Bronchial Asthma in Children: A Clinical, Diagnostic and Management Primer

Bronchial Asthma in Children: A Clinical, Diagnostic & Management Primer

Bronchial Asthma in Children:

A Clinical, Diagnostic & Management Primer

Keya R Lahiri Professor and Head Department of Paediatric Medicine Seth GS Medical College and KEM Hospital Mumbai

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi

Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd EMCA House, 23/23B Ansari Road, Daryaganj New Delhi 110 002, India Phones: 23272143, 23272703, 23282021, 23245672, 23245683 Fax: 011-23276490 e-mail: [email protected] Visit our website: http://www.jpbros.20m.com Branches • 202 Batavia Chambers, 8 Kumara Kruppa Road Kumara Park East, Bangalore 560 001, Phones: 2285971, 2382956 Tele Fax : 2281761 e-mail: [email protected] • 282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza Pantheon Road, Chennai 600 008, Phone: 8262665 Fax: 8262331 e-mail: [email protected] • 4-2-1067/1-3, Ist Floor, Balaji Building, Ramkote Cross Road, Hyderabad 500 095, Phones: 6590020, 4758498 Fax: 4758499 e-mail: [email protected] • 1A Indian Mirror Street, Wellington Square Kolkata 700 013, Phone: 2451926 Fax: 2456075 e-mail: [email protected] • 106 Amit Industrial Estate, 61 Dr SS Rao Road Near MGM Hospital, Parel, Mumbai 400 012 Phones: 24124863, 24104532 Fax: 24160828 e-mail: [email protected] Bronchial Asthma in Children: A Clinical, Diagnostic & Management Primer © 2003, Keya R Lahiri All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters to be settled under Delhi jurisdiction only. First Edition : 2003 Publishing Director : RK Yadav ISBN 81-8061-079-9 Typeset at JPBMP typesetting unit Printed at Gopsons Papers Ltd. A-14, Sector 60, Noida

This maiden venture “Bronchial Asthma in Children—A Clinical, Diagnostic and Management Primer” is specially dedicated to my father, Mr. GP Lahiri. My father has been the driving force behind all my achievements and also my inspiration in all my academic pursuits. My sister, Dr Karobi Lahiri deserves special mention. I have always admired her unparalled acumen, commitment and zest and just her presence and optimism will assist me in future endeavours. I wish to pay my respect to my teachers Late Dr PM Udani, Dr. AG Desai, Dr PW Kandoth and Dr. MD Shah. They have been instrumental in shaping my future and I shall always remember them with reverence.

Foreword Asthma is a serious global health problem. People of all ages in countries throughout the world are affected by this chronic airway disorder that can be severe and sometimes fatal. Prevalence of asthma is increasing everywhere, specially amongst children. While there are many general textbooks on respiratory disorders of childhood, it is remarkable that this is the only book of its kind dedicated to childhood asthma. Dr Lahiri is a leading paediatric pulmonologist of this country with vast experience as regards asthma in children and relevant research. The author has done a commendable job in providing a comprehensive textbook on childhood asthma entitled “Bronchial Asthma in Children: A Clinical, Diagnostic & Management Primer. This book would be of immense help for the undergraduates, postgraduates, practising paediatricians, general practitioners and pulmonologist. As the topic unfolds, it is evident that the pathogenesis, initial assessment of an asthmatic child, categorisation, principles of asthma exacerbations have been aptly and lucidly described. The subject of chronic persistent asthma and its follow up has been given a practical and an innovative touch. It is interesting to know that special emphasis has been laid on control measures for environmental factors and patient education. This definitely reflects the best of current thinking about proper approach to this reversible disorder. It would be a fine reference material on this vast topic. I am confident that this book will gain the reputation of being the Bible of “Childhood Asthma” in the days to come by. Dr Uday B Nadkarni MD, DCH, DNB, Senior Specialist Paediatric Intensivist & Pulmonologist In Charge of Paediatric Chest Clinic Division of Child Health Royal Hospital, Muscat Sultanate of Oman

Preface A comprehensive and practical review of Bronchial Asthma in Children has been the need of the day and the more I read and delivered lectures on this topic, it dawned on me that it was indeed necessary to address this subject for the students and practitioners. The approach to asthma in children is simple and practical provided one realises that each child’s therapy should be individualised and tailored after categorising him and grading his/her severity at every stage of follow up. It is mandatory to clinch a reactive airway diagnosis, start appropriate therapies, monitor and follow up into adolescence. I have tried to highlight the essential aspects of this disease and as the topic unfolds, one would realise the petility of one’s fears in the management of this very treatable ailment. It must be realised that asthma is a clinical diagnosis clinched further on by PEF, monitored by PEF and pulse oximetry and a range of inhalation modes at your disposal with minimal side effects. It is a reversible disease and needs early diagnosis to lessen morbidity. I am grateful to Jaypee Brothers Medical Publishers (P) Ltd, and their dedicated staff for this publication. Keya R Lahiri

Contents 1. Definition, Pathophysiology and Severity

1

2. Early Diagnosis

5

3. Environment and Patient Education 9 4. Managing Acute/Severe Exacerbations of Asthma

13

5. Managing Chronic Persistent Asthma

22

6. Leukotriene Modifiers

26

7. Future Aspects of Therapeutic Strategies

32

Index

37

1 CHAPTER

Definition, Pathophysiology and Severity

As we stand at the threshold of the new millenium, it is time to take stock; evaluate our achievements, analyse past failures and mistakes and perform a medical audit. This is the appropriate time to look ahead, readapt our skills and put emerging technology to mass usage. Hyperreactive airway disease would be affecting a large number of children in the coming decade. Hence protecting and salvaging the child’s lung would be our major concern. It would be pertinent to delve into the diagnostic, management and preventive aspects of childhood asthma. The NHLBI EPR-2, 1997 have prepared recommendations for use by clinicians, working in diverse health settings that address the practical decision making issues in the diagnosis and management. Early diagnosis, and effective management should reduce school and work absenteeism, hospitalisation and emergency department visits and deaths due to asthma. How do We Define Childhood Asthma? Asthma is a symptom complex to mean either a symptom, an exacerbation (attack) or underlying diseases of the airway. It is a reversible obstructive airway disease (ROAD) coupled with bronchial hyperresponsiveness (BHR) and airway inflammation. Asthma = Road + BHR Asthma, whatever the severity is a chronic inflammatory disorder of the airways. This has implications for the diagnosis, management and prevention of the disease. Which are these Cells and Mediators Giving Rise to this Chronic Inflammatory and Hyperreactive State? Airway inflammation leads to airflow limitation, hyperresponsiveness, recurrent episodes of cough, wheezing, breathlessness and chest tightness. Acute

2 Bronchial Asthma in Children bronchoconstriction, oedema, mucous plug formation and airway wall remodelling lead to bronchial obstruction and disease chronicity. Inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Histopathological features of asthma include: (i) Denudation of airway epithelium. (ii) Mast cell activation. (iii) Inflammatory cell infiltration with eosinophils, lymphocytes (TH-2 like cells) and neutrophils (seen in sudden onset and fatal asthma exacerbations). (iv) Collagen deposits beneath basement membrane. (v) Oedema. Atopy, the genetic predisposition for the development of an IgE mediated response to common aeroallergens is the strongest identifiable predisposing factor for developing asthma. The episodes or attacks are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. Viewing asthma as an immunological disorder, dendritic cell/macrophage and its communication with T-cells provides a mechanism for the induction of allergen related asthma probably through elaboration of cytokines which augment the IgE response (IL-4), encourages the proliferation, recruitment and priming of mast cells (IL-3, IL-5) and eosinophils (IL-3, IL-5, GM-CSF). The various cellular and mediator components indicate a special form of inflammation involving a repertoire of cytokines that augment IgE, mast cell and eosinophilic responses in the airways. Thus, asthma results from complex interactions among inflammatory cells, mediators, and other cells and tissues in the airway. Research has substantiated that sub-basement membrane fibrosis contribute to persistent abnormalities in lung function. The traditional view that mast cell was the most important cell no longer holds true. Antigens, allergens are taken up by macrophages, processed and presented to the lymphocytes which produce cytokines recruiting neutrophils and eosinophils. Eosinophil cationic protein damages epithelium, shedding occurs exposing nerve endings. Thus irritants via reflex pathways causes contraction. It is evident that inflammation occurs first. With the further advent of flexible scope, it was learnt that children with mild and newly detected, disease showed disrupted, damaged epithelium with few ciliated cells,

Definition, Pathophysiology and Severity 3 indistinct membrane and oedema between cells. Below the basement membrane, infiltration of eosinophils, basophils and mast cell occurs. Due to inflammation and epithelial shedding, patients become hyperresponsive to variety of inhaled irritants. Hyperresponsiveness is a prerequisite for smooth muscle contraction, thus increasing the tendency of the airways to react to non-specific stimuli. Assessing Severity and Patient Categorisation in Childhood Asthma Since there is no universally accepted definition of asthma and the processes that result in symptoms unknown, it is not yet possible to determine the severity of the disease or how to measure it? Asthma is loosely used to mean one of the following: (i) A symptom (ii) An exacerbation/attack (iii) Underlying disease of the airways. Hence severity could be applied to any one of the above. Methods: Assessing Severity The Underlying Disease The level of airway hyperreactivity to histamine/ methacholine is probably the best guide to the mechanical abnormality that allows airway to narrow too much and too easily to provoking stimuli. Most authors assume that symptom score or the variability of PEF measurements indicate severity. Forced vital capacity (FVC) may be a better correlate of symptoms and perhaps the severity of an attack. Good Parameters for Assessing Severity Symptom scores, peak expiratory flow (PEF) on waking, bronchodilator use. Scores Table 1.1: Symptom score (Previous 3 months) Symptom

Score

NIL for 3 months < 1 per week > 1 per week Most days, waking at night < 1 per week Waking at night, > 1 per week

0 1 2 3 4

4 Bronchial Asthma in Children Table 1.2: Peak expiratory flow (PEF) (Previous 4 weeks) Morning PEF% Personal best (PB)

Score

> 93 85-93 78-85 70-78 < 70

0 1 2 3 4

Table 1.3: Bronchodilator score (Previous 3 months) Bronchodilator use

Score

NIL for 3 months < 1 per week > 1 per week, not everyday 1-3 times a day 4 or more times a day

0 1 2 3 4

The above scores are calculated during a period when the child is free from exacerbations and it has been seen that a combined score correlates well with airway hyperreactivity. The most severe case would document a score of 12. There has been uniform consensus that there is no gold standard to measure the score. Night Symptoms + PEF Variability Assess Severity Fairly Well Measurement of severity of inflammation is not yet available. Nitrous oxide measurement and eosinophilic products in sputum may be the modalities for the future. “Relationship between severity of inflammation and clinical manifestations of the disease has not yet been shown”.

2 CHAPTER

Early Diagnosis

An Early Diagnosis would Go a Long Way ... Since time immemorial, paediatricians have regarded asthma as an episodic disease of variable airway obstruction producing symptoms of cough, wheeze and breathlessness. It is the very reversibility of the disease that provides one of the surest way of estabilishing a diagnosis. Thus, asthma represents a highly satisfying diagnosis to make the prognosis being good if detected early and treatment protocols highly effective. Why then there is growing concern by the medical consultants and people at large about this seemingly benign, treatable disorder? Diagnosis of Asthma is Based on • Episodic symptoms of airflow obstruction • Airflow obstruction is partially reversible • Alternative diagnosis are ruled out. A careful medical history, physical examination, pulmonary function tests and allergic status would ensure a correct diagnosis. It must be remembered that asthmatic children are heterogeneous in presentation and the signs and symptoms vary widely not only from time to time but also with each child over a period of time. Taking a New Look at Asthma! In childhood asthma, the chronic inflammatory status causes: Recurrent episodes of cough, wheezing, breathlessness and chest tightness. Cough variants could very often present as chronic cough, nocturnal and early morning cough. Inflammation makes the airways sensitive to stimuli such as: viral infections, allergens (dust, mite, cockroach, animal dander, mold and pollen) exercise, occupation, environment, irritants (tobacco smoke, odours, pollutants,

6 Bronchial Asthma in Children chemicals, dust, vapours and gases), stress, emotions, drugs (aspirin, beta-blockers, NSAID) foods (egg white shell, fish, chocolate, ice-cream, cold drinks, peanuts, cow’s milk, tomatoes, lemon, citrus fruits) additives and preservatives, changes in weather, exposure to cold, menses. History related to allergic status, eczema, dermatitis, urticaria should also be elicitated. Breastfeeding, response to bronchodilator/steroid therapy, past hospitalisation, compliance, birth history and immunisation status should be highlighted. Past history of bronchiolitis, recurrent upper respiratory tract infection and tuberculosis could give further insights. Family history constitutes a very important component in diagnosing childhood asthma and other allergies. Examination should Include Growth centiles, ear/nose/throat examination for otitis, sinusitis, post-nasal drip and adenoids, congestion and / or bleeds in the eye and slit lamp for posterior capsular cataract. Flexor creases should be checked for signs of allergy, atopic dermatitis; lips and nailbed pallor, cyanosis and clubbing. Heart rate and blood pressure should also be checked. Chest should be examined for increased anteroposterior diameter and wheezing. Liver may be pushed down as result of hyperinflation. Importance of Spirometry in Asthma Diagnosis Spirometry provides an excellent objective measurement of pulmonary function in an asthmatic child specially for clinching the diagnosis as history and physical examination are not reliable means of excluding other diagnosis or characterising the status of lung impairment. For diagnostic purposes, spirometry is generally recommended over measurements by a peak flow meter because of the wide variability. Vital capacity and forced vital capacity are timed measurements viz. forced volume of air that can be expired in one second (FeV1). It tells us how well the lungs are functioning, used in clinic and hospital settings. However, it is expensive and time consuming. Peak flow meter measures the peak expiratory flow (PEF) i.e.the fastest rate at which air can move through the airways during a forced expiration starting with fully inflated lungs. PEF is fairly comparable with FeV1. It is a small, portable,

Early Diagnosis 7 convenient, inexpensive instrument and it is a must in any clinic, hospital and also with an asthmatic child. It is a tool to establish a fairly reliable diagnosis, assess severity and evaluate response to therapy. It serves as an excellent monitoring tool and also gives one warning hours/days before the symptoms are felt so as to take action and prevent an attack. The Various Measurements 1. FeV1 or PEF before and after bronchodilator. 15% improvement indicates reversibility. 2. A diurnal variation in PEF > 20% (on bronchodilator) and > 10% (not on bronchodilator) and between morning and afternoon values. PEF [Afternoon after SAβ 2 agonist]–PEF [morning before SAβ2 agonist] × 100 PEF (Afternoon) 3. Post-exercise fall of PEF/FeV 1 by 15% and 20% respectively. (i) Pre-exercise PEF – Post-exercise PEF

× 100 (> 15%) Pre-exercise PEF (ii)Pre-exercise FeV1 – Post-exercise FeV1 ×100(> 20%) Pre-exercise FeV1 Bronchoprovocation It is done with methacholine, histamine or exercise challenge and may be useful when asthma is suspected and spirometry is normal or near normal. It should be performed by a trained individual and is not recommended if FeV1 is < 65% predicted. A negative bronchoprovocation may be helpful to rule out asthma. Chest X-ray is done to rule out alternative diagnosis or complications that may be detected as a consequence of asthma viz. pneumonia, pneumothorax, pneumomediastinum or persistent chest shadow. Allergen testing aids as an adjunct to the diagnosis of asthma and has definite educative value. The specific categories of allergens to be tested are area specific and would include house dust, mite, animal dander (cats, dogs, horses), insects (housefly, cockroach, grasshopper, mosquitoes), pollen, molds and food. Radiological evaluation for mastoiditis, sinusitis and adenoids. Scintigraphy on 24 hours pH monitoring for gastrooesophageal reflux specially in the preschool age group. Sputum for eosinophils End Nitrous oxide (NO)

8 Bronchial Asthma in Children Alternative Diagnosis to be Ruled Out (i) Upper airways: Allergic rhinitis and sinusitis (ii) Obstruction involving large airways • Foreign body • Vocal cold dysfunction • Enlarged lymph nodes • Vascular rings/laryngeal web • Laryngotracheomalacia • Tracheal/bronchial stenosis • Mediastinal tumour. (iii) Obstructions Involving Small Airways • Viral bronchiolitis/obliterative bronchiolitis • Cystic fibrosis • Bronchopulmonary dysplasia. (iv) Other Causes • Recurrent cough • Gastro-oesophageal reflux or swallowing dysfunction causing aspiration • Mitral valve prolapse. Assessing the “Personal Best PEF” The personal best PEF is the highest peak flow value obtained during a 2-3 weeks period when a child has no asthma symptoms. The child should stand, set the indicator to zero position and perform the test three times. The highest of the three measurements before and after each treatment is then recorded. PEF does not correlate with the degree of obstruction. Children 5 years of age or older are able to perform PEF fairly well but it is effort and technique dependent. An artificially elevated PEF can be produced by placing a finger over the outlet port or using tongue to create back pressure. It does not detect mild decreases in FeV1.

3 CHAPTER

Environment and Patient Education

We must realise that patient education has become one of the most integral part of any disease management, more so with the current scenario of hyper-reactive airway disease (HRAD) mainly ASTHMA and virus induced BRONCHIOLITIS. It is necessary to avoid identifiable allergens, irritants and ensure environmental control measures. However, the environmental control must reflect the child’s needs. It is necessary to instruct the child and caregivers in these measures and review them regularly. It would be necessary to provide educational material in simple, depictive language (preferably their mother tongue) and through videotapes. Child’s Room/Bedroom The child spends maximum time in the bedroom and hence it should be simple, clean and sunlit. The room should have cotton curtains with metal/cane furniture and specially no rugs, heavy draperies or stuffed chairs and plush sofa sets. The doors and windows should close well and there should not be any unnecessary storage. Dusting should be avoided and one should resort to damp cleaning. The child should avoid the room during dusting and 3-4 hours post-dusting. Bedding should be exposed to sunlight and washed every week with hot water. Dacron and foam pillows would be preferable. Toys should be plastic/wooden with no pets and plants. An air-conditioner would be ideal to maintain humidity between 35-40% but with regular cleaning of the filters every month. It is best to avoid sprays and perfumes. The Mites The unseen and unheard “Mites” are found in housedust, love the furnishings and mattresses and thrive in moist climate and surroundings. It feeds on human scales and its allergenic component is in its faeces. A single mattress

10 Bronchial Asthma in Children houses 200,000 mites; 2 μgm/gm of dust is enough to sensitize a child and 10 μgm/gm of dust to initiate an attack or exacerbation. It is known that higher altitudes reduces the mite load. How do We Trick Them? It would be wise to encase the mattress/pillows in plastic and expose them to sunlight. Weekly washing of bedclothes and removal of heavy furnishings would be ideal. The acaricide known to denature mite allergen are benzyl benzoate and 3% tannic acid. The ideal humidity to be maintained in the room should be between 35-40%. The Cats/Dogs It has been adequately shown that 40% of the asthmatics have skin test positive to Fel dI. The allergenic material resides in the saliva and sebaceous glands and these particles remain airborne and adhere to the walls. There is a definite degree of increased sensitisation when a child has been exposed to cat allergen in the first year of life. Similarly dog dander is also allergenic. How Do We Tackle Them? Obviously, the removal of the cat/dog would be an ideal but uphill task. It would be empiric to wash the pet once a week and once again, removal of sofas, carpets, furnishings and/or denaturing with 3% tannic acid would be necessary. Air filtration devices for particle size < 3 μm would be preferable. It must be known that the levels of Fel dI could linger on for months after removal of the pet. Cockroaches: Use poison bait/traps to control. Do not leave food or garbage exposed. Molds Universal molds could be reduced by repairing leakages, applying whitewash or bleach once a year. House plants should be avoided and the refrigerator should be clean and dry. One could also apply fungicides viz lipol, tilex to the surfaces. Other Forms of Indoor Pollution Smoking should be avoided at all costs either in the house or car. Cooking media viz kerosene, wood and charcoal would prove harmful and hence smokeless chullas or gas is preferable. An exhaust fan should be filled into the kitchen area and tight fitting lids should be used on

Environment and Patient Education 11 cooking vessels. It would be ideal to minimise the use of sprays, perfumes, soaps and mosquito repellants. Food It is very common to see an asthmatic child who is underweight. This happens because of asthma and also curtailing of essential food items which are believed to be allergenic. One must remember that an occasional food item would be allergenic and hence do not omit essential items viz rice, wheat milk and cereals from the child’s diet. A definite history of cough/breathlessness and wheeze following ingestion of a certain food item would call for vigilance and observation after omitting that particular item subsequently it could be gradually introduced at a later date. Yes, it is definitely advisable to cut out on ice-cold/ chilled food or drink. The child could however still enjoy an ice-cream by partially melting it or keeping the cold drink/water for some time at room temperature. It is pertinent to remember that we are dealing with little ones and their lifestyle needs to modified and not cramped. Drugs and Food Additives It is best to avoid drugs like NSAIDs, β-blockers, aspirin and propranolol. Home cooked food would be ideal and it would be best to avoid junk food and items with preservatives and colouring agents. Tartrazine and sulfites are best avoided. No Chinese/Italian/Mexican or Thai food. Outdoor Pollution It is becoming more and more difficult to combat pollution arising due to increasing vehicles, mills and industries. The routine burning of wood, cloth and tyres outside chattels (zopadpatlis) should be discouraged. Lighting of fire is specifically done in order to dispel mosquitoes or heating bath water. A good neighbourly advise and/or taking the help of media could achieve results. Children should also avoid exposure during high pollen counts, specially during the afternoon. They should avoid gardens or smelling of flowers. Pollen calender depicting pollen counts are available. We are also signatory to the Montreal Contract and should encourage the use of CFC free inhalers.

12 Bronchial Asthma in Children Child Labour Child labour has emerged as a sad but stark reality and the various occupational hazards that are associated with it. Poverty and child labour are in unison; one notices them at signals selling goods, at construction sites, in industries (weaving beedis, glass, cracker etc.); as hotel boys, boot polish boys, as sewage cleaners, spraying flower beds and the list goes on. A good history is the key tool. It is mandatory to induce safe working conditions. The use of mask should be discouraged as it increases the work of breathing, dead space ventilation and resistance to air flow. The mask may help in the case of irritant exposure (if it is the only option) but it gives a false sense of security in a sensitizing exposure. The bottom line is: “exposure must cease”.

4 CHAPTER

Managing Acute/Severe Exacerbations of Asthma

Asthma exacerbations are acute or subacute episode of progressively worsening shortness of cough, breathlessness, wheezing and chest tightness. Exacerbations are characterised by decreases in expiratory flow rate that can be documented by measurement of lung function. These objective measures indicate the severity of an exacerbation rather than the severity of symptoms. Bronchospasm was once thought to be the primary component of asthma but “Inflammation” is now recognised as the principle event and management is aimed at controlling and decreasing inflammation. However, during on acute exacerbation, treatment of acute bronchoconstriction remains an important element of management. Treatment Goals 1. Correction of hypoxemia by administering supplemental oxygen. 2. Rapid reversal of airflow obstruction. This is achieved by: (i) repetitive or continuous administration of an inhaled β2 agonist. (ii) administration of systemic corticosteroids. 3. Reducing the likelihood of recurrence of severe airflow obstruction by intensifying therapy with a short course (burst therapy) of systemic/oral steroids. Understanding the Goals Hypoxia is an exacerbation is due to “ventilation-perfusion mismatch”. The national institute of health guidelines recommends 90% as the cut off point. Oxygenation is most accurately assessed by measurement of PaO2 or estimated using pulse oximetry. • SaO2 90% is comparable with PaO2 60 mmHg. • SaO2 75% is comparable with PaO2 40 mmHg.

14 Bronchial Asthma in Children In children with PaO2 < 60 mmHg, not responding to O2 therapy either pneumothorax, pneumomediastinum and atelectasis should be considered. β agonists may accentuate this mismatch by causing certain degree of vasodilatation in the pulmonary vasculature, supplying an area of the lung with poor ventilation. The pulse oximeter probe can be placed on a finger or toe, placing a sock over a toe which could help warm the foot and prevent removal by the child. The number recorded on the pulse oximeter must equal the heart rate. The Logistics of Ventilation-Perfusion Mismatch in Asthma The understanding of ventilation-perfusion mismatch in childhood asthma could emerge as a good objective modality for understanding the severity of the disease, follow-up on treatment and prognosticating the outcome. This is an excellent tool to assess the functional aspect of the lung and could assist in long-term minimal therapies and child’s activities. Ventilation can be assessed by measurement of carbon dioxide (CO2) in arterial blood or PCO 2. The partial pressure of CO2 from capillary blood gas level or PcCO2 is often higher than PaCO2 especially in sick children with poor perfusion. PcCO2 can be used to follow PCO2 over a period of time but cannot be used to assess the adequacy of ventilation in an emergency setting. End-tidal CO2 cannot be used to accurately assess CO2 due to significant airway obstruction with rapid respiratory rate preventing movement of CO 2 from peripheral air spaces to the mouth. Thus underrepresenting the true value of alveolar CO2 (equivalent to PaCO2). Patients with SaO2 > 90 to 92% and PEFR > 25 to 30% are unlikely to have an elevated PaCO2. Early in the course of an exacerbation, ventilation increases (↑) to compensate for decreased (↓) PaO2 caused by ventilation-perfusion mismatch with mucus plugging. Respiratory failure is detected by an elevation (↑) of PaCO2 > 60 mmHg or impending respiratory failure is noted by rapidly increasing PaCO2 i.e. > 5 mmHg/hour. Tachypnoea with elevated PaCO2 suggests poor ventilation and may be an early sign of muscle fatigue and impending respiratory failure. This PaCO2 35-45 mmHg can be worrisome and these children need to be monitored closely. ABG’s should be considered for children with SaO2 < 90% on maximal O2 therapy, no improvement despite aggressive treatment and changes in the mental status.

Managing Acute/Severe Exacerbations of Asthma 15 The most common cause of respiratory failure in children with acute asthma is ineffective ventilation caused by severe obstruction and muscle fatigue. IMPENDING RESPIRATORY FAILURE/ RESPIRATORY FAILURE Assessing Exacerbation • History and Examination It is pertinent to ask and record ê Grading severity ê Duration of an episode; severity of previous episode ê Medications used ê Last aminophylline dosing ê Precipitating factors viz infection, exercise, drugs, stress and season. • ê ê ê ê ê ê ê

Examine Sensorium Respiratory rate Accessory muscles Heart rate Colour Breath sounds Wheeze.

Measure : • PEF • SaO2 It must be understood that history and examination should be quickly and efficiently carried out because quick, accurate assessment would assure effective management and better outcome. Table 4.1: Grading severity of exacerbation/attack Mild

Symptoms • Breathless

• Talks • Alertness

Moderate Severe

Walking Talking can lie can sit down feeding possible SentencesPhrases Not agi- Agitated tated

Respiratory arrest imminent

At rest upright stops feeding Words Agitated Drowsy Contd...

16 Bronchial Asthma in Children Contd... Mild

Moderate Severe

Signs • Respiratory rate Normal ↑ Normal upto 2 months: < 60/min 2 months-1 year: < 50/min 1-5 years: < 40/min > 5 years: < 30/min • Pulse normal < 100 100-120 2 months-1 year: < 160/min 1-2 years: < 120/min 2-8 years: < 110/min • Pulsus < 10 10-25 Paradoxus mmHg mmHg

• Accessory muscles • Wheeze

↑

> 120

Bradycardia

Absence suggests muscle fatigue Not Affected Affected Paradoxical affected thoracoabdominal End Throug- Inspira- Absent expira- hout tion tion expira- + tion expira -tion

Functional Assessment PEF > 80% % PB (Personal best) PaO 2 Normal >60 mmHg PaCO2 < 42 mmHg SaO2 % > 95 (on air) at sea level Ref: NHLBI—EPR2

Respiratory arrest imminent

60-80%

20-40 mmHg

< 60%

< 33%

< 60 mmHg cyanosis < 42 > 42 mmHg mmHg 91-95 < 91

Managing Acute/Severe Exacerbations of Asthma 17 Pulmonary Score (PS Score) The pulmonary score correlates well with PEFR in children with mild to severe exacerbations. Table 4.2: PS and care with PEFR in children Score

Respiratory rate Wheezing < 6 years > 6 years

0 1

< 30 31-45

< 20 21-35

2

46-60

36-50

3

> 60

> 50

Accessory muscle use

None End-expiration

None Slight increase Entire expiration Increase apparent Inspiration + Maximal expiration/ No wheeze

Management of Acute/Acute Severe Asthma At home and while travelling to the hospital • Reassure parents and relatives and tell them to keep their cool. • Push 4-8 puffs through an MDI into a spacer with a mouth piece/face mask of β2 agonist and start inhaling. • To take a tablet of Prednisolone (5, 10 mgm) stat. • Carry your nebuliser solutions of β 2 agonist, ipratropium, budesonide with personal Hudson’s chamber, tubes and a venturi mask. • To carry the treatment file. • Report at the earliest to the nearest hospital. When Child Reports to the Hospital After a quick history taking, examination, PEF and SaO2 recording, follow the following recommendations step by step. Treatment - First hour O2 5 litres/min, SaO2 > 92%

β2 agonist neb 0.15 mgm/kg/dose, 20 minutes (3 doses) ↓ Or β2 agonist, 4-8 puffs (MDI + spacer + mask), 20 minutes (10-20 puffs in 1 hour). Steroids Prednisolone—1-2 mgm/kg/dose - oral Hydrocortisone—10 mgm/kg/dose 6 hourly IV Methylprednisolone—1-2 mgm/kg/dose IV.

18 Bronchial Asthma in Children Nonavailability of MDI/neb Adrenaline/Terbutaline 0.01 mgm/kg → 0.3 - 0.5 mgm, 20 minutes, 3 doses, subcutaneously. Assessment at End of 1 Hour Symptoms / Signs / PEFR Good response ↓ Alert ↓ HR, RR, PP < 10 mmHg No distress PEFR > 70% (PB) SaO2 > 92% ↓ • Discharge • Continue β2 agonist 8 hourly (MDI)

Incomplete response Mild/moderate symptoms and signs PEFR 50-70% (PB) •Continue O2 •β2 agonist inhalations every 20-30 minutes •Monitor HR and K levels •Add ipratropium 250 μgm every 20 minutes, 6 hourly and may also require

• Steroid 1-2 mgm/kg, oral 12 hourly, 3-10 days • Education: Review after 1 week •Aminophylline Draw action plan infusion / mgm/kg/ Follow-up hour • Continue to assess every hour • Continue same treatment for 4 hours If Improvement after 6 Hours • Cut down β2 agonist inhalations every 1-4 hours • Steroids 1-2 mgm/kg/day, 12 hourly, 3-10 days. However if the Child Deteriorates

In the presence of • Confusion, drowsiness • Exhaustion, shallow respiration • Hypoxia • Coma, respiratory arrest • pH < 7.25, PaO2 < 60 mm of Hg, PaCO2 > 10 mm of Hg or rising > 5 mm of Hg/1 hour • PEFR < 33-50% PB It is time to intubate and ventilate after shifting to PICU.

Managing Acute/Severe Exacerbations of Asthma 19 Important Points on Intubation • Rapid sequence induction is required for intubation in the emergency department because of the likelihood of full stomach. • Child should be preoxygenated and placed on respiratory and cardiac monitors with suction available. • Ketamine (1-3 mgm/kg) is recommended because of its bronchodilatory effects. • Elomidate (0.2-0.4 mgm/kg) may also be used for induction. • Anticholinergic agent is added to reduce oral secretions. • Midazolam (benzodiazepine) 0.05 mgm/kg is used to reduce the risk of an emergence reaction or dysphoria when awakening from sedation. • Succinylcholine (2-4 mgm/kg) or altracurium could be used as a rapidly acting paralytic agent. • Sellick maneuver (cricoid pressure) during intubation can decrease the risk of aspiration. • Correct placement of ET tube is monitored by end-tidal CO2 monitor, equal bilateral breath sounds, visualisation of chest movement and radiography. Ventilatory Management The goals of mechanical ventilation: a. Provide adequate oxygenation b. Provide adequate ventilation c. Decrease the work of breathing. “Permissive Hyperapnea or Controlled Hypoventilation is recommended” • PaCO2 is allowed to remain higher than usual by decreasing ventilator settings. The aim is to reduce hyperinflation and barotrauma. • Tidal volume is set in such a way so as to minimise peak inspiratory pressure (PIP). • Prolong the expiratory phase by increasing expiratory flow and decreasing the respiratory rate. • Elevated PaCO2 levels carries a small risk of cardiac dysrhythmias and hypertension. • FiO2 is regulated to maintain oxygen saturation levels of > 90% and FiO2 rather than PEEP (positive end expiratory pressure) is increased to prevent barotrauma. • Close attention should be given to maintaining or replacing intravascular volume because hypotension commonly accompanies the initiation of PIP. • Expert panel recommends that intubations not be delayed once it is deemed necessary.

20 Bronchial Asthma in Children Since intubation of severely ill asthma patient is difficult, additional ancillary treatments are attempted. (i) Intravenous MgSO4 is given as a bolus of 25-50 mgm/kg to a maximum of 2 gm. Side effects would be flushing, tachycardia, bradycardia, hypotension and muscle weakness. Nebulised MgSO4 therapy is ineffective. Magnesium works by modulating calcium channels causing a decrease in acetylcholine with subsequent bronchodilatation and inhibition of histamine release from mast cells. (ii) Epinephrine 0.01 mgm/kg upto 0.3-0.5 mgm subcutaneously in addition to inhaled short acting β2 agonist. (iii) Intravenous terbutaline infusion, bolus 10 μg/kg, then continue as a drip 0.2 μg/kg/min. Continue to monitor the child for ventricular dysrhythmias or myocardial ischaemia. (iv) Helium and oxygen combination [80:20; 70:30). The lower density of heleox allows this mixture to pass through a narrow airway with less turbulence than oxygen alone and can improve distal oxygen delivery. Ventilator Mode ê ê ê ê ê ê ê

Pressure/volume cycled FiO2 = 0.6 Tidal volume = 10-12 ml/kg RR = 2/3 of normal rate I : E = 1 : 2, 1 : 3, 1 : 4 PIP = 20-22 cm of H2O PEEP = 3-4 cms of H2O.

Newer Trends Non-invasive positive pressure ventilation has been shown to achieve the same goals of mechanical ventilation without intubation. It decreases the work of breathing, alleviates muscle fatigue and allows spontaneous ventilation. Non-invasive positive pressure ventilation is applied with a tight fitting face or nasal mask, with a continuous positive airway pressure of 2 to 6 cm H2O. The NHLBI recommends that regular visits with their primary care providers (four times a year). Instituting an action plan at the beginning of an acute exacerbation may prevent progression to a more severe condition.

Managing Acute/Severe Exacerbations of Asthma 21 General Principles and Goals for Managing Asthma Exacerbations • Early treatment is the best strategy - a written action plan - recognition of early indicators of an exacerbation i.e. PEF/FEV1 - prompt communication between the patient and clinician - intensification of therapy often including a short course of steroids - withdrawal from allergic or irritant particles in the environment • Infants require special attention due to their early onset respiratory failure.

5

Managing Chronic Persistent Asthma

CHAPTER

MANAGING CHRONIC PERSISTENT ASTHMA One has to view asthma specially chronic persistent on a long-term basis. At the outset grading the severity is mandatory and also reviewing the severity at each visit inorder to optimise therapy. The second important point would be that even when asymptomatic, the child has to continue therapy as advised viz long-term anti-inflammatory therapy. What would concern a paediatrician would be the child’s growth velocity, daily activities, school absenteeism and side effects of the drugs. Our experience has shown that the child and mother settles very well to the baseline long-term therapy once control is achieved and they are convinced that the child can combat this crippling disease. Hence the goals would be: 1. Prevent symptoms viz cough and breathlessness at night, early morning or post-exercise. 2. Maintain normal activity levels. 3. Maintain near normal pulmonary function. 4. Prevent recurrent exacerbations and minimise the need for emergency visits and hospitalisation. 5. Provide optimal therapy with minimal or no side effects. 6. Meet patients’ and families’ expectations of and satisfaction with care. Thus, any child with chronic persistent asthma needs a proper grading and one must closely assign the child in the grade as depicted. This would make the long term management strategies very easy, however one should grade the child at each visit in order to revise i.e. step up or step down his/her schedule. At this point it is important to review the pharmacological aspects of the anti-inflammatory, anticholinergics, methylxanthines and the bronchodilators.

Managing Chronic Persistent Asthma

23

Table 5.1: Classification of severity of chronic persistent asthma Grade Day Mild intermittent

Mild persistent

Moderate persistent

Severe persistent

Symptoms Night

< 2 times/ week Asymptomatic normal PEF between attacks Attack (hrs, days) < 2/week, < 1/day Attacks affect severity Daily, short acting b2 daily Attacks > 2/ week Lasts days Continuous Limited physical activity. Frequent attacks

Lung function PEF/FEV1 PB% Variability %

< 2 times/ month > 80

>2/ month

> 80

< 20

20-30

> 1/week 60-80

30

Frequent

> 30

< 60

(i) Corticosteroids Steroids are the most potent and effective long-term control medication for asthma. They suppress the generation of cytokines, recruitment of airway eosinophils and release of airway mediators. Twice a day dosing schedule maintains control of asthma. Their clinical effects include reduction in the severity of symptoms, improvement in PEFR and spirometry, diminished airway hyperresponsiveness, prevention of exacerbations and possibly the prevention of airway wall remodelling. Children with mild distress tolerate oral prednisolone well, but vomiting may occur frequently due to bad taste. Intravenous steroids should be given to children with marked distress, inability to take oral medications, vomiting or a worsening clinical picture. Methylprednisolone can be given intramuscularly but is painful

24 Bronchial Asthma in Children and carries the risk of subcutaneous fat necrosis. Oral prednisolone is given 2 mgm/kg/day till improvement occurs i.e. PEFR > 70% PB after 48-72 hours. (ii) Nedocromil and Cromolyn Sodium The above drugs are categorised under the mild to moderate anti-inflammatory medications and may be used as initial choice for long-term control. It is appropriately used prior to exercise or unavoidable exposure to known allergens. They inhibit the early and late asthmatic response. The mechanism appears to involve the blockade of chloride channels and they modulate the mast cell mediator release and eosinophil recruitment. The drugs are administered four times a day and have a strong safety profile. However, their clinical response when compared to steroids is less predictable. (iii) Bronchodilators β2 agonists are used primarily for the management of acute bronchoconstriction in an acute/acute severe attack or a chronic persistent case with an exacerbation. The immediate need in such a case is bronchodilatation along with an anti-inflammatory drug. Not only there is near immediate relief but also better drug delivery through the dilated bronchi. They work by attaching to the β receptors on bronchial smooth muscle, resulting in activation of cyclic AMP. This leads to bronchodilatation, enhanced mucociliary clearance, vascular integrity and inhibits inflammatory mediator release. Several minutes after the attachment to the receptor, the β receptor gets phosphorylated and is internationalised below the cell surface. With prolonged exposure, the number of receptors is decreased by down regulation of mRNA: thus resulting in tolerance, a cause for concern in chronic asthmatic children. Inhaled short acting salbutamol/albuterol is administered 2-4 puffs every 15-20 minutes; 2.5 ml diluted in 2-3 ml saline every 15-20 minutes or 5 to 10 mgm diluted in 4-6 ml saline continuously every 30-60 minutes. Face mask is used for children < 5 years and mouthpiece for cases > 5 years of age. Children old enough to perform PEF do well with dry powder inhaler because young children have trouble generating enough flows for adequate delivery.

Managing Chronic Persistent Asthma

25

Ipratropium Bromide This is an anticholinergic medication used for bronchospasm. It is similar to atropine but contains an ammonium group that prevents systemic absorption. It blocks acetylcholine receptors at the neuromuscular function of bronchial smooth muscle, resulting in broncho-dilatation. It reduces intrinsic vagal tone and decreases mucus gland secretion. It may provide additive effects to β2 agonist and is an alternative for children with intolerance to β2 agonists. However, it is not recommended by itself as the first line therapy. Inhaled or nebulised MDI starts acting within 30-90 minutes, the dose being 250-500 μgm singly or added to β2 agonist. Methylxanthines Theophylline It gives very effective long-term control and especially prevents nocturnal symptoms. It causes smooth muscle relaxation from phosphodiesterase inhibition; affects eosinophilic infiltration as well as decrease in Tlymphocyte numbers. It increases diaphragm contractility and neucociliay clearance. It is important to maintain steady state serum concentration between 5 and 15 µg/ml because of significant toxicities and narrow therapeutic range and individual differences in metabolic clearance. Dose related toxicities include tachycardia, nausea and vomiting, tachyarrythmias, hyperglycaemia and hypokalaemia. Dose for < 1 year of age : 0.2 (age in weeks) + 5 = mgm/kg/day. Maintain serum theophylline level of 5-15 μgm/ml/> 1 year of age: 16 mgm/kg/day.

6 CHAPTER

Leukotriene Modifiers

LEUKOTRIENE MODIFIERS Leukotrienes are potent biochemical mediators released from mast cells, eosinophils and basophils that contract airway smooth muscle, increase vascular permeability, increase mucus secretion, and attract and activate inflammatory cells in the airways of children with asthma. Leukotriene modifiers, zafirlukast and zileuton are available as oral tablets for the treatment of asthma. These drugs diminish symptoms, used effectively in aspirin and exercise induced asthma, improve lung function i.e. modest improvement of FEV1, around 11% over placebo and reduces the need for short-acting inhaled β2 agonists. They may be used as the first line or alternative to inhaled corticosteroids in mild persistent asthma. However, the experience in various trials have been in children above 12 years of age. Zafirlukast, a leukotriene receptor antagonist also attenuates the late response to inhaled allergen and post allergen induced bronchial responsiveness. Prothrombin time needs to be monitored if given with warfarin. They are available as 20 mgm tablets (Dose: 10 mgm 12 hourly) to be administered 1 hour before or 2 hours after meals in children more than 12 years of age. Zileuton This drug is a 5 lipo-oxygenase inhibitor, improves FeV1, reduces the need for oral steroids, attenuates bronchoconstriction from exercise and aspirin. Hepatic enzymes needs to be monitored with the usage of this drug. It is also a microsomal enzyme inhibitor that can inhibit the metabolism of terfanidine, warfarin and theophylline and hence, dose of these drugs have to monitored. They are available as 300 mgm tablets. The dose is 150 mgm 6 hourly for children more than 12 years of age.

Leukotriene Modifiers 27 Montelucast Long-acting Inhaled β2 Agonist The long-acting β 2 agonist, i.e. Salmeterol could be beneficial to patients when added to inhaled corticosteroid therapy, especially for night time symptoms and exercise induced asthma. It is not used for the treatment of acute symptoms or exacerbations. Children are to continue the use of antiinflammatory therapy while taking salmeterol even though their symptoms may significantly improve. The recommended dose is 25 μgm 12 hourly. Inhaled Corticosteroids The inhaled form of corticosteroids are well tolerated and safe at recommended dosages; the potential but small risk of adverse events from the use of inhaled corticosteroids is well balanced by their efficacy specially in low and medium doses. Local Adverse Events Oral Candidiasis (Thrush) This is the most common adverse effect of inhaled corticosteroid. Positive throat cultures of Candida can be identified in 45-58%, whereas clinical in only 0-34%. With low doses it is less than 5%. Prevention and Treatment • One should use a spacer/holding chamber to reduce the incidence of colonisation. • Rinse mouth with water after inhalation. • Administer inhaled steroids 12 hourly. • Topical or oral antifungal drugs to be used to treat active infections. Dysphonia This adverse effect is reported in 5-50 percent of the patients and is associated with vocal stress and increasing doses of inhaled steroids. Prevention and Treatment • Use a spacer/holding chamber • Reduce the dosage • Rest for vocal stress.

28 Bronchial Asthma in Children Reflex Cough and Bronchospasm • Reduced by slower rates of inspiration • Use of spacer/holding chamber • Pretreatment with an inhaled β2 agonist prior to each dose of inhaled steroid increases intra-pulmonary delivery of the inhaled steroid or reduces dosage requirement. SYSTEMIC ADVERSE EFFECTS The potential effects of inhaled steroids on children’s growth are important because the drugs are more likely to be used for longer periods although it is well recognised that poorly controlled asthma itself may result in retarded linear growth along with concomitant atopy, asthma severity and male sex. Childhood asthma is associated with delayed maturation and a longer period of reduced growth prior to puberty. A recent meta-analyses do not demonstrate a negative effect on growth with dosages of 400-800 μgm/day. Bone Metabolism/Osteoporosis Low and medium dosages of inhaled corticosteroid appear to have no major adverse effects on markers of skeletal metabolism viz serum osteocalcin. Serum alkaline phosphatase and urinary hydroxyproline: creatinine ratio. Elderly female patients may be more at risk due to preexisting osteoporosis, previous use of steroids, a sedentary lifestyle and the normal changes of oestrogen in ageing that effect calcium utilization. Prevention and Treatment • Concurrent treatment with calcium supplements and vitamin D. • Oestrogen replacement where applicable. Disseminated Varicella There is no evidence that recommended doses of inhaled corticosteroids are immunosuppressive. Cases have been reported with systemic corticosteroids. Prevention and Treatement The vaccine should be administered to patients who are receiving systemic corticosteroids (2 mgm/kg or 20 mgm/ day of prednisolone for more than one month), unless this dosage is discontinued for atleast one month.

Leukotriene Modifiers 29 Children who have completed a short course of prednisolone may receive varicella vaccine and children on steroids who have not been immunised against varicella and are exposed to varicella infection are candidates for zoster immunoglobulin and therapy with a cyclovir. If these children develop clinical varicella, intravenous acyclovir with or without zoster immunoglobulin should be given. Dermal thinning and increased ease of skin bruising has not been seen in children Hypothalamic Pituitary Axis (HPA) Function Several studies indicate that low-to-medium doses of inhaled steroids do not appear to have significant effects on HPA function. Fluticasone caused greater adrenal suppression at doses of 400-2000 μgm than budesonide in equivalent doses. Cataracts There appears to be no association between inhaled corticosteroids and posterior subcapsular cataracts. Glucose Metabolism Inhaled steroids failed to affect fasting glucose or glycated haemoglobin at dosages from 400-1000 μgm/day (budesonide). Table 6.1: Factors affecting serum theophylline concentrations Factor Viral illness

Theophylline concentration ↓ ↑

Action

↓ Metabolism Serum level, ↓ Dose by 50% if level not available ↓ Metabolism Serum level

Hypoxia, CCF, cirrhosis Age ↑ Metabolism ↓ Metabolism Serum level (1-9 years) (< 60 month) Food ↓ Delays absorp- ↑ Rate of absotion of SRT rption (fatty food) Diet ↑ Metabolism ↓ Metabolism high protein (high CHO) Phenobarb, ↑ Metabolism phenytoin, carbamazepine Contd...

30 Bronchial Asthma in Children Contd... Factor

Theophylline Concentration ↓ ↑

Macrolides Quinolones Rifampin Cimetidine

↑ Metabolism

Action

↓ Metabolism ↓ Metabolism ↓ Metabolism

Table 6.2: Doses quick relief medications Short acting β2 agonists MDI Salbutamol 90 μgm/ puff (200 puff)

DPI

200 μgm 5 mgm/ml capsule (0.5%)

Albuterol “ “ Terbutaline 200μgm/ puff (300 puff)

Anticholinergic Ipratropium 18 μgm/ puff (200 puff)

Budesonide Chromolifn Prednisolone 5 mgm Methyl Pred. 2, 4, 8, 16, 32 mgm Theophy10 ml-100 mgm lline SR 200, 300, 400

Bambudil Oral

Neb

“

.25 μgm/ml (0.025%)

Dose 1-2 puff for 8 hourly 1-2 caps 8-6 hourly 1.25-5 mgm (.25-1cc) in 2-3 cc of saline 8 hourly 1-2 puff 6 hourly 0.25-0.5 mgm 6 hourly

0.5 mm/2 ml 1 mgm/2 ml 20 mgm/2 ml

9 9-12 12-16 16 + >

24 mgm/hr 20 mgm/hr 18 mgm/hr 13 mgm/hr 900 mgm

10 20 mm/ml (1.60 ml)

How to Use a Peak Flow Meter? 5 Steps 1. Move the indicator to the bottom of the scale 2. Stand up. 3. Take a deep breath, fill in your lungs completely

Leukotriene Modifiers 31 4. Place the mouthpiece in your mouth and close your lips around it. Do not put your tongue inside the hole 5. Blow out as hard and fast. Key Points in the Long-term Management of Asthmatic Children • Persistent Asthma is most effectively controlled with daily long-term anti-inflammatory therapy. • Initiate therapy at a higher level at the onset to establish prompt control and then step down. • Continuous monitoring is essential. • Minimum medication must be administered to maintain control. • Regular follow-up visits (1-3 monthly). • Patient education about the knowledge of subject, inhaler use, compliance, patient diary, PEF reading, managing an acute attack and visiting the same doctor with file and medications and personal hudsons with tubes, peak-flow meter and spacer. • At each step, patient should be advised to control allergens, irritants and other triggers. • In infants, a diagnostic trial of inhaled bronchodilators and anti-inflammatory medications may be helpful. • Before starting anti-inflammatory therapy for mild persistent asthma, a trial of cromolyn/nedocromil is given for its safety profile. • Step down therapy in infants should be attempted once control of symptoms is established and sustained. Alternative diagnosis and therapies should be considered if clear benefit is not observed. Step Down Review treatment every 3-6 months, if control is sustained for atleast 3 months then a gradual stepwise reduction is possible. Step Up If control is achieved, consider step up. It is important to review patient education, technique, compliance and environmental control (allergens and trigger factors). Patients should avoid/control trigger at each step. All therapies must include patient/parent education. A rescue course of steroid may be needed at any time or step.

7 CHAPTER

Future Aspects of Therapeutic Strategies

FUTURE ASPECTS OF THERAPEUTIC STRATEGIES Most therapies are based on improvements in existing therapies or on a better understanding of the cellular and molecular aspects in atopic diseases. Many new therapies in development are aimed at inhibiting components of the allergic inflammatory response but there are possibilities of preventative and curative treatment. A. Bronchodilators This class is used for symptom relief but have no effect on underlying inflammatory process. Inhaled β2 agonists are safe and effective and there is no parallel to this drug. They relex smooth muscle by increasing the concentration of cyclic AMP and by opening up potassium channels. Hence, the attention has shifted to the development of treatment that suppress or prevent the atopic inflammatory process. B. Corticosteroids Steroids provide the standard against which new therapies are judged, however, high doses of oral steroids would lead to systemic side effects. Inhaled steroids have revolutionized the treatment of asthma, nasal steroids for the management of allergic rhinitis and topical steroids for atopic dermatitis but dermal atrophy has restricted its use. New generation steroids viz. budesonide fluticasone propionate and mometasone furoate have minimal side effects as the swallowed fraction of the drug is removed by hepatic metabolism. However, these drugs are absorbed from the lung or nasal mucosa and may have side effects at high doses; hence the need for steroids that are metabolised locally viz “Soft Steroids” i.e. Ciclesonide seem promising as they have less side effects. Steroids inactivated in the plasma are now in development.

Future Aspects of Therapeutic Strategies 33 C. Mediator Antagonists Antihistamines Older antihistamines caused sedation whereas the new generation viz fexofenadine and loratidine cause no sedation and improve health related quality of life. They are of immense benefit in allergic rhinitis, and atopic dermatitis. Antileukotrienes 5-LO inhibitor i.e. Zileuton and cysteinyl-leukotriene receptor (cyst-LT1) antagonists (pranlucast, zafirlukast, and montelucast) have been developed as an adjuvant. They improve symptoms, exercise induced asthma, lung function and reduce the need for rescue bronchodilator and useful in aspirin sensitive asthma. They are effective orally and have no specific side effects. They have no benefit over nasal corticosteroids in allergic rhinitis. Selective inhibitors of inducible No synthetic (iNOS) are now in development. Tryptase inhibitors (APC 366) is poorly effective in asthmatic patients. More potent tryptase inhibitors and PAR-2 antagonists are now in development. D. Cytokine Modulators a. Anti IL-5 Interleukin (IL-5) is crucial in orchestrating the eosinophilic inflammation of asthma. Humanized monoclonal antibodies to IL-5 can be used as a single injection reducing blood eosinophils for several weeks. b. Anti IL-4 IL-4 is critical for synthesis of IgE by β lymphocyte and also eosinophil recruitment to the airways. Inhibition of IL-4 may be effective and soluble IL-4 receptors are in clinical development. c. Anti IL-13 IL-13 causes AHR and mucous hypersecretion and may be an important target for the development of new therapies. d. Anti-TNF Tumor necrosis factor (TNF) α amplifies asthmatic inflammation; hence soluble TNF receptors are a logical approach to asthma therapy.

34 Bronchial Asthma in Children e. Chemokine Inhibitors Chemokines are rantes, MCP-3, MC-4 and eotoxin; may be crucial in the recruitment of eosinophils in atopics. E. Anti-inflammatory Cytokines They have anti-inflammatory activity in atopic inflammation. IL-10 inhibits synthesis of proteins. IFN-j inhibits Th2 cells, thereby reducing inflammation. IF-12 determines the balance between Th1 and Th2. F. New Anti-inflammatory Drugs These are PDES, transcriptor inhibitors, MAP kinase inhibitors, tyrosine kinase inhibitors, immunosuppressants and cell adhesion blockers. G. Specific Anti-allergy Drugs a. Cromones Cromones(cromoglycate sodium and nedocromil sodium) are the most specific anti-allergy drugs. Topical application is effective in asthma, rhinitis and conjunctivitis, but effects are less marked and effective only in mild disease. b. Th2 Cell Inhibitors Cyclosporin A and tacrolimus are relatively less effective CD4 + (Keliximab) which reduces circulating CD4+, seems to have some effect on asthma. c. Anti-IgE Rhu-MAb-E25 (humanised monomanine Ab) reduces early and late responses to inhaled allergen. Preventive Strategies Atopy seems to be due to deviation from Th1 to Th2 cells which may arise because of failure to inhibit the normal Th2 preponderance at birth which in turn may result from environmental factors such as Th1 response to infectious agent. • Immunotherapy: Specific allergen vaccine. • Peptide immunotherapy: Peptide fragment block T-cell responses. • Vaccination: Induces protective Th1 responses to prevent sensitization and thus prevent atopy. BCG vaccination has been associated with a reduction in

Future Aspects of Therapeutic Strategies 35 atopic diseases in Japan, but this has not been confirmed in Swedish population. Gene Therapy Atopy being polygenic, there is no role of gene therapy in long-term treatment. One needs to target genes in IL-4 and IL-5 cluster. Adances in therapy would be facilitated through development of more specific anti-allergy drugs that lack side effects. If it can be taken orally, it would treat asthma, rhinitis and eczema which often coincide. The possibility of developing a cure is remote but strategies to inhibit the development of sensitization in early childhood offer such as prospect in future.

Index A Anti-inflammatory cytokines 34 Asthma 2, 5, 9, 13, 19 diagnosis 5 environment 9 examination 6 general principles 21 histopathological features 2 importance of spirometry 6 important points on intubation 19 managing acute/severe exacerbations 13 newer trends 20 patient education 9 taking a new look 5 treatment goals 13 various measurements 7 ventilation-perfusion mismatch 14 ventilatory management 19

B Bone metabolism/osteoporosis 28 Bronchial hyperresponsiveness (BHR) 1 Bronchiolitis 9 Bronchodilator score 4 Bronchodilators 24 Bronchoprovocation 7

C Cataracts 29 Child labour 12

Childhood asthma 1, 3 assessing severity 3 patient categorisation 3 Chronic persistent asthma 22 Corticosteroids 23 Cough 1 Cromolyn sodium 24 Cytokine modulators 33

D Disseminated varicella 28

G Gene therapy 35 Glucose metabolism 29

H Hyperresponsiveness 1 Hypothalamic pituitary axis (HPA) 29

I Impending respiratory failure 15 Indoor pollution 10 Ipratropium bromide 25

L Leukotriene modifiers 26

M Mediator antagonists 33 Montelucast 27

N Nedocromil 24 New anti-inflammatory drugs 34

38 Bronchial Asthma in Children O

S

Outdoor pollution 11

Specific anti-allergy drugs 34

P

T

Peak expiratory flow (PEF) 4 Personal best PEF 8 Preventive strategies 34 Pulmonary score (PS score) 17

Therapeutic strategies future aspects 32

R Reversible obstructive airway disease (ROAD) 1

Z Zileuton 26