

16.2.1 Eyelid Cosmetics Eyelids are also a common site for cosmetic adornment. There are more individual colored cosmetics for the eyelid area than any other body area to include mascara, eyeliner, eye shadow, and eyebrow pencil.

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These cosmetics and the products used to remove them can be a source of both allergic and irritant contact dermatitis. The most common cause of cosmetic eyelid dermatitis is the use of light-reflective pigments in eye shadow powders or creams. Mica, bismuth oxychloride, fish scale, and ground minerals are used to create the iridescent appearance of the cosmetic when applied to the eyelid skin. These small particles can create irritation when placed on sensitive eyelid skin, resulting in an irritant contact dermatitis. Cosmetic-induced eyelid dermatitis can be prevented by selecting matte finish eyelid cosmetics without the light-reflective particles.

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Wash, P & G) an appropriate moisturizer must be selected that will provide an environment for healing while the intercellular lipids are resynthesized (Cetaphil Cream, Galderma).

16.3 Cheilitis

The most common cause of eyelid dermatitis is barrier disruption from xerotic eczema. Since the eyelid is relatively poor in oil glands, dry eyelid skin is frequently seen due to overly aggressive removal of lipids. This may be due to the use of a strong cleanser or products designed to solubilize oil-based waterproof cosmetics, such as mascara and eyeliner. Anything that damages the intercellular lipids or the corneocytes will result in eyelid eczema. Thus, eyelid hygiene must achieve a careful balance between the removal of excess sebum and old cosmetics to prevent eyelash infections and seborrheic blepharitis, while preventing damage to the intercellular lipids and ensuing eyelid eczema. Moisturizers for the eye area should be composed of occlusive substances that have minimal chance for allergic or irritant reactions, reduced ability to enter the eye, and excellent moisturizing properties (CeraVe, Coria).

Inflammation of the lip tissues, known as cheilitis, can be related to a variety of causes including lip-licking, irritant contact dermatitis, allergic contact dermatitis, actinic damage, and eczema. Cheilitis is a condition that combines both medical and cosmetic treatments, since lip balms and lipsticks may be an important part of disease prevention, or in some cases, the cause of the cheilitis. Cheilitis is basically an inflammation of the lips. This inflammation may be due to defective cellular repair from actinic damage, which leads to leukoplakia and chronic lip peeling. This is perhaps the most common cause of cheilitis in men. Alternatively, cheilitis may be due to an allergic reaction to cosmetics. The most common culprit is castor oil, which is found in the majority of lipsticks. Irritation from medications or lip-licking may also contribute. The irritation may be due to retinoids applied elsewhere on the face migrating to the lips or maceration from repeated wetting and drying of the lips. Lastly, there may be individuals who have defective oil production from the tiny oil glands found on the periphery of the lip where the transitional mucosa meets the keratinized skin. These sebaceous glands, also known as Fordyce spots, appear as yellow dots within the red vermillion. These individuals could be viewed as having a type of lip eczema.

16.2.3 Eyelid Cleansers

16.3.1 Xerotic Cheilitis

The use of eyelid moisturizers should be complemented by the formulation of cleansers designed to maintain the biofilm around the eye area. Cleansing of the eyelid tissue is indeed a delicate task. Typically, the skin should be handled very gently, due to its thin nature, and cleansing should remove excess sebum while preserving the intercellular lipids. Lipid-free cleansers (Table 16.2) are excellent to prevent eyelid dermatitis. If more aggressive cleansing is required, such as provided by a foaming face wash (Olay Foaming Face

In the female patient, lipsticks can be used to prevent and treat xerotic cheilitis. Lipsticks are mixtures of waxes, oils, and pigments in varying concentration to yield the characteristics of the final product. A moisturizing lipstick designed to prevent cheilitis should contain a high concentration of waxes combined with some oils to create an environment optimal for maintenance of the transitional lip barrier. The waxes commonly incorporated into lipstick formulations are white beeswax, candelilla wax, carnauba wax, ozokerite wax,

16.2.2 Eyelid Moisturizers

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lanolin wax, ceresin wax, and other synthetic waxes. Usually, lipsticks contain a combination of these waxes carefully selected and blended to achieve the desired melting point. Oils are then selected (i.e., castor oil, white mineral oil, lanolin oil, hydrogenated vegetable oils) to form a film suitable for application to the lips. The oils provide emolliency in the lipstick, making the lips feel smooth and soft. Lip balms can also be used in the treatment and prevention of cheilitis. They can be viewed as moisturizers for the lips without the pigments contained in the previously discussed lipsticks. Lip balms are designed to reduce TEWL creating an environment optimal for lip healing. The best prevention for xerotic cheilitis is the use of lip balm at night prior to bed (Lip Moisture SPF15, Neutrogena). The lips are at rest at night and the lip balm the greatest effect when applied at this time.

16.3.2 Allergic Contact Cheilitis Allergic contact dermatitis is also a cause of cheilitis, which can be difficult to diagnose. Several ingredients unique to lipstick formulation can cause allergic contact dermatitis in the sensitized patient.1 Castor oil, found in almost all lipsticks due to its excellent ability to dissolve bromo acid dyes, is a cause of allergic contact lip cheilitis.2–4 Another common lipstick sensitizer is the bromo acid dyes, one of which is eosin (D and C Red No. 21).5 Eosin is used in the indelible red lipsticks designed to stain the lips and extend the amount of time color remains on the lips. Many long-wearing lip products contain this allergen. In addition to causing allergic contact dermatitis, the

bromo acid dyes may also cause irritant contact dermatitis and worsen lip dryness. Other ingredients in lipstick that may cause allergic contact dermatitis include: ricinoleic acid,6 benzoic acid,7 lithol rubine BCA (Pigment Red 57–1),8 microcrystalline wax,9 oxybenzone,10 propyl gallate,11 and C18 aliphatic compounds.12

16.4 Postinflammatory Hyperpigmentation Postinflammatory hyperpigmentation is a common cosmetic problem of the entire body that is best prevented rather than treated. The prevention of postinflammatory hyperpigmentation may be difficult, especially in Fitzpatrick skin types III and higher. This unsightly pigmentation can occur after casual or deliberate sun exposure, unintended injury to the skin, or following skin surgery. A successful treatment must remove existing pigment from the skin, shut down the manufacture of melanin, and prevent the transfer of existing melanin to the melanosomes. Currently, there is no topical prescription or OTC product that achieves these three goals. The following discussion divides the prevention and treatment of postinflammatory hyperpigmentation into the prescription pigment-lightening agents such as hydroquinone mequinol, tretinoin, and azelaic acid (Table  16.3); and the botanical OTC agents such as ascorbic acid, licorice extract, alpha lipoic acid, kojic acid, aleosin, and arbutin. There is no doubt that the prescription products are more effective than the botanical derivatives, but both are discussed for completeness.

Table 16.3  Skin-lightening ingredients for postinflammatory hyperpigmentation Skin-lightening ingredient Effect on melanogenesis

Relative efficacy

Hydroquinone

Inhibits tyrosinase by interfering with copper binding reducing conversion of dihydroxyphenylanlanine (DOPA) to melanin

Highest

Azelaic acid

Inhibits tyrosinase by interfering with copper binding reducing conversion of DOPA to melanin

Moderate

Kojic acid

Inhibits tyrosinase by interfering with copper binding reducing conversion of DOPA to melanin

Moderate

Arbutin

Decreases tyrosinase activity without affecting messenger RNA expression

Moderate

Liquirtin

Increases melanin granule dispersion

Low

Vitamin C

Interacts with copper ions to reduce dopaquinone and blocks dihydrochinindol-2-carboxyl acid oxidation

Low

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16.4.1 Prescription Hyperpigmentation Topical Agents 16.4.1.1 Hydroquinone The gold standard for hyperpigmentation therapy in the United States remains hydroquinone. This substance is actually quite controversial, having been removed from the OTC markets in Europe and Asia. Concern arose because oral hydroquinone has been reported to cause cancer in mice fed large amounts of the substance. While oral consumption probably is not related to topical application, hydroquinone remains controversial because it actually is toxic to melanocytes. Hydroquinone, a phenolic compound chemically known as 1,4 dihydroxybenzene, functions by inhibiting the enzymatic oxidation of tyrosine and phenol oxidases. It covalently binds to histidine or interacts with copper at the active site of tyrosinase. It also inhibits RNA and DNA synthesis and may alter melanosome formation, thus selectively damaging melanocytes. These activities suppress the melanocyte metabolic processes inducing gradual decrease of melanin pigment production.13 Hydroquinone is available in both the OTC and prescription markets in the US. The maximum concentration in OTC formulations is 2% while most prescription formulations are 4%. It is possible to compound hydroquinone creams as high as 8%, but the formulations are unstable with rapid oxidation represented by browning of the product. In all formulations, hydroquinone is unstable, turning brown upon contact with air. Once the hydroquinone has oxidized, it is no longer active and should be discarded. Prescription hydroquinone formulations have tried to increase the potency of formulations by adding penetration enhancers such as glycolic acid, sunscreens, and tretinoin as a supplemental pigment lightening agent. Other prescription formulations have added microsponges to create time delivery of hydroquinone to the skin while others have placed the hydroquinone in a special canister dispenser. The initiation of hydroquinone prior to elective cosmetic surgery is the best preventative for minimizing and possibly eliminating postinflammatory hyperpigmentation. Hydroquinone can be used to decrease pigment production prior to the skin surgery that will ultimately drive pigment production.

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16.4.1.2 Mequinol Mequinol is the newest prescription skin-lightening agent approved in the US. It has also received approval in Europe. It is chemically known as 4-hydroxyanisole. Other names include methoxyphenol, hydroquinone monomethyl ether, and p-hydroxyanisole. Mequinol is available in the US in a 2% concentration and is commercially marketed as a prescription skin lightener in combination with 0.01% tretinoin as a penetration enhancer and vitamin C, in the form of ascorbic acid and ascorbyl palmitate, to enhance skin lightening. These active agents are dissolved in an ethyl alcohol vehicle. The exact mechanism of action accounting for the skin-lightening properties of mequinol is unknown; however, it is a substrate for tyrosinase, thereby acting as a competitive inhibitor in the formation of melanin precursors. It does not damage the melanocyte as does hydroquinone. Mequinol can be irritating to the skin and cause hyperpigmentation in persons with sensitive skin. Prior to picking this ingredient for the prevention of postinflammatory hyperpigmentation, a small test site should be selected to daily application for 2 weeks. If no skin darkening occurs, the mequinol may be suitable for the prevention of postinflammatory hyperpigmentation. It may actually be the 0.01% tretinoin that is the irritant in the presently available commercial mequinol formulation, rather than the mequinol itself (Solage, barrier therapeutics). 16.4.1.3 Tretinoin Topical tretinoin is used alone and in combination with hydroquinone as prescription pigment lightening treatment. Tretinoin has an effect on skin pigmentation as seen by a decrease in cutaneous freckling and lentigenes.14 It is the irregular grouping and activation of melanocytes that accounts for the dyspigmentation associated with photoaging,15 but normalization of this change has been histologically demonstrated with retinoids.16 While this effect is more dramatic with topical tretinoin, topical retinol has been thought to provide similar effects as a cosmeceutical. For persons with difficult-to-manage postinflammatory hyperpigmentation, tretinoin can be combined with hydroquinone and a topical corticosteroid, to reduce inflammation, in a presently marketed combination formulation (TriLuma, Galderma).

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16.4.1.4 Azelaic Acid

16.4.2.2 Licorice Extract

Azelaic acid is available currently as a 15% gel approved in the US for the treatment of rosacea (Finacea, Intendis). It is a 9-carbon dicarboxylic acid obtained from cultures of Pityrosporum ovale that may be a treatment alternative for individuals allergic to hydroquinone. Although its lightening effects are mild, several large studies done with a diverse ethnic background population have compared its efficacy to that of hydroquinone.17,18 It too interferes with tyrosinase activity, but may also interfere with DNA synthesis. It appears to have a specificity for abnormal melanocytes and for this reason has been used to suppress the progression of lentigo maligna to lentigo maligna melanoma. Azelaic acid may be an alternative to the previously mentioned prescription formulations in persons with sensitive skin or an allergy to other pigment lightening ingredients for the prevention of postinflammatory hyperpigmentation.

Licorice extracts are being used as topical anti-inflammatories to decrease skin hyperpigmentation. The active agents are known as liquiritin and isoliquertin, which are glycosides containing flavenoids.20 Liquiritin induces skin lightening by dispersing melanin. It is typically applied to the skin in a dose of 1  g/day for 4 weeks to see a clinical result. Irritation is fortunately not a side effect.

16.4.2 Nonprescription Hyperpigmentation Topical Agents There are a variety of nonprescription topical agents that are available in cosmeceuticals and cosmetics to prevent postinflammatory hyperpigmentation. None of these ingredients are as efficacious as hydroquinone; however, they are considered safe for use both in the US and worldwide.

16.4.2.1 Ascorbic Acid Ascorbic acid, also known as vitamin C, is used in the treatment and prevention of postinflammatory hyperpigmentation. It interrupts the production of melanogenesis by interacting with copper ions to reduce dopaquinone and blocking dihydrochinindol-2-carboxyl acid oxidation.19 Ascorbic acid, an antioxidant, is rapidly oxidized when exposed to air and is of limited stability. High concentrations of ascorbic acid must be used with caution as the low pH can be irritating to the skin actually precipitating postinflammatory hyperpigmentation.

16.4.2.3 Alpha Lipoic Acid Alpha lipoic acid is found in a variety of antiaging cosmeceuticals to function as an antioxidant, but it may also have very limited value in postinflammatory hyperpigmentation. It is a disulfide derivative of octanoic acid that is able to inhibit tyrosinase. However, it is a large molecule and cutaneous penetration to the level of the melanocyte is challenging.

16.4.2.4 Kojic Acid Kojic acid, chemically known as 5-hydroxymethyl-4Hpyrane-4-one, is one of the most popular cosmeceutical skin-lightening agents found in cosmetic counter skin-lightening creams distributed worldwide. It is a hydrophilic fungal derivative obtained from Aspergillus and Penicillium species. It is the most popular agent employed in the Orient for the treatment of melasma.21 Some studies indicate that kojic acid is equivalent to hydroquinone in pigment-lightening ability.22 The activity of kojic acid is attributed to its ability to prevent tyrosinase activity by binding to copper. It may be useful in postinflammatory hyperpigmentation.

16.4.2.5 Aleosin Aleosin is a low-molecular-weight glycoprotein obtained from the aloe vera plant. It is a natural hydroxymethylchromone functioning to inhibit tyrosinase by competitive inhibition at the dihydroxyphenylanlanine (DOPA) oxidation site.23, 24 In contrast to hydroquinone, it shows no cell cytotoxicity; however, it has a limited ability to penetrate the skin due to its hydrophilic nature. It is

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sometimes mixed with arbutin to enhance its skin-­ are the PABA derivatives, salicylates, and cinnamates; lightening abilities. substances that absorb both UVB and UVA are titanium dioxide and zinc oxide. Most quality sunscreens to prevent postinflammatory hyperpigmentation combine these ingredients to yield a product with excellent 16.4.2.6 Arbutin photoprotection that is cosmetically elegant. Arbutin is obtained from the leaves of the vaccinicum vitis-idaca and other related plants. It is a naturally occurring gluconopyranoside that causes decreased tyrosinase activity without affecting messenger RNA expression25. It also inhibits melanosome maturation. Arbutin is not toxic to melanocytes and is used in a variety of pigment-lightening preparations in Japan at concentrations of 3%. Higher concentrations are more efficacious than lower concentrations, but a paradoxical pigment darkening and postinflammatory hyperpigmentation may occur.

16.4.3 Sunscreens Sunscreens are another product category that can be used to prevent postinflammatory hyperpigmentation by minimizing the pigmenting effect of ultraviolet (UV) radiation. Sunscreens are designed to absorb UVA radiation (320–360 nm), accounting for pigmentation, and UVB radiation (290–320 nm), accounting for sunburn. Table  16.4 summarizes the more commonly used UVA and UVB filters. The primary UVA absorbers on this list are the benzophenones, anthralinates, and avobenzone. The primary UVB absorbers Table 16.4  Cosmeceutical sunscreens Sunscreen Spectrum of categories protection

Ingredients

Organic UVB filters

290–320 nm

Octyl methoxy cinnamate, ocytocrylene, octyl salicylate

Organic UVA filters

320–360 nm

Ecamsule, avobenzone, oxybenzone, menthyl anthranilate

Inorganic UVB/ UVA filters

Total reflection of all radiation

Zinc oxide, titanium dioxide

16.4.3.1 UVA Filters and Prevention of Tanning Response The UVA absorbers are most important in the prevention of postinflammatory hyperpigmentation. UVA absorbers can be divided into organic and inorganic subgroups. The organic subgroup undergoes a chemical reaction, known as resonance delocalization, to transform the UVA energy into heat. The main organic UVA absorber in sunscreens that prevent postinflammatory hyperpigmentation is avobenzone. Avobenzone must be combined with other organic filters because it is rapidly degraded by UV exposure. Almost 36% of the avobenzone in a sunscreen formulation becomes chemically inactive on initial exposure. Thus, avobenzone is combined with oxybenzone and octocrylene to enhance its photostability. Other UVA organic filters, such as the anthranilates (menthyl anthranilate), can be added as secondary agents. However, some of the most effective UVA photoprotectants are the organic filters zinc oxide and titanium dioxide. These white powders primarily reflect UVA radiation, but may also absorb a small amount. They also reflect UVB radiation. Zinc oxide is available as a microfine powder, but it cannot be used in high concentration due to the white-skin appearance created. Typically, zinc oxide is only used in concentrations of 2% or less for this reason. The newer nanoparticle zinc oxide is transparent, but very controversial. The controversy revolves around the ability of nanoparticle zinc oxide to penetrate the skin and create a permanent nonreactive dermal reservoir. The safety of this reservoir is unknown at this writing, leading the cosmetics industry to voluntarily refrain from use of this material until a better understanding of its skin effects can be obtained. Titanium dioxide is typically used in a larger particle size than zinc oxide. The term micronized is used to describe these particles because they are of many different sizes as compared to the even size of microfine

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particles. The microfine formulations produce less skin whitening than the micronized formulations. Both particulates are often silicone-coated to decrease the generation of secondary oxygen radicals when struck by UV radiation. Thus, the most effective inorganic sunscreens for preventing postinflammatory hyperpigmentation are zinc oxide and titanium dioxide while the most effective organic sunscreen is stabilized avobenzone. However, the sunscreen filter is just as important as the ability of the sunscreen to stay on the skin preventing postinflammatory hyperpigmentation.

16.4.3.2 Sunscreen Longevity Providing superior longevity of the sunscreen film on the skin surface and preventing postinflammatory hyperpigmentation can be accomplished by imparting water-resistant characteristics, since sweat, humidity, and a moist environment are the three most common factors that result in sunscreen failure (Table  16.5).

Table 16.5  Water-resistant sunscreens Chemical technology Mechanism of efficacy Water-in-oil emulsions

Oil is the main ingredient and resists removal by water

Silicones

Hydrophobic oily liquid that resists removal by water and forms film over skin surface

Acrylate crosspolymer

No emulsifier required which prevents water from dissolving the sunscreen, used in titanium dioxide preparations

Liquid crystal gels

Hydrophobic emulsifiers used that resist water, used in titanium dioxide preparations

Phospholipid emulsifiers

Substances engineered to mimic natural sebum (potassium cetyl phosphate) with water-resistant properties

Film forming polymers

Thin polymer film formed over the skin with inherent water resistance

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Water resistance is predicated on the fact that water soluble and oil-soluble substances do not mix. Thus, if a sunscreen is predominantly oil, with minimal water, it will not dissolve in the presence of water or perspiration. However, oil-dominant sunscreens are greasy and sticky, imparting poor aesthetics. This has led to development of silicone-based sunscreens, since silicone is an oil that is not greasy or sticky and has excellent water-resistant properties. Another method of imparting water resistance to a sunscreen is to alter or eliminate the emulsifier. The emulsifier allows water and oil-soluble ingredients to coexist as one continuous phase. Unfortunately, the sunscreen emulsifier will also allow perspiration or swimming pool water to mix with the oily ingredients, facilitating removal. This has led to the development of acrylate cross polymers and liquid crystal gels as the vehicle without an emulsifier. This increases the longevity of the sunscreen, an important consideration on areas such as the face that are prone to pigmentation following surgery. The last method used to confer sunscreen longevity in a moist environment is predicated on creating a film resistant to water removal. This can be accomplished with phospholipids, structurally similar to natural sebum, that create a thin oily film on the skin. Polymers can also be used to create a thin water-resistant film on the skin surface.

16.4.3.3 SPF and Sunscreen Efficacy Another important consideration in sunscreen efficacy is the amount of photoprotection afforded by the product. It has been traditionally thought that a sunscreen with an SPF of 15 was sufficient. Recently, newer sunscreen formulations have been introduced with higher SPF ratings, providing added benefits. While an SPF of 15 was thought to be sufficient for the prevention of sunburn, it is not optimal for protection against postinflammatory hyperpigmentation. A higher SPF cannot be achieved without providing additional UVA photoprotection. At present, no rating system exists for the UVA qualities of a sunscreen. In summary, a sunscreen to prevent postinflammatory hyperpigmentation should contain broad-spectrum UVA photoprotective ingredients, water-resistant qualities, and a high SPF.

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16.5 Hyperhidrosis Another common cosmetic problem is unwanted axillary perspiration. Clearly, the biggest advance in the treatment of this condition is the injection of botulinum toxin, which produces dramatic long-term sweat reduction. Yet antiperspirants remain a viable effective alternative in some patients. Antiperspirants can even be combined with botulinum toxin to prolong or increase the effect. Antiperspirants function to reduce both apocrine and eccrine sweat. Eccrine sweat is a clear, odorless fluid of pH 4–6.8 composed of 98–99% water, sodium chloride, lower fatty acids, lactic acid, citric acid, ascorbic acid, urea, and uric acid. Apocrine sweat is a turbid, viscous, odorless fluid of pH 6–7.5 that has high content water, in addition to protein, carbohydrate waste materials, and sodium chloride. The amount of eccrine perspiration is much greater than the amount of apocrine perspiration. An effective antiperspirant must reduce both types of perspiration.

16.5.1 Antiperspirant Mechanism of Action To reduce axillary hyperhidrosis, the antiperspirant must reach some 25,000 eccrine glands and coagulate the sweat duct protein. Antiperspirants contain metal salts that alter intraductal keratin fibrils to cause eccrine duct closure and formation of a horny plug, which obstructs sweat flow to the skin surface.26 The plug is formed by aluminum and zirconium metal salts.27 The original antiperspirant formulation was a 25% solution of aluminum chloride hexahydrate in distilled water, but it was extremely irritating.28 More modern antiperspirant formulations contain aluminum chloride, aluminum chlorohydrate, aluminum zirconium chlorohydrate, and buffered aluminum sulfate.29 These metals provide a better balance between efficacy and skin irritation. An effective antiperspirant must reduce sweat by at least 20% as mandated by the FDA, since antiperspirants are regulated as OTC drugs. Antiperspirants labeled as highly effective must reduce sweat by at least 30%. The antiperspirant must create a long-lasting plug

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in the sweat duct ostia quickly. This is best accomplished by evenly spreading the antiperspirant in the axillary vault. If the antiperspirant does not touch the sweat duct, it will not work. The active agent in the newer antiperspirants is aluminum-zirconium tetrachlorohydrex-gly complex. This complex can reduce axillary perspiration by 40–60%. These aluminum salts have an acidic pH of 3.0–4.2.30 Irritation is reduced by incorporating skin conditioning agents, such as dimethicone or cyclomethicone, into the formulation. The silicone imparts skin soothing properties to the skin irritated by the antiperspirant ingredients.

16.5.2 Optimizing Antiperspirant Efficacy Antiperspirants can fail to control hyperhidrosis for many reasons. The most common reason is use of a poor formulation that does not contain an optimal active ingredient mix and appropriate vehicle construction to deliver results. Antiperspirants also fail because an even film cannot be obtained that covers the entire armpit. The antiperspirant must be in contact with each and every eccrine and apocrine duct in the armpit to work. Thus, the applicator should be domed to fit into the axilla and dispense a thick even film of product. The film must be somewhat water-resistant or it will be rinsed away by perspiration before the plug can be formed in the ducts. For this reason, the armpit should be dry when the product is applied. Many dermatologists recommend that patients apply an OTC or prescription antiperspirant and then occlude the armpit with plastic wrap. If the patient sweats profusely under the occlusion, the perspiration may wash away the active ingredients before a plug can be formed. Thus, the occlusion may decrease the efficacy of the antiperspirant rather than increase efficacy due to enhanced penetration. Another possible cause for antiperspirant failure is inconsistent application. Compliance is important to achieve optimal results. It takes about 10 days of antiperspirant application for the complete plug to be formed in the sweat duct. If the patient decides after 3 days of application that the antiperspirant has not worked sufficiently, they have not given the product an adequate trial. Furthermore, the plug is completely gone 14 days after the last application. Continuous daily application

16  Prevention of Cosmetic Problems

is necessary to achieve and maintain the sweat reduction effect. Another consideration is the depth of the plug within the sweat duct. Plugs that are more deeply placed in the sweat gland will provide better sweat reduction than those that are superficially situated. If the plug is very close to the surface, it is possible that it can be removed by the rubbing of clothing or shaving. Patients who complain that antiperspirants do not work may wish to wear loose fitting clothing around the armpits and use only light razor pressure when shaving the armpits. The deepest plugs are created by prescription aluminum chloride solutions, but these formulations must be used carefully as they can irritate skin and ruin natural fabrics, such as rayon, cotton, and silk. More superficial plugs are created by OTC antiperspirants containing aluminum chlorohydrate. Intermediate depth plugs are created by OTC antiperspirants containing aluminum zirconium chlorohydrate. Optimizing antiperspirant efficacy requires the use of a well-formulated product that is consistently applied to the entire armpit as a thin film. One of the newer formulations uses aluminum-zirconium tetrachlorohydrex-gly complex, which has good efficacy with minimal skin irritation (Secret Platinum, P & G). This irritation is further reduced by the presence of dimethicone in the vehicle, which also provides for easy spreadability of a thin water-resistant film. Efficacy can be further enhanced by applying the antiperspirant twice daily. The bedtime application is actually more important than the morning application because the body is at rest and sweating reduced. The reduced sweating decreases the removal of the antiperspirant from the armpit and allows the active ingredient to remain in contact with the skin longer creating a stronger plug. Thus, antiperspirants can be optimized to provide prevention for the cosmetic problem of hyperhidrosis.

16.6 Acne Perhaps the most bothersome cosmetic problem to prevent is acne. Many skin care products have been accused of causing or worsening acne. Is there a true cause-andeffect relationship between skin care or cosmetic product use and the onset of acne? Sometimes this is difficult to ascertain. The final topic of discussion in this chapter

183

addresses the issue of acne cosmetica, a term used to describe acne caused by the application of topical products.

16.6.1 Acne Cosmetica Acne cosmetica is a concept that was developed many years ago when there was concern that cosmetics could indeed cause comedones formation. The issue of comedogenicity in relation to cosmetics arose in 1972 when Kligman and Mills described a low-grade acne characterized by closed comedones on the cheeks of women ages 20–25.31 Many of these women had not experienced adolescent acne. The authors proposed that substances present in cosmetic products induced the formation of closed comedones and, in some cases, a papulopustular eruption. Presently, personal conversations with Dr. Kligman indicate that he no longer believes currently marketed cosmetics cause comedones formation, yet acne related to cosmetics remains a problem. Lists remain in the literature of ingredients that supposedly cause acne, yet it is practically impossible to find formulations devoid of these substances. The list contains some of the most effective emollients (octyl stearate, isocetyl stearate), detergents (sodium lauryl sulfate), occlusive moisturizers (mineral oil, petrolatum, sesame oil, cocoa butter), and emulsifiers found in the cosmetic industry.32 A product line that excluded all these ingredients would exhibit poor efficacy and aesthetics. The skin care industry has developed the nomenclature of noncomedogenic and nonacnegenic to assure the consumer that the product does not cause acne; however, these claims carry no scientific validity as they are strictly for marketing purposes. The claims were developed to create a new consumer image for cosmetic lines designed to minimize acne. While testing is not required to make these claims, most large companies voluntarily will use established industry tests to ensure product safety and substantiate their claims. Many manufacturers, however, make noncomedogenic and nonacnegenic claims based on the safety profiles of the individual ingredients in the formulation. This is inaccurate. Noncomedogenic and nonacnegenic claims should be made based on clinical testing of the finished formulation. There are several established methods of testing cosmetic products.

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16.6.2 Comedogenicity Testing Comedogeniticity testing is typically carried out on either the rabbit ear or the human upper back. Rabbit ear testing is forbidden in the European Union and has been largely abandoned in the US as most companies wish to advertise that their products do not involve animal testing. Human testing is conducted on the upper back of individuals who have demonstrated the ability to form comedones. This is confirmed by performing a cyanoacrylate biopsy on the upper back of volunteers. The biopsy is obtained by placing cyanoacrylate glue on a microscope slide and allowing the acrylate to polymerize, adhering the stratum corneum to the glass slide. The slide is then peeled from the upper back and a thin layer of stratum corneum along with follicular contents is removed. The number of comedonal plugs removed is counted and should be at least ten to provide an adequate sample size. The cosmetic for comedogenicity testing is applied to the upper back under occlusion Monday through Friday for 2 weeks. At the end of the testing period, the cyanoacrylate biopsy is repeated. One negative control patch is applied with no cosmetic and one positive control patch is applied with coal tar. The final counts are obtained by viewing the slide upside down with a low magnification microscope and counting in a 1-cm squared field. If the number of comedonal plugs increases as compared to baseline, the cosmetic is considered comedogenic. If the number of comedonal plugs remains the same or decreases, the cosmetic can be labeled noncomedogenic. This type of human testing is safe and appears to accurately predict the comedogenic potential of a cosmetic.

16.6.3 Comedogenic Ingredients There are many frequently used cosmetic ingredients that have been associated with comedones formation. Perhaps mineral oil is the most common. Several cosmetic lines have been founded on the premise that mineral oil is a “bad” ingredient and avoidance of this material creates a “good” facial cosmetic. Mineral oil is a lightweight, inexpensive oil that is odorless and tasteless. Mineral oil may have been comedogenic in the past, but in current forms used in cosmetic formulations it is not comedogenic. Mineral oil is available

Z. D. Draelos

for purchase in industrial and cosmetic grades. Industrial grade mineral is used as a machine lubricant and may be contaminated with tar by-products, which are comedogenic. However, cosmetic grade mineral oil is certified pure by the supplier and is noncomedogenic. No quality cosmetic company would use industrial grade mineral oil in their products. Most of the ingredients of old that were considered comedogenic were derived from petroleum distillates. It is well-known in dermatology that tar is comedogenic. If a raw material is contaminated with tar, it may cause comedones formation. With new mass spectroscopy and better control on the manufacture of cosmetic materials, by-product contamination is rare. Most cosmetic companies require purity testing from their suppliers and then retest shipments of raw materials for purity in their own laboratories. The risk of ruining a good reputation based on a poor-quality raw material is too great in today’s competitive market. The old lists of comedogenic substances probably need to be retired in the modern marketplace.

16.6.4 Acneiform Eruptions and Cosmetics Acnegenicity must be distinguished from comedogenicity. While comedogenicity is rare, acnegenicity is much more common from skin care products. Comedogenicity results in the formation of comedones while acnegenicity results in the formation of inflammatory perifollicular papules. These papules may represent true acne with the involvement of the sebaceous gland or may simply represent a perifollicular acneiform eruption, which is undoubtedly more common. Many patients note the occurrence of “breakouts” following the use of moisturizers, facial foundations, sunscreens, etc. These patients typically present with perifollicular papules and pustules in a random distribution over the face. This eruption appears within 24–48 h after wearing the facial product. This is insufficient time for true acne to develop as evidenced by follicular rupture. However, it is sufficient time for an irritant contact dermatitis to develop. Most liquid formulations contain an emulsifier that allows the oily and water-soluble ingredients to coexist in one continuous phase. These emulsifiers can also emulsify sebum and create perifollicular irritation. Most companies test their product for

16  Prevention of Cosmetic Problems

acnegenicity for this reason. The tests usually involve an in-use test where volunteers use the product for 12 weeks with every 4-week evaluation by a dermatologist. All adverse reactions are recorded. If these perifollicular eruptions do not occur, the product can then accurately claim the formulation to be nonacnegenic. Persons who are prone to acneiform eruptions should prevent cosmetic problems by use-testing a new cosmetic or skin care product inside the elbow for five consecutive nights. If no problems arise, the product can then be applied to an area lateral to the eye for five consecutive nights. If no problems present, the product can be applied to the entire face. This type of testing can best prevent a total facial eruption.

16.7 Summary This chapter has discussed prevention of the common cosmetic problems including facial eczema, eyelid dermatitis, cheilitis, postinflammatory hyperpigmentation, hyperhidrosis, and acne. The proper selection of skin care products can aid in prevention. Adequate treatment of these conditions is best addressed through the use of pharmaceuticals in conjunction with OTC drugs, such as sunscreens and antiperspirants, along with the use of skin care products, such as moisturizers, skin-lightening agents, and cleansers. A complete understanding of cosmetic problems involves understanding all the product categories available for therapeutic intervention.

References   1. Sulzgerger MD, Boodman J, Byrne LA, Mallozzi ED. Acquired specific hypersensitivity to simple chemicals. Cheilitis with special reference to sensitivity to lipsticks. Arch Dermatol. 1938;37:597–615   2. Sai S. Lipstick dermatitis caused by castor oil. Contact Derm. 1983;9:75   3. Brandle I, Boujnah-Khouadja A, Foussereau J. Allergy to castor oil. Contact Derm. 1983;9:424–425   4. Andersen KE, Neilsen R. Lipstick dermatitis related to castor oil. Contact Derm. 1984;11:253–254   5. Calan CD. Allergic sensitivity to eosin. Acta Allergol. 1959;13:493–499   6. Sai S. Lipstick dermatitis caused by ricinoleic acid. Contact Derm. 1983;9:524

185   7. Calnan CD. Amyldimethylamino benzoic acid causing lipstick dermatitis. Contact Derm. 1980;6:233   8. Hayakawa R, Fujimoto Y, Kaniwa M. Allergic pigmented lip dermatitis from lithol rubine BCA. Am J Contact Derm. 1994;5:34–37   9. Darko E, Osmundsen PE. Allergic contact dermatitis to lipcare lipstick. Contact Derm. 1984;11:46 10. Aguirre A, Izu R, Gardeazabal J, et al Allergic contact cheilitis from a lipstick containing oxybenzone. Contact Derm. 1992;27:267–268 11. Cronin E. Lipstick dermatitis due to propyl gallate. Contact Derm. 1980;6:213–214 12. Hayakawa R, Matsunaga K, Suzuki M, et al Lipstick dermatitis due to C18 aliphatic compounds. Contact Derm. 1987;16:215–219 13. Halder RM, Richards GM. Management of dischromias in ethnic skin. Dermatol Ther. 2004;17:151–157 14. Weinstein GD, Nigra TP, Pochi PE, et al Topical tretinoin for treatment of photodamaged skin. Arch Dermatol. 1991;127:659–665 15. Gilchrest BA, Blog FB, Szabo G. Effects of aging and chronic sun exposure on melanocytes in human skin. J Invest Dermatol. 1979;73:141–143 16. Bhawan J, Serva AG, Nehal K, et al Effects of tretinoin on photodamaged skin a histologic study. Arch Dermatol. 1991;127:666–672 17. Fitton A, Goa KL. Azelaic acid. a review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs. 1991;5:780–798 18. Balina LM, Graupe K. treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol. 1991;30(12):893–895 19. Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma. Int J Dermatol. 2004; 43(8):604–607 20. Amer M, Metwalli M. Topical Liquiritin improves melasma. Int J Dermatol. 2000;39(4):299–301 21. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Derm Surg. 1999;25:282–284 22. Garcia A, Fulton JE Jr. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg. 1996;22(5):443–447 23. Choi S, Lee SK, Kim JE, et al Aloesin inhibits hyperpigmentation induced by UV radiation. Clin Exp Dermatol. 2002;27:513–515 24. Jones K, Hughes J, Hong M, et al Modulation of melanogenesis by aloesin: a competitive inhibitor of tyrosinase. Pigment Cell Res. 2002;15:335–340 25. Hori I, Nihei K, Kubo I. Structural criteria for depigmenting mechanism of arbutin. Phytother Res. 2004;18:475–469 26. Shelley WB, Hurley HJ Jr. Studies on topical antiperspirant control of axillary hyperhidrosis. Acta Derm Venereol. 1975;55:241–260 27. Jass HE. Rationale of formulations of deodorants and antiperspirants. In: Frost P, Horwitz SN, eds. Principles of Cosmetics for the Dermatologist. St. Louis: CV Mosby; 1982:98–104 28. Emery IK. Antiperspirants and deodorants. Cutis. 1987; 39:531–532

186 29. Morton JJP, Palazzolo MJ. Antiperspirants. In: Whittam JH, ed. Cosmetic Safety: A Primer for Cosmetic Scientists. New York: Marcel Dekker; 1987:221–263 30. Calogero AV. Antiperspirant and deodorant formulation. Cosmet Toilet. 1992;107:63–69

Z. D. Draelos 31. Kligman AM, Mills OH. Acne cosmetica. Arch Dermatol. 1972;106:843 32. Fulton JE, Pay SR, Fulton JE. Comedogenicity of current therapeutic products, cosmetics, and ingredients in the rabbit ear. J Am Acad Dermatol. 1984;10:96–105

Nutrition, Vitamins, and Supplements

17

Evangeline B. Handog and Trisha C. Crisostomo

Everyone has the right to a standard of living adequate for the health and well-being of himself and his family, including food. Universal Declaration of Human Rights

Adequate nutrition is essential for health and for the management of disease. From the earliest stages of life until old age, proper food and good nutrition is fundamental for survival, physical growth, mental development, performance and productivity, health and well-being. The right to food and nutrition, and the right to be free from hunger and malnutrition are international human rights being promoted by the World Health Organization (WHO) and other intergovernmental organizations since 1948. In the Rome Declaration on World Food Security (World Food Summit, 1996), heads of state and governments reaffirmed “the right of everyone to have access to safe and nutritious food, consistent with the right to adequate food and the fundamental right of everyone to be free from hunger.”1 The various nutrients, vitamins, and minerals can be acquired through a balanced diet, but more often than not, supplements are needed to maintain this equilibrium and prevent malnutrition. In 2000, WHO reported 150 million children less than 5 years old having protein–energy malnutrition, but this figure is slowly decreasing. It is distressing to note that WHO also reported 49% of the 10.7 million deaths among children less than 5  years old

E. B. Handog (*) Section of Dermatology, Research Institute for Tropical Medicine, Department of Health, Muntinlupa, Alabang, Philippines e-mail: [email protected]

each year in the developing world are associated with malnutrition.1 Malnutrition is most commonly caused by a deficiency in nutrients. It may be caused by insufficient ingestion, abnormal absorption or inadequate utilization of nutrients. However, it may also be caused by an intake excess. WHO reports an emerging epidemic of obesity. Three hundred million adults are diagnosed with obesity, 17.6 million of which are children in developing countries.1 Nutritional diseases may present initially or eventually with cutaneous signs and symptoms. This chapter aims to describe the common nutritional disorders encountered by dermatologists and how to prevent them.

17.1 Definition 17.1.1 Nutrition Nutrition is the process by which a living being takes in substances such as food and nutrients and uses them for life, growth, and the preservation of health.2 Nutrients are substances not synthesized by the body in enough amounts and thus must be supplemented by the diet. These include proteins, fats, carbohydrates, vitamins, minerals, and water. The required amounts of each essential nutrient differ according to the age and physiologic state of the individual.3

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_17, © Springer-Verlag London Limited 2010

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Table 17.1  Body mass index (BMI) classification BMI (kg/m2) Classification <18.5

Underweight

18.5–24.9

Normal

25.0–29.9

Overweight

30.0–39.9

Obese

>40 Morbidly obese BMI = weight (kilograms)/[height(meters)]2

17.1.2 Body Mass Index Body mass index (BMI) is computed by dividing the person’s weight in kilograms by the square of his height in meters. A BMI within the range of 18.5– 24.9 kg/m2 is normal, a BMI of 25.0–29.9 kg/m2 is categorized as overweight, a BMI of 30.0–39.9 kg/m2 is considered obesity and a BMI of >40 kg/m2 is morbid obesity. WHO suggests that a BMI over 25 is responsible for 64% of male and 77% of female cases of noninsulin-dependent diabetes mellitus (NIDDM). A BMI below 18.5 is considered underweight. BMI measurement is a very quick and simple way of assessing malnutrition, but it does not reflect differences in frame size.4 Table  17.1 summarizes the BMI value and its corresponding classification.

17.1.3 Degrees of Malnutrition and Treatment 17.1.3.1 Protein–Energy Malnutrition A lack of intake of protein and energy causes loss of both body mass and adipose tissue, although both may not be necessarily found in a given individual. This disorder is found in conditions wherein the socioeconomic factors limit the quantity and quality of food. The problem is heightened when energy intake is insufficient so that the dietary proteins are utilized as fuel rather than for the synthesis of body protein.5 Protein–energy malnutrition may occur in adults. The most observable change is the loss of subcutaneous fat from prominent deposits. The skin turns dry and rough and loses its elasticity. Follicles become more prominent. Follicular hyperkeratosis ensues, giving the skin texture similar to a nutmeg grater. Brown pigmentation

develops around the oral, orbital, and malar areas. Patients with acne observe that this condition disappears, yet lesions resume when nutrition is restored. Hair growth is slow. It falls out prematurely and turns gray. Nail growth is impeded. Bacterial infections such as furunculosis, impetigo, skin ulcers, and sores are common due to associated unsanitary environment.2 Malnourished children from developing countries may present with either of two conditions. The first is marasmus, which in Greek means “wasting.” It is a prolonged deficiency of protein and calories, and is a major contributing factor to mortality in infancy and early childhood. It is usually caused by weaning problems due to disease, poor hygiene, poverty, and cultural factors. Symptoms include dry, wrinkled loose skin due to a marked loss of subcutaneous fat. The loss of fat pads in the buccal area brings about the “monkey facies.” Hair is thin, grows slowly, and easily falls out or breaks. Nails may be fissured and nail growth is retarded. There is no edema or dermatosis in this condition.2 The second condition is kwashiorkor, which in Ghana language literally means “the first child gets when the second is on the way.” It is a severe deficiency in protein, usually occurring when the child is weaned onto a starchy diet. Changes in pigmentation may be found around the perioral area, the lower extremities, and around previous wounds, ulcerations, and other injuries. In children with fair skin, depigmentation starts with blanchable erythema evolving into small, dusky purple patches that do not blanch. In children with dark-skinned complexion, depigmentation is more obvious, evolving into waxy “enamel paint” spots on the trunk, diaper area, trochanters, knees, and ankles. The lesions have sharp edges and are elevated. Large areas of erosions that resemble “flaky paint” or “crazy paving” are seen in severe cases. Linear fissures can be found around the pinna, popliteal, antecubital and axillary areas, interdigits, in the center of the lips, and at the edge of the foreskin of the penile shaft. These lesions are brought about by intermittent tension. The skin is easily damaged; therefore, care must be taken to avoid acute trauma and chronic pressure injuries in bedridden children. Hair findings show the “flag sign,” wherein there are alternating bands of dark and pale hair. These bands reflect the alternating periods of adequate and inadequate nutrition.2 Protein–energy malnutrition rarely occurs alone. Concomitant nutritional deficiencies commonly seen include deficits in folic acid, thiamine, riboflavin, nicotinic acid, pyridoxine, and vitamin A.

17  Nutrition, Vitamins, and Supplements

17.1.3.2 Obesity Malnutrition may also be due to excess in nutrients. Obesity may be seen as an interplay of environmental and genetic factors. It is a condition wherein there is an excess of adipose tissue. This term is not analogous to being overweight, for the reason that muscular individuals may exceed their ideal weight for height without having an excess of adipose tissue. Aside from the BMI, we may measure adiposity by skin-fold thickness (anthropometry), underwater weighing (densitometry), or getting the waist-to-hip ratio, wherein abnormal values would be >0.9 for women and >1.0 in men.6 Body fat and fat distribution are affected by gender, age, degree of physical activity, and a number of drugs such as phenothiazines, antidepressants, antiepileptics, and steroids. Body fat increases with age in both men and women.6 The WHO reports that obesity in school children is estimated at 10% in industrialized countries such as Japan, US, and some countries in the European continent. Overweight and obesity during childhood lead to an increased risk of becoming overweight and obese in adulthood, as well as an increased prevalence of obesity-related disorders.1 In adults, the prevalence of obesity is 10–25% in most countries of Western Europe, 20–25% in some countries in the Americas, up to 40% in some countries in Eastern Europe, and more than 50% in some countries in the Western Pacific.1 With obesity, there is an increased risk of hypertension, cardiovascular disease, diabetes, gall bladder ­disease, sleep apnea, and osteoarthritis. Cutaneous man­ifestations associated with obesity include intertrigo due to friction between excessive fat folds, striae, and acrochordons. Acanthosis nigricans is characterized by a gray–brown velvety plaque found on the face, inner thighs, antecubital and popliteal fossae, umbilicus, and perianal area.2

189

coined by Funk in the early 1900s which came from two words: “amine,” which was the chemical that he was able to isolate from rice polishings, which he believed to preserve life, “vita.” He further went on to define avitaminosis and deficiency disorders.7

17.2.2 Recommended Dietary Allowance The recommended dietary allowances or recommended daily allowances (RDA) are based on the evaluation of the Food and Nutrition Board of the National Research Council on the correct amount of essential nutrients sufficient to meet the needs of a healthy individual. It is defined as the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all healthy individuals of a specific sex, age, life stage, or physiologic condition (pregnancy or lactation).3 RDAs are based on many types of evidence on nutrients, including replacement studies in persons with deficiency, biochemical assessments of function in relation to intake, epidemiologic studies, and extrapolation of data from animal experiments. The objective of these recommendations is to provide a safety factor appropriate to each nutrient by exceeding the actual requirements of most individuals.8 Water-soluble vitamins include the vitamin B-complex and vitamin C (Tables 17.2 and 17.3). Fat-soluble vitamins include vitamins A, D, E, and K (Tables 17.4 and 17.5). A balanced diet will ensure an individual of both water-soluble and fat-soluble vitamins (Tables 17.6 and 17.7).

17.2.3 Hypervitaminosis/ Hypovitaminosis 17.2.3.1 Vitamin A

17.2 Vitamins 17.2.1 Definition Vitamins are organic compounds that cannot be synthesized by humans and therefore must be ingested to prevent metabolic disorders. The term “vitamine” was

Vitamin A consists of all naturally occurring active forms, which include retinol and retinyl esters, and the carotenoids. This fat-soluble vitamin is essential for normal epithelial proliferation, keratinization, and the transduction of visual images by the retina.9 The major causes of vitamin A deficiency are inadequate diet, malabsorption of fat and liver disease. It can be assessed by taking the serum retinol level.2

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E. B. Handog and T. C. Crisostomo

Table  17.2  Recommended dietary allowances (RDA) of water-soluble vitamins for children (modified from dietary reference intakes of the Food and Nutrition Board of the National Research Council) Vitamin B2 (riboflavin) mg/day

Vitamin B3 (niacin) mg/day

Vitamin B5 (pantothenic acid) mg/day

Vitamin B6 (pyridoxine) mg/day

Vitamin B12 (cyanocobalamin) mg/day

Folate mg/ day

Vitamin C (ascorbic acid) mg/day

Vitamin H (biotin) mg/day

Infants 0–6 months 0.2 7–12 months 0.3

0.3 0.4

 2  4

1.7 1.8

0.1 0.3

0.4 0.5

  65   80

40 50

 5  6

Children 1–3 years 4–6 years

0.5 0.6

0.5 0.6

 6  8

2 3

0.5 0.6

0.9 1.2

150 200

15 25

 8 12

Males 9–13 years 14–18 years

0.9 1.2

0.9 1.3

12 16

4 5

1.0 1.3

1.8 2.4

300 400

45 75

20 25

Females 9–13 years 14–18 years

0.9 1.0

0.9 1.0

12 14

4 5

1.0 1.2

1.8 2.4

300 400

45 65

20 25

Life-stage group

Vitamin B1 (thiamin) mg/day

Vitamin A deficiency may have ocular manifestations such as night blindness and diseases of the conjunctiva, sclera and cornea, such as xerosis conjunctivae, Bitot spots, xerosis corneae, and keratomalacia. Cutaneous manifestations include dermomalacia where in the large areas of the body have dry, wrinkled skin covered with fine scales. Phrynoderma or “toad skin”

is a type of follicular hyperkeratosis which is also seen in vitamin A deficiency. Lesions may present as fleshcolored or hyperpigmented filiform, conical or large papules with large horny centers usually seen on the elbows and knees.2 WHO has strategies for controlling vitamin A deficiency which aim to provide an adequate intake through

Table 17.3  RDA of water-soluble vitamins for adults (modified from dietary reference intakes of the Food and Nutrition Board of the National Research Council) Vitamin B1 (thiamin) mg/day

Vitamin B2 (riboflavin) mg/day

Vitamin B3 (niacin) mg/ day

Vitamin B5 (pantothenic acid) mg/day

Vitamin B6 (pyridoxine) mg/day

Vitamin B12 (cyanocobalamin) mg/day

Folate mg/day

Vitamin H Vitamin C (biotin) (ascorbic acid) mg/day mg/day

Males 19–30 years 31–50 years 50–70 years >70 years

1.2 1.2 1.2 1.2

1.3 1.3 1.3 1.3

16 16 16 16

5 5 5 5

1.3 1.3 1.7 1.7

2.4 2.4 2.4 2.4

400 400 400 400

  90   90   90   90

30 30 30 30

Females 19–30 years 31–50 years 50–70 years >70 years

1.1 1.1 1.1 1.1

1.1 1.1 1.1 1.1

14 14 14 14

5 5 5 5

1.3 1.3 1.5 1.5

2.4 2.4 2.4 2.4

400 400 400 400

  75   75   75   75

30 30 30 30

Pregnancy <18 years 19–30 years 31–50 years

1.4 1.4 1.4

1.4 1.4 1.4

18 18 18

6 6 6

1.9 1.9 1.9

2.6 2.6 2.6

600 600 600

  80   85   85

30 30 30

Lactation <18 years 19–30 years 31–50 years

1.4 1.4 1.4

1.4 1.4 1.4

17 17 17

7 7 7

2.0 2.0 2.0

2.8 2.8 2.8

500 500 500

115 120 120

35 35 35

Life-stage group

17  Nutrition, Vitamins, and Supplements

191

Table 17.4  RDA of fat-soluble vitamins for children (modified from dietary reference intakes of the Food and Nutrition Board of the National Research Council) Life-stage Vitamin A Vitamin D Vitamin E Vitamin K group (mg/day) (mg/day) (mg/day) (mg/day) Infants 0–6 months 400 7–12 months 500

5 5

 4  5

2.0 2.5

Children 1–3 years 4–6 years

5 5

 6  7

30 55

300 400

Males 9–13 years 14–18 years

600 900

5 5

11 15

60 75

Females 9–13 years 14–18 years

600 700

5 5

11 15

60 75

a combination of dietary improvement including breastfeeding, supplementation, and food fortification.1 Acute vitamin A intoxication may occur after ingestion of 500,000 IU or greater by adults or proportional amounts by children (over 100 times the RDA). Symptoms

Table  17.5  RDA of fat-soluble vitamins for adults (modified from dietary reference intakes of the Food and Nutrition Board of the National Research Council) Life-stage Vitamin A Vitamin D Vitamin E Vitamin K group (mg/day) (mg/day) (mg/day) (mg/day) Males 19–30 years 31–50 years 50–70 years >70 years

900 900 900 900

 5  5 10 15

15 15 15 15

120 120 120 120

Females 19–30 years 31–50 years 50–70 years >70 years

700 700 700 700

 5  5 10 15

15 15 15 15

  90   90   90   90

Pregnancy <18 years 19–30 years 31–50 years

750 770 770

 5  5  5

15 15 15

  75   90   90

Lactation <18 years 19–30 years 31–50 years

1,200 1,300 1,300

 5  5  5

19 19 19

  75   90   90

Table  17.6  Common food sources of water-soluble vitamins (modified from dietary reference intakes of the Food and Nutrition Board of the National Research Council) Vitamin Food Source Vitamin B1 (thiamin)

Enriched, fortified, or whole-grain products; bread and bread products, mixed foods whose main ingredient is grain, and ready-to-eat cereals

Vitamin B2 (riboflavin)

Organ meats, milk, bread products, and fortified cereals

Vitamin B3 (niacin)

Meat, fish, poultry, enriched and whole-grain breads and bread products, fortified ready-to-eat cereals

Vitamin B5 (pantothenic acid)

Chicken, beef, potatoes, oats, cereals, tomato products, liver, kidney, yeast, egg yolk, broccoli, whole grains

Vitamin B6 (pyridoxine)

Fortified cereals, organ meats, fortified soy-based meat substitutes

Vitamin B12 (cyanocobalamin)

Fortified cereals, meat, fish, poultry

Folate

Enriched cereal grains, dark leafy vegetables, enriched and whole-grain breads and bread products, fortified ready-to-eat cereals

Vitamin C (ascorbic acid)

Citrus fruits, tomatoes, tomato juice, potatoes, brussels sprouts, cauliflower, broccoli, strawberries, cabbage, and spinach

Vitamin H (biotin)

Liver and smaller amounts in fruits and meats

Table  17.7  Common food sources of fat-soluble vitamins (modified from dietary reference intakes of the Food and Nutrition Board of the National Research Council) Vitamin Food Source Vitamin A

Liver, dairy products, fish, darkly colored fruits, and leafy vegetables

Vitamin D

Fish liver oils, flesh of fatty fish, liver and fat from seals and polar bears, eggs from hens that have been fed vitamin D, fortified milk products, and fortified cereals

Vitamin E

Vegetable oils, unprocessed cereal grains, nuts, fruits, vegetables, meats

Vitamin K

Green vegetables (collards, spinach, salad greens, broccoli), brussels sprouts, cabbage, plant oils, and margarine

192

include skin desquamation, abdominal pain, nausea, vomiting, and muscle weakness. Chronic intoxication occurs after intake of 50,000 IU/day for several months. Symptoms include desquamation, pruritus, facial dermatitis, dryness of the mucous membranes, erythema, brittle nails, cheilitis, and alopecia, which are reversible upon cessation of overdosing.2

17.2.3.2 B Vitamins Vitamin B1 (thiamine) deficiency may present as either of two conditions. Beri-beri is commonly found in Asians and presents with symptoms of fatigue, peripheral neuropathy, polyneuritis, heart failure, edema, angular stomatitis, and glossitis. WernickeKorsakoff syndrome presents as thiamine deficiency with symptoms of apathy, loss of memory, and confabulations. A deficiency in this vitamin may be associated with other B-complex vitamin and folate deficiency.2 A deficiency in riboflavin or vitamin B2 may result in glossitis, angular stomatitis or perlèche, cheilosis of vertical fissures of the lip, and lesions resembling seborrheic dermatitis distributed along the nasolabial folds, cheeks, forehead, and postauricular area.2 Pellagra is the deficiency in vitamin B3 or niacin and is characterized by the triad of dermatitis, diarrhea, and dementia. Cutaneous symptoms are found on areas that are exposed to the sun or localized pressure. It begins as erythema of the dorsal aspect of both hands with associated pruritius, burning, and edema. Vesicles may appear, coalesce to form bullae then burst. Dry brown scales may form. These scales are thicker and larger on the face, and may evolve into pustules. These lesions may become hard, rough, cracked, blackish, and brittle. Painful fissures develop in the palms and digits. In severe cases, the skin is covered with scales and blackish crusts due to hemorrhages. Lesions on the upper extremities may follow a “glove” or “gauntlet” distribution, while lesions on the lower extremities do not exceed the proximal malleoli, giving a “boot” distribution. On the face, lesions are usually found on the nose, forehead, cheeks, and chin giving a “butterfly” appearance. Lesions on the neck seen as a broad band encircling the neck are known as the Casal’s necklace.2 There have been no reported cutaneous changes in humans deficient in vitamin B5 or pantothenic acid.2

E. B. Handog and T. C. Crisostomo

Vitamin B6 (Pyridoxine) deficiency reveals seborrhea-like lesions on the face, scalp, neck, shoulders, buttocks, and perineum. Similar to riboflavin deficiency, one may also find angular stomatitis, cheilosis, and glossitis. Other symptoms include anorexia, nausea, vomiting, and neurologic findings such as hyperesthesia, ascending paresthesia, altered vibration and position sense, and hypoactive deep tendon reflexes.2 Cutaneous findings of a deficiency in cyanocobalamin or vitamin B12 include generalized hyperpigmented macules and patches found on flexural areas, palmar creases, soles, knuckles, and oral mucosa. Nail plates may also develop longitudinal, hyperpigmented streaks. Individuals with this deficiency may also present with graying of hair and a beefy red tongue.2 Cutaneous changes due to a deficiency in folic acid are rare but it has been reported to cause scaly papules and plaques on the face, trunk and extensor aspects of the extremities, stomatitis, and glossitis. Megaloblastic anemia is found in individuals deficient in folic acid. When treating this deficiency, it is important to check for a concomitant deficiency in vitamin B12. If this is overlooked, treatment with folate supplements will improve the anemia, but can progress to neurologic damage due to the cyanocobalamin deficiency.2 Biotin, also known as vitamin H, is found in the diet, but is also synthesized by bacteria found in the human intestines. A deficiency in this vitamin may either be acquired or inborn. An acquired deficiency is commonly caused by an excessive intake of the avidincontaining egg whites, which blocks the absorption of biotin. Symptoms include fine desquamation on the extremities, periorificial eczema, alopecia, pallor and atrophy of the tongue. Inborn deficiencies of the enzymes holocarboxylase synthetase or biotinidase may cause biotin deficiency due to malabsorption and ineffective metabolism. Symptoms include a generalized erythematous scaly rash similar to ichthyosis or seborrheic dermatitis, alopecia of the scalp, eyebrows and eyelashes, absence of lanugo hair. Corneal ulcers and keratoconjunctivitis may develop.2

17.2.3.3 Vitamin C Ascorbic acid, ascorbate, or vitamin C is a watersoluble vitamin most commonly found in citrus fruits and green vegetables. It is critical in wound healing

17  Nutrition, Vitamins, and Supplements

due to its important role in collagen synthesis. It also has a role in regenerating active vitamin E and increases cholesterol excretion.10 Scurvy or the deficiency in the intake of vitamin C begins with symptoms of follicular hyperkeratosis and the appearance of corkscrew hairs. Perifollicular purpura then ensues, seen commonly on the lower extremities. There is poor wound healing and old scars may break down. Other associated symptoms include edema of the lower extremities and gingival necrosis. Marginal deficiencies increase the risk of cancer, cardiovascular disease, hypertension, decreased immunity, diabetes and cataracts.2 An increased intake of vitamin C may cause dosedependent symptoms. An intake of greater than 1 g/day may cause an increase in oxalate excretion. Those taking 2 g/day may produce kidney stones in some cases. Doses greater than 2 g/day may cause diarrhea, nausea, stomach cramping, excess urination, and skin rashes.11

193

apathy, inability to concentrate, staggering gait, low thyroid hormone levels, decrease immune response, and anemia. Marginal deficiency in vitamin E is more common and is associated with an increased risk of cardiovascular disease and cancer. Vitamin E toxicity will cause adverse effects such as increased risk of bleeding, diarrhea, abdominal pain, fatigue, reduced immunity, and transiently raised blood pressure.13

17.2.3.6 Vitamin K Vitamin K deficiency causes hemorrhage due to an abnormal coagulation. This may occur in any part of the body, but this may manifest cutaneously as purpura. The confirmatory test that can be requested is a prothrombin time measurement.2

17.3 Supplements 17.2.3.4 Vitamin D Vitamin D is a steroid hormone which is important in calcium regulation and tissue growth and differentiation, including the skin. It comprises a number of related molecules, wherein only a few can be ingested, namely, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). A deficiency of this vitamin may cause an abnormality in the absorption and transport of calcium into the bone. An acquired deficiency of this vitamin is caused by inadequate diet, malabsorption, or a decreased exposure to ultraviolet B (UVB) radiation. Symptoms include osteomalacia, muscle weakness, and alopecia. Chronic ingestion of excessive amounts of vitamin D (50,000–100,000 U/day) may produce hypervitaminosis D with symptoms such as weakness, lethargy, headache, nausea and polyuria, and metastatic calcification.12

17.2.3.5 Vitamin E Vitamin E is a group of eight fat-soluble compounds, with a-tocopherol as the only active form found in humans. Deficiency of this vitamin is rare and occurs in individuals with chronic liver disease and fat malabsorption syndromes such as celiac disease and ­cystic fibrosis. Symptoms include nerve damage, lethargy,

17.3.1 Antioxidants Two types of chemical reactions occur widely in nature, namely oxidation and reduction. Oxidation involves the loss of electrons, while reduction is the gain of electrons. Oxidation and reduction reactions always occur together. Highly reactive molecules can oxidize molecules that were formerly stable causing them to become unstable species, such as free radicals. A free radical is defined as a chemical with an unpaired electron that can be neutral, positively charged, or negatively charged. Therefore, without antioxidants, a single free radical can cause damage to numerous molecules. However, despite the actions of antioxidant nutrients, some oxidative damage will still occur, and accumulation of this damage throughout life is believed to be a major factor in aging and disease.13 An antioxidant is any substance that significantly decreases the adverse effects of reactive species, such as reactive oxygen and nitrogen species, on the normal physiological function in humans.14 Human cells, most especially those found in the epidermis, possess an efficient antioxidant system, including enzymatic and nonenzymatic reductants, that deactivate reactive oxygen species (ROS) and reduce oxidized molecules such as lipid peroxides.14

194 Fig. 17.1  Interacting network of nonenzymatic endogenous antioxidants

E. B. Handog and T. C. Crisostomo Radicals

Membrane PUFAs

ROO°

ROOH

RO°

ROH

-Tocopherol -Tocolniend

Dehydroascorbale

Dihydrolipoic acid Reduced Giutalnione (GSH)

NAD(P)*H*

17.3.1.1 Endogenous Antioxidants Endogenous antioxidants are those found inherently in the epidermis, using either enzymatic and nonenzymatic reductants deactivating the ROS and reducing oxidized molecules. These include tocopherols (vitamin E) and ascorbic acid (vitamin C).14 The main advantage of endogenous antioxidants is their low toxicity potential since they are innate components of the organism (Fig. 17.1).14 Alpha-Lipoic Acid Lipoic acid is a very powerful antioxidant due to its being both aqueous and lipid-soluble, its anti-inflammatory activity, and its easy penetrability in the skin when topically applied due to it being a small, stable molecule.15 Its mechanism of action of preventing UV-induced photo-oxidative damage is due to the down-modulation

Vitamin E Cycle

-Tocopheroxyl− -Tocolnienoxyl−

Vitamin C Cycle

Thiol Cycle

Ascorbale

Alpha-lipoic acid Oxidised Giutalnione (GSSG)

GSH Reductase

NAD(P)H

of NF-B activation and inhibition of tyrosinase activity by chelating the copper ions.

Coenzyme Q10 Coenzyme Q10 (CoQ10) is a powerful free radical inhibitor that acts on hindering lipid peroxidases from forming plasma membranes. It also has a very important role in cellular energy production and works in  the mitochondrial adenosine triphosphate (ATP) energy-producing pathway of the cell. It may also play a role in preventing oxidative stress-induced cellular apoptosis since it is in the mitochondria where the final apoptotic signal is dispatched. It is reported that oral CoQ10 improves cellular energy production while topical CoQ10 is shown to inhibit collagenase expression in UV-irradiated human fibroblasts.15 It can regenerate reduced tocopherol 3 to 30 times greater than tocopherol within membranes.

17  Nutrition, Vitamins, and Supplements

Glutathione The glutathione system, also called the “master antioxidant,” is our first line of defense against peroxidation in the body. The liver contains the greatest amount while the heart and muscles show lower quantities. It is found both in the epidermis and the dermis, particularly within the fibroblasts. Glutathione peroxidase is a major detoxifier of hydrogen peroxide in the cytoplasm, along with catalase.10 17.3.1.2 Exogenous Antioxidants An immense inflammation can overpower the antioxidant defense system of the skin and lead to tissue destruction, thus the use of exogenous antioxidants, both topical and systemic. These include a-hydroxy acids (AHAs) and the various plant antioxidants such as anapsos, silymarin, soybeans, and tea. They are Table 17.8  Common food sources of exogenous antioxidants Antioxidant Food Source Carotenoids Beta-carotene Lutein, zeaxanthin Lycopene Flavonoids Anthocyanidins Flavanols (catechins, epicatechins, procyanidins) Flavanones Flavonols Proanthocyanidins

Isothiocyanates Sulforaphane

Phenols Caffeic acid, ferulic acid Sulfides/thiols Diallyl sulfide, allyl methyl trisulfide Dithiolthiones Whole grains

Carrots, various fruits Kale, collards, spinach, corn, eggs, citrus Tomatoes and processed tomato products Berries, cherries, red grapes Tea, cocoa, chocolate, apples, grapes Citrus foods Onions, apples, tea, broccoli Cranberries, cocoa, apples, strawberries, grapes, wine, peanuts, cinnamon

195

naturally occurring organic acids that are often referred to as fruit acids because they are found mostly in citrus fruits, apples, and grapes (Table 17.8). Anapsos Anapsos comes form the tropical fern P. leucotomos, which has in  vitro antioxidant and immunomodulating properties. It has been used in the treatment of psoriasis and vitiligo. It is shown to inhibit lipid peroxidation, ROS formation, phototoxicity, and acute sunburn in humans in vivo following acute ultraviolet (UV) light exposure.14 Isoflavone Genistein Genistein is a soy derivative which has been reported to have antioxidant, anticarcinogenesis, particularly breast and prostate cancers, and estrogen-like properties, thus improving the skin condition of postmenopausal women. Its action is in the protection of oxidative and photodynamically damaged DNA and downregulation of UVB-activated signal transduction cascade.16

Procyanidins The seeds of red grapes are the richest source of procyanidins. Similar to polyphenols, it has antioxidant properties and is shown to inhibit lipid peroxidation.15

17.3.1.3 Botanical Antioxidants

Cauliflower, broccoli, broccoli sprouts, cabbage, kale, horseradish

All plants protect themselves from oxidation following UV exposure in the outdoor environment. They work by quenching singlet oxygen and ROS. Most of these botanical antioxidants can be classified as flavonoids, carotenoids, and polyphenols.17

Apples, pears, citrus fruits, some vegetables

Chamomile

Garlic, onions, leeks, scallions Cruciferous vegetables (broccoli, cabbage, bok choy, collards) Cereal grains

Chamomile or Matricaria recutita inhibits UVBinduced pigmentation by avoiding ET-1-induced DNA synthesis. Its main ingredient is a-bisabolol. It has antiallergic, antineoplastic, and analgesic properties. Studies have shown that it has antimicrobial effects

196

against Staphylococcus sp. and Candida sp. It has also been shown to promote wound healing and exhibit anti-inflammatory activity.18

E. B. Handog and T. C. Crisostomo

polyphenols. In humans, polyphenols has been shown to inhibit UV-induced erythema and inflammation.14

Licorice Curcumin Curcumin is a polyphenol antioxidant extracted from the tumeric root. Its effect has been shown to be greater than that of vitamin E. Tetrahydrocurcumin is added to cosmetic products and functions as an antioxidant. It prevents the lipids from the moisturizer from becoming rancid.17

The roots of the licorice plant contain saponosides (glycyrrhizine) which serve as an emollient, flavonoids which are antioxidants, and glycyrrhetinic and glycyrrhizinic acids which have anti-inflammatory and wound healing effects. Glabridin is the main ingredient of licorice extract. It inhibits tyrosinase activity in vitro without affecting DNA synthesis.

Echinacea

Pycnogenol

Echinacea contains polysaccharides and glycoproteins, flavonoids, caffeic and ferulic acid derivatives, volatile oils, alkamides, polyenes, and pyrrolizine alkaloids which stimulate immunity and protect collagen.18

Pycnogenol is derived from the bark of the French maritime pine (Pinus pinaster). It is several times more powerful than vitamins C and E. It recycles vitamin C, regenerates vitamin E, and increases the endogenous antioxidant enzyme system. Its active ingredient is proanthocyanidin.17

Garlic Garlic has potent antimicrobial and antioxidant activity primarily due to alkylcysteine sulfoxides, specifically alliin. Other components include polysaccharides, saponins, and vitamins A, B2, and C. It also stimulates immunity and has anti-yeast activity.18

Resveratrol Resveratrol is a phytoalexin found in grape seeds and Mulberry tree (Morus alba). It has anti-inflammatory effects and inhibits cyclooxygenase and hydroperoxidase functions.19

Gingko Biloba Silymarin Gingko biloba contains unique polyphenols such as terpenoids, flavonoids, and flavonol glycosides that have anti-inflammatory effects that have been linked to anti-radical and anti-lipoperoxidant effects in experimental fibroblast models. There is increased collagen and extracellular fibronectin as demonstrated by radioisotope assay.17

Silymarin comes from the extract of the thistle Silybum marianum and has been used in the treatment of liver diseases due to its powerful antioxidant properties. It has been reported to inhibit the actions of UV radiation on living cells, and thus is a potential topical reagent in preventing and treating photodamage.14

Green Tea

Soybean

Polyphenols can be found in tea (Camellia sinensis) and is produced during the tea leaf processing. Green tea contains predominantly monomeric polyphenol catechins, whereas black tea contains polymeric

Soybean milk extracts has been shown to reduce the melanin deposition within the swine epidermis. It prevents UVB-induced pigmentation in  vivo, similar to soybean trypsin inhibitor STI.20

270

7−12 months

800

4−8 years

1,300

14−18 years

1,300

1,300

9−13 years

14−18 years

Females

1,300

9−13 years

Males

500

1−3 years

Children

210

Infants 0−6 months

24

21

35

25

15

11

5.5

0.2

890

700

890

700

440

340

220

200

3

2

3

2

1

0.7

0.5

0.01

150

120

150

120

90

90

130

110

15

8

11

8

10

7

11

0.27

360

240

410

240

130

80

75

30

1.6

1.6

2.2

1.9

1.5

1.2

0.6

0.003

43

34

43

34

22

17

3

2

1,250

1,250

1,250

1,250

500

460

275

100

55

40

55

40

30

20

20

15

Table 17.9  RDA of minerals for children (modified from dietary reference intakes of the Food and Nutrition Board of the National Research Council) Life-stage Calcium Chromium Copper Fluoride Iodine Iron Magnesium Manganese Molybdenum Phosphorus Selenium group (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day)

9

8

11

8

5

3

3

2

Zinc (mg/day)

17  Nutrition, Vitamins, and Supplements 197

44 45 45

1,300 1,300 1,300

3 3 3

3 3 3 290 290 290

220 220 220 10 9 9

27 27 27

18 18 8 8

360 310 320

400 350 360

310 320 320 320

2.6 2.6 2.6

2.0 2.0 2.0

1.8 1.8 1.8 1.8

50 50 50

50 50 50

45 45 45 45

1,250 700 700

1,250 700 700

700 700 700 700

700 700 700 700

70 70 70

60 60 60

55 55 55 55

55 55 55 55

13 12 12

12 11 11

8 8 8 8

1,300 1,000 1,000

1,000 1,000 1,000

150 150 150 150

45 45 45 45

Lactation £18 years 19–30 years 31−50 years

29 30 30

3 3 3 3

2.3 2.3 2.3 2.3

1,300 1,000 1,000

900 900 900 900

400 420 420 420

Pregnancy £18 years 19–30 years 31–50 years

25 25 20 20

8 8 8 8

1,000 1,000 1,200 1,200

150 150 150 150

Females 19−30 years 31–50 years 50–70 years >70 years

4 4 4 4

11 11 11 11

900 900 900 900

1,000 1,000 1,200 1,200

Males 19−30 years 31–50 years 50–70 years >70 years

35 35 30 30

Zinc (mg/day)

Table 17.10  RDA of minerals for adults (modified from dietary reference intakes of the Food and Nutrition Board of the National Research Council) Life-stage Calcium Chromium Copper Fluoride Iodine Iron Magnesium Manganese Molybdenum Phosphorus Selenium group (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day) (mg/day)

198 E. B. Handog and T. C. Crisostomo

17  Nutrition, Vitamins, and Supplements Table 17.11  Common food sources of minerals Mineral Food Source Calcium

Almonds, figs, beans, carrots, pecans, raisins, brown rice, apricots, garlic, dates, spinach, sesame seeds, brazil nuts, cashews, papaya, avocados, celery

Chromium

Brewer’s yeast, clams, cheese, corn oil, whole grains

Copper

Soy beans, brazil nuts, bone meal, raisins, legumes, seafoods, black strap molasses

Iodine

Kelp, dulse, beets, celery, lettuce, irish moss, grapes, mushrooms, oranges

Iron

Kelp, raisins, figs, beets, soy beans, bananas, asparagus, carrots, cucumbers, sunflower seeds, parsley, grapes, watercress

Magnesium

Honey, almonds, tuna, kelp, pineapple, pecans, green vegetables

Manganese

Celery, bananas, beets, egg yolks, bran, walnuts, pineapples, asparagus, whole grains, leafy green vegetables

Phosphorus

Mushrooms, cashews, oats, beans, squash, pecans, carrots, almonds

Potassium

Spinach, apples, tomatoes, strawberries, bananas, lemons, figs, celery, mushrooms, oranges, papaya, pecans, raisins, pineapple, rice, cucumbers, brussels sprouts

Selenium

Brazil nuts, meats, tuna, plant foods

Sodium

Turnips, raw milk, cheese, wheat germ, cucumbers, beets, string beans, seafoods, lima beans, okra, pumpkins

Sulfur

Bran, cheese, eggs, cauliflower, nuts, onions, broccoli, fish, wheat germ, cucumbers, turnips, corn

Zinc

Mushrooms, liver, seafoods, soy beans, sunflower seeds, brewer’s yeast

17.3.2 Minerals 17.3.2.1 Recommended Dietary Allowances The RDA of minerals differ according to life-stage group (Tables 17.9 and 17.10). These mineral nutrients can be acquired through a balanced intake of the following common food sources (Table 17.11).

199

17.3.2.2 Calcium In an adult, there is approximately 1–2 kg of calcium present in the body, 99% of which is found in the skeletal system. RDA ranges from 1,000 to 1,200 mg/day. However, some individuals increase their oral supplementation to 1,500–2,000 mg/day to prevent osteoporosis. A feedback mechanism exists to regulate hormonal regulation of intestinal absorption of calcium, resulting in an almost constant daily net calcium absorption of approximately 200–400 mg/day.12 An inadequate intake of calcium during growth may increase the risk of osteoporosis later in life. Osteoporosis is defined as a reduction of bone mass or density, characterized by a decrease in bone strength. In taking calcium supplements, it should be taken in doses <600 mg at a time, as the calcium absorption fraction decreases at higher doses. Calcium supplements should be computed based on the elemental calcium content, and not the weight of the calcium salt. Calcium carbonate is best taken with food since it requires acid for solubility. Calcium citrate can be taken at any time. Although side effects from calcium supplements are rare, individuals with a history of kidney stones should have a 24-h urine calcium determination before starting calcium to avoid hypercalciuria.12

17.3.2.3 Copper Copper plays an integral role in iron metabolism, melanin synthesis, and central nervous system function. Deficiency of this mineral is rare, although it may be found in premature infants who are fed mild diets and in infants with malabsorption. Patients with malabsorptive diseases and nephritic syndrome and in patients treated for Wilson’s disease with chronic high doses of oral zinc, which can interfere with copper absorption, may acquire copper deficiency anemia. Menkes kinky hair syndrome, a cross-linked metabolic disease of copper metabolism presents with symptoms such as mental retardation, hypocupremia, and decreased circulating ceruloplasmin. Children diagnosed with this disease often die within 5 years due to dissecting aneurysms or cardiac rupture.11 Copper deficiency is diagnosed by a finding of low serum levels of copper (<65 mg/dL) and low ceruloplasmin levels (<18 mg/dL).11

200

Copper toxicity can, in severe cases, cause kidney failure, liver failure, and coma. In Wilson’s disease, mutations in the copper-transporting ATP7B gene lead to accumulation of copper in the liver and brain. However, low blood levels of copper are detected due to decreased ceruloplasmin.11

17.3.2.4 Iron Chronic iron deficiency may manifest as anemia, ­glossitis, cheilosis, koilonychia, and hair loss. Hemosiderosis or chronic excess intake of iron would cause a bronze pigmentation of the skin, cirrhosis of the liver, diabetes mellitus, cardiomyopathy, and an increased risk in porphyria cutanea tarda.2

17.3.2.5 Selenium The mineral selenium is necessary for the function of glutathione peroxidase, an antioxidant enzyme. A deficiency in selenium causes cardiomyopathy, muscle pain and weakness, nail changes similar to Terry’s nails (found in patients with hepatic cirrhosis), dyschromotrichia, and macrocytosis. Selenium poisoning can occur after ingestion of water containing large amounts of the metal. Acute selenium intoxication may cause cutaneous findings such as alopecia, paronychia, possible nail loss, and reddish pigmentation of the nails, hair, and teeth.2

E. B. Handog and T. C. Crisostomo

and leukocytosis. Contamination of dialysis fluids with zinc from the adhesive on the dialysis coils or from galvanized pipes may also cause zinc toxicity with symptoms such as anemia, fever, and central nervous system disturbances.22

17.4 Conclusion An excess or deficiency in certain vitamins and minerals may manifest characteristically in the skin. The “toad skin” appearance found in hypovitaminosis A, the Casal’s necklace in hypovitaminosis B3, and the perifollicular purpura found in scurvy are just a few examples of distinctive dermatologic manifestations. Armed with the knowledge of this chapter, if one is to be presented with a patient with these symptoms, a diagnosis is very hard to miss. The WHO, together with the different health sectors and their national programs, has come up with a global strategy to fight malnutrition. However, prevention is always superior to cure. A well-balanced diet, along with the various supplements available in the market, will ensure a healthy individual. Our vision is of a world where people everywhere, at every age, enjoy a high level of nutritional well-being, free from all forms of hunger and malnutrition. World Health Organization

17.3.2.6 Zinc

References Zinc is essential for the formation and function of the immune system. It plays a role in the sense of taste and in wound healing. Acrodermatitis enterohepatica is an autosomal recessive disease that may cause zinc deficiency due to a defect in zinc absorption. The initial manifestations are usually seen when an infant is weaned from human to cow’s milk. Hallmark features include dermatitis, diarrhea, and alopecia.21 Toxicity may be caused by inhalation, oral ingestion, or intravenous administration. Inhalation of zinc oxide fumes by welders leads to a condition called metal-fume fever or brass chills, with symptoms such as fever, chills, excessive salivation, headaches, cough,

  1. World Health Organization. Nutrition for Health and Development: A global agenda for combating malnutrition. World Health Organization; 2000. http:/whqlibdoc.who.int/ hq/2000/WHO_NHD_00.6.pdf; 2007 Accessed 11.12.07   2. Nieves D, Goldsmith L. Cutaneous changes in nutritional disease. In: Freedberg I, Eisen A, Wolff K, et  al, eds. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York: McGraw-Hill; 2003   3. Dwyer J. Nutritional requirements and dietary assessment. In: Kasper D, Braunwald E, Fauci A, et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005   4. Denke M, Wilson J. Assessment of nutritional status. In: Fauci A, Braunwald E, Isselbacher K, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill; 1998

17  Nutrition, Vitamins, and Supplements   5. Denke M, Wilson J. Protein and energy malnutrition. In: Fauci A, Braunwald E, Isselbacher K, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill; 1998   6. Flier J, Maratos-Flier E. Obesity. In: Kasper D, Braunwald E, Fauci A, et  al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005   7. Bereston E. Vitamins in dermatology. A J Clin Nutr. 1954;2(2):133–139   8. Denke M, Wilson J. Nutrition and nutritional requirements. In: Fauci A, Braunwald E, Isselbacher K, et  al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill; 1998   9. Meyers D, Maloley P, Weeks D. Safety of antioxidant vitamins. Arch Int Med. 1996;156(9):925–935 10. Pugliese P. The skin’s antioxidant systems. Dermatol Nurs. 1998;10(6):401–416 11. Russell R. Vitamin and trace mineral deficiency and excess. In: Kasper D, Braunwald E, Fauci A, et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005 12. Bringhurst FR, Demay M, Krane S. Bone and mineral metabolism in health and disease. In: Kasper D, Braunwald E, Fauci A, et  al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005 13. Quiroga R. Anti-aging medicine as it relates to dermatology. In: Burgess C, ed. Cosmetic Dermatology. Berlin: Springer; 2005

201 14. Sorg O, Antille C, Saurat J. Retinoids, other topical vitamins, and antioxidants. In: Rigel D, Weiss R, Lim H, et al, eds. Photoaging. New York: Marcel Dekker; 2004 15. Graf J. Anti-aging skin care ingredient technologies. In: Burgess C, ed. Cosmetic Dermatology. Berlin: Springer; 2005 16. Wei H, Saladi R, Yuhun L, et al Isoflavone genistein: photoprotection and clinical implications in dermatology. J Nutr. 2003;133:3811S–3819S 17. Draelos ZD. Cosmeceutical botanicals: part 1. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders; 2005 18. Thornfeldt C. Cosmeceutical botanicals: part 2. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders; 2005 19. Jang M, et al Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275(5297): 218–220 20. Paine C, et al An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway. J Invest Dermatol. 2001;116(4):587–595 21. Neldner K. Acrodermatitis enterohepathica and other zincdeficiency disorders. In: Freedberg I, Eisen A, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York: McGraw-Hill; 2003 22. Falchuk K. Disturbances in trace elements. In: Fauci A, Braunwald E, Isselbacher K, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill; 1998

Part Sexually Transmitted Diseases, Viral Diseases, and Vaccines

III

Vaccines for Viral Diseases

18

Ivan D. Camacho and Brian Berman

Vaccination against viral agents has considerably alleviated the burden associated with viral diseases and has saved millions of lives worldwide. Global vaccination eradicated diseases like polio and other vaccines have led to a significant decline in infection rates and related complications of viral diseases. Important criteria for a disease to be susceptible of global elimination are that the disease is specific to humans and that there are no animal reservoirs for the infection. Three types or viral vaccines are currently available: • Attenuated live viral vaccines: these vaccines contain viruses that have been modified to produce an immune response without causing the disease. A risk of mutation to a pathogenic form is possible. These include measles, mumps, oral polio, rubella, varicella, and yellow fever. • Killed viral vaccines: these vaccines contain viral particles that have been deactivated, causing an immune reaction but not an infection. These include influenza, rabies, Japanese encephalitis, etc. • Recombinant antigens: specific immunogenic viral proteins are subtracted to induce antibody formation against that virus. The hepatitis B vaccine is one example of this kind of vaccine. The efficacy of a vaccine is measured by the length of immunity and the percentage of vaccinated individuals displaying immunity. Vaccines stimulate the production of IgG and IgA secretory antibodies by B-cell lymphocytes and the elimination of human leukocyte

antigen-matched infected cells by CD8+ T lymphocytes. CD4+ T lymphocytes present antigens to B-cells resulting in long-lasting immunity, even without antibody test results.1

18.1 Paramyxoviruses Paramyxoviruses encompass a heterogeneous family of RNA viruses including measles virus, mumps virus, parainfluenza virus, and respiratory syncytial virus. Vaccination for measles, mumps, and rubella is typically given in combination in the MMR vaccine, providing efficacious immunity with fewer immunizations and to a large target population. MMR is part of the US centers for disease control and prevention (CDC) Recommended Immunization Schedule. MMR is a live attenuated virus vaccine that is provided as a first dose for children 12–18 months of age and a second dose for children 4–6 years of age. Second doses may be given to adolescents ages 11–18 (if not received before) and adults that were either recently exposed to measles, previously vaccinated with killed measles vaccine, healthcare workers, or international travelers. MMR should not be administered to immunocompromised patients, patients with allergy to neomycin, and pregnant women. Pregnancy should be avoided in the following 4 weeks to an immunization.2

18.1.1 Measles (Rubeola) I. D. Camacho (*) Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, FL, USA e-mail: [email protected]

Measles virus is a highly contagious airborne virus that causes the typical prodrome of fever, malaise, conjunctivitis, photophobia and cough, followed 48 h later

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by a characteristic maculopapular rash. About 75% of household contacts to infected patients will develop the disease. Measles virus is related to orthomyxoviruses, which cause mumps and influenza, but is not related to togaviruses, which cause German measles or rubella. Since humans are the only reservoir to the infection, global eradication of measles is feasible, with a goal date of 2010. The measles vaccine is produced by culturing the Moraten virus strain in chick embryo cells. Vaccination produces 95–99% serologic evidence of immunity after two doses of vaccine and life-long immunity.3 The vaccination produces a mild noncontagious infection, with occasional fever (15%) and a transient viral exanthem. Encephalitis and subacute sclerosing panencephalitis are rare adverse effects.4 In the last decade, an aerosolized measles vaccine has been administered, providing superior immunogenicity and fewer side effects.5

18.1.2 Mumps Live attenuated mumps vaccine produces a mild, noncommunicable infection, providing 93–97% of serological evidence of immunity after one vaccination. However, the duration of the immunity is not clear, with efficacy rates ranging from 75 to 95% as demonstrated during outbreaks. Low-grade fever, mild parotitis, and a viral exanthema are the most common side effects.6,7

18.1.3 Rubella (German Measles) The rubella vaccine is grown in human diploid fibroblast cell cultures, producing high antibody titers in 97% of immunized individuals and lifelong protection.8 Arthritis is a common side effect in adults (40%), followed by fever, lymphadenopathy, and a viral exanthema (15%).

18.2 Human Herpes Viruses Herpesviruses comprise eight types of viruses that are known to be pathogenic in humans.

I. D. Camacho and B. Berman

Herpes simplex virus type 1 (HSV-1) is one of the most prevalent viruses, causing oral and perioral gingivostomatitis, and the most common type of herpesvirus infections. Although several topical and systemic antiviral medications are routinely used for treatment and prophylaxis of HSV-1 infections, no successful vaccines have been developed. Herpes simplex virus 2 (HSV-2) is generally a cause of herpetic genital lesions, although oral lesions have been reported. Epstein–Barr virus (HSV-4) is associated with multiple presentations, including infectious mononucleosis, Burkitt’s lymphoma in African children, nasopharyngeal carcinoma in Asian populations, and oral hairy leukoplakia. Cytomegalovirus (HSV-5) may present as sialadenopathy in immunocompetent individuals, birth defects in infected fetuses, and stomatitis in immunosuppressed patients. Human herpesvirus type 6 (HSV-6) is the cause of exanthema subitum (roseola infantum). Herpes virus type 8 (HSV-8 or Kaposi’s sarcomarelated herpes virus [KSHV]) is the etiologic agent for Kaposi’s sarcoma in patients with AIDS. HSV-8 has also been associated with primary effusion lymphoma and multicentric Castelman’s disease, both encountered in HIV-positive patients, as well as myeloma multiple and lymphoproliferative disorders. From this group of viruses, only the varicella zoster virus (VZV) (HSV-3) has an approved vaccine available.

18.2.1 Varicella Zoster Virus (HSV-3) VZV is an enveloped double-stranded DNA virus that causes varicella (chicken pox) as a primary infection and presents in the form of herpes zoster (shingles) as a reactivation of a latent VZV in the sensory ganglia of previously infected individuals. VZV is an airborne pathogen and the virus also sheds from infected vesicles. The varicella vaccine was developed using a liveattenuated Oka strain varicella virus, and was approved for use in 1995, proving to be safe, effective, and reducing the rate of infection by 60–90%.9 Varicella vaccination is currently recommended for all people at high risk for exposure who do not have a reliable history of varicella infection or serological evidence of VZV infection, including healthcare workers, those who live or work in environments where transmission is likely (corrections, military bases, daycare centers, colleges, etc.), women wanting to become pregnant,

18  Vaccines for Viral Diseases

and international travelers. Susceptible children may be vaccinated after 12 months of age; susceptible individuals over 13 years of age should receive two doses, at least 4 weeks apart. The varicella vaccine is contraindicated in pregnant women and pregnancy should be avoided for 4 weeks after immunization. The live attenuated Oka strain varicella vaccine does not effectively prevent herpes zoster or postherpetic neuralgia because it does not provide enough antigenic load to enhance the cell-mediated immune response to VZV. A herpes zoster live vaccine (Zostavax, Merck) developed to reduce the manifestation of shingles and its complications was approved by the FDA in 2006, for use in patients over 60 years of age. The zoster vaccine contains 18,700–60,000 plaque-forming units of virus and is estimated to be 14 times more potent than the varicella vaccine. The vaccine proved to be safe and efficacious in reducing the morbidity in immunocompetent elderly patients. The vaccine reduced the incidence of herpes zoster by more than 50% and reduced pain and discomfort of affected individuals by 61.1%, compared to the placebo group. The incidence of postherpetic neuralgia decreased by 66.5%, and the severity and duration of pain in those who develop the disease was 61% less than the control group.10 Erythema, swelling, and pain at the injection site are the most common side effects. Varicella-like rashes may also develop. The live attenuated vaccine is contraindicated in immunocompromised patients and is given as a single subcutaneous dose. Further studies on long-term effectiveness and cost-effectiveness will provide important information for the extended use of this vaccine. Although the effect of the zoster vaccine on the incidence of herpes zoster was less among individuals over 70-years old compared to individuals with ages ranging from 60 to 69 years (65.5 vs. 55.4%) the effect of the vaccine on the severity of illness and the development of postherpetic neuralgia was greater among the older age group (66.8 vs. 65.7%).11

18.3 Human Papillomavirus Human papillomavirus (HPV) is a nonencapsulated, double-stranded DNA virus that affects the skin and mucoses, and is the cause of common diseases such as cervical neoplasia and anogenital warts. In the US,

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over six million cases of HPV infection are documented each year, and approximately 50% of people will carry HPV at some point in their life. Two distinct groups have been identified: oncogenic stains and nononcogenic strains. Fifteen HPV types are considered high risk for cervical cancer, types 16 and 18 being the most common, accounting for about 70% of cervical cancers in women. HPV types 6 and 11 cause more than 90% of anogenital warts. Vaccination prevention with a vaccine could be 90%.12 A HPV quadrivalent vaccine (Gardasil, Merck) against the most prevalent high-risk HPV types was approved by the FDA to reduce the incidence of cervical, vaginal and vulvar cancer, and anogenital warts. This vaccine contains recombinant HPV type-specific virus-like particles made of L1 capsid protein of types 6, 11, 16, and 18. The vaccine has proven to be successful in the prevention of cervical cancer and genital warts by 90% in the vaccine group when compared with placebo.13 This vaccine is FDA-approved for use in females 9–26 years of age, and a priority review was announced to extend the potential use to women aged 27 through 45. The vaccine should be given to patients in the approved ages even if they are already carries of other HPV types or have suffered HPV disease. The vaccine is given intramuscularly, at days 1, 60, and 180, covered by most health insurance plans or may be provided through a patient assistance program. Pain, swelling, and local erythema at the site of injection are the most common adverse reactions. Many experts believe that boys and young men as well as immunosuppressed organ transplant recipients and HIV-positive individuals may benefit from HPV vaccination, protecting themselves against anogenital warts, penile, and anal carcinomas. The European Commission approved the use of this vaccine in males ages 9–15 in an effort to decrease the incidence of genital warts, penile and anal cancers, and reduce cervical cancer in sexual contacts of these individuals. The effectiveness of vaccination in males still needs further investigation. A bivalent prophylactic vaccine containing viruslike particles of HPV 16 and 18 was also investigated, showing good efficacy against HPV infection (91.6%), but requires further investigation regarding its duration of protective effects and administration standards.14 However, virus-like particle HPV vaccines failed to improve the rate of viral clearance in women already

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infected with HPV types 16 and 18, and should not be used to treat the infection.15 Therapeutic vaccines in which induced enhanced cell-mediated immunity produces lesion regression have been studied, showing lack of efficacy in human trials for the treatment of genital warts but some promising results in a patient with metastatic cervical cancer.16,17 Further trials will explore other therapeutic vaccination strategies to include multiple HPV types and using different antigens.18

18.4 Poxviruses Poxviruses are an extensive family of viruses that include molluscipoxvirus (molluscum contagiosum virus), orthopoxvirus (vaccinia), parapoxvirus (orf), pseudocowpox, yatapoxvirus (tanapox), and cowpox virus, the causing agent of smallpox (variola) and the only virus in this group with an approved vaccine.

18.4.1 Cowpox (Smallpox: Variola) The smallpox vaccine was the first human vaccine, created by Edward Jenner in 1796, becoming the model for success of viral vaccines. Smallpox was finally eradicated worldwide in 1977 and just over the past years became a concern that it could be used for bioterrorist purposes since it is highly contagious and has a high mortality rate. Smallpox is an airborne and fomite transmitted virus from active skin lesions, and characteristically presents with a febrile prodrome followed by a deep-seated papulo-vesicular rash with subsequent pustule and scab formation. The smallpox vaccine is a suspended live vaccine derived from the vaccinia virus, similar to the cowpox virus. Although this vaccine is not routinely administered, it is provided to US military personnel and reserves are maintained in case of a bioterrorist outbreak. Pustule formation, local erythema, and pain are common adverse effects, but in the new era of smallpox vaccination other side effects such as erythema multiforme-like rashes and urticarial hypersensitivity reactions have been seen.19 Postvaccinal encephalomyelitis and death have occurred. Generalized vaccinia is also rare reported complication of smallpox vaccination.20

I. D. Camacho and B. Berman

Some physicians are not familiar with the estimated rate of death related to smallpox vaccination (1 in 1,000,000), and vaccination contraindications such as myocardial infarction, angina, congestive heart failure, steroid eye drop use, and the nonemergency vaccination of those younger than age 18.21 Coadministration of smallpox vaccine with vaccine immune-globulin (VIG) decreases the severity of smallpox in exposed individuals, if administered within 4 days of known exposure. The development of recombinant vaccines will result in good immunity with fewer complications. A second-generation smallpox vaccine (ACAM2000) was approved in 2007 by the FDA for the inoculation of people at high risk of exposure to smallpox and could be used to protect individuals and populations during a bioterrorist attack.

References   1. Plotkin SA. Immunologic correlates of protection induced by vaccination. Pediatr Infect Dis J. 2001;20(1):63–75   2. Watson JC, Hadler SC, Dykewicz CA, et al Measles, mumps, and rubella – vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1998;47(RR-8):1–57   3. Watson JC, Pearson JA, Markowitz LE, et al An evaluation of measles revaccination among school-entry-aged children. Pediatrics. 1996;97(5):613–618   4. Peltola H, Heinonen OP. Frequency of true adverse reactions to measles-mumps-rubella vaccine. A double-blind placebocontrolled trial in twins. Lancet. 1986;1(8487):939–942   5. Bennett JV, Fernandez de Castro J, Valdespino-Gomez JL, et  al Aerosolized measles and measles-rubella vaccines induce better measles antibody booster responses than injected vaccines: randomized trials in Mexican schoolchildren. Bull World Health Organ. 2002;80(10):806–812   6. Kim-Farley R, Bart S, Stetler H, et al Clinical mumps vaccine efficacy. Am J Epidemiol. 1985;121(4):593–597   7. Hersh BS, Fine PE, Kent WK, et  al Mumps outbreak in a highly vaccinated population. J Pediatr. 1991;119(2):187–193   8. Chu SY, Bernier RH, Stewart JA, et al Rubella antibody persistence after immunization. Sixteen-year follow-up in the Hawaiian Islands. JAMA. 1988;259(21):3133–3136   9. Vázquez M, LaRussa PS, Gershon AA, et al Effectiveness over time of varicella vaccine. JAMA. 2004;291(7):851–855 10. Kimberlin DW, Whitley RJ. Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med. 2007;356(13): 1338–1343 11. Oxman MN, Levin MJ, Johnson GR, et  al Shingles Prevention Study Group. A vaccine to prevent herpes zoster

18  Vaccines for Viral Diseases and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271–2284 12. Muñoz N, Bosch FX, de Sanjosé S, et  al International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348(6):518–527 13. Villa LL, Costa RL, Petta CA, et al Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005;6(5):271–278 14. Harper DM, Franco EL, Wheeler C, et al GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 viruslike particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004;364(9447):1757–1765 15. Hildesheim A, Herrero R, Wacholder S, et al Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007;298(7):743–753

209 16. Santin AD, Bellone S, Gokden M, et  al Vaccination with HPV-18 E7-pulsed dendritic cells in a patient with metastatic cervical cancer. N Engl J Med. 2002;346(22):1752–1753 17. Vandepapeliere P, Barrasso R, Meijer CJ, et al Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis. 2005;192(12):2099–2107 18. Urman CO, Gottlieb AB. New viral vaccines for dermatologic disease. J Am Acad Dermatol. 2008;58(3):361–370 19. Bessinger GT, Smith SB, Olivere JW, James BL. Benign hypersensitivity reactions to smallpox vaccine. Int J Dermatol. 2007;46(5):460–465 20. Lewis FS, Norton SA, Bradshaw RD, et al Analysis of cases reported as generalized vaccinia during the US military smallpox vaccination program, December 2002 to December 2004. J Am Acad Dermatol. 2006;55(1):23–31 21. Dellavalle RP, Heilig LF, Francis SO, et al What dermatologists do not know about smallpox vaccination: results from a worldwide electronic survey. J Invest Dermatol. 2006;126(5): 986–989

Prevention of Sexually Transmitted Diseases from Office to Globe

19

Kim K. Dernovsek

19.1 Introduction My interest in prevention of sexually transmitted diseases (STDs) was borne out of my own frustration in managing the maladies of my dermatologic patients over the last 25 years. As they suffered the consequences of what they had understood would be “safe” sex, via condom use, I began to contemplate that strategy. “Safe sex” originated in the early 1980s as the “buzz-word” for promotion of condom use to high-risk population groups to prevent sexual transmission of HIV/AIDS. Since condoms doubled as barrier contraceptive devices, it was not long before “safe sex” became the prevention strategy of the era. With the use of a simple “prophylactic” device, the condom, adults and teens alike could, in theory, prevent both HIV transmission and pregnancy. They could be “safe” in their sexual practices. In the 1980s and 1990s, it became customary for physicians to caution patients to “practice safe sex.” Then, during the late 1990s, as rising rates of chronic, viral, skin-to-skin transmitted STDs became an increasingly widespread public health problem, the medical literature quietly transitioned to the more accurate description, “safer” sex. Yet “safe sex,” long written into classroom curricula and medical pamphlets, was in its second-generation as the prevention strategy for the general public. It was not until one of those people got a sexually transmitted disease (STD) and ended up as a patient that the idea that “sex” was not really “safe” had become a reality for that patient and doctor. I began to feel the havoc wreaked in the lives of my

K. K. Dernovsek Departments of Dermatology and Family Medicine, University of Colorado Health Sciences Center, Pueblo, CO, USA e-mail: [email protected]

patients by diseases that could have been prevented by different choices. Ultimately, I came full circle in my own thinking, from my early venereal-disease–clinic years of “see ’em and treat ’em,” to becoming an advocate for primary prevention via behavior change. Certainly there are few physicians who want to manage STDs and the complexities of coinfections, reportability, contact tracking, and the coincidental emotional overlay. It follows that the dermatologist who is least interested in managing STDs would be most interested in encouraging prevention, lest a patient with an STD show up for a clinic appointment. Surely, practicing physicians everywhere would unanimously concur that prevention of STDs would be a goal worth achieving for patients and doctors alike. How to really prevent the now-myriad STDs has become increasingly complex with vaccines, palliative treatment, condoms, etc. Is it any wonder that there is a grassroots movement toward a holistic approach of utter simplicity? Yet the generations since the 1960s are quick to dismiss the concept of true primary prevention, via behavior change, labeling it as religious or political ideology or simply calling it “unrealistic.” What is realistic is that the patients of this millennium are concerned about their health. They want healthy skin, healthy genitalia, healthy reproductive tracts, and they want to live. They don’t want to die of an STD. The scientific evidence establishes the failure of the condom “risk reduction” approach used over the last 25 years and the data support that people can change their sexual behavior to healthy lifestyles, i.e., primary prevention via “risk avoidance.” In this chapter I present the magnitude of the problem, the failure of the past paradigm, the current trends in sexual behavior, a directive counseling approach to patients in the office, and a low-cost vision for health based on the world’s best success against HIV to date. There is no other area

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of public health where we as physicians might, with such a simple approach, have a positive impact and save lives. Whether in the office caring for individual patients, or whether in implementing a new public health paradigm in our local community or around the globe, the opportunity exists for all physicians and healthcare providers to play a role. The vision is to put an end to the suffering and death from STDs the world over by motivating patients to choose healthy sexual lifestyles.

19.2 The Magnitude of the Problem of STDs The possible adverse consequences of sexual intercourse are varied and well-documented in the literature and include in excess of 25 sexually transmitted infections.1 More than 65 million people in the United States alone are living with an incurable STD2 and the financial burden of management of STDs is at an estimated cost to our healthcare system of 17 billion dollars annually.1 Dermatologists diagnose and treat lice, molluscum contagiosum, and scabies, all of which can be transmitted by sexual activity and yet are so readily transmitted that nonsexual skin-to-skin contact is their most common presentation. Such skin-to-skin transmission is well-understood by dermatologists who are likewise the experts for diagnosing the manifestations of lymphogranuloma venereum (LGV), syphilis, granuloma inquinale, chancroid, herpes simplex virus (HSV), and genital warts from human papilloma virus (HPV). Physicians may be called upon to manage long-term sequelae such as pelvic inflammatory disease and infertility caused by gonorrhea or chronic asymptomatic chlamydia infection. Sexually acquired hepatitis (A, B, or C) can induce serious morbidity via chronic active hepatitis leading to cirrhosis or resulting in liver transplantation. Patients can die from HIV/AIDS or HPV-induced cervical or penile cancer and will at the least require ongoing medical care. Due to the chronicity, pathology, and impairment of function caused by most sexually transmitted infections, the intentional use of the traditional terminology, STDs is warranted. Euphemistic deviation from this descriptive nomenclature is misleading to patient and doctor alike. A sexually transmitted infection can be treated and sometimes cured; such that the anatomical

K. K. Dernovsek

area involved can be returned to normalcy. However, a return to normal is certainly not possible for those suffering from venereal infections which are either chronic, intermittently recurring, or cause permanent pathologic damage to the involved tissues and hence by definition, are diseases, which are transmitted sexually, i.e., STDs. At particular risk are current and future generations of youth since 48% of the 18.9 million new cases occurring annually are in sexually active young people aged 15–24 years.3 It is known that young women are biologically more susceptible to chlamydia, gonorrhea, and HIV infections.2 This is due to the ectropion of the adolescent cervix, in which there is exposed columnar epithelium for which chlamydia and gonorrhea have a predilection.4 The squamous-columnar cell junction is likewise more exposed in the adolescent cervix, making this metaplastic transformation zone more susceptible to HPV infection.5 Unequivocally, STDs pose a more serious health threats to our adolescent patients, whom we diagnose and treat, yet in the case of the viral STDs, cannot cure. Two of these, HSV II (progenitalis) and HPV (genital warts) are seen so regularly in dermatologic office practice so as to warrant more detailed discussion.

19.3 Dermatologic Perspective on Herpes Simplex Virus Genital herpes (HSV I or HSV II) is most commonly caused by HSV II, which is also known to be a potent facilitator of sexual transmission of HIV infection.6 Genital herpes is a recurrent, lifelong viral infection7 affecting at least 50 million Americans age 12 years and older.7 Ninety percent of these patients are unaware of their status8 due to asymptomatic intervals between herpes outbreaks and/or undetected signs of lesions especially when hidden on mucosal surfaces of the vagina, cervix, or anus. The virus can be detected in genital secretions of most HSV-II seropositive patients who give no history of having genital herpes9; such asymptomatic cutaneous viral shedding likely contributes to the ease with which HSV-II is transmitted. No effective vaccine exits, intermittent or suppressive antiviral treatment does not eradicate the organism from secretions or lesions, nor does condom use fully protect. This is because both HSV-1 and HSV-2 are transmitted through direct contact: kissing, sexual

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contact (vaginal, oral, or anal sex), or skin-to-skin contact and can be transmitted with or without the presence of sores or other symptoms.6 While our nondermatologic colleagues may be baffled by herpes gladiatorum or herpetic whitlow, dermatologists understand the ease of skin-to-skin transmission where pressure, rubbing, or even simple contact is involved. This is true especially with direct droplet transmission of the infectious agent and enhanced where skin barrier alteration via erosion or microscopic fissure from xerosis exists. In the simplest of terms, there is no dermatologist who would with ungloved finger knowingly touch a herpetic vesicle, a syphilitic chancre, the rash of secondary syphilis, or the sore or drainage of chancroid or lymphogranuloma venereum (LGV). Indeed, most dermatologists would likely glove-up to do diagnostic scrapings of scabies or to curette lesions of molluscum contagiosum, even in the years predating “universal precautions.” According to the National Health and Nutrition Examinations Survey (NHANES), which is the key American ongoing population-based study, the HSV II seroprevalence rates rose 30% from 1976 to 1994.8 It is during this same period of time that a societal liberalization of sexual mores and wide promotion of the “safe” sex condom strategy in clinics and schools was ongoing. In more recent times, alternative sexual practices are changing the natural history of genital herpes infections which had traditionally been HSV II in type. Up to 50% of first-episode genital herpes is HSV-110 with oral sex the most likely source, from shedding in the mouth.11 A review of Herpes genital isolates showed that HSV I increased from 31% in 1993 to 78% in 2001, with HSV I having become the most common cause of new genital herpes on a Midwestern college campus.10 On a positive note, from 1999 to 2004, there has been a downward trend in HSV II seroprevalence rate toward 17%.12 Interestingly, this correlates time-wise with implementation of the Sect. 510 Title V abstinence education initiative in 1999 when abstinence was increasingly emphasized in character-based, sex education school curriculae.13 Simultaneously during these same years there has been a counter-cultural backlash toward “virginity” among the youth themselves.14 Condom use had also gone up during this period of time however this is of uncertain significance due to the theoretical offset of “risk compensation.” Risk compensation is the increase in the actual risky behavior (i.e., sexual intercourse) due to the perception of

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being at reduced risk (i.e., via condom use), which thereby paradoxically increases the frequency of the risky behavior (i.e., sexual intercourse). What is known with certainty is that HSV II seroprevalence rates are higher if intercourse is initiated under 18 years of age at 21.1% compared to 18 years of age and older at 14.3%.12 HSV II seroprevalence rates are also higher if there is a greater number of lifetime partners. For example, HSV II seroprevalence is 39.9% if more than 50 partners, 20.8% if five to nine partners, and 3.8% with only one lifetime partner.12 Therefore, delay of sexual debut and limitation of lifetime partners is paramount to a successful genital herpes prevention strategy.

19.4 Dermatologic Perspective on Human Papilloma Virus The second STD that dermatologists frequently manage is HPV infection, in particular, genital warts, which can be found in 1.5–13% of sexually active adults, dependent on the population group studied.2 Any clinician has experienced the time-consuming agony of the patient newly diagnosed with either Herpes II or HPV (genital warts). It is not unusual for those newly diagnosed with genital warts to experience disclosure anxiety, relationship breakdown, depression, and fears about recurrence and transmission,15 ,16 and to reduce numbers of partners (14%), use a condom (41%), or abstain from sexual intercourse (26%).15 Fortunately our patients can be reassured that 90% of genital warts are caused by noncarcinogenic HPV types 6 and 11, although carcinogenic HPV types 16, 18, 31, 33, and 35 are found occasionally and have been associated with cervical neoplasia in females and squamous cell carcinoma in situ, bowenoid papulosis, erythroplasia of Queyrat and Bowen’s disease, and squamous cell carcinoma of the anogenital and head and neck region in males and females.17

19.5 Gynecologic Perspective on Human Papilloma Virus Our gynecology and primary care colleagues regularly encounter subclinical genital HPV infection since 5.5 million such new cases occur annually and it is

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estimated that 20 million people are currently infected, with the prevalence ranging from 28 to 46% in women under age 26.2 Due to the ubiquitous nature of HPV genital infection in our sexually active patients, it behooves us as dermatologists to fully understand its natural history so as to correctly counsel patients in prevention. Regarding the natural history of subclinical genital HPV infection, it is reported that among sexually active college women, 26% of 608 studied were already infected at outset. Forty-three percent became infected over 3 years with 9% of them remaining infected at 2 years.18 In another investigation, 19.7% of 553 enrolled were already infected at outset and 38.8% of the remaining 444 became infected over 2 years.19 It is from these studies that we understand that at least 90% of subclinical HPV infections spontaneously clear. Nevertheless, persistent infection with a high-risk HPV type for at least 6 months is associated with the risk of developing a squamous intraepithelial lesion.18 It is known that 95% of cervical cancer is associated with 8 types of HPV16, 18 and that HPV 16 alone accounts for over 50% of cervical cancers and high-grade dysplasias.20 From a public health concern, it is the potential carcinogenicity of subclinical genital HPV infection that sets it apart from genital herpes infection. Unfortunately, just as treatment for visible herpetic blisters does not prevent future viral shedding, likewise treatment of visible genital warts possibly reduces, but does not eradicate HPV infectivity. Our dermatologic aim is always to remove the visible genital warts, destructively, surgically, or via a topical immune modulator. Yet it remains unclear whether reduction of HPV DNA in genital tissue impacts future transmission.17 Both HSV II and HPV have been generally rising in prevalence over the last 30 years despite widespread and increasing condom use by adolescents documented over the 14 years from 1991 to 2005.21 While this may be due to “risk compensation,” (above), the inadequacy of condoms to protect uncovered skin during skin-toskin transmission is the most likely explanation. The herpes lesion may occur on skin that is not covered by the condom or may be transmitted either when visibly present or during asymptomatic periods of viral shedding. In 2001 a panel of 28 experts reviewed 138 papers and concluded that there was no epidemiologic evidence that condom use reduced the risk of HPV transmission although they “might afford some protection.”22 The center for disease control and prevention

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(CDCP) reported that prevention of genital HPV infection involved (1) refraining from any genital contact with another, (2) long-term mutual monogamy, (3) reduction in the number of partners and careful partner selection, and (4) that the available scientific evidence was not sufficient to recommend condoms as a primary prevention strategy.23 In a recent study of newly sexually active college women, when partners used condoms consistently and correctly, there was a 70% reduction in HPV infection.24 The discerning reader will recognize the terms consistently and correctly as significant detractors from these results (see Sect. 19.8). A CDCP publication for clinicians, in discussion of the use of condoms for decreasing efficiency of transmission of HPV, states that infections can happen in the scrotum, vulva, or perianus areas unprotected by a condom.25

19.6 The HPV Vaccine An HPV vaccine that targets HPV 16, 18, 6, and 11 was developed and licensed by the Food and Drug Administration (FDA) in 2006. HPV 16 and 18 cause up to 70% of CIN II/III and anogenital cancer and HPV 6 and 11 cause up to 90% genital warts.26 The vaccine, made from noninfectious HPV-like particles, was tested in thousands of 9–26 year-olds and found to be safe with no serious side effects.27 Pain at the injection site occurs in 80%, site redness or swelling in 20%, fever (100°F) in 10%, site itching in 3%, and fever (102°F) in 2%.28 These side effects and fainting comprise most of the adverse events reports on the vaccine. The serious reports (7%) have included Guillain-Barre Syndrome, blood clots, and 39 deaths, although careful analysis by experts has not found a pattern suggestive of causation by the vaccine.29 The vaccine has nearly 100% efficacy against HPV 16, 18, 6, and 11 of at least 5 years duration with no waning immunity.27 It is recommended for 11–26 yearold nonpregnant females and contraindicated in yeast-allergic patients.27 Administered in a series of three injections, the total cost is $375.30 The costeffectiveness for HPV 16 and 18 vaccination of 12-year-old girls is estimated at $43,600 per quality adjusted life year (QALY) and cost of extension of vaccination to older girls and women is not costeffective.31 Since the vaccine is effective only against

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carcinogenic HPV types 16 and 18, women remain unprotected against 30% of cervical cancer and preimmunization counseling is to include a recommendation for continued Pap testing after vaccine administration. Additionally, vaccine providers should notify vaccinated females that “they should continue to practice abstinence or protective sexual behaviors (i.e., condom use), since the vaccine will not prevent other sexually transmitted infections.”27 Less than a year after FDA approval of the HPV vaccine, the governor of Texas made it mandatory, provoking widespread public concern that later resulted in overturn of this decision. The state of Virginia has made the vaccine mandatory, but with very generous opt-out provisions. Salmon et al, in a Lancet publication expressed concern that generous religious and conscientious exemptions to the HPV vaccine could cause legislators to extend the same to other childhood vaccinations, which would then be detrimental to the public’s health.32 A 2007 Journal of the American Medical Association (AMA) editorial stated: “Given that the overall prevalence of HPV types (16 and 18) associated with cervical cancer is relatively low (2.3%)33 and that the long-term effects are unknown, it is unwise to require a young girl with a very low lifetime risk of cervical cancer to be vaccinated without her assent and her parent’s consent.”34 A New England Journal of Medicine editorial,35 in commenting on a large study of the quadrivalent HPV vaccine in preventing high-grade cervical lesions,36 raised concerns that evidence was insufficient to infer the effectiveness of vaccination in prevention of CIN III or adenocarcinoma in situ and “… a cautious approach may be warranted in light of important unanswered questions about overall vaccine effectiveness, duration of protection, and adverse effects that may emerge over time.” A more recent NEJM editorial raised further reasons for caution, including whether vaccinated women will be less likely to pursue cervical cancer screening and whether other HPV strains will emerge as significant oncogenic serotypes.37 The American Cancer Society, citing probable diminished vaccine efficacy as the number of lifetime sexual partners increases, does not recommend universal vaccination among women between 18 and 26 years of age.38 Lastly, general questions have been raised about the applicability of the traditional compulsory vaccination paradigm to vaccination against HPV. HPV is not a highly infectious airborne disease. There is a cost to society at a loss of

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something else.34 Finally, does the patient (parent) retain the right to decline a prevention modality that by one’s own behavior and by regular cervical cancer screening can be prevented?

19.7 Prevention of Cervical Cancer here and Abroad In the United States it is estimated that there were 11,270 cases and 4,070 deaths from cervical cancer during 2009.39 Since 95% of cervical cancer is caused by asymptomatic carcinogenic HPV present on the cervix longer than 6 months, it seems to follow that primary prevention of genital HPV infection be the method of preventing cervical cancer. “However, in populations that are screened regularly, as is typical in the U.S., cervical cancer develops rarely in women, even with persistent HPV infection. This is because women with high-grade precursor lesions are usually identified through cytologic screening, and the development of cancer can be prevented through early detection and treatment.”25 Since most cervical precancers develop slowly, nearly all cases can be prevented if a woman is screened regularly.39 Four separate studies of women who were diagnosed with cervical cancer showed that 28.540 and 30.1%41 had never had a Pap test and 5342 and 56%43 had not had a Pap test within the 3 years prior to diagnosis. The CDCP summarizes that “The single most important factor associated with invasive cervical cancer is the factor of never or rarely being screened for cervical cancer.”25 Underscoring the role of preventive cervical screening it is noted that prior to PAP testing programs in the USA, the cervical cancer incidence per 100,000 was 38.0 whereas current rates in developed countries are less than 14.5.44 Globally, cervical cancer killed 274,000 women in 2002 and age-standardized incidence rates per 100,000 were highest in Southern Africa at 38.2 and Eastern Africa at 42.7.44 These sobering statistics emphasize the role of cervical Pap testing in prevention of cervical cancer and the effect of the asymptomatic progression of a long-term infection with a carcinogenic HPV subtype in settings where screening is unavailable. It is unlikely that the HPV vaccine will ever be a feasible prevention modality in the developing world countries that need it most due to high cost ($375)30 and required administration as a series of three

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injections widely separated over time. Fortunately for countries where vaccines and Pap testing are unlikely to ever reach the masses, there remains a low-cost strategy, one in fact recommended by the CDCP, which states: “The surest way to prevent HPV infection is to abstain from any genital contact, including nonpenetrative intimate contact of the genital area.”25

19.8 The Failure of the Condom Strategy To interpret the literature on condoms and determine their role in prevention of STDs from office (individual) to globe (public health), the first step is to review the mechanism of action of the condom. The condom is a latex sheath that covers the penile shaft and glans penis with a receptacle at the tip to contain ejaculate and which must be applied by a human being, during a state of sexual arousal, to the erect penis. By design, a condom is a barrier to transmission of ejaculate containing sperm, i.e., a contraceptive device. The condom therefore is mechanically suited for protection against those pathogens known to be delivered via ejaculate: HIV, gonorrhea, and syphilis. The condom in theory provides at least some protection against those organisms that could be present in ejaculate, on the penile shaft/glans, or against any infectious organisms that might present in the recipient. Therefore condoms theoretically have the potential to be useful protecting against HSV I and II, Herpes, HPV, chlamydia, and any infectious lesion or organism covered by the condom. However, numerous STDs are or can be transmitted by skin-to-skin contact and the condom does not cover all of the potentially infected skin. So even at very best, “perfect and always” use of the condom, the condom by design will never protect against all STDs in real life. How are condoms assessed as prophylactic devices? The FDA regulates manufacturer’s pre- and postmarket compliance with industry standards of testing condom lots via the “water leak” and “air-burst” tests prior to sale. The air-burst test examines strength to resist breakage during use and the water leak test specifies that the average defect rate should not exceed four leaking condoms per 1,000, although industry standards are more stringent at 1 per 400, with the FDA draft regulations now recommending the same.45

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The water leak test, “under ideal conditions, is able to detect a hole 3 mm in diameter, but, in practice, the sensitivity (diameter of the smallest hole reliably detectable) is approximately 15 mm.”46 The normal human sperm has a width range of 2.5–3.5 mm (microns, i.e., 2,500 nm) and a length range of 4–5 mm.47 Since sexually transmitted viruses vary in diameter from 0.04 to 0.15 mm,48 a conservative, sensitive test of condoms was developed to further evaluate condoms already purchased through retail distributors (and thereby presumably having passed the water leak test).48 This virus penetration assay was used to evaluate a broad range of condom types and brands and found that 2.6% of latex condoms allowed some virus penetration of particle size 0.032 mm.48 By comparison, the size of HPV is 0.060 mm.49 Hepatitis B is 0.040 mm, HIV is 0.10 mm, Herpes simplex is 0.14 mm.42 However, the relative importance of holes is related to the volume of semen that contains an “infectious dose” of the given STD and it has been concluded that “for infectious agents with low titer and low infectivity (such as HIV), leakage through pores too small to be detected by the water leak test is not the primary public health risk of condom use.”50 In addition to virus titer, it is known that transmission through a small hole also depends upon transcondom pressure, time for passage, viscosity of the carrier fluid, and condom thickness.48 Fluid flow is the most important determinant of viral passage through a hole.22 It has been demonstrated that (1) there is a “strong dependence of virus penetration on hole diameter,” such that virus penetrations varied over four to five orders of magnitude, whereas the hole size varied over one (from 2 to 21.5 mm), i.e., roughly correlating with the Poiseuille equation of fluid flow through a cylindrical hole varying as the hole diameter to the forth power and that (2) most virus penetration is complete or nearly complete by 2 min.51 Results from the laboratory tests were applied to determine the hypothetical relative risk of exposure to semen as a function of semen volume attributable to various independent condom use events and it was concluded that the data showed condoms to be a highly effective barrier to transmission of particles of similar size to those of the smallest STD viruses; with a strong probability of condom effectiveness when used correctly, where the etiology of STD transmission is linked to containment of preejaculate and seminal fluids or barrier coverage of lesions of the penis and there is no slippage or

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breakage. It was additionally noted however that for many STDs the risk of infection might not be proportional to exposure to a volume of semen and that estimation of risk requires further extrapolation because it depends also on the concentration, infectivity, and mode of transmission of the specific STD.22 Thus it can be summarized that even if minute leakage of viral-sized particles occurs,48 condoms do protect against STDs and in a controlled laboratory setting, transmission of infection is highly unlikely.19, 42 Such laboratory testing is for efficacy, i.e., the improvement, achieved in a desired health outcome in a research setting in expert hands under ideal conditions. To achieve something close to efficacious use of the condom in actual life, “perfect use” must be achieved: i.e., use of the condom 100% of the time and 100% correctly each time of use. Unfortunately, in “real life,” the condom often fails to protect.52–56 That is because in actuality the best that can be achieved is “typical” use of the condom, which includes using the condom “some,” “most,” or “all” of the time and using it both correctly and incorrectly. Hence it is effectiveness, i.e., the amount of improvement in the health outcome in actual life with typical implementation, which is clinically applicable. Condoms are known to fail in protection against pregnancy at a rate of 14%52 and in protection at variable rates against ejaculate-delivered pathogens, the specific purpose for which they were designed.45,46,48 Failure can occur due to “method” or “user” failure or both. “Method” failure occurs when the condom itself, as a device, fails. Types of “method” failure would result from defects incurred during manufacture or improper storage, and could include leakage or breakage during intercourse or withdrawal, or slippage during intercourse, either partially or completely.53, 55, 57–60 “User” failure refers to the condom being used incorrectly and represents the human component, i.e., one’s (in)ability to comply with proper use during arousal and sexual intercourse. Examples of “user” failure include genital contact before condom application61 (preejaculatory secretions can contain both infectious pathogens and sperm), flipping condom over after initial application (noting the condom to be applied “upside-down” so that when turned over contact with preejaculatory secretions on the now-exposed condom surface occurs), holes poked in condom (fingernails or jewelry from piercings), use of oil-based lubricants (known to weaken condom strength),

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improper positioning of condom, not holding on to condom during withdrawal resulting in ejaculate spillage and not withdrawing while penis erect (falling asleep after intercourse).53,62 To approach laboratory-setting efficacy of condoms in real life, “perfect condom use” (i.e.,“always” (consistently) and “correctly” with each use), would need to be achieved. What scientific evidence exists for one’s ability to achieve perfect use in real life? In one study of college-educated males with an average of more than 5 years of condom experience who were “consistent, 100%” condom users, it was found that altogether at least 13% of condom uses had resulted in exposure to risks of unprotected intercourse due to breakage, slippage, or failure to use condoms throughout intercourse. This calculated to 33% of the consistent condom users having been exposed to risks of disease or pregnancy in the prior month.62 Similarly, of 186 females aged 15–21, who had reported vaginal sex in the past 14 days and who were self-described consistent (100%) condom users, 34% were found to have sperm present in vaginal fluid via Y-chromosome polymerase chain reaction assay.63 In a study of the value of consistent condom use in adolescent females, 17.8% acquired at least one STD (chlamydia, trichomoniasis, gonorrhea) despite consistent (100%) condom use.64 Lastly, in a study of HIV serodiscordant heterosexual couples, in which 171 always used condoms, three seroconversions occurred over 24 months (1.1% incidence rate).65 Therefore, either method (device) or user failure (incorrect use) must have occurred in order for seroconversion to HIV positivity to have taken place for any of them. On a lighter note, a personal observation of an academically embarrassing demonstration of the complexities of correct condom use is recalled from the AIDS and STD Symposium of the 2002 American Academy of Dermatology meeting. The speaker was explaining how teens are taught in school programs to correctly use condoms by ordering steps known to be necessary for correct condom usage. To press the point he ordered dermatologists from the audience to the front, divided them into two groups and gave them each a card with a “step” in the condom use process, to put in proper order. In competition against their colleagues, the dermatologists, presumably both intelligent and manually adroit, appeared to have a great deal of difficulty ordering the steps. Ultimately each group came up with a different order of steps. In the comedy

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that ensued, it was never confirmed whether either group had correctly ordered the steps involved in using a condom. Since each group came up with a different order of steps, what can be concluded is that one of the groups of physicians was wrong. The fact remains that despite years of condom public education, people still fail to use condoms correctly. What does the evidence show about whether people are able to use condoms “always,” i.e., “consistently?” Three studies are concerning that, for whatever reason, people don’t or won’t or can’t use condoms consistently. First, among a nationally representative sample of unmarried sexually experienced females aged 15–44 years who stated they “used condoms” for disease prevention, only 18.5% always used condoms.66 Second, we know that among Herpes discordant couples, despite counseling to always use a condom (11 visits during 18 months), and in a vaccine trial where it was not known whether the seronegative partner had received the HSV subunit vaccine or a placebo, that only 8% “always used” a condom and 15.5% used a condom for 51–99% of sex acts.67 In a parallel clinical trial of an HSV-2 vaccine subsequently found to be ineffective, 13% “always used” a condom and 16% used a condom for 76–99% of sexual acts, despite the counseling protocol described above and provision of free condoms at the 11 study visits.68 Lastly is a prospective study, done prior to the development of effective antiretroviral therapy, of HIVnegative subjects whose only risk of HIV infection was a stable heterosexual relationship with an HIV-infected partner. Every 6 months the subjects were interviewed, tested for HIV, and counseled about safe sexual practices and despite the knowledge that they were at risk for a fatal disease, only 48.4% of these HIV discordant couples “always” used a condom.69 In addition to the problems of correct and consistent use of condoms outlined above, there are additional factors influencing condom failure in the real-life setting. The adequacy of protection against STDs will depend on the degree of infectivity of the particular STD, the prevalence of the STD in the community, the number of acts of intercourse, the user’s prior experience with condoms, the age and sex of the individual, the natural immunity of the individual, and whether lesions of other STDs are present.70 Earlier in the chapter was described the discouraging conclusions reported by three government agencies on the existing scientific evidence for condom effectiveness in preventing HPV. Equally discouraging are the experts’ conclusions

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regarding prevention of other STDs. Regarding chlamydia, gonorrhea in women, and trichomoniasis they concluded that the available epidemiologic literature does not allow an accurate assessment of the degree of potential protection.22 Regarding genital herpes, syphilis, and chancroid they stated that the data were insufficient to draw meaningful conclusions about the effectiveness of the latex male condom to reduce the risk of transmission.22 The data were clear regarding the “strong evidence” for the effectiveness of condoms for reducing sexually transmitted gonorrhea for men and HIV/AIDS: that with HIV/AIDS, consistent condom use decreased the risk of HIV/AIDS transmission by approximately 85%.22 In the more recent Sexually Transmitted Diseases Treatment Guidelines 2006, the CDCP states that “HIV-negative partners in heterosexual serodiscordant relationships in which condoms were consistently used were 80% less likely to become HIV-infected compared with persons in similar relationships in which condoms were not used.”71 The scientific evidence has supported cautions offered during the early years of AIDS prevention strategy development. For example, Judson, et  al. who in 1989 stated after describing the factors related to condom effectiveness: “Thus it would seem prudent not to place excessive reliance on latex condoms alone for prevention of sexually transmitted infections.”55 In 1994, d’Oro et al. reviewed barrier methods in prevention of STDs and concluded, “A consistent and strong protection may well be acceptable for treatable diseases and rare exposures, but a similar protection is clearly not satisfactory for frequent exposures and, particularly, serious or severe diseases.”56 Certainly there is no other fatal disease where it is acceptable public health policy to widely and primarily promote, around the globe, to young and old alike, a risk reduction modality in which the chance of becoming infected still remains 20%, at the universal exclusion of a risk avoidance strategy in which the chance of infection is 0%. We have assumed that our patients cannot abstain from sex even though we understand that sex is not a mandatory biologic reflex like micturation, defecation, or sleep. We must consider the possibility that our own bias based on personal life experience has skewed our medical approach. Perhaps when we do not or have not modeled the proposed sexual behavior change, it becomes more uncomfortable for us to endorse and/or recommend it. Nevertheless we are ethically obligated to give our patients the best medical recommendation

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for health preservation. Therefore, for the health of our patients, is it time to rethink our STD prevention strategy from office to globe?

19.9 Defining Terminology: Safe Sex, Sex, and Abstinence Although the medical literature currently refers to the condom method as “safer” sex, confusion over what people understand to be “safe” has prevailed. This is exemplified by varied verbiage describing condom effectiveness on packaging, such as, “safer sex, give protection, protect, are highly effective, effective, may help, will help, can reduce the risk, will reduce the risk and significantly reduce the risk.”72 As a result, directed by Public Law 106–554, the FDA proposed rules in 2005 to designate a special controls guidance document with labeling recommendations for latex condoms. The FDA concluded that condoms reduce the overall risk of STD transmission although the degree of risk reduction for different types of STDs varies with their routes of transmission. The FDA now proposes that labeling consistently utilize the terminology, “sexually transmitted diseases” and address incorrect and inconsistent use which “undermines” condom effectiveness. The FDA also proposes that labeling address the limited benefits and risks presented by N-9 spermicidal lubricant since frequent use can cause mucosal irritation, which may increase the risk of transmission of HIV.73 Twenty-plus years of the “safe sex” paradigm have resulted in terminology confusion for youth. In a 2000 survey of 12–17 year olds, 88% reported having heard the expression “safe sex,” yet when asked to specify which behavior(s) they considered safe, 86% said not having sex/abstinence was “safe sex,” 72% said “safe sex” was using a condom, 46% said birth control pills were “safe sex” and 21% said oral sex was “safe sex.”74 Regarding the practice of oral sex, specifically, a 2003 survey of 15–17 year olds revealed that 46% thought oral sex was “not as big of a deal” as sexual intercourse. Thirty-nine percent considered oral sex “safer sex” and 19% did not know you could get an STD through oral sex.75 These misconceptions exist despite clearly listing as “can be transmitted by oral sex” in a 2000 CDCP fact sheet: HIV, herpes, syphilis, gonorrhea, HPV, intestinal parasites (amebiasis), and hepatitis A.76 It is not clear to teens that oral sex is a form of sexual intercourse. In the

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youth surveys, 63% said they had “never had sex” but 13% of those had had oral sex.75 It is therefore paramount that we retain a precise definition: Sexual intercourse is the stimulation of a partner to orgasm via vaginal, oral, anal, nongenital activity, i.e., mutual masturbation.77 As we communicate with clarity the correct definition of sexual intercourse, then our patients (who are themselves, community members, teachers, parents and teens) can correctly counsel that it follows that abstinence is by definition, abstinence from all forms of sexual intercourse. Adding an appropriate endpoint to abstinence makes it clear that “abstinence” is not just until the next Saturday night date, but that it is a lifestyle to be continued until a certain predefined time. Thus derives the terminology, “lifestyle abstinence,”78 that being a lifestyle of abstaining from all sexual activity until marriage, i.e., selection of lifelong faithful partner, i.e., until sustained mutual monogamy. “Lifestyle abstinence” as a lifestyle choice will ensure freedom from all sexually transmitted diseases as will sustained mutual monogamy in the case where both  partners have abstained until this relationship. Encouraging these health-preserving behaviors is in keeping with most global societal standards. Our patients deserve to understand the health risk that exists with the lifestyle of “serial monogamy,” i.e., monogamy for some period of time followed by termination of that relationship followed by monogamy for another period of time with a different individual, and so forth. With each new monogamous relationship, that new partner brings with them a past sexual health history that may not be healthy. If the periods of serial monogamy are each of brief duration then the risk to the health of the individual may not be much improved over networks of concurrent sexual partners. This latter category of sexual lifestyle, whether called concurrency, polygamy, prostitution, sex work, promiscuity, or guised in slang terms of “hooking up,” “anonymous partnering,” or “friends with benefits” are all highly risky sexual lifestyles for both the individual and for the health of the society (Fig. 19.1).

19.10 STD Prevention in the Office: Recommended Guidelines The medical and scientific practice guidelines clearly recommend counsel regarding behavior change in prevention of STDs and their sequelae. In response to the

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Sexual Lifestyle Choices

Abstinence (Celibacy)

Concurrency Polygamy Promiscuity Anonymous Partnering Hooking-up

Mutual Monogamy

Serial Monogamy

Fig. 19.1  There is no risk of contracting a sexually transmitted disease (STD) in lifestyle abstinence or sustained mutual monogamy with an uninfected partner but with each new sexual partner, who may be an asymptomatic STD carrier due to past or current sexual relationships, STD risk occurs and is highest with multiple sexual partners. Adapted from a video by Stephen J. Genuis, courtesy Stephen J. Genuis

growing health threats of STDs for our adolescent patients and to assist primary care physicians and other health providers to make preventive services a greater component of their clinical practice, the AMA Guidelines for Adolescent Preventive Services (1997) first recommended that annual “health guidance” regarding responsible sexual behavior include “counseling that abstinence from sexual intercourse is the most effective way to prevent pregnancy and STDs, including HIV infection.”79 The CDCP state in both the 2002 and the 2006 Guidelines for Treatment of STDs that “the most reliable way to avoid transmission of STDs is to abstain from sexual intercourse (i.e., oral, vaginal, or anal sex) or to be in a long-term, mutually monogamous relationship with an uninfected partner.”80,81 The guidelines further state that “counseling that encourages abstinence from sexual intercourse is crucial … for persons who wish to avoid the possible consequences of sexual intercourse (e.g., STD/HIV and unintended pregnancy).”80,81 A 2005 clinical report from the Committee on Adolescence, American Academy of Pediatrics (AAP), makes as the first, and presumably primary, recommendation to pediatricians the following: “Encourage adolescents to postpone early sexual activity and encourage parents to educate their children and adolescents about sexual development, responsible sexuality, decision-making, and values.”82 Nevertheless, adolescents are not routinely being encouraged by physicians to postpone early sexual

activity since only 42.8% females and 26.4% males indicated having discussed STD, HIV, or pregnancy prevention at a healthcare visit in the preceding year83 and counseling in HIV/STD transmission has been reported to occur in only 6.2% of well visits.84 Barriers to sexual history taking were reported to be difficulties asking sexual history questions, fear of offending patients, and lack of time in more than half of physicians surveyed.85 Even in the less sensitive realm of counseling young patients in smoking cessation, the perception that counseling is time-consuming and the fear that the parent would be angered were reported as perceived barriers to counseling by over 50% of physicians surveyed.86

19.11 STD Prevention in the Office: A Directive Approach Within my own community private practice of dermatology, I examined the validity of two perceived barriers to abstinence counseling (fear of offending and perception of inadequate time) by observing whether the physician–patient relationship is adversely affected, as assessed by frequency of return for care. I additionally determined whether abstinence counseling is timeconsuming by observing its effect on usual scheduling patterns. Due to the broad implications in the area of physician health maintenance counseling, adolescent sexual health, and our role as dermatologists in this realm, I report my findings within this chapter. My solo private practice is one of four dermatology practices (all of which are open to new patients [NPs]) in Pueblo County, Colorado (population 141,47287). The study practice has a payer mix of managed care, preferred provider organizations, private pay, Medicaid, and indigent community clinic patients. Ethnicity was estimated by my observation to be 77% Caucasian, 22% Hispanic, <1% African American, and <1% other. The county served is 57.7% Caucasian, 38% Hispanic, 1.9% African American, and 2.3% other.87 Ethnicity breakdown and description of payer mix are provided for ease of evaluating applicability of results to other communities and to demonstrate that the practice draws widely from the community. Scheduling allots NPs 20 or 30 min (physician referral) and established patients (FUs) 10 (acne or postoperative) or 15  min. Scheduling is done by the same staff member who has performed in this capacity since 1993.

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I undertook to initiate medical guideline recommended abstinence counsel to all youth in my practice and then observe whether return to the office was inhibited by such abstinence counseling beginning on 01 Nov 1998 and continuing to 01 Jan 2001. During this time male and female NPs and FUs, aged 13–19, nonrandomized, regardless of reason for visit, were counseled by me. The NP and FU control groups consisted of the cohorts of male and female patients aged 13–19 not instructed in abstinence in the immediate 10-months prior to the study, January through October of 1998. Analysis showed the control and abstinencecounseled groups to be age and gender matched. The physician counseling style was concerned, casual, simple, and brief, allowing silence for patient response. After forewarning that an unexpected topic would be initiated, “This has nothing to do with the reason for your visit, but is also important for your health,” counseling in the style of asking, informing, and advising began: While handing an abstinence pamphlet88 I asked, “Have you ever heard of abstinence?” Physician silence followed. Then “lifestyle abstinence”78 was defined as a lifestyle choice requiring restraint from all forms of sexual intercourse until selection of lifelong partner. Third, the patient was advised that lifestyle abstinence could be initiated despite past or current behavior, thereby preventing disease transmission and ensuring health preservation. Physician silence followed. Throughout, counseling was adapted according to patient response (Fig. 19.2). If a patient confirmed abstinence/virginity, this was reinforced by physician’s affirmation of this behavior as “healthiest,” sustained abstinence was encouraged and the patient was enlisted to advise peers and pass the pamphlet on. If a patient declared sexual activity, counseling was modified to risk reduction via an “informed condom recommendation,” hereby strictly defined: First, informing the patient of condom inadequacy in complete protection against all STDs. Second, recommending condom usage as the next best alternative to lifestyle abstinence. Third, advising that lifestyle abstinence could be resumed, variously termed by peers as renewed-, recycled-, or secondary virginity. Fourth, the option of conversion of the relationship to lifelong monogamy was raised for the patient’s consideration. If there was no verbal response, didactic directive education began with one of the following, “A lot of kids don’t realize that … condoms don’t fully protect

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them against diseases22, 23, 78 … one in five people over age 12 already have genital herpes8 or HPV89 … dermatologists have to treat STDs … even their skin doctor wants them to stay healthy … that this is a message for boys and girls” ending with, “I don’t want my patients to say that I never warned them about STDs and how to prevent them. Now is the time for you to decide where you will stand in this matter.” The patient and/or parent response to lifestyle abstinence counseling was observed and whether the patient returned for care was determined. A return was recommended only as warranted by the patient’s medical condition and the adolescent received medical counsel and treatment regardless of presence or absence of the parent; as per the standard of care for the practice. Counsel in sexual abstinence, specifically, is as recommended by both the CDCP80,81 and the AAP82; it is primary prevention (risk elimination) counsel of universal benefit and therefore no patients were intentionally excluded. Finally, the rate of return to the practice was not calculated for either control or observed cohort until the observation was complete. Results of in-office adolescent abstinence counsel revealed that 135 new and established patients were counseled. Lifestyle abstinence counseling did not require schedule alteration; hence the observation was not terminated prematurely as had been intended if the physician schedule could not be maintained. In all 51.9% NPs (61.5% females, 42.9% males) not instructed in abstinence returned compared to 69.7% NPs (75.0% females, 64.7% males) who were instructed, (P = 0.151, P = 0.473, P = 0.206); 74.5% FUs (75.9% females, 72.7% males) not instructed in abstinence returned compared to 78.3% FUs (80.6% females, 75.8% males) who were instructed, (P = 0.667, P = 0.764, P = 1.00). Statistical analysis (Fisher’s Exact Test, 2-sided) failed to detect a significant difference in population groups, indicating that the abstinencecounseled patients (NPs, FUs, males, females) were at least as likely to return as those who had not been counseled (Fig. 19.3). Ninety-seven percent (131/135) of patient responses varied from neutral to positive; 12% (16/135) of patient responses were so positive as to result in role reversal with the patient enumerating reasons for abstinence until marriage with four describing renewed virginity and 12 intending to “stay virgins.” Three percent (4/135) of the responses were categorized as negative: All were parents who questioned the “reality” of abstinence.

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K. K. Dernovsek Counseling style: Concerned, Casual, Simple, Brief, Didactic, Directive Silence allows response. Adapt counsel to response FEMALES Medication Review: Hormonal Contraceptive (BCP)? On BCP “Did you know that there is no protection from BCP against STDs?”

Uses condoms also

Not aware

Therapeutic BCP (Not for contraception) Clarify: “…meaning, that you could get pregnant?”

“I guess so.”

NO BCP

Clarify: “…not sexually active or sexually active and not on BCP?” Sexually active

Not sexually active

Not sexually active

Patient declares sexual activity: Modify to risk reduction “Informed Condom Recommendation” (strictly defined) Inform of condom inadequacy for complete protection against all STDs Recommend condoms as “next best” to abstinence Advise resumption of abstinence: “Renewed-, Recycled-, Secondary Virginity” Consider conversion of the relationship to life-long monogamy

Didactic Directive Education “A lot of kids don’t realize that…” Condoms don’t fully protect them against diseases22, 23, 64, 65 1 in 5 people over age 12 already have genital herpes8 or HPV2 Dermatologists have to treat STDs Even their skin doctor wants them to stay healthy This is a message for boys and girls ending with “I don’t want my patients to say that I never warned them about STDs and how to prevent them. Now is the time for you to decide where you will stand.”

Fig. 19.2  Algorithm for sexual abstinence counsel of the adolescent

MALES “This has nothing to do with the reason for your visit, but it is also important for your health…” Asking: “Have you ever heard of abstinence?” “Too late for me.”

“You bet, I’m all for it.”

Sexually active

Not sexually active

Patient confirms abstinence/virginity Physician Reinforcement Affirm Behavior as healthiest Encourage Sustained abstinence Enlist Patient to advise peers, “pass pamphlet on”

The Silent Patient… Respect Modesty. Give Pamphlet. Inform. Advise.

Informing: Lifestyle Abstinence78 Restraint from all forms of sexual intercourse until selection of lifelong partner Give abstinence pamphlet 88 Advising: Abstinence can be started regardless of past/current behavior to prevent STDs and stay healthy.

19  Prevention of Sexually Transmitted Diseases from Office to Globe

However, two of four parents were immediately challenged by the adolescent patient who defended abstinence: One countered, “Mom, chastity is cool!” Another muttered, “My mother needs your lessons.” Two patients were on oral contraceptives at the next visit: evidence of their commitment to sexual activity, but also evidence that the physician–patient relationship was not adversely affected by the patient’s knowledge that the physician recommended sexual abstinence as ideal. A separate patient returned for an STD examination, newly motivated to address health risks of prior sexual activity. This observation undertaken in a general practice of dermatology shows that new and established patients counseled in lifestyle abstinence were at least as likely as those who had not been counseled to return for care, apparently not inhibited by the abstinence instruction. Furthermore, from 01 Jan 2001 through 01 Jan 2004, since most FUs had already been counseled, this physician continued to counsel NPs (n = 32, 47% males, average age 15.3 years; 53% females, average age 15.6 years); 62.5% (20/32) returned. Statistical analysis (Fisher’s exact test, 2-sided) of this group compared to the original control group fails to detect a significant difference in population groups (P = 0.440), again indicating that the abstinence-counseled patients were at least as likely to return as those who had not been counseled (Fig. 19.3). This physician continues counseling in lifestyle abstinence, time-efficiently, with unaltered scheduling to this date.

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This in-office observation is limited firstly by failure to enumerate observations; for example, the parental silently mouthed, “thank you” response predominated, yet frequency was not recorded. Secondly, 24 NPs and 22 FUs, i.e., 25% (46/181) of patients in the abstinencecounseled population were not counseled due to severity of illness, psychiatric disorder, mental retardation, current pregnancy, and if already on birth control, received an “informed condom recommendation.” Thirdly, other barriers to lifestyle abstinence counseling may exist, including inadequate physician knowledge; the physician is encouraged to review the myriad STDs, their consequences, and the scientific evidence on condom effectiveness (or lack thereof) for STD prevention.22,23 Finally, no attempt is made to determine whether the patients followed the lifestyle abstinence counsel given; a follow-up survey is under consideration. This clinical observation of correct counsel of youth in abstinence per guideline recommendations has shown that the physician need not fear offending the patient or disrupting the schedule when providing lifestyle abstinence counseling, even in a dermatology practice, where the advice was somewhat unexpected. Explanation of the relationship between the skin and STDs actually facilitated patient and parent education, since (1) it is no longer commonly known that until 1955, ours was the specialty of dermatology and syphilology and (2) patients and their parents were seldom aware that condoms do not fully protect from

FU Males

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FU Total

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64.7

61.5

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Fig. 19.3  The percentage of new (NP) and established (FU) male and female adolescent patients (aged 13–19) returning for care: comparison of those who received sexual abstinence counseling with those who did not

80

N

Returning for Continued Care (%)

90

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the skin-to-skin transmission of HSV90 and HPV.23 Educating that lifestyle abstinence is “restraint from all forms of sexual intercourse until selection of lifelong partner” is important because disease transmission also occurs with nontraditional forms of sexual intercourse and adolescents who abstain for the longest periods of time will be at least risk. For these reasons, dermatologists and other physicians caring for adolescents can be encouraged to incorporate lifestyle abstinence counseling in health maintenance advice alongside skin cancer prevention instruction.

19.12 STD Prevention: Trends and Expectations Aligned with the AMA,79 CDCP,80,81 and AAP82 recommendations, 91–95% adults and 92–94% adolescents surveyed annually from 2001 to 2004 agree that it is important for teens to be given “a strong message from society to abstain from sex until they are at least out of high school.”91–95 The community physician likely recognizes the importance of such a message since survey has shown that 49% of people with an STD had gone to a private practice for treatment.96 Furthermore, sexual abstinence counseling may be most effective if done specifically by the physician since patients who received physician advice on other topics, such as diet and exercise were significantly more likely to engage in risk reduction activities97 and when physicians provide brief simple advice on smoking cessation there is a small but significant increase in cessation rates.98 Primary care and pediatrics practices, where health maintenance advice for the adolescent is expected, can be encouraged to include lifestyle abstinence counseling alongside routine counsel against tobacco, drinking, illicit drug use, and promotion of exercise and healthy diet. However, since childhood immunizations are completed at age 12,99 the primary care provider may have fewer opportunities to advise the adolescent than the dermatologist. Ramsay et al. reported in 1986 that both dermatologists and dermatology training program directors overwhelmingly supported an increase in dermatology’s role in the treatment of sexually transmitted disease and in public awareness of our interest and ability.100 More than 20 years later it is expected that dermatologists, who understand skin-to-skin transmission of

K. K. Dernovsek

disease and still regularly treat genital HSV, genital warts and other STDs, are sufficiently motivated to prevent these infections and will assume a leadership role as physicians in educating adolescent patients, of whom they have many. In 1997, a panel addressed the “hidden epidemic” of STDs and called for private sector organizations and for clinicians to assume more leadership in and responsibility for STD prevention especially among adolescents.1 For example, if dermatology, as a specialty, were to publish a pamphlet for facilitation of youth counsel in abstinence by dermatologists and primary care physicians alike, we might positively impact the sexual health of untold numbers of adolescent patients. This opportunity for prevention is certainly more desirable than the necessity of treatment. Lowell A. Goldsmith, MD, the Clarence S. Livingood, MD lecturer, said in his address at the national meeting of the American Academy of Dermatology in 2001 that dermatologists should have a goal to think about health promotion every day and to promote the concept to their patients. Aligned with that vision, there is a daily opportunity to reduce morbidity and mortality by encouraging adolescent patients toward the healthiest sexual behavior. Yet, in a 2004 survey of clinicians, 91% of whom agreed that abstinence was a highly effective method for prevention of HPV infection acquisition, only 54% recommended abstinence to their adolescent patients.101 It appears that we are reluctant to counsel abstinence to our adolescent patients perhaps because we hold little hope that they might choose it. The evidence shows otherwise: the Youth Risk Behavior Surveys showed a reversal from 1991 to 2001 in what had been in prior years, elevating trends of teen sexual experience (“ever having had sexual intercourse”),102 and in both 2007 and 2005, 52–53% of high school students described themselves as not yet having experienced first sexual intercourse.103,104 Surveys in 2003 of slightly younger adolescents, aged 15–17, revealed 63105 and 67%106 had never had sexual intercourse. Dermatologists have the expertise in STDs and see adolescents regularly as patients and thus are ideally situated to correctly counsel them. Even if the abstinence counsel were followed only temporarily, postponement of sexual activity would reduce the number of lifetime partners, in turn reducing the risk of STD acquisition. On the other hand, if the lifestyle abstinence counsel were heeded, it would positively impact that patient’s health for a lifetime.

19  Prevention of Sexually Transmitted Diseases from Office to Globe

19.13 Sexual Behavior Change Yields Health Is there evidence that people can change sexual behavior with a resultant improvement in health? The answer is found in the story of Uganda. This sub-Saharan African nation reversed what had been the highest rates of HIV/AIDS in the world – and did so without Western world public health direction. Ugandan leadership inspired culturally appropriate sexual behavior change as the means by which to save lives, their culture, and their youth. What followed was a dramatic drop in HIV prevalence rates, as was said in 2003, and still holds true today: “… Uganda has experienced the most significant decline in HIV prevalence of any country in the world…”107 Without a doubt, what happened in Uganda, at an estimated cost of only$1.80 per adult per year over a 10-year period (1989– 1998)108 is the greatest public health achievement of this millennium. The scientific evidence demonstrating population level risk-avoidance behavior change which in turn resulted in reduced HIV prevalence rates should irrefutably and without delay shift global public health strategy in the fight against AIDS. The Ugandan strategy is a low-cost model with potential for eradicating global AIDS if other countries can implement similar risk-elimination behavior change. During the years from 1986 to 2001 the dramatic drop in HIV prevalence was observed in Uganda while simultaneously elsewhere in sub-Saharan Africa the HIV prevalence was rising.109 This remarkable anomaly was first reported in 2002, in a landmark presentation to USAID in which the authors reported that “The most important determinant of the reduction in HIV incidence in Uganda appears to be a decrease in multiple sexual partnerships and networks.” They further concluded that “The effect of HIV prevention interventions in Uganda (particularly partner reduction) during the past decade appears to have had a similar impact as a potential medical vaccine of 80% efficacy.”108 Most notable was that this strategy was a conceptually simple, financially achievable, culturally appropriate indigenous response incorporating broad-sector community involvement under presidential leadership. The Ugandan president, Yoweri Museveni had entered office in 1986 and found a high percentage of the military infected with HIV. In those tenuous years immediately following the regimes of Idi Amin and Milton Obote, and until about 1995, Uganda was without

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Western world influences on public health strategy development. President Museveni encouraged Ugandan community leaders in medicine, religion, media, and education to work together toward the goal of preventing AIDS, in order to save Uganda. He and First Lady Janet Museveni (who was to became a key youth motivator via the Uganda Youth Forum) heightened awareness about AIDS, dispelled myths about its cause, and warned people that AIDS caused death, but that AIDS could be stopped. AIDS was a danger to Uganda’s survival, so appropriate to African context, they sent out an “alarm” to “call” to all Ugandans that, by their own sexual behavior of abstaining from sexual activity and being faithful in marriage, they could completely avoid death from AIDS.110 This homegrown public health campaign was disseminated widely in schools, from pulpits and taken up by the media and performing arts. It was culturally appropriate and easily understood by an African agrarian population. For example, the idea of sticking only to one partner was called “zero grazing.” This concept was easily understood by rural people via communication of a metaphor that made sense to them: “You tether your animal around a tree, and it can only feed where it is tethered.”111 The First Lady encouraged youth to abstain at every opportunity, stating about her efforts, “Young people must be taught the virtues of abstinence, self-control and postponement of pleasure and sometimes sacrifice” and teaching them a different lifestyle “will ensure their survival.”112 When the Ugandan success was summarized to USAID in 2002, it described the “matter-of-fact,” inspirational approach used by President Museveni and thousands of community, religious, and government leaders who encouraged “delayed sexual activity, abstaining, being faithful, ‘zero grazing’ and using condoms (roughly in that order).”108 As Mrs. Museveni herself has noted, the condom message was targeted to adults who were “already infected with HIV” or were “set in their ways” and unlikely to change their risky behaviors.110 Uganda’s unique strategy had been under scientific scrutiny since the late 1990s by WHO and other organizations and was sometimes “conveniently” abbreviated ABC although “Uganda did in fact emphasize A (abstinence) and B (being faithful) before advising C (condoms).”113 In other words, the elements of the abbreviation were not equivalent; “their rank order reflects the priority in which they arguably ought to be considered, since it is a basic public health maxim that avoiding a risk is inherently better than reducing a risk.”113

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Others have likewise concluded that the emphasis was on A and B, abstinence and being faithful: “condoms were a minor component of the original strategy.”114 It is reported that prior to 1995 in Uganda there were “few” condoms available in 1987, 15 million in 1989, 12 million in 1991, 10 million in 1992, and 22 million in 1993.115 Given 4,548,701 men over age 15 in Uganda in 1990116 it can be calculated that at best, prior to 1995, each Ugandan man had two to five condoms in a year that he had any condoms at all. In fact, condom distribution by the Ministry of Health did not begin until the early to mid-1990s and condom sales did not reach substantial levels until the later 1990s when Population Services International began its more successful condom sales program in 1997.117 During this time of limited condom availability, the data show that HIV prevalence nationally among pregnant women had peaked in 1991 at 21.1% and already by 1998 had declined to 9.7% (a decline of 54% apparent in both rural and urban settings) (Fig. 19.4).114 It has been concluded that “nearly all of the decline in HIV incidence (and much of the decline in prevalence) had already occurred by 1995” in response to social acceptance of the sexual behavior change messages of abstinence and faithfulness.117 The role of primary risk avoidance behavior change (reflective of the A, Abstinence) is substantiated by analysis of Ugandan population-based surveys of HIV behavioral risk indicators between 1989 and 1995 which show increase in the age of sexual debut in all youth aged 15–24 except

40 35

rural females,114 who traditionally marry young, such that their age of sexual debut remained unchanged (Fig. 19.5). Partner reduction (reflective of the B, Be faithful) is demonstrated by a 60% reduction in persons reporting casual sexual partnerships in the previous year in all population groups studied. (male and female, urban, and rural) (Fig. 19.5). The authors conclude that “HIV reductions in Uganda resulted from public-health interventions that triggered a social process of risk avoidance manifested by radical changes in sexual behavior.”114 Given the historical and scientific data, it is not surprising that there are Ugandans who reflect that their success would have been more aptly called “AB,” write out the abbreviation as ABc while vocalizing, “AB, little c” (personal communications and observations. Dernovsek, KK. Mbarara and Kampala, Uganda, 1–31 Oct 2003), or say it was simply, “AB-Stop!” or “AB-Full stop!”118 Indeed, in Washington DC (2003), the Uganda Youth Forum Coordinator wrote out, “Abstinence and Being faithful are the best Choices.”119 In federal testimony, Edward C. Green, PhD, Senior Research Scientist with the Harvard Center for Population and Development Studies, reported concern about a gradual change away from the original endogenously developed Ugandan strategy toward “medical solutions” with less emphasis on sexual behavior. He concluded, “The distinctive Uganda ABC model of the earlier period, the one developed primarily by Ugandans for Ugandans, is the one that seems to have worked best,

Kampala Kampala age 15-19 Kampala age 20-24 Other urban Rural

Fig. 19.4  HIV prevalence rates (%) in pregnant women surveyed at antenatal sentinel surveillance sites in Uganda in urban Kampala, other urban sentinel sites, and rural sites from 1985 to 2001. Adapted from Stoneburner.114 Used with permission

HIV prevalence (%)

30 25 20 15 10 5 0 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

19  Prevention of Sexually Transmitted Diseases from Office to Globe Males non-regular partner Females non-regular partner

45%

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40% 35%

36% 32%

30% affirmative response

Fig. 19.5  Changes in the proportion of persons reporting sex with a nonregular partner in the previous 12 months and persons aged 15–24 reporting never having had sex in Uganda among adult populations, measured by population-based behavioral surveys performed in 1989 and in 1995, by sex and population characteristics. Adapted from Stoneburner.114 Used with permission

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25% 20%

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15%

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and is the one that has most to teach the rest of the world.”120 It is no wonder, with increasing condom social marketing117 to the general population, including youth, that Ugandans should feel frustrated to the point of staging abstinence marches and rallies to “stop abstinence stigma” (personal communication from participant, Oct 2006, Kampala Uganda), finding it counterproductive that the Western world promotes condoms in their country instead of supporting what the evidence showed was successful: their own grassroots AB method of primary behavior change.

19.14 Preventing STDs: The New Global Paradigm During the last 25 years, a risk-reduction, condom/ safe/safer sex public health paradigm has been applied broadly, including to youth, in the United States and around the globe. The evidence reported herein indicates that both, youth in the United States and the generalized population of Uganda, Africa are capable of risk-avoidance via abstinence, lifetime monogamy (being faithful), and/or motivated toward those lifestyles for personal/social/health reasons. The numbers of STDs, the serious health consequences, the variable effectiveness of existing prevention parameters (condoms, vaccines, microbiocides, treatment) has complicated individual patient management and inevitably will overwhelm an already overburdened healthcare system, especially at the global level.

1989

1995 Rural

We stand at a crossroads in public health paradigm that could alter forever the survival of the inhabitants of sub-Saharan Africa, (i.e., the black race), and those human beings in all areas in the world facing the AIDS pandemic. The grim statistics indicate that every 8 seconds a person is infected with HIV somewhere in the world. This equates to 6,800 new infections per day. Sixty-eight percent of the 33.2 million people with HIV live in Sub-Saharan Africa.121 It has been a number of years since the HIV prevalence in Uganda reached its low in 2001 at 5% and was reported to the world in 2003. At last survey in 2007, Ugandan HIV prevalence was holding at 5.4%.122 What role increasing condom social marketing, occurring over the objections of the Ugandans themselves, will have on their success is yet to be observed. Hearst and Chen have shown graphically that in Cameroon, Kenya, and Botswana, from 1990 to 2001, “urban and rural HIV prevalence have gone up right along with condom sales.”123 Likewise, from 1989 to 2000, South Africa, Botswana and Zimbabwe, had the highest rates of condom availability (seven to ten condoms per year per man) yet had the highest HIV prevalence rates, ranging from 20 to 36%.124 While causality is unproven, there likewise “is no evidence at the national level in Africa that more condoms have resulted in less AIDS.”124 In 2005, Kajubi et al. reported that gains in condom use by Ugandan men in a condom promotion program seemed to have been offset by increases in the number of sex partners.125 This phenomenon of “risk compensation” (discussed in Sect. 19.3) refers to the perception of reduced risk being

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compensated for by a paradoxical increase in risky behavior. In a 2006 commentary published in British Medical Journal, the authors questioned whether vaccines, microbicides, and male circumcision could be compensated for by an increase in risky behavior and thus concluded that with regard to HIV prevention, “successful approaches to change behavior must be studied, adapted, and applied with at least the same vigor as the promising host of technological innovations under development.”126 Time is short as we confront the most serious of all STDs in the global AIDS pandemic. The UNAIDS/ WHO 2006 AIDS Epidemic Report challenges all of us who counsel youth: “The future course of the world’s HIV epidemics hinges in many respects on the behaviors young people adopt or maintain, and the contextual factors that affect those choices.”127 If we take aim with a goal to prevent all STDs, especially in youth, we need to move quickly and, following the example set by Uganda, align with the same risk avoidance message. The available scientific evidence supports that the risk-reduction, “safe/safer sex” or “vaccinate, condomize and treat” paradigm was and is not enough. Also established is that the risk-avoidance, Absti­ nence/Be faithful paradigm is both “realistic” and effective and it is consistent with existing medical guidelines. It is an “umbrella approach,” that is best suited to protect vast numbers of people from all STDs whether in-office or around the globe. Subset at-risk populations can be targeted specifically to their risk behavior but always with the goal of moving them toward the healthiest behavior, no different than what a physician would do in the office with an individual patient. The Ugandan model has demonstrated that behavior can be changed, that sexual behavior can be changed, that health can be preserved and that lives can be saved. Dermatologists/venereologists, other physicians, scientists, and leaders, capable of capturing this vision and willing to learn from a developing nation, should be given the lead to establish risk-avoidance strategies worldwide. The Ugandan success model is low cost and simple but requires that community leaders get “on the same page” with a single, clear message that Abstinence and Being faithful are the best Choices. That is what the scientific evidence indicates needs to be done for the health of all people around the globe. There is no time to lose.

K. K. Dernovsek

References   1. Executive summary, committee on prevention and control of sexually transmitted diseases. Institute of medicine. In: Eng TR, Butler WT, eds. The Hidden Epidemic: Confronting Sexually Transmitted Disease. Washington, DC: National Academy; 1997:1–17   2. Centers for Disease Control and Prevention. Tracking the hidden epidemics 2000. Available at: http://www.cdc.gov/ std/Trends2000/Trends2000.pdf; 2009 Accessed 29.05.09   3. Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004; 36(1):6–10   4. Neinstein LS. Adolescent Health Care: A Practical Guide. 4th ed. Philadelphia: Lippincott Williams and Wilkins; 2002   5. Kahn JA, Hillard PA. Human papillomavirus and cervical cytology in adolescents. Adolesc Med Clin. 2004;15: 301–321   6. Corey L, Handsfield HH. Genital herpes and public health: addressing a global problem. JAMA. 2000;283(6):791–794   7. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR 2006:55(No. RR-11):16   8. Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, St Louis ME. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med. 1997;337(16): 1105–1111   9. Wald A, Zeh J, Selke S, et al Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med. 2000;342(12):844–850 10. Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003;30 (10): 797–800 11. Tyring SK. Drugs with antiviral activity in clinical dermatology. Dialogues in Dermatology. 1998 Jul;42(4) 12. Xu F, Sternberg MR, Kottiri BJ, et al Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296(8):964–973 13. Sonfield A, Gold RB. States’ implementation of the Section 510 abstinence education program, FY 1999. Fam Plann Perspect. 2001;33(4):166–171 14. Ali L, Scelfo J. Choosing virginity. Newsweek. 2002;140(24): 60–64, 66 15. Maw RD, Reitano M, Roy M. An international survey of patients with genital warts: perceptions regarding treatment and impact on lifestyle. Int J STD AIDS. 1998;9(10):571–578 16. Reitano M. Counseling patients with genital warts. Am J Med. 1997;102(5A):38–43. Review 17. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR 2006; 55[No.RR-11]63. Available at: http://www.cdc.gov/std/ treatment/2006/rr5511.pdf; 2009 Accessed 27.05.09 18. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338(7):423–428 19. Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection:

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19  Prevention of Sexually Transmitted Diseases from Office to Globe   88. Abstinence because. Austin, Texas:The Medical Institute for Sexual Health   89. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102(5A):3–8   90. Whitley RF, Gnann JW. Herpes simplex virus. In: Tyring S, Yen-Moore A, eds. Mucocutaneous Manifestations of Viral Diseases. 1st ed. New York, NY: Marcel Dekker; 2002:103   91. With One Voice: America’s adults and teens sound off about teen pregnancy. Washington, DC: National Campaign to Prevent Teen Pregnancy. April 2001. Available at: http:// www.teenpregnancy.org/resources/data/pdf/chrtbook.pdf; 2009 Accessed 27.05.09   92. With One Voice: America’s adults and teens sound off about teen pregnancy. Washington, DC: National Campaign to Prevent Teen Pregnancy. December 2002. Available at: http://www.teenpregnancy.org/resources/data/pdf/ WOV2002_fulltext.pdf; 2009 Accessed 27.05.09   93. With One Voice 2003: America’s adults and teens sound off about teen pregnancy. Washington, DC: National Campaign to prevent Teen Pregnancy. December 2003. Available at: http://www.teenpregnancy.org/resources/data/pdf/ wov2003.pdf; 2009 Accessed 27.05.09   94. Albert B. With One Voice 2004: America’s adults and teens sound off about teen pregnancy. Washington, DC: National Campaign to Prevent Teen Pregnancy. December 2004. Available at: http://www.teenpregnancy.org/resources/data/ pdf/WOV2004.pdf; 2009 Accessed 27.05.09   95. Albert B. With One Voice 2007: America’s adults and teens sound off about teen pregnancy. Washington, DC: National Campaign to Prevent Teen Pregnancy. February 2007. Available at: http://www.teenpregnancy.org/product/ pdf/6_9_2007_15_17_14WOV2007_fulltext.pdf; 2009 Accessed 27.05.09   96. Brackbill RM, Sternberg MR, Fishbein M. Where do people go for treatment of sexually transmitted diseases? Fam Plann Perspect. 1999;31(1):10–15   97. Center for Disease Control and Prevention. Physician advice and individual behavior about cardiovascular disease risk reduction B seven states and Puerto Rico, 1997. MMWR. 1999;48:74–77   98. Lancaster T, Stead LF. Physician advice for smoking cessation. The Cochrane Database of Systemic Reviews 2005;3   99. Center for Disease Control and Prevention. Recommended Immunization Schedules for persons aged 0 through 18 years – United States, 2009. MMWR 1–2–09;57(51&52);Q1-Q-4. Available at: http://www.cdc.gov/mmwR/preview/ mmwrhtml/mm5751a5.htm; 2009 Accessed 29.05.09 100. Ramsay DL, Weiss R, Brademas ME. Margolies, R. National survey of dermatologists and residency training program directors on dermatology’s role in treating sexually transmitted diseases. J Am Acad Dermatol. 1986;14 (3):527–531 101. Centers for Disease Control and Prevention. STD-Prevention Counseling Practices and Human Papillomavirus Opinions Among Clinicians with Adolescent Patients – United States, 2004. MMWR 2006;55(41)1117–1120. Available at: http:// www.cdc.gov/mmwr/preview/mmwrhtml/mm5541a1.htm; 2009 Accessed 27.05.09 102. Center for Disease Control and Prevention. Trends in Sexual Risk Behaviors Among High School Students – United States, 1991–2001. MMWR 9–27–02 /51(38);

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232 population-ages-0-14-total&date=1990 and http://www. nationmaster.com/red/graph/peo_pop_fem_of_totpeople-population-female-of-total&date=1990&ob=ws; 2009 Accessed 29.05.09 117. Green EC, Halperin DT, Nantulya V, Hogle JA. Uganda’s HIV prevention success: the role of sexual behavior change and the national response. AIDS Behav. 2006;10(4): 335–346 118. Ssempa M. Presentation at the International Leadership Conference sponsored by the National Abstinence Clearing­ house. Kansas City KS. Jun 8, 2006 119. Bampata EK. Presentation at “HIV/AIDS Prevention for Young People in Developing Countries,” a conference sponsored by USAID Office of HIV/AIDS, Institute for Youth Development, YouthNet/Family Health International. 24 July 2003. Washington DC 120. Green EC. Senior Research Scientist. Harvard Center for Population and Development Studies. Testimony before the African subcommittee U.S. Senate. Available at: foreign. senate.gov/testimony/2003/GreenTestimony030519.pdf; 2008 Accessed 18.05.09 121. Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO) AIDS Epidemic update December 2007. Available at: http://data.unaids.

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Current Vaccinations in Dermatology

20

Kamaldeep Singh and Robert A. Norman

20.1 Introduction

20.2 Varicella Zoster Virus

Vaccines have been called medicine’s greatest life savers. They have helped eradicate vexing diseases such as smallpox and effectively prevented diseases such as rubella and rubeola. In the present medical landscape vaccinations occupy enormous ground and from first world nations to third world countries they have become part of government policies and legislation to prevent disease. One does not need to study the countless studies and trials that focus on disease reduction from the use of vaccines, but only to go back in history and see the triumph of vaccines over horrific diseases such as polio and tetanus. Edward Jenner would have never envisioned that his use of cowpox to prevent smallpox would have such a paramount impact on medicine. Although the idea behind vaccinating is older than Jenner and records of inoculations can be found as far back as a millennium before Jenner’s time, history credits him as being the father of vaccine because his vaccine was safer than inoculation. Edward Jenner’s vaccine was also the first against a disease with cutaneous manifestations and since then many vaccines have been developed including the ones that prevent against diseases with cutaneous components such as measles, mumps, and rubella and more recently diseases caused by varicella zoster virus (VZV) and human papilloma virus. The focus of this chapter is to review the natural history, epidemiology, and diagnosis of VZV and HPV and to emphasize vaccination strategies including the latest CDC guidelines.

VZV, also known as human herpes 3 (HHV3), is a human neurotropic virus belonging to the family of DNA viruses known as herpesviridae. Its single, linear double-stranded DNA molecule is enclosed within an icosapentahedral capsid making it very similar to herpes simplex virus 1 and 2. The distinguishing factor that is responsible for each virus’s unique properties is the lipid envelope consisting of polyamines, lipids, and glycoproteins that encloses this 162 capsomere capsid. More specifically, the glycoproteins are responsible for the distinctive properties of each virus as well as the antigenic capabilities of eliciting an immune response in the host. For example, VZV glycoproteins (gB, gC, gE, gH, gK, gL) correspond with those in the HSV, but HSV gD is not found in the VZV lipid envelope. VZV puts forth a considerable challenge in terms of studying the virus for its biological and pathogenic properties because it only replicates in human cells and tissues for reasons currently unknown.

K. Singh (*) Internal Medicine Resident, Stony Brook University Hospital, Stony Brook, NY, USA

20.2.1 Epidemiology Varicella (chickenpox) and herpes zoster (shingles) are both caused by VZV. Chickenpox is a very common childhood illness with peak incidence between 1 and 9 years of age resulting in 90% of the population having positive serology by adolescence and 100% of the population being seropositive by the age of 60. VZV infections are more widespread in winter and spring seasons and have a tendency of epidemics every 2–5 years. The disease is highly contagious and spreads from person to person via direct contact with fluids from vesicles or respiratory inhalation of viral

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fomites. In immunocompetent persons varicella is a mild-to-moderate illness while immunocompromised persons can suffer from severe complications including death. Shingles is caused by the reactivation of the latent VZV. It is a disease most commonly of the elderly and immunocompromised and incidence increases with age because of declining immunity. At 60 years of age incidence is reported between 2.5 and 5% and increases to 3–6.8% the age of 70 with lifetime risk of 15–30%. Shingles can also occur in seemingly healthy individuals with incidence of 1.2–3.4%. The disease is worrisome because it poses the potential for severe and debilitating complications such as herpes opthalmicus, postherpetic neuralgia, paresis, myelopathy, myocarditis, depression, and others.

20.2.2 Virus Life Cycle The VZV life cycle consists of three stages, the primary infection, latent period, and reactivation. The virus gains access to the host’s peripheral nervous system via the mucocutaneous surfaces; it replicates, spreads, and causes an immune response resulting in usually self-limiting disease of chickenpox. Thereafter, the virus enters the axonal endings within the mucocutaneous surfaces and travels to the dorsal root ganglia where it remains latent until reactivation. Latency is the presence of viral genome without production of the infective particle. Reactivation occurs in response to stimulus such as immunosuppression, hormonal changes, stress, nerve damage, etc. and causes the virus to once again become active and replicate itself causing shingles. Latency is once again established and potential to reactivate remains.

20.2.3 Varicella (Chickenpox) Mucocutaneous surfaces most susceptible to VZV are the upper respiratory mucosa and conjunctiva. Upon entering these surfaces VZV replicates in the regional lymph nodes for the next 2–4 days, followed by primary viremia in 4–6 days and then leading to viral replication in the liver, spleen, and other organs. Secondary viremia occurs in 14–16 days leading to the

K. Singh and R. A. Norman

dissemination of the virus to the skin and vicera and producing the typical vesicular lesions. Prodromal symptoms include fever, malaise, anorexia, and headache. In the United States, universal vaccination policy against varicella was adopted in 1995 and has led to significant reduction in morbidity and mortality associated with VZV (Table 20.1).

20.2.4 Herpes Zoster (Shingles) Reactivation of the latent VZV causes herpes zoster or shingles. The virus that had remained latent inside the neuronal nucleus maintaining the ability to replicate reverts to its infectious state. It is not clearly known why the reactivation happens but the fact that the disease is more prevalent in the elderly and the immunoincompetent leads to the theory that declining cell-mediated immunity is the culprit. Support for this theory stems from the experimental evidence that, over time, even person with apparent immunity to varicella exhibit T cells with reduced ability to proliferate and produce VZV-specific interferon gamma when exposed to VZV antigen in vitro. Fifty percent of the estimated one million causes of herpes zoster in the United States occur in individuals aged 50 years or older and 50% of individuals 85 or older are expected to develop herpes zoster. Another 300,000 cases occur in the immunocompromised with bone marrow transplant recipients and HIV patients having the highest vulnerability. In contrast to the primary varicella infection, reactivation tends to occur locally and within dermatomes where the highest viral load was present during the primary infection. Most often these sites are the thorax and the trigeminal distribution of the face. Clear vesicular eruptions appear within a dermatome, becoming turbid and eventually crusting within 5–10 days. Preherpetic neuralgia sometimes precedes shingles and is defined as parasthesias, itching and pain sometimes severe enough to suggest coronary artery ischemia or abdominal conditions. The most common and worrisome complication of the disease is when the pain and itching, usual concomitants of the eruptions, become chronic and lead to the condition known as postherpetic neuralgia. Although self-limiting, postherpetic neuralgia can be debilitating, often difficult to treat, and can leave the patient with poor quality of life leading to social withdrawal and depression.

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Table 20.1  Summary of the recommendations of the advisory committee on immunization practices for prevention of varicella – United States, 1996, 1999, and 2007 Category Recommendations 1996 1999 2007 Routine childhood schedules

One dose at age 12–18 months

No change

Two dosesFirst at age 12–15 months Second at age 4–6 years

Adults and adolescents aged ³13 years

Two doses, 4–8 weeks apart

Two doses, 4–8 weeks apart

Recommended for susceptible persons who have close contact with persons at high risk for serious complicationsHealth-care workers Family contacts of immunocompromised persons

No change

Two doses, 4–8 weeks apart Recommended for all adolescents and adults without evidence of immunity

Should be considered for susceptible persons at high risk for exposurePersons who live or work in environments in which transmission of VZV is likely (e.g., teachers of young children, childcare employees, residents and staff in institutional settings) Persons who live and work in environments in which transmission can occur (e.g., college students, inmates and staff of correctional institutions, military personnel) Nonpregnant women of childbearing age International travelers

Recommended for susceptible persons at high risk for expose or transmissionPersons who live or work in environments in with the transmission of VZVa is likely (e.g., teachers of young children, daycare employees, residents and staff in institutional settings) Persons who live and work in environments in which transmission can occur (e.g., college students, inmates and staff of correctional institutions, military personnel) Nonpregnant women of childbearing age International travelers Adolescents and adults living in households with children

Is desirable for other susceptible adolescents

No change

Second dose recommended for all persons who received one dose previously

Two doses, 3 months apart

Two doses, 3 months apart Should be considered for HIV-infected children with age-specific CD4+ T-lymphocyte percentages ³15%

Catch-up vaccination

One dose for all susceptible children age 19 months – 12 years (i.e., those with no history of varicella or vaccination)

HIVb-infected persons

Contraindicated

Should be considered for asymptomatic or mildly symptomatic HIV-infected children in CDC immunologic and clinical categories N1 or A1 with age-specific CD4+ T-lymphocyte percentages ³25%

May be considered for adolescents and adults with CD4 counts ³200/mL (continued )

236 Table 20.1  (continued) Category

K. Singh and R. A. Norman

Recommendations 1996

1999

2007

Antenatal screening

None

None

Recommended prenatal assessment and postpartum vaccination

Outbreak control vaccination

None

Should be considered

Recommended two-dose vaccination policy

Postexposure vaccination

None

Recommended within 3–5 days

No change

Vaccination requirements

None

Recommended for children without Recommended for children attending evidence of immunity attending child-care centers, childcare centers and entering students in all elementary school grade levels, and Should be considered for middle persons attending school and junior high school college or other students without other evidence postsecondary of immunity educational institutions

Varicella zoster virus Human immunodeficiency virus From Centers for disease control and prevention. Prevention of varicella. Recommendations of the advisory committee on immunization practices (ACIP). MMWR 2007; 56(RR-4):3 a

b

Various drugs including antivirals and steroids are used to treat and reduce the severity of acute herpes zoster but none can prevent postherpetic neuralgia or other herpes zoster complications. In 2006, the Food and Drug Administration (FDA) approved Zostavax, a live attenuated preparation of VZV. The vaccine has been shown to boost the recipient’s immunity to VZV making the reactivation of VZV and development of herpes zoster less likely. The pivotal Shingles Prevention Study, on which basis the FDA approved Zostavax, showed a reduction in the cases of herpes zoster by half and postherpetic neuralgia by two-thirds in a sample of 38,000 older adults.

Contraindications are: • A history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine • A history of primary acquired immunodeficiency states • On immunosuppressive therapy • Women of childbearing age, and is not to be administered to pregnant females

20.3 Human Papilloma Virus 20.2.5 ACIP Provisional Recommendations A single dose of herpes zoster vaccine is recommended for adults 60 years of age and older whether or not they report a prior episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless contraindications or precautions exist for their condition.

Human papilloma viruses belong to their own family of viruses known as papillomaviridae. These doublestranded DNA viruses are species-specific and infect the skin and mucous membranes of their host. There are more than 100 types of human papilloma viruses that have been identified with each type containing approximately 7,900 base pairs and sharing 90% of DNA base pair homology with other identified types.

20  Current Vaccinations in Dermatology

Infections with different HPV types result in illness ranging from clinically silent infections, benign skin lesions, and malignant cancers. Certain HPV types associated with squamous intraepithelial lesions and anogential malignancy including cervical, vaginal, and vulvar and anal carcinomas prompt tremendous research effort in order to reduce morbidity and mortality caused by these diseases and to better the treatment and prevention of HPV infections. Types linked to cervical cancer are classified as either high (16, 18), intermediate (31, 33, 35, 39, 45, 51, 52, 58) or low risk (6, 11, 42, 43, 44). Although the high-risk types are linked to 70% of all cases of cervical cancers not all infections with types 16 and 18 lead to cervical cancer. It is the oncogenic potential of different variants of these high-risk types that determine whether a HPV infection has a potential to develop into cervical cancer. HPV infections are also associated with anal cancer and the same high-risk types implicated in cervical cancer have been identified as the culprits for anal cancer. A group of researchers have identified 29 individual HPV types and 10 HPV groups from anal canal of homosexual men.

20.3.1 Virus Life Cycle and Pathogenicity The pathogenicity of HPV is thought to be caused by proteins E6 and E7 encoded by the HPV DNA. These proteins are part of six early (E) proteins implicated in modifying the cell cycle of infected host cells. Once the HPV virion infects the epithelial tissue through micro abrasions, it gains access to the nucleus of basal epithelial cells via several complex transport mechanisms including alpha integrins, laminins, and several chemical mediators involved in endocytosis within the cell wall and nuclear membrane. Once inside the host keratinocyte the HPV lifecycle follows the keratinocyte’s differentiation program. The oncogenes E6 and E7 are thought to modify the function of tumor suppressor gene p53 and retinoblastoma, leaving the keratinocytes cell cycle unchecked. The evidence for oncogenes E6 and E7’s role in epithelial cancers is supported by the presence of HPV DNA in tumor biopsies and more specifically the expression of E6 and E7 in tumor material. Additionally, E6 and E7 proteins are required to maintain the malignant phonotype of cervical carcinoma cell lines.

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20.3.2 Epidemiology Currently the bulk of research and emphasis in studying infections caused by human papilloma viruses is placed on genital tract infections that lead to precancerous or cancerous conditions in healthy individuals including cervical intraepithelial neoplasia, cervical cancer, Bowen’s disease, and verrucous carcinoma of the penis. Other less severe types lead to mostly benign skin lesions or even clinically silent infections. The prevalence of anogenital tract HPV infection in the United States is quite high with an estimated 20 million infected individuals. The annual incidence is 5.5 million. Incidence is highest among sexually active persons and according to some estimates more than 50% of these individuals are expected to be infected with anogenital HPV infection in their lifetime. With approximately 9,710 cases of cervical cancer and 3,700 deaths annually the cost related to HPV infections are enormous to health care. One study based on a database of cases in Maryland states that the cost of one HPV-related disease alone (the JORRP) costs $57,996 per case with annual cost of between $40 million and $123 million. Combine this with financial burden created by other anogenital diseases caused by HPV infections in both men and women and the dollar figure grows astounding.

20.3.3 Intervention The CDC states that by age 50, more than 80% of American women will have contracted at least one strain of genital HPV, making them at highest risk of developing HPV-induced cancers, more specifically cervical cancer. Fortunately, development of cervical cancer induced by HPV infection is a slow process requiring many years, giving physicians an opportunity to screen individuals considered to be at risk for HPV-induced cervical cancer. Papanicolaou (pap) testing is a popular screening test used to detect cervical cytology changes during the developmental phase of HPV-induced cervical cancer. Cells from the cervix are smeared onto a slide and examined under the microscope for presence of precancerous or abnormal cells. The test is 70–80% effective in detection of abnormal cervical cytology caused by HPV. Variations of the test are used to increase the

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sensitivity including liquid-based cytology known as the thin prep (sensitivity 85–95%), and a pap-HPV DNA test mainly used for women over the age of 30. Adjunct testing including the use of colposcopy and hybrid capture test (the newest FDA-approved method for detecting high risk HPV DNA) may be used if abnormal cytology is suspected. The CDC has several targeted guidelines for routine HPV testing in women to help detect and prevent HPV-induced cervical cancer.

20.3.4 Vaccine Cervical cancer is the second leading cause of cancerrelated deaths in women worldwide and nearly all cases are caused by HPV infections. Although early detection via pap testing has significantly reduced the risk of invasive cervical cancer, there still exists considerable risk. In 2006, a prophylactic HPV vaccine (Gardasil) was approved by the FDA and is currently being marketed by Merck. The vaccine is based upon one of the late proteins of the HPV DNA. The L1 protein is a capsid protein and has the ability to form a virus-like antigenic particle capable of eliciting an immune response and production of high levels of neutralizing antibodies. Gardasil protects against the highrisk type 16 and 18 and types responsible for 90% of genital warts, 6 and 11.

20.3.5 ACIP Recommendations 20.3.5.1 Routine Vaccination of Females Aged 11–12 Years ACIP recommends routine vaccination of females aged 11–12 years with three doses of quadrivalent HPV vaccine. The vaccination series can be started as young as age 9 years.

K. Singh and R. A. Norman

20.3.5.2 Catch-Up Vaccination of Females Aged 13–26 Years Vaccination also is recommended for females aged 13–26 years who have not been previously vaccinated or who have not completed the full series. Ideally, vaccine should be administered before potential exposure to HPV through sexual contact; however, females who might have already been exposed to HPV should be vaccinated. Sexually active females who have not been infected with any of the HPV vaccine types would receive full benefit from vaccination. Vaccination would provide less benefit to females if they have already been infected with one or more of the four vaccine HPV types. However, it is not possible for a clinician to assess the extent to which sexually active persons would benefit from vaccination, and the risk for HPV infection might continue as long as persons are sexually active. Pap testing and screening for HPV DNA or HPV antibody are not needed before vaccination at any age. Vaccines for melanoma, nonmelanoma skin cancers (NMSCs) such as squamous cell and basal cell cancers, molluscum contagiosum, common warts, and chlamydia have been in trial with mixed results.

20.4 Conclusion Although many of the cutaneous diseases reviewed in this chapter are self-limiting, they sometimes lead to serious sequelae. While herpes zoster vaccine, Zostavax, prevents shingles and related complications, Gardasil decreases HPV-induced cervical cancer and genital warts. Although yet to be seen, the universal vaccination policy against varicella is further set to decrease the incidence of herpes zoster. The future of medicine is practicing preventative medicine and we only need to study the past starting with Edward Jenner to come to such realization.

Part Wounds, Surgery, and Dermatological Prevention

IV

Prevention of Skin Infections

21

Dirk M. Elston

21.1 Bacterial Infections Methicillin-sensitive Staphylococcus aureus accounts for most cutaneous infections, including wound infection (Fig. 21.1), folliculitis (Fig. 21.2), and impetigo. Cutaneous injuries commonly become infected. Topical antiseptics can reduce the incidence of infection, but may be contact sensitizers. While topical antibiotics may reduce the overall incidence of infection, they may also cause contact dermatitis. Those with a gram-positive spectrum may increase the likelihood that the infecting organism with be gram negative. Wound care is discussed more thoroughly in the section on prevention of surgical wound infections. Community-acquired methicillin-resistant Staphy­ lococcus aureus (CA-MRSA) has recently emerged as an important skin pathogen. CA-MRSA infections have a high attack rate among wrestlers, football players, weight lifters, and members of amateur and professional sports teams.1–3 Pre-existing cuts or abrasions and sharing of fomites such as towels and bars of soap are important risk factors for infection. Nasal carriage is ­associated with sharing of towels and serves as a reservoir for recurrent infection.4 Carriage also occurs in other moist areas, such as the axillae, groin, and perianal region. Eczematous skin is commonly colonized. CA-MRSA has also been isolated from whirlpools and taping gel.5 CA-MRSA strains typically contain the type IV staphylococcal chromosomal cassette that codes for methicillin resistance. Panton-valentine leukocidin (PVL) has been identified as a potent virulence factor.6 PVL imparts

D. M. Elston Department of Dermatology, Geisinger Medical Center, Danville, PA, USA e-mail: [email protected]

a survival advantage to the organism, and it rapidly replaces other strains of staphylococci. Colonization easily spreads to close contacts. Those who are colonized have a high attack rate of clinical infection.7,8 Clinical infection with CA-MRSA generally begins with folliculitis and rapidly evolves into an abscess (Fig. 21.3). Early in the course of disease, pain is often severe and out of proportion to physical findings. Infection commonly begins at sites of minor abrasions such as turf-burns. In weightlifters, abscesses commonly involve the axillae. In women and young children, the thighs and buttocks are often involved. Other common sites of involvement include the neck, back, extremities, nose, and external ear canals.9 Prevention of cutaneous CA-MRSA infections requires preventive measures to reduce the incidence of cutaneous injury, elimination of bar soap, policies against sharing of towels, decontamination of mats and equipment, as well as treatment of carriers. Cosmetic body shaving is a risk factor for CA-MRSA infection, and should be discouraged.10 Sodium hypochlorite (bleach) at a dilution of two tablespoons per bathtub of water can be used to reduce colonization of eczematous skin lesions, axillae, and groin regions. Chlorhexidine gluconate washes can also be effective, although resistance is emerging.11,12 Seventy percent ethanol is an effective agent for decontamination of mats and equipment.13 The combination of alcohol and chlorhexidine has also been effective.14 Triclosan-based hand sterilizers are suitable for use on skin and some equipment. As with chlorhexidine, triclosan resistance is emerging.15,16 Mupirocin is commonly used for nasal colonization, but resistant strains are now common and eradication may be achieved in fewer than half of those so treated.17,18 Retapamulin is a newer alternative, but its effectiveness in this setting must be validated in clinical studies.

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_21, © Springer-Verlag London Limited 2010

241

242

Fig. 21.1  Impetiginized wound

D. M. Elston

Fig.  21.3  CA-MRSA commonly presents as folliculitis that rapidly evolves to a painful abscess

Exposure to fresh or salt water is associated with an increased incidence of skin infection.20 Pseudomonas infections are associated with exposure to water and commonly present as folliculitis restricted to covered or intertriginous areas (hot tub or swimming pool folliculitis). The follicular papules and pustules are typically more pruritic than tender (Fig.  21.4). Warm weather or heated water are risk factors for infection, as free chlorine levels are harder to maintain in the heat. Both chlorine and bromine treated water can be a source of infection, as can contaminated plastic, rubber, or natural loofah sponges.21, 22 The implicated strain is typically type O:11, although types O:1, O:3, O:8, O:10, and O:16 have also been implicated.23 Most cases of Pseudomonas folliculitis resolve spontaneously, although fluoroquinolone treatment may be required.24 Prevention involves elimination of standing water and wet sponges, prompt removal of wet bathing suits, and adequate chlorination. Alter­native water treatments such as ozone ionization have also been used.

21.2 Viral Infections

Fig. 21.2  Staphylococcal folliculitis

Group A streptococcal infections complicating cutaneous injuries can result in impetigo, glomerulonephritis, erysipelas, and lymphangitis.19 Prevention of streptococcal infections is similar to that for staphylococcal infections.

Herpes infections (Fig. 21.5) may occur through sexual exposure or by any skin-to-skin contact. Infections are particularly common among wrestlers (herpes gladiatorum), where attack rates are as high as 34%.25 Ocular involvement can be particularly devastating. Those with genital lesions should refrain from sexual activity during outbreaks and should be aware that asymptomatic shedding occurs. Barrier protection is only partially effective, but oral prophylaxis with

21  Prevention of Skin Infections

243

Fig. 21.5  Herpes simplex virus infection

wrestling matches. Footwear should be worn in locker rooms and other areas with foot traffic and moist floors.

Fig. 21.4  Hot tub folliculitis

acyclovir, valcyclovir, or famciclovir can prevent or reduce the spread of disease. Abrasive shirts create potential portals of entry and are a risk factor for herpes infections among wrestlers.26 Policies to ban infected individuals from competition and discourage abrasive clothing should be enforced. Blood-borne pathogens can be spread in the healthcare setting, during sexual intercourse, or during competition. Universal precautions should be observed at all times in healthcare settings. Those with open wounds should be barred from competition. Minor wounds may be covered with impermeable adhesive dressings.

21.3 Fungal Infections Tinea infection is common among military recruits, wrestlers, and swimmers.27 Asymptomatic carriers are common, and fungal spores are easily recovered from moist surfaces such as the floors around swimming pool.28,29 There is an inherited susceptibility to Trichophyton rubrum infection which may be inherited in an autosomal dominant fashion. Although much of the population is predisposed to infection, it is not inevitable and can certainly be delayed by simple precautions. Those with active tinea should not participate in

21.4 Prevention of Surgical Wound Infections The incidence of wound infections following cutaneous surgery is quite low (just over 1%), the benefits of routine antibiotic prophylaxis must be carefully weighed against the cost of treatment, the risks of adverse drug reactions, and the potential for emergence of resistant organisms.30 The risk of infection for Mohs surgery is slightly higher (about 2.5%). For any prolonged surgery, the risk of infection can be reduced by avoiding buried suture or allowing the wound to heal by secondary intention. A single preoperative or intraoperative dose of antibiotic can also reduce the risk of infection, but there is no benefit to courses of antibiotic longer than 48 h.31 Many surgeons favor a single dose of a prophylactic antibiotic before surgery on a site such as the hand where a postoperative infection could be catastrophic. An alternative to prophylaxis with a systemic antibiotic is to add clindamycin to the local anesthetic.32 This results in a reduction in surgical site infection (to below 1%) with undetectable blood levels and no risk of contributing to the emergence of resistant organisms. Clindamycin is also suitable for use in patients with a history of penicillin allergy. The solution is prepared by adding 0.15 ml of clindamycin (150 mg/ml) to 50 mg of lidocaine with 5 ml 8.4% bicarbonate. This results in at concentration of ­clindamycin of 408 mg/mL.

244

D. M. Elston

Elimination of nasopharyngeal staphylococcal c­ olonization with chlorhexidine intranasal ointment and oropharyngeal rinse 4 times daily during the preand postoperative periods reduced the incidence of nosocomial infections including respiratory infection, bacteremia, and deep surgical site infections.33 Data on the use of intranasal mupirocin have generally been disappointing. Studies are needed to determine if newer topical antibiotics such as retapamulin will perform better. Postoperative use of a topical antibiotic ointment results in a small decrease in the incidence of wound infection at the expense of a significant risk of allergic contact dermatitis. In a randomized, double-blind trial of white petrolatum compared to bacitracin ointment, the infection rate was 1.5% with the former and 0.9% with the latter.34 Allergic contact dermatitis occurred in 0.9% of those treated with bacitracin. Infections in the bacitracin group were more likely to be gram negative infections, and antibiotics needed to treat them were more expensive. These data make a strong case for the routine use of white petrolatum postoperatively.

21.5 Prevention of Arthropod-Borne Infections

Fig. 21.6  Rocky mountain spotted fever

Insect bites and stings commonly become infected. Vector-borne illnesses such as leishmaniasis present mainly in the skin. Other diseases such as Rocky Mountain spotted fever (Fig.  21.6) and viral fevers may present with petechial or hemorrhagic skin lesions. Avoidance of infested areas as well as consistent use of repellents and protective clothing can reduce the incidence of infection. Chemoprophylaxis and attention to screening or mosquito netting is important when traveling. At home, public health measures to reduce mosquito and tick populations are important. In the United States, mosquitoes are vectors for West Nile fever, St. Louis encephalitis, equine encephalitis, dengue, and malaria. North American ticks carry Lyme disease, Rocky Mountain spotted fever, ehrlichiosis, Colorado tick fever, relapsing fever, tularemia, and babesiosis. Homeless patients with ectoparasitic infestation have a high prevalence of infection with Bartonella quintana, a cause of endocarditis.35–37 Fleas transmit plague, bacillary angomatosis, and endemic typhus. Sandflies transmit leishmaniasis. In the United

States, Leishmania mexicana produces chronic crusted and ulcerative lesions, while L. donovani can produce subcutaneous nodules. Primary prevention of vector-borne disease requires drainage of stagnant water, insecticide spraying programs, use of repellents, and prompt tick removal. Secondary prevention can be accomplished with chemoprophylaxis or early treatment of illness. Anopheline mosquitoes that carry malaria feed mostly at night. Transmission is prevented by staying indoors at night, use of repellents and pyrethroid-impregnated mosquito netting. Mosquitoes that carry dengue tend to bite during the day, and repellents and protective clothing are especially important to prevent transmission.38,39 Carbon-dioxide–emitting mosquito traps such are helpful. Chemical attractants such as octenol and butanone are often used, although some Culex mosquitoes are repelled by octenol.40–42 DEET (N,N-diethyl-3-methylbenzamide) is the most commonly used repellent for the prevention of mosquito and sandfly bites. Overall, it has a good safety

21  Prevention of Skin Infections

record, although rare cases of bullous dermatitis, ­anaphylaxis, and toxic encephalopathy have been reported.43–46 The American Academy of Pediatrics recommends slow-release products that plateau in efficacy at concentrations of 30%. Many extended duration products formulated for children have concentrations of 10% of less. DEET can be applied to exposed skin and to clothing. The addition of permethrin-treated clothing increases efficacy against a wide range of biting arthropods.47,48 For those who cannot use DEET, picaridin is a good alternative. A soybean-oil-based product (Bite Blocker for Kids) is suitable for those who wish to avoid chemical repellents. It is not as effective as DEET or picaridin. Citronella has limited efficacy.49 Neem oil performs better.50 Permethrin, applied to clothing, has good efficacy against ticks and chiggers.47,48 The effect lasts through a number of wash cycles.51 Permethrin can be applied to clothing, tents, sleeping bags, and mosquito netting. Although southwest Asian camel ticks are attracted by permethrin, this phenomenon has not been reported in North America.52 Exclusion of deer by means of fencing has been shown to be effective in reducing the number of disease-carrying ticks.53,54 Feeding stations can be outfitted to deliver topical acaricides to deer.55–57 Leaf debris should be removed, as ticks are susceptible to dehydration if they do not have access to a layer of leaf debris.58,59 Ticks are unlikely to transmit disease if they are removed promptly.60–62 When removing the tick, care should be taken not to squeeze it.63 The Tick Nipper is an inexpensive plastic device that makes tick removal quite easy. Fleas can be controlled with lufenuron, a maturation inhibitor that prevents fleas from becoming fertile. It is marketed in oral and injectable formulations for both cats and dogs. Fipronil can be applied to pets to prevent flea and tick infestation.64 Pet owners should consult a veterinarian for specific recommendations.

References   1. Cohen PR. Cutaneous community-acquired methicillinresistant Staphylococcus aureus infection in participants of athletic activities. South Med J. 2005;98(6):596–602   2. Arnold FW, Wojda B. An analysis of a community-acquired pathogen in a Kentucky community: methicillin-resistant Staphylococcus aureus. J Ky Med Assoc. 2005;103(5):206–210

245   3. Centers for Disease Control and Prevention (CDC). Methicillin-resistant Staphylococcus aureus infections among competitive sports participants – Colorado, Indiana, Pennsylvania, and Los Angeles County, 2000– 2003. MMWR Morb Mortal Wkly Rep. 2003;52(33): 793–795   4. Nguyen DM, Mascola L, Brancoft E. Recurring methicillinresistant Staphylococcus aureus infections in a football team. Emerg Infect Dis. 2005;11(4):526–532   5. Kazakova SV, Hageman JC, Matava M, et  al A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med. 2005;352(5):468-475   6. Carleton HA, Diep BA, Charlebois ED, et  al Communityadapted methicillin-resistant Staphylococcus aureus (MRSA): population dynamics of an expanding community reservoir of MRSA. J Infect Dis. 2004;190(10):1730-1738   7. Calfee DP, Durbin LJ, Germanson TP, et  al Spread of ­methicillin-resistant Staphylococcus aureus (MRSA) among household contacts of individuals with nosocomially acquired MRSA. Infect Control Hosp Epidemiol. 2003;24(6):422–426   8. Ellis MW, Hospenthal DR, Dooley DP, et al Natural history of community-acquired methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis. 2004;39(7):971–979   9. Wang J, Barth S, Richardson M, et al An outbreak of methicillin-resistant Staphylococcus aureus cutaneous infection in a saturation diving facility. Undersea Hyperb Med. 2003;30(4):277–284 10. Begier EM, Frenette K, Barrett NL, et al Connecticut bioterrorism field epidemiology response team. A high-morbidity outbreak of methicillin-resistant Staphylococcus aureus among players on a college football team, facilitated by cosmetic body shaving and turf burns. Clin Infect Dis. 2004;39(10):1446–1453 11. Block C, Robenshtok E, Simhon A, et al Evaluation of chlorhexidine and povidone iodine activity against methicillinresistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis using a surface test. J Hosp Infect. 2000;46(2):147–152 12. Zhang YH, Liu XY, Zhu LL, et al Study on the resistance of methicillin-resistant Staphylococcus aureus to iodophor and chlorhexidine. Zhonghua Liu Xing Bing Xue Za Zhi. 2004;25(3):248–250 13. Suzuki J, Komatsuzawa H, Kozai K, et al In vitro susceptibility of Staphylococcus aureus including MRSA to four disinfectants. ASDC J Dent Child. 1997;64(4):260–263 14. Kampf G, Jarosch R, Ruden H. Limited effectiveness of chlorhexidine based hand disinfectants against methicillinresistant Staphylococcus aureus (MRSA). J Hosp Infect. 1998;38(4):297–303 15. Brenwald NP, Fraise AP. Triclosan resistance in methicillinresistant Staphylococcus aureus (MRSA). J Hosp Infect. 2003;55(2):141–144 16. Bamber AI, Neal TJ. An assessment of triclosan susceptibility in methicillin-resistant and methicillin-sensitive Staphylococcus aureus. J Hosp Infect. 1999;41(2):107–109 17. Harbarth S, Dharan S, Liassine N, et  al Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1999;43(6):1412–1416

246 18. Mulvey MR, MacDougall L, Cholin B, et al Saskatchewan CA-MRSA Study Group. Community-associated methicillin-resistant Staphylococcus aureus, Canada. Emerg Infect Dis. 2005;11(6):844–850 19. Falck G. Group A streptococcal infections after indoor association football tournament. Lancet. 1996;347:840 20. Shephard RJ. Science and medicine of canoeing and kayaking. Sports Med. 1987;4:19 21. Penn C, et al Pseudomonas folliculitis: and outbreak associated with bromine-based disinfectants. Can Dis Wkly Rep. 1990;16:31 22. Zichichi L, Asta G, Noto G. Pseudomonas aeruginosa folliculitis after shower/bath exposure. Int J Dermatol. 2000; 39:270–273 23. Maniatis AN, et al Pseudomonas aeruginosa folliculitis due to non-O:11 serotypes: acquisition through the use of contaminated synthetic sponges. Clin Infect Dis. 1995;21:437 24. Rolston KV, et al Pseudomonas aeruginosa infection in cancer patients. Cancer Invest. 1992;10:43 25. Belogna EA, et al An outbreak of herpes gladiatorum at a high school wrestling camp. N Engl J Med. 1991;325:906 26. Strauss RH, et al Abrasive shirts may contribute to herpes gladiatorum among wrestlers. N Engl J Med. 1989;320:598 27. Adams B. Tinea corporis gladiatorum: a cross-sectional study. J Am Acad Dermatol. 2000;43:1039–1041 28. Bolanos B. Dermatophyte feet infection among students enrolled in swimming pool courses at a university pool. Bull Assoc Med Puerto Rico. 1991;83:181 29. Auger P, et al Epidemiology of tinea pedis in marathon runners: prevalence of occult athlete’s foot. Mycoses. 1993;36:35 30. Whitaker DC, Grande DJ, Johnson SS. Wound infection rate in dermatologic surgery. J Dermatol Surg Oncol. 1988;14: 525–528 31. Griego RD, Zitelli JA. Intra-incisional prophylactic antibiotics for dermatologic surgery. Arch Dermatol. 1998;134:688–692 32. Huether MJ, Griego RD, Brodland DG, Zitelli JA. Clindamycin for intraincisional antibiotic prophylaxis in dermatologic surgery. Arch Dermatol. 2002;138:1145–1148 33. Segers P, Speekenbrink RG, Ubbink DT, et al Prevention of nosocomial infection in cardiac surgery by decontamination of the nasopharynx and oropharynx with chlorhexidine gluconate: a randomized controlled trial. JAMA. 2006;296(20): 2460–2466 34. Smack DP, Harrington AC, Dunn C, et  al Infection and allergy incidence in ambulatory surgery patients using white petrolatum vs bacitracin ointment. A randomized controlled trial. JAMA. 1996;276:972–977 35. Guibal F, de La Salmoniere P, Rybojad M, et al High seroprevalence to Bartonella Quintana in homeless patients with cutaneous parasitic infestations in downtown Paris. J Am Acad Dermatol. 2001;44:219–223 36. Foucault C, Barrau K, Brouqui P, Raoult D. Bartonella quintana bacteremia among homeless People. Clin Infect Dis. 2002;35(6):684–689 37. Raoult D, Foucault C, Brouqui P. Infections in the homeless. Lancet Infect Dis. 2001;1(2):77–84 38. Coosemans M, Van Gompel A. The principal arthropod vectors of disease. What are the risks of travellers’ to be bitten? To be infected? Bull Soc Pathol Exotique. 1998;91:467–473 39. Carnevale P. Protection of travelers against biting arthropod vectors. Bull Soc Pathol Exotique. 1998;91:474–485

D. M. Elston 40. Rueda LM, Harrison BA, Brown JS, et  al Evaluation of 1-octen-3-ol, carbon dioxide, and light as attractants for mosquitoes associated with two distinct habitats in North Carolina. J Am Mosq Control Assoc. 2001;17(1):61–66 41. Kline DL. Comparison of two American biophysics mosquito traps: the professional and a new counterflow geometry trap. J Am Mosq Control Assoc. 1999;15(3):276–282 42. Kline DL, Mann MO. Evaluation of butanone, carbon dioxide, and 1-octen-3-OL as attractants for mosquitoes associated with north central Florida bay and cypress swamps. J Am Mosq Control Assoc. 1998;14(3):289–297 43. Brown M, Hebert AA. Insect repellents: an overview. J Am Acad Dermatol. 1997;36:243–249 44. Fradin MS. Mosquitoes and mosquito repellents: a clinician’s guide. Ann Intern Med. 1998;128:931–940 45. McKinlay JR, Ross V, Barrett TL. Vesiculobullous reaction to diethyltoluamide revisted. Cutis. 1998;62:44 46. Miller JD. Anaphylaxis associated with insect repellent. N Engl J Med. 1982;307:1341–1342 47. Young GD, Evans S. Safety and efficacy of DEET and permethrin in the prevention of arthropod attack. Mil Med. 1998;163:324–330 48. Gupta RK, Sweeny AW, Rutledge LC. Effectiveness of controlled-release personal use arthropod repellent and permethrin-treated clothing in the field. J Mosq Contr Assoc. 1987;3:556–560 49. Lindsay LR, Surgeoner GA, Heal JD, Gallivan GJ. Evaluation of the efficacy of 3% citronella candles and 5% citronella incense for protection against field populations of Aedes mosquitoes. J Am Mosq Contr Assoc. 1996;12:293–294 50. Caraballo AJ. Mosquito repellent action of Neemos. J Am Mosq Contr Assoc. 2000;16:45–46 51. Schreck CE, Mount GA, Carlson DA. Wear and wash persistence of permethrin used as a clothing treatment for personal protection against the lone star tick (Acari: Ixodidae). J Med Entomol. 1982;19:143–146 52. Fryauff DJ, Shoukry MA, Schreck CE. Stimulation of attachment in the camel tick, Hyalomma dromedarii (Acari: Ixodidae): the unintended result of sublethal exposure to permethrin-impregnated fabric. J Med Entomol. 1994;31:23–29 53. Stafford KC 3rd. Reduced abundance of Ixodes scapularis (Acari: Ixodidae) with exclusion of deer by electric fencing. J Med Entomol. 1993;30(6):986–996 54. Daniels TJ, Fish D, Schwartz I. Reduced abundance of Ixodes scapularis (Acari: Ixodidae) and Lyme disease risk by deer exclusion. J Med Entomol. 1993;30(6):1043–1049 55. Mount GA, Haile DG, Daniels E. Simulation of management strategies for the blacklegged tick (Acari: Ixodidae) and the Lyme disease spirochete, Borrelia burgdorferi. J Med Entomol. 1997;34(6):672–683 56. Pound JM, Miller JA, George JE. Efficacy of amitraz applied to white-tailed deer by the ‘4-poster’ topical treatment device in controlling free-living lone star ticks (Acari: Ixodidae). J Med Entomol. 2000;37(6):878–884 57. Solberg VB, Miller JA, Hadfield T, et al Control of Ixodes scapularis (Acari: Ixodidae) with topical self-application of permethrin by white-tailed deer inhabiting NASA, Beltsville, Maryland. J Vector Ecol. 2003;28(1):117–134 58. Strey OF, Teel PD, Longnecker MT, Needham GR. Survival and water-balance characteristics of unfed Amblyomma cajennense (Acari: Ixodidae). J Med Entomol. 1996;33:63–73

21  Prevention of Skin Infections 59. Slowik TJ, Lane RS. Nymphs of the western black-legged tick (Ixodes pacificus) collected from tree trunks in woodlandgrass habitat. J Vector Ecol. 2001;26(2):165–171 60. Katavolos P, Armstrong PM, Dawson JE, Telford SR ­3rd. Duration of tick attachment required for transmission of granulocytic ehrlichiosis. J Infect Dis. 1998; 177(5):1422–1425 61. Berger BW, Johnson RC, Kodner C, Coleman L. Cultivation of Borrelia burgdorferi from human tick bite sites: a guide to the risk of infection. J Am Acad Dermatol. 1995;32(2 Pt 1): 184–187

247 62. Piesman J, Mather TN, Sinsky RJ, Spielman A. Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol. 1987;25(3):557–558 63. Piesman J, Dolan MC. Protection against lyme disease spirochete transmission provided by prompt removal of nymphal Ixodes scapularis (Acari: Ixodidae). Med Entomol. 2002;39(3):509–512 64. Young DR, Arther RG, Davis WL. Evaluation of K9 Advantix vs. Frontline Plus topical treatments to repel brown dog ticks (Rhipicephalus sanguineus) on dogs. Parasitol Res. 2003;90(Suppl 3):S116–S118

Wound Prevention

22

Cynthia A. Fleck

As the US population ages, the number of persistent and recurring wounds will continue to rise. Knowledge of key prevention practices and guidelines will help save patients from possible pain and suffering, as well as keep treatment costs to a minimum. Chronic wounds are caused by a variety of issues. Among the many factors, the aging process by itself takes its toll, predisposing the skin to wounds and other problems such as xerosis and skin tears. The clinical implications of aging are numerous and contribute greatly to the incidence and prevalence of wounds. For example, dry, inelastic skin with larger, more irregular epidermal cells leads to decreased barrier function.1 Flattening of the dermal–epidermal junction (rete ridges) has been observed with the height of the dermal papillae declining by 55% from the third to ninth decade of life.2 As the spaces between the well-vascularized dermis and epidermis increases, several functional changes occur: • A 30–50% decrease in epidermal turnover rate during the 30s–80s.1 • Loss of sub-Q fat reduces protection from injury from pressure, shear, and friction. • Decreased sensory perception increases risk of mechanical forces such as pressure. A cross-sectional diagram of the changes that occur during the aging process are illustrated in Fig. 22.1. Wound prevention in the geriatric patient therefore, requires a multifaceted approach, considering the etiology of each wound type. Within this chapter, the

C. A. Fleck The American Academy of Wound Management (AAWM), Past President, The Association for the Advancement of Wound Care (AAWC), Past Director, Medline Industries, Inc., Vice President, Clinical Marketing, St. Louis, MO, USA e-mail: [email protected]

most prevalent wound categories will be described with practical measures for preventing these troublesome wounds, as well as other prevention topics related to wounds, such as skin care, support surfaces, and nutrition.

22.1 Venous Insufficiency Ulcers Venous ulcers, also known as venous hypertension ulcers or venous insufficiency ulcers are caused by problems with venous blood return to the heart potentially produced by nonfunctioning or inadequate calf muscle pump, incompetent perforator valves, ineffectual valves in the vein, arteriovenous (AV) fistulas, venous obstruction, and varicose veins,3 all leading to venous hypertension as venous blood pools in lower extremities and feet. Chronic venous disease is most likely the underlying cause in 80–95% of lower leg ulcers.4,5 The skin is often firm, indurated and hyperpigmented, or “stained” a brown or deep color (Fig. 22.2).6

22.1.1 Lower Limb, Calf Pump, Maintenance Compression, ABI/TBI, ETC Some prevention tactics that should be embraced by individuals with venous insufficiency include: • • • • •

Do not smoke. Consume adequate nutrition. Keep skin clean and well lubricated. Elevate the legs above the heart. Avoid sitting with the legs crossed.

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_22, © Springer-Verlag London Limited 2010

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Fig. 22.1  (a) Cross-section of youthful skin; (b) cross-section of elderly skin. (Courtesy Medline Industries, Inc. Used with permission)

Fig. 22.2  Venous insufficiency ulcer

• • • • • • • • •

Avoid standing for prolonged periods of time. Ambulate as tolerated several times a day. Take medications as prescribed. Use compression therapy as prescribed applying every morning before rising. Take care of your skin. Follow-up with the healthcare provider. Elevate the foot off the bed while sleeping. Exercise the feet and ankles when the legs are elevated. Avoid the use of constrictive clothing.

Patients should undergo a lower-extremity examination, including determination of circulatory status via appropriate diagnostics (duplex imaging, Doppler, Doppler ultrasonography, air plethysmography, venography),

pedal pulses, skin temperature, venous refill, color changes, skin changes (edema, hemosiderosis, venous dermatitis, atrophie blanche, varicose veins, ankle flare, scars from previous ulcers, tinea, or lipodermatosclerosis) and presence of paresthesias. A simple, noninvasive indirect method to assess arterial flow by comparing systolic blood pressure in the ankle to brachial pressure is called an ankle brachial index (ABI).7 It is also known as the ankle brachial pressure index (ABPI), ankle/arm index (AAI), and the resting pressure index (RPT). This measurement provides the best noninvasive approximation of central systolic pressure.8 The ABI is a screening test to identify large-vessel peripheral arterial disease by comparing systolic blood pressures in the ankle to the higher of the brachial systolic pressures. Its purpose is to detect large-vessel peripheral arterial disease in lower extremities,9 determine adequate arterial blood flow in the lower extremities, and provide documentation of adequate arterial blood flow in lower extremities before applying compression therapy.10 If the ABI is higher than 1.3, indicating severe peripheral vascular disease (PVD), a toe brachial index (TBI) is recommended.11 This is often true in diabetics or patients with renal failure where the ABI may not be properly diagnosed due to calcified vessels not allowing compression. In that case, ABI values will be false because the blood pressure will be overestimated. Both examinations compare favorably with angiographic studies in lower extremity arterial disease (LEAD) diagnosis.12 Patients with untreated varicosities and/or a history of deep vein thrombosis are at higher risk for development

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Fig. 22.4  Diabetic ulcer

Fig.  22.3  Compression hosiery for lower extremity venous insufficiency and venous wound prevention

of venous insufficiency wounds. Maintenance compression with stockings (that are replaced every 3 months to provide optimal compression) (Fig. 22.3) or other compression devices are the mainstay for prevention of venous edema and venous related wounds, which tend to recur frequently. With regard to recurrence, the evidence is insufficient to support the use of medications such as anabolic steroids13 or the performance of vein surgery13 to prevent these ulcers. In addition, active treatment of any varicosities should include attention to one’s weight and a regular exercise program, as well as an articulated education plan that includes avoidance of leg crossing, wearing of constricting garments, etc. Diabetic/neuropathic wounds are caused by pressure and/or trauma, secondary to peripheral neuropathy and/or arterial insufficiency and poor microvascular circulation, inadequate blood sugar control and/or lack of sensation (Fig. 22.4). Foot ulcerations are extremely common in the neuropathic patient. These ulcers often lead to complications that can result in amputation. Therefore, it is imperative that these wounds be prevented. The following

measures can decrease the potential for developing a diabetic/neuropathic wound. These actions should be taught to the patient and family members to decrease the incidence of developing these wounds: • Perform daily foot care (inspect the feet, wash and dry well between toes, wear clean socks that wick moisture away from the skin and preferably have no seams or mended areas to irritate or cause pressure). • Prevent xerosis of the feet by applying a good-quality moisturizing cream after drying the feet. Do not apply it between the toes however, as this could increase the likelihood of fugal manifestation. • Avoid soaking the feet. • Avoid wearing shoes without stockings or socks, and do not wear sandals with thongs between the toes. • Visit a healthcare professional for foot care for toenails, corns, and calluses. • Avoid over-the-counter medications for corns and calluses, antiseptic solutions, and adhesive tape. • Avoid crossing the legs. • Reduce pressure on bony prominences, especially on the foot. • Avoid temperature extremes (cold and hot). • Avoid external heat sources, including heating pads, hot water bottles, hydrotherapy, and other hot surfaces.

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• Follow-up with a healthcare provider on a routine basis. Notify the provider immediately if a sore, blister, cut, or scratch develops. • Avoid smoking. • Keep diabetes under control. • Consider referral to an appropriate dietician or nutritionist. • Be aware of poor eyesight and its affect on the overall self care of the patient. Footwear specifics for lower extremity neuropathic disease as recommended by the Wound, Ostomy and Continence Nurses Society14 include: • Avoid friction from ill-fitting shoes. • Wear well-fitting, therapeutic, customized shoes that effectively off-load problematic feet and deformities. • See a foot wear specialist such as an orthotist or pedorthist who can choose or manufacture appropriate foot wear. • Follow shoe design recommendations: • Allow for 0.5 in. of space beyond the longest toe. • Allow adequate width/depth for toe spread. • Ensure adequate ball width. • Check for adequate heel-to-ball fit. • Shoes should match the shape of the foot. • Follow shoe fitting recommendations: • Shoes should be fitted in the afternoon when edema tends to peak. • Patients should stand and walk when being fitted for shoes. • Socks or stockings that would normally be worn with the shoes should be worn when fitting new shoes. • Both feet should be measured and shoes fitted to the larger foot. • Wearing of new shoes should be increased gradually 1–2 h at a time with a routine foot inspection to check for areas of pressure following each wearing session. • Appropriate commercially available shoes include: –– Made of natural materials such as leather. –– Have cushioned outer soles and removable inner liners. –– Have a deep toe box. –– Secure with laces or hook-and-loop fasteners. • Wear orthotic footwear to correct an altered gait or orthopedic deformities. • Inspect the inside of shoes every day for foreign objects, nail points, torn linings, and rough areas.

C. A. Fleck

Patients who used therapeutic footwear showed lower foot pressures as compared to those who did not. New ulcer occurrence is significantly higher in those patients who did not wear therapeutic gear.15 Research also suggests that only 22% of individuals who own diabetic shoes wear them all day as prescribed, although most wear them periodically.16,17 A multidisciplinary prevention approach is recommended for persons with diabetes, insensate feet, and peripheral neuropathy.18 Individuals at risk for foot ulceration (considering loss of protective sensation, history of previous ulceration or amputation, elevated plantar pressure, rigid foot deformity, poor diabetes control [HgA1c > 7%], diabetes of greater than 10 years duration) need to be identified early.18 High-risk individuals should be referred to foot care specialists for on-going preventative care and lifelong surveillance.18 A neuropathic foot screening to identify current foot problems and initiate a prescription for appropriate prevention measures and treatment, based on risk category, should be performed at regular intervals.19 It is recommended that a lower extremity amputation prevention program be undertaken, including annual foot screening for at-risk individuals, on-going patient education, assistance with appropriate footwear selection, patient teaching of daily foot assessment, and management of simple foot problems.20

22.2 Arterial and Ischemic Ulcers LEAD is a progressive and persistent disorder affecting about 33% of US seniors (see Fig. 22.5).21 LEAD is triggered by cholesterol deposits (atherosclerosis), PVD, and blood clotting disorders (emboli). Insufficient arterial blood supply to the lower limb leads to full or partial obstruction of the artery resulting in tissue ischemia and ultimately, necrosis.21 Advanced age, hyperlipidemia, tobacco use, diabetes mellitus, hypertension, obesity, inactivity, and a family history of cardiovascular disease predispose one to LEAD.22 LEAD negatively influences individuals, families, and ultimately, society. Ten to twenty-five percent of individuals with LEAD progress to critical limb ischemia within 5 years and 3–8% experience limb loss.22 The overall price to treat lower limb ulcers is approximately $1 billion annually in the US alone, not including the countless lost work days. In addition, the annual cost

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253

Fig. 22.5  Arterial ulcer

Fig. 22.6  Perineal dermatitis

of LEAD-induced amputations in the United States is about $5 billion.21 Early diagnosis is often a challenge due to fewer than 50% of individuals with LEAD exhibiting typical clinical signs and symptoms connected with LEAD. Therefore, clinicians frequently use unpredictable assessment techniques for diagnosing disease.21 These wounds may be present in patients with diabetes and as mentioned earlier, PVD. It has been estimated that PVD affects 30% of older individuals, ages 55–74.23 Risk factors include high blood pressure, coronary artery disease, age, diabetes, obesity, hyperlipidemia, and smoking. The patient will often complain of pain upon leg elevation and/or nocturnally, and frequently prefer to dangle their legs for optimal blood flow.24 Patients should be educated on life-style changes to minimize situations that cause vasoconstriction including: avoidance of smoking, exposure to cold, and wearing constricting clothing, as well as how to alleviate ischemic pain by ambulation or dangling their legs. If able, the patient with a high-risk of arterial ulcers and/or compromised arterial blood flow should be encouraged to ambulate and take part in a regular exercise program.

prolonged use of a diaper or underpad trapping urine and/or feces close to the skin. It is caused by an interaction between several factors:

22.3 Perineal Dermatitis and Denudation Perineal or “diaper” dermatitis (Fig. 22.6) is a cutaneous eruption in the diaper area caused by frequent and

• Frequent and prolonged skin wetness from occlusion and urine caught close to the skin. • Friction by movement of the skin against skin, the diaper, the plastic leg gatherings, or the fastening tape. • The presence of fecal enzymes that may cause cutaneous irritation coupled with bacterial or yeast growth in a dark, moist environment on inflamed, damaged skin. Perineal dermatitis is common in infants and those adults who wear basic incontinence products that do not adequately wick away moisture.25 If this type of dermatitis is present for longer than 3 days, there is likely to be secondary Candida albicans infection.26 Generally, perineal dermatitis presents clinically as bright red, painful erythema with or without papules, erosions, scale and/or maceration, initially sparing the skin creases, on the lower abdomen, groin, perineum, buttocks, labia majora, scrotum, penis, or upper thigh. Maintaining perineal skin integrity is one of the biggest challenges in long-term and extended-care settings, where 50–70% of patients suffer from urinary incontinence.27 Perineal skin injury has been found in as many as one-third of hospitalized adults.28 Though rarely used in clinical practice, the literature describes two different assessment tools: the Perineal Dermatitis Grading Scale and the perirectal skin assessment tool (PSAT). The PSAT measures the degree of skin breakdown while the Perineal Dermatitis

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Grading Scale is more like a wound and skin assessment, specifically targeting location of dermatitis, skin color and integrity, amount of skin involvement, and symptoms, such as pain. The scale also includes an area for a brief description of the skin assessment or the patient’s symptoms.29 A validated tool developed by Nix can be used to assess risk for perineal skin damage30 The perineal assessment tool (PAT) is an instrument that identifies four determinants of perineal skin breakdown: duration of irritant, intensity and type of irritant, perineal skin condition, and contributing factors causing diarrhea. Each subscale reflects degrees of risk factors. All subscales are rated from one (least risk) to three (most risk). Each rating has a descriptor and a description of each level of the scale. Total scores can range from 4 (least risk) to 12 (most risk). A score between four and six on the PAT scale is considered a low risk, and a score between 7 and 12 is considered a high risk (Fig. 22.7).30 This tool may be added to the assessment, along with the Braden Risk Assessment Score (Fig. 22.8). The Wound, Ostomy and Continence Nurses Society guidelines for prevention and management of pressure ulcers offers these interventions for preventing perineal dermatitis: • Establish a bowel and bladder program for patients with incontinence. • Avoid excess friction on the skin.

• Cleanse skin gently at each time of soiling with pHbalanced cleansers. • Use incontinent skin barriers as needed to protect and maintain intact skin. • Select underpads, diapers, or briefs that are absorbent to wick incontinence moisture away from the skin. • Consider using pouching system or collection device.31 The use of absorptive and/or occlusive devices has been identified as a large contributor to the problem of incontinence-associated dermatitis, leading to wounds. Prolonged occlusion of the skin under an absorptive incontinent product for 5 days has been shown to cause an increased sweat production and compromised barrier function, resulting in increased transepidermal water loss (TEWL), CO2 emission, and pH; microflora of the skin undergoes a marked increase in coagulasenegative staphylococcus.32 Novel disposable underpads that allow air flow and offer advanced polymer technology provide super absorbing capacity (absorbing power of three or more pads) while locking fluid deep within the pad, keeping the patient’s skin dry for better odor control and skin care (Fig.  22.9). In addition, the underpads provide a healthier skin environment, allowing air flow while acting as a barrier to moisture. They also lower overall costs (reducing the need

PerinealAssessment Tool P.A.T. Intensity of irritant Type and consistency of irritant Duration of irritant Amount of time that skin is exposed to irritant Perinealskin condition Skin integrity Contributing factors Low albumin, antibiotics, tube feeding, or C. Difficile infection, other

2 Soft stool with or without urine

1 Formed stool and/or urine

2 Linen/pad changes at least every 4 hours

1 Linen/pad changes every 8 hours or less

3 Denuded/eroded with or without dermatitis

2 Erythema/dermatitis with or without candidiasis

1 Clear and intact

3 3 or more contributing factors

2 2 contributing factors

1 0-1 contributing factor

3 Liquid stool with or without urine 3 Linen/pad changes at least every 2 hours

•Score of 4-6 on the PAT scale is considered “low”risk •Score of 7-12 is considered “high”risk.

Fig. 22.7  Perineal assessment tool (PAT)30

22  Wound Prevention

255 BRADEN SCALE FOR PREDICTING PRESSURE SORE RISK

Patient’s Name _____________________________________ SENSORY PERCEPTION ability to respond meaningfully to pressure-related discomfort

MOISTURE degree to which skin is exposed to moisture

ACTIVITY

ability to change and control body position NUTRITION usual food intake pattern

FRICTION & SHEAR

Date of Assessment

2. Very Limited Responds only to painful stimuli. Cannot communicate discomfort except by moaning or restlessness OR has a sensory impairment which limits the ability to feel pain or discomfort over ½ of body.

3. Slightly Limited Responds to verbal commands, but cannot always communicate discomfort or the need to be turned. OR has some sensory impairment which limits ability to feel pain or discomfort in 1 or 2 extremities.

4. No Impairment Responds to verbal commands. Has no sensory deficit which would limit ability to feel or voice pain or discomfort..

1. Constantly Moist Skin is kept moist almost constantly by perspiration, urine, etc. Dampness is detected every time patient is moved or turned.

2. Very Moist Skin is often, but not always moist. Linen must be changed at least once a shift.

3. Occasionally Moist: Skin is occasionally moist, requiring an extra linen change approximately once a day.

4. Rarely Moist Skin is usually dry, linen only requires changing at routine intervals.

1. Bedfast Confined to bed.

2. Chairfast Ability to walk severely limited or non-existent. Cannot bear own weight and/or must be assisted into chair or wheelchair.

3. Walks Occasionally Walks occasionally during day, but for very short distances, with or without assistance. Spends majority of each shift in bed or chair

4. Walks Frequently Walks outside room at least twice a day and inside room at least once every two hours during waking hours

1. Completely Immobile Does not make even slight changes in body or extremity position without assistance

2. Very Limited Makes occasional slight changes in body or extremity position but unable to make frequent or significant changes independently.

3. Slightly Limited Makes frequent though slight changes in body or extremity position independently.

4. No Limitation Makes major and frequent changes in position without assistance.

1. Very Poor Never eats a complete meal. Rarely eats more than ¹/³ of any food offered. Eats 2 servings or less of protein (meat or dairy products) per day. Takes fluids poorly. Does not take a liquid dietary supplement OR is NPO and/or maintained on clear liquids or IV’s for more than 5 days.

2. Probably Inadequate Rarely eats a complete meal and generally eats only about ½ of any food offered. Protein intake includes only 3 servings of meat or dairy products per day. Occasionally will take a dietary supplement. OR receives less than optimum amount of liquid diet or tube feeding

3. Adequate Eats over half of most meals. Eats a total of 4 servings of protein (meat, dairy products per day. Occasionally will refuse a meal, but will usually take a supplement when offered OR is on a tube feeding or TPN regimen which probably meets most of nutritional needs

4. Excellent Eats most of every meal. Never refuses a meal. Usually eats a total of 4 or more servings of meat and dairy products. Occasionally eats between meals. Does not require supplementation.

1. Problem Requires moderate to maximum assistance in moving. Complete lifting without sliding against sheets is impossible. Frequently slides down in bed or chair, requiring frequent repositioning with maximum assistance. Spasticity, contractures or agitation leads to almost constant friction

2. Potential Problem Moves feebly or requires minimum assistance. During a move skin probably slides to some extent against sheets, chair, restraints or other devices. Maintains relatively good position in chair or bed most of the time but occasionally slides down.

3. No Apparent Problem Moves in bed and in chair independently and has sufficient muscle strength to lift up completely during move. Maintains good position in bed or chair.

degree of physical activity

MOBILITY

Evaluator’s Name________________________________

1. Completely Limited Unresponsive (does not moan, flinch, or grasp) to painful stimuli, due to diminished level of con-sciousness or sedation. OR limited ability to feel pain over most of body

Total Score

© Copyright Barbara Braden and Nancy Bergstrom, 1988 All rights reserved

Fig. 22.8  Braden risk assessment score (Copyright Barbara Braden. Used with permission)

soft, non-woven topsheet Soft against skin for increased comfort Advanced SuperCare absorbent sheet Thermo-bonded to provide pad integrity and exceptional skin dryness

Fig. 22.9  Super-absorbent polymer underpad (Courtesy Medline Industries, Inc. Used with permission)

multiple pads, reusable pads and draw sheets) and make for easier care, as they may be used on regular or low-air-loss beds.

AquaShield Film Traps moisture,providing leakage protection Innovative Backsheet Air permeability means skin comfort

Denudation is a form of partial thickness injury related to friction and shearing forces and chemical and enzyme irritation from incontinence.33

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22.4 Maintaining Skin’s Integrity Skin care is a four-pronged approach with cleansing, moisturizing, protecting, and now nourishing being the key steps. The largest organ of the body, the integument, receives one third of the human body’s cardiac output, feeding and nourishing it from the inside.34 Nutrition and antioxidant protection can also take place endermically with the advent of advanced skin care products. See Table 22.1 for the hierarchy or generations of available skin care products.

C. A. Fleck

Soap and surfactant detergent-type cleansers can be damaging and abusive to patients’ skin. Soap strips the skin of cell-binding lipids and ceramides and makes it much more vulnerable to assaults of daily living, such as skin tears. Sodium lauryl sulfate, ammonium laureth sulfate, and sodium laureth sulfate are associated with irritation and stripping skin lipids, especially when left on the skin in the “no-rinse” products. Repeated surfactant use leads to increased skin dehydration and potential damage. Another caveat to consider is to customize bathing according to patient needs. Daily baths with a bath basin and bar of high alkaline soap can be extremely detrimental to the integument.

22.4.1 Cleansing Cleanser technology has come a long way from merely cleansing for the removal of sebum, soil, dirt, and bacteria to providing mildness, moisture, and now nourishment to the skin in addition to cleaning it. Harsh soaps and surfactants in cleansers can cause damage to skin proteins and lipids, inflammation and swelling of the stratum corneum, and alter lipid rigidity. This leads to tightness, dryness, barrier damage, irritation, pH disruption, increased water loss or dehydration of the skin, and itching.35 Shocking as it may seem, soaps touted as “natural” and “safe” often have the highest and, therefore, most damaging pH. For instance, Ivory soap has a pH of 10.5 and Dial measures in at 10.0. This simple pH study looked at products commonly used in nursing homes.36 In order for cleansers to provide skin care benefits, they must first minimize the damage of surfactants to skin proteins and lipids. This can be accomplished by using the least harmful surfactants or, better yet, phospholipids to clean. Phospholipids are ingredients derived from selected vegetable oils that can bind both water and fat, providing excellent cleansing and conditioning properties and incredible after-feel due to their mildness. They contain naturally occurring polyunsaturated fatty acids (PUFAs), which can contribute to the activation of cellular metabolism. They are superior cleansers that do not strip, dehydrate, or inflame the epidermis. Cleansers must secondly deposit and deliver beneficial agents, such as occlusive skin lipids, humectants, amino acids, and vitamins, under wash conditions to improve skin hydration as well as mechanical and visual properties.

22.4.2 Hydration The epidermis contains lipids that play a vital role in maintaining healthy skin and regulating moisture loss. With age, the use of detergents and damage, such as burns or wounds, cause the skin to lose some or all of its ability to retain moisture. Skin becomes dry and with this dryness comes skin breakdown. Skin needs to be protected from the environment to reduce the effects of aging. To do so, the use of skin moisturizers and protectants is beneficial. Moisturizers are complex formulations designed to maintain skin flexibility, smoothness, and barrier integrity while maintaining the water content of the skin between 10 and 30%. For skin to appear and function normally, the water content of the stratum corneum must be at least 10%. Cells are composed of 70% water. Since the skin is made up of cells, maintaining a high level of moisture in the skin is necessary. Skin that is water deficient, such as thickened skin over the heels, is often rough to the touch and fissures easily. There are two means by which to moisturize the skin. One way is to add back moisture to the skin. The other way is to block or inhibit TEWL. Moisture is mandatory for an organ that is in constant motion. Skin hydration is important to maintain an intact barrier protection. The application of topical moisturizing and protectant products, coupled with the use of surfactant-free cleansers, helps reduce dryness and stop TEWL. In order for moisturizers to work, they must be coupled with moisture in the form of water. It either comes from the dermis (internally) or

22  Wound Prevention Table 22.1  Hierarchy of skin care products Product First-generation products category

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Second-generation products

Third-generation products

Surfactants – synthetic detergents Soaps – oldest amphiphilic such as sodium lauryl sulfate, cleaning agent, highly tea lauryl sulfate, cocoamalkaline. Examples include phocarboxyglaycinate, sodium cocoyl, sodium disodium oleamido mea tallowate, sodium sterate, sulfosuccinate, sodium laureth sodium dodycelbenzensulsulfate, ammonium laureth foate, sodium cocoate, sulfate, etc. sodium palmitate, etc.

Phospholipids – mimic the body’s natural lipid requirements, ingredients derived from selected vegetable oils that can bind both water and fat providing excellent cleansing and conditioning without stripping or drying. Examples include: cocamidoproryl PG-dimonium phosphate, linoleamidopropyl PG > dimonium chloride phosahpte dimethicone, disodium lauromphodiacetate

Lotions, creams and ointments Lotions, creams and ointments Moisturizers containing first-generation containing lanolin, emollients ingredients plus ingredients glycerin, mineral oil, humectants such as carbohydrates like aloe propylene glycol, vera, vitamins like retinyl petrolatum, cocoa butter, palmitate (vitamin A), paraffin, etc ergocalcifrol (vitamin D), glycosaminoglycans such as hyaluronic acid, polyhydroxy hydroxy acids, urea, etc.

Lotions, creams and ointments containing first- and secondgeneraton ingredients plus nutritive ingredients such as amino acids, vitamins and cofactors, high-quality oils and lipids such as shea butter or grape seed oil, antioxidants such as hydroytyrosol, advanced silicones and methylsulfonylmethane

Cleansers

Protectants and barriers

Creams and ointments containing petrolatum, octyl hydroxysterate, etc

Creams and ointments containing dimethicone, allantoin, zinc oxide, calamine, karaya gum, etc.

Creams and ointments containing first- and second-generation ingredients plus nutritive ingredients such as amino acids, vitamins and cofactors, high-quality oils and lipids such as shea butter or grape seed oil, antioxidants such as hydroytyrosol, advanced silicones and methylsulfonylmethane

Copyright Cynthia A. Fleck®

externally applied water, such as immediately following a bath or shower. The National Eczema Association for Science and Education recommends sealing in skin’s moisture with a high-quality moisturizer within 3 min of showering or bathing.

22.4.2.1 Xerosis Xerosis is dry skin that appears when there is dehydration of the stratum corneum and is one of the most common skin conditions to affect the elderly (Fig. 22.10).37 It is most common in the aged who have decreased epidermal free-fatty acids, compared to younger skin. Xerotic skin additionally has a reduced amino acid content.38 The patient will usually complain

of dryness and itching. The condition is more prevalent in the lower legs and feet but can occur anywhere on the body. It also tends to exacerbate in winter months, and in cold and dry climates or low humidity conditions. Moisturizers are primarily intended to help the skin to function properly in conditions where temperature and humidity are low and mimic the role of naturally occurring epidermal lipids. They are sold as creams, lotions, and in some cases serums. Lotions are the lightest and provide less protection. The most important moisturizer, and really the only true moisturizer, is water. To maintain the water content of the skin, we can use occlusive ingredients to keep the moisture from evaporating, such as petrolatum or mineral oil, or apply water to the skin and bind

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Fig.  22.10  Xerosis or dry skin with typical flaky or scaly, almost transparent appearance

it with humectants (e.g., glycerin, hyaluronic acid, chitosan, beta glucan 1–3), emollients (e.g., shea butter, avocado butter, cocoa butter), or nonocclusive ingredients, such as natural oils and silicones. One caveat is that mineral oil and petrolatum are hydrocarbons and do not contribute to lipid replacement. Better choices include high-quality oils like borage oil, olive oil, and rose hip seed oil.

22.4.3 Skin Protectants When the skin needs extra protection from incontinence, periwound maceration, wound, stoma, fistula, or access site drainage or leaking, partial-thickness wounds, and denudation, barriers provide the answers. Since incontinence affects 13 million Americans or about 10–35% of adults and at least half of the 1.5 million nursing home residents,39 incontinent dermatitis is a common skin dilemma that often results when urine comes in contact with dry, cracked skin. It provides an excellent environment for the growth of bacteria, resulting in the production of ammonia. Ammonia increases the pH of the skin, reducing the acid mantle’s protective capacity as a bacterial barrier subsequently presenting the opportunity for chemical irritation by urine, feces, and excess moisture leading to skin breakdown.27 Protectants or barriers provide a physical barrier between the skin and caustic bodily fluids. Ointments and creams that contain petrolatum are inexpensive and readily accessible but need to be applied frequently

C. A. Fleck

as they melt off and wash away quickly. They can also inhibit the absorbency of briefs, under pads, and dressings. An example is A and D Ointment. Products containing zinc oxide stay on the skin longer, providing better protection. They are thicker and allow the caregiver to simply “fill in the blanks” when reapplying after cleansing. Dimethicone and other silicones provide sophisticated additions in many skin protectants. These ingredients provide long-lasting protection, remaining on the skin through multiple washings or cleansings. The percentage of dimethicone cannot be judged by itself since combinations of various silicones can offer better protection than just a high percentage of dimethicone alone.

22.4.4 Skin Nutrition Maintaining healthy skin is vital to a person’s overall health. As we age, the skin, like other organs in the body, begins to function less effectively, and therefore, special care is required. The use of advanced cleansers that are gentle and do not strip the skin and moisturizers and protectants to defend the skin from dryness and TEWL is essential. The replacement of soaps with cleansing lotions and surfactant-free products that protect skin lipids and aid in skin integrity is also vital. There is a new generation of skin care products that do more than clean, protect, and moisturize. These advanced skin care products can actually nourish the skin by providing vital amino acids, vitamins, lipids, and antioxidants that were developed to protect skin from breakdown and to minimize the risk of dryness, decreased skin integrity, and invasion of pathogens. The products also bring nutrients to the skin that help restore its protective acid mantle, help reestablish collagen, and help defend against free radical damage while protecting from stinging and pain. In addition, they have been shown to decrease the prevalence of pressure ulcers and skin tears.40 One retrospective, longitudinal study studied the changes in pressure ulcer prevalence rates and the economic effect of introducing a silicone-based dermal nourishing emollient regimen into an existing pressure ulcer protocol.41 The results showed a decrease from 17% incidence rate down to 0% and an average cost

22  Wound Prevention

savings of $6,677 per patient. Think of these thirdgeneration advanced skin care products as a form of “corneotherapy,” feeding and nourishing the stratum corneum. Key ingredients and nutrients can be applied and absorbed via the skin to deliver nourishment and provide healing and health to this vulnerable organ. This is termed endermic nutrition. Enhancing the skin with the topical application of amino acids, antioxidants, and lipids may be the only external way to improve the health of this vital organ. Nutrients enter the epidermis from the dermis or the stratum corneum. Advanced skin care products truly address the needs of the cells, providing the proper nutrients in the correct forms for the skin to assimilate them, helping protect the cells against free radical damage while supplying amino acids that are the main building blocks of collagen.

22.5 Pressure Ulcers Pressure ulcers are one of the largest dilemmas facing long-term care providers and clinicians who care for geriatric patients. Two thirds of pressure sores occur in patients older than 70 years of age.42 Pressure ulcer prevalence is estimated to be around 15% in acute care, up to 28% in long-term care and up to 29% in home care.43 Pressure ulcers account for $2.2–3.6 billion/year in expenditures,44 can cost up to $70,000 to treat,45 and kill 60,000 people in the US every year.46 Patients inclined to pressure ulcers are at higher risk of morbidity and mortality, with infection, osteomyelitis, and sepsis being the most common major complications. Pressure ulcers are any lesions caused by unrelieved pressure resulting in damage of underlying tissue.47 Pressure ulcers have affected us throughout the ages. Yet, dealing with the general management of pressure ulcers has only just begun to gain notoriety among national and worldwide healthcare concerns. In spite of present attention and development in the areas of medicine, surgery, nursing care, physical therapy, and self-care education, pressure ulcers continue to be a major source of morbidity and mortality. This is especially true for our elders and for those with impaired sensation and prolonged immobility.48

259

Fig. 22.11  Pressure ulcer

It is theorized that pressure ulcers are caused by localized pressure or shear forces that lead to ischemia and cell death, thus causing skin and tissue breakdown (Fig. 22.11). Pressure is equal to force, divided by area. So the greater the surface area of the load, the less pressure exerted. For instance, a sitting individual is at higher risk of developing a pressure ulcer than a person who is lying supine. Kosiak proved that tissue compression and ischemia can lead to tissue destruction and pressure ulcer formation. He also showed that the amount of pressure and the duration of the pressure are inversely proportional.49 For instance, low amounts of pressure over longer periods of time can be just as detrimental as high pressure for shorter times (Fig. 22.12).50

22.5.1 Causes Although prolonged, uninterrupted pressure is the main cause of pressure ulcers, impaired mobility is probably the most common reason patients are exposed to unrelieved pressure. This is common in those who are neurologically impaired, heavily sedated or anesthetized, restrained, demented, or those suffering traumatic injury such as a pelvic or femur fracture. These patients are incapable of assuming the responsibility of altering their position to relieve pressure. Moreover, this immobility, if prolonged, leads to muscle and soft tissue atrophy, decreasing the bulk over which bony prominences are supported, further increasing the risk of developing a pressure ulcer.

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C. A. Fleck

Pressure, mm Hg

700 600 500 400 300

Unacceptable

200 100

Acceptable

0 2

4

6

8

10

12

14

16

18

Hours of continuous pressure

Fig. 22.12  Guidelines for sitting duration. Maximum suggested pressure/time application over bony prominences50

22.5.2 Heel Pressure Ulcers The heel presents a problematic source of pressure due to its bony prominence, especially in the recumbent individual. Care should be taken to mobilize the immobile, providing good skin care and off-loading with pressure relief equipment, to the vulnerable heel area. The heel is one of the most difficult anatomical areas to address by prevention products.51 Studies have demonstrated that support surface, including special beds, mattresses, and overlays, do not provide complete pressure relief in the heel region.52 Be aware of antiembolism stockings, TED hose, and compression devices as they can camouflage the heels and preclude thorough assessment. Floating the heels is recommended by many experts as well as prevention guidelines as the only viable method to completely alleviate heel pressure and prevent ulcers.53

22.5.3 Prevention Basics Healthy individuals with normal sensation, mobility, and mental faculty usually do not succumb to pressure ulcers. Feedback, both conscious and unconscious, from the areas of compression leads us to change our position. We constantly make micro-movements to compensate. This shifts the pressure from one area to another prior to any irreversible ischemic damage to the tissues. Weight shifting for insensate individuals or those with poor mobility should take place every 15 min in the seated person and at least every 2 h in the recumbent individual.54–56

Pressure ulcer prevention encompasses alleviating the possible causative factors. If we consider that lack of viable blood flow to the tissue is the main cause of pressure ulcers, we can further classify that damage into pressure, shear, friction, moisture and heat and thus, better support the host. We can also prevent pressure ulcers by managing the following negative effects. These prevention recommendations are adapted from the 1992 agency for healthcare policy and research (AHCPR), now the Agency for Healthcare Policy and Research (AHRQ) clinical practice guidelines53 and the Wound Ostomy and Continence Nurse Association’s 2003 Guidelines for Prevention and Management of Pressure Ulcers.57

22.5.3.1 Pressure • Pressure can be lessened by establishing a patient turning schedule that can be documented. The standard of care for turning and repositioning is every 2 h in the recumbent individual and every 15 min in the seated person. • Use the 30° lateral position in a supine patient instead of placing a patient side lying at 90°. This dramatically decreases the peak pressure caused by the greater trochanter. • Implement an appropriate pressure-redistribution support surface to both the seated and recumbent surfaces that the patient’s body contacts at the first sign of risk. • For cushioning a seated client, avoid the use of invalid rings, “donuts”, rubber rings or any technology that has a “cut-out” since this can actually increase pressure, especially over bony prominences. • Limit the time that the patient spends on the commode or bedpan. • Off-load the heels with a pillow, heel protection device or wedge.

22.5.3.2 Shear • Limit the elevation of the head of the bed to 30° or less. • Use draw sheets to turn and reposition patients. • Use the bed’s side rails and consider adding a trapeze to the bed frame to optimize mobility and decrease shear forces.

22  Wound Prevention

• Never perform massage over bony prominences that have been compressed. This can cause tissue damage, although there is conflicting information in the literature.58 22.5.3.3 Miscellaneous • Apply high-quality moisturizers to the skin to increase the water content and thus pliability and strength. Apply moisturizers anytime water comes in contact with the skin, especially after the bath or shower. Look for products that allow the skin to breath while decreasing excessive transepidermal water loss (e-TEWL). • Use a skin prepping solution or sealant before using tape on a patient’s skin. • Teach the patient and care givers to visually inspect the skin daily for early detection. • Encourage proper hydration and nutrition. • Institute an active or passive range-of-motion routine. • Calculate a risk assessment score on every patient to identify those at high risk for development of pressure ulcers (see risk assessment, Braden Scale). • Apply transparent dressings or skin sealants to protect the epidermis. 22.5.3.4 Moisture • Protect the skin from body fluids and drainage by absorption. • Decrease baths and address a patient’s need for skin cleansing individually and by body region. • Use moisturizing, soap-free cleansers with a neutral or slightly acidic pH. • Apply barrier creams that remain in contact with the skin despite cleaning to offer protection from incontinence episodes. Good examples of ingredients include zinc oxide, dimethicone, and other high-quality silicones. Products containing petrolatum-based protectants should be avoided since they protect for a very short time and do not remain in contact with the skin. • Institute a bowel and bladder program that is customized to each resident and can be documented. • Consider the use of some of the newer high-tech polymer-based incontinent products (briefs, pad, etc.) and customize to each resident’s needs.

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22.5.3.5 Seated Dependent • Avoid uninterrupted sitting. • Teach the patient to perform a weight shift (stand up with assist, push-up, bend at the waist, or shift from side to side) every 15 min. • If the patient is not able to perform an independent weight shift, they should be repositioned or put back to bed once per hour. • Utilize a high-quality pressure redistribution cushion (high-density foam, air or viscous gel) for all seated dependent individuals. Recently, the New Jersey Hospital Association Collabora­ tive achieved a 70% reduction in the incidence of pressure ulcers in 2 years,59 from 18% down to 5%. They accomplished this by focusing on prevention, developing, and delivering 2-day sharing and learning sessions and continuation of best practice.

22.5.4 Support Surfaces In the pursuit of prevention and management of skin and tissue breakdown, support surface selection remains an important decision for the clinician. Pressure ulcers are caused by a myriad of intrinsic and extrinsic factors. Support surfaces can have significant influence over extrinsic factors such as pressure, shear, friction, moisture, and temperature.60 These factors directly impact deformation of the soft tissue, blood flow, tissue ischemia and necrosis, and pressure ulcer development, especially in the immobile patient. The manner by which support surfaces manage these extrinsic factors can be used by clinicians as they select support surfaces for their patients. Support surfaces are specialized devices for pressure redistribution designed for management of tissue loads, microclimate, and/or other therapeutic functions as adjunctive devices to pressure ulcer prevention. External pressure, especially over the bony prominences, has been identified as the major etiology in pressure ulcer development. Additional associated origins consist of the degree of shear and friction forces and the further effects of temperature and moisture. All of these factors can be affected by, and are correlated to, the characteristics of the support surface selected for an individual.

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Clinicians typically use the term “pressure” to reflect normal pressure or interface pressure – the force per unit area that acts perpendicular to the tissue. The forces that result in normal pressure on the tissues are typically due to gravity; body weight is resting on the supporting surface. With respect to support surfaces, this normal loading may be the most significant, but it is not the only force that impacts tissue integrity. Various clinical strategies exist to manage these extrinsic factors, especially for patients exhibiting the two greatest risk factors for pressure ulcers, diminished mobility, and/or lack of sensation. Turning and repositioning are the most effective ways to counteract impaired mobility. However, the accepted protocol of turning and repositioning a patient every 2 h may not be enough.61 An individualized care plan must be developed that includes support surfaces as integral components to prevention and management of pressure ulcers. Support surfaces choice and selection is one of many important decisions the clinician and team must assess, plan, implement, evaluate, and discuss for both prevention and treatment of pressure ulcers.

22.6 Skin Tears It is important to mention skin tears, traumatic sores that tend to occur to some of the same individuals as pressure ulcers (Fig. 22.13). As the skin ages, the basement membrane (junction between the epidermis and

Fig. 22.13  Skin tear

C. A. Fleck

the dermis) flattens, making it “loose,” thus more prone to traumatic injury and unintentional separation, in essence, a skin tear. The anatomy of aging skin makes skin tears nearly inevitable in the elderly. In addition, harsh soaps and surfactant cleansers as well as nonnutritional moisturizers and protectants containing hydrocarbons such as petroleum and mineral oil, which do not contribute to lipid replacement, further add to the skin’s vulnerability. Choosing a skin care regime that replaces soap and harsh surfactant cleansers (detergent type) with pH balanced mild cleansers and phospholipids cleansers can decrease the incidence of skin tears, additionally providing overall cost savings and comfort.

22.7 Nutrition By far, one of the most incriminating intrinsic risk factors for the development of pressure ulcers as well as other wounds is malnutrition. Many studies cite a strong link between deteriorating nutritional status and the development and healing of chronic, nonhealing wounds such as pressure ulcers.62–64 Up to 85% of residents in nursing homes suffer from malnutrition.65 It is no wonder that this group of individuals is also at highest risk for the development of pressure ulcers. A nutritional assessment can help the provider identify whether a patient has nutritional risk factors for impaired wound healing. When is a nutritional assessment indicated? There are many “red flags” to alert the provider to potential risk. An obvious one is involuntary weight loss and/or a change in the individual’s appetite. Some not so apparent indicators may include impaired cognitive patterns, altered communication/ hearing/vision, impaired mood/behavior, and diminished physical and functional capabilities. A Braden scale risk-assessment score below the threshold of 18 in older populations can indicate risk for development of pressure ulcers. This is an assessment that is most likely already being performed and can serve as an early warning to initiate further nutritional investigation. A nutritional assessment investigates four basic categories: anthropometric information, biochemical data, clinical facts, and dietary history66 , and should be conducted by a registered dietician on every at-risk individual.

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22.7.1 Biochemical Data

22.7.2 Vitamins and Minerals

Biochemical data includes laboratory tests, such as serum albumin, serum prealbumin, serum transferrin, total lymphocyte count (TLC), and nitrogen balance. Serum albumin is the major circulating plasma protein synthesized by the liver. It is an inexpensive blood test and common indicator of the resident’s protein stores. Its half life (how long it will take before we see decreases in lab data) is about 3 weeks, so the blood you draw from your resident today will indicate their protein stores from 3 weeks ago. Mild depletion is considered 3.5  gm/100  mL. Serum albumin below 3.0 gm/dL (hypoalbuminemia) is associated with tissue edema, which further increases risk of pressure ulcers. Serum albumin levels are often used as an indicator of overall nutrition. Low serum albumin increases risk of infection, morbidity, and mortality. It impairs or prevents wound healing and decreases wound tensile strength. Serum prealbumin is a more sensitive indicator of visceral protein status in acute stages of malnutrition. Its half life is only 2–3 days and can be helpful to evaluate the adequacy of nutritional therapy. Mild depletion is <15 mg/dL. Severe depletion is <5 mg/dL. If the resident has chronic renal failure, prealbumin may be falsely elevated, since it is eliminated in the kidneys. Serum transferrin has a half life of a little over a week and is an indicator of protein stores as well. A level below 200 mg/dL is considered low. This blood test may not be useful in the presence of liver disease or estrogen use, since transferrin levels will be abnormally high. Also of note, liver disease, burns, cortisone or testosterone therapy, and chronic infection can lower serum transferrin levels. TLC reflects the visceral (contained in the body’s organs) protein stores of the body and immunity. TLC is more useful as a screening parameter in noncritical individuals. A TLC below 2,000 cells/mm3 indicates an impaired immune system. Nitrogen balance is also useful for assessment of protein requirements, since protein is 16% nitrogen. Nitrogen balance is the difference between nitrogen intake and output. It helps determine needs for protein maintenance and anabolism. Accurate measurements of food and fluid intake over a 24-h period and a 24-h continuous urine sample are needed. Nitrogen balance results can be questionable in the presence of renal disease.

Many registered dietitians include multivitamin/mineral supplements as part of their preventative protocol for residents at high risk for ulcers or with existing ulcers. Mega-doses should not be administered without the recommendation of a physician or registered dietitian. Consider supplementation of a 100% recommended daily allowance (RDA) vitamin/mineral supplement that is automatically incorporated into the care plan. Supplementation beyond the RDA is not advised unless the resident has a known deficiency.67 Vitamin and mineral assays are useful to confirm suspected deficiencies. This goes for vitamin C and zinc as well. Unless the individual has a known deficit, supplementation has not been shown to be of any benefit.

22.8 Prevention and Reimbursement The centers for medicare and medicaid services (CMS) issued a new regulation beginning October 2008. Medicare and Medicaid will no longer provide additional reimbursement to hospitals for pressure ulcers that occurred during the patient’s stay.68 CMS believes pressure ulcers are preventable. Average extra cost for one pressure ulcer, for one patient in acute care is $40,000.68 The challenge will be to put the law into practice without destroying our healthcare system. Success will be achieved if facilities align policies, procedures, and personnel to prevent these nosocomial events or hospital acquired conditions (HAC) from occurring and offer quality patient care. It is recommended that hospitals ramp up education and programs to prepare for these changes. This will include the development of key relationships to provide costeffective products and programs to streamline care and save money. A similar prospective payment system has been in place within long-term care (LTC) since 2004.

22.9 Prevention, Full-Circle Wound prevention can be equated to the care and maintenance of inanimate objects or things such as automobiles or our homes; similar to getting a “tune

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up” on our automobile or replacing the shingles on a house. The human body, however, is a living system, ultimately capable of healing itself and maintaining the skin barrier function with the proper prevention measures. Although a complex process, most wounds can be prevented with the right protocols, products, personnel, education, and policies and procedures. As the old adage states, “an ounce of prevention is worth a pound of cure.” Not only does wound prevention save facilities and payers time, money and possible litigation, but ultimately the patient will be spared ache and anguish, increasing the quality of life.

References   1. Norman RA, Menendez R. Structure and function of aging skin. In: Norman RA, ed. Diagnosis of Aging Skin Diseases. London: Springer; 2008   2. Baranoski S, Ayello EA, eds. Skin: An Essential Organ, Chapter 4 in Wound Care Essentials Practice Principles. Philadelphia, PA: Lippincott Williams and Wilkins; 2004:49   3. Goldstein DR, et al Differential diagnosis: assessment of the lower extremity ulcer. Is it arterial, venous, neuropathic? Wounds. 1998;10:125–131   4. Rutherford RB. The vascular consultation. In: Rutherford RB, ed. Vascular Surgery. 4th ed. Philadelphia, PA: WB Saunders; 1995   5. Young JR. Differential diagnosis of leg ulcers. Cariovasc Clin. 1983;13(2):171–193   6. Beylin M. Treating venous stasis ulcers in the lower extremity. Podiatry Today. 2004;17(10):68–74   7. Fleck CA. Measuring ankle brachial index. Adv Skin Wound Care. 2007;20(12):645–649   8. Vowden K, Vowden P. Doppler and the ABPI: how good is our understanding? J Wound Care. 2001;10:197–202   9. Criqui MH, Browner D, Fronek A, et  al Periperal arterial disease in large vessels is epidemiologically distinct from small vessel disease. Am J Epidemiol. 1989;129:1110–1119 10. Wound, Ostomy, and Continence Clinical Practice Ostomy Subcommittee. Ankle Brachial Index: Best Practice for Clinicians; 2005:1 11. Wound Ostomy Continence Nurses Society. Guidelines for Management of Wounds in Patients with Lower Extremity Arterial Disease. Glenview, IL; 2002 12. Criqui M. Systemic atherosclerosis risk and the mandate for intervention in atherosclerotic peripheral disease. Am J Cardiol. 2001;88(7B):433–447 13. Nelson EA, Cullum N, Jones J. Compression for preventing recurrence of venous ulcers. Cochrane Review, The Cochrane Library, Issue 2; 2003 14. Wound, Ostomy and Continence Nurses Society Guideline for Management of Wounds in Patients with Lower-Extremity Neuropathic Disease, WOCN Clinical Practice Guideline Series number 3. Glenview, IL; 2004

C. A. Fleck 15. Vijay V, Saraswathy G, Gautham A, et  al Effectiveness of different types of footwear insoles for the diabetic neuropathic foot. A follow-up study. Diabet Care. 2004;27(2): 474–477 16. Knowles EA, Boulton AJM. Do people with diabetes wear their prescribed footwear? Diabet Med. 1996;13:1064 17. Armstrong DG, Lavery LA, Kimbriel HR, et al Activity patterns of patients with diabetic foot ulcers: patients with active ulceration may not adhere to a standard pressure offloading regimen. Diabet Care. 2003;26:2595–2597 18. American Diabetes Association. Consensus Statement: Diabetes Care, Consensus Development Conference on Diabetic Foot Wound Care. Alexandria, VA; 2003 19. Birke JA, Rolfsen RJ. Evaluation of a self-administered sensory testing tool to identify patients at risk of diabetes-related foot problems. Diabet Care. 1998;21:23–25 20. Birke JA, Patout CA, Foto JG. Factors associated with ulceration and amputation in the neuropathic foot. J Orthop Sports Phys Ther. 2000;30(2):91–97 21. Dillingham T, Pezzin L, Mackenzie E. Limb amputation and limb deficiency. South Med J. 2002;95:875–883 22. Schainfield R. Management of peripheral arterial disease and intermittent claudication. J Am Board Fam Pract. 2001;14: 443–445 23. Federman DG, Trent J, Frelich C, Deinovic J, Kirsner R. Epide­ miology of peripheral vascular disease: a predictor of systemic vascular disease. Ostomy Wound Manage. 1998;44:58–66 24. Taylor LM, Porter JM. Natural history and nonoperative treatment of chronic lower extremity ischemia. In: Moore WS, ed. Vascular Surgery: A Comprehensive Review. Philadelphia, PA: W.B. Saunders; 1993 25. Fleck CA. How to avoid perineal skin care problems. Extended Care Product News. 2004;96(6):1, 13–16 26. Hill MJ. Dermatology Nursing Essentials: A Core Curriculum. 2nd ed. Pittman, New Jersey: Anthony J. Jannetti Publication Management; 2003 27. Sibbald RG, Campbell K, Coutts P, Queen D. Intact skin – an integrity not to be lost. Ost Wound Manag. 2003;49(6):27–41 28. Nix DH. Prevention and treatment of perineal skin breakdown. In: Milne CT, Corbett LQ, Duboc D, eds. Wound Ostomy and Continence Nursing Secrets. Philadelphia, PA: Hanley and Belfus; 2003:373–377 29. Storer-Brown D. Perineal dermatitis: can we measure it? Ost Wound Manag. 1993;39(7):8–30,32 30. Nix DH. Validity and reliability of the perineal assessment tool (PAT). Ostomy Wound Manag. 2002;48(2):43–49 31. Wound, Ostomy and Continence Nurses Society. Guidelines for Prevention and Management of Pressure Ulcers. WOCN Clinical Practice Guidelines Series. Glenview, IL. WOCN Society; 2003:14 32. Gray M, et al Incontinence-associated dermatitis: a consensus. J WOCN. 2007;314(1):45–54 33. Calhoun JH, et al Diabetic foot ulcers and infections: current concepts. Adv Skin Wound Care. 2002;15(2):31–42 34. Bryant RA, ed. Acute and Chronic Wounds: Nursing Management. 2nd ed. St. Louis, MO: Mosby-Yearbook; 2000 35. Ananthapadmanabhan KP, Moore DJ, Subramanyan K, Misra M, Meyer F. Cleansing without compromise: the impact of cleansers on the skin barrier and the technology of mild cleansing. Dermatol Ther. 2004;17(suppl 1):16–25

22  Wound Prevention 36. Lutz J. Cleansing lotions vs bar soap for skin care use. Presented at the Wound Ostomy and Continence Nurses Society National Conference; 1998 37. Norman RA. Causes and management of xerosis and pruritis in the elderly. Ann Long Term Care. 2001;9(12):35–40 38. Fleck CA, McCord D. The dawn of advanced skin care. Extended Care Product News. 2004;95(5):32, 34–39 39. Fantl JA, Newman DK, Colling J, et al Managing Acute and Chronic Urinary Incontinence, Clinical Practice Guideline. Quick Reference Guide for Clinicians, No. 2, 1996 Update. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service. Agency for Health Care Policy and Research. AHCPR Pub. No. 96–0686. March 1996 40. Groom M, Shannon RJ, Chakravarthy D, Fleck CA., An evaluation of cost and effects of a nutrient-based skin care program for prevention of skin tears in an extended convalescence center; accepted for publishing, Journal of Wound, Ostomy and Continence Nursing, in press, 2010 41. Shannon RJ, Coombs M, Chakravarthy D. Reducing Hospital-Acquired Pressure Ulcers with a Siliconebased Dermal Nourishing Emollient-Associated Skincare Regimen, Advances in Skin and Wound Care. 2009;22(10):461–467 42. Revis DR. Decubitus Ulcers, October 2005, eMedicine at http://www.emedicine.com 43. Cuddigan J, et al, eds. Pressure Ulcers in America: Prevalence, Incidence and Implications for the Future. Reston, VA: National Pressure Ulcer Advisory Panel (NPUAP); 2001 44. Beckrich K, Aronovitch S. Hospital acquired pressure ulcers: a comparison of costs in medical vs. surgical patients. Nurs Econ. 1999;17(5):263–271 45. Young ZF, Evans A, Davis J. Nosocomial pressure ulcer prevention: a successful project. J Nurs Adm. 2003;33:380–383 46. Allman RM. Pressure ulcers among the elderly. N Engl J Med. 1989;320(13):850–853 47. National Pressure Ulcer Advisory Panel. Available at: http:// www.npuap.org 48. Abrussezze RS. Early assessment and prevention of pressure ulcers. In: Lee BY, ed. Chronic Ulcers of the Skin. New York: McGraw-Hill; 1985:1–9 49. Kosiak M. Etiology and pathology of ischemic ulcers. Arch Phys Med Rehabil. 1959;40(2):62 50. Reswick J, Rogers J. Experiences at Rancho Los Amigos Hospital with Devices and Techniques to Prevent Pressure Sores. Bedsore Biomechanics. London: University Park; 1976 51. Walsh JS, Plonczynski DJ. Evaluation of a protocol for prevention of facility-acquired heel pressure ulcers. JWOCN. 2007;34(2):179 52. Coats-Bennet U. Use of support surfaces in the ICU. Crit Care Nurs Q. 2002;25:22–32 53. Panel for the Prediction and Prevention of Pressure Ulcers  in  Adults: Pressure Ulcers in Adults: Prediction and Prevention. Clinical Practice Guidelines, No. 3 AHCPR Publication No. 92–0047. Rockville, MD, Agency for Health  Care Policy and Research, Public Health Service,

265 U.S. Department of Health and Human Services, May 1992 54. Fleck C. Reducing the pressure: methods for effective wound care management. Contin Care. 2002;3(1):37–42 55. Kosiak M. Etiology of decubitus ulcers. Arch Phys Med Rehabil. 1961;42(1):19–28 56. Reddy M, Gill SS, Rochon PA. Preventing pressure ulcers: a systematic review. JAMA. 2006;296(8):974–984 57. Ratliff C, Bryant D. (2003) Guideline for Prevention and Management of Pressure Ulcers. WOCN Clinical Practice Guideline Series, No. 2 Wound, Ostomy and Continence Nurses Society. Available at: http://www.wocn.org 58. Duimel-Peeters I, et  al The Effects of Massage to Prevent Pressure Ulcers. A Review of the Literature. Ostomy Wound Manag. 2005;51(4):70–80 59. Holmes A, Edelstein T. Envisioning a world without pressure ulcers. ECPN. 2007;122:24–29 60. Fleck CA, Sprigle S. Support surfaces: tissue integrity, terms, principles and choice (Chapter 62). In: Krasner D, Rodeheaver G, Sibbald G, eds. Chronic Wound Care: A Clinical Sourcebook for Healthcare Professionals. Malvern, VA, USA. 4th ed. Health Management Publications; 2007 61. Clark M. Repositioning to prevent pressure sores – what is the evidence? Nurs Stand. 1998;13(3):58–60, 62, 64 62. Breslow R. Nutritional status and dietary intake of patients with pressure ulcers: review of research literature 1943– 1989. Decubitus. 1991;4:16–21 63. Pinchofsky-Devin G, Kaminski M. The correlation of pressure sores and nutritional status. J Am Geriatr Soc. 1986;37: 173–183 64. Allman RM, Goode PS, Patrick MM, Burst N, Bartolucci AA. Pressure ulcer risk factors among hospitalized patient with activity limitation. JAMA. 1995;273:865–870 65. Morley J, Silver A. Nutritional issues in nursing home care. Ann Intern Med. 1995;123:850–859 66. Flanigan KH. Nutritional aspects of wound healing. Adv Wound Care. 1997;10(2):48–52 67. Thomas DR. Nutritional factors affecting wound healing. Ostomy Wound Manag. 1996;42(5):40–48 68. CMS Inpatient PPS Final Rule for FY 2008 available at: http://www.cms.hhs.gov.AcuteInpatientPPS /downloads/ CMS-1533-FC.pdf

Helpful Websites Association for the Advancement of Wound Care (AAWC) – www.aawconline.org American Academy of Wound Management (AAWM) – www. aawm.org Advancing the Practice – www.advancingthepractice.org Wound, Ostomy and Continence Nurses Association (WOCN) – www.wocn.org

Prevention of Surgical Complications

23

Michael R. Hinckley

23.1 Introduction One of the defining characteristics of dermatology is wide array of procedures that are performed on the skin. Whether for diagnostic or treatment purposes, dermatologic procedures are an important constituent contributing to the personality of this specialty. Dermatologic surgery is one of the most important of these procedures and although not common, adverse events can result, which are troublesome both for the patient and the physician. An appropriate knowledge of how to prevent such undesirable occurrences is mandatory for any physician wishing to engage in dermatologic surgery. It is hoped that this chapter will contribute to this important body of knowledge.

23.2 Bleeding Bleeding is an unavoidable part of any surgical procedure but a typical dermatologic surgery should involve minimal bleeding. Several steps can be taken preoperatively, perioperatively, and postoperatively to decrease the potential of bleeding. The preoperative history should review all medications and the physician should verbally inquire about any history of abnormal bleeding or use of anticoagulant or antiplatelet medication. While some patients might be familiar with the blood thinning effects of medicines such as warfarin, heparin, aspirin, and clopidogrel, they

M. R. Hinckley Department of Dermatology, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA e-mail: [email protected]

may not realize that numerous other substances can cause thinning of the blood. Like aspirin, nonsteroidal antiinflammatory drugs (NSAIDS) act as platelet inhibitors, although in contrast to aspirin, their antiplatelet effect is reversible.1 Other products with antiplatelet effect include alcohol, fish oil (Omega three polyunsaturated fatty acids), ginseng, gingko biloba, garlic, ginger, feverfew, vitamin E, and green tea.1–3 As patients may not know of these products’ potential to thin blood, it is prudent to specifically ask about the use of these substances. Finding purpura on physical examination can also indicate a clotting problem or use of a blood thinner. Some patients can safely discontinue the use of some blood thinners before cutaneous surgery, and if so, they should be told how far in advance to stop the medicine. The antiplatelet effect of some common blood thinners is shown in Table  23.1.4, 5 Cutaneous surgery on a patient taking common blood thinners is considered safe and most reports have shown no increase of surgical complications.6, 7 Physicians should be aware that patients taking more than one blood thinner may be at increased risk of bleeding compared to those who took only one or no blood thinning agents.8 In any patient with a medical necessity for warfarin, the medication should be continued through surgery.7 Patients on aspirin that is medically necessary should also continue the medication unless the surgery will be involving “deep tissue resection or dissection.”7 If surgery is performed on a patient taking warfarin, some surgeons request an international normalized ratio (INR) between two and three unless the prescribing physician specifies otherwise.9 One study reported safety of surgical procedures with INR of less than 3.5 and recommended preoperative testing of INR preferably within 24 h of surgery.10 In the preoperative history, it should also be ascertained if the patient has any inherited bleeding

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_23, © Springer-Verlag London Limited 2010

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M. R. Hinckley

Table 23.1  Duration of blood thinning effect of various agents (days) Aspirin

8–10

Warfarin

2–5

Clopidogrel

5

disorders. In such patients, a hematology consultation is warranted to ensure that appropriate measures are taken to prevent excessive bleeding.11, 12 Perioperatively, the use of the vasoconstrictor epinephrine in the local anesthetic will help decrease bleeding.13 Moreover, absorption of the anesthetic is reduced and the risk of toxicity is lessened.13 Methods of stopping bleeding during surgery include the use of electrosurgery, electrocautery, pressure, and tying off vessels. Hydrophilic polymers with potassium salt and microporous polysaccharide hemispheres are products that can help with hemostasis.14 Hydrophilic polymers with potassium salt should only be used on wounds where second-intention healing will be allowed.14 Postoperatively covering the excision site with a pressure dressing can theoretically decrease bleeding. When bleeding does occur after surgery, a hematoma may form. Evacuation of early hematomas is advised and even if not treated early, it is still probably best to evacuate hematomas that are expanding or large and have become fibrous.1 Observation is acceptable for a hematoma that is stable and small.1 If control of bleeding has been difficult during performance of a large multilayered closure or flap, hematoma formation may be prevented by drain placement.1 If an intraoral hematoma forms after surgery on the cheek, it is best to avoid intervention through the mucosa because of the risk of forming a fistula to the cheek wound on the outside.15 Furthermore, involvement of an oral and maxillofacial surgeon is advisable.15

23.3 Infection Dermatologic surgeons have been fortunate to enjoy a low incidence of postoperative infection. Different rates have been reported, but one recent publication found an overall infection incidence of 0.7%.16 Patient risk factors that may affect the rate of infection are shown in Table 23.2.17, 18 While diabetes and smoking has been thought to increase infection risk, one study found no increased risk of infection in diabetics or smokers.16 Many patient risk factors are chronic and are difficult to alter immediately prior to surgery, but those with potential risk factors that can be controlled should be. Patients with diabetes can work to achieve optimal blood glucose control and those who use tobacco or alcohol can be encouraged to decrease the amount used. Increased rate of infection can also be seen in skin grafts, ear or lip wedge resections, and in surgery performed in the groin and below the knee.16 Other factors that might affect rate of infection include longer

Table 23.2  Some risk factors for infection Male gender Advancing age Immunosuppression Malnutrition Diabetes mellitus Obesity Peripheral vascular disease Alcohol use Tobacco use Bacterial colonization Chronic renal insufficiency Transfusion of blood products during surgery Concurrent remote infection

23.2.1 Key Points • Be aware of blood thinners patients are using. • Blood thinners used for primary prevention can be stopped. • Do not discontinue medically necessary blood thinners. • Evacuate early or expanding hematomas.

Corticosteroid use Skin grafts Ear or lip wedge resections Surgery in the groin and below the knee Longer surgery duration Reconstructive procedures Surgery on the nose, ear, and facial region

23  Prevention of Surgical Complications

surgery duration, reconstructive procedures, and ­surgery on the nose, ear, and facial region.18 Use of prophylactic antibiotics should be considered in the proper scenarios. Although it might be assumed that the use of sterile gloves during surgery would decrease potential for infection, not all data support this. One report has demonstrated that the use of nonsterile gloves during Mohs micrographic surgery resulted in no increased infection rates except in patients who underwent fenestration of cartilage with secondary healing and removal of melanomas.19 Another study showed almost no difference in infection rates in simple excisions with or without sterile glove use (1.7% without sterile gloves, 1.6% with sterile gloves).18 However, this same report found incidence of infection to be 14.7% when sterile gloves were not used in excisions with a reconstructive procedure and 3.4% with the use of sterile gloves.18 An advisory statement published in 2008 by physicians at the Mayo Clinic provides a number of scenarios where prophylactic antibiotics are appropriate. • High risk of surgical site infection: lower extremity, especially leg; groin; wedge excisions of the lip or ear; skin flaps on the nose; skin grafts; extensive inflammatory skin disease. • Prevention of infective endocarditis: Prosthetic cardiac valve, previous infective endocarditis; cardiac transplantation recipients who develop cardiac valvulopathy; congenital heart disease (CHD) (unrepaired cyanotic CHD, including palliative shunts and conduits, during the first 6 months after complete repair of congenital heart defects with prosthetic material or device placed by surgery or catheter intervention); repaired congential heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization). • Prevention of hematologic total joint infection: The first 2 years following joint replacement; previous prosthetic joint infections, immunocompromised/immunosuppressed patients (inflammatory arthropathies such as rheumatoid arthritis, systemic lupus erythematosus, drug- or radiationinduced immunosuppression); insulin-dependent type I diabetes; HIV infection; malignancy; malnourishment; hemophilia.20 The American Heart Association guidelines published in 2007 for infective endocarditis (IE) prophylaxis

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state that “Antibiotic prophylaxis is reasonable for ­procedures on respiratory tract or infected skin, skin structures, or musculoskeletal tissue only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE.”21 That report lists the following conditions: • Prosthetic cardiac valve or prosthetic material used for cardiac valve repair • Previous IE • CHD −− Unrepaired cyanotic CHD, including palliative shunts and conduits. −− Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure. −− Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization). • Cardiac transplantation recipients who develop cardiac valvulopathy21 Another report listed the following noncardiac conditions as high risk: orthopedic prosthesis, central nervous system (CNS) shunts, and shunt or fistula with nearby or inflamed tissue.17 This same report noted that antibiotic prophylaxis may be appropriate in situations such as closures with high tension, procedures performed on the hand, infected or inflamed skin of a surgical site, when a flap or graft is done on the ear and nose, and when several procedures are done at once.17 If infection would lead to serious consequences such as in immunosuppressed patients, prophylactic antibiotics for surgery performed in the axillae and mucosal surfaces are given.17 The American Academy of Orthopedic Surgeons website recommends prophylactic antibiotics for those who have had a joint replacement in particular scenarios if a patient is undergoing certain dental and urologic procedures.22, 23 If a patient with a prosthesis is to undergo skin surgery, the dermatologic surgeon might consider the use of preoperative antibiotics if the prosthesis was placed within the previous 2 years. However, the orthopedic surgeon who placed the prosthesis can be contacted if there is any question. Prophylaxis should be timed appropriately to allow for adequate accumulation of the antimicrobial in the coagulum.17 While therapy should be tailored with gram-positive organisms in mind, surgery done in moist

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areas, below the knees, or on diabetics might also have a high density of gram-negative organisms.24 When it is determined that antibiotic prophylaxis is appropriate, different regimens can be employed depending on the site. For nonoral skin, 2  g of oral cephalexin or dicloxacillin is given 0.5–1  h prior to surgery.17 Alternatives for penicillin-allergic patients are 600  mg of oral clindamycin or 500  mg of oral azithromycin given 0.5–1 h prior to surgery.17 For nasal and oral mucosa 2 g of oral amoxicillin or if penicillinallergic 600  mg of oral clindamycin, 500  mg of oral azithromycin, or if nontype one reaction  2  g of oral cephalexin can be given ½–1  h prior to surgery.17 Unless surgery lasts longer than 6 h, the preoperative dose could be sufficient for endocarditis and prosthesis prophylaxis.17 In a patient believed to be at high risk for infection of a wound, up to 10 days of antibiotics can be given postoperatively in addition to the preoperative dose, twice a day for cephalosporins rather than 4 times a day.17 Preoperative preparation of the surgical site is a step the surgical staff can take in an effort to decrease postoperative wound infection. Chlorhexidine gluconate and povidone-iodine are antiseptics commonly employed for skin surgery. While povidone-iodine has been used as an antimicrobial for many years, it has a number of disadvantages. It might be inactivated by blood25 and it can be toxic to human fibroblasts and thus slow the rate of wound healing.26 Furthermore, as compared to chlorhexidine, it is more likely to cause an allergic reaction,27 it is less effective at clearing of microbes,28 and it has less sustained activity than chlorhexidine.29 Chlorhexidine gluconate can also be problematic as keratopathy has been reported30 and ototoxicity has been found with its use in animal studies.31, 32 Thus, this is probably an unwise choice for cleansing in the auricular region or to prepare the skin around the eyes. Alcohol has a rapid onset of action but duration of action is limited.29 An optimal combination is chlorhexidine gluconate and alcohol, thus providing the potential for rapid onset and prolonged duration of action.29 Surrounding the surgical site with sterile draping, either disposable or washable, might also help keep the area clean and prevent infection. Postoperatively, an antibiotic ointment can be placed with an overlying dressing. Ointments include bacitracin, mupirocin, neomycin, erythromycin, polymyxin, and combinations of the different topicals.33

M. R. Hinckley

Mupirocin is effective against gram-positive and some gram-negative organisms and is less likely to cause contact dermatitis than some other topical antibiotics.33 Neomycin is bactericidal against most gram-negatives bacteria and against staphylococci but not against streptococci.33 Neomycin-induced allergic contact dermatitis has been reported to occur in 1–6% of people.33 Bacitracin is effective against various gram-positive and gram-negative microbes33 but along with neomycin can cause contact dermatitis.34 Polymyxin is most effective at killing some gram-negative bacteria, and when used in combination with other topical antibiotics, the preparation has increased spectrum of activity.33 Erythromycin 2% ointment has bactericidal activity against gram-positive bacteria with little risk of sensitization.35 Silver sulfadiazine is bactericidal against gram-negative and gram-positive bacteria.33 Retapamulin is a topical antibiotic for the treatment of impetigo with activity against Streptococcus pyogenes and Staphylococcus aureus.36 Petrolatum can be used as an alternative to antibiotic ointment following surgery. One study was unable to find a statistically significant difference in the rate of postoperative infections in patients who had used white petrolatum vs. bacitracin (2 vs. 0.9%).37 Moreover, there was no difference in healing that was clinically significant noted at day 1, 7, or 28.37 No contact dermatitis was seen in the white petrolatum group.37 In addition, anaphylaxis to bacitracin has been reported.38 Another study found no statistically significant difference between petrolatum and gentamycin ointment in prevention of postoperative suppurative auricular chondritis.39 Furthermore, inflammatory chondritis was much more likely in patients who used gentamycin ointment compared to petrolatum.39 In light of the potential for side effects and resistance, as well as the lack of strict guidelines for antibiotic use in skin surgery, the need for oral and topical antibiotics should be determined on a case-by-case basis.

23.3.1 Key Points • Infection in dermatologic surgery is low. • Petrolatum can be safely used on postoperative sites instead of antibiotic ointment. • Use antibiotic prophylaxis when appropriate.

23  Prevention of Surgical Complications

23.4 Allergic Reactions Every preoperative medical history should elicit information about drug allergies. Adverse drug reactions can range from mild annoyances to fatalities. A study looking at adverse drug events estimated that over 700,000 people in the United States are treated annually in emergency departments for such events.40 While few medications are used in conjunction with dermatologic surgery, the surgeon should be aware of those that are most likely to be problematic (Table  23.3). Semisynthetic penicillinase-resistant penicillins and first-generation cephalosporins are the most common antibiotics used for prophylaxis in skin surgery.41 Although 0.7–10% claim such an allergy, of these individuals around 10–30% show a positive IgE-mediated reaction on skin testing.42 Although cross-reactivity between cephalosporins and penicillin can occur, it is probably less than once thought.43 Historically, 10% cross-reactivity has been reported, but this number may have resulted from penicillin compounds that were contaminated with cephalosporins.43 Approximately 1–3% of patients can experience an allergic or immunemediated reaction to cephalosporins.43 If a patient does have a penicillin or cephalosporin allergy and an antibiotic is warranted, clindamycin can be used as an alternative.17 Antiseptics can also cause an allergic reaction in dermatologic surgery. Povidone-iodine-containing antiseptics are the most common antiseptics to cause allergic contact dermatitis.27 Anaphylaxis due to the povidone component of povidone-iodine has been reported.44 Local anesthetics used in cutaneous surgery typically belong to the amide class of anesthetics. Allergy to local anesthetics is rare, particularly among the

Table 23.3  Potential allergens in a surgical setting Antibiotics (oral and topical) Antiseptics Anesthetic Latex Nickel (surgical instruments) Suture Colophony (adhesive tape)

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amide class.45–47 Anesthetics from the ester class are more likely to cause a reaction than those from the amide class and this is due to p-aminobenzoic acid, an ester metabolite.27 Patients can experience side effects from epinephrine, which is sometimes mixed with anesthetic and such adverse affects are more likely in patients with hyperthyroidism, significant cardiac disease, who are very anxious or who are taking a nonselective beta-blocker.48 Such reactions include palpitations, tachycardia, tremor, headache, diaphoresis, chest pain, nervousness, light-headedness, and increased blood pressure.48 If a patient is worried about side effects of epinephrine or has a condition that could result in increased sensitivity to epinephrine, the surgeon should discuss the adverse effects of the epinephrine with the patient and decide if anesthetic without epinephrine would be preferable. If epinephrine is not used, the surgeon and the patient should understand that bleeding will likely be greater and the duration of the anesthetic effect will probably be shorter. Perioperative allergic reactions can result from rubber products (such as latex), acrylates (found in electrosurgical plates), formaldehyde (formaldehyde gas emanating from an open biopsy specimen container), nickel (found in surgical instruments), and suture (prolene allergy is rare but has been reported).27 Postoperative contact dermatitis can result from adhesives and topical antibiotics.27 Both neomycin and bacitracin were listed among the top ten allergens in a Mayo Clinic report investigating allergens over a 5-year period.34 These same two topicals were among the top ten relevant allergens in an investigation of causes of allergic contact dermatitis in patients with hand dermatitis.49 Use of these medications may give a postsurgical wound the appearance of infection when the true issue is contact allergy. Bacitracin-induced anaphylaxis has been reported.38 Petrolatum can be considered for use on surgical sites in place of topical antibiotics. Adhesive tape can contain colophony, a cause of contact dermatitis.27 Band-aid Liquid Bandage and Dermabond contain 2-octyl cyanoacrylate and colorant,27 and benzalkonium chloride and methylparaben are also found in Liquid Bandage27; these four sensitizers can result in allergy.27 Physicians should be aware of patient allergies and be able to recognize allergic reactions, which could result in misdiagnosis of the real problem. For example,

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if a patient returns to clinic after surgery for suture removal and the surgical area appears inflamed, the cause may be a reaction to the topical antibiotic or tape used postoperatively and not due to infection. Diagnosing an allergic response as infection could lead to improper use of antibiotics.

23.4.1 Key Points • Local anesthetics rarely cause true allergic reactions. • Potential allergens use in cutaneous surgery include latex, povidone-iodine, adhesive, suture, antibiotics. • Inflammation at a surgical site may be secondary to a topical antibiotic.

23.5 Postoperative Scars, Pain, and Pruritus Scarring is an inevitable result of surgery and should be expected in all cases. While several steps can be taken to minimize the size and appearance of surgical scars, during the explanation of the surgical procedure and in the informed consent, it should be made clear to the patient that a scar will result. Location can affect how a scar forms50 and the physician may want to inform the patient of this. In the preoperative assessment, a patient should be asked about history of hypertrophic scarring or keloid formation. Physical examination is also helpful as a hypertrophic scar, or keloid might be noted by the physician that was not mentioned by the patient. A variety of patient-related factors can affect scar outcome. Sun exposure can worsen the appearance of scars.51 Diabetes is a risk factor for infection17 and infection can affect wound healing and result in a poor scar.1 One study found that the most significant patient risk factors contributing to wound complications following skin biopsy appeared to be corticosteroid use and cigarette smoking.52 Nicotine acts as a vasoconstrictor resulting in ischemia.52 Avoidance of vigorous activities helps with split thickness skin graft survival,53 and thus it might be assumed that refraining from such activity after other types of surgical repair will aid in healing. It seems that poor nutrition can affect healing

M. R. Hinckley

as certain nutrients appear to be important for proper healing.54, 55 Corticosteroid use can affect healing56, 57 , presumably due to the affect on the inflammatory response.56 Chronic alcohol intake may negatively affect wound healing by decreasing activity and proliferation of T cells.58 Stress can possibly result in poorer wound healing by affecting cytokine production.59, 60 It could be concluded that any factor that can affect wound healing will, as a result, have the potential to affect the scar formation. Several physician-influenced factors can affect scar outcome. Perioperative handling of tissue can affect scarring.61 High tension of a wound can result in scar spread1 and choice of repair can influence tension. Suture track scars are more likely to develop the longer they are left in place.1 If wound edges are not everted, the scar that forms may be more noticeable.62 Wound separation can result from a hematoma1 , which could lead to a poor scar; thus, inadequately controlling bleeding intraoperatively could ultimately affect the scar. Putting suture lines on the boundary of a cosmetic subunit can help with scar formation63, and how the excision is placed in relation to relaxed skin tension lines can affect cosmesis.63 Management options for keloids and hypertrophic scars include interferon or corticosteroid injections, occlusive dressings, radiotherapy, compression therapy, cryotherapy, laser, surgical excision, dermabrasion, surgical revision, fillers, peels, cryosurgery, cosmetics, punch excisions and grafts, pressure bandages, and massage.50, 64 Approximately 3 weeks after surgery, a patient can massage the surgical site in an effort to achieve improved scar appearance. Topical preparations to help scars are available but one study has demonstrated no advantage of an onion extractbased gel over a petrolatum-based ointment.65 Use of a silicone gel cushion and silicone sheeting for hypertrophic scars and keloids has resulted in decreased volume and symptoms of scars.64 Silicone elastomer sheeting appears to be useful in the prevention and treatment of keloid scars and hypertrophic scars.66 It may be that hydration rather than silicone is what is helping.67 Patients should be warned that scar maturation can take up to 1 year and improvement can be seen up until that time. Proper education of patients and skillful surgeons can do much to achieve acceptable scars for patients. Pain, pruritus, and numbness of surgical sites are benign but relatively common symptoms reported by

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23.6.1 Key Points

patients. Some topical treatments might improve symptoms. Retinoic acid applied daily to hypertrophic and keloid scars has been reported to decrease pruritus and tenderness, and tocoretinate ointment has resulted in decreased pruritus in mature hypertrophic scars.68 Silicone-containing products used for hypertrophic scars and keloids have resulted in decreased tenderness and pruritus.64 Topical lidocaine could also be tried for symptomatic relief of scars. Postoperative pain in dermatologic surgery will rarely be a serious problem. After simple excisions and repairs, acetaminophen should be adequate to control pain. Patients should be warned that other over-the-counter painkillers such as aspirin, ibuprofen, naproxen, or other NSAIDS can cause bleeding. In larger excisions or more advanced repairs, patients might need a prescription for stronger analgesics. If a prescription is given for a compound containing acetaminophen, the patient should be warned that use of the prescription medication in addition to acetaminophen could result in toxicity.

Although local anesthesia is safer than general anesthesia,71 toxicity can result, and the CNS and cardiovascular system are the two main organ systems where adverse reactions occur72 (Table 23.4). CNS side effects include circumoral numbness, light-headedness, double vision, a metallic taste, tremors, slurred speech, respiratory arrest, and seizure.72 Cardiovascular effects include hypotension, dysrhythmias, palpitations, shortness of breath, diaphoresis, and chest pain.73 Epinephrine can cause several side effects (Table 23.5) and should be used cautiously in patients on a beta-blocker

23.5.1 Key Points

Table 23.4  Symptoms of anesthetic toxicity Central nervous system Cardiovascular

• Tension, bleeding, infection, and vigorous activity can result in an undesirable scar. • Placing an incision within relaxed skin tension lines can help hide a scar. • Occlusive dressings, massage, corticosteroid injection can improve scar appearance. • Protect scars from the sun.

• Can result from too much tension, inadequate undermining, when length-to-width ratio is less than 3:1. • Standing cones can sometimes resolve over time.

23.7 Anesthetic Toxicity

Circumoral numbness

Hypotension

Light-headedness

Dysrhythmias

Double vision

Palpitations

Metallic taste

Shortness of breath

Tremors

Diaphoresis

Slurred speech

Chest pain

Respiratory arrest Seizure

23.6 Standing Cones Standing cones (“dog ears”) are more likely to result when length-to-width ratio of a fusiform excision is less than 3–4:1, when opposing sides of a wound are of unequal length, or if the angles at the wound apices are too big.69 Too much tension can cause depression of the center of the wound and the skin at the ends to be elevated, thus giving the look of dog ears.69 Inadequate undermining can accentuate dog ears and if during a fusiform excision the scalpel angle is not at 90° while approaching the apices, dog ears can result.69 Standing cones can sometimes resolve over time.70

Table 23.5  Potential side effects of epinephrine Palpitations Tachycardia Tremor Headache Diaphoresis Chest pain Nervousness Light-headedness Increased blood pressure

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and with heart disease.13 Conversing with the patient during surgery may allow the physician to identify toxicity by noticing problems such as a change in mental status or dysarthria.74 Epinephrine is helpful in the setting of local anesthetic as its use results in less absorption of the anesthetic, the need for a smaller amount of the anesthetic, and decreased risk of toxicity.13 Absorption of anesthetic also depends on the vascularity of the area being injected.75 Aspirating during injection can reduce the chance of injecting a large amount of the anesthetic intravascularly.74 Recommended maximum doses of anesthetic are: 4–5 mg/kg alone and 7 mg/kg with epinephrine for lidocaine, and 175 mg alone and 225 mg with epinephrine for bupivacaine.73 Bupivacaine has the advantage of a longer duration of action but also can be particularly cardiotoxic.73 Lidocaine is metabolized by the liver, and thus hepatic dysfunction can lead to increased risk of toxicity.74 Local anesthetics are predominantly excreted in urine,72 but renal failure does not lead to decreased clearance because of inactivation of amides in the liver and hydrolysis of esters in the plasma.75 If toxicity does occur, supportive care and crash cart materials should be available.

23.7.1 Key Points • Talking to a patient during surgery can help the physician become aware of anesthetic toxicity such as slurred speech. • Epinephrine can decrease absorption of the anesthetic, thus decreasing the risk of toxicity. • Hepatic failure can increase toxicity due to decrease metabolization of the anesthetic.

23.8 Nerve Damage Nerve damage can be one of the most devastating results of cutaneous surgery. Sensory deficits will be suffered in many cases but sensory nerves frequently regenerate though it may be some months.76 Injury to sensory nerves resulting in permanent paresthesia or injury to motor nerves resulting in functional impairment can be more problematic. Unfortunately, excision

M. R. Hinckley

of large or infiltrative tumors may make damage of certain nerves unavoidable. When a tumor is not large or infiltrative but located in the vicinity of an important nerve, the solution to preventing nerve damage is to have an appropriate knowledge of anatomy, particularly in the facial and neck regions. The superficial muscularoaponeurotic system (SMAS) is a useful landmark in the face as sensory nerves ordinarily course through the superficial portion of the SMAS while motor nerves course through the deeper part of the SMAS.63 The SMAS is typically found above the muscles but deep to the subcutaneous tissue.63 The predominant source of sensory innervation to the face is the fifth cranial nerve or trigeminal nerve.63 The trigeminal nerve branches into the ophthalmic, maxillary, and mandibular portions.63 Cranial nerve seven or the facial nerve supplies muscles of facial expression with motor innervation.63 The temporal branch provides innervation to the muscles of the upper face and transection of this branch results in lack of ability to elevate the eyebrow and in ptosis.63 This nerve passes superficially over the middle part of the zygoma rendering it susceptible to injury.63 The marginal mandibular nerve runs superficially near the chin and mandible, and transection leads to a droopy lip and drooling.63 The spinal accessory nerve is susceptible to injury when surgery is being performed on the neck and can result in arm, shoulder and girdle weakness, shoulder sagging, and scapula winging.77 Various methods for locating this nerve have been described.77 One technique is to obliquely stroke a needle over the lateral neck, marking the hyperaesthetic points, then connect these points, which can indicate the course of the nerve.77 Local anesthetics work rapidly on unmyelinated sensory fibers but over time, myelinated motor fibers can also be affected resulting in temporary paralysis of facial muscle.63 Both the surgeon and the patient should be aware of this possibility to avoid unnecessary concern. While nerve damage can result in morbidity, proper patient education can mitigate the emotional affect if such injury does occur. If tumor size, type or location makes it possible that excision will result in nerve damage, the patient should be warned what the affect of surgery may be prior to the procedure. Through proper education of patients and vigilant attention to nerve identification and surgical technique, undesired outcomes from nerve damage can be avoided or minimized.

23  Prevention of Surgical Complications

23.8.1 Key Points • Damage to nerves such as the temporal branch of the facial nerve, the marginal mandibular nerve, and the spinal accessory nerve can result in important loss of function for patients. • If a tumor is located in the vicinity of nerves that can result in impairment, the patient needs to be forewarned of this possibility. • Local anesthetics can result in temporary paralysis of nerves. • Transected sensory nerves can regenerate but may require months to do so.

23.9 Spitting Sutures Spitting sutures do not pose a serious problem but can be a nuisance for patients. Superficial placement of suture may increase the possibility of spitting.78 Monofilament absorbable suture is less reactive than vicryl and may be less likely to result in spitting.79 Spitting sutures can be gently removed by the physician if troublesome to the patient.

23.9.1 Key Points • Superficial placement of sutures may increase the likelihood of spitting sutures. • Monofilament absorbable suture may be less likely than vicryl to result in spitting.

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on someone with a pacemaker or ICD may include the use of short bursts, low voltage, bipolar forceps, and avoiding electrosurgery in the area of the device.80, 81 Preoperative consultation with a cardiologist should be considered if there are any concerns or questions.

23.10.1 Key Point • In patients with pacemakers or defibrillators, electrocautery is a safe alternative to electrosurgery for hemostasis.

23.11 Trap Door (Pincushioning) Deformities Trapdoor deformity is the bulging of tissue seen in C-, V-, or U-shaped scars and may be due to a variety of causes, including scar contracture, hypertrophy, and excessive tissue.82 It seems that this problem may be related to undermining.83, 84 The bilobed flap is a repair design that can lead to pincushioning but the rhombic bilobed flap may decrease the incidence of pincushioning.85 It has also been suggested that pincushioning secondary to the bilobed flap repair may be minimized if transposition of each flap is only 45° for a total of 90–100°.86 This defect may also be more likely to occur with flaps in the medial or superior portion of the face.84

23.11.1 Key Point 23.10 Defibrillators and Pacemakers Electrosurgery is used as a primary method of hemostasis in dermatologic surgery. Although use of electrosurgery in most patients does not seem to result in major complications, it has been reported to cause firing of implantable cardioverter-defibrillators (ICDs) and pacemaker reprogramming.80 Interference has been reported with electrocautery use80 but because no electrical current is generated with this method, it should be considered a safe alternative to electrosurgery in a patient with a pacemaker or ICD. Other precautions when operating

• Adequate undermining may decrease the likelihood of trapdoor deformities.

23.12 Flap and Graft Necrosis Skin flaps and grafts allow dermatologic surgeons to close large surgical defects in a way that results in optimal cosmesis. Unfortunately, flaps and grafts may

276

necrose and compromise cosmetic outcome. However, steps can be taken to decrease the risk of necrosis. Patients smoking a pack or more a day have been found to have an increased risk of full-thickness graft or flap necrosis compared to those who never smoked or those who smoked less than a pack a day.87 While some patients may not be willing to quit smoking prior to surgery, the surgeon should at least encourage the patient to try to decrease the amount smoked for a period both before and after surgery. Skin tension can predispose a flap to some necrosis88 and flap design should attempt to limit the amount of tension of the repair. Delicate surgical technique has been employed to decrease the likelihood of necrosis.89 Bolsters may be used but may not be needed for securing of fullthickness skin grafts in order to decrease the chance of necrosis.89 Full-thickness skin grafts are more likely to necrose than split thickness grafts and necrosis is more likely in composite grafts than other graft types.53 Recipient-site blood supply affects survival of a graft.53

23.12.1 Key Points • Encourage smokers with a flap or graft to decrease smoking, at least while the defect is healing. • Limit tension in repairs involving a flap or graft. • Recipient site blood supply can affect the viability of a graft.

23.13 Vasovagal Reaction A vasovagal reaction can result in patient harm if the patient falls and strikes a body part. In one study, 1% of surgical patients experienced vasovagal syncope, which occurred before, during, and after surgery.90 Fear, emotional stress, or acute pain may be triggers but the cause is often not identified.47 Skin may become cool and pale, bradycardia may follow tachycardia, blood pressure may drop initially, and acute brief loss of consciousness may occur.47 If a vasovagal reaction occurs, patient should be placed in a recumbent position.47

M. R. Hinckley

23.13.1 Key Points • Vasovagal reactions can occur in surgery patients, which can result in patient harm due to falling. • Patients who experience a vasovagal reaction should be placed in a recumbent position.

23.14 Litigation Perhaps every physician in the United States is affected in some way by litigation. Whether by the indirect effect of malpractice costs or the direct effect of utilizing resources to confront a lawsuit, litigation can be an influential aspect of medical practice. While preventing complications should help prevent lawsuits, other steps can be taken that might aid in avoiding litigation. Communication with patients and families, record keeping, informed consent, and availability of the attending doctor or an associate can potentially prevent lawsuits.91 While attention to all of these details is important, a good physician-patient relationship is likely the best way to prevent litigation.92 Such relationships between dermatologic surgeons and their patients should be an important part of every surgical practice.

23.14.1 Key Point • Communication and a good physician–patient relationship can help avoid litigation.

23.15 Conclusion Dermatologic surgery has proven to be a safe and effective method for treating skin disease. With a proper understanding of this field of medicine and by taking appropriate precautions, the majority of significant surgical complications can be kept to a minimum. Such practices will result in satisfying outcomes for physicians and healthier, happier patients.

23  Prevention of Surgical Complications

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M. R. Hinckley 52. Wahie S, Lawrence CM. Wound complications following diagnostic skin biopsies in dermatology inpatients. Arch Dermatol. 2007;143(10):1267–1271 53. Adams DC, Ramsey ML. Grafts in dermatologic surgery: review and update on full- and split-thickness skin grafts, free cartilage grafts, and composite grafts. Dermatol Surg. 2005;31(8 Pt 2):1055–1067 54. Lazareth I, Hubert S, Michon-Pasturel U, Priollet P. Vitamin C deficiency and leg ulcers. A case control study. J Mal Vasc. 2007;32(2):96–99 55. Rojas AI, Phillips TJ. Patients with chronic leg ulcers show diminished levels of vitamins A and E, carotenes, and zinc. Dermatol Surg. 1999;25(8):601–604 56. Wicke C, Halliday B, Allen D, et al. Effects of steroids and retinoids on wound healing. Arch Surg. 2000;135:1265–1270 57. Dostal GH, Gamelli RL. The differential effect of corticosteroids on wound disruption strength in mice. Arch Surg. 1990;125(5):636–640 58. Gordon AJ, Olstein J, Conigliaro J. Identification and treatment of alcohol use disorders in the perioperative period. Postgrad Med. 2006;119(2):46–55 59. Kiecolt-Glaser JK, Loving TJ, Stowell JR, et al. Hostile marital interactions, proinflammatory cytokine production, and wound healing. Arch Gen Psychiatry. 2005;2(12):1377–1384 60. Glaser R, Kiecolt-Glaser JK, Marucha PT, et  al. Stressrelated changes in proinflammatory cytokine production in wounds. Arch Gen Psychiatry. 1999;56(5):450–456 61. Chen MA, Davidson TM. Scar management: prevention and treatment strategies. Curr Opin Otolaryngol Head Neck Surg. 2005;13(4):242–247 62. Zitelli JA. Wound healing by second intention. In: Roenigk RK, Ratz JL, Roenigk HH Jr, eds. Roenigk’s Dermatologic Surgery: Current Techniques in Procedural Dermatology. 3rd ed. New York: Informa Healthcare; 2007 63. Orengo I, Iyengar V. Anatomy in cutaneous surgery. Emedicine. December 15, 2006. At: http://www.emedicine. com/derm/topic820.htm; 2007 Accessed 12.12.07 64. Berman B, Flores F. Comparison of a silicone gel-filled cushion and silicon gel sheeting for the treatment of hypertrophic or keloid scars. Dermatol Surg. 1999;25(6):484–486 65. Chung VQ, Kelley L, Marra D, Jiang SB. Onion extract gel versus petrolatum emollient on new surgical scars: a prospective double-blinded study. Dermatol Surg. 2006;32(2):193–197 66. Berman B, Perez OA, Konda S, et al. A review of the biologic effects, clinical efficacy, and safety of silicone elastomer sheeting for hypertrophic and keloid scar treatment and management. Dermatol Surg. 2007;33(11):1291–1302 67. Chang CC, Kuo YF, Chiu HC, et al. Hydration, not silicone, modulates the effects of keratinocytes on fibroblasts. J Surg Res. 1995;59:705–711 68. Zurada JM, Kriegel D, Davis IC. Topical treatments for hypertrophic scars. J Am Acad Dermatol. 2006;55(6):1024–1031 69. Weisberg NK, Nehal KS, Zide BM. Dog-ears: a review. Dermatol Surg. 2000;26(4):363–370 70. Lee KS, Kim NG, Jang PY, et al. Statistical analysis of surgical dog-ear regression. Dermatol Surg. 2008;34(8): 1070–1076 71. Robinson JK. The eye and eyelid. In: Roenigk RK, Ratz JL, Roenigk HH Jr, eds. Roenigk’s Dermatologic Surgery: Current Techniques in Procedural Dermatology. 3rd ed. New York: Informa Healthcare; 2007

23  Prevention of Surgical Complications 72. Revis DR, Seagle MB. Local anesthetics. Emedicine. October 26, 2005. At: http://www.emedicine.com/ent/ topic20.htm; 2007 Accessed 12.12.07 73. Zamanian RT, Olsson JK, Ginther B. Toxicity, local anesthetics. Emedicine. June 20, 2005. At: http://www.emedicine.com/emerg/topic761.htm; 2007 Accessed 12.12.07 74. Peralta R, Bastings E, Guzofski S. Toxicity, Lidocaine. April 25, 2007. Emedicine. At: http://www.emedicine.com/med/ topic1297.htm; 2007 Accessed 12.12.07 75. Cox B, Durieux ME, Marcus MA. Toxicity of local anaesthetics. Best Pract Res Clin Anaesthesiol. 2003;17(1): 111–136 76. Stasko S, Clayton AS. Surgical complications and optimizing outcomes. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. New York: Mosby; 2003 77. Fisher DA. A simple method of identifying the spinal accessory nerve. Dermatol Surg. 2000;26(4):384–386 78. Alam M, Goldberg LH. Two-lobed advancement flap for cutaneous helical rim defects. Dermatol Surg. 2003;29(10): 1044–1049 79. See A, Smith HR. Partially buried horizontal mattress suture: modification of the Haneke-Marini suture. Dermatol Surg. 2004;30(12 Pt 1):1491–1492 80. El-Gamal HM, Dufresne RG, Saddler K. Electrosurgery, pacemakers and ICDs: a survey of precautions and complications experienced by cutaneous surgeons. Dermatol Surg. 2001;27(4):385–390 81. Matzke TJ, Christenson LJ, Christenson SD, et  al. Pacemakers and implantable cardiac defibrillators in dermatologic surgery. Dermatol Surg. 2006;32(9):1155–1162 82. Koranda FC, Webster RC. Trapdoor effect in nasolabial flaps. Causes and corrections. Arch Otolaryngol. 1985;111(7): 421–424

279 83. Fader DJ, Johnson TM. Ear reconstruction utilizing the subcutaneous island pedicle graft (flip-flop) flap. Dermatol Surg. 1999;25(2):94–96 84. Albertini JG. Regarding the modified Burow’s wedge flap for upper lateral lip defects. Dermatol Surg. 2000;26(10): 981–982 85. Dinehart SM. The rhombic bilobed flap for nasal reconstruction. Dermatol Surg. 2001;27(5):501–504 86. Zitelli JA. The bilobed flap for nasal reconstruction. Arch Dermatol. 1989;125:957–959 87. Goldminz D, Bennett RG. Cigarette smoking and flap and full-thickness graft necrosis. Arch Dermatol. 1991;127: 1012–1015 88. Dixon AJ, Dixon MP. Reducing opposed multilobed flap repair, a new technique for managing medium-sized low-leg defects following skin cancer surgery. Dermatol Surg. 2004;30(11):1406–1411 89. Cook JL, Perone JB. A prospective evaluation of the incidence of complications associated with Mohs micrographic surgery. Arch Dermatol. 2003;139(2):143–152 90. Amici JM, Rogues AM, Lasheras A, et  al. A prospective study of the incidence of complications associated with dermatological surgery. Br J Dermatol. 2005;153(5):967–971 91. Colon VF. 10 ways to reduce medical malpractice exposure – doctors, lawyers and lawsuits. Physician Executive March, 2002. At: http://findarticles.com/p/articles/mi_m0843/ is_2_28/ai_84236558/pg_1; 2007 Accessed 12.12.07 92. Rice B. 10 ways to guarantee a lawsuit: medical mishaps are only part of the malpractice story. Here’s how to prevent the nonclinical errors that get doctors in legal trouble. Medical Economics Jul 8, 2005. At: http://www.memag.com/memag/ article/articleDetail.jsp?id=168737&sk=&date=&%0A% 09%09%09&pageID=3; 2007 Accessed 12.12.07

Prevention of Keloids

24

Hillary E. Baldwin

24.1 Introduction

24.2 Epidemiology

Unlike many skin disorders discussed in textbooks, keloids have been described in detail dating back to 3,000 bc.1 The Yoruba tribe of Western Africa recorded their knowledge of keloids in painting and sculpture ten centuries prior to modern times.2 Despite this considerable head start, we have made remarkably little progress since the Yorubas toward understanding keloid etiology. This fundamental ignorance is partially responsible for our current lack of consistently reliable, safe treatment, and prevention measures. Since treatment methods are inadequate in many and challenging in all, prevention becomes vitally important. Here, too, our efforts may be thwarted. There are aspects of keloids that are preventable; one can avoid trauma resulting from voluntary and elective procedures to adorn, augment, or improve. Aggressive prevention of keloids after accidental trauma and necessary surgery is also within our abilities. However, some putative causative factors of keloid formation are out of our control: ethnicity, skin pigmentation, age, gender, and genetic makeup. This chapter will focus on two aspects of prevention: avoidance techniques for the keloid prone and prevention of recurrence after surgical intervention. First, it will briefly review what is known about keloid epidemiology and pathogenesis to gain insight into the development of a rational prevention plan for these unsightly lesions.

The reported incidence of keloid formation has ranged from a low of 0.09% in England to a high of 16% in Zaire.3 Such variation is explained by numerous variables, including race and degree of skin pigmentation. In predominately black and Hispanic populations, incidences between 4.5 and 16% have been reported.4 Darkly pigmented individuals form keloids 2–19 times more frequently than Caucasians.5, 6 But ethnicity, regardless of pigment intensity, is also a factor. In Aruba, more children of the lighter-skinned Polynesian population form keloids than those of African descent.7 In Malaysia, those of Chinese decent are more prone to keloid formation than are the darker-skinned Indians and Malays.8 Although Caucasians form keloids less frequently, those who do can have a very light complexion. These patients are often among the most difficult to treat. Keloids can occur at any age. New keloid formation is relatively less common in the very young and the elderly. In young children, this may be a function of low trauma frequency and severity. Aging fibroblasts may be less capable of collagen over production.9, 10 Keloid regression after menopause has been reported.11 In an unpublished study of 212 Caribbean-American and African-American keloid-formers at Kings County Hospital, we found that age as an isolated factor did not correlate with keloid frequency. Rather, the timing of the pierce relative to puberty was predictive of keloid incidence. Small gender differences that have been reported in the literature are likely to have resulted from cultural trends and reporting bias. Multiple ear pierces are far more common in women than men as are the resulting keloids. Additionally, women may more readily seek medical attention for cosmetic improvement.

H. E. Baldwin  Department of Dermatology, SUNY – Brooklyn, Brooklyn, New York, USA e-mail: [email protected]

R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_24, © Springer-Verlag London Limited 2010

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24.3 Etiology The plethora of existing theories regarding the etiology of keloids is indicative of our lack of understanding of the condition. The factors that are most consistent are some form of skin trauma occurring in individuals with a genetic predisposition for keloids.

24.3.1 Trauma “Spontaneous” keloids arising in nontraumatized skin have been suggested. It is more likely however that the severity of the trauma was so minor as to go unnoticed by the patient. Minor abrasions and burns, insect bites, varicella and zoster, vaccinations and tattoos can result in significant keloiding. Acne lesions of the anterior chest and deltoid areas often morph imperceptibly into keloids. Isotretinoin treatment in these patients can prevent additional keloids even when the acne lesions are not readily identifiable. Deep and significant surgical wounds are often less likely to keloid than are the minor wounds described above. However, trauma is merely the precipitating etiologic factor. Most patients experiencing the same trauma do not keloid. Intrapatient variation is also common. Acne lesions immediately adjacent to each other, bilateral pierces, or adjacent pierces often have different outcomes. Lastly, areas prone to trauma such as the hands and feet rarely keloid.

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wound tension. Skin grafts may be preferable to ­primary closure of a tight wound, however, the donor wound may also be subject to keloid formation. The use of tissue expanders to stretch the skin preoperatively offers an alternative that both reduces wound closure tension and applies pressure preoperatively that might help reduce fibroblast function. Wound tension as a primary etiologic factor in keloid formation loses credibility when one considers the high incidence of earlobe keloids following piercing. The only tension on this wound is that of the minor edema that results from the trauma of the pierce. Chronic edema has been reported to increase glycosaminoglycans (GAGs) in the dermis.15 It is possible that the chronic edema caused by the pierce (and subsequent reaction to the presence of a metal foreign body) could result in increased incidence of keloid formation.

24.3.3 Infection There is no evidence to support the supposition that the infectious agents themselves cause keloids. However, the trauma, edema, and increased tension that occur as a result of wound infection might incite keloid formation. This possibility highlights the importance of assiduous avoidance and aggressive treatment of wound infections, especially in the keloid-prone individual.

24.3.4 Endocrine Factors 24.3.2 Skin Tension Keloids appear most commonly on areas in which skin tension is the highest, namely the anterior chest, upper back, and deltoid areas. The fleshy earlobes are obvious exceptions to this rule. As keloids progress in these areas, they tend to stretch along skin tension lines forming linear or bow-tie shaped lesions. Closing a wound against the relaxed skin tension lines results in a wound with twice the tension of one closed along Langer’s lines.12 Postsurgical wound tension has been implicated in the literature as a contributing factor in keloid formation.13, 14 The loss of tissue that results from surgical excisions also increases

Multiple and diverse endocrine factors have been associated with keloid incidence although causality is unproven. Keloids have been reported to grow more readily or to appear de  novo during pregnancy.11, 13 Keloids have been shown to be more common after puberty than before. This was well known by the Yorubas in the 1600s who knew to pierce ears early in life to prevent keloiding. They also used this knowledge to perfect ritual keloiding in intricate designs after the age of puberty. In our King’s County Hospital study, ear pierces that resulted in keloids occurred at a median age of 6.4 years postmenarche, whereas those that did not keloid were pierced at a median age of 4.25 years premenarche.16

24  Prevention of Keloids

Melanocyte-stimulating hormone (MSH) has been postulated to play a role in keloid formation. This hypothesis is based on the observation that keloids are more common in patients with hyperpigmentation associated with pregnancy, puberty, and hyperthyroidism. Melanocytes in patients with skin of color may be more reactive to MSH than Caucasians, explaining the higher incidence of keloids in darker-skinned patients. Additionally, keloids are rare on the melanocyte-poor regions of the palms and soles. However, the highly pigmented area of the genitalia is also an infrequent site of keloid formation. Finally, there has never been a reported case of keloid development in an albino patient, even one of African descent.

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Keloids are believed to have a familial predisposition, although the pattern of inheritance is unclear.3, 17 In our study at King’s County Hospital, we found a familial pattern in 32% of keloid formers. However, it is possible that the familial tendency to keloid is more a factor of similarity of skin coloration between family members than it is genetically inherited.

the plentiful new and dilated capillaries. Collagen ­synthesis and GAG synthesis are markedly increased; collagen synthesis is 20 times greater in keloids than in normal skin.18, 19 The absolute number of fibroblasts within the entire keloid is not increased, and they appear histologically normal, but the activity of proline hydroxylase is markedly elevated, suggesting that the rate of collagen biosynthesis is increased in a normally-sized fibroblast population.18, 20 Keloidal fibroblasts also appear to resist programmed cell death.21, 22 Defective apoptosis within keloids may be due to a dysfunctional form of p53. As we will see, injectable interferon may be effective in treating keloids by its enhancement of native p53. Although collagenase is also increased, collagen degradation is not, possibly due to an increased deposition of alpha-globulins within the keloid.23, 24 Serum alpha-globulins are known inhibitors of collagenase.23 Estrogens increase the level of serum alpha-globulins, which may help to explain the increased incidence of keloids in pregnant women.23 Corticosteroids, in contrast, have been shown to reduce the alpha-globulin deposits within keloids.23 They too may act by increasing activation of collagenase with subsequent breakdown and resorption of the excessive collagen and clinical flattening.

24.4 Pathogenesis

24.5 Preventative Therapy

Our understanding of keloid pathogenesis is composed of numerous isolated facts that as yet fail to form a cohesive picture. The simple answer to the pathogenesis puzzle is that keloid formation is caused by an increase in anabolic activity in the absence of increased catabolism. Why this happens is not known. After normal wounding takes place, various signals are sent to the neighboring fibroblasts to increase collagen and GAG production. Upon completion of the rebuilding task, signals are again sent to the fibroblasts to return to their prewound status. Abnormalities in these signals, particularly those that indicate reduction in collagen production, are believed to be responsible for keloid growth. Interferons may be one of those “stop” signals. In normal wounds, there is regression of connective tissue elements after the third week. In keloid tissue, however, fibroblasts proliferate around

In any medical inquiry, a literature review of available therapy requires attention to study design and validity of conclusions. This is nowhere more evident than in the field of keloidal scarring in which one must sift through large numbers of anecdotal reports and pure conjecture. The problem begins with the delineation of hypertrophic scars (HTSs) from keloids. Many studies include both entities in the admittance criteria yet fail to reveal, which lesions ultimately responded to therapy. Other patient and lesion characteristics routinely omitted from these studies include such important factors as patient race and age, lesion age and symptomatology, lesion size and location, recurrence vs. virgin lesion and lesion morphology (sessile vs. pedunculated or dome-shaped). Most reports also suffer from inadequate follow-up time of less than 6 months. It is an undisputable truth that keloid removal is easy; the trick is preventing recurrence or occurrence.

24.3.5 Genetic Predisposition

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In a recent review article, Shaffer et al. conclude that despite a plethora of papers on the topic of keloids, “there are no definitive treatment protocols.”25 This is a result of poorly designed and uncontrolled studies in which the endpoint of therapy (cosmesis, function, or symptoms) is rarely identified. Only radiation therapy (RT) in combination with surgery met their standards for proven therapy. Mustoe et  al also lamented the absence of well-controlled studies and concluded that corticosteroid injection and silicone gel sheeting (SGS) are the “… only treatments for which sufficient evidence exists to make evidence-based recommendations.”26 Durani and Bayat found SGS and laser therapy to have the highest level of support, albeit sub par.27 Leventhal et al noted that “most treatments for keloidal and hypertrophic scarring offer minimal likelihood of improvement.”28 Other treatments at this time are still lacking the proof of efficacy that arises only from a well-designed, randomized, placebo-controlled trial with adequate patient numbers. The nature of keloid therapy is such that a comparison of various techniques is often not amenable to double-blinding. We look forward to more studies in which single techniques are compared to controls, vehicles, or dummy therapy. At the present time, we must recognize that keloid prevention techniques are not necessarily evidencebased. We are using techniques for which definitive data does not exist. Presented below are the techniques that have become the standard of care in the field.

24.5.1 Corticosteroids Because of their ease of administration, low cost, and low risk, intralesional corticosteroids alone and in combination are the work horses of keloid occurrence and recurrence prevention. Although no solid evidence-based literature supports their use in this role, they have become the first-line approach of most physicians dealing with this condition worldwide.

24.5.1.1 Corticosteroids as Monotherapy for Keloid Prevention Triamcinolone acetonide (TAC) is the most commonly utilized corticosteroid. Concentrations from 10 to 40  mg/kg are used. Injections can be repeated every

H. E. Baldwin

2–4 weeks, depending on the total dose of steroid used and the size of the injected space. The most common cause of steroid “failure” is the use of inadequate concentrations. Concentrations less than 10 mg/mL are rarely effective in prevention. To avoid the risk of hypothalamic-pituitary axis suppression, this author does not inject more than 40 mg/session. This means that the total area treated in one session will be limited by total safe dose constraints. Better to inject an efficacious dose in a smaller area than to spread it so thin that it is ineffective. This concept must be kept in mind when planning the surgical excision of an existing keloid. It is imprudent to remove more keloid volume than can be subsequently injected for recurrence prevention; staged excisions may therefore be preferable. Although additional areas may be injected on the following weeks, it is best not to inject the same area with high doses at less than 2-week intervals. The depot effect of the injected steroids is such that repeat injections done too frequently can result in atrophy. Hypopigmentation is also more likely in this setting. With subsequent treatments, the strength of the steroid is often reduced in order to fine-tune the ultimate outcome.

24.5.1.2 Corticosteroids as Part of Polytherapy for Keloid Prevention Corticosteroids can be combined with any other treatment modality to improve outcome. Following surgical excision, many authors have shown a reduction in recurrence rates with the addition of postoperative corticosteroids.29, 30 Combinations with cryotherapy and silicone gel sheets have been shown to be superior to either modality alone.31 Corticosteroids plus alpha interferon have been shown to be more effective than corticosteroids alone.32, 33 Combinations with lasers and alpha interferon also have shown promise (see Sect. 24.5.10).34 Corticosteroids are an integral part of keloid prevention – both de novo occurrence in a new surgical wound and recurrence following keloid excision. This author follows the following injection schedule. On the day of surgery, and then at 2, 4, and 6 weeks, the wound margins are injected with TAC 40 mg/mL regardless of the appearance of the wound. At 2 months, and every month thereafter, injections are given as clinically necessary. At that point, dosage of the corticosteroids given at each session is determined

24  Prevention of Keloids

clinically by the site, size, degree of firmness, and symptoms the patient is experiencing. Preventative therapy is best carried out for 1 full year; early discontinuation is associated with a higher incidence of unnecessary recurrences. Common side effects of steroid injections include hypopigmentation and skin atrophy. The hypopigmentation can be pronounced and may last 6–12 months before resolving. However, hypopigmentation can also be used as a marker of clinical success. Both hypopigmentation and atrophy can be reduced by avoiding injecting into the surrounding normal tissue. Skin atrophy is often a necessary consequence of adequate therapy. After treatment, the atrophic surface may appear wrinkled or shiny, and telangiectasias are common. This appearance improves with time. Alternatively, vascular lasers can be utilized to lessen the telangiectasias.

24.5.2 Surgical Methods to Prevent Keloid Recurrence Surgical removal of large, bulky keloids is often necessary. However, monotherapy results in a high incidence of recurrence, often 50–100%.30, 35 Surgery must be combined with adjunctive techniques such as RT, steroids, or interferon.

24.5.2.1 Use the Smallest Incision as Possible The smallest incision possible is made, extending less than the entire length of the keloid. Dissect off any usable epidermis from the keloid for ease of closure.

24.5.2.2 Remove all Keloidal Tissue Unless it would result in gross deformity or loss of function, all of the keloid material should be removed. Care should be taken to remove any trapped hairs.

24.5.2.3 Minimize Wound Tension Closure should be done with the least amount of tension. Surgery followed by grafting alone results in a

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superior nonrecurrence rate over primary closure (59%).17 However, donor-site keloids are likely. As a result, tissue expanders may be preferable.

24.5.2.4 Suture Considerations Whenever possible monofilament suture should be used to reduce the incidence of wound infection, abscess formation and inflammation along the suture line. Sutures often need to be left in longer than usual to prevent dehiscence. This is especially true when steroids are injected postoperatively. If the resulting wound is fairly superficial or very broad, and the patient is amenable, allowing the wound to heal by secondary intention often results in better cosmetic outcome and a lower incidence of recurrence.

24.5.3 Earlobe Keloids Earlobes keloids need to be considered separately. Many authors have noted a lower rate of keloid recurrence in the earlobe.36, 37 Studies have shown a recurrence rate of only 41% respectively after surgery alone.38 Studies utilizing both surgery and steroids have shown recurrence rates of 1–20%.39 – 41 Surgery with adjunctive RT has resulted in recurrence rates of 0–8.6%.39, 42 – 44 With careful, aggressive therapy and using multiple modalities, earlobe keloids rarely recur. Better surgical results on earlobes are probably the result of several factors. First-time earlobe lesions tend to be very discrete, and easily separated from the surrounding dermis and epidermis. Complete removal of all keloidal tissue is thus easier to accomplish. Most earlobe keloids occur in women who are profoundly motivated to wear earrings again, and are far more compliant than the average keloid patient. The fleshy tissue of the ear makes closure without tension easier to accomplish. Postoperative pressure is easily applied with the use of pressure earrings. These earrings are not particularly cosmetically appealing, but the patients find them easy to wear and comfortable. They also make an ideal postoperative dressing, obviating the need for bulky, and often, inadequate pressure dress­ ings.

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24.5.4 Laser Surgery After initial excitement over the demonstrated ability of the CO2 laser to decrease fibroblast activity in vitro, its use in keloid therapy was a disappointment.44 – 47 Used in the defocused mode, recurrence rate is extremely high.48 In the focused mode, recurrence rate is similar to surgery alone (50–70%).46, 49 The Nd-YAG laser has been demonstrated to cause an in vitro selective bioinhibition of collagen production, but recurrence rates of 53–100% in vivo.50 The pulsed dye laser (PDL) has been reported to improve hypertrophic scar (HTS) symptoms, decrease scar height, and improve skin texture. Alster and Williams showed a 57–83% improvement with the 585 nm flashpump PDL in the prevention of keloids in sternotomy scars.51 They noted the importance of starting therapy early for the best results. It has been proposed that the PDL decreases the microvasculature in early keloids and HTSs resulting in anoxia. Several combination studies have shown that PDL works better in combination with other modalities, including corticosteroids, interferon, and carbon dioxide laser.24, 52 – 55

24.5.5 Radiation Therapy The mechanism of action of RT in prevention of keloids is unknown. It may decrease fibroblast collagen synthesis.56 Alternatively, it may act by decreasing vascular hyperplasia.57 For prophylaxis in keloid-prone individuals, X-radiation, electron beam, and interstitial radiation have all been reported to result in similar cure rates (recurrence rates near 20%, which are far superior to other modalities).58 – 60 Dosing schedule and fractionation have varied greatly from one study to another, but outcomes are similar. A minimum of 1,000 rads or equivalent appears to be the common consensus for successful outcome.61 Kal and Veen concluded that RT should be done within 2 days of surgical removal, and that short treatment durations and “relatively high doses” are necessary.62 In a study of earlobe keloids, surgery plus RT was compared to surgery plus corticosteroids.39 Recurrence rates were 12.5 and of 33%, respectively. Recurrence rates of 4.7% with high-dose-rate brachytherapy,63 21% with interstitial iridium-192,64 16, 19, and

H. E. Baldwin

32% with electron beam65 – 67 have been demonstrated. Recurrence rates have been shown to be higher in areas of high tension such as the chest, scapula, and suprapubic areas in three studies.66 – 68 The short treatment plan required with RT may aid in patient compliance. Despite its high incidence of success in preventing keloid recurrence, RT is avoided by many clinicians due to largely unfounded concerns regarding the longterm risks of malignancy of the skin or underlying structures. Numerous large studies report a 0% ­carcinogenesis rate.61 Only one reported case of squamous cell carcinoma arising in postkeloid radiation site is evident in the literature, and the causality is unclear.69 Botwood et  al attempted to put these concerns into perspective.61 In more than 100 years in clinical use, there are only three case reports of malignancies occurring postkeloid RT. Breast cancer in a 57-year-old woman occurring 29 years after RT to a chest keloid was reported in 1999.61 Breast cancer in a 36-year-old woman 23 years after chest wall keloid radiation was reported in 198270 In both cases, confounding variables were also evident (7-year history of hormone replacement therapy and evidence of unusually high radiation doses, respectively). A single case report of thyroid cancer occurring in a 27-year-old man 8 years after RT to a keloid of the chin has also been reported.71 Histopathology revealed a medullary carcinoma; radiation-induced carcinomas of the thyroid are exclusively papillary carcinomas.72 Based on dosimetry studies, RT in standard dosages to the ear with proper shielding would expose the ipsilateral thyroid lobe to only 2 rads.61 Studies therefore do not warrant a high level of concern. Common side effects to consider are skin atrophy, radiation dermatitis, abnormal skin pigmentation, and local alopecia. RT is not recommended in children with keloids; if used, metaphyses must be shielded to prevent retardation of bone growth, which may occur at doses of 400 R and less.73

24.5.6 Compression Therapy Compression therapy – applying pressure greater than that of capillary pressure [24 mmHg) – causes a reduction in soft tissue cellularity. Histopathology shows increased interstitial space and collagen bundles that are more widely dispersed.74 It is theorized that pressure

24  Prevention of Keloids

creates hypoxia resulting in fibroblast degeneration and subsequent collagen degradation. Dressings, which apply 15–45 mmHg, worn 24 h a day for 4–6 months are often successful in reducing keloid recurrence rates postoperatively. Not all areas are amenable to pressure dressings, which in any event are uncomfortable, hot, and unsightly. Ears are the exception to this rule. Newer pressure earrings have large compression plates that are more comfortable to wear. “Sleeper” styles are less bulky and less con­ spicuous.

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SGS has been touted in many studies to be efficacious in preventing the development of HTSs and keloids.75 – 77 These studies are marred by the absence of blinding and control, small patient numbers and inadequate follow-up time. SGS has been shown in small studies to reduce HTS formation by as much as 70% when used consistently.77 It must be worn over a scar for 2–3 months, 12–24  h a day to prevent development.78 Sheets are available in varying thicknesses and consistency. Adhesive tape is necessary for consistent application. A new formulation of silicone gel has recently been reported.79, 80 The gel is self-drying and forms a flexible and transparent sheet after application, obviating the need for tape. The mechanism of action of SGS is unknown. SGS is known to retard epidermal water loss. The drier agents have been shown to create static electricity, which some believe to play a role in its effectiveness. In a controlled, prospective nonblinded study, SGS was compared to an occlusive dressing without silicone.81 SGS was not found to be superior, leading the authors to conclude that it was wound hydration, not the presence of silicone that was responsible for the clinical effect.

and collagen. Interferons are one of these signals. Berman and Duncan reported that short-term intralesional interferon alpha-2b treatment of a keloid resulted in a selective and persistent normalization of keloidal fibroblast collagen, GAG and collagenase production in vitro, and a rapid reduction in the area of the keloid.82 Interferon has also been shown to upregulate native p53 that is dysfunctional in keloidal fibroblasts.83 This might promote the natural cell death of the overactive fibroblasts. Both alpha and gamma interferon are available for use. Initial clinical trials with gamma interferon were disappointing and it is no longer in use.84 Granstein has reported on an unpublished study where 18 of 19 keloid reexcisions were accomplished without recurrence at 1 year by two postoperative injections of interferon alpha (Granstein, Personal communication, 1996). Berman reported response in 11/12 recurrent keloids of the head and neck after surgical excision and interferon alpha 2b.85 Berman and Flores reported a recurrence rate of 51.5% following surgery alone, 58.4% after surgery and corticosteroids, and 18.7% when surgery was combined with both interferon and corticosteroid injections.32 At Kings County Hospital, we have found that interferon alpha injections can be used to decrease keloid recurrence after earlobe keloid excisions in which keloidal tissue was left behind. Injections of interferon alpha-2b are done on the day of surgery and then 1 week postoperatively directly into the wound. One million units per linear centimeter are injected into the wound base and margins. In the case of a wound allowed to heal by secondary intention, injections are given approximately every square centimeter. Side effects are reduced by limiting total dose to less than five million units per treatment. Side effects of interferon alpha-2b include a flu-like syndrome, which can be reduced or eliminated by the prophylactic use of acetaminophen, and timing of the injection late in the afternoon so that mild febrile reactions pass unnoticed during sleep.

24.5.8 Interferon

24.5.9 Imiquimod Application

As discussed previously, fibroblast activity increases dramatically after wounding. Once the wound is adequately stabilized, signals are sent to the fibroblasts to shut off this excessive production of ground substance

Imiquimod 5% cream is a potent and rapid inducer of interferon after topical application. Topical application of imiquimod to keloids has been shown to significantly alter gene expression of markers of apoptosis.83

24.5.7 Silicone Products

288

As such, its use in keloid therapy was a logical ­continuance from injectable interferon. Berman and Kaufman reported its use postoperatively in an uncontrolled pilot study of 13 keloids removed from 12 patients.86 Applications were done twice daily, beginning on the day of surgery and continuing for 8 weeks. At 24 weeks, none of 11 keloids (ten earlobe, one trunk) evaluated had recurred. The authors have subsequently reported one recurrence in the lesion removed from the back. Since then, several other small, uncontrolled trials have suggested that imiquimod is most effective on the  earlobes. Stashower showed no recurrence at 12 months in four patients with eight earlobe keloids.87 Martin-Garcia and Busquets reported a 25% recurrence rate in eight earlobe keloids.88 Chaungsuwanich and Gunjittisomram showed an overall 6-month recurrence rate of 28.6% in 35 patients.89 Recurrences on the pinna were rare (2.9%) and those of the chest common (83.3%). Malhotra et al showed an improvement after surgical excision of three presternal keloids in two patients over the 8-week treatment phase, but recurrence 4 weeks later in all patients.90 In an ongoing study, we have found a modest reduction in keloid recurrence in nonearlobe keloids treated with imiquimod. In a placebo-controlled, double-blind study of six patients with 12 nonadjacent keloids, we found a 50% reduction in keloid reformation. The recurrences in the imiquimod-treated areas occurred later and were easier to treat than placebo-treated recurrences. More controlled studies need to be performed to assess the effectiveness of this treatment modality. In all of the studies mentioned, there were few topical and no systemic side effects noted. Application of imiquimod to open wounds was mostly nonirritating. Discontinuation for several days was adequate to control this unlikely side effect.

24.5.10 Combination Therapy There is no medical reason to limit preventative treatment to a single agent or modality. Prevention of recurrence or occurrence can be greatly improved when all available modalities are utilized simultaneously. Interferon injections at day 1 and day 8 combined with RT can deliver two adjunctive therapies in the first 2 weeks post-op when patient compliance is at its peak.

H. E. Baldwin

Pressure dressings if possible, imiquimod application and continue corticosteroid injections as previously delineated can be used in conjunction to maximize outcome.

24.6 Keloid Avoidance Behaviors The first goal of therapy is, of course, prevention of unnecessary trauma. Cosmetic procedures should be discouraged. Ears from which keloids have been removed should not be repierced. Early and aggressive treatment of accidental wounds or nonelective surgeries is crucial in keloid-prone individuals. Necessary surgical procedures should be closed parallel to relaxed skin tension lines with minimal stress. Skin grafts, tissue expanders, and healing by secondary intention should be considered to minimize wound tension. Wounds should be covered with SGS and/or pressure garments whenever possible. Preventative intralesional corticosteroids should be injected at the time of the procedure and regularly thereafter. Intralesional interferon and RT should also be considered. Often this must be coordinated in advance with the patient’s general surgeon. Such interference is not always appreciated and it is prudent to elicit the help of the patient in convincing the surgeon of the importance of early intervention. Patients in whom acne lesions tend to form keloids must be carefully monitored and treated. They should be educated to present at the first sign of an inflammatory acne lesion for intralesional steroids. Multiple lesions are an indication for oral antibiotics or a course of isotretinoin. Similarly, in dark-skinned individuals with a family history of keloid formation, varicella or zoster should be aggressively treated with antiviral agents.

24.7 Summary Keloids are a challenging problem for which there is no quick fix, or indeed the promise of a fix at all. Beyond the futility of telling a patient not to get injured, many aspects of keloids cannot be changed. Age, ethnicity, skin coloration, genetic makeup, and hormonal influences are not alterable. Preventative care therefore, is

24  Prevention of Keloids

more focused on prevention of occurrence of new lesions in a keloid-prone individual and the prevention of recurrence after surgical removal.

References   1. Breasted JH. The Edwin Smith Surgical Papyrus, Vol I: Hieroglyphic Translation and Commentary. Chicago: University of Chicago; 1930:403–406   2. Omo-Dare P. Yoruban contribution to literature on keloids. J Nat Med Assoc. 1973;65:367–406   3. Bloom D. Heredity of keloids: review of the literature and report of a family with multiple keloids for five generations. N Y State J Med. 1956;56:511   4. Abrahms B, Benedetto A, Humeniuk H. Exuberant keloidal formation. JAOAC Int. 1993;93:863–865   5. Brenizer A. Keloid formation in the Negro. Ann Surg. 1915; 61:87   6. Fox H. Observations on skin diseases in the American Negro. J Cutan Dis. 1908;26:67   7. Alhady SM, Sivanantharajah K. Keloids in various races; a review of 175 cases. Plast Reconstr Surg. 1969;44:564   8. Arnold H, Graver F. Keloids: etiology and management. Arch Dermatol. 1959;80:772   9. Rockwell W, Cohen I, Erlich H. Keloids and hypertrophic scars. A comprehensive review. Plast Reconstr Surg. 1989; 84:827–837 10. Davies D. Scars, hypertrophic scars and keloids. Plast Reconstr Surg. 1985;290:1056–1058 11. Kelly P. Keloids. Dermatol Clin. 1988;6:413–424 12. Flint M. The biological basis of Langer’s lines. In: Longacre JJ, ed. The Ultrastructure of Collagen. Springfield IL: Charles C Thomas; 1976:132–140 13. Stucker F, Shaw G. An approach to management of keloids. Arch Otolaryngol Head Neck Surg. 1992;118:63–67 14. Asboe-Hansen G. Hypertrophic scars and keloids; etiology, pathogenesis and dermatologic therapy. Dermatologia. 1960;120:178 15. Kormoczy B. Enormous keloid (?) on a penis. Br J Plast Surg. 1978;31:268 16. Lane J, Waller J, Davis L. Relationship between age of ear piercing and keloid formation. Pediatrics. 2005;115: 1312–1314 17. Cosman B, Crikelair G, Ju M, Gaulin J, Lattes R. The surgical treatment of keloids. Plast Reconstr Surg. 1961;27:335–345 18. Abergel R, Pizzurro D, Meeker C, et al Biochemical composition of the connective tissue in keloids and analysis of collagen metabolism in keloid fibroblast cultures. J Invest Dermatol. 1985;84:384–390 19. Cohen I, Keiser H, Sjoerdsma A. Collagen synthesis in human keloid patients. Plast Reconstr Surg. 1979;63:689 20. Tan E, Rouda S, Greenbaum S, et al Acidic and basic fibroblast growth factors downregulate collagen gene expression in keloid fibroblasts. Am J Pathol. 1993;142:463–470 21. Sayah DN, Soo C, Shaw WW, et al Downregulation of apoptosis-related genes in keloid tissues. J Surg Res. 1999;87: 209–216

289 22. Akasaka Y, Fujita K, Ishikawa Y, et al Detection of apoptosis in keloids and a comparative study on apoptosis between keloids, hypertrophic scars, normal healed fibrotic scars, and dermatofibroma. Wound Repair Regen. 2001;9:501–506 23. Diegelmann R, Bryant C, Cohen I. Tissue alpha globulins in keloid formation. Plast Reconstr Surg. 1977;59:481 24. Bauer E, Eisen A, Jeffrey J. Regulation of vertebrate collagenase activity in  vivo and in  vitro. J Invest Dermatol. 1972;59:50–55 25. Shaffer J, Taylor S, Cook-Bolden F. Keloidal scars: a review with a critical look at therapeutic options. J Am Acad Dermatol. 2002;46:S63–S97 26. Mustoe T, Cooter R, Gold M, et al International clinical recommendations on scar management. Plast Reconstr Surg. 2002;110:560–571 27. Durani P, Bayat A. Levels of evidence for the treatment of keloid disease. J Plast Reconstr Aesthet Surg. 2008;61:4–17 28. Lenventhal D, Furr M, Reiter D. Treatment of keloids and hypertrophic scars: a meta-analysis and review of the literature. Arch Facial Plast Surg. 2006;8:362–368 29. Lahiri A, Tsiliboti D, Gaze N. Experience with difficult keloids. Br J Plast Surg. 2001;54:633–635 30. Lawrence W. In search of the optimal treatment of keloids: report of a series and a review of the literature. Ann Plast Surg. 1991;27:164–178 31. Yosipovitch G, Widijanti Sugene M, Goon A, et  al A Comparison of the combined effect of cryotherapy and corticosteroid injections versus corticosteroids and cryotherapy on keloids: a controlled study. J Dermatol Treat. 2001;12:87–90 32. Berman B, Flores F. Recurrence rates of excised keloids treated with postoperative triamcinolone injections of interferon alpha 2b. J Am Acad Dermatol. 1997;37:755–757 33. Lee J, Kim S, Lee A. Effects of interferon-alpha2b on keloid treatment with triamcinolone acetonide intralesional injection. Int J Dermatol. 2008;47:183–186 34. Akoz T, Gideroglu K, Akan M. Combination of different techniques for the treatment of earlobe keloids. Aesthetic Plast Surg. 2002;26:184–188 35. Darzi M, Chowdi N, Kaul S, et  al Evaluation of various methods of treating keloids and hypertrophic scars: a 10-year follow-up study. Br J Plast Surg. 1992;45:374–379 36. Ogawa R, Miyashita T, Hyakusoku H, et  al Postoperative radiation protocol for keloids and hypertrophic scars: statistical analysis of 370 sites followed for over 18 months. Ann Plast Surg. 2007;59:688–691 37. Narkwong L, Thirakhupt P. Postoperative radiotherapy with high-dose-rate iridium 192 mould for prevention of earlobe keloids. J Med Assoc Thai. 2006;89:428–433 38. Rauscher G, Kolmer W. Treatment of recurrent earlobe keloids. Cutis. 1996;38:67–68 39. Sclafani A, Gordon L, Chadha M, Romo T. Prevention of earlobe keloid recurrence with postoperative corticosteroid injections versus radiation therapy. Dermatol Surg. 1996;22: 569–574 40. Shons A, Press B. The treatment of earlobe keloids by surgical excision and postoperative triamcinolone injection. Ann Plast Surg. 1983;10:480–482 41. Rosen D, Patel M, Freeman K, Weiss P. A primary protocol for the management of ear keloids: results of excision combined with intraoperative and postoperative steroid injections. Plast Reconstr Surg. 2007;120:1395–1400

290 42. Akita S, Akino K, Yakabe A, et al Combined surgical excision and radiation therapy for keloid treatment. J Craniofac Surg. 2007;18:1164–1169 43. Ragoowansi R, Cornes P, Glees J, et al Earlobe keloids: treatment by a protocol of surgical excision and immediate postoperative adjuvant radiotherapy. Br J Plast Surg. 2001;54: 504–508 44. Chaudhry M, Akhtar S, Duvalsaint F, et al Earlobe keloids, surgical excision followed by radiation therapy: a 10-year experience. Ear Nose Throat J. 1994;73:779–781 45. Stern J, Lucente F. Carbon dioxide laser excision of earlobe keloids. Arch Otolaryngol Head Neck Surg. 1988;113: 1107–1111 46. Kantor G, Wheeland R, Bailin P, et al Treatment of earlobe keloids with carbon dioxide laser excision: a report of 16 cases. J Dermatol Surg Oncol. 1985;11:1063–1067 47. Driscoll B. Treating keloids with carbon dioxide lasers. Arch Otolaryngol Head Neck Surg. 2001;127:1145 48. Alster T. Laser treatment of hypertrophic scars, keloids, and striae. Dermatol Clin. 1997;15:419–429 49. Apfelberg D, Maser M, White D, Lash H. Failure of carbon dioxide laser excision of keloids. Lasers Surg Med. 1989;9: 382–388 50. Sherman R, Rosenfeld H. Experience with the NDYAG laser in the treatment of keloid scars. Ann Plast Surg. 1988;24: 231–233 51. Alster T, Williams C. Treatment of keloid sternotomy scars with 585 nm flashlamp-pumped pulsed-dye laser. Lancet. 1995;345:118–200 52. Connell P, Harland C. Treatment of keloid scars with pulsed dye laser and intralesional steroids. J Cutan Laser Ther. 2000;2:147–159 53. Maniskiatti W, Fitzpatrick R. Treatment response of keloidal and hypertrophic, sternotomy scars: comparison among intralesional corticosteroid, 5-fluorouracil, and 585-nm flashlamp-pumped pulsed-dye laser treatments. Arch Dermatol. 2002;138:1149–1155 54. Asilian A, Darougheh A, Shariati F. New combination of triamcinolone, 5-fluorouracil, and pulsed-dye laser for treatment of keloid and hypertrophic scars. Dermatol Surg. 2006;32:907–915 55. Alster T, Handrick C. Laser treatment of hypertrophic scars, keloids, and striae. Semin Cutan Med Surg. 2000;19:287–292 56. Order S, Donaldsen S. Radiation Therapy for Benign Disease. Springer; 1990:147–153 57. Borok T, Brav M, Sinclair I, et al Role of ionizing irradiation for 393 keloids. Int J Radiat Oncol Biol Phys. 1988;15:865–870 58. Ollstein R, Siegel H, Gillooley J, et al Treatment of keloids by combined surgical excision and immediate postoperative X-ray therapy. Ann Plast Surg. 1981;7:281–285 59. Khumpar D, Murray J, Anscher M. Keloids treated with excision followed by radiation therapy. J Am Acad Dermatol. 1994;31:225–231 60. Darzi M, Chowdi N, Kaul S, Kahn M. Evaluation of various methods of treating keloids and hypertrophic scars: a 10-year experience. Int J Radiat Oncol Biol Phys. 1989;17:77–80 61. Botwood N, Lewanski C, Lowdell C. The risks of treating keloids with radiotherapy. Br J Radiol. 1999;72:1222–1224 62. Kal H, Veen R. Biologically effective doses of postoperative radiotherapy in the prevention of keloids. Dose-effect relationship. Strahlenther Onkol. 2005;181:717–723

H. E. Baldwin 63. Guix B, Henriquez I, Andres A, et al Treatment of keloids by high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. 2001;50:167–172 64. Escarmant P, Zimmerman S, Amar A, et al The treatment of 783 keloid scars by iridium 192 interstitial radiation after surgical excision. Int J Radiat Oncol Biol Phys. 1993;26:245–251 65. Maarouf M, Schleicher U, Schmachtenberg A, Ammon J. Radiotherapy in the management of keloids. Clinical experience with electron beam irradiation and comparison with X-ray therapy. Strahlenther Onkol. 2002;178:330–335 66. Bischof M, Krempien R, Debus J, Treiber M. Postoperative electron beam radiotherapy for keloids: objective findings and patient satisfaction in self-assessment. Int J Dermatol. 2007;46:971–975 67. Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T. Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: retrospective study of 147 cases followed for more than 18 months. Plast Reconstr Surg. 2003;111:547–553 68. Wagner W, Alfrink M, Micke O, et al Results of prophylactic irradiation in patients with resected keloids: a retrospective analysis. Acta Oncol. 2000;39:217–220 69. Mizuno H, Cagri Uysal A, Koike S, Hyakusoku H. Squamous cell carcinoma of the auricle arising from keloid after radium needle therapy. J Craniofac Surg. 2006;17:360–362 70. Bilbey J, Muller N, Miller R, Nelemus B. Localized fibrous mesothelioma of pleura following external ionizing radiation therapy. Chest. 1988;94:1291–1292 71. Hoffman S. Radiotherapy for keloids? Ann Plast Surg. 1982; 9:265 72. Sampson R, Kev C, Buschler C, Iijima S. Thyroid carcinoma and radiation. JAMA. 1969;209:65 73. Doornbos J, Stoffel T, Hass A, et al The role of kilovoltage irradiation in the treatment of keloids. Int J Radiat Oncol Biol Phys. 1990;18:833–838 74. Kosaka M, Kamiishi H. New concept of balloon-compression wear for the treatment of keloids and hypertrophic scars. Plast Reconstr Surg. 2001;108:1454–1455 75. Gold M. A controlled clinical trial of topical silicone gel sheeting in the treatment of hypertrophic scars and keloids. J Am Acad Dermatol. 1994;30:506–507 76. Fulton J. Silicone gel sheeting for the prevention and management of evolving hypertrophic and keloid scars. Dermatol Surg. 1995;21:947–951 77. Ahn S, Monafo W, Mustoe T. Topical silicone gel: a new treatment for hypertrophic scars. Surgery. 1989;106:781–786 78. Berman B, Perez O, Konda S, et al A review of the biologic effects, clinical efficacy, and safety of silicone elastomer sheeting for hypertrophic and keloid scar treatment and management. Dermatol Surg. 2007;33:1291–1302 79. Mustoe T. Evolution of silicone therapy and mechanism of action in scar management. Aesthetic Plast Surg. 2008;32: 82–92 80. Signorini M, Clementoni M. Clinical evaluation of a new self-drying silicone gel in the treatment of scars: a preliminary report. Aesthetic Plast Surg. 2007;31(2):183–187 81. Viana de Oliveira G, Nunes T, Magna L, et al Silicone versus nonsilicone gel dressings: a controlled trial. Dermatol Surg. 2001;27:721–726 82. Berman N, Duncan M. Short-term keloid treatment in vivo with human interferon alfa-2b results in a selective and

24  Prevention of Keloids persistent normalization of keloidal fibroblast collagen, glycosaminoglycans and collagenase production in  vitro. J Am Acad Dermatol. 1989;21(4 Pt 1):694–702 83. Jacob S, Berman B, Vincek V. Topical application of imiquimod 5% cream to keloids alters expression genes associated with apoptosis. Br J Dermatol. 2008;149:62–65 84. Granstein R, Rook A, Flotte T, et al Intralesional interferon gamma treatment for keloids and hypertrophic scars. Arch Otolaryngol Head Neck Surg. 1990;118:1159–1162 85. Berman B, Bieley H. Adjunct therapies of surgical management of keloids. Dermatol Surg. 1996;22:126–130 86. Berman B, Kaufman J. Pilot study of the effect of postoperative imiquimod 5% cream recurrence rate of excised keloids. J Am Acad Dermatol. 2002;47:S209–S211

291 87. Stashower M. Successful treatment of earlobe keloids with imiquimod after tangential shave excision. Dermatol Surg. 2006;32:380–386 88. Martin-Garcia R, Busquets A. Postsurgical use of imiquimod 5% cream in the prevention of earlobe keloid recurrences: results of an open-label, pilot study. Dermatol Surg. 2005;31:1394–1398 89. Chuangsuwanich A, Gunjittisomram S. The efficacy of 5% imiquimod cream in the prevention of recurrence of excised keloids. J Med Assoc Thai. 2007;90:1363–1367 90. Malhotra A, Gupta S, Khaitan B, Sharma V. Imiquimod 5% cream for the prevention of recurrence after excision of presternal keloids. Dermatology. 2007;215:63–65

1

Appendix Patient Handouts: Preventive Dermatology Topics Robert A. Norman and Lana H. McKinley

1.1 Your General Health Achieving healthy skin involves establishing and maintaining your general health. This includes obtaining optimal nutrition, exercising regularly, and caring for your overall mental and physical health. • Consume a variety of foods and beverages within the basic food groups that are nutrient-dense. Limit the intake of saturated and trans fats, cholesterol, added sugars, salt, and alcohol. • For those who do drink alcoholic beverages, moderation is key. One drink per day for women, and up to two drinks per day for men. • Reduce a sedentary lifestyle by engaging in regular physical activity. This will help promote your psychological well-being and help you maintain a healthy body weight. –– Engage in at least 30 min of moderate-intensity physical activity, above usual activity, at work or home on most days of the week. This will help reduce the occurrence of chronic disease in adulthood. –– Greater health benefits can be obtained by engaging in physical activity of more vigorous intensity or longer duration. It is important to check with your physician regarding the intensity, frequency, and duration of your exercise routine. –– Concentrate on cardiovascular conditioning, stretching exercises, and resistance exercises for muscle strength and endurance.

R. A. Norman (*) Nova Southeastern University, Ft. Lauderdale, Florida and Private Practice, Tampa, FL, USA e-mail: [email protected]

• Do not smoke. • Schedule regular visits with your physician.

1.1.1 Helpful Websites http://www.americanheart.org/ http://www.mayoclinic.com/health/

1.2 Sun Damage and Skin Cancer Prevention General skin health can be maintained by avoiding damage to the skin by acute irritations, such as sunburn, or chronic damage resulting in precancerous and cancerous lesions. Photodamage from natural or artificial sunlight can affect people differently depending on their skin type. However, no skin type is totally immune from the long-term exposure to ultraviolet radiation.

1.2.1 Tips on Prevention • Avoid peak sunlight hours (10:00 am to 3:00 pm). • Avoid artificial sources of ultraviolet radiation, especially tanning beds and sunlamps. • Make sun exposure gradual by limiting the first day to 15 min, 30 min the second, and 45 min the third even if you use sunscreen each time. • Be aware of any photosensitizing medications such as certain antibiotics; avoid ultraviolet radiation during the course of the medication.

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• Use a sunscreen rated SPF-15 or higher that is PABAfree on all areas of exposed skin 30–45  min before going out into sun. Do not forget to include your lips. • Remember that the sun can still be harmful on cloudy days. Reapply sunscreen every 2–3 h when in the sun. • Wear sunglasses, hats, and protective clothing when in the sun. • Educate your children about the harmful effects of sunlight. • Inspect your skin monthly for changes and visit your dermatologist routinely to be examined for precancerous or cancerous skin growths. Skin changes to be aware of include: scaly red patches that itch or bleed and do not heal, elevated growths, and open sores. • Other skin changes to watch out for are moles that appeared after the age of 21, which have increased in thickness or size, or have changed in color, shape, or texture. • Discuss treatment options for precancerous lesions such as actinic keratoses with your dermatologist. Treating these lesions early can prevent the potential for cancerous transformation.

1.2.2 Helpful Websites

R. A. Norman and L. H. McKinley

drying and peeling, and medications that help free blocked pores. One or all may be necessary to help control acne. Severe nodular and cystic acne may require more aggressive therapy and often is treated with isotretinoin.

1.3.2 Tips on Prevention • Keep face clean with gentle washings once or twice daily. • Avoid picking or “pimple popping” as this may promote scarring. • Wash pillow cases and towels often. • Shower and wash face shortly after workouts. • Throw out old makeup and be sure to clean cosmetic brushes. • Use nonclog-forming, oil-free cosmetics, and suntan lotions. • Keep hair off face, neck, and shoulders by pulling it back if it is long. • Hair conditioner or oil-based hair products should be avoided. • Avoid tight fitting clothing on acne prone areas. • Regular exercise works to promote increased circulation and oxygenation to the skin. • Avoid aggressive scrubbing of face; this tends to only irritate and cause existent acne.

http://www.skincancer.org/squamous/ http://www.cancer.org

1.3.3 Helpful Websites 1.3 Acne Acne is the term for pimples, clogged pores, or even cysts that can be found on the face, back, neck, shoulders, and upper arms. It is very common in teenagers, but may persist into adulthood. There are many different variants of acne. Acne scarring varies from patient to patient.

1.3.1 Treatments Treatment of acne often involves a variety of different combinations of medications. These include both oral and topical antibiotic therapy, agents that promote

http://www.acne.org/ http://www.acne.com/ http://www.acneguide.ca/

1.4 Rosacea Rosacea is a disorder of the skin characterized by reddening and flushing of the face that is sometimes mistaken for acne. Often the skin will consist of red pimples and visible small blood vessels on the cheeks, nose, forehead, and chin. This condition typically lasts for years, sometimes with periods of improvement.

Appendix 1 Patient Handouts: Preventive Dermatology Topics

1.4.1 Treatments

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of topical steroids with effective moisturizers may allow less overall topical steroid use.

Topical as well as systemic antibiotics are usually needed to control rosacea.

1.5.2 Tips on Prevention 1.4.2 Tips on Prevention • Sun exposures can often exacerbate rosacea. • Avoid excessive washing of the face. • Avoid facial lotions and cosmetics that may irritate rosacea. • Avoid alcohol, especially red wines which may worsen rosacea. • Emotional stress may play a part. • Stay away from spice foods, excessive caffeine, and smoking. • Avoid extremes of hot and cold. • Certain prescription drugs may cause rosacea-like symptoms; be sure to discuss these symptoms with your doctor.

1.4.3 Helpful Websites http://www.rosacea.org/ http://www.rosaceaguide.com/

• Children should take daily baths or showers using a gentle cleanser. • Immediately after bathing, dry excess water and apply thick moisturizer. • Keep skin hydrated using fragrance-free moisturizers at least twice daily and especially when skin becomes increasingly dry and itchy. • Excessive sweating should be avoided. • Stress reduction can be helpful. • Choose soft, light cotton clothing as wool and synthetic fibers can be irritating. • Always wash new clothing with a mild detergent before wearing. • It is sometimes helpful to add an extra rinse cycle when doing laundry to remove residual irritants. • Keep fingernails short and clean to reduce scratching and infections. • Control aggravating external factors by remaining in a consistent, comfortable environment. • Protect the skin from the sun with moisturizing SPF 15 or higher sunscreen.

1.5 Atopic Dermatitis

1.5.3 Helpful Websites

Sometimes referred to as hereditary eczema, atopic dermatitis is the most common childhood skin disorder that usually appears on the hands, face, limbs, and is accompanied by an intense itch. The skin tends to be sensitive and may flare up during times of stress, changes in weather, or for no apparent reason. In about half of cases, this condition goes away on its own in early adulthood but could be lifelong in some people.

http://www.kidshealth.org/parent/infections/skin/ eczema_atopic_dermatitis.html http://dermnetnz.org/dermatitis/atopic.html

1.5.1 Treatments Topical steroids or immune modulators, antibiotics, and oral antihistamines are often used alone or in combination to help with flare-ups. Alternating applications

1.6 Contact Dermatitis Skin inflammation (especially on the hands, feet, and groin) caused by contact with an irritating substance. Contact with irritants such as sprays, acids, or solvents remove the fatty layer of the skin causing shrinking of the surface cells. Common irritants include metals in jewelry, poison ivy, chemicals in cosmetics, and certain topical medications. Contact dermatitis is not contagious. Skin is often itchy, red, and often cracks.

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1.6.1 Treatment

1.7.2 Tips on Prevention

Effective treatments involve eliminating allergens, avoiding irritants and other precipitating factors, and relieving itching and inflammation. Topical creams, ointments, or lotions can be used. These may include steroid preparations to reduce inflammation or lubricants to preserve moisture.

• If irritants can be identified, avoid if possible. • Avoid frequent hand washing. • When washing hands, use moisturizing soaps or nonsoap cleansers and use lukewarm water. • Moisturizing lotions can be very helpful, especially during the winter months when the air tends to be dry. • Wear nonlatex gloves when doing household cleaning and washing dishes as frequent wet work may exacerbate the condition.

1.6.2 Tips on Prevention • Avoid constant exposure to hot water, detergents, or any irritant that changes the moisture content of skin. • Avoid occupations or hobbies that bring you in contact with irritants. • Avoid contact with irritants that have caused dermatitis in the past. • Wearing protective gloves may be helpful. • Protect skin from sunburn and other burns. • Use bath oil or glycerin-based soap instead of soap for bathing. Pat skin dry rather than rubbing it. • Remove rings before doing housework. • Do not use fabric softeners in the wash or antistatic sheets in the dryer.

1.6.3 Helpful Websites http://www.eczemaguide.ca/

1.7 Hand Eczema Hand eczema can sometimes be caused by substances that come in contact with the skin and cause an irritation. Atopic hand eczema or dishidrotic eczema can occur without any outside causes. Hands often become itchy, dry, red, and scaly. In some cases, blisters can develop.

1.7.1 Treatment Treatment usually consists of a topical steroid cream. Other nonsteroid creams may be helpful as well.

1.7.3 Helpful Websites http://www.eczemaguide.ca/ http://www.skincarephysicians.com

1.8 Herpes Simplex Herpes simplex is a virus that can cause a blisteringtype rash on almost any part of the body. Sometimes the initial or primary infection can occur without symptoms. This is when most transmission of the virus occurs. However, the virus can remain “dormant” for long periods of time, and can be reactivated under times of stress on the body. Type I herpes simplex is usually associated with oral infections (usually presents like a “cold sore”), while type II is associated with genital infections.

1.8.1 Treatments Antiviral therapy may be indicated for the treatment of herpes simplex depending on the extent of disease. Cold compresses to the area can help alleviate some discomfort. Docosanol is an over-the-counter medication that can be applied topically to cold sores. This generally shortens healing time.

1.8.2 Tips on Prevention • Patients should take measures to prevent spread of herpes simplex virus (HSV) by avoiding contact with open lesions.

Appendix 1 Patient Handouts: Preventive Dermatology Topics

• Avoid sharing drinking glasses or razors with others. • Condoms should be used to prevent transmission of HSV-2 during intercourse. • Athletes, especially in contact sports such as wrestling, should be aware of the potential to transmit the virus by direct skin-to-skin contact.

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1.9.3 Helpful Websites http://www.aocd.org/skin/dermatologic_diseases/dry_ skin.html

1.10 Psoriasis 1.8.3 Helpful Websites http://cdc.gov/std/Herpes/ http://www.herpesguide.ca/

1.9 Dry Skin (Xerosis) Dry skin is a common problem, especially during the winter months. The skin becomes scaly and rough. The incidence of dry skin increases with age.

1.9.1 Treatment Daily moisturizers can help skin retain water and prevent dryness. Creams containing urea can also be helpful.

1.9.2 Tips on Prevention • Apply moisturizers immediately after shower or bath to lock-in water within the skin. • Decrease frequency of showers or baths and use moderately warm water to avoid scalding or further irritation. • Use mild soaps for sensitive skin. • Decision on over-the-counter moisturizer is based on effectiveness, cost, and ease of application. • Scaly skin can be treated by ammonium lactate which must be prescribed by your dermatologist. • Use gloves when washing dishes or cleaning around the house. • Wear gloves, socks, hats, when the weather is cold for added protection. • Humidifiers may or may not be helpful.

Psoriasis is a common, chronic, inflammatory disease of the skin most commonly found on the elbows, knees, and scalp. Psoriasis is considered to be an immunologic disease and about 30% of people with psoriasis have a family history of the condition. Severity of disease varies widely and is characterized by red and silvery scaly areas of skin. Some forms of psoriasis can also affect the nails and joints.

1.10.1 Treatments Treatment of psoriasis involves one or a combination of topical, systemic, and phototherapy (ultraviolet light) depending on the extent of disease. For severe disease immunomodulatory therapy may be indicated.

1.10.2 Tips on Prevention • Psoriasis is often worsened by emotional anxiety and stress. • Excess alcohol may aggravate the condition. • Eliminate smoking and excess weight. • A warm and humid climate, combined with natural sunlight is helpful. Plan moderate exposure to sunlight without burning. • Keep skin moist with gentle skin moisturizers. • Certain medications may trigger or worsen psoriasis, be sure to discuss this with your physician if you suspect a medication may be responsible.

1.10.3 Helpful Websites http://www.psoriasis.org http://www.psoriasisguide.com/

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1.11 Molluscum Contagiosum Molluscum contagiosum is a skin condition characterized by rounded discrete lesions that are flesh-toned or yellow-white which are caused by a virus. They can occur anywhere on the body. Most commonly affects young healthy children, adults who are sexually active, and HIV positive patients.

1.11.1 Treatment Most lesions disappear without treatment within 6–12 months. However, available treatments include removing the lesion with a skin curette, topical treatments, ucryotherapy, laser vaporization, or light electrodesiccation.

1.11.2 Tips on Prevention • Avoid contact with others if they have suspicious lesions. • Avoid contact with objects which may come into contact with lesions. • Avoid picking or scratching the lesions. • When lesions are present on the penis, condoms may provide protection. • Those who come into close physical contact with the person with lesions should be examined and treated.

1.11.3 Helpful Websites http://www.mayoclinic.com/health/molluscumcontagiosum

1.12 Warts Warts are very common skin growths caused by a type of virus called human papilloma virus (HPV). There are several different types of warts including common, plantar, and flat warts. Warts are transmitted by simple contact, usually in areas of skin trauma. Warts appear

R. A. Norman and L. H. McKinley

as flesh-colored, dome-shaped pimples. Common sites include hands, knees, elbows, and feet.

1.12.1 Treatment Warts can be treated with over-the-counter salicyclic acid preparations, cryotherapy, light electrocautery, or blunt dissection.

1.12.2 Tips on Prevention • Do not bite or pick at the warts. Doing so can promote spreading to other areas on the body. • Shaving should be avoided as flat warts easily spread within these areas.

1.13 Genital Warts Genital warts are caused by a specific type of HPV but not the same viruses that cause the common wart. Most often, these are spread by sexual contact and are seen in the regions of the penis, vulva, cervix, vagina, and anus.

1.13.1 Treatment Genital warts are treated differently than common warts because of the very sensitive skin. There are no treatments that actually destroy the virus.

1.13.2 Tips on Prevention • Some spread of warts can be lessened by use of condoms.

1.13.3 Helpful Websites http://www.kidshealth.org/kid/ill_injure/aches/warts.html http://www.cdc.gov/STD/HPV/STDFact-HPV.htm

Appendix 1 Patient Handouts: Preventive Dermatology Topics

1.14 Fungal Infections Fungal infections are caused by microscopic plants that become parasites on your skin. Eventually they grow enough to cause infectious colonies. Ringworm of the skin or scalp, athlete’s foot, and jock itch are caused by mold-fungi. Ringworm can appear as red scaly expanding rings that sometimes itch. Yeast or candida infections can cause diaper rash, infections in folds of skin of overweight people, and oral infections (thrush). Another yeast called tinea versicolor is a thin coating of fungus on the skin that appears as patches of discolored skin.

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1.15 Onychomycosis (Nail Fungus Infection) Onychomycosis is caused by many different species of fungus that infect the nail plate of the finger or toe.

1.15.1 Treatment Topical antifungal are less effective than oral therapy. Removing the infected nail plate first provides higher cure rates.

1.14.1 Treatment Topical or oral antifungal therapy is used to treat fungal infections. A combination may be necessary depending on the extent of disease. Shampoos are also available which can be lathered all over the affected area and rinsed in the shower.

1.14.2 Tips on Prevention • Maintaining good hygiene is helpful in preventing fungal infections. • Address care of minor skin or nail injuries as these may be sites of entry for infection. • Moist skin may also increase susceptibility especially to yeast infections. It is helpful to keep folded skin areas as dry as possible. • Losing weight may help decrease susceptibility to yeast infections. • To help prevent another infection with tinea versicolor, it is best to be treated with antifungal therapy before the warm season. • Certain medications including antibiotics may increase your susceptibility to infection. • You are more likely to get a fungal infection if you have a weakened immune system. Discuss your concerns with your physician.

1.14.3 Helpful Websites www.dermnetnz.org/fungal/tinea.html

1.15.2 Tips on Prevention • Keep nails short. • File down irregular nails. • Avoid trauma or irritants to nails such cotton and vinyl gloves for wet work or heavy cotton gloves for dry work. • Do not use same instruments on both infected and uninfected nails. • Wear properly fitting shoes with good support and a wide toe box, and avoid high heels and narrow toed shoes. • Take your own instruments when receiving pedicures or manicures at nails salons. • Use antifungal foot powder daily. • Keep feet cool and dry.

1.15.3 Helpful Websites http://www.emedicinehealth.com/onychomycosis/ article_em.htm

1.16 Keratosis Pilaris Keratosis pilaris is a skin condition most commonly seen on the upper arms, buttocks, and thighs. It is caused by the accumulation of dead skin (keratin) around hair follicles. The condition is generally worse

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in the winter months. Keratosis pilaris often improves by adulthood.

physician may prescribe antibiotics (such as penicillin or erythromycin) to be taken orally.

1.16.1 Treatment

1.17.2 Tips on Prevention

Lac-hydrin cream or lotion prescribed by your dermatologist can reduce roughness and help appearance. Tretinoin is occasionally prescribed for severe cases. Prescription antibiotics or low potency topical corticosteroids may be needed if the spots are very red and inflamed.

• Keeping children’s skin clean is the best way to keep it healthy. • Several washings daily with antibacterial soap or cleanser soften crusts so that they can be gently removed. • Wash clothing, bedding, and towels frequently and do not share them with anyone else in the family. • Physical contact including scratching can spread the infection to other parts of the body or even other people; it is therefore necessary to wash hands frequently. • Wear gloves when applying antibiotic ointments to your children. • Cut nails to avoid scratching.

1.16.2 Tips on Prevention • Daily intensive moisturizing is essential. • Avoid scratching the skin or using gritty body scrubs to prevent aggravating the condition. • Using glycolic acid moisturizing lotions and washes may help. • Plugged pores can be removed by taking long, hot soaking tub baths and then gently rubbing with a coarse wash cloth. • Avoid wearing tight-fitting clothing.

1.17.3 Helpful Websites www.kidshealth.org/parent/infections/bacterial_viral/ impetigo.html www.dermnetnz.org/bacterial/impetigo.html

1.16.3 Helpful Websites

1.18 Folliculitis

www.helpforkp.com/

Folliculitis is the name given to a group of skin conditions with inflamed hair follicles. The causes of folliculitis include bacterial infection, contact reactions, and inflammatory skin diseases.

1.17 Impetigo Impetigo is a fairly common superficial skin infection caused by bacteria staphylococci or streptococci. It may occur on normal skin, but the bacteria usually invade at the site of a skin scratch or abrasion. It appears as a sore with yellow or gray crusts on face, legs, or arms.

1.17.1 Treatment Topical antibiotic medications are effective in limited and minor infections. For extensive infections, your

1.18.1 Treatment If the causative agent is infectious, topical or oral antibiotics may be needed depending on the extent of the skin condition.

1.18.2 Tips on Prevention • Shaving, waxing, plucking, and use of any epilday may cause persistent folliculitis. Stop removing hairs with this method.

Appendix 1 Patient Handouts: Preventive Dermatology Topics

• Use a ladies’ electric razor which is the gentlest method of hair removal. • Overuse of topical steroids may produce folliculitis. • Friction, tight-fitting clothing, and heat should be minimized. • Antibacterial soaps are helpful. • Change razors frequently to avoid reinfection. • Avoidance of close shaving is helpful. • Certain chemicals such as coal tar or cutting oils may cause irritant folliculitis. Avoiding contact with these products will prevent folliculitis.

1.18.3 Helpful Websites www.aocd.org/skin/dermatologic_diseases/folliculitis.html

1.19 Scabies Scabies are tiny mites that can cause skin to be extremely infection most often at night. Usually, scabies affects more than just one member of a family. Scabies appears as a rash most often found between the fingers, the sides of the hands and feet, the belly button, and wrists.

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1.20.1 Treatment Permethrin rinse is an over-the-counter preparation usually used to treat lice infections. Other various shampoos and lotions can be prescribed by your physician. Nit removal with special combs is also essential for treatment.

1.20.2 Tips on Prevention • All bed linens, towels, and undergarments should be washed with hot water. • Once a family member is suspected to have scabies or lice, it is best to treat everyone in the household. • Do not share hair brushes with anyone suspected of having lice.

1.20.3 Helpful Websites www.headlice.org www.mayoclinic.com/health/scabies www.kidshealth.org/parent/infections/skin/scabies. html

1.21 Neurodermatitis 1.19.1 Treatment Permethrin cream by prescription is used to treat the skin condition. Typically this cream is kept on overnight and washed off in the morning. It is normal to itch for days to weeks after treatment, but it is usually less intense. Oral medications (ivermectin) are also used.

Neurodermatitis is itching aggravated by nervous tension or anxiety. Although the conditions are not precisely the same, the names neurodermatitis and lichen simplex chronicus are used interchangeably. In simple terms, these common skin disorders consist of small flat growths of various sizes with definite margins that have become thickened and leather-like. Longstanding neurodermatitis may lead to brownish pigmentation.

1.20 Lice Lice are wingless insects that infest the hair of the body, especially on the scalp and pubic region. Usually this causes mild itching at the neck or no symptoms at all. Infestation is highly contagious. Nits are small white eggs that can be seen in the hair.

1.21.1 Treatment The primary treatment of these skin problems is to stop scratching. Perhaps by understanding the disorder, you may be able to stop or minimize the tendency

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to continue irritating the skin by scratching. Steroid creams may be recommended by your physician to decrease itching and inflammation. Sedatives may also be helpful.

1.21.2 Tips on Prevention • Seek avenues for stress reduction. • Resist the urge to scratch with fingernails and gently rub with a soft cloth instead.

R. A. Norman and L. H. McKinley

• To minimize nighttime itching, covering affected skin may be helpful. • Use gentle body cleansers and moisturizers.

1.21.3 Helpful Websites http://www.skincarephysicians.com/eczemanet/neurodermatitis.html http://www.mayoclinic.com/health/neurodermatitis/DS00712

2

Appendix  Skin Performance Assessment Questionnaire Robert A. Norman

Complete my questionnaire to assess your level of skin health! Give yourself zero points for each “Never” response, one point for each “Sometimes” response, and two points for each “Always” response. Add up your responses.

Always (2 points)

Sometimes (1 point)

Never (0 points)

Lifestyle 1.

I use sun block and avoid the sun as much as possible, especially during the hours of 10 am to 4 pm

2.

I use a sunscreen with a skin-protection factor of 15 or greater and always wear a hat and sunglasses outdoors

3.

If I have a fair complexion, blue eyes, and blond hair I know I am the most susceptible to melanomas

4.

I make sure my children avoid sunburns

5.

I have no addictions or any self-destructive behavior

6.

I laugh a lot and enjoy a good sense of humor

7.

If I choose to tattoo or pierce, I am aware of the possible transmission of dangerous blood-borne diseases, infections, and keloid formation among other problems

R. A. Norman Nova Southeastern University, Ft. Lauderdale, Florida and Private Practice, Tampa, FL, USA e-mail: [email protected] R. A. Norman (ed.), Preventive Dermatology, DOI: 10.1007/978-1-84996-021-2_A2, © Springer-Verlag London Limited 2010

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R. A. Norman Always (2 points)

8.

If I want to get a tan, I avoid sun-tanning parlors and only use spray-on products. I exercise at least 3 times a week for better health and great skin

9.

I take precautions to not develop cold sores

10.

If I have had a history of blistering sunburns during childhood, I make sure I am especially diligent about doing self-examinations to detect skin cancers

11.

I rarely get less than 8 h sleep a night and I go to sleep and wake at consistent times

12.

I get regular, age-appropriate health check-ups and tests

13.

I have many healthy ways to relax

14.

I practice deep breathing, meditation, and other ways to relieve stress

15.

I use mental imagery to prepare myself for my best health and skin care

Diet questions 16.

I eat healthy foods and drink plenty of healthy liquids such as water and green tea

17.

My alcohol and sugar intake is low

18.

I avoid eating a diet high in fat

19.

I take proper vitamin supplementation to enhance my energy levels and my skin

20.

I plan my day and I am prepared by including healthy snacks

21.

I do not go through big ups and downs in my eating habits and intake

Skin therapies 22.

I know there are many products for under $25 that are safe and effective for my skin

23.

I do not use products that make my skin feel and look greasy

24.

I do not use products that make my skin turn dry and flaky

25.

My skin cleansers, moisturizers, toners, and night creams all do not have irritating fragrances and work quite well

26.

I use a moisturizer with a sun block of at least SPF 15

Sometimes (1 point)

Never (0 points)

Appendix 2 Skin Performance Assessment Questionnaire

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Always (2 points) 27.

I take the time to learn my skin type so I can match it with the correct products

28.

My skin seldom gets red and blotchy

29.

My skin shows few fine lines and wrinkles from sun damage (photo-aging), solar hyperpigmentation (brown spots from sun)

30.

I use just the minimal amount of products to be safe and effective and no more

31.

My skin most often looks refreshed

32.

I keep up with tips on health and my skin and avoid products that can’t be backed up by good studies

Sometimes (1 point)

Never (0 points)

Motivation 33.

I use a common-sense philosophy of life and keep it simple

34.

I am up and ready to go in the morning

35.

I am an optimist and live life fully

36.

While I am on the Internet, I use sites such as “http://www.aolhealth.com” to help improve my life and attitude

37.

I keep myself on task when it comes to problem-solving and know what I want to accomplish

38.

I have people that I can trust to discuss and help with my skin and health problemsI never give up because I know that things may change for the better as time goes on

Add them up Total score: _______________

2.1 Preventive Dermatology Questionnaire By using this questionnaire, you have an excellent teaching tool for your patients. Go over the results and find ways your patients can practice prevention and improve their health. There are no grades given, except that 76 is an A+! Here are the tips: Lifestyle Habits – Explain in simple terms how to evaluate any problems, prevent diseases, and intervene when it is needed. To solve skin problems and improve the

patient’s skin, always address the patient’s diet, nutrient intake, medications, natural dietary supplements, sleep quality and quantity, exercise, sun exposure, cigarette smoking, alcohol, recreational drugs, and more. By having this information, you can quickly identify the areas that need to be changed and give the patient some simple steps to make these changes—quickly. Diet Tips – Often a patient’s skin condition (or appearance) is linked to his or her diet. Tips to include in any patient program include key information on dietary fats (saturated, polyunsaturated and trans fats) and their link to skin inflammation and skin cancer, aging

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skin, the Glycemic Index and acne, phytochemicals and antioxidants that can improve wrinkled or sun damaged skin, and more. Skin Therapies – Our patients have many questions that give us a chance to talk about prevention. They may ask about self-tanners, the best skincare regimen for the adult that still gets acne, their skin type and what particular skin concerns they have related to the type, how to choose “anti-aging” products and practical tips on avoiding the marks and growths of aging skin, the best soaps, shampoos, diapers, powders, and lotions for their baby, and many other questions. Motivation – anticipate questions and answers that your patients can use to improve their skin. If you have a patient with acne, rosacea, or any other skin problem that has tried most conventional therapies without success, what do you do now? What if you are treating a 45-year-old man who smokes a pack a day and has extensive skin rhytides? What can you advise? What if

R. A. Norman

a patient asks about supplements to improve his or her skin health? Can you advise a patient about getting into the best skin-saving exercise program?

References Norman R. 100 Questions and Answers about Aging Skin Jones and Bartlett 2009 Norman R. 100 Questions and Answers about Atopic Dermatitis Jones and Bartlett 2010 Norman R, Reusher L. 100 Questions and Answers about Chronic Illness Jones and Bartlett 2009 Norman R, Reusher L. 100 Questions and Answers about Lupus Jones and Bartlett 2010 Langley R. Psoriasis—Everything You Need to Know Firefly Books 2005 Day D. 100 Questions and Answers about Acne Jones and Bartlett 2005 Bergstrom K. 100 Questions and Answers about Psoriasis Jones and Bartlett 2004 McClay E. et al 100 Questions and Answers about Melanoma and Other Skin Cancers Jones and Bartlett 2003 Day D. 100 Questions and Answers about Acne Jones and Barlett 2005

Index

A Acne acne cosmetica, 183 acnegenicity vs. comedogenicity, 184 acneiform eruptions and cosmetics, 184–185 comedogenic ingredients, 184 comedogenicity testing, 184 occupational acne, 105 prevention tips, 294 treatment, 294 websites, 294 Acrodermatitis enterohepatica, 200 Advisory Committee on Immunization Practices (ACIP) recommendations catch-up vaccination, 238 HPV vaccine, 238 routine vaccination, 238 VZV vaccine, 236 Aleosin, 179–180 Alpha lipoic acid, 179, 194 American Academy of Pediatrics (AAP), 220, 221, 224 Amiodarone, 69 Anapsos, 195 Anesthetic toxicity bupivacaine, 274 epinephrine, 273–274 lidocaine, 274 symptoms, 273 Ankle brachial index (ABI), 250 Ankle brachial pressure index (ABPI), 77, 78 Antimicrobial therapy, atopic eczema, 146 Antioxidants, 193 alpha-lipoic acid, 194 anapsos, 195 botanical antioxidant, 195–196 chamomile, 195–196 coenzyme Q10 (CoQ10), 194 curcumin, 196 echinacea, 196 endogenous antioxidant, 194–195 exogenous antioxidant, 195 garlic, 196 gingko biloba, 196 glutathione, 195 green tea, 196 isoflavone genistein, 195



licorice, 196 nonenzymatic endogenous antioxidants, 194 procyanidins, 195 pycnogenol, 196 resveratrol, 196 silymarin, 196 soybean, 196 Apocrine perspiration, 182 Arbutin, 180 Arterial and ischemic ulcers LEAD, 252–253 PVD, 253 vasoconstriction, 253 Arthropod-borne infections, 244–245 Artificial dermis, 58 Ascorbic acid, 179, 192–193 Athletes. See Sports dermatology Atopic dermatitis (AD), 53, 295 Atopic eczema (AE) allergologic workup, 141–142 allergy, 139 antimicrobial therapy, 146 antipruritic treatment, 146–147 azathioprine, 147 clinical presentation, 140 cyclosporine, 147 diagnostic criteria, 140–141 dietary restrictions, 146 differential diagnoses, 142 genetics, 138–139 immunology, 139 mycophenolate mofetil, 147 nonpharmacological intervention strategies, 147–148 pathophysiology, 138–140 prevalence, 137 prevention, 142–148 primary prevention, 142–143 secondary prevention, 143–144 skin physiology, 138 Staphylococci and Herpes virus infection, 140 stress and itch, 139–140 systemic immunosuppression, 147 topical therapy, 144–146 UV light therapy, 146 Atopy patch test (APT), 142. See also Patch testing Autoimmune bullous diseases. See Bullous diseases

307

308 Avobenzone, 85 Azelaic acid, hyperpigmentation, 179 B Bacterial infections antibacterial agents, 241 methicillin-resistant Staphylococcus aureus, 241–242 Pseudomonas folliculitis, 242, 243 Biologics combination therapy/concomitant medications, 100 definition, 93 dosage and administration, 94 elderly, 100–101 indications, 93–94 side effects anaphylaxis/allergic reactions, 96–97 autoantibodies and autoimmunity, 96 blood disorders, 96 cardiovascular disease, 95 hepatitis/hepatic dysfunction, 95–96 infections, 95 malignancy, 96 neurological disease, 95 pregnancy/breast-feeding, 97 skin irritation, 94 treatment risk reduction strategies baseline screening tests, 97–98 periodic monitoring, 98 therapy, withdrawal of, 99–100 treatment exclusion criteria, 97 tuberculosis risk, 99 vaccinations, 99 Biotin, 192 Bleeding antiplatelet effect, blood thinners, 267–268 hematomas, 268 vasoconstrictor epinephrine, 268 Body mass index (BMI), 188 Brass chills, 200 Bullous diseases bullous pemphigoid clinical variants, 123 ELISA index, 124 indirect immunoflourescence (IIF), 123, 124 prevention, 124 dermatitis herpetiformis, 126–127 epidermolysis bullosa COL7A1 gene, 117 collagen IV, immunohistochemical staining, 118 DDEB and RDEB, 117 Dowling-Meara type of EB simplex (EBS-DM), 115 fetal skin biopsy, 118 gastrostomy, RDEB-HS, 117 generalized severe type, 117 Herlitz JEB, 115, 116 laminin 5, 116 main inherited subtypes, 115, 116 muscular dystrophy, 115 preimplantation genetic diagnosis (PGD), 118 prenatal genetic diagnosis (PND), 118 pyloric atresia, 116

Index epidermolysis bullosa acquisita, 125–126 infective causes erythema multiforme (EM), 128 herpes simplex virus (HSV), 128 herpes zoster (HZ), 129 oral acyclovir, 129 Orf virus, 129 linear IgA dermatosis, 127–128 mucous membrane pemphigoid, 125 neonatal pemphigus acantholysis, 122 in-vivo immunoadsorbent, placenta, 123 nonthiol nonphenol drugs, 122 oral corticosteroids and plasmapheresis, 122 pemphigus vulgaris (PV), 122 phenol drugs, 122 thiol drugs, 122 vaginal delivery, 122 pemphigoid gestationis, 124–125 pemphigus acantholysis, 119 desmoglein 3 and 1, 119 endpoints, 121 enzyme-linked immunosorbent assay (ELISA), 119 paraneoplastic pemphigus (PNP), 119, 120 pemphigus foliaceus (PF), 120 pemphigus vulgaris (PV), 119–121 relapse/flare, 121 treatment failure, 121 Tzanck phenomenon, 119 variants, 119 toxic epidermal necrolysis (TEN), 128 Bullous pemphigoid, 123–124 Burns airbag injuries, 112 anhydrous ammonia, 111 betadine, 112 burn severity, 111 cement burns, 111–112 chemical agents and medical management, 112 chemical burns, workplace, 110–112 chromic acid, 111 degrees, 111 fluid resuscitation, 112 hydrofluoric (HF) acids, 110–111 necrosis, 110 oral burns, 111 patient care, 112 phenol, 111 physical examination, 111 scars and pruritus, 110 sulfur mustard, 112 systemic effect, 112 white phosphorus, 112 C Calcitriol, 86 Care delivery method, 59 Casal’s necklace, 192 Center for disease control and prevention (CDCP) report, 214–216, 219–221, 224

Index Cervical cancer CIN II/III vaccination, 214, 215 HPV 16 and 18, 214–215 pap testing, 215 sexually transmitted diseases, 215–216 vaccine, 238 Chamomile, 195–196 Cheilitis allergic contact, 177 occurrence, 176 xerotic, 176–177 Chemically bonding collagen, 58 Child abuse prevention and treatment act (CAPTA), 36 Child sexual abuse. See Sexual abuse Cholecalciferol, 193 Chronic stasis dermatitis, 71 Chronic venous leg insufficiency (CVI), 52 Coenzyme Q10 (CoQ10), 194 Combination therapy, keloids, 288 Compression therapy, keloids, 286–287 Condoms air-burst test, 216 clinical trials, 218 effectiveness, 218 laboratory tests, 216–217 mechanism of action, 216 “method” failure, 217 prophylactic devices, 216 public education, 217–218 sexual behavior change, 218–219 “user” failure, 217 water leak test, 216 Contact dermatitis, 295–296 eyelid dermatitis, 175 inflammation, 167–169 occupational (see Occupational contact dermatitis) perineal dermatitis, 253–255 Corneotherapy, 259 Corticosteroids, 67 monotherapy, 284 polytherapy, 284–285 Cosmetic problems acne, 183–185 cheilitis, 176–177 eyelid dermatitis, 175–176 facial eczema, 173–175 hyperhidrosis, 182–183 over-the-counter (OTC) drug, 173 postinflammatory hyperpigmentation, 177–181 Cowpox, 208 Curcumin, 196 Cutaneous drug reactions clinical classification drug-induced erythema multiforme, 66 exanthematous reactions, 65 fixed drug eruptions, 65–66 Stevens–Johnson syndrome, 66 toxic epidermal necrolysis, 66 urticaria and angioedema, 65 frequency, 63–64 Gell-Coombs classification, hypersensitivity reactions, 65

309 general prevention principles, 66 nondermatologic symptoms, 66 preventability, 64 serious and life-threatening, 64 specific medications amiodarone, 69 anticonvulsants, 68 corticosteroids, 67 topical calcineurin inhibitors, 67–68 tumor necrosis factor alpha inhibitors, 68–69 Cyanocobalamin, 192 D Defibrillators, 275 Dermatitis herpetiformis, 126–127 Diabetic ulcers footwear specifics, 252 incidence reduction, 251–252 multidisciplinary prevention approach, 252 Diaper dermatitis. See Perineal dermatitis N, N-Diethyl-3-methylbenzamide (DEET), 244–245 Dimethicone, skin protectants, 258 Diphenhydramine, 147 Dog ears. See Standing cones Domestic violence, abuse, and neglect abusers, common characteristics of, 37 assessment and diagnoses, 41 clinical assessments and diagnosis, dermatologist, 45 definition sexual abuse, 35, 36 United States Centers for Disease Control and Prevention, 35 healthcare provider, role of, 37, 39 identification and assessment, patient admissibility, records, 44–45 physical examination, 43–44 record/chart, 44 mandatory reporting, 37 multidisciplinary approach, 45 prevalence Bureau of Justice statistics, 41 violence-related injury, 42–43 statistics coin rubbing, 41 cupping, 40–41 dermatitis, 41 female genital mutilation (FGM), 40 male victims, 39 moxibustion, 40 women and children victims, 39, 40 victims, common characteristics of children, 36 elder abuse, 36 warning signs, 37, 38 Doxepin, 147 Dystrophic epidermolysis bullosa (DEB), 115, 117, 118 E Earlobe keloids, 285 Eccrine perspiration, 182 Echinacea, 196

310 Eczema Craquelé, 71, 72 Efalizumab, 97 EFUDEX®, 54, 55 Elder sexual abuse. See Sexual abuse Emotional immaturity, 37 Epidemiology health literacy document literacy, 23 prose literacy, 22 quantitative literacy, 23 stasis dermatitis, 77 stress, 7 xerosis, 73 Epidermolysis bullosa, 115–119 Epidermolysis bullosa acquisita, 125–126 Epidermolysis bullosa simplex (EBS), 115, 118 Ergocalciferol, 193 Eyelid dermatitis cleansers, 176 eczema, 176 eyelid, 175 eyelid cosmetics, 175–176 irritant and allergic contact dermatitis, 175 moisturizers, 176 F Face transplants, 59 Facial eczema cleansers, 174–175 face, 173 moisturizers, 173–174 Female genital mutilation (FGM), 40 Fish oil, 88 Flap and graft necrosis, 275–276 Folliculitis, 300–301 Foot ulceration, 251–252 Fungal infections, 243, 299 G Garlic, 196 General health, 293 Genistein, 195 Genital warts, 298 Gingko biloba, 196 Glutathione, 195 Green tea, 86, 196 H Hair growth and transplantation, 59 Hand eczema, 296 Healthcare, multidisciplinary work assessment and plan, 54 challenges, 48–49 clinic follow-up, 55 collaborative experience, 47 communication, 50 dermatological care, 48 dermatological clinical staff call, 54 disorders atopic dermatitis (AD), 53 melanoma, 52–53 wound healing, 52

Index medications, 55 patient care, 54 patient history, 53–54 physical examination, 54 scope, 48 Senior Health Clinic note, 54–55 social work staff, 47 team creation, 49 training, 50 various patient groups gerontological patients, 50–51 language difficulties, 52 pediatric patients, 50 psychiatric patients, 51 Health literacy age, 25–26 American Medical Association (AMA), 22, 29 assessment tools newest vital sign (NVS), 23–24 rapid estimate of adult literacy in medicine (REALM), 23 test of functional health literacy in adults (TOFHLA), 23, 24 childhood and adolescent, 27 cultural preferences, 30 culture, race and ethnicity, 27 definition, 22 diabetic retinopathy rate, increase, 25 education, 25 effective patient–physician communication, 22, 29 epidemiology document literacy, 23 prose literacy, 22 quantitative literacy, 23 hospitalization rates, 24 Institute of Medicine (IOM), 22, 29, 32 joint commission on accreditation of healthcare organizations (JCAHO), 29 mortality, 27–29 national assessment of adult literacy (NAAL), 22 oral communication, 30 parents and pediatric health, 26–27 plain language, 30 poor glycemic control, 25 REALM-Teen, 31 teach back strategy, 30 Tuskegee syphilis study, 31 Heel pressure ulcers, 260 Hemosiderosis, 200 Herpes gestationis factor, 125 Herpes simplex virus (HSV) dermatologic perspective, STD, 212–213 genital herpes, 212–213 herpes gladiatorum, 213 HSV II seroprevalence, 213 skin infection, 242–243 treatment, 296–297 types, 296 websites, 297 Herpes zoster (shingles), 234, 236 HIV reduction, Uganda

Index abstinence and faithfulness, 226–227 condom use, 226, 227 global paradigm, 227–228 pregnant women, 226 President Museveni, 225 Hot tub folliculitis, 243 Human herpes 3 (HHV3). See Varicella zoster virus (VZV) Human papilloma virus (HPV), 207–208 ACIP recommendations, 238 anogenital cancer, 214 CDCP report, 214 CIN II/III, 214 dermatologic perspective, 213 epidemiology, 237 genital warts, 213, 214 gynecologic perspective, 213–214 infection, 237 intervention, 237–238 life cycle, 237 papillomaviridae family, 236 pap testing, 215 pathogenicity, 237 structure, 236 types 16 and 18 vaccination, 214–215 vaccine, 214–215, 238 viral shedding, 214 Hydroquinone, 178 Hydroxycine, 147 5-Hydroxymethyl-4H-pyrane-4-one. See Kojic acid Hygiene hypothesis, 137, 143 Hyperhidrosis antiperspirant efficacy optimization, 182–183 antiperspirant mechanism of action, 182 perspiration, 182 Hypertrophic scars (HTSs), 283 Hypothalamic-pituitary-adrenal (HPA) axis, 3, 4, 6 I Imiquimod, 287–288 Immunotherapy, atopic eczema, 143–144 Impetiginized wound, 241, 242 Impetigo, 300 Implantable cardioverter-defibrillators (ICDs), 275 Infections antibiotic ointment, 270 chlorhexidine gluconate, 270 cleansing, 162 general infection techniques, 161–163 Herpes gladiatorum, 163 itraconazole, tinea corporis gladiatorum, 164 MRSA, 163 petrolatum, 270 pitted keratolysis, 163–164 postoperative wound infection, 270 preventative measures, tinea pedis and tinea ungium, 161, 162 prevention techniques, skin infection, 161, 162 prophylactic antibiotics, 269–270 Pseudomonas folliculitis, 163 risk factors, 268–269 skin-to-skin contact, 161–162 specific infection techniques, 163–164

311 Staphylococcus transmission, fomites, 161, 162 sterile surgical gloves, 269 wrestlers, 162–163 Inflammation allergic contact dermatitis, 167 exercise-induced anaphylaxis, 168, 169 irritant contact dermatitis, 167–169 urticaria, 168 Inherited bullous diseases. See Bullous diseases Insect bites DEET, 244–245 fipronil, 245 lufenuron, 245 mosquitoes, 244 neem oil, 245 permethrin, 245 ticks, 245 vector-borne disease, 244 Interferon, keloids, 287 Intranasal FluMist vaccine, 99 Isoflavone genistein, 195 Itchscratch cycle, 53 J Junctional epidermolysis bullosa (JEB), 115, 116, 118 K KEFLEX®, 55 Keloids combination therapy, 288 compression therapy, 286–287 corticosteroids, 284–285 earlobe keloids, 285 endocrine factors, 282–283 epidemiology, 281 etiology, 282–283 genetic predisposition, 283 imiquimod, 287–288 infection, 282 interferon, 287 keloid avoidance behaviors, 288 laser surgery, 286 pathogenesis, 283 preventative therapy, 283–288 radiation therapy, 286 silicone products, 287 skin tension, 282 surgical method, 285 trauma, 282 Keratosis pilaris, 299–300 Koebner phenomenon, 157 Kojic acid, 179 L Laser surgery, keloids, 286 Leg ulcers, 51 Lice, 301 Licorice, 179, 196 Lifestyle abstinence, 219, 220 Linear IgA dermatosis, 127–128 Lower extremity arterial disease (LEAD), 252–253

312

Index

M Malnutrition obesity, 189 protein–energy malnutrition, 188 Measles (Rubeola), 205–206 Melanoma, 52–53 Menkes kinky hair syndrome, 199 Mequinol, 178 Methicillin resistant Staphylococcus aureus (MRSA), 163, 241, 242 Microfine zinc oxide, 85 Minerals acrodermatitis enterohepatica, 200 adults, 198 balanced intake, 199 calcium, 199 children, 197 copper, 199–200 hemosiderosis, 200 hypercalciuria, 199 iron, 200 Menkes kinky hair syndrome, 199 metal-fume fever, 200 osteoporosis, 199 RDA, 197–199 selenium, 200 Wilson’s disease, 199–200 zinc, 200 Molluscum contagiosum, 298 Mucous membrane pemphigoid, 125 Mumps, 206

Occupational contact dermatitis allergic contact dermatitis, 106 antimicrobial allergy, 107 barrier creams and moisturizers, 110 causes, 106–108 gloves, 110 hairdressers and dog groomers, 107 irritant contact dermatitis, 106 latex allergies, 107–108 patch test, 108–110 prevention and treatment, 110 seafood processing, 107 women, 107 Occupational dermatology burns, 110–112 chrome holes, 106 diagnosis, 103–104 occupational acne, 105 occupational dermatitis, 106–110 occupational skin cancers, 105 occupational skin infections, 105, 106 phototoxic and photoallergic reactions, 105 pigment changes, 105 segmental vibration, 106 skin notations, 105 worker’s compensation system, 104–105 Occupational skin cancers. See Skin cancer occupational skin cancers, 105 Octinoxate, 84 Onychomycosis, 299 Oxybenzone, 84

N N-acetylcysteine (NAC), 88 Nail fungus infection, 299 Narcissism, 37 National Elder Abuse Incidence Study, 37 National Health and Nutrition Examinations Survey (NHANES), 213 Neonatal pemphigus, 121–123 Nerve damage, surgery, 274–275 Neurodermatitis, 301–302 Nitrogen balance, 263 Nutrition. See also Malnutrition; Supplements; Vitamins biochemical data, 263 definition, 187 malnutrition, 262 nitrogen balance, 263 nutritional assessment, 262 risk factors, 262 vitamins and minerals, 263 WHO report, 187

P Pacemakers, 275 Pantothenic acid, 192 Pap testing, 215 Paramyxoviruses, 205–206 Paraneoplastic pemphigus (PNP), 119, 120 Parental health literacy. See Health literacy Patch testing Finn chamber test, 109–110 TRUE test, 108–109 Pathogenesis stasis dermatitis, 77 xerosis, 72–73 Patient interviews, 39 Pemphigoid gestationis, 124–125 Pemphigus, 119–121 Perineal dermatitis absorptive and/or occlusive devices, 254 assessment tools, 253–254 Braden risk assessment score, 255 causes, 253 denudation, 255 grading scale, 253–254 interventions, 254 perineal skin injury, 253 underpads, 254–255 Peripheral vascular disease (PVD), 252–253

O Obesity and nutrition obesity prevention and nutritional education, 19 prevention programs, 19 risk synergy and integrating prevention, 19–20 skin complications, 18–19 skin disorders, 19

Index Perirectal skin assessment tool (PSAT), 253–254 Photoprotection recommendations and rationales automobile glass, 90 clothing, 88–89 hats, 89 inorganic filters, 85 makeup, 89 organic ultraviolet A (UVA) filters, 84–85 organic ultraviolet B (UVB) filters, 84 shade, 88 shadow rule, 82 sunglasses, 89–90 sunless tanning agents, 89 sunscreen, 82, 83, 85–86 topical, oral, and dietary photoprotection agents, 86–88 vitamin D oral supplementation, 83 window glass, 90 ultraviolet (UV) radiation, cutaneous effects, 81–82 Polidocanol, 146 Polypodium leucotomos, 88 Postinflammatory hyperpigmentation nonprescription topical agents, 179–180 prescription topical agents, 178–179 skin-lightening ingredients, 177 sunscreens, 180–181 Postoperative scars, pain, and pruritus, 272–273 Poxviruses, 208 Pressure ulcers causes, 259 geriatric patient, 259 guidelines, 260 heel pressure ulcers, 260 prevalence, 259 prevention, 260–261 skin and tissue breakdown, 259 support surfaces, 261–262 Procyanidins, 195 Psoriasis amevive, 156, 159 anthralin cream, 157 biologics, 156, 158–159 Crohn’s disease, 153 cyclosporine, 155–156, 158 depression, 154 diet, 157 dovonex, 154, 157 genetics, 152–153 health education, 159 inflammatory bowel disorders, 153 methotrexate, 156, 158 myocardial infarction (MI), 154 obesity, 153 onset, 151 oral medications, 158 pathogenesis, 151 phototherapy, 156–157, 159 prevalence/incidence, 151 prevention, 157–159 prevention tips, 297

313 psoralen, 159 remicade, 156, 159 risk factors/triggers, 153–154, 157 severity/types/distribution, 152 soriatane, 156, 158 systemic therapy, 155–156 taclonex, 155, 157 tazorac, 155, 157–158 topicals, 154–155 topical steroids, 155, 158 treatment, 154–157, 297 websites, 297 Psychodermatologic disorders, 51 Pycnogenol, 196 Pyridoxine, 192 R Radiation therapy (RT), keloids, 286 Raynaud’s phenomenon, 106 Recommended daily allowances (RDA) fat-soluble vitamins, 191 minerals, 197–199 water-soluble vitamins, 190 Resveratrol, 196 Riboflavin, 192 Rocky mountain spotted fever, 244 Rosacea, 294–295 Rubella (German measles), 206 S Safe sex, 219 Scabies, 301 Serum albumin, 263 Sexual abuse, 35–37, 40, 44, 45 Sexually transmitted diseases (STD) abstinence, 219, 220 adverse consequences, 212 age and gender matched abstinence analysis, 221 center for disease control and prevention (CDCP) report, 214 cervical cancer, 215–216 clinical manifestation, 211–212 condom strategy, 216–219 dermatologic perspective, 212–213 ethnicity, 220 global paradigm, 227–228 herpes simplex virus, 212–213 human papilloma virus, 213–215 lifestyle abstinence counseling, 221, 223 management, 211 oral sex, 219 patient response, counseling, 221, 223 physician counseling style, 221 prevention in office, 219–224 prophylactic device, 211 recommended guidelines, 219–220 return for care, 221, 223 risk elimination counsel, 221 safe sex, 219 sexual abstinence counsel, 221, 222

314 sexual behavior change, 225–227 skin and STD relationship, 223–224 trends and expectations, STD prevention, 224 Uganda, 225–227 Silicone gel sheeting (SGS), 284, 287 Silymarin, 196 Skin cancer, 105, 293–294 Skin care cleanser, 256 dry skin, 257–258 moisturizers, 256–257 products, 257 skin hydration, 256–258 skin nutrition, 258–259 skin protectants, 258 soaps and surfactants, 256 xerosis, 257–258 Skin infections arthropod-borne infections, 244–245 bacterial infections, 241–243 fungal infections, 243 surgical wound infections, 243–244 viral infections, 242–243 Skin performance assessment, 303–305 Skin tears, 262 Smallpox (Variola), 208 Smoking collagen and elastin, damage, 18 health education programs, 18 hydrophobic agents, 17 poor wound healing, 17, 18 premature aging, 17, 18 premature wrinkling, 18 risk synergy and integrating prevention, 19–20 Soybean, 196 Spitting sutures, 275 Sports dermatology athletic clothing, 170 environmental encounters, 168–170 green hair, 170 infections, 161–164 inflammation, 167–168 insect attacks, 170 sun safety, 169–170 trauma, 164–167 ultraviolet damage, 168–169 Standing cones, 273 Staphylococcal folliculitis, 241, 242 Stasis dermatitis compression, 78 deep venous thrombosis (DVT), 77 emollient therapy, 78 epidemiology, 77 exercise, 78 gaiter, 76 leg elevation, 78 pathogenesis, 77 pharmaceutical interventions, 78 predisposing factors, 77

Index Stress acute and chronic, 3 allostasis, 3–4 epidemiology, 7 fight-or-flight response, 3 General Adaptation Syndrome, 3 immune function and skin atopic dermatitis, 6 catecholamine (CA), 4 central neuroendocrine stress mediators, 5 flares and psoriasis, 6 glucocorticoids (GC), 4, 5 hypothalamic-pituitary-adrenal (HPA) axis, 4, 6 lipopolysaccharides, 4–5 malignancy, 6, 7 matrix metalloproteinases (MMPs), 6 nerve growth factor (NGF), 6 squamous cell carcinomas (SCCs), 7 Th1 and Th2-derived cytokines, 4 tissue inhibitors of metalloproteinases (TIMPs), 6 Stress-reducing modalities aromatherapy, 9–10 autogenic training, 11–12 biofeedback, 11 deep breathing, 8 hypnosis, 12 massage therapy, 10 mindfulness meditation, 10–11 prayer, 12–13 progressive muscle relaxation, 9 QI Gong/Reiki/healing touch, 12 Tai Chi, 8–9 yoga, 7–8 Sun damage, 293–294 general risk, 19 risk synergy and integrating prevention, 19–20 Sun protection factor (SPF), 81–86, 89, 91 Sunscreen, 82, 83 compensation hypothesis, 85 contact, photocontact, and phototoxic reactions, 85 hormonal effects, 85–86 Sunscreens cosmeceutical, 180 efficacy, 181 longevity, 181 sun protection factor, 181 tanning response, 180–181 UVA filters, 180–181 water-resistant, 181 Supplements. See also Nutrition; Vitamins antioxidants, 193–196 minerals, 197–200 Surgical complications allergic reactions, 271–272 anesthetic toxicity, 273–274 bleeding, 267–268 defibrillators and pacemakers, 275 flap and graft necrosis, 275–276 infection, 268–270 litigation, 276 nerve damage, 274–275

Index postoperative scars, pain, and pruritus, 272–273 spitting sutures, 275 standing cones, 273 trap door (pincushioning) deformities, 275 vasovagal reaction, 276 Surgical wound infections, 243–244 T Teledermatology, 59 T4 endonuclease V (T4N5), 57 Thiamine, 192 Tinea infection, 243 Titanium dioxide, 85 Toad skin, 190, 200 Toe brachial index (TBI), 250 Topical calcineurin inhibitors, 67–68 Topical therapy aleosin, 179–180 alpha lipoic acid, 179 antiperspirants, 165 arbutin, 180 ascorbic acid, 179 azelaic acid, 179 calcineurin inhibitors, 145–146 clothing, 144 corticosteroids, 145 dovonex, 154–155 emollients, 144 hydroquinone, 178 imiquimod, 287–288 Kojic acid, 179 licorice extract, 179 lidocaine, 273 mequinol, 178 skin care, 144 synthetic detergents, skin, 144 taclonex, 155 tazorac, 155 tretinoin, 178 Transepidermal water loss (TEWL), 173–174 facial moisturizers, 173–174 lip balms, 177 perineal dermatitis, 254 skin hydration, 256 skin nutrition, 258 Trapdoor deformity, 275 Trauma acne mechanica, 167, 168 callosities, 165–166 friction bullae, 164–165 nodules, 166–167 shoe lacing techniques, 164, 165 toenail abnormalities, 167 Tretinoin, 178 Triamcinolone acetonide (TAC), 284 Tumor necrosing factor-alpha (TNF-a), 68–69, 95 U Ulcers arterial and ischemic, 252–253 diabetic, 251–252

315 pressure, 259–262 venous insufficiency, 249–252 V Vaccines, viral diseases. See also Viral vaccines Edward Jenner’s vaccine, 233 human papilloma virus, 236–238 varicella zoster virus, 233–236 vexing diseases, 233 Varicella (chickenpox), 234 Varicella zoster virus (VZV), 206–207 ACIP provisional recommendations, 236 epidemiology, 233–234 herpesviridae family, 233 herpes zoster (shingles), 234, 236 immunization practices, 235–236 life cycle, 234 structure, 233 varicella (chickenpox), 234 Vasovagal reaction, 276 Vector-borne disease, 244 Venous insufficiency ulcers ankle brachial index (ABI), 250 causes, 249, 250 circulatory status determination, 250 compression hosiery, 251 diabetic ulcer, 251–252 peripheral vascular disease (PVD), 250 prevention tactics, 249–250 Vexing diseases, 233 Viral infections, 242–243 Viral vaccines cowpox, 208 efficacy, 205 human herpes viruses, 206–207 human papillomavirus, 207–208 measles, 205–206 measles, mumps, and rubella (MMR) vaccine, 205 mumps, 206 paramyxoviruses, 205–206 poxviruses, 208 rubella, 206 smallpox (variola), 208 types, 205 varicella zoster virus, 206–207 Vitamin C. See Ascorbic acid Vitamins. See also Nutrition; Supplements acute vitamin A intoxication, 191–192 adults, 190, 191 anemia, 192 balanced diet, 191 B vitamins, 192 children, 190, 191 definition, 189 fat-soluble vitamins, 191 hemorrhage, 193 hypervitaminosis/hypovitaminosis, 189–193 pellagra, 192 phrynoderma, 190 recommended daily allowances (RDA), 189, 190 scurvy, 193

316 vitamin A, 189–192 vitamin C, 192–193 vitamin D, 193 vitamin E, 193 vitamin K, 193 water-soluble vitamins, 190 W Warts, 298. See also Genital warts Wounds infections bacitracin vs. petrolatum, 244 clindamycin, 243 incidence, 243 retapamulin, 244 risk, Mohs surgery, 243 prevention aging, chronic wounds, 249 arterial and ischemic ulcers, 252–253

Index full-circle-prevention, 263–264 nutrition, 262–263 perineal dermatitis and denudation, 253–255 pressure ulcers, 259–262 prevention and reimbursement, 263 skin care, 256–259 skin functional changes, 249, 250 skin tears, 262 venous insufficiency ulcers, 249–252 X Xerosis, 257–258, 297 epidemiology, 73 moisturizer and soap-substitute, 75 moisturizing, adverse effects, 76 occupational factors, 76 pathogenesis, 72–73 prevention, 73–74 specific body areas, 76