An Atlas of Investigation and Management
EMERGING INFECTIONS Robert A Salata, MD, FACP, FIDSA Professor of Medicine and Vice-chair Department of Medicine Chief, Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
David Bobak, MD, FIDSA Associate Professor of Medicine Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
CL INICA L P U B L IS H ING OXFORD
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Contents Preface
vii
Contributors
viii
Abbreviations
ix
1 HIV and AIDS BENIGNO RODRÍGUEZ AND ROBERT A SALATA Introduction Etiology and pathogenesis Global epidemiology Clinical manifestations Management Conclusions Further reading
1
2 Hepatitis C LUCILÉIA TEIXEIRA AND DAVID BOBAK Introduction Etiology and pathogenesis Global epidemiology Clinical manifestations Diagnosis Management Illustrative case history Conclusions Further reading 3 Emerging viral respiratory illnesses NANDHITHA NATESAN AND RANA B HEJAL Introduction SARS coronavirus Human metapneumovirus Avian influenza Conclusions References Further reading
1 1 3 5 24 28 28 31 31 31 34 38 39 41 46 47 47 49 49 51 63 68 76 77 78
vi
4 Tuberculosis C SCOTT MAHAN AND JOHN L JOHNSON Introduction Etiology and pathogenesis Global epidemiology Clinical manifestations Diagnosis Management Conclusions Further reading 5 Malaria ARLENE DENT AND CHARLES H KING Introduction Etiology and pathogenesis Global epidemiology Clinical manifestations Laboratory findings Diagnosis Management Prevention Illustrative cases Conclusions Further reading
79 79 79 81 82 92 96 98 99 101 101 101 103 104 106 106 108 110 112 115 115
6 Diarrheal disease KEITH B ARMITAGE AND DALIA EL-BEJJANI Introduction Clostridium difficile Travelers’ diarrhea Giardia Cryptosporidium Cyclospora Cholera Escherichia coli 0157:H7 Norovirus Conclusions References Further reading
117 117 119 123 123 124 126 127 128 129 129 130
Index
131
117
vii
Preface
Infectious diseases have plagued humans since the earliest times of civilization. The early history of infectious diseases was marked by unpredictable, sudden outbreaks of epidemic proportion. By the middle of the 20th century, the introduction of antibiotics and the development of effective vaccines resulted in the control and prevention of many infectious diseases, especially in industrialized countries. Despite the fact that infections remain the leading cause of death worldwide, attention to infectious diseases diminished in the 1970s and 1980s as there was a shift in focus to chronic degenerative diseases. This complacency regarding the control and prevention of infectious diseases has been associated with outbreaks of disease and the emergence of new pathogens. Emerging infectious diseases have been defined as those that newly appear in the population or have been known but are rapidly increasing in incidence or geographic distribution. New infectious diseases, frequently with unknown long-term impact, continue to be identified. Factors responsible for the emergence of infectious diseases are complex but include: ecologic changes in agriculture,
economic development, climate, human behavior and demographics, travel and commerce, technology and industry, microbial adaptation and change and erosion of public health measures. Old and new infections will occur in the future as they have in the past. Effective global surveillance efforts will be needed to blunt the emergence of such infections and to forestall epidemics and pandemics. Surveillance will need to be coupled with broad-based research efforts to devise new strategies for diagnosis, treatment, and prevention. It will also be necessary to develop new insights into microbial pathogenesis and genetics as well as host immune responses to these invading microbial pathogens. In this atlas, six emerging infectious diseases (HIV-1, hepatitis C, respiratory viruses, tuberculosis, malaria and diarrheal disease) are reviewed in terms of evolving epidemiology, microbial pathogenesis, clinical features, and important approaches to diagnosis and management. Robert A Salata, MD David Bobak, MD
viii
Contributors
Keith B Armitage, MD Professor of Medicine Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
Charles H King, MD, MS, FACP, FRSTMH Professor Center for Global Health and Diseases Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
David Bobak, MD, FIDSA Associate Professor of Medicine Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
C Scott Mahan, MD Attending Physician Division of Infectious Diseases MetroHealth Medical Center Cleveland, Ohio, USA
Arlene Dent, MD, PhD Instructor Center for Global Health and Diseases Department of Pediatrics Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA Dalia El-Bejjani, MD Attending Physician Division of Infectious Diseases MetroHealth Medical Center Cleveland, Ohio, USA Rana B Hejal, MD Associate Professor of Medicine Division of Pulmonary and Critical Care Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA John L Johnson, MD Associate Professor of Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
Nandhitha Natesan, MD Fellow Division of Pulmonary/Critical Care Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA Benigno Rodríguez, MD Assistant Professor of Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA Robert A Salata, MD, FACP, FIDSA Professor of Medicine Department of Medicine Chief, Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA Luciléia Teixeira, MD, MS Clinical Associate Division of Infectious Diseases Cleveland Clinic Foundation Cleveland, Ohio, USA
ix
Abbreviations
AASLD American Association for Liver Diseases AFB acid-fast bacillus AFP alpha fetoprotein AIDS acquired immunodeficiency syndrome ALT alanine aminotransferase ARDS acute respiratory distress syndrome AST aspartate aminotransferase BCG Bacille Calmette–Guérin CDAD Clostridium difficile-associated disease CDC (US) Centers for Disease Control and Prevention CIN cervical intraepithelial neoplasia CK creatine kinase CMV cytomegalovirus CNS central nervous system COPD chronic obstructive pulmonary disease CRP C-reactive protein CSF cerebrospinal fluid CT computed tomography DNA deoxyribonucleic acid DOTS directly observed therapy, short course EBV Epstein–Barr virus EIA enzyme immunosorbent assay EKG electrocardiogram ELISA enzyme-linked immunosorbent assay ETEC enterotoxigenic Escherichia coli EVR early virologic response G6PD glucose-6-phosphate dehydrogenase GBS Guillain–Barré syndrome HAART highly active antiretroviral therapy HAI hemagglutination-inhibition HCC hepatocellular carcinoma HCV hepatitis C virus HIV human immunodeficiency virus hMPV human metapneumovirus HPV human papilloma virus HRCT high resolution chest computed tomography IBS irritable bowel syndrome
IF immunofluorescence INH isoniazid IRIS immune reconstitution inflammatory syndrome KS Kaposi’s sarcoma LCR ligase chain reaction LDH lactate dehydrogenase LTBI latent tuberculosis infection MAI Mycobacterium avium-intracellulare MDR multidrug resistant MGIT mycobacterial growth indicator tube MRI magnetic resonance imaging NHL non-Hodgkin’s lymphoma NNRTI non-nucleoside reverse transcriptase inhibitor NRTI nucleoside reverse transcriptase inhibitor OC opportunistic complications OHL oral hairy leukoplakia PCNSL primary CNS lymphoma PCP Pneumocystis jirovecii pneumonia PCR polymerase chain reaction PGL persistent generalized lymphadenopathy PI protease inhibitor PML progressive multifocal leukoencephalopathy RBM Roll Back Malaria (Program) RIBA recombinant immunoblot assay RNA ribonucleic acid RSV respiratory syncytial virus RT-PCR reverse transcriptase polymerase chain reaction SARS-CoV severe acute respiratory syndrome-associated coronavirus SIL squamous intraepithelial lesions SP sulfadoxine-pyrimethamine STD sexually transmitted disease SVR sustained virologic response TB tuberculosis TST tuberculin skin test WHO World Health Organization
Chapter 1
1
HIV and AIDS Benigno Rodríguez, MD and Robert A Salata, MD, FACP, FIDSA
Introduction The acquired immunodeficiency syndrome (AIDS) was first recognized in 1981, when a cluster of cases of uncommon opportunistic infections and malignancies was reported among otherwise healthy men who had sex with men in San Francisco, Los Angeles, and New York. Alert clinicians and immunologists recognized the unusual infections as indicative of a profound cellular immunodeficiency, a notion promptly confirmed by a diversity of laboratory assays. Alternative routes of acquisition, including parenteral, perinatal, and transfusion-associated were quickly identified, and further reports that an indistinguishable illness had been known for decades in sub-Saharan Africa began to emerge. Subsequent developments occurred at a remarkably fast pace, unprecedented for a novel infectious disease: the retrovirus now known as human immunodeficiency virus (HIV) was identified as the causative agent within 2 years of the first case reports by independent groups in France, Bethesda, and San Francisco; a serological test became available shortly thereafter; the genome was fully sequenced in 1985; and the first clinically usable therapeutic compound, zidovudine, became commercially available in 1987. Since then, combinations of drugs that act at different stages of the virus’ life cycle (see below), known as highly active antiretroviral therapy (HAART) have proven capable of suppressing viral replication to extremely low levels, and to restore, at least partially, the impaired cellular immune function that is ultimately responsible for the increased susceptibility to opportunistic infections in AIDS patients. The HIV pandemic, however, continues virtually unabated, having spread to every continent, and to all
demographic groups throughout the world. Moreover, no curative treatment is available, and predictions for the time to development of an effective, widely available, preventive vaccine are measured in decades. Thus, HIV infection and AIDS remain major health problems that concern virtually every practicing clinician, and the complexity of their management can only be expected to increase in coming years. This chapter focuses mostly on the clinically relevant aspects of HIV infection and AIDS. Excellent reviews of the biology, immunology, and virology of HIV have been published elsewhere.
Etiology and pathogenesis HIV-1 is the etiologic agent of the majority of AIDS cases worldwide. A closely related agent, HIV-2, also causes AIDS in parts of West Africa; sporadic cases occur elsewhere. Throughout the remainder of this chapter, ‘HIV’ is used to refer to HIV-1, unless otherwise indicated. HIV is a member of the lentiviridae family with a plus-stranded ribonucleic acid (RNA) genome that encodes structural, regulatory and accessory proteins, as well as the enzymatic activities; the genomic organization of HIV is shown in Fig. 1.1, and the structure of the infective viral particle is shown in Fig. 1.2. The hallmark of HIV infection is depletion of CD4+ helper T lymphocytes, with ensuing loss of immune competence. Many other immune defects are evident as HIV disease progresses, however, and not all of them can be readily accounted for by the loss of help associated with
2
HIV and AIDS
5’ LTR
gag
Integrase p7
p17
vpr vif tat vpu
pol
Protease
Reverse transcription
env
gp120
rev
nef
3’ LTR
gp41
p24
rev
tat
Fig. 1.1 The genomic organization of HIV. The complete genome is approximately 10 kb in size, and is similar to the general structure of other retroviruses. In the figure, the most relevant genes are represented in different colors, and the most important proteins they encode for are shown inside the corresponding symbols. Not all gene products are shown.
Glycoprotein 120 RNA Outer protein core Lipid membrane Inner protein core Reverse transcriptase
Fig. 1.2 Schematic view of HIV structure. CD4+ T cell destruction. Among these, defects in B cell proliferation and antibody production, impaired cytotoxic lymphocytic responses, decreased dendritic cell number and function, and profound perturbations of the cytokine milieu have all been shown, particularly in advanced stages of HIV infection. The precise mechanism by which HIV infection leads to these wide-ranging defects is incompletely understood, although they are related to HIV replication, and can be partially corrected by effective antiretroviral therapy that suppresses plasma viremia to very low levels. The vital cycle of HIV is complex and includes multiple steps that can be targeted for therapeutic purposes. These
steps are summarized in Fig. 1.3. Active HIV replication is lytic to some, but not all infected cells. Because the predominant target of HIV is the CD4+ T cell, it has been proposed that direct destruction of these cells by HIV is the predominant mechanism of immunodeficiency in progressive HIV infection. More recent evidence, however, shows that the number and distribution of infected cells, the rate of CD4+ T cell turnover and the loss of large numbers of uninfected cells through indirect, or ‘bystander’, mechanisms do not support this model as the sole explanation for HIV-related immune deficiency. Moreover, studies in HIV-infected persons receiving clinical care show that the level of HIV viremia predicts poorly the subsequent rate of CD4+ T cell loss at the individual level, further highlighting that other, indirect mechanisms in effect lead to immunodeficiency in HIV infection. Uncontrolled immune activation is an additional feature of HIV infection that may underlie the CD4+ T cell loss and other immune derangements that eventually culminate in full-blown AIDS. Similarly, advanced HIV infection is associated with depletion of thymocytes and loss of thymic function, as well as impaired bone marrow activity, all of which limit the ability to restore the accelerated CD4+ T cell losses induced by HIV. The net result is a progressively increased susceptibility to a diversity of opportunistic complications that, in the era before the introduction of HAART, were almost invariably fatal within a short period after the initial diagnosis of AIDS.
HIV and AIDS 3
Global epidemiology
HIV virion Attachment inhibitors act here
1
CD4
3 2 CCR5
Fusion inhibitors act here
CXCR4 Reverse transcriptase
Integrase
CD4+ lymphocyte
4
Nucleus
Genomic RNA
Proviral DNA
Cytoplasm
Reverse transcriptase inhibitors act here
5
Integrase inhibitors act here
Integrated proviral DNA
Viral mRNA
6
Chromosomal DNA
7
RNA polymerase
8 Genomic RNA
9
Protease inhibitors act here
Few human infections fit the description of an emerging disease better than HIV infection and AIDS. In the 25 years since its initial description, 75 million individuals worldwide have been infected with HIV, and the epidemic is now present throughout the world. The World Health Organization (WHO) estimates that, by the end of 2006, there were 39.5 million persons living with HIV/AIDS in the world, and 4.3 million acquired HIV in the previous year alone. Over 90% of these persons live in the developing world (62.5% in sub-Saharan Africa alone) and heterosexual intercourse is the route of acquisition in the vast majority of cases. Current estimates of the extent of the HIV epidemic worldwide are shown in Fig. 1.4. In addition to the sheer number of cases, the HIV epidemic has changed dramatically over the past several years, leading to a truly re-emerging epidemiological pattern worldwide. Large epidemics are expanding rapidly in eastern Europe, Asia, and India, which is now the single country with the largest number of cases worldwide. Moreover, the proportion of cases occurring in women is increasing at an alarming pace. Close to 50% of all adults living with HIV/AIDS worldwide are women, and the proportion approaches 66% in parts of sub-Saharan Africa. In the United States and western Europe, the introduction of HAART has produced dramatic reductions in HIV-related morbidity and mortality (Fig. 1.5), but trends in sex distribution are similar to those observed worldwide (Fig. 1.6). Furthermore, new cases are occurring disproportionately more often among minorities and disadvantaged populations, further changing the face of the epidemic.
Fig. 1.3 Vital cycle of HIV and sites targeted by current anti-HIV medications. After HIV binds to its primary receptor, CD4 (1), the viral envelope undergoes a conformational change that facilitates binding to another cellular coreceptor, the most important of which are the chemokine receptors CCR5 and CXCR4 (2). Interaction with the coreceptor triggers further conformational changes in the envelope that bring the viral and cellular membranes into close proximity, thereby permitting their fusion (3) through insertion of the newly exposed fusion domain of the envelope protein gp41 into the host cell membrane. The HIV nucleocapsid then enters the cytoplasm, where the RNA genomic material of the virus is reverse transcribed into DNA (4) by the virally encoded reverse transcriptase. Next, the double-stranded viral DNA enters the nucleus, where it integrates into the host genome with the aid of the HIV-encoded enzyme integrase (5). The integrated proviral DNA is then transcribed into messenger RNA (6), which serves as the template for assembly of the main viral structural proteins (7). The protein complex is cleaved by a protease into functional segments (8), thus allowing assembly and budding of the new viral particles (9) to proceed.
HIV and AIDS
Fig. 1.4 Global estimates of the HIV/AIDS epidemic at the end of 2006. (Adapted from UNAIDS and WHO, 2006 Report on the Global HIV epidemic, Geneva, UNAIDS, 2006.)
Western & Central Europe 740,000 (550,000–950,000)
North America 1.4 million (770,000–2.1 million)
North Africa & Middle East 460,000 (250,000–720,000)
Caribbean 250,000 (240,000–420,000)
Eastern Europe & Central Aisa 1.7 million (1.0–2.3 million) East Asia 750,000 (420,000–1.1 million) South & South-East Asia 7.8 million (5.1–11.7 million)
Sub-Saharan Africa 24.7 million (231.6–27.4 million)
Latin America 1.74 million (1.2–2.4 million)
Oceania 81,000 (48,000–170,000) Total 39.5 (33.4–46 million)
40 35
Percentage
Deaths per 100,000 population
4
30 25 20 15 10
100 90 80 70 60 50 40 30 20 10 0 1987
5
1989 1991
1993 1995 1997 1999
2001 2003
Male
0 1987 1989 1991 1993 1995 1997 1999 2001 2003 Unintentional injury HIV disease Cancer Heart disease Suicide Homicide Chronic liver disease Stroke Diabetes
Fig. 1.5 Trends in annual rates of death due to the nine leading causes among persons 25–44 years old, USA, 1987–2004. HIV disease was the leading cause of death among person 25–44 years old in 1994 and 1995. With the introduction of HAART in 1995, the rank of HIV disease fell to 5th place from 1997 through 2000, and to 6th place in 2001 and 2002. The spike in the death rate due to homicide in 2001 resulted from the terrorist attack on September 11. (Adapted from CDC data.)
Female
Fig. 1.6 Trends in the percentage distribution of deaths due to HIV disease by sex, USA, 1987–2004. The proportion of females among persons who died of HIV disease increased from 10% to 26% during this period, highlighting the increasing burden of disease among females in the US, as is the case in other countries. Because heterosexual transmission is emerging as the predominant mode of transmission, this trend can be expected to grow in the coming years. (Adapted from CDC data.)
HIV and AIDS 5
Clinical manifestations The clinical manifestations of HIV infection and AIDS are diverse and can affect virtually any organ system. The time to development of specific symptoms or syndromes varies considerably from person to person, and many cases remain asymptomatic for very prolonged periods. Nevertheless, HIV-related immunodeficiency develops in most cases as a predictable sequence of events, in which the massive depletion of CD4+ T cells that characterizes AIDS occurs only after a clinically silent interval. During this period, few clinical indications of HIV infection exist, despite vigorous viral replication in the lymphoid tissues and ongoing plasma viremia. This sequence of events is summarized in Fig. 1.7. The first clinical manifestation of HIV infection may be a mononucleosis-like syndrome, termed acute retroviral syndrome, which occurs in over 50% of cases within 2–6 weeks of initial infection. Symptoms are nonspecific and may include fever, sore throat, lymph node enlargement, arthralgias, and headache and usually persist for several days to 3 weeks; in a significant proportion of symptomatic cases, the manifestations are severe enough to warrant medical attention. A maculopapular rash is common, as is
nonspecific lymphadenopathy (Fig. 1.8), and some patients may present with self-limited aseptic meningitis, which manifests as cerebrospinal fluid (CSF) pleocytosis and isolation of HIV from CSF. In some cases, the acute retroviral syndrome may be accompanied by thrush or even opportunistic infections during the transient CD4+ T cell decline seen early in the disease course. Table 1.1 summarizes the most common clinical manifestations of acute retroviral syndrome. From the laboratory standpoint, the acute retroviral syndrome can be diagnosed on the basis of a negative HIV enzyme-linked immunosorbent assay (ELISA) and a positive antigen-based or HIV RNA test in a patient with risk factors. After the acute retroviral syndrome, the majority of subsequent clinical manifestations are due to complications emerging from progressive immunodeficiency. These infections will be discussed according to the stage at which they characteristically present. It should be kept in mind, however, that while diseases that are typical of profound immunodeficiency rarely appear at earlier stages, those that occur with high CD4+ T cell counts can obviously also
CD4+ T lymphocyte count (cells/mm3)
HIV RNA copies/ml plasma
Culturable plasma viremia (dilution titer)
Fig. 1.7 Natural history of Primary infection 1200 107 Opportunistic untreated HIV disease. Shortly Death ± Acute HIV syndrome disease 1100 after infection, viremia reaches Wide dissemination of virus 1000 Seeding of lymphoid organs extremely high levels, while CD4+ 106 1/512 900 count decreases to levels that Clinical latency 1/256 800 may be sufficient for the 105 1/128 700 Constitutional development of certain 1/64 symptoms 600 opportunistic complications. 1/32 500 104 During this period, patients may 1/16 400 experience the manifestations of 1/8 300 the acute retroviral syndrome, and 103 1/4 200 are highly infectious, thus making 1/2 100 a high index of suspicion of 102 0 0 paramount importance. After this 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 initial phase, viremia decreases to Weeks Years a level (referred to as ‘set point’) at which it will remain, relatively constant, during the subsequent phase. At the same time, CD4+ T cell count rebounds, but does not return to pre-infection levels. A relatively asymptomatic period follows, during which there is ongoing viral replication and a slow but demonstrable decline in CD4+ T cell count. This phase ends years after infection with a precipitous fall in CD4+ T cell count and an exponential rise in plasma HIV RNA level, which heralds the beginning of AIDS. (Adapted from Fauci AS, Pantaleo G, Stanley S, et al. Immunopathic mechanisms of HIV infection. Ann Intern Med 1996;124:654.)
6
HIV and AIDS
Complications occurring with CD4+ T cell counts >500/mm3
Table 1.1 Clinical manifestations of acute retroviral syndrome Sign or symptom Fever Lymphadenopathy Pharyngitis Rash Myalgia/arthralgia Diarrhea Headache Nausea/vomiting Hepatosplenomegaly Thrush Neurologic symptoms
% 96 74 70 70 54 32 32 27 14 12 12
(Data from Kahn JO, Walker BD. Human immunodeficiency Virus Type 1 infection. N Engl J Med 1998;339:33.)
occur at later stages. A useful classification that includes both clinical and laboratory markers is the US Centers for Disease Control (CDC) staging system, shown in Table 1.2.
Persistent generalized lymphadenopathy (PGL) can begin with the acute retroviral syndrome (Fig. 1.8), and is defined as two or more extrainguinal regions with lymphadenopathy persisting for at least 3–6 months in the absence of an alternative explanation. Up to 50–70% of HIV-infected patients may develop PGL, but PGL is not associated with adverse consequences in those individuals. Excluding a treatable etiology is critical, particularly with more localized lymphadenopathy. Some patients will experience constitutional symptoms (low-grade fevers, fatigue, and night sweats), diarrhea, or unexplained weight loss during the early stages of HIV infection; again, excluding other etiologies is imperative. Oral and vaginal candidiasis (Fig. 1.9) can also appear at all stages of HIV disease, although they increase in frequency as the CD4+ T cell count falls below 500 cells/mm3. Thrush presents as adherent, nonpainful, off-white exudates that can be scraped off with a tongue depressor, leaving a denuded area of mucosa. Dermatomal herpes zoster (Fig. 1.10) is another frequent early manifestation; in more advanced stages, the presentation may involve multiple dermatomes, prolonged persistence of lesions, or systemic dissemination.
Table 1.2 US Centers for Disease Control 1993 revised classification system for HIV infection in adults and adolescents CD4+ T cell category
Category 1: ≥500 cells/mm3 Category 2: 200–499 cells/mm3 Category 3: <200 cells/mm3
Clinical category Category A: asymptomatic, PGL or acute viral syndrome
Category B: symptomatic conditions, non-AIDS-defining1
Category C: AIDS-defining conditions
A1 A2 A3
B1 B2 B3
C1 C2 C3
Patients can be classified according to CD4+ T cell count and spectrum of clinical manifestations; increasing categories represent increasing degrees of immunodeficiency, although this classification was primarily created for surveillance purposes. PGL: persistent generalized lymphadenopathy. 1Conditions in this category include, but are not limited to, bacillary angiomatosis; thrush; persistent or refractory vaginal candidiasis; moderate to severe cervical dysplasia and cervical carcinoma in situ; constitutional symptoms including chronic diarrhea; oral hairy leukoplakia; recurrent or multidermatomal herpes zoster; idiopathic thrombocytopenic purpura; listeriosis; pelvic inflammatory disease; peripheral neuropathy.
HIV and AIDS 7
Fig. 1.8 Maculopapular rash consistent with acute HIV infection.
A
B
Fig. 1.9 Mucosal candidiasis in moderately advanced HIV infection. A:Thrush (oropharyngeal candidiasis). Typical white exudates that can be removed with a tongue depressor are seen covering the oral mucosa. B: Vaginal candidiasis. The similarity of the exudates covering the vaginal wall is obvious. (A: courtesy of Dr S Silverman, CDC; B: courtesy of CDC.)
Fig. 1.10A, B Multidermatomal herpes zoster (shingles) in a patient with advanced HIV infection and incomplete CD4+ T cell replenishment after highly active antiretroviral therapy. Note the characteristic erythematous-vesicular rash that does not cross the midline and involves A B several dermatomes. Some of the lesions have begun to crust, while others (e.g. on the upper arm) are in a pustular phase.
8
HIV and AIDS
Complications occurring with CD4+ T cell counts 200–500/mm3 Oral hairy leukoplakia (OHL) is the main differential diagnosis for oral candidiasis, as it also presents as a white, raised lesion of the oral mucosa (Fig. 1.11). OHL, however, typically presents on the lateral margin of the tongue and cannot be scraped off easily. Worldwide, the most common complication at this stage is tuberculosis (TB), both in pulmonary and extrapulmonary forms. TB can occur at any stage of HIV disease, however, and its clinical presentation relates to the CD4+ T cell count; thus, ‘typical’ cavitary forms are more commonly seen at early stages (Fig. 1.12), whereas
more diffuse pulmonary and extrapulmonary forms become more frequent as the immunodeficiency progresses (Fig. 1.13). Kaposi’s sarcoma (KS) is a vascular neoplastic disorder characteristically seen in homosexual men that presents as red-purple nodules involving the skin and/or mucous membranes (Fig. 1.14); visceral involvement also occurs (Fig. 1.15), particularly with more advanced stages of disease. Recurrent bacterial pneumonia (most often due to Streptococcus pneumoniae) and other serious bacterial infections are common during this stage, and their
Fig. 1.11 Oral hairy leukoplakia. This lesion is associated with Epstein–Barr infection of the keratinized epithelium of the tongue and the buccal mucosa, and can be distinguished from oral candidiasis by the characteristic location on the lateral surface of the tongue, its resistance to scraping with a tongue depressor and its failure to respond to antifungal therapy. OHL can be seen at relatively early stages of HIV disease, but its prevalence increases with decreasing CD4+ T cell counts. (Courtesy of Dr S Silverman, DDS.)
Fig. 1.12 Cavitary pulmonary tuberculosis in a Ugandan patient with AIDS. This person was not known to be HIV infected when he presented to the TB clinic complaining of subacute respiratory symptoms, fevers, and diaphoresis. Note the characteristic right upper lobe location of the lesion, and the air–fluid level, indicative of a cavitating lesion in that location. At the time of this visit, the patient’s CD4+ T cell count was approximately 400 cell/mm3.
HIV and AIDS 9
A
B
Fig. 1.13 Tuberculosis in advanced AIDS. A: Pleural tuberculosis. This massive pleural effusion resolved completely after anti-TB treatment. B: Tuberculous adenitis. This mass (arrows) can easily be mistaken for a neoplasia, leading to unnecessary interventions. C: Miliary tuberculosis in a patient with advanced AIDS. Note the finely micronodular infiltrate involving virtually all the pulmonary parenchyma. CD4+ T cell count at the time of diagnosis was <5 cells/mm3. (A and B courtesy of Dr R Kalayjian.)
C
10
HIV and AIDS
frequency increases with progressive immunodeficiency. The risk of bacterial pneumonia is up to 100-fold greater in HIV infection. Other encapsulated organisms such as Hemophilus influenzae and highly virulent pathogens such as Pseudomonas aeruginosa are also more common in HIVinfected patients. Pneumococcal pneumonia typically presents with a similar clinical picture to that in HIVnegative patients (Figs. 1.16, 1.17), but mortality is increased in HIV-infected patients, particularly with advanced disease, when atypical presentations including subtle interstitial infiltrates and a protracted course reminiscent of Pneumocystis jirovecii can be seen. Concomitant bacteremia is especially common in this setting, making blood cultures an important part of the diagnostic evaluation. Nodular and cavitary lesions, in addition to mycobacterial and fungal disease, should raise
Fig. 1.14 KS of the skin in a patient with advanced AIDS. KS is an avascular neoplastic disorder caused by human herpes simplex virus-8 (HHV-8), also known as KSassociated HSV. Cutaneous lesions often resolve with HAART, but more effective and better tolerated forms of chemotherapy have recently become available for treatment of the more extensive and invasive forms of the disease.
suspicion for less common bacterial pulmonary pathogens including Nocardia species (Fig. 1.18) and Rhodococcus equi, particularly in the setting of clinical manifestations in other organ systems (Fig. 1.19). HIV-infected women have an increased risk of squamous intraepithelial lesions (SIL) and cervical intraepithelial neoplasia (CIN), both of which are related to human papilloma virus (HPV) infection, and are often the first HIV-related symptom in HIV-positive women in the developed world (Fig. 1.20). Progression of SIL has been associated with declining CD4+ T cell counts; thus, regular screening for cervical lesions is especially important for HIV-infected women, in particular those with advanced disease. Condylomata acuminata are also often diagnosed at this stage, and tend to become more exuberant with disease progression (Fig. 1.21).
Fig. 1.15 Visceral KS. Note the bronchial thickening apparent in this chest radiograph (arrow). While cutaneous KS can and often does present at intermediately advanced stages of HIV disease, extensive visceral involvement is more characteristic of advanced disease. Pulmonary KS can present as hemoptysis, sometimes massive, and can frequently be diagnosed by bronchoscopy, during which typical lesions are often seen and can be readily biopsied. Other frequent radiologic findings include nodules, hilar adenopathy and large pleural effusions. (Courtesy of Dr R Kalayjian.)
HIV and AIDS 11
Fig. 1.17 Sputum Gram stain of the patient in Fig. 1.16. Abundant polymorphonuclear cells and Gram-positive diplococci in chains, some with visible capsule, are seen. (Courtesy of Dr R Kalayjian.) Fig. 1.16 Pneumococcal pneumonia in a patient with AIDS. Note the lobar consolidation with air bronchograms, indistinguishable from the expected presentation in an HIV-negative person. (Courtesy of Dr R Kalayjian.)
Fig. 1.18 Nocardia pulmonary infection in an HIVinfected patient. There is marked right-sided hilar adenopathy with pulmonary nodules in that area. (Courtesy of Dr R Kalayjian.)
Fig. 1.19 CT of the brain of the patient in Fig. 1.18. There are multiple discrete focal masses consistent with Nocardia abscesses. Markedly immunosuppressed patients, including patients with AIDS, are at increased risk of disseminated Nocardia infections, such as in this case. The relatively rarity of Nocardia-related complications in HIV infection is likely due to the partially protective effect of cotrimoxazole, used for prophylaxis of Pneumocystis jiroveci pneumonia. (Courtesy of Dr R Kalayjian.)
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HIV and AIDS
Fig. 1.20 Low-grade squamous intraepithelial lesion in a woman with HIV infection. The lesion, highlighted here by the application of acetic acid, covers an extensive area of the cervix. (Courtesy of Dr R Debernardo, MD.)
Fig. 1.21 Condyloma acuminatum in a patient with advanced HIV disease. These exophytic lesions occur in both men and women, and can expand rapidly with declining immune competence. The fleshy, verrucous appearance is characteristic.
Complications occurring with CD4+ T cell counts 100–200/mm3 In the pre-HAART era, Pneumocystis jirovecii pneumonia (PCP) was the most common AIDS-defining complication in industrialized countries, and it remains an important entity today among patients who are not aware of their HIV status or who are poorly compliant with treatment (Figs. 1.22, 1.23). Patients typically present with a subacute course of progressive exertional dyspnea, dry cough, chest pain, and fever. Severe hypoxemia is a poor prognostic marker, and in-hospital mortality from respiratory failure remains high, despite a decreasing incidence since 1990. Other complications include the development of thin-walled cysts (Fig. 1.24) and pneumothoraces (Fig. 1.25). Less commonly, disseminated infection may occur (Fig. 1.26). Neurologic complications also become prominent at this stage. Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by the polyomavirus JC that affects almost exclusively the central nervous system (CNS)
white matter (Fig. 1.27). Patients present most commonly with focal neurologic symptoms including limb palsies, mental status changes, ataxia, and neuroophthalmological disorders. Imaging shows non-enhancing, hyperintense lesions in the subcortical white matter, typically without mass effect or edema (Fig. 1.28). HIV encephalopathy, also known as AIDS dementia complex, occurs in up to 15% of AIDS patients, and can manifest with a diversity of cognitive, behavioral and motor symptoms, including gait and coordination disturbances. The diagnosis of HIV encephalopathy requires exclusion of other, treatable conditions; imaging typically shows subcortical atrophy with or without white matter changes (Fig. 1.29). Several other neurologic syndromes can present at various stages of HIV infection; Fig. 1.30 shows the relation of these syndromes to the degree of immunodeficiency.
HIV and AIDS 13
A Fig. 1.22 Pneumocystis jirovecii pneumonia. The perihilar distribution of the patchy, predominantly interstitial infiltrate that spares the apices and the absence of a pleural effusion despite extensive parenchymal disease are characteristic. (Courtesy of Dr R Kalayjian.)
B
Fig. 1.24 Thin-walled cysts in a patient with Pneumocystis jirovecii pneumonia. These lesions can grow to reach the proportion of true bullae. Pneumothorax (Fig. 1.25) may result from rupture of one of these cysts. (Courtesy of Dr R Kalayjian.)
Fig. 1.23 Microscopic specimens from cases of Pneumocystis jirovecii pneumonia. A: Characteristic appearance of the organism on a silver stain of a bronchoalveolar lavage specimen from a patient with AIDS. Although the organism is relatively large and has a complex life-cycle reminiscent of that of certain protozoans, analyses of ribosomal RNA unequivocally place Pneumocystis jirovecii as a fungus. It does not respond to conventional antifungal agents, however, but it does to antimicrobial agents active against some protozoans, such as sulfas, atovaquone, clindamycin, and primaquine. B: Histologic specimen of a lung biopsy from a patient with PCP. The frothy, proteinaceous material in the alveolar space is characteristic, and experimented pathologists can confidently recognize a case of PCP based on this finding even before special stains showing the microorganism are available. (Courtesy of Dr R Kalayjian.)
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HIV and AIDS
A
Fig. 1.25 Spontaneous pneumothorax in a patient with Pneumocystis jirovecii pneumonia. The collapsed lung on the left can be seen as a faint outline next to the heart (arrows). Note also the lack of vascular markings on the left side. (Courtesy of Dr R Kalayjian.)
B Fig. 1.26 Disseminated Pneumocystis jirovecii infection in a patient with advanced AIDS. A: Splenic lesions in a patient with profound AIDS-related immunodeficiency. B: Pneumocystis choroiditis. The lesions appear as white–yellow irregular patches. The eye is one of the sites where lesions can be seen in these uncommon cases, but bone marrow, liver, lymph node, and small bowel involvement have also been reported. The ocular lesion is characteristically a posterior choroiditis without vitreal inflammation, as illustrated in this image. Prophylaxis with aerolized pentamine is a risk factor for disseminated disease, due to the low proportion of the drug that enters the systemic circulation. Fig. 1.27 Autopsy specimen from a case of progressive multifocal leukoencephalopathy. Note the location of the lesion involving exclusively the white matter. (Courtesy of Dr R Kalayjian.)
HIV and AIDS 15
Fig. 1.28 Progressive multifocal leukoencephalopathy in a patient with AIDS. The location of the lesions (bright white areas, similar in intensity to CSF in the ventricles) in the subcortical white matter and the absence of a mass effect are characteristic. With the introduction of HAART, cases of ‘inflammatory’ PML have been described, in which the lesions enhance with magnetic contrast medium and can be surrounded by edema. This is considered a form of immune reconstitution syndrome. (Courtesy of Dr R Kalayjian.)
Fig. 1.29 AIDS dementia complex. There is extensive subcortical atrophy, with compensatory ex vacuo hydrocephalus, as well as non-specific white matter changes. (Courtesy of Dr R Kalayjian.)
CD4+ T cell count Seroconversion
>500/mm3
Aseptic meningitis
200–500/mm3
<200/mm3
Chronic meningitis
CNS
AIDS dementia Vacuolar myelopathy Mononeuritis (e.g. facial palsy) Inflammatory demyelinating polyneuropathy
PNS
Chronic meningitis Mononeurosis multiplex Distal sensorypolyneuropathy Myopathy
Fig. 1.30 Timing of different neurologic complications of HIV infection according to the degree of CD4+ T cell loss. Up to 50% of persons with HIV infection will experience neurologic symptoms throughout the course of the disease, and up to 80% of autopsies on HIV-infected persons show evidence of central nervous system involvement.
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HIV and AIDS
Complications occurring with CD4+ T cell counts <100/mm3 With advanced HIV disease, focal brain masses, mostly due to either Toxoplasma encephalitis or primary CNS lymphoma (PCNSL) begin to emerge. Both present with a subacute course ranging from weeks to 1–2 months, during which headache, mental status changes, lethargy, and various focal neurologic deficits can occur. Seizures are common with both diseases; fever is more frequent with Toxoplasma encephalitis. On magnetic resonance imaging (MRI), both present as space-occupying lesions with surrounding edema and ring-like enhancement after contrast (Figs. 1.31, 1.32). Toxoplasma lesions are more commonly multiple, and are characteristically located at the corticomedullary junction, in the white matter, or in the basal ganglia. PCNSL is less frequently multilesional, and more often involves the periventricular white matter, the cortex, or the corpus callosum. The two can be indistinguishable, however, but the patient’s Toxoplasma antibody status and history of exposure to prophylactic agents can help in the differential diagnosis (Table 1.3). In patients with extremely low CD4+ T cell counts, Toxoplasma can also cause disseminated disease, with pulmonary and multisystemic involvement (Figs. 1.33, 1.34); the prognosis in these cases is usually poor. An
Table 1.3 Probability of having Toxoplasma encephalitis among HIV-infected patients presenting with focal brain lesions accompanied by mass effect, according to Toxoplasma serologic status and exposure to prophylactic agents with activity against Toxoplasma
Toxoplasma antibody Positive Negative
Receiving Toxoplasma prophylaxis Yes (%) No (%) 59 87 0 22
The radiological pattern, although suggestive, has limited or no value for differential diagnosis in this setting, and the actual antibody titers are similarly not informative. As seen from the table, serologic status is particularly helpful with a negative result, which should always decrease the suspicion for Toxoplasma encephalitis considerably, regardless of prophylaxis history. (Data from Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997;48:687–694.)
Fig. 1.31 Toxoplasma encephalitis. Note the multiple lesions, their annular shape, and the significant mass effect and vasogenic edema around them. In the United States, Toxoplasma was the most common cause of focal brain lesions in HIV-infected patients during the early phase of the HIV epidemic, but it has become a much less common complication with the widespread use of prophylaxis and combination antiretroviral therapy. (Courtesy of Dr R Kalayjian.)
HIV and AIDS 17
Fig. 1.32 PCNSL in an AIDS patient. The periventricular location, single lesion, and marked perilesional edema with compression of adjacent structures are all highly suggestive of PCNSL, but are not sufficiently specific to differentiate this mass from those caused by Toxoplasma infection. Compare with Fig. 1.31. Virtually all PCNSL in HIV infection are positive for Epstein–Barr virus, and most occur at very low CD4+ T cell count levels. (Courtesy of Dr R Kalayjian.)
Fig. 1.34 Toxoplasma tachyzoites (arrow) in lung tissue in an AIDS patient with pulmonary toxoplasmosis. (Courtesy of Dr R Kalayjian.)
Fig. 1.33 Toxoplasma pneumonitis in a patient with AIDS. There are subtle interstitial infiltrates that are out of proportion with the severity of the clinical picture, most likely as a consequence of the limited ability of these very advanced patients to mount a vigorous inflammatory response. Pulmonary involvement is almost invariably a reflection of systemic dissemination, and patients with this form of invasive Toxoplasma infection often present with a sepsis-like syndrome, with high fevers and hypotension. The prognosis is poor. (Courtesy of Dr R Kalayjian.)
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HIV and AIDS
additional important location for Toxoplasma complications is the eye, where it can infrequently cause a necrotizing chorioretinitis, commonly accompanied by vitreous inflammation (Fig. 1.35). Other causes of retinal disease in HIV infection include varicella-zoster, syphilis, and HIV itself, but cytomegalovirus (CMV) is by far the most common cause of retinitis. Active CMV retinitis presents with extensive exudates and hemorrhages following a
vascular pattern and marked vitreal inflammation (Fig. 1.36). CMV retinitis can be sight-threatening, and can lead to acute retinal detachments with sudden loss of vision. In the CNS, CMV causes a form of encephalitis with periventricular inflammation that can be seen on MRI (Figs. 1.37–1.39); other sites of CMV pathology in AIDS patients include the gastrointestinal tract, lungs, spinal cord, and disseminated disease.
Fig. 1.35 Toxoplasma chorioretinitis. Note the discrete, rounded necrotizing lesions and the vitreous haze, indicative of vitreal inflammation. (Courtesy of Dr R Kalayjian.)
Fig. 1.36 Cytomegalovirus retinitis. There are confluent white exudates along vascular paths, with several areas of hemorrhage. Patients with this type of complication complain of progressive loss of visual acuity, blurry vision, ocular discomfort, and ‘floaters’. Symptoms are often unilateral initially, but eventual involvement of both eyes is common. CMV retinitis has become less frequent with the advent of HAART.
HIV and AIDS 19
Fig. 1.37 Cytomegalovirus ventriculoencephalitis. Marked periventricular enhancement is seen in this MRI study in a patient with AIDS. The clinical presentation can mimic that of HIV encephalopathy, but tends to have a more acute course. Concomitant focal lesions and extraneural CMV involvement are commonly present. Detection of CMV DNA in the CSF helps to establish the diagnosis. (Courtesy of Dr R Kalayjian.)
Fig. 1.38 Autopsy specimen in a case of cytomegalovirus encephalitis. Note the inflammatory and necrotizing changes in and around the ventricles. (Courtesy of Dr R Kalayjian.)
Fig. 1.39 Histologic findings in cytomegalovirus encephalitis. There are cells with CMV inclusions, that give them the almost pathognomonic appearance of ‘owl’s eyes’ (arrow). (Courtesy of Dr R Kalayjian.)
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HIV and AIDS
Fungal disease is also prominent in late HIV disease. Candida esophagitis (Fig. 1.40) is a common cause of dysphagia in these patients. The frequency of cryptococcal disease also rises dramatically at very low CD4+ T cell counts. Cryptococcal meningitis (Fig. 1.41) is one of the most common manifestations, but pulmonary syndromes (Fig. 1.42), focal neurologic disease (Fig. 1.43) and disseminated infection can also occur. In endemic areas, infection with the dimorphic fungus Histoplasma capsulatum can be a significant problem; in addition to pulmonary disease (Fig. 1.44), systemic forms can be seen in AIDS patients (Fig. 1.45). Atypical mycobacteria, especially Mycobacterium avium-intracellulare (MAI) complex (Fig. 1.46), become a major source of morbidity and mortality when CD4+ T cell counts drop below 50 cells/mm3. Chronic, intractable diarrhea is common at this stage. The coccidian parasites Cryptosporidium parvum (Fig. 1.47) and Isospora bellii and those in the phylum Microsporidia are frequently responsible, but mixed infections are often present. Other causes of gastrointestinal symptoms,
sometimes severe, include CMV colitis and enteritis, MAI intestinal involvement, and dysbacteriosis. In the era of HAART, many cases of chronic diarrhea in advanced AIDS patients do not have an identifiable cause; HIV itself is known to infect certain cellular populations in the gastrointestinal epithelium and can be directly responsible for some of these cases. Malignancies have become an increasingly prominent cause of morbidity and mortality in AIDS patients, as the use of HAART has increased survival and the HIV-infected population, at least in the developed world, becomes older. Non-Hodgkin’s lymphoma (NHL) (Fig. 1.48) is 100–1,000 times more common in HIVinfected than in HIV-negative persons. NHL can occur at any level of CD4+ T cell depletion, but its aggressiveness and prognosis are worse in advanced stages of the disease. In addition to primary CNS locations (discussed above, see Fig. 1.32), AIDS-related NHL is more often extranodal than in the general population. Hepatocarcinoma related to hepatitis B or C coinfection and invasive cervical carcinoma are other examples of important neoplastic complications of HIV infection.
Fig. 1.40 Candida esophagitis in a patient with AIDS. The white exudates overlaying an erythematous mucosa are characteristic. Orophyrangeal candidiasis (thrush) is a common manifestation of early HIV disease, but involvement of the esophagus, as seen here, typically occurs only with lower CD4+ T cell counts. Candida esophagitis is one of the most frequent causes of dysphagia in this setting; many experienced clinicians treat empirically with antifungals when a patient with AIDS presents with thrush and dysphagia, pursuing endoscopic studies only if there is no or incomplete clinical response. Other causes of dysphagia and esophageal pain in this setting include CMV, HSV, and aphthous ulcers. (Courtesy of Dr J Conklin, UCLA.)
HIV and AIDS 21
A
B
Fig. 1.41 Systemic cryptococcosis in a patient with AIDS. This patient had <50 CD4+ T cells/mm3 when he presented with a 3-week history of fever and headaches. On exam he was lethargic, and had multiple cutaneous papular lesions with central umbilication on the face and extremities. CSF and blood cultures both yielded Cryptocococcus neoformans. A: Yeast cells on an India ink stain of the CSF. B: Cutaneous lesions resemble those of moluscum contagiosum, a viral disease that is also common in AIDS patients.
Fig. 1.42 Severe cryptococcal pneumonia. The portal of entry for Cryptococcus is almost always the respiratory tract, and pulmonary manifestations can occur even in immunocompetent hosts. Severe progressive disease, however, is largely confined to profoundly immunocompromised persons. In this case, the presentation was in the form of necrotizing pneumonia with cavitation of the right upper lobe, mimicking pulmonary tuberculosis. Compare with Fig. 1.12. (Courtesy of Dr R Kalayjian.)
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HIV and AIDS
Fig. 1.43 Cryptococcoma of the CNS in an AIDS patient. While CNS involvement in cryptococcal disease is most frequently in the form of subacute meningitis, focal lesions, as seen in this case, can occur particularly with advanced immunosuppression. These lesions can produce focal findings and seizures; in some cases, they can expand and become clinically more apparent with immune recovery after HAART. (Courtesy of Dr R Kalayjian.)
Fig. 1.45 Disseminated histoplasmosis. Many yeast forms of Histoplasma capsulatum can be seen in this peripheral blood smear from a patient with HIV. While Histoplasma can cause severe disease in both immunocompromised and immunocompetent hosts, depending on the size of the inoculum, immunocompromised hosts are much more susceptible to disseminated forms.
Fig. 1.44 Chest radiograph (detail) of an AIDS patient with histoplasmosis. Several pulmonary nodules (arrows) can be seen. Although Histoplasma capsulatum is a ubiquitous fungus, there are areas of increased endemicity throughout the world. In the United States, the valleys of the Ohio, Mississippi, and St Lawrence rivers are the most important. The organism grows best in soils with high nitrogen content, especially those contaminated with bird manure or bat droppings. (Courtesy of Dr R Kalayjian.)
HIV and AIDS 23
Fig. 1.46 Lymph node biopsy in a case of MAI. Large numbers of acid-fast bacilli, seen here as clumps of red elongated forms, are present throughout the node parenchyma. In AIDS patients, disseminated MAI infection is a late and often terminal complication that presents as an insidious, debilitating febrile illness accompanied by severe wasting, liver enzyme abnormalities, and various systemic symptoms. The organism can often be isolated from blood cultures in these patients. (Courtesy of Dr E Ewing, CDC.)
Fig. 1.48 NHL in a patient with AIDS. There is a large pulmonary mass in the right parahilar region, which was confirmed by biopsy to correspond to NHL. While recent large-scale epidemiologic studies have confirmed that the incidence of AIDS-related NHL is declining since the introduction of HAART, the rate at which it is doing so is the slowest of all opportunistic complications. Histologically, most cases are large B cell or Burkitt’s lymphomas. Up to 60% of non-CNS lymphomas and virtually all primary CNS lymphomas in HIV infection are EBV-positive. A unique clinical form, primary effusion lymphoma, occurs almost exclusively in HIV-infected patients and is associated with HHV-8, the etiologic agent of KS. Primary effusion lymphoma presents with large pleural or peritoneal effusions in the absence of identifiable masses or bone marrow involvement. (Courtesy of Dr R Kalayjian.)
Fig. 1.47 Cryptosporidium parvum in the gallbladder epithelium of a patient with AIDS. Cryptosporidium is a common parasite of animals, and can cause self-limiting diarrheal disease in immunocompetent humans, sometimes in epidemic form. In AIDS patients with very low CD4+ T cell counts, however, it is associated with a protracted, copious diarrhea that is often intractable. The biliary tree is a frequent location of Cryptosporidium replication, and can be associated with cholangitis and other local complications. Cryptosporidium has become infrequent as a cause of AIDS-related chronic diarrhea with the introduction of HAART. (Courtesy of Dr E Ewing, CDC.)
HIV and AIDS
Management
Table 1.4 Currently approved antiretroviral agents NRTI Abacavir Didanosine Emtricitabine Lamivudine Stavudine Zidovudine Tenofovir NNRTI Delavirdine Efavirenz Nevirapine
PI Amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir hard gel tablet Tipranavir Fusion inhibitor Enfuvirtide
NRTI: nucleoside/nucleotide reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor
this remains true in the era of HAART (Fig. 1.49); recent data, however, suggest that the HIV RNA level may be less helpful in deciding the timing of initiation of HAART. Moreover, the presence of clinical complications remains the most important criterion. Table 1.6 shows current recommendations for initiation of HAART. At least as important as HAART in reducing the morbidity and mortality of HIV infection has been the routine use of prophylactic antimicrobials to prevent the most common opportunistic complications (OC); current recommendations for OC prophylaxis are shown in Table 1.7. With increasing numbers of patients receiving HAART, the limitations of these treatments have become apparent. Many antiretroviral agents have significant toxicities that
3-year probability of AIDS (%)
As discussed above, HAART has dramatically altered the natural course of HIV disease in industrialized countries, resulting in a precipitous decrease in AIDS-related complications and deaths (see Fig. 1.5). All currently approved antiretroviral agents target HIV’s reverse transcriptase, protease, or fusion, but new agents are being introduced that work at other stages of the virus’ life cycle (see Fig. 1.3). Currently approved drugs for treatment of HIV are listed in Table 1.4. Large clinical trials have established the superiority of combinations of antiretroviral agents over single agents for the management of HIV; currently recommended regimens are summarized in Table 1.5. Both the CD4+ T cell count and the plasma HIV RNA level predict the likelihood of progression to AIDS and death in HIV-infected patients, and
3-year probability of AIDS (%)
24
100 80 60 40 20 0 >55
20–55 7–20 1.5–7 <1.5 HIV-1 RNA concentration (x103 copies/ml)
100 80 60 40 20 0 >55
20–55 7–20 1.5–7 HIV-1 RNA concentration 3 (x10 copies/ml)
<1.5
<200 201–350 351–500 501–750 >750 CD4 count (cells/ml)
<200 201–350 351–500 501–750 >750 CD4 count (cells/ml)
Fig. 1.49 Prognosis according to CD4+ cell count and viral load in the pre-HAART and HAART eras. The bars represent the probability of progression to AIDS or death according to CD4+ T cell count and plasma HIV RNA level before the HAART era (top) or at the time of initiation of HAART (bottom). (Adapted from Egger A, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002;360:119–29.)
HIV and AIDS 25
Table 1.5 Preferred regimens for HIV-infected patients beginning antiretroviral treatment
Column A components Preferred components
Plus
NNRTI Efavirenz
Column B components Tenofovir/emtricitabine (co-formulated) Or
Or Zidovudine/lamivudine (co-formulated) PI Atazanavir + ritonavir Fosamprenavir + ritonavir (BID) Lopinavir/ritonavir (co-formulaed, BID)
Alternative to preferred components
NNRTI Nevirapine
Abacavir/lamivudine (co-formulated) Or
Or Didanosine + (emtricitabine or lamivudine)
PI Atazanavir Fosamprenavir Fosamprenavir + ritonavir (QD) Lopinavir/ritonavir (co-formulated, QD)
A regimen is constructed by selecting one component from column A (either an NNRTI or a PI) and one option from column B BID: twice a day; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; QD: once a day
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HIV and AIDS
Table 1.6 Recommendations for initiation of antiretroviral therapy in HIV-infected patients
Clinical category
CD4+ cell count
Plasma HIV RNA
Recommendation
AIDS-defining illness or severe symptoms
Any value
Any value
Treat
Asymptomatic
<200/mm3
Any value
Treat
Asymptomatic
200–350/mm3
Any value
Offer treatment following full discussion of risks/benefits
Asymptomatic
>350/mm3
>100,000
Defer therapy in most cases; some clinicians will treat
Asymptomatic
>350/mm3
<100,000
Defer therapy
Table 1.7 Guidelines for prophylaxis against selected opportunistic infections in HIV-infected patients
Pathogen
Indication
First choice
Alternatives
Pneumocystis jiroveci
CD4+ T cell count <200/mm3
Cotrimoxazole, 1 doublestrength tablet qd
Dapsone, 100 mg qd Atovaquone, 1500 mg qd Pentamidine, aerosolized, 300 mg q mo
Mycobacterium tuberculosis Isoniazid-sensitive
TST (t) reaction >5 mm,or prior positive TST without treatment, or contact with case of active tuberculosis
Isoniazid, 300 mg po, plus pyridoxine, 50 mg qd, x 9 mo
Rifampin, 600 mg, and pyrizinamide, 800 mg, qd x 2 mo
Toxoplasma gondii
IgG antibody to Toxoplasma and CD4 count >100/mm3
Cotrimoxazole, 1 double -strength tablet qd
Dapsone, 50 mg po qd, plus pyrimethimine, 50 mg po q wk
Mycobacterium avium-intracellulare
CD4+ T cell count <50/mm3
Azithromycin, 1200 mg q wk
Clarithromycin, 500 mg po bid
limit the ability of many patients to adhere to prescribed regimens. Certain nucleoside reverse transcriptase inhibitors (NRTIs), such as abacavir, and most non-nucleoside reverse transcriptase inhibitors (NNRTIs) can cause hypersensitivity reactions; several protease inhibitors (PIs) cause diarrhea and other gastrointestinal and hepatobiliary sideeffects; certain NRTIs can cause anemia and bone marrow inhibition; the PIs indinavir and atazanavir produce indirect hyperbilirubinemia. Beyond these acute side-effects, several antiretrovirals are associated with chronic metabolic disturbances, including lipid abnormalities, fat distribution
changes (Figs. 1.50, 1.51), mitochondrial toxicity, and hyperlactatemia. Additionally, exposure to antiretroviral agents leads to rapid selection of HIV mutants that are resistant to the effect of those agents. Several techniques are currently available that allow for detection of those mutants and help predict the alternative agents that may be active in a subsequent regimen. Recommendations for HIV resistance testing are shown in Table 1.8, and suggested regimens for salvage after failure of various initial regimens are shown in Table 1.9.
HIV and AIDS 27
Fig. 1.50 Lipodystrophy, fat wasting. This patient had a history of non-Hodgkin’s lymphoma, which responded satisfactorily to treatment, and had an optimal response to HAART, with CD4+ T cell counts within normal levels. However, she developed marked body fat redistribution, which became disturbing enough for her to decide to interrupt HAART for almost 1 year. This image shows the loss of subcutaneous fat in the lower extremities, leading to the ‘masculine’ appearance due to the prominence of muscles and superficial blood vessels. Note the difference from AIDS wasting, in which muscle mass is also severely lost.
Fig. 1.51 Lipodystrophy, fat redistribution (same patient as in Fig. 1.50). This image shows the enlarged abdominal girth secondary to central fat accumulation, typical of lipodystrophy syndromes. Unlike usual obesity, in lipodystrophy the fat accumulation occurs intraabdominally, as demonstrated by CAT scans and other imaging techniques. Several antiretroviral agents are associated with lipodystrophy, lipoatrophy and other metabolic syndromes; some of the most common culprits include the thymidine analogs stavudine and zidovudine and several protease inhibitors.
Table 1.8 Clinical circumstances in which HIV resistance testing is currently recommended
Clinical setting/recommendation
Rationale
Virologic failure during combination antiretroviral therapy
Determine the role of resistance in drug failure and maximize the number of active drugs in the new regimen, if indicated
Suboptimal suppression of viral load after antiretroviral therapy initiation
Determine the role of resistance and maximize the number of active drugs in the new regimen, if indicated
Acute HIV infection, if decision is made to initiate therapy
Determine if drug-resistant virus was transmitted to help design an initial regimen or to change regimen accordingly (if therapy was initiated prior to test results)
Chronic HIV infection before therapy initiation
Available assays might not detect minor drug-resistant species. However, should consider if significant probability that patient was infected with drug-resistant virus (i.e. if the patient is thought to have been infected by a person receiving antiretroviral drugs)
Both genotypic and phenotypic HIV resistance tests are currently available. Interpretation of these tests is complex, and the criteria for HIV susceptibility to the various antiretrovirals are in permanent flux; therefore, seeking expert advice is usually recommended when managing patients with resistant viruses
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HIV and AIDS
Table 1.9 Recommended regimens to substitute a failing initial HAART combination
Initial regimen
Recommended change
2NRTIs + NNRTI
2 NRTIs (based on resistance testing) + PI (with or without low-dose ritonavir)
2NRTIs + PI (with or without 2 NRTIs (based on resistance testing) + NNRTI low-dose ritonavir) 3NRTIs
2 NRTIs (based on resistance testing) + NNRTI or PI (with or without low-dose ritonavir) NNRTI + PI (with or without low-dose ritonavir) NRTI(s) (based on resistance testing) + NNRTI + PI (with or without low-dose ritonavir)
The likelihood of achieving durable suppression of HIV viral replication diminishes dramatically with each subsequent regimen; therefore, every effort should be made to preserve the initial regimen for as long as possible.
Conclusions • HIV infection is one of the most explosive and widespread emerging infectious diseases in the recent history of mankind, having affected tens of millions of persons within 20 years of the beginning of the pandemic. The majority of cases continue to occur in the developing world. • The pathogenesis of CD4+ T cell loss and other immune defects in HIV is incompletely understood, but it likely involves indirect mechanisms beyond the direct cytopathic effect of the virus. Non-specific immune activation is a prominent feature of HIV infection that is associated with disease progression. • Many of the complications of HIV and AIDS tend to occur at specific stages of disease progression. The clinical presentation of these complications tends to become more atypical and severe with more advanced degrees of immunodeficiency. • HAART has dramatically reduced the morbidity and mortality of AIDS, and should be offered to all patients with symptoms or advanced immunosuppression. Effective HAART regimens consist of combinations of antiretroviral agents, typically belonging to at least two different classes. • Prophylactic antimicrobials can significantly reduce the morbidity of HIV infection. Specific prophylactic agents are recommended for different stages of HIV disease.
• Despite its extraordinary success, HAART is associated with severe toxicities and long-term metabolic complications, as well as with the emergence of resistant HIV strains, which limit its effectiveness in many patients.
Further reading DHHS panel on clinical practices for treatment of HIV infection: Guidelines for the use of antiretroviral agents among HIV-infected adults and adolescents. Bethesda, Department of Health and Human Services, October 10th, 2006. (Available at: http://aidsinfo.nih.gov/guidelines/) The current recommendations for antiretroviral treatment in the US, this document contains many useful tables that summarize the characteristics of all currently approved antiretrovirals. Egger M, May M, Chêne G, et al., and the ART Cohort Collaboration. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002;360:119–129. A pivotal observational study that helped demonstrate the importance of CD4+ T cell level in determining the outcome of combination antiretroviral therapy. Guidelines for preventing opportunistic infections among
HIV and AIDS 29
HIV-infected persons 2002: Recommendations of the US Public Health Service and the Infectious Diseases Society of America. Morb Mortal Wkly Rep 2002;51:1–52. The current recommendations for prophylaxis against opportunistic infections in HIV-infected patients. This document also contains current knowledge on criteria to discontinue prophylaxis after HAART-induced immune reconstitution. Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK. Treating opportunistic infections among HIV-infected adults and adolescents; Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Clin Infect Dis 2005;40:S131-S235. An extremely useful document outlining the current guidelines for treatment of the various opportunistic complications of HAART, including side-effects, drug–drug and drug–food interactions, and dosing of drugs used to treat opportunistic infections in the presence of renal insufficiency. Hirsch M, Brun-Vizinet F, D’Aquila RT, et al. Antiretroviral drug testing in adult HIV-1 infection. J AMA 2002;283:2417–2426.
Review of current concepts on the clinical use and techniques of antiretroviral drug resistance testing for HIV infection. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853–860. A classical paper that first showed the dramatic effect of HAART on HIV-related mortality.
Chapter 2
31
Hepatitis C Luciléia Teixeira, MD, MS and David Bobak, MD, FIDSA
Introduction About 200 million people worldwide are infected with the hepatitis C virus (HCV) and up to 4 million persons are newly infected each year. Because the majority of infected individuals have persistent, lifelong infection, HCV is associated with considerable global morbidity due to complications such as cirrhosis and hepatocellular carcinoma (HCC). For these reasons, HCV is the leading worldwide indication for liver transplantation as well. Unfortunately, no vaccine is currently available to prevent HCV infection. In addition, the standard forms of treatment for chronic hepatitis C are too costly for practical use in most developing countries. Much like HIV infection then, the greatest impact of hepatitis C continues to be felt among populations with the least amount of health care resources available. Recent advances in HCV cell culture systems and
understanding of the virus’ life cycle have given rise to new hope for the successful development of an effective vaccine and more efficacious and more cost-effective treatment regimens.
Etiology and pathogenesis HCV is classified in the Flaviviridae family, although its genome is sufficiently distinct from related viruses to permit it to be placed in its own genus, Hepacivirus (Table 2.1). The structure of HCV is an enveloped ribonucleic acid (RNA) virus contained in a roughly spherical particle approximately 50 nm in diameter. The HCV genome is a positive-sense, single stranded RNA molecule approximately 9.6 kb in
Table 2.1 Characteristics of the hepatitis C virus
• • • • • • • •
Envelope-containing, positive-strand RNA virus Spherical particles approximately 50 nm in diameter Member of the Flaviviridae family, has its own genus Hepacivirus Related to members of the Flavivirus (yellow fever and dengue viruses) and Pestivirus genera Genome is approximately 9.6 kb with an ORF of ~9 kb Viral ORF encodes a 3000 amino acid residue polyprotein processed into 10 known proteins Highly conserved 5’ and 3’ untranslated regions involved in replication and translation Genomic diversity characterized by the existence of quasispecies and genotypes
ORF: open reading frame
Hepatitis C
HCV polyprotein Structural proteins C Capsid
E1
Non-structural proteins E2
p7
Envelope
NS2
NS3
NS4A
NS4B
NS5A
NS5B
Protease/helicase
Polymerase
Fig. 2.1 Hepatitis C virus genome.
length, with highly conserved untranslated regions. There is a single large open reading frame of about 9 kb in length, which encodes a very large polyprotein (~3000 amino acid residues) (Fig. 2.1). This protein undergoes co- and posttranslational processing by various viral and host cellular proteases to yield the individual structural and non-structural viral proteins. In an infected individual, more than 10 trillion HCV particles are produced per day, even in the chronic phase of infection. HCV exhibits considerable genetic diversity due to the presence of an RNA polymerase that is deficient in proofreading ability. Over the course of infection, large numbers of similar, but distinct, strains of HCV develop. These strains are known as quasispecies and are present in all HCV-infected persons. In addition, families of HCV with more distinct genetic characteristics have also developed over long periods of time into six major and distinct families of HCV known as genotypes. HCV genotype varies considerably in worldwide distribution and, in addition, has clinical implications for predicting response rates to currently available therapy (as discussed in more detail below). The major target of HCV infection and replication is the hepatocyte. HCV RNA has been detected in several other cell types including B- and T lymphocytes, and monocytes; however, the significance of HCV infection of these cell types is not well understood. The central theme of HCV infection is that of viral persistence and, as such, HCV infection causes little direct cytotoxicity to hepatocytes. In only a minority of individuals (~15%) is the host immune response able to clear HCV infection (Figs. 2.2, 2.3). The majority of HCV-infected individuals (~85%) go on to develop persistent HCV infection (Figs. 2.3, 2.4). The efficiency of the innate and adaptive host immune responses determines whether the acute infection is cleared and, in those with chronic infection, the level of end organ
Anti-HCV Symptoms +/-
Titer
32
HCV RNA
ALT
Normal 0 1 2 Months
3
4
5
6
1 2 Years Time after exposure
3
4
Fig. 2.2 Time course of acute hepatitis C.
cytotoxicity (i.e. clinical hepatitis) that occurs. The intensity of the host immune and inflammatory response may also be correlated with the risk of developing cirrhosis and/or HCC late in the course of infection. HCV has developed a variety of strategies to evade primary and adaptive immune responses by the host, allowing for persistent infection lasting up to 40 years or longer. Chronic HCV infection causes persistent hepatic inflammation and promotes fibrosis, two pathophysiologic conditions that predispose infected individuals to develop cirrhosis and/or HCC, the two most serious outcomes of chronic hepatitis C (Figs. 2.3, 2.5).
Hepatitis C 33
100 patients
Exposure (acute phase) 15% (15)
HIV and alcohol accelerate
85% (85)
Resolved
Chronic 80% (68)
20% (17)
Stable
Cirrhosis 76% (13)
24% (4)
Slowly progressive
Hepatocellular carcinoma
Fig. 2.3 Clinical outcomes for hepatitis C infection.
Anti-HCV Symptoms +/-
Titer
HCV RNA ALT
Normal 0 1 2 Months
3
4
5
6
1 2 Years Time after exposure
Fig. 2.4 Time course of chronic hepatitis C.
3
4
34
Hepatitis C
A
B
C
D
E
F
Global epidemiology Hepatitis C has been found in essentially every country in the world, indicating that it is a long-standing infection of humans. Based on available data, it is estimated that as many as 200 million people may be infected with HCV worldwide (Figs. 2.6, 2.7). In the United States, as in most developed countries, the prevalence of HCV infection is approximately 2%. This is in contrast with Egypt, a country where up to 30% of the population is believed to be infected with HCV. Based on genomic sequence homology, HCV has been classified into 11 major genotypes (designated 1–11), more than 50 subtypes (designated a, b, c ...), and about 100 different strains (numbered 1, 2, 3 ...) (Table 2.2). Genotypes 1–4 comprise the majority of HCV infections and genotypes 1–3 have a generally worldwide distribution (Fig. 2.8). Types 1a and 1b are the most common, accounting for about 60% of global infections. These genotypes predominate in Europe, North America, and
Fig. 2.5 Histopathologic changes of hepatitis C. A: chronic hepatitis C infection (x10); B: chronic hepatitis C infection (x100); C: normal liver architecture (x20); D: progressive disease with bridging fibrosis (arrows) (x20); E: cirrhosis with regenerative nodules (RN); F: hepatocellular carcinoma (x40). (Reprinted with permission from Lauer GM, Walker BD. Medical progress: hepatitis C infection. N Engl J Med 2001; 345:41–52.)
Table 2.2 Hepatitis C genotypes
• Eleven known genotypes, four major types (1–4) • Genotypes 1–4 most common overall, but there is considerable worldwide variation • Genotypes are much more genetically diverse than HIV-1 subtypes • Marked variability exists in the response rate to interferon/ribavirin therapy between genotypes
Japan. Type 3 is endemic in South East Asia and has a variable prevalence elsewhere. Genotype 4 is principally found in the Middle East, Egypt, and central Africa. Other genotypes are generally rare, type 5 is almost exclusively found in South Africa and genotypes 6–11 are widely distributed throughout Asia.
Hepatitis C 35
Fig. 2.6 Worldwide prevalence of hepatitis C.
Anti-HCV prevalence >5% high 1.1–5% intermediate 0.2–1% low ≤0.1% very low Unknown
Fig. 2.7 Worldwide burden of hepatitis C infection.
USA 5 million
Western Europe 5 million
Eastern Europe 10 million
Far East Asia 60 million
South East Asia 35 million
Africa 40 million Americas 15 million
Australia <1 million
Fig. 2.8 Distribution of hepatitis C genotypes.
1a, 1b, 2a, 2b, 3a
1b, 2a, 2b, 2c, 3a
1b 2a
4 4
1b, 3a 1b, 6 3b
5a
1b, 3a
36
Hepatitis C
Transmission of HCV requires entry of HCV into the bloodstream with subsequent infection of hepatocytes. Not surprisingly, parenteral forms of transmission, such as intravenous drug use or transfusion of infected blood products, are the most commonly identified risk factors in individuals with hepatitis C (Figs. 2.9–2.11, Table 2.3). HCV can be detected with molecular techniques in other body fluids such as semen and saliva, but the significance of these findings related to transmission risk are unclear. Most epidemiological studies indicate that the actual infection risk associated with exchange of body fluids through oral or sexual contact is very low (Table 2.4). Since the introduction of highly sensitive screening tests for HCV among blood product donors in the early 1990s, infusion-related infections have become extremely rare in most developed countries (Fig. 2.11). Infection risk to health care workers following percutaneous exposure to
blood is estimated at between 1 and 2%. No proven prophylactic intervention is currently available for persons sustaining a high-risk type of exposure. Transmission of HCV infection via organ or hematologic transplantation is rare, but recipients of such transplants from a HCV-positive donor have a very high risk of developing hepatitis C. Vertical transmission is uncommon, with most estimates of the risk of perinatal transmission from HCV-infected mother to infant ranging from 3 to 5% (Table 2.5). HIV infection may increase the likelihood of perinatal or sexual transmission. HCV patients infected with HIV share many characteristics with other HCV-infected individuals, but coinfected patients have many other issues related to the pathophysiology and clinical management of their infections. Interested readers are referred to the reference section and specialty journals for detailed information about HCV/HIV coinfection.
Table 2.3 Factors associated with increased risk of hepatitis C virus transmission
Table 2.4 Sexual activity and risk of hepatitis C transmission
High-risk factors: • History of intravenous drug use • History of blood product transfusion • History of sexual activity with an intravenous drug user
• Most likely occurs, although estimated risk appears to be extremely low • Probable higher risk in individuals coinfected with HIV • Possible higher risk associated with anal intercourse or activities resulting in blood to mucosal surface exposures • Potential non-sexual household blood exposures confounds some data analyses (e.g. sharing toothbrushes or razor blades) • No clear-cut evidence as yet that ‘safe sex’ practices and condom use decrease rate of transmission • Certain organizations, including the United States Public Health Service and the American Association for Liver Diseases, do not currently recommend routine barrier precautions for sexual activity between long-term monogamous partners
Moderate to low-risk factors: • Incarceration in a jail or penitentiary • Religious scarification • Percutaneous blood exposure • Body piercing Listed in estimated descending rank order of relative risk
Hepatitis C 37
Percent anti-HCV positive
Hemophilia Injecting drug users Hemodialysis STD clients General polulation adults Surgeons Pregnant women Military personnel 0 10 20 30 40 50 60 70 80 90 Anti-HCV positive (%)
6
Male
5 4
Total
3
Female
2 1 0 6-11 12-19 20-29 30-39 40-49 50-59 60-69 70+
Age in years
Fig. 2.9 Risk factors for hepatitis C infection. (Adapted from US Centers for Disease Control data.)
Sexual 21% Sexual 15%
Transfusions 10% (without screening) Occupational 4% Other 1% Unknown 10%
Injection drug use 60%
Fig. 2.10 Risk factors for hepatitis C infection, pre-1992. (Adapted from US Centers for Disease Control data.)
Occupational 3% Other 3% Transfusions 3% (none since 1994) Unknown 10%
Injection drug use 60%
Fig. 2.11 Risk factors for hepatitis C infection, post-1992. (Adapted from US Centers for Disease Control data.)
Table 2.5 Perinatal transmission of hepatitis C virus
• • • • •
Occurs uncommonly, risk is estimated at 3–5% but varies widely among studies Increased risk may be associated with extremely high levels of hepatitis C virus viremia at time of delivery HIV coinfected individuals appear to have slightly increased risk of transmission Elective Cesarean section is not routinely recommended for hepatitis C-infected mothers Infants born to hepatitis C-infected mothers need to have negative viral RNA determinations during the at age 12–18 months to confidently exclude infection • In contrast to HIV, there is no evidence that breast-feeding by a hepatitis C-infected mother is associated with a significant transmission risk for the infant
38
Hepatitis C
Clinical manifestations Based on infusion-related infections, the incubation period for acute hepatitis C is estimated to average 7–8 weeks with a range of 2–26 weeks (Figs. 2.2). Antibody to HCV can be detected in 80% of patients within 15 weeks after exposure and in >97% by 6 months after exposure. Most patients with acute HCV infection are asymptomatic. In cases of symptomatic hepatitis C, most patients display very mild symptoms such as fatigue, malaise, and nausea. Only about 20% of those with acute hepatitis C develop jaundice. Laboratory evaluation usually only consists of mild, fluctuating elevations in serum transaminases. Fulminant hepatitis is rare, although the risk of developing this condition may be increased in those patients with chronic hepatitis B. Only a small number (~15%) of HCV-infected individuals completely resolve the infection with clearance of viremia and normalization of alanine aminotransferase (ALT) levels. Most HCV-infected individuals (~85%) develop chronic infection (Fig. 2.4). These patients are generally asymptomatic, but infection may be accompanied by nonspecific symptoms such as fatigue, low-grade fever, myalgias and/or anorexia. These patients usually have few specific laboratory abnormalities, the most common being elevated serum transaminase levels. The development of chronic liver disease is usually insidious, progressing at a slow rate in the majority of patients during the first two or more decades after infection. Commonly, chronic hepatitis C is not recognized in asymptomatic individuals until they are found to have HCV-positive serology as part of the screening process for blood donation or during the evaluation of elevated ALT levels detected during routine physical examinations. Although 60–80% of infected individuals will suffer no significant medical complications from HCV infection during their lifetime, ~20% of patients will go on to develop cirrhosis, usually over a period of 20–40 years following the acute infection (Figs. 2.3, 2.12). A proportion of those who develop HCV-related cirrhosis will progress to decompensated cirrhosis (liver failure) and/or HCC. For many HCV-infected patients with cirrhosis, the estimated rate of developing HCC can be as high as 1–4% per year (Fig. 2.12). Many factors are believed to accelerate clinical progression of hepatitis C and include alcohol intake (>50 g/day), male sex, and age over 40 years at time of infection (Fig. 2.12, Table 2.6). Certain laboratory findings indicate
Table 2.6 Factors associated with development of cirrhosis in hepatitis C-infected individuals
• • • • •
Duration of hepatitis C infection >10 years Alcohol ingestion Coinfection with HIV Human leukocyte antigen type B54 Viral genotype 1b
Table 2.7 Signs of advancing fibrosis in hepatitis C
• • • • •
Elevated prothrombin time Thrombocytopenia Hypoalbuminemia Reversed albumin to globulin ratio Aspartate aminotransferase (AST) level > alanine aminotransferase (ALT) level
advancing fibrosis in the patient with chronic hepatitis C (Table 2.7). In addition, persons who have chronic liver disease are at increased risk for fulminant hepatitis A. Chronic HCV infection can be associated with a wide variety of extrahepatic manifestations ranging from skin disorders such as porphyria cutanea tarda and lichen planus to serious lymphoproliferative disorders such as B cell lymphoma. The nature of this association is unclear for many extrahepatic syndromes. Because HCV is able to replicate in certain types of lymphoid cells, however, it is often speculated that HCV-mediated dysregulation of the host immune system may play a role in the development of some of these conditions. Laboratory evidence of cryoglobulinemia, for example, can be found in up to 50% of patients, although only 10–15% of these patients have specific signs or symptoms of this disorder (weakness, arthralgias, and purpura). HCV-infected patients often complain of arthralgias and the occasional patient will develop true polyarthritis. Again, there is a suggestion that
Hepatitis C 39
Female sex, young age at infection Slow
Rate of progression
≥30 years
Normal liver
Acute infection
Chronic infection develops in ~85%
Chronic hepatitis
Cirrhosis develops in 20%
Risk of carcinoma, 1–4% per year
Alcohol use, coinfection Fast
≤20 years
Fig. 2.12 Disease progression rates following acute hepatitis C infection.
the underlying pathophysiology is, at least in part, related to some aspect of the HCV infection itself. Similarly, certain forms of chronic renal disease, such as membranoproliferative glomerulonephritis, appear to be associated with chronic hepatitis C. In certain instances, eradication of viremia by HCV therapy may show a beneficial effect on the severity of some of these extrahepatic syndromes.
Diagnosis HCV infection is most commonly diagnosed by a screening test for antibody to HCV using a specific enzyme immunosorbent assay (EIA) designed to detect certain HCV proteins (Fig. 2.13). The second generation of this test, the EIA-2, is the most commonly used serologic test in the United States. This assay detects antibodies directed to recombinant antigens derived from the core and nonstructural proteins 3 (NS3) and 4 (NS4) of the HCV. EIA2 identifies at least 95% of chronically infected patients, but detects only 50–70% of acute infections. Because HCV EIA tests have been optimized for sensitivity (i.e. for screening), a positive or indeterminate EIA-2 test is usually followed by
performance of a confirmatory assay. The most commonly used confirmatory test is another serologic assay known as the recombinant immunoblot assay-version two (RIBA-2). The RIBA-2 measures immunoreactivity against specific antigenic bands representing HCV polypeptides. RIBA-2 is most often helpful in evaluating positive or indeterminate results obtained with the EIA-2 in low-risk populations. The third generation of the HCV EIA, the EIA-3, has been approved for screening blood products in the United States and has started to be used for diagnosis as well. The EIA-3 detects an additional antigen derived from the non-structural region (NS5). This test can detect antibody against HCV as early as 6 weeks following infection. The overall sensitivity of the EIA-3 is estimated to be greater than 97% and appears likely to decrease the incidence of indeterminate results observed in certain screening scenarios. No medical agency currently advocates routine screening for HCV infection in the general population. Certain organizations have identified several characteristics believed to place individuals at increased risk for hepatitis C and recommend such individuals be screened for HCV infection (Table 2.8). A positive serological test for HCV cannot distinguish
40
Hepatitis C
Negative
Screening test for anti-HCV
STOP
Positive OR
RIBA for anti-HCV
Negative
STOP
Nucleic amplification test for HCV RNA
Indeterminate
Positive
Additional laboratory evaluation (e.g. PCR, ALT) Negative PCR Normal ALT
Positive
Medical evaluation
Positive PCR Abnormal ALT
Fig. 2.13 Flow chart for diagnostic testing of hepatitis C infection.
Table 2.8 Indications for hepatitis C virus testing1
Routine testing recommended: • Ever injected illegal drugs • Received blood products and/or organ transplantation before July 1992 • Received clotting factors manufactured before 1987 • Ever received chronic hemodialysis • Laboratory evidence of liver disease • Current or long-term sexual partners of a hepatitis C-infected person2 • Child born to a hepatitis C-infected mother • Received a needle stick or high-risk mucosal exposure to hepatitis C-infected blood 1Adapted
Uncertain risk, consider individualized testing3: • Casual or short-term sexual partner of a hepatitis C-infected person • History of multiple sexually transmitted diseases • Ever used non-injection illegal drugs • Ever received a body piercing or tattoo • Received a tissue transplant • Received acupuncture or religious scarification while residing in highly endemic area
from the recommendations of the United States Centers for Disease Control and Prevention (CDC) and the American Association for the Study of Liver Diseases (AASLD) 2Recommended only by AASLD 3Not recommended routinely by CDC or AASLD
Hepatitis C 41
past from current infection. In order to determine if the patient has active HCV infection, a molecular assay designed to measure the presence of HCV RNA should be performed. Qualitative and quantitative HCV RNA assays are commercially available and tests are based on nucleic acid signal amplification (bDNA) or the polymerase chain reaction (PCR). In most instances, PCR-based assays have become the favored technique due to their generally higher sensitivities. Differences in the currently available HCV PCR tests are based primarily in the lower limit of detection achievable, and the usable overall range of results that are obtainable. In general, qualitative tests are slightly more sensitive and are the primary confirmatory test used in most countries. Quantitative HCV RNA tests are also very helpful and are used to assess the level of viremia present in an infected individual. These quantitative determinations have some value in assessing the level of disease activity (e.g. if very low or very high), but are most useful in following a patient’s response to therapy and for the detection of relapse following completion of therapy (see below). HCV genotype testing is recommended for all HCVinfected individuals because the likelihood of response to standard HCV therapy varies widely based on genotype (see below). Although liver biopsy is not required to make the diagnosis of hepatitis C, this technique remains the only definitive way to assess the stage of liver inflammation and fibrosis and is helpful in predicting the possible rate of disease progression (Fig. 2.5). Although the value of routine liver biopsy for all patients with hepatitis C continues to be debated, for a number of patients biopsy results provide very useful information. A number of serum markers are being evaluated in an effort to develop a non-invasive way of determining the stage of liver inflammation and fibrosis, but no assays are yet fully accepted as an adequate substitute for the information that can be provided by a liver biopsy in selected patients.
Management Current treatment regimens for hepatitis C produce sustained virologic responses in a subset of patients with hepatitis C. For this reason, every HCV-infected patient should be evaluated for suitability of possible antiviral treatment. Even those patients deemed not eligible for antiviral treatment can, and should, make lifestyle changes that can favorably impact on the progression of their disease.
Paramount among these interventions is limiting or eliminating the ingestion of alcohol, a known cofactor for progression of HCV infection. In addition, administration of potentially hepatotoxic medications should be avoided when possible. Most experts believe that a low dose of acetaminophen (e.g. not more than 2 g over 24 hours) is safe for those HCV-infected patients with normal hepatic function. Because HCV-infected individuals are at risk of contracting a more severe form of acute hepatitis A or B, immunization against these diseases should be provided to susceptible patients. Screening HCV-infected patients for HCC is commonly recommended, although the efficacy of this practice for patients without cirrhosis is not well established. Serum alpha fetoprotein (AFP) levels and abdominal ultrasound examinations are the most commonly performed screening techniques. AFP levels are not specific for HCC and are frequently modestly elevated due to the effects of HCV infection itself. Ultrasound examinations are sensitive enough to detect even small hepatic lesions, but the frequency with which the test should be performed has not been established. It should be noted that some patients with hepatitis C, especially those with cirrhosis, appear to still be at risk for the development of HCC even after successful completion of antiviral therapy. Work continues into developing more sensitive and specific serum markers for the detection of HCC at an early stage. As noted above, all patients with chronic hepatitis C should be evaluated for possible antiviral treatment regimens. Many factors influence the decision to treat any specific patient and include age, genotype, assessment of disease activity, and the presence of comorbid medical, psychological, or substance abuse issues. In general, adults younger than 70 years old with evidence of active inflammation on liver biopsy or elevated ALT are considered to be potential candidates for treatment. Indications for treatment of patients with very mild disease on liver biopsy or normal ALT levels are less clear-cut, although there has been increased support for treatment in these types of patient as well. Patients with compensated cirrhosis can be evaluated for treatment, but those individuals with advanced cirrhosis secondary to hepatitis C should generally be referred for evaluation for possible liver transplantation. Hepatitis C is the leading indication for liver transplantation in most countries where transplantations are performed. All currently available treatment regimens for hepatitis C
42
Hepatitis C
Table 2.9 Forms of interferon currently available for treatment of hepatitis C
Table 2.10 Improvements to interferon-α by pegylation
• • • • •
• • • • • •
Interferon-α-2a Interferon-α-2b Pegylated-interferon-α-2a Pegylated-interferon-α-2b Consensus interferon
are based on the use of various injectable forms of recombinant human interferon-α (Table 2.9). The exact mechanism of action of the interferons in the treatment of HCV infection is incompletely understood, but most evidence indicates that interferon-α can directly enhance immune-mediated activity against HCV and augment cellular mechanisms that interfere with the intracellular replication cycle of HCV as well. Recombinant forms of interferon-α-2a, interferon-α-2b, and consensus interferon are approved for use in the United States and many other countries for the treatment of hepatitis C. Pegylated forms of interferon-α-2a and -α-2b are available and allow for weekly dosing because of their prolonged half-life. Several large studies have shown that the pegylated forms produce superior response rates when compared with their related non-pegylated formulations (Table 2.10). For almost all patients, interferon is combined with an orally administered analog of guanosine known as ribavirin. This combination therapy markedly increases the rate of sustained virologic response (SVR) as compared with interferon-α monotherapy (Table 2.11). SVR is commonly defined as negative molecular assays for HCV RNA 6 months to 1 year following completion of therapy. Relapse of HCV infection following SVR is extremely rare. The duration of the treatment regimen as well as the predicted likelihood of response for patients with hepatitis C varies dramatically depending on their particular HCV genotype (Fig. 2.14). For example, patients with genotype 1 infections are generally treated for a total duration of 48 weeks and have an expected rate of SVR of 30–40%. In contrast, patients with genotype 2 or 3 infections have an expected rate of SVR of 80–90% and are usually treated for only 24 weeks (i.e. twice the achievable rate of SVR when treated for only half the time of genotype 1 patients). As
Improved absorption Optimized distribution Decreased rate of clearance Reduced proteolysis Decreased immunogenicity Improved efficacy
Table 2.11 Overall hepatitis C SVR rates for interferon (INF)-based treatments
INF-α (24 wks) IFN-α (48 wks) IFN-α/ribavirin (24 wks) IFN-α/ribavirin (48 wks) Peg-IFN-α/ribavirin (48 wks)
6% 16% 33% 41% 54%
Average overall sustained virologic response (SVR) rate pooled from published studies and registration trials
noted above, a large number of factors must be taken into consideration in order to decide whether treatment should be recommended for any particular patient. It is important to estimate both the level of disease activity and likelihood of treatment-related toxicities when formulating a treatment plan. Examples of relative or absolute contraindications to interferon/ribavirin therapy are varied and include decompensated cirrhosis, pregnancy, serious cardiac disease, significant renal disease, certain autoimmune diseases, active intravenous drug use, major psychiatric disorders, pre-existing cytopenias, and renal transplantation (Tables 2.12, 2.13). Those patients who undergo combination therapy receive a quantitative HCV assay 12 weeks after the initiation of treatment (Fig. 2.14). An individual whose HCV viral load has become non-detectable or which has decreased by at least two logs compared with pre-treatment values is considered to have achieved an early virologic response
Hepatitis C 43
PEG IFN/ribavirin treatment Baseline genotype and quantitative HCV RNA
Week 12
Re-test quantitative HCV RNA
HCV RNA decreased 2 log vs. baseline
HCV RNA undetectable
HCV RNA not decreased 2 log vs. baseline
HCV RNA detectable
STOP
Repeat HCV RNA at 12 weeks
Complete treatment: A: genotype 1 (36 more weeks) B: genotypes 2 or 3 (12 or more weeks)
Negative
Positive
STOP
Fig. 2.14 Treatment decision timepoints for hepatitis C.
(EVR). EVR is highly predictive of developing a subsequent SVR (Fig. 2.14) and such patients are continued on therapy until the stop date is reached. Patients who do not achieve an EVR are usually withdrawn from therapy because several large studies have shown that their likelihood of achieving an SVR is minimal. Patients who remain HCV PCR negative 6–12 months after the completion of therapy are considered to have achieved SVR. A proportion of patients who achieve EVR will stop therapy due to significant treatment-related toxicities (Tables 2.14, 2.15). Again, adverse effects of interferon/ribavirin combination therapy are numerous and include myalgias,
fatigue, anemia and other cytopenias, thyroid disease, exacerbation of underlying autoimmune disease, rash, and psychiatric disorders (especially major depression). Many of these adverse effects can be managed sufficiently to allow continuation of therapy. Anemia is a particularly common and bothersome problem because it can be caused by both interferon and ribavirin. Early recognition of anemia and institution of erythropoietin treatment permit many patients to complete therapy without significantly reducing doses of interferon or ribavirin. This effect is important because recent evidence suggests that achieving adequate levels of ribavirin are imperative to optimize a patient’s chance of
44
Hepatitis C
Table 2.12 Contraindications for interferon-α treatment
Absolute: • Decompensated cirrhosis • Symptomatic cardiovascular disease • Severe anemia, neutropenia, or thrombocytopenia • Seizure disorder (active) • Solid organ transplant (except liver) • Current or previous psychosis • Severe depression Relative: • Active autoimmune disease • Thyroid disorders • Poorly controlled diabetes mellitus • Active substance use (alcohol or intravenous drug) (Adapted from Lauer GM, Walker BD. Medical progress: hepatitis C infection. N Engl J Med 2001; 345:41–52.)
Table 2.13 Contraindications for ribavirin treatment
Absolute: • Pregnancy • Inability or unwillingness to use reliable contraception • Severe or end-stage renal disease • Significant anemia • Symptomatic cardiovascular disease
Table 2.14 Side-effects of interferon-α treatment
Incidence >30%: • Fever • Chills/rigors • Myalgia • Arthralgia • Headache • Fatigue • Thrombocytopenia • Autoantibody formation Incidence 1–30%: • Malaise • Anorexia • Nausea • Diarrhea • Retinopathy • Activation of autoimmune disease • Taste alteration • Rash • Irritability • Insomnia • Emotional lability • Depression • Cognitive disorders • Decreased libido • Anemia • Leukopenia
Relative: • Poorly controlled hypertension • Elderly
Incidence <1%: • Polyneuropathy • Optic neuritis • Hearing loss • Seizures • Cardiovascular toxicity • Glucose intolerance
(Adapted from Lauer GM, Walker BD. Medical progress: hepatitis C infection. N Engl J Med 2001; 345:41–52.)
(Adapted from Lauer GM, Walker BD. Medical progress: hepatitis C infection. N Engl J Med 2001; 345:41–52.)
Hepatitis C 45
Incidence >30%: • Nausea • Hemolysis Incidence 1–30%: • Pruritus • Sinus congestion • Rash • Anemia Incidence <1%: • Gout (Adapted from Lauer GM, Walker BD. Medical progress: hepatitis C infection. N Engl J Med 2001; 345:41–52.)
Table 2.16 Treatment options for hepatitis C patients who do not respond to or relapse after initial combination therapy with Peg-interferon-α and ribavirin
Repeat/switch therapy (estimated SVR rate of 5–15%) • If received Peg-IFN-α-2a/ribavirin, re-treat with standard regimen using Peg-IFN-α-2b/ribavirin • If received Peg-IFN-α-2b/ribavirin, re-treat with standard regimen using Peg-α-2a/ribavirin Consensus interferon therapy (estimated SVR rate of 30–40%): • Combination therapy with daily dosed consensus interferon; and Suppression therapy (estimated SVR rate unknown, likely low, <10%): • Monotherapy with Peg-IFN-α-2a or 2b at reduced dose for up to 3 years Few published studies exist for any of these options, estimated sustained virologic response (SVR) is based on gross estimates from abstracts, preliminary data, and published reports
achieving EVR, especially for those infected with HCV genotype 1. Patients who do not respond to, or relapse after, standard courses of therapy may be considered for alternative treatments (Fig. 2.15, Table 2.16). Combination therapy for hepatitis C is expensive due to the costs of the medications, laboratory monitoring, and management of side-effects. It is not surprising then, that treatment of most patients residing in developing or poorer countries is cost prohibitive. Because no vaccine is currently available, efforts aimed at prevention are especially important, particularly with regard to screening of all blood donors, minimizing health care-associated exposures, and identification and control of intravenous drug use-related HCV infection. Because the majority of genotype 1 patients will not respond to therapy, several investigators and companies are actively attempting to develop new therapeutic agents (Table 2.17). Efforts are currently focused on developing a variety
Treatment course Non-response HCV RNA level
Table 2.15 Side-effects of ribavirin
Partial response
Relapse
Sustained response
HCV RNA undetectable
EVR
Time
SVR
Fig. 2.15 Patterns of response to treatment of hepatitis C.
46
Hepatitis C
Table 2.17 Investigational treatments for hepatitis C
• Hepatitis C virus (HCV) cell entry inhibitors • Modified interferons (e.g. albumin-bound interferon-α) • Ribavirin analogs and derivatives • Guanine nucleotide synthesis inhibitors • HCV NS3/NS4/NS5 protease inhibitors • HCV RNA polymerase inhibitors • Immune-modulating/enhancing agents and biologicals • Hepatic fibrogenesis inhibitors • HCV RNA disrupting agents (antisense and ribozyme therapies) • Therapeutic polypeptide or nucleic acid vaccines
of novel treatments and include immune-enhancing biologicals, antifibrosis modalities, viral protease inhibitors, RNA polymerase inhibitors, and RNA disrupting agents (e.g. ribozymes, antisense oligonucleotides). Based on patterns of success developing antiviral agents for HIV and hepatitis B infection, certain investigational HCV protease or polymerase inhibitors appear to hold the greatest promise for the near future.
Illustrative case history A 34-year-old female (G2 P1 Ab1) presented for evaluation of persistently elevated ALT during the first trimester of her pregnancy. She had recently been notified that a previous sexual partner had tested positive for hepatitis C. Serologic testing for hepatitis A and B infection was negative. HCV EIA-2 and RIBA-2 were positive. HCV RNA testing was positive and her HCV genotype was 2a. Because she was pregnant, HCV therapy was planned to begin 6 months after the delivery of her child. During her second trimester she developed generalized skin pruritus, increased liver function tests, and was diagnosed with cholestasis of pregnancy. The patient had
Fig. 2.16 Thrombocytopenia and cryoglobulinemia in a pregnant woman infected with hepatitis C. (Reprinted with permission from Shakil OA, DiBisceglie AM. Images in clinical medicine: vasculitis and cryoglobulinemia related to hepatitis C. N Engl J Med 1994; 331:1624.)
spontaneous vaginal delivery at 38 weeks’ gestation. Immediately post-partum she developed moderate thrombocytopenia which persisted and subsequently also developed a petechial rash on her lower extremities. Tests for essential mixed cryoglobulinemia were positive and it was believed that her thrombocytopenia was due to this syndrome (Fig. 2.16). However, to exclude other hematologic problems she had further hematologic evaluation (including bone marrow biopsy) and was subsequently diagnosed with splenic marginal zone lymphoma with splenomegaly and focal involvement of the bone marrow. Even though she was only 12 weeks post-partum, the decision was made to institute combination therapy for hepatitis C with Peg-interferon-α-2a and ribavirin. This decision was based primarily on anecdotal published reports indicating that a subset of patients with HCV-associated lymphoma may exhibit partial or complete remission of their lymphoma as a result of standard hepatitis C treatment alone. The patient was HCV RNA PCR negative at 12 weeks and 24 weeks of therapy. She is currently in remission from her lymphoma. HCV RNA testing of her infant was negative at 12 months of age.
Hepatitis C 47
Conclusions • Rates of hepatitis C are expected to increase worldwide due to continued and increasing intravenous drug use in industrialized countries as well as often ineffective blood product screening and inconsistent application of rigorous blood-borne pathogen precautions in many developing countries. • Chronic hepatitis C remains a leading global cause of cirrhosis, liver failure, HCC and liver transplantation. • HCV combination therapy is effective for selected individuals; however, treatment is very expensive and not currently tenable for many patients in developing countries. • Patients eligible for HCV therapy must be carefully selected because the treatment regimen is associated with a variety of potentially serious adverse effects. • Currently available HCV therapy is suboptimal for most patients infected with genotypes 1 or 4. • No vaccine for hepatitis C is currently available. • New discoveries in HCV cell culture techniques and structural analysis of HCV proteins bring hope for development of vaccines and new forms of antiviral therapy.
Further reading De Francesco R, Migliaccio G. Challenges and successes in developing new therapies for hepatitis C. Nature 2005;436:953–960. Everson GT. Management of cirrhosis due to chronic hepatitis C. J Hepatol 2005; 42(Suppl1):S65–S74. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 2005;436:967–972. Fung SK, Lok AS. Update on viral hepatitis in 2004. Curr Opin Gastroenterol 2005;21:300–307. Heathcote J, Main J. Treatment of hepatitis C. J Viral Hepat 2005;12:223–235. Heller T, Rehermann B. Acute hepatitis C: a multifaceted disease. Semin Liver Dis 2005;25:7–17. Houghton M, Abrignani S. Prospects for a vaccine against the hepatitis C virus. Nature 2005;436:961–966. Kim AI, Saab S. Treatment of hepatitis C. Am J Med 2005;118:808–815.
Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005;436:933–938. Moreno-Otero R. Therapeutic modalities in hepatitis C: challenges and development. J Viral He pat 2005;12:10–19. Pawlotsky JM. Current and future concepts in hepatitis C therapy. Semin Liver Dis 2005;25:72–83. Rodriguez B, Bobak DA. Management of hepatitis C in HIV-infected patients. Curr Infe c t Dis Re p 2005;7:91–102. Tillmann HL, Manns MP, Rudolph KL. Merging models of hepatitis C virus pathogenesis. Se m in Live r Dis 2005;25:84–92. http://www.cdc.gov/ncidod/diseases/hepatitis/c/ (Hepatitis C @ National Center for Infectious Diseases website) http://www.who.int/csr/disease/hepatitis/en/ (Hepatitis C @ World Health Organization website) https://www.aasld.org (American Association of Liver Diseases website) http://www.easl.ch/ (European Association for the Study of the Liver website) http://www.apaslindia2004.com (Asian Pacific Association for the Study of Liver website) http://clinicaloptions.com/hep/ (Clinical Care Options for Hepatitis C website) http://www.hivandhepatitis.com/ (HIV and Hepatitis website)
Chapter 3
49
Emerging viral respiratory illnesses Nandhitha Natesan, MD and Rana B Hejal, MD
Introduction Respiratory tract infections remain a major cause of morbidity and mortality throughout the world. A number of viruses are known to infect the respiratory tract producing different clinical syndromes (Table 3.1). Recently, several
previously unrecognized viruses have come to the forefront of both media and scientific attention as important causes of acute respiratory illnesses. In this chapter, we will focus on three of these newer agents; namely, severe acute respiratory
Table 3.1 Respiratory viral infections and corresponding clinical syndromes in the immunocompetent host
Virus
Common cold
Clinical syndromes Pharyngitis Croup
Adenoviruses
Rare
Uncommon
Rare
Uncommon
Uncommon
Coronaviruses Group I–III SARS-CoV
Common Rare
Rare Rare
Rare Rare
Rare Rare
Uncommon Very common
Herpesviruses Cytomegalovirus Epstein–Barr virus Herpes simplex virus Varicella-zoster virus
Rare Rare Rare Rare
Uncommon Common Common Rare
Rare Rare Rare Rare
Rare Rare Rare Rare
Uncommon Uncommon Uncommon Uncommon
Orthomyxoviruses Influenza A, B, C
Uncommon
Common
Uncommon
Uncommon
Common
Rare Uncommon Rare
Rare Common Uncommon
Rare Very common Common
Rare Common Common
Uncommon Rare Common
Rare
Uncommon
Common
Very common
Common
Uncommon Very common
Rare Common
Rare Uncommon
Rare Uncommon
Rare Rare
Paramyxoviruses Measles Parainfluenza 1,2,3 Respiratory syncytial virus Metapneumovirus Picornovirus Enterovirus Rhinovirus
Bronchiolitis
Pneumonia
50
Emerging viral respiratory illnesses
A
B 1755
665 180 33
238 186 251
300
13 41 349
5327
Canada
Hong Kong
Singapore
China
Taiwan
Others
Fig. 3.1 Summary of SARS cases (A) and deaths (B) by country. (Adapted from WHO data.)
Spike glycoprotein
Hemagglutinin acetylesterase glycoprotein
Small envelope glycoprotein
Nucleocapsid phosphoprotein
A
Membrane glycoprotein RNA
B
Fig. 3.2 A: Structure of coronavirus virion. (Adapted from Holmes KV. SARS-associated coronavirus. N Engl J Med 2003; 348(20):1948–1951.) B: The negative stain electron micrograph of coronavirus. Coronaviruses have a halo, or crown-like (corona) appearance when viewed under electron microscopy. (Courtesy of CDC.)
Emerging viral respiratory illnesses 51
syndrome-associated coronavirus (SARS-CoV), human metapneumovirus (hMPV) and a novel strain of avian influenza A (H5N1).
the pathogen and clinical and epidemiologic spectrum of this syndrome in order to arrest the spread of a threatened pandemic.
Virology
SARS coronavirus Background In late 2002, an outbreak of severe, atypical pneumonia began in southern China. Within months, the illness named SARS had affected more than 8,000 patients in 29 countries, leading to more than 900 fatalities worldwide (Fig. 3.1). Led by the World Health Organization (WHO), a massive global collaboration was undertaken to identify
Coronaviruses are large enveloped, single stranded, positivesense ribonucleic acid (RNA) viruses that cause the ‘common cold’ in humans as well as a variety of illnesses in other species (Table 3.2). They have been divided into three groups based on serologic cross-reactivity, but more recently on genomic sequence homology. When the SARS-CoV genome was identified, it appeared similar to other coronaviruses in its organization, but quite different in phylogenic analysis and sequence comparisons, making it
Table 3.2 Spectrum of coronavirus species, hosts, and corresponding clinical syndromes
Host
Clinical syndrome
Group I Human respiratory coronavirus Human coronavirus-Netherlands Porcine transmissible gastroenteritis virus Canine respiratory coronavirus Feline enteric coronavirus Feline infectious peritonitis virus Rabbit coronavirus
HCoV-229E HCoV-NL TGEV/PRCoV CCoV FECoV FICoV RbCoV
Human Human Pig Dog Cat Cat Rabbit
Colds, pneumonia Colds, pneumonia Enteric, pneumonia Enteric Enteric Systemic, peritonitis Enteric
Group II Human respiratory coronavirus Bovine respiratory coronavirus Hemagglutinating encephalitis virus Rat coronavirus Sialodacryoadenitis virus Murine hepatitis virus
HCoV-OC43 BCoV HEV RCoV SDAV MHV
Human Cow Pig Rat Rat Mouse
Colds, pneumonia Enteric, pneumonia Respiratory, enteric, neurologic Respiratory Neurologic Hepatitis, encephalitis
Group III Avian bronchitis virus Turkey respiratory coronavirus
IBV TCoV
Chicken Turkey
Tracheitis, hepatitis, renal Respiratory, enteric
SARS-CoV
Human
Pneumonia, enteric
?Group IV Severe acute respiratory syndrome-associated coronavirus
52
Emerging viral respiratory illnesses
A
B
Fig. 3.3 Exotic animals regarded as a delicacy in Guangdong, China believed to harbor SARS-CoV. A: Masked palm civets (Paguma larvata). B: Raccoon dog (Nyctereutes procyonoides).
likely the representative of a new fourth group of coronaviruses (Fig. 3.2). In fact the sequence analysis suggested that this new virus is an animal virus that has gained the ability to cross the species barrier. The SARSCoV has four major proteins: the envelope (E), membrane (M), spike (S), and nucleocapsid protein (N). It is the S protein that binds to a species-specific host cell and along with the host’s immune responses determines the virulence of the organism. Several antigenically diverse strains were identified in China; however, only one went on to be responsible for the major outbreak and global spread of SARS.
Epidemiology The SARS-CoV is believed to be of animal origin, and to have spread from animals to humans in crowded, open air, live animal markets, which are common in east Asia. Precursors of this virus with 99% homology have been identified in several species of exotic animals sold at these markets, including civets and raccoon dogs (Fig. 3.3). It remains unclear whether these animals represent the natural reservoirs of this virus, or serve as amplifiers. The principle mode of transmission is thought to be close person-toperson contact with exposure to infected body secretions, including respiratory droplets, infected fomites, feces, and other bodily fluids. SARS emerged in the Guangdong province of China in
November 2002. By January 2003, multiple independent outbreaks had occurred within this province. A physician who had been in the Guangdong province, caring for SARS patients, returned to Hong Kong where he seeded at least 17 guests at a hotel (Fig. 3.4). Many of these guests traveled out of the country in the following days, and were responsible for the spread of this virus to Vietnam, Singapore, and Canada. The unexplained respiratory illness was first reported to the WHO in February of 2003. Standard public health measures, along with advanced screening and communication measures, were quickly implemented. A virtual network was established, with daily teleconferences enabling real time sharing and application of information. In addition, global health alerts and travel advisories were issued and updated regularly. Many countries implemented screening for elevated body temperatures and quarantines in airports. In late March, three independent labs identified a novel coronavirus from patients with SARS from different countries. The identified virus fulfilled the six Koch’s postulates, as modified by Rivers for pathogenic viruses (Table 3.3). On April 16, 2003 WHO announced this new virus to be the definitive cause of SARS. By July of 2003, human-to-human spread of this virus was under control leading to the successful averting of the threatened pandemic. SARS-CoV largely affects adults. A disproportionate
Emerging viral respiratory illnesses 53
Guangdong Province, China
Hong Kong SARS 95 HCW
F, G A
A
F, G 11 close contacts
Hotel M Hong Kong
A H, J
Canada 18 HCW
H, J
K
I, L, M
K
B
Ireland 0 HCW
C, D, E B
>100 close contacts
Vietnam 37 HCW
I, L, M C, D, E
Ireland 0 HCW
Singapore 34 HCW 21 close contacts 37 close contacts
Fig. 3.4 Effect of travel and missed cases on the SARS epidemic. Spread from Hotel M, Hong Kong. Case A from Guangdong Province, China and two hotel guests who became ill, cases H and J, started outbreaks of SARS in three Hong Kong hospitals involving at least 95 health care workers (HCW) and more than 100 contacts. (Adapted from CDC data.)
Table 3.3 Koch’s postulates as modified by Rivers for viruses
• • • • • •
Isolation of the virus from each of the suspected cases Cultivation of the virus in host cell Proof of filterability Production of a comparable disease in related species Re-isolation of the same organism Detection of specific host immune response to the virus
Emerging viral respiratory illnesses
4000
People probably infected
24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
3500 3000 2500 2000 1500 1000 500
China Hong Kong Canada Taiwan Other Total
3 July
18 June
3 June
19 May
4 May
19 April
4 April
0 20 March
54
Mortality rate Average mortality rate
number of cases were in health care workers (greater than 40% of cases in China and Canada). The global average case fatality rate was just over 10% (Fig. 3.5); however, for patients requiring intensive care and/or mechanical ventilation, fatality rates greater than 50% were reached. Predictors of mortality include increasing age, presence of comorbidities, atypical initial symptoms, and some abnormal laboratory findings (Table 3.4).
Clinical features The vast majority of patients pass through three phases in this illness: exposure, early prodrome, and late respiratory
Fig. 3.5 The evolution of the people probably infected, by main countries (moving average of 7 days) and the mortality rates for the last 2 weeks. People probably infected = cumulative case x number of deaths x number of people discharged. Mortality rate = deaths / (deaths + discharged). (Adapted from WHO data.)
Table 3.4 Risk factors for death or admission to an Intensive Care Unit
Risk factor
Relative risk or odds ratio 1.8 28 3.5 1.57 19.9
95% CI
Author
1.16–2.81 3.1–253.3 1.2–10.2 1.26–1.95 11.7–33.8
Lee N, et al., 2003 Peiris J, et al. (A), 2003 Chan JWM, et al., 2003 Tsui PT, et al., 2003 Leung GM, et al., 2004
Diabetes mellitus
3.1 9.1
1.4–7.2 2.8–29.1
Booth CM, et al., 2003 Chan JWM, et al., 2003
Comorbid illness
2.5 5.2
1.1–5.8 1.4–19.7
Booth CM, et al., 2003 Chan JWM, et al., 2003
Increased neutrophil count
1.6 1.28
1.03–2.50 1.13–1.46
Lee N, et al., 2003 Tsui PT, et al., 2003
Increased lactate dehydrogenase
2.09 1.35 2.3
1.28–3.42 1.11–1.64 1.4–3.8
Booth CM, et al., 2003 Tsui PT, et al., 2003 Leung GM, et al., 2004
Age >60 years
Emerging viral respiratory illnesses 55
Recovery (89%)
Exposure to SARS
‘Flu-like’ illness
Non-productive cough, shortness of breath
Incubation period
Prodrome
Lower respiratory phase
~2–10 days Up to 13 days reported
Few days
From day 4 onwards
Outcome
Death (11%)
Fig. 3.6 The clinical phases of SARS.
phase (Fig. 3.6). The incubation period varies between 2 and 10 days. Unlike many of the common viral respiratory pathogens, evidence suggests that there are rather few asymptomatic or mild illnesses associated with SARS-CoV, except for children, in whom the disease is uncommon, generally mild, and self limited. Typical adult illness begins with a prodrome of non-specific symptoms including highgrade fever, chills/rigors, myalgias, headache, and diarrhea (Fig. 3.7). Upper respiratory tract symptoms are less common. The clinical course tends to be insidious, and patients frequently improve transiently prior to developing lower respiratory symptoms in the second week of illness, with non-productive cough, dyspnea, and hypoxia. In 10–20% of hospitalized patients, symptoms progress to respiratory failure requiring intubation and mechanical ventilation. It is unclear whether this clinical deterioration is due to ongoing viral replication or uncontrolled immune response mediated by host defenses. Lymphocytopenia at presentation is common. Patients often go on to develop leukopenia and thrombocytopenia with the onset of respiratory symptoms. Elevated aminotransferases, creatinine kinase, and lactate dehydrogenase are also reported (Fig. 3.8). Moreover, these variables tend to worsen at different time points over the disease course (Fig. 3.9).
Fever Chills/rigors headache Myalgia Malaise Rhinorrhea Sore throat Cough Dyspnea Pleurisy Anorexia Nausea/vomiting Diarrhea 0
20
40 60 Percentage
80
100
Fig. 3.7 SARS clinical symptoms at presentation. (Data from almost 2000 patients are compiled from several series, including Avendano M, et al., 2003; Booth CM, et al., 2003; Chan PK, et al., 2003; Donnelly CA, et al., 2003; Hsu LY, et al., 2003; Lee N, et al., 2003; Peiris JS, et al., (B), 2003; Poutanen SM, et al., 2003; Rainer TH, et al., 2003; Tsang KW, et al., 2003; Zhong NS, et al., 2003.)
56
Emerging viral respiratory illnesses
Anemia
10.3
Defervescence Initiation of steroid Worst CXR findings ALT LDH AST CRP CK Leukopenia Lymphocytopenia Thrombocytopenia
Leukopenia Lymphocytopenia Thrombocytopenia Increased ALT Increased LDH 0
20
40 60 Percentage
80
8 9.6 13.3 10.8 10.3 8.5 7.8 7.5 7.0 6.9
0
100
5 10 15 Days after disease onset
20
Fig. 3.8 Initial laboratory abnormalities in patients with SARS. (Data from close to 500 patients are compiled from several series, including Booth CM, et al., 2003; Hsu LY, et al., 2003; Lee N, et al., 2003; Peiris JS, et al. (B), 2003; Poutanen SM, et al., 2003; Tsang KW, et al., 2003; Zhao, Z, et al., 2003.) (LDH: serum lactate dehydrogenase level; ALT: serum alanine aminotransferase.)
Fig. 3.9 The time relationships between the time points of defervescence, initiation of steroid, and when chest radiographic finding, as well as various laboratory parameters became most severe. Mean and standard deviation (days) are presented. (CXR: chest radiography; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; AST: aspartate aminotransferase; CRP: C-reactive protein; CK: creatine kinase.) (Adapted from CDC data.)
Chest radiographs in SARS are usually abnormal (Table 3.5). Approximately 50% of patients present with unilateral focal consolidation. Lower lobe predominance is rather common. While patients presenting early can have a normal film initially, they uniformly develop some abnormality by
the seventh day of their illness. In the setting of high clinical suspicion and normal chest X-ray, high resolution chest computed tomography (HRCT) may identify early parenchymal abnormalities and should be considered. Illustrative cases are shown in Figs. 3.10–3.12.
Table 3.5 Radiographic features of severe acute respiratory syndrome
Chest radiograph • Normal, only early in course • Peripheral alveolar infiltrates (most common): – Basilar predilection – Often multifocal – Nodular infiltrate (early) • Non-cardiogenic pulmonary edema • Pleural effusion rarely • Pneumomediastinum • Absence of: – Adenopathy – Cavitation
High resolution computed tomography • Ill-defined ground-glass opacification • Reticulation • Irregular interlobular septal thickening • Subpleural reticulation • Late manifestations (patients surviving respiratory failure): – Bronchiectasis – Honey-combing and fibrosis
Emerging viral respiratory illnesses 57
A
B
Fig. 3.10 A 55-year-old healthy man with history of recent travel to Hong Kong presents with fever, dyspnea, and cough. A: Initial chest radiograph with extensive bilateral reticulo-nodular infiltrates. B: Chest radiograph 12 hours later with marked progression to acute respiratory distress syndrome. (From Nicolaou S, et al., 2003.)
A
B
C
Fig. 3.11 A 48-year-old male who presented with myalgias, headache, dry cough, leukopenia, and fever of 38°C. A: Initial chest radiograph demonstrates focal areas of consolidation in the left lower lobe and right suprahilar area. B: Chest radiograph obtained 5 days after admission reveals progression of consolidation and decreased lung volumes. C: Chest radiograph obtained 9 days after admission shows marked clearing with associated clinical improvement. (Copyright 2003, contributed by Yeun-Chung Chang, MD, Taipei, Taiwan, all rights reserved. From Armed Forces Institute of Pathology website.)
58
Emerging viral respiratory illnesses
A
C
B
Fig. 3.12 High-resolution computed tomography scan findings in patients with SARS. A: Involvement in multiple segments. Lesions are of various sizes, and are distributed in a peripheral manner. B: Ground-glass opacification. Underlying vascular architecture (arrow) is clearly visible. The bronchi are dilated. C: Mixed ground-glass opacification and consolidation. Air bronchogram (arrow) is present in the center of the consolidation. D: Ground-glass opacification and thickened interlobular septa (arrow) and intralobular interstitium (crazy-paving pattern). (From Wong KT, et al., 2003.)
D
Pathology There are no specific histologic features for this disease. The principal pathologic process is that of diffuse alveolar damage at its various stages. Bronchiolar fibrin deposition, pneumocyte cytomegaly, atypia, and multinucleated giant cells are commonly observed (Fig. 3.13). Later, during the organizing phase, fibroblast proliferation tends to occur in the interstitium and alveolar spaces. Although inclusion bodies are not seen commonly, electron microscopy can detect viral particles consistent with coronavirus in infected cells (Fig. 3.14).
Laboratory diagnosis The isolation of this organism by culture is most successful on Vero-E6 cells or fetal rhesus monkey kidney cells (Fig. 3.15). However, this process is complex and not widely available. Moreover, early isolation of the SARS-CoV is tricky due to the initial low viral load in the respiratory epithelium. Thus, other methods are implemented to confirm the diagnosis (Table 3.6).
Table 3.6 Diagnostic tests for severe acute respiratory syndrome-associated coronavirus and their corresponding diagnostic yield over time Test
Diagnostic yield (%) Reverse transcriptase polymerase chain reaction Nasopharyngeal aspirate 80 in first 3 days 68 day 14 Stool
97 day 14
Urine
42 day 15
Serum (quantitative SARS-CoV RNA)
80 day 1 75 day 7 45 day 14
Serology Immunoglobulin G to SARS-CoV
15 day 15 60 day 21 >90 day 28
Emerging viral respiratory illnesses 59
A
B
C
D
Fig. 3.13 Pathologic findings in SARS. A: Homogeneous-appearing hyaline membranes (arrow) edematous alveolar walls (H&E stain, x200). B: Organizing diffuse alveolar damage is characterized by loose fibroblastic proliferation in alveolar spaces (arrow) and within the interstitium (arrowhead) and type II pneumocyte hyperplasia (H&E stain, x100). C: Acute bronchopneumonia is characterized by polymorphonuclear leukocytes filling alveolar spaces, in this case associated with alveolar hemorrhage (H&E stain, x200). D: Cytologically atypical epithelial cells are present within alveolar spaces (H&E, x400). (Courtesy of Armed Forces Institute of Pathology.)
Fig. 3.14 Coronavirus-infected cell in broncho-alveolar lavage. (Courtesy of CDC.)
60
Emerging viral respiratory illnesses
Reverse transcriptase polymerase chain reaction (RTPCR) is the preferred method for laboratory confirmation of SARS. Optimal specimen for viral detection depends on the phase of the illness (Table 3.7) and site of care (Fig. 3.16).
Fig. 3.15 This thin section electron micrograph of an infected Vero-E6 cell reveals particles of coronavirus. Note the coronaviruses contained within cytoplasmic membrane-bound vacuoles, and cisternae of the rough endoplasmic reticulum. (Courtesy of CDC.)
Table 3.7 Specimens for severe acute respiratory syndrome-associated coronavirus testing: priority specimens and timing for collection Specimen by test type
<1 week after symptom onset
1–3 weeks after symptom onset
>3 weeks after symptom onset
+3
++
+
Bronchoalveolar lavage, tracheal aspirate, or pleural fluid tap4
+
++
+
Nasopharyngeal wash/aspirate
+
++
+
Nasopharyngeal and oropharyngeal swabs
+
++
+
Serum (serum separator tube)
++
+
Not recommended
Blood (plasma) (EDTA/purple top tube for plasma)
++
+
Not recommended
++
++
++
RT-PCR1 for viral RNA Sputum2
EIA1 for antibody detection Serum5 (serum separator tube)
The likelihood of detecting infection is increased if multiple specimens, e.g. stool, serum, and respiratory tract specimens are collected during the course of illness 1Because
of the investigational nature of both the SARS RT-PCR (reverse transcriptase-polymerase chain reaction) and the SARS EIA (enzyme immunoassay), it is recommended that the clinician obtain a signed informed consent form from the patient. In the US the consent forms for these tests can be found at: www.cdc.gov/ncidod/sars/lab/rtpcr/consent.htm. and www.cdc.gov/ncidod/sars/lab/eia/consent.htm
2A
sputum specimen is preferred if the patient has a productive cough
3The
more checks, the better the results from a particular specimen at a specific point in the illness
4Consider 5Also
these specimen types if sputum is not available
collect a convalescent specimen >28 days post-onset
Emerging viral respiratory illnesses 61
can be done as well, with enzyme immunoassay as the preferred technique. However, the mean time to seroconversion is close to 20 days, making serologic testing of limited value in early diagnosis confirmation.
Nasopharyngeal aspirates or nose or throat swabs are best in the first few days, whereas lower respiratory secretions, stool, and urine have a higher yield towards the second week of the illness. Serologic testing for antibodies to SARS-CoV
Recommended specimens for evaluation of potential cases of SARS
Outpatient
Inpatient
Fatal
Upper respiratory tract Nasopharyngeal wash/aspirate Nasopharyngeal and oropharyngeal swabs
Upper respiratory tract Nasopharyngeal wash/aspirate Nasopharyngeal and oropharyngeal swabs
Lower respiratory tract Sputum
Lower respiratory tract Broncheoalveolar lavage, tracheal aspirate, or pleural fluid tap Sputum
Tissue Fixed tissue from all major organs (e.g. lung, heart, spleen, liver, brain, kidney, adrenals) Frozen tissue from lung and upper airways (e.g. trachea, bronchus)
Blood Serum – acute and convalescent (>28 days postonset) Blood (plasma) Stool
Blood Serum – acute and convalescent (>28 days post-onset) Blood (plasma) Stool
Upper respiratory tract Nasopharyngeal wash/aspirate Nasopharyngeal and oropharyngeal swabs Lower respiratory tract Broncheoalveolar lavage, tracheal aspirate, or pleural fluid tap Blood Serum Blood (plasma) Stool
Fig. 3.16 Recommended specimen collection for SARS laboratory testing. (Adapted from CDC data.)
62
Emerging viral respiratory illnesses
Treatment
Outcomes
Although many modalities of treatment were used during the SARS outbreak, no definite evidence points towards any specific therapy. Antiviral agents, ribavirin and, less frequently, protease inhibitor combination lopinavir/ritonavir were used empirically to treat patients with SARS. Ribavirin, unable to inhibit SARS-CoV in vitro, was cited as beneficial in several case reports but not in a conducted controlled trial. Its use was typically confounded by the addition of other agents mainly steroids, and a multitude of adverse reactions including hemolytic anemia, hypocalcemia, and hypomagnesemia. On the other hand, the lopinavir/ritonavir combination, used towards the end of the outbreak, was shown to have in vitro activity against the SARS-CoV and, when used early, improved outcomes. Steroids were the mainstay of therapy during the SARS outbreak. While some studies associated steroid use with improved outcomes, others did not. Additional agents, investigated late in the outbreak, have been successful in vitro, and may be of value in a future SARS outbreak. These include viral binding inhibitors, fusion inhibitors, glycyrrhizin, non-steroidal immunemodulators like interferon, and nitric oxide.
Retrospective studies of SARS survivors revealed that many complain of physical limitation due to generalized weakness and/or shortness of breath in the months following hospital discharge. In this population, 15–25% of confirmed SARS cases had pulmonary diffusion abnormalities and associated fibrosis in follow-up testing. Fibrotic lung changes were most common in patients with severe illness. Significant improvement of pulmonary function over time was noted, suggesting that the mechanism of lung injury in SARS may be different from that seen with other pulmonary diseases.
Prevention Prevention of SARS is centered upon controlling the possible routes of re-emergence of the SARS-CoV. These routes include persistent shedding from previously infected human hosts, spread from animal reservoirs, and accidental laboratory exposures. Several isolated incidents of laboratory-acquired SARS have been reported, highlighting the importance of adherence to biosafety guidelines (Table 3.8).
Table 3.8 Summary of CDC recommendations for expanded precautions Category Contact precautions
Elements • Single patient room (preferred) • Gloves for all contact with patient and environment of care • Isolation gown for all patient contact
Droplet precautions
• Single patient room (preferred) • Surgical mask within 3 feet (1 m) of patient • Eye protection within 3 feet (1 m) of patient
Airborne infection isolation
• Private room with monitored negative air pressure relative to surrounding areas and 6–12 air exchanges per hour • Appropriate discharge of the air to the outdoors or monitored high-efficiency filtration of room air before recirculation • Doors closed except as needed for entry and exit • National Institute for Occupational Safety and Health (NIOSH) approved respiratory protection (e.g. N-95 respirator) for entry to rooms of patients with infectious pulmonary or laryngeal M. tuberculosis, draining skin lesions with M. tuberculosis, SARS-CoV disease, smallpox, and viral hemorrhagic fevers
Emerging viral respiratory illnesses 63
In order to prevent possible future outbreaks of SARS, ongoing surveillance is necessary in high-risk areas. Even in low-risk areas, the US Centers for Disease Control and Prevention (CDC) has recommended consideration of the diagnosis of SARS in patients requiring hospitalization for radiologically confirmed pneumonia or acute respiratory distress syndrome (ARDS) in the absence of person–person transmission of SARS, only if the patient has one of the following risk factors in the 10 days prior to onset of symptoms:
Human metapneumovirus Background Human metapneumovirus (hMPV) was first isolated by van den Hoogen in 2001. Initially described in a group of 28 epidemiologically unrelated children in the Netherlands, this new member of the paramyxovirus family has since been recognized as an important pathogen of acute respiratory tract infections in all age groups, worldwide.
Virology • Travel to high-risk areas (China, Hong Kong, or Taiwan) or close contact with a symptomatic person with recent travel to these areas. • Employment in a high-risk occupation (i.e. health care worker or laboratory worker in contact with live virus). • Patient is a part of a cluster of unexplained cases of atypical pneumonia. Additionally, SARS-CoV vaccines are in progress of development. Current trials are focusing on conventional, inactivated formulations which have proven safe and effective in animals. Others, on the other hand, are using virus vector recombinants expressing the viral S protein, which is necessary for the initial virus attachment. Lastly, monoclonal antibodies against the SARS-CoV are being developed for possible use in post-exposure prophylaxis, and have proven highly effective when studied in vitro.
Fig. 3.17 Electron micrograph of human metapneumovirus collected from the supernatant of rhesus monkey kidney (LLC-MK2) cell culture. A virionreleasing nucleocapsid is shown. (Courtesy of CDC.)
hMPV is an enveloped single stranded, negative-sense RNA virus that represents the first mammalian virus in the metapneumovirus genus (Fig. 3.17). This genus previously contained a single member: the avian pneumovirus formerly know as turkey rhinotracheitis virus. Although there is a close phylogenetic relationship between the human and avian viruses, hMPV is unlikely to be of the same origin. When investigated, it was unable to infect turkeys or chickens in experimental models, suggesting that it is a true human virus and not a zoonotic crossover infection from birds. Genomic sequencing studies have also revealed at least two major groups of hMPV, A and B, both of which can cause human disease and circulate at the same time in a given season.
Emerging viral respiratory illnesses
Epidemiology Although the hMPV was recently isolated, serologic surveys suggest that it has been circulating in the human population since the 1950s. Delays in its identification are thought to have been due to the indistinct nature of associated symptoms, and the non-standard techniques necessary for its isolation. Reports from several countries indicate widespread prevalence of this pathogen with seasonal variation that is different in different parts of the world. Cases of hMPV are usually identified in late winter to early spring in Europe and America, and in late spring to early summer in Asia (Fig. 3.18). The organism is transmitted by close contact with contaminated secretions, such as aerosolized particles, droplets, or fomites. hMPV has been detected in patients of all ages, but predominantly in infants, children, and young adults. Several studies have suggested that hMPV may be second only to respiratory syncytial virus (RSV) as a cause of respiratory tract infections in children.
Clinical features The clinical manifestations associated with hMPV infection are variable, but fall upon the same spectrum of disease as most viral respiratory pathogens that include mild upper respiratory tract symptoms, bronchitis, bronchiolitis,
20 18 16 14 12 10 8 6 4 2 0
pneumonia, and ARDS. In addition, hMPV may play a role in acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations. Although the range of clinical syndromes is broad, most illnesses appear to be minor and self-limited, particularly in the immunocompetent host. An incubation period of 3–5 days is usually followed by a constellation of symptoms. In children the most frequent are fever, rhinitis, cough, and wheezing (Fig. 3.19). The clinical diagnosis is most commonly bronchiolitis, followed by croup, asthma exacerbation, and pneumonia. The hospitalization rate in children is approximately 2%, and severe disease has been associated with coinfection with RSV. Rates of infection with hMPV among adults are highest in the younger population, presumably due to increased exposure to children. The infected young adult is often asymptomatic, or has a mild illness that does not require medical attention. In adults presenting to a physician, the spectrum of disease is similar to that described in children except for increased rates of hoarseness in the young and dyspnea in the elderly (Fig. 3.20). As for hospitalized patients, the most common admitting diagnoses are COPD or asthma exacerbations, followed by bronchitis and pneumonia. Severe infections in the adult population are seen primarily in the elderly or immunocompromised hosts. The clinical diagnosis of this pathogen is difficult since
Fever Congestion Rhinorrhea Hoarseness Cough Dyspnea Wheezing
Study break
0
20
40 60 Percentage
80
100
Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May
Percent of all patients
64
2000
2001
2002
Fig. 3.18 Seasonal variation of respiratory viruses in Finland; N=293 hospitalized children. Respiratory syncytial virus (red), rhinovirus (blue), enterovirus (green), and human metapneumovirus (brown) during the study period. (Adapted from CDC data.)
Fig. 3.19 Common symptoms at presentation in children infected with human metapneumovirus. (Compiled data from Boivin G, et al., 2002, 2003; Peiris JS, et al. (C), 2003; van den Hoogen BG, et al., 2001; Esper F, et al., 2003; Williams JV, et al., 2004.)
Emerging viral respiratory illnesses 65
syndromes associated with hMPV are virtually indistinguishable from those associated with other common viruses including RSV, parainfluenza, influenza, and
adenovirus. Chest imaging has also been found to be nonspecific, with a number of possible findings. Illustrative cases are shown in Figs. 3.21–3.25.
Fever Constitutional Sx Congestion Rhinorrhea Sore throat Hoarseness Cough Sputum Dyspnea Wheezing
0
20
40 60 Percentage
80
100
Fig. 3.20 Common symptoms at presentation in adults infected with human metapneumovirus. (Constitutional Sx: constitutional symptoms; a combination of a few of the following: loss of appetite, fatigue, generalized weakness, decreased energy levels, and weight loss.) (Compiled data from Boivin G, et al., 2003; Falsey AR, et al., 2003.)
Fig. 3.21 A 6-month-old infant with human metapneumovirus bronchiolitis. Chest radiograph shows hyperinflation and diffuse perihilar infiltrates. (From Williams JV, et al., 2004.)
A 3.22 High resolution computed tomography of the chest in a 58-year-old man, known to have acute myeloid leukemia, who developed human metapneumovirus pneumonia 40 days after receiving an allogeneic hematopoietic stem cell transplant. A: A small nodule surrounded by a halo of ground-glass attenuation is present in left upper lobe (arrow). A nodular opacity is also seen in the right upper lobe (arrowhead). B: Multiple subpleural lung nodules are present in the left lower lobe. Bronchiolar wall thickening and poorly defined centrilobular nodules are seen in the middle (black arrow) and right lower (white arrows) lobes. Also seen are bilateral subpleural areas of ground-glass opacification. (From Franquet T, et al., 2005.)
B
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A
B
Fig. 3.23 High resolution computed tomography of chest of a 58-year-old male with a history of acute myeloid leukemia, who developed human metapneumovirus pneumonia 80 days after receiving an allogeneic hematopoietic stem cell transplant. A: Poorly defined nodules present in both lungs (arrows). Also seen are bilateral subpleural areas of groundglass opacification. B: Multiple centrilobular nodules (arrows), a few branching opacities (tree-in-bud pattern, short arrows), and focal areas of consolidation (asterisk) with adjacent ground-glass opacification in the left lower lobe. (From Franquet T, et al., 2005.)
A
B
C
D
Fig. 3.24 Computed tomography (CT) images of chest of a 44-year-old male with acute myeloid leukemia and human metapneumovirus pneumonia, who developed acute respiratory distress syndrome and spontaneous pneumomediastinum 60 days after receiving an allogeneic hematopoietic stem cell transplant. A: Bilateral and multiple lobular areas of groundglass attenuation in both lungs (arrows). B: Bilateral perihilar areas of consolidation. C: One week after scan in B, shows extensive pneumomediastinum (arrows). A small cyst is also seen in the right upper lobe (arrowheads). D: Follow-up CT scan obtained 2 months after the scan in C shows residual architectural distortion (arrows) and fibrosis. (From Franquet T, et al., 2005.)
Emerging viral respiratory illnesses 67
A B Fig. 3.25 Pathologic findings of lung tissue sections from a previously healthy 40-year-old man who presented with acute pneumonia during the outbreak of SARS in southern China. He died in 8 days from respiratory failure. Human metapneumovirus was the only pathogen isolated in the post-mortem examination. A: Pulmonary congestion and edema C D (H&E stain, original magnification x100). B: A mild degree of interstitial lymphocytic infiltration. Intra-alveolar organizing exudative lesion was occasionally found. Detached atypical pneumocytes are indicated by the arrow (H&E stain, original magnification x200). C: Atypical multinucleated pneumocytes were occasionally identified. Definite viral inclusion was not apparent (H&E stain, original magnification x400). D: Fibrin thrombi were frequently noted in small pulmonary arteries and arterioles (H&E stain, original magnification x200). (Courtesy of CDC.)
Laboratory diagnosis
Treatment
Diagnosis of hMPV may be undertaken using several methods. Serologic testing can be performed using ELISA or virus neutralizing antibodies. Since seropositivity is estimated to be close to 100% by the age of 5 years, serologic diagnosis has been based on either seroconversion or a greater than fourfold increase in antibody titers over time. RT-PCR is the most sensitive tool for diagnosis, but is not yet widely available. Lastly, culture and isolation of hMPV are well known to be difficult. Initial studies identified the rhesus monkey kidney cells (LLC-MK2) as the most sensitive growth medium for this organism; however, more recent reports suggest that when used in combination with universal RT-PCR, culture on human laryngeal cancer cells (HEp-2) may be more sensitive.
Treatment is supportive. To date, no clinical data exist on the use of antiviral therapy in hMPV. However, in vitro testing has suggested activity of ribavirin against this virus.
Prevention As with any viral respiratory pathogen, standard control measures should be applied, particularly in a hospital setting. Consideration may be given to separating patients with known RSV from those with hMPV given the risk of severe disease. Experimental vaccines using parainfluenza vectors are currently being tested on animal models. Initial studies are promising.
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Avian influenza Background Recently, several avian influenza viruses have been reported to cause infections in humans through direct bird-to-human contact. The most striking of these are a series of outbreaks, the first of which occurred in Hong Kong in 1997 caused by a highly pathogenic strain of influenza A, namely H5N1. This virus has received attention worldwide due to the severe illness it causes in humans, its predilection for the young, and strikingly high mortality rates. Since the fall of 2003, this strain has spread throughout Asia, causing an endemic in poultry, infecting a gradually growing number of humans and thus, causing mounting concerns for an impending pandemic.
Virology Influenza viruses are classified into types A, B, and C. While types B and C typically occur in humans, type A can infect birds as well as a few mammals including humans. These viruses belong to the Orthomyxovirus family. The influenza A virus, in particular, is an enveloped organism containing 8 segments of negative stranded RNA. The envelope is internally lined by a matrix protein (M), and externally with two surface proteins: a rod-shaped hemagglutinin protein (HA) and a mushroom-shaped neuroaminidase protein (NA), of which there are 15 (H1–15) and nine (N1–9)
A
distinct subtypes respectively. The latter two proteins are responsible for the antigenic definition of the different virus subtypes and are included in the WHO nomenclature of each virus (Fig. 3.26). All subtypes of influenza A can infect birds; however, of the 15 known avian subtypes essentially H5, H7, and H9 have been implicated in direct bird-tohuman spread and secondary human disease. The influenza A virus and its strains are constantly evolving secondary to antigenic variation in the genes encoding for HA and NA. There are two described mechanisms by which these changes occur: antigenic drift and antigenic shift (Fig. 3.27A, B). An antigenic drift is a process in which point mutations occur due to inefficient ‘proof-reading’ at some stage in viral RNA transcription, leading to accumulation of new antigenic variants, which allows the virus to evade the host’s immune defenses and secondarily give rise to yearly epidemics. On the other hand, an antigenic shift is a process by which new strains are formed. These novel viruses are produced when human and avian subtypes coinfect the same intermediate host, usually swine, ‘swap’ or ‘reassort’ RNA segments, resulting in a human virus with new surface proteins to which the population is immunologically naïve; hence, affording a high potential for outbreaks and pandemics.
Fig. 3.26 Influenza A. A: Structure of influenza A virion. B: Transmission electron micrograph, negative stain image of the influenza A virus. (Courtesy of CDC.)
B HA gene HA antigen (1-15) NA antigen (1-9)
NA gene
A/chicken/HongKong/258/97 (H5N1) Virus type
Host if not Geographic human origin
Strain number
Year of isolation
Virus subtype
Emerging viral respiratory illnesses 69
Fig. 3.27A Illustration of antigenic drift. (Adapted from NIAID data.)
1 Each year’s flu vaccine contains three flu strains – two A strains and one B strain – that can change from year to year 2 After vaccination, your body produces infection-fighting antibodies against the three flu strains in the vaccine Antibody
3 If you are exposed to any of the three flu strains during the flu season, the antibodies will latch on to the viruses’s HA antigens, preventing the flu virus from attaching to healthy cells and infecting them 4 Influenza virus genes, made of RNA, are more prone to mutations than genes made of DNA Viral RNA
Mutation
5 If the HA gene changes, so can the antigen that it encodes, causing it to change shape
HA gene HA antigen
6 If the HA antigen changes shape, antibodies that normally would match up to it no longer can, allowing the newly mutated virus to infect the body’s cells
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The genetic change that enables a flu strain to jump from one animal species to another, including humans, is call antigenic shift. Antigenic shift can happen in three ways
Bird influenza A strain
Bird host
2 Without undergoing genetic change, a bird strain of influenza A can jump directly from a duck or other aquatic bird to humans
The new strain may further evolve to spread from person to person. If so, a flu pandemic could arise
Human influenza A strain
3 Without undergoing genetic change, a bird strain of influenza A can jump directly from a duck or other aquatic bird to an intermediate animal host and then to humans
1A A duck or other aquatic bird passes a bird strain of influenza A to an intermediate host, such as a chicken or pig
1B A person passes a human strain of influenza A to the same chicken or pig. Note: reassortment can occur in a person who is infected with two flu strains 1C When the viruses infect the same cell, the genes from the bird strain mix with genes from the human strain to yeild a new strain
Viral entry intermediate host cell
New influenza strain
Genetic mixing
Intermediate host
1D The new strain can spread from the intermediate host to humans
Fig. 3.27B Illustration of antigenic shift. (Adapted from NIAID data.)
Emerging viral respiratory illnesses 71
Epidemiology There have been three influenza A pandemics and multiple outbreaks over the past century, each of which is associated with a distinct new subtype of avian origin (Fig. 3.28). The most notable of these is the ‘Spanish Flu’, which occurred from 1918–1919 and was caused by a new subtype, the H1N1. This pandemic claimed the lives of 20–50 million people worldwide. Over half of the dead were young, previously healthy adults. This subtype (H1N1) was reintroduced to the human population in the 1970s and is currently among the subtypes which circulate in the population today.
The natural reservoir for avian influenza viruses is wild birds, particularly migratory waterfowl. These hosts are not usually susceptible to illness, but can spread the virus to domesticated birds by contaminating water resources and common grounds. The virus is then transmitted to humans or intermediate hosts through saliva, secretions, or feces (Fig. 3.29). All viral strains can be divided into two pathotypes, low (LPAI) and high (HPAI) pathogenicity, based on the severity of illness induced in poultry. Most avian influenza outbreaks among birds are of low pathogenicity, with little or no illness noted in infected birds,
Fig. 3.28 Timeline of emergence of influenza A viruses in humans.
Bird to human transmission
Pandemics (number of dead globally [millions])
Avian influenza H9
H7
H5
H5
2005
2003
1977 1998/99
1977
Russian influenza Hong Kong H1 Asian influenza influenza H3 H2
1968
1918
Spanish influenza H1
1–4
1957
20–50
1–4
Fig. 3.29 Cycle of avian influenza viruses in animals and humans.
Domestic birds
Shore birds
Mammals (primarily swine)
Waterfowl
Natural avian influenza cycle
Pandemic disease cycle
Humans
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and associated low mortality rates. Highly pathogenic strains in poultry, on the other hand, are extremely contagious, produce severe systemic illness secondary to viremia and have mortality rates of up to 100%. The strains of H5N1 now endemic in Asia belong to the highly pathogenic group. Humans at increased risk of contracting avian influenza are those with close contact to live poultry. Open air wildlife markets in which domesticated and wild animals are kept in close proximity, and frequently culled on site, are common in several parts of east Asia. These markets are often crowded and unsanitary, providing ample close contact between humans, wild and domesticated birds, promoting bird-to-bird and bird-to-human spread of infection. In addition, these markets provide a fertile breeding ground for viral coinfection and genetic reassortment in human and animal hosts (Fig. 3.30). The first known outbreak of H5N1 virus among humans
occurred in 1997 in a live market in Hong Kong, with 18 identified human cases and a mortality rate of 33%. This prompted the culling of the entire poultry population in Hong Kong comprised of greater than one million birds. This rapid response is thought to have averted a pandemic. However, in 2003 the H5N1 subtype re-emerged in two confirmed and one suspected case in Hong Kong. Since then, human outbreaks with variants of this strain have been documented in Thailand, Vietnam, Cambodia, and Indonesia (Fig. 3.31). As of October 19th 2006, the total number of reported human cases is 256 with 151 deaths. Thus far, only limited human-to-human transmission has been identified. However, the multiple H5N1 outbreaks in poultry occurring throughout the far east, and more recently Europe (Romania, Russia, and Turkey) raise concerns about genetic alteration in the current strains leading to H5 hybrid subtypes easily transmissible to humans and, hence, an imminent pandemic.
Human population Coinfected human cell
New virus strain spreads in human population
Bird population
Influenza A (human strain) New reassorted virus strain Pig population Poultry with influenza A (H5N1)
Coinfected pig cell
New reassorted virus strain
Fig. 3.30 Generation of a potentially pandemic strain of influenza through reassortment. (Adapted from Hien TT, et al., (A), 2004.)
100 90 80 70 60 50 40 30 20 10 0
Fever Headache Myalgia Rhinorrhea Sore throat Cough Sputum Dyspnea Vomiting Diarrhea Abdominal pain
Alive
Vietnam
Turkey
Thailand
Iraq
Indonesia
Egypt
Djibouti
China
Cambodia
Dead
Azerbaijan
Number of patients with H5N1
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0
20
40 60 Percentage
80
100
0
20
40 60 Percentage
80
100
Pulmonary infiltrates Lymphocytopenia
Fig. 3.31 Countries with reported human cases and fatalities from avian influenza (as of October 2006).
Thombocytopenia Increased aminotransferases
Fig. 3.32 Clinical symptoms of H5N1 infection at presentation. (Clinical and laboratory data from around 50 patients are compiled from several series, including Yuen K, et al., 1998; Chan PK, 2002; Chotpitayasunondh T, et al., 2005; Hien TT, et al., (B), 2004.)
Clinical features Clinical manifestations of infection with avian influenza viruses are similar to those seen with human influenza disease. Presentation may range from typical ‘flu-like’ symptoms such as fever, cough, sore throat, and myalgias, to more severe illnesses like pneumonia, ARDS, progression to multisystem organ failure and, ultimately, death. Clinical manifestations and severity of illness are at least in part determined by the infecting strain. Outbreaks caused by avian influenza H7 strains, for example, have been associated with high rates of conjunctivitis, while those caused by H5 subtypes have been associated with respiratory failure and high fatality rates. The full clinical spectrum of H5N1 influenza is not yet known. Thus far, reports from H5N1 influenza outbreaks revealed clinical manifestations similar to those seen in more severe cases of human influenza. The majority of affected patients were previously healthy children or adults, with an identifiable recent exposure to poultry. Estimated incubation period, based on known exposure, was from
2–4 days. Common presenting symptoms included fever and lower respiratory and gastrointestinal tract symptoms (Fig. 3.32). Clinically, infected individuals deteriorated rapidly, and most required mechanical ventilation within 48 hours of admission. Risk factors associated with increased severity of disease included older age and delayed admission to hospital. Mortality rates have been estimated upwards of 50%. Laboratory studies in patients with H5N1 influenza may show lymphocytopenia, thrombocytopenia, and liver dysfunction. Radiological abnormalities are usually significant, developing within a median of 7 days from the onset of fever. A spectrum of abnormalities has been reported including interstitial or alveolar infiltrates in a focal or multilobar distribution. Progression to bilateral groundglass infiltrates compatible with non-cardiogenic pulmonary edema is often seen. Illustrative cases are shown in Fig. 3.33 and Fig. 3.34.
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A
B
Fig. 3.33 Chest radiograph of a 39-year-old woman presenting with rapidly progressive pneumonia 1 week after onset of fever and diarrhea. A: Chest radiograph on hospital day 5 shows patchy infiltration at bilateral lower lung fields. B: Chest radiograph 24 hours later shows rapidly progressive pneumonia in both lung fields, compatible with adult respiratory distress syndrome. (Courtesy of CDC.)
A
B
C
D
Fig. 3.34 Histopathologic and immunohistochemical evidence of avian influenza A (H5N1) virus in leopard lung. A: Diffuse alveolar damage in the lung: alveoli and bronchioles (between arrowheads) are flooded with edema fluid and inflammatory cells. B: Inflammatory cells in alveolar lumen consist of alveolar macrophages (arrowhead) and neutrophils (arrow). C: Many cells in affected lung tissue express influenza virus antigen, visible as brown staining. D: Expression of influenza virus antigen in a bronchiole is visible mainly in nuclei of epithelial cells.
Emerging viral respiratory illnesses 75
Diagnosis Avian influenza infection should be considered in any patient presenting with an acute febrile illness, with recent travel to areas with documented H5N1 endemic in its poultry flock (Table 3.9). Standard laboratory testing for all suspected cases of influenza include rapid antigen tests, RTPCR, viral isolation in cell cultures, and serology. An ideal specimen for laboratory testing is usually a nasopharyngeal aspirate obtained within 3 days of onset of symptoms. Unlike human influenza A, the diagnostic yield of pharyngeal swabs is higher than nasal ones, given the at least 10-fold increase in the viral load in the former location. Although rapid antigen testing is less sensitive than RTPCR or viral isolation in detecting influenza A, particularly when H5N1 is the infecting strain, it is often helpful in the initial assessment. However, further testing is needed to identify the subtype. This can be accomplished by using immunofluorescence (IF) assays with specific monoclonal antibodies on collected or cultured specimens, hemagglutination-inhibition (HAI) of cell culture medium, or RTPCR. There are few cell lines that will grow H5 strains in culture; the Madin-Darby Canine Kidney (MDCK) cell line is the preferred one (Fig. 3.35). Lastly, serologic testing for subtype determination is least useful in acute diagnoses, since antibodies require at least 14 days from onset of illness to increase. A titer is considered positive if a fourfold increase is demonstrated in the convalescent phase.
Table 3.9 Countries with influenza A H5N1 outbreaks in poultry and wild birds
Reported in 2003 • Cambodia • China • Indonesia • Japan • Russia • South Korea • Thailand • Vietnam
Reported in 2004 • Laos • Malaysia • Mongolia Reported in 2005 • Kazakhstan • Romania • Russia • Turkey
Treatment
Prevention
The care is mainly supportive. The Food and Drugs Administration has approved the use of four antiviral drugs in the management of influenza viruses: amantadine, rimantadine, oseltamivir, and zanamivir. Current recommendation for suspected H5N1 influenza is for the use of the neuroaminidase inhibitors, since H5N1 strains from the most recent outbreaks have demonstrated drug resistance to amantadine and rimantadine, but susceptibility to oseltamivir and zanamivir. The optimal dose and duration of therapy are not yet known. It is believed, however, that early administration of oseltamivir is associated with reduction in viral shedding, and perhaps improved outcome.
Surveillance within the bird population continues. Consideration is being given to the widespread vaccination of birds. Preventative measures for those with close contact with poultry should include contact precautions such as masks and gloves, frequent and thorough hand washing, and vaccination against seasonal flu. There have been no known cases of the spread of influenza virus through consumption of poultry. However, raw poultry should be handled hygienically, and cooked to temperatures greater than 70ºC well prior to consuming. Phase 1 vaccine trials are currently underway. Prophylaxis with oseltamivir has been recommended for those with known, or expected high-risk exposure.
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Collect nasopharyngeal specimen
Rapid antigen detection by influenza A-specific monoclonal IF
Positive
Virus isolation in MDCK cells
Cytopathic effect
Negative
H5 monoclonal Ab IF H5 specific RT-PCR
Negative
H5 monoclonal Ab IF H5 specific RT-PCR
Positive
Positive
Negative
Case of H5N1 influenza
Fig. 3.35 Diagnostic strategy for laboratory confirmation of H5N1 infection.
Conclusions • Emerging respiratory viruses continue to threaten global health with potential pandemics. WHO, in collaboration with health authorities throughout the world, has averted the potential pandemic of SARS and hopefully avian influenza in the near future. • Knowledge of epidemiologic patterns of SARS, avian influenza, and hMPV is crucial in assessing patients with respiratory, gastrointestinal, and/or constitutional complaints. • While the symptoms produced by the above noted viruses are non-specific, the disease they induce is usually severe, often fatal in immunocompetent hosts infected with SARS-CoV and H5N1 and, to a lesser degree, immunosuppressed hosts infected with hMPV.
• Several diagnostic tests are currently available for viral isolation or detection offered only in specialized labs across the world. Consulting with these establishments early in patients’ courses is quite helpful. • Supportive care is the mainstay in management for the majority of patients. Antiviral therapy and immune modulating agents may play some role in selected groups. Infection control measures are key in containing outbreaks. Vaccines, now being developed, are essential in preventing pandemics. • One needs to keep updated on the evolution of bird flu by contacting CDC and WHO.
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References Avedano M, Derkach P, Swan S, et al. Clinical course and management of SARS in health care workers in Toronto: a case series. CMAJ 2003;168(13):1649–1660. Boivin G, Abed Y, Pelletier G, et al. Virological features and clinical manifestations associated with human metapneumovirus: a new paramyxovirus repsonsible for acute respiratory-tract infections in all age groups. J Infect Dis 2002;186(9):1330–1334. Boivin G, DeSerres G, Cote S, et al. Human metapneumovirus infections in hospitalized children. Emerg Infect Dis 2003;9(6):634–640. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003;289:2801–2809. Chan JWM, Ng CK, Chan YH, et al. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS). Thorax 2003;58:686–689. Chan PK. Outbreak of avain influenza A (H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis 2002;34:Suppl2:S58–S64. Chan PK, Ip M, Ng KC, et al. Severe acute respiratory sundromw-associated coronavirus infection. Emerg Infect Dis 2003;9(11):1453–1454. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 2005;11:201–209. Donnelly CA, Ghani AC, Leung GM, et al. Epidemiology determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong. Lancet (2003);361(9371):1761–1766. Esper F, Boucher D, Weibel C, et al. Human metapneumovirus infection in the United States: clinical manifestations associated with a newly emerging respiratory infection in children. Pediatrics 2003; 111(6 Pt 1):1407–1410. Falsey AR, Erdman D, Anderson LJ, et al. Human metapneumovirus infections in young and elderly adults. J Infect Dis 2003;187(5):785–790. Franquet T, Rodriguez S, Martino R, et al. Human metapneumovirus infection in hematopoietic stem cell transplant recipients: high-resolution computed tomography findings. J Comput Assist Tomogr 2005;29(2)223–227.
Hien TT, de Jong M, Farrar J, (A). Avian influenza – a challenge to global health care structures. N Engl J Med 2004;351(23):2363–2365. Hien TT, Liem NT, Dung NT, et al., (B). Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004;350:1179–1188. Hsu LY, Lee CC, Green JA, et al. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and inital contacts. Emerg Infect Dis 2003;9(6):13–717. Lee N, Hui D, Wu A, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003;348:1986–1994. Leung GM, Hedley AJ, Lai-Ming Ho, et al. The epidemiology of severe acture respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann Intern Med 2004;141(9):662–673. Nicolaou S, Al-Nakshabandi NA, Muller NL. SARS: imaging of severe acute respiratory syndrome. Am J Roentgenol 2003;180:1247–1249. Peiris J, Ch C, Cheng V, et al. (A). Clinical progression and viral load in a community outbreak of coronavirusassociated SARS pneumonia: a prospective study. Lancet 2003;361:1767–1772. Peiris JS, Yuen KY, Osterhaus, et al. (B). The severe acute respiratory syndrome. N Engl J Med 2003;349(25);2431–2441. Peiris JS, Tang YL, Chan KH, et al. Children with respiratory disease associated with metapneumovirus in Hong Kong. Emerg Infect Dis 2003;9(6):628–633. Poutanen SM, Low DE, Henry B, et al. Identification of severe acute respiratory syndrome in Canada. N ENGL J Med 2003;348(20):1995–2005. Rainer TH, Cameron PA, Smit D, et al. Evaluation of WHO criteria for identifying patients with severe acute respiratory syndrome out of hospital: prospective observational study. BMJ 2003;326(7403):1354–1358. Tsang KW, Ho PL, Ooi GC, et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003;348(20):1977–1985. Tsui PT, Kwok ML, Yuen H, et al. Severe acute respiratory syndrome: clinical outcome and prognositc correlates. Emerg Infect Dis 2003;9:1064–1069.
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van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 2001;7(6):719–724. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350(5):443–450. Wong KT, Antonio GE, Hui DS, et al. Thin-section CT of severe acute respiratory syndrome: evaluation of 73 patients exposed to or with the disease. Radiology 2003;228(2):395–400. Yuen K, Chan M, Peiris M, et al. Clinical features and rapid viral disgnosis of human disease associated with avain influenza A H5N1 virus. Lancet 1998;351:467–471. Zhao Z, Zhang F, Xu M, et al. Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol 2003;52(Pt8):715–720. Zhong NS, Zheng BJ, Li YM, et al. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February, 2003. Lancet 2003;362(9393):1353–1358.
Further reading Beigel JH, et al. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005;353(13):1374–1385. Concensensus document on the epidemiology of SARS. WHO/CDC/CSR/GAR/2003.11.Geneva. Last accessed October 20 2005 at: http://www.who.int/csr/sars/en/WHOconsensus.pdf. Leung GM, Hedley AJ, Ho LM, et al. The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann Intern Med 2004;141(9):662–673. Levy MM, Baylor MS, bernard GR, et al. Clinical issues and research in respiratory failure from severe acute respiratory syndrome. Am J Respir Crit Care Med 2005;171(5):518–526. Peiris JS, Yuen KY, Osterhaus AD, et al. The severe acute respiratory syndrome. N Engl J Med 2003;349(25): 2431–2441.
van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Me d 2001;7(6):719–724. WHO interim guidelines on clinical management of humans infected by influenza A(H5N1). Last assessed October 20 2006 at http://www.who.int/csr/disease/avian_influenza/guideline s/Guidelines_Clinical%20Management_H5N1_rev.pdf. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350(5):443–450. In the Absence of SARS-CoV Transmission Worldwide: Guidance for surveillance, Clinical and Laboratory Evaluation, and Reporting Version 2. Last accessed October 20 2006 at: http://www.cdc.gov/ncidod/sars/pdf/absenceofsars.pdf. The following websites have several resources worth browsing for updates and education: http://www.who.int/csr/sars/en/ http://www.cdc.gov/ncidod/sars/ http://www.who.int/csr/disease/avian_influenza/en/ http://www.cdc.gov/flu/avian/
Chapter 4
79
Tuberculosis C Scott Mahan, MD and John L Johnson, MD
Introduction
Etiology and pathogenesis
Tuberculosis (TB) is a chronic necrotizing granulomatous disease caused by Myc o b ac te rium tub e rc ulo sis and, occasionally, by two closely related species, M. bovis and M. afric anum . The global toll of TB is staggering. TB disproportionately affects poor, malnourished, and immunocompromised persons (Fig. 4.1, Tab le 4.1). Pulmonary disease is the most common manifestation of TB, but any organ can be involved including the lymph nodes, pleura, bones, joints, and central nervous system.
TB is caused by the M. tuberculosis complex, which includes M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canetti; M. tuberculosis is responsible for the most disease in humans. M. tuberculosis is an obligate aerobic, non-motile bacillus that stains acid fast, meaning it retains a deep red tint after staining with carbol-fuchsin followed by washing with acid-alcohol (Fig. 4.2). Humans are the only reservoir for M. tuberculosis.
Rates per 100,000, all forms of TB 0–24 25–49 50–99 100–299 ≥300
Fig. 4.1 Estimated worldwide tuberculosis incidence rate 2004. (Adapted from WHO data.)
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Table 4.1 Persons at increased risk for developing active tuberculosis
• Human immunodeficiency virus-infected • Elderly • Immunosuppressed persons and persons receiving corticosteroids or other immunosuppressive therapy or cancer chemotherapy • Comorbidities such as diabetes mellitus, silicosis, alcoholism, and chronic renal insufficiency • Institutionalized persons in jails, prisons, nursing homes, and chronic care facilities • Health care workers • Close contacts of infectious cases of tuberculosis • Malnourished persons • Prior arrested tuberculosis as evidenced by apical scarring or fibrosis on chest radiography
Tuberculosis is spread when an infected person coughs, sneezes, or speaks creating small (1–5 μm) aerosolized droplets of bacilli that can be inhaled by another person and deposited in the new host’s alveoli. Once tubercle bacilli reach the alveoli, several different events can occur: local tissue macrophages may kill the organism and clear it before infection is established; alternatively, the bacteria may enter the macrophages, multiply, and spread via the lymphatics and the bloodstream throughout the body. Over 90% of immunocompetent individuals are able to mount an effective cell-mediated immune response and contain the initial infection, leaving only small parenchymal scars, a Ghon focus (Fig. 4.3), or no evidence of infection except for a positive tuberculin skin test. Persons who fail to mount an adequate immune response may develop progressive primary TB. Illustrative cases are shown in Figs. 4.2–4.4.
Fig. 4.2 Ziehl–Neelsen stain of sputum sample showing red acid-fast bacilli in a patient with cavitary pulmonary tuberculosis. Fig. 4.3 A calcified Ghon focus is visible in the right lower lung field with associated hilar adenopathy. The combination of a Ghon focus (arrowhead) and a calcified draining lymph node is known as a primary (Ranke) complex (arrow). These radiographic findings are consistent with resolution of primary tuberculosis infection. (Courtesy of Dr Catherine Curley.)
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Fig. 4.4 Chest radiograph showing apical scarring due to arrested tuberculosis (Simon’s foci) in an asymptomatic 55-year-old male.
HIV prevalence in TB cases, 15–49 years (%) 0–4 5–19 20–49 ≥50 No estimate
Fig. 4.5 Estimated prevalence rates of human immunodeficiency virus coinfection in patients with tuberculosis worldwide, 2004. (Adapted from WHO data.)
Global epidemiology TB is a major global health problem that has been exacerbated by poverty, poor public health infrastructure, the acquired immunodeficiency syndrome (AIDS) epidemic and the emergence of multidrug resistant TB. Worldwide, the number of TB cases increased by 1.8% annually between 1997 and 2000. The World Health Organization (WHO) estimates that one-third of the world’s population is infected with TB. In 2005, over 9 million new cases of TB and more than 2 million deaths due to TB occurred worldwide. Ninety-five percent of all TB cases and 98% of all deaths due to TB occur in persons living in developing countries. Conditions of intense overcrowding, inadequate
sanitation, malnutrition, and lack of access to medical care all contribute to the epidemic. Human immunodeficiency virus (HIV)/AIDS and TB are closely linked. HIV coinfection is the greatest risk factor known for the progression of latent TB infection to active TB (Fig. 4.5). Increasing rates of HIV coinfection in countries in sub-Saharan Africa have led to rapid increases in the incidence of TB despite the introduction of more effective TB treatment strategies. TB is the most frequent serious opportunistic infection in adults with AIDS worldwide.
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Clinical manifestations Primary pulmonary TB
Reactivation TB
Primary TB is the development of active TB soon after infection with the tubercle bacillus in the non-immune host. Most healthy individuals are asymptomatic after TB infection, and the event is marked only by the development of a positive tuberculin skin test (TST) 4–6 weeks after infection. Infants and children are more likely than adults to develop active TB after infection. About 10% of infants and children develop symptomatic primary TB heralded by mild fever, non-productive cough, and malaise. Radiologic manifestations may include hilar or mediastinal lymphadenopathy, mid- or lower-lung infiltrates, and transient pleural effusions. Among immunocompetent adolescents and adults infected with TB, only 5–10% will develop active disease, with roughly one-half of cases occurring during the first 2 years after infection. Illustrative cases are shown in Figs. 4.6–4.8.
As noted earlier, most immunocompetent individuals are able to contain their initial infection with TB. Although these individuals have an effective immune response to initial infection, small numbers of viable, slow growing bacilli remain that are walled off in granulomas (Fig. 4.9). Later in life, during periods of waning immunity, these walled off lesions can break down and lead to local and disseminated disease. The most frequent symptoms of reactivation TB in the adult include fever, anorexia, productive cough (with or without hemoptysis) for more than 3 weeks, night sweats, and malaise. Typical chest radiographic findings include upper lobe fibrocavitary lesions and infiltrates classically involving the apical and posterior segments of the upper lobes followed in frequency by involvement of the superior segments of the lower lobes. Atypical radiographic manifestations of TB in the adult include lower lobe infiltrates similar to pyogenic pneumonia and intrathoracic adenopathy. Lower lobe TB is more frequent in patients with diabetes mellitus. Illustrative cases are shown in Figs. 4.10–4.14.
Fig. 4.6 Chest radiograph of a 4-year-old child presenting with low-grade fever and non-productive cough. There is a visible parenchymal infiltrate (Ghon focus) in the right lower lung field (arrowhead) and associated right hilar lymphadenopathy (arrow). The primary (Ranke) complex consists of the parenchymal lesion and the associated enlarged ipsilateral lymph nodes. (Courtesy of Dr Charles Daley.)
Fig. 4.7 Tuberculous pneumonia with left upper lobe infiltrate in a 4-year-old with fever and progressive primary tuberculosis. (Courtesy of Dr Charles Daley.)
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Fig. 4.8 Lobar collapse due to extrinsic bronchial compression from enlarged right hilar lymph nodes and endobronchial tuberculosis in a 5-year-old child with fever and chronic cough. (Courtesy of Dr Charles Daley.)
Fig. 4.10 Left upper lung cavity in patient with reactivation tuberculosis who presents with fever, productive cough, and weight loss.
Fig. 4.9 Pulmonary granuloma (H&E, x100). Notice the area of central caseation (arrow) with a surrounding rim of lymphocytes, mononuclear cells, multinucleated giant cells, and fibrosis.
Fig. 4.11 A chest radiograph from a 38-year-old male with 1 month of fever, weight loss, and productive cough. His chest radiograph shows a right upper lobe cavitary lesion with spreading throughout the right upper lobe and into the right lower lobe. This is an example of how caseous material and tubercle bacilli from an open cavitary lesion can spread endobronchially to other areas of the lung.
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Fig. 4.12 Chest radiograph of a 48-year-old male presenting with wasting and a productive cough. It shows right upper lung involvement with a cavitary lesion and an air bronchogram.
Fig. 4.13 Chest radiograph of a 34-year-old male with intermittent fever, weight loss, and no pulmonary symptoms. He was found to have miliary tuberculosis. Although the chest radiograph may be normal in a minority of cases, it usually shows classic miliary lesions, which are diffuse 1–2 mm rounded opacities (similar in size to millet seeds) scattered throughout all lung fields. Sometimes these lesions are best seen on a lateral view. Miliary tuberculosis is due to lymphatic and hematogenous seeding of tubercle bacilli to all areas of the lungs and other organs.
Fig. 4.14 Gross view of lungs from a fatal case of miliary tuberculosis. (Courtesy of Dr Rosana Eisenberg.)
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TB in HIV/AIDS and the immunocompromised Persons infected with HIV are at an 80–100-fold increased risk for active TB after infection by the tubercle bacillus. In the immunocompetent individual, the risk of reactivation of latent TB is about 10% over the course of their lifetime; however, in an HIV-positive individual, the risk is about 8–10% per year. Early in the course of HIV, when host defenses are less impaired, patients usually present with typical upper lung field fibrocavitary disease, similar to reactivation TB in HIV-uninfected adults. In advanced
HIV/AIDS (CD4+ count <200/mm3), patients are more likely to present atypically with non-cavitary lower lobe infiltrates or extrapulmonary or disseminated TB. In addition, sputum acid-fast bacilli (AFB) smears are more likely to be negative in patients with advanced HIV/AIDS. Table 4.2 presents the clinical and laboratory manifestations of active TB in early and late infection with HIV. Illustrative cases are shown in Figs. 4.15–4.18.
Table 4.2 Clinical and laboratory manifestations of active tuberculosis in early and late infection with human immunodeficiency virus Early (CD4+ >200/mm3)
Late (CD4+ ≤200/mm3)
TST
Usually positive (5 mm or greater induration)
Usually negative
Adenopathy
Uncommon
Common
Affected lung areas
Upper lobes
Lower and middle lung fields
Cavitary disease
Frequent
Uncommon
Extrapulmonary disease
15%
30–50%
Sputum AFB smear
60% positive
40% positive
Fig. 4.15 Chest radiograph of a 28-year-old male with advanced acquired immunodeficiency syndrome (CD4+ count of 80/mm3) presenting with pleuritic right-sided chest pain and productive cough. A right mid-lung field infiltrate and associated hilar adenopathy are visible.
Fig. 4.16 Multilobar disease with associated hilar adenopathy in a patient with advanced human immunodeficiency virus/acquired immunodeficiency syndrome.
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Fig. 4.17 Chest radiograph of a 35-year-old HIV-infected man with classic upper lobe fibrocavitary disease. Chest radiographic findings in patients with early HIV (CD4+ >200/mm3) are similar to findings in HIV-uninfected persons.
Fig. 4.18 Chest radiograph of the same patient as seen in Fig. 4.17 after 6 months of standard antituberculous chemotherapy showing an excellent response to therapy. Clinical response to chemotherapy is similar in both HIV and non-HIV infected persons, although the rate of recurrence after treatment is slightly higher among HIVinfected persons.
Immune reconstitution inflammatory reactions Patients starting on antituberculous chemotherapy may develop acute worsening of their symptoms or existing tuberculous lesions or new lesions; these are termed paradoxical or immune reconstitution inflammatory syndrome (IRIS) reactions. IRIS reactions occur more frequently in HIV-infected patients with TB (7–36% of patients) and are more common when highly active antiretroviral therapy (HAART) and anti-TB treatment are started at the same time. The cause of IRIS reactions is unclear, but they may be due to reconstitution of the host immune response and an increased inflammatory response to mycobacterial antigens after beginning HIV and anti-TB therapy. Most occur within 4–12 weeks after starting HAART. IRIS reactions are more common in patients with extrapulmonary TB or low CD4+ lymphocyte counts. New or worsening adenopathy, fever, and new pulmonary infiltrates or pleural effusion are the most common presentations. After excluding other opportunistic infections, non-adherence with TB treatment, and drug resistant TB, management is by treatment of symptoms. Adjunctive corticosteroids may be helpful in severe cases. HAART therapy can usually be continued. Illustrative cases are shown in Figs. 4.19–4.21.
Fig. 4.19 A 35-year-old HIV-infected man (CD4+ 100/mm3) who developed severe cervical lymphadenitis 1 month after beginning treatment for HIV and pulmonary tuberculosis. IRIS reactions most commonly occur within 4–12 weeks after beginning HAART therapy. (Courtesy of Dr Stephen Weis.)
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Figs. 4.20, 4.21 Tuberculous pleurisy as a manifestation of IRIS presenting as recurrent fever and chest pain in a 30year-old HIV-infected man with CD4+ 30/mm3 after beginning HAART therapy. After diagnostic thoracentesis to exclude other etiologies, the patient was treated symptomatically with ibuprofen, HAART, and anti-TB treatment with resolution of the pleural effusion over the next 3 weeks. HAART therapy can be continued along with antituberculous therapy in most instances. (Courtesy of Dr Stephen Weis.)
Extrapulmonary manifestations of TB Nearly every organ can be infected with TB. Children and young adults in developing countries often present with extrapulmonary TB. In the developed world, extrapulmonary TB is more frequent in elderly patients or compromised hosts who present with reactivation TB in the setting of waning cell-mediated immunity. The incidence of extrapulmonary and disseminated TB is greatest in HIVinfected persons. Patients with extrapulmonary TB are often difficult to diagnose. A high clinical suspicion for TB must be maintained in the appropriate setting. Patients with extrapulmonary TB may present with fever and local symptoms. Tuberculin skin tests should be done but are often negative. Chest radiographs are normal in one-quarter to one-third of patients with many forms of extrapulmonary TB. Repeated smears and cultures of infected body fluids
and biopsy of affected tissues may be required for diagnosis. The following cases illustrate common forms of extrapulmonary TB (Figs. 4.22–4.34). Other forms of extrapulmonary TB include tuberculous lymphadenitis, which is the most common form of extrapulmonary TB in developing countries. Cervical lymph nodes are most commonly involved, a form of mycobacterial lymphadenitis classically called scrofula (Fig. 4.19). Involved nodes are enlarged and non-tender without local warmth or inflammation. Draining sinuses may form. Tuberculous lymphadenitis can be diagnosed by aspiration or biopsy with smears and cultures. Other less common forms of extrapulmonary TB include cutaneous lesions (multiple manifestations), adrenal TB (the most common cause of adrenal insufficiency in developing countries), and otitis.
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Fig. 4.23 Gross appearance of a central nervous system parenchymal tuberculoma. (Courtesy of Dr Richard Hewlett.)
Fig. 4.24 Another manifestation of central nervous system involvement is tuberculous spondylitis as seen in this 28-year-old male who presented with 1 month of neck stiffness and pain. Over the past 2 weeks he had developed weakness in both arms and had difficulty walking. The spinal magnetic resonance image shows destruction of the C5 vertebral body with an epidural abscess tracking posteriorly behind the C4–C7 vertebrae and resultant spinal cord compression. Involvement of the lumbar region of the spine is also present.
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Fig. 4.25 Cranial magnetic resonance image of a large right-sided tuberculoma with associated mid-line shift. The patient presented with focal left leg weakness. (Courtesy of Dr Richard Hewlett.)
Fig. 4.26 A child with tuberculous meningitis. Tuberculous meningitis can present with meningeal signs, new or evolving cranial nerve palsies, lethargy, a chest radiograph consistent with tuberculosis, and cerebrospinal fluid profile of hypoglycorrhachia, elevated cerebrospinal fluid protein, and lymphocytic pleocytosis. Tuberculous meningitis is usually due to reactivation disease in the elderly, but often is a post-primary event in children.
Fig. 4.27 An 8-year-old child with tuberculous spondylitis (Pott’s disease). Tuberculous spondylitis frequently involves the anterior portion of the vertebral body with subsequent spread to the intravertebral disc and adjacent vertebral bodies. Anterior collapse with secondary posterior spinal swelling and tenderness results in the classic kyphotic gibbus deformity (arrow). The lower thoracic spine is affected most commonly, followed by the lumbar spine. Tuberculosis also may involve the large weight-bearing joints such as the hips and knees.
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Fig. 4.28 Chest radiograph of a 79-year-old female with unexplained fever, anorexia, and weight loss. Radiographic findings are consistent with miliary tuberculosis. Miliary lesions are diffuse 1–2 mm nodular lesions scattered throughout all lung fields due to lymphohematogenous seeding of the tubercle bacilli. Patients often present with generalized non-specific symptoms. Many patients have central nervous system involvement. Laboratory confirmation is frequently difficult because only about onequarter of patients are sputum smear-positive. The diagnosis often is presumptive and based on the clinical setting and radiographic findings. Definitive diagnosis often requires histologic and culture confirmation by liver, bone marrow, or transbronchial lung biopsy.
Fig. 4.29 Radiograph of a retrograde pyelogram of a 65year-old patient with weight loss and pyuria. Findings are consistent with a diagnosis of genitourinary tuberculosis. Multiple ureteric strictures, dilated minor calices, and poor definition of the renal papillae are present. Many patients with renal tuberculosis have evidence of pulmonary tuberculosis. Sterile pyuria is suggestive of renal tuberculosis. Intravenous pyelograms or retrograde pyelograms are usually abnormal, often showing papillary necrosis, ureteral strictures (arrow), hydronephrosis, and focal calcification. Infection can spread from the initial renal foci to involve the prostate, seminal vesicles, epididymis, and testes in men. Women may have involvement of the endometrium, ovaries, cervix, and vagina.
Figs. 4.30, 4.31 Chest radiographs of a child with tuberculous pericarditis before and after treatment. Tuberculous involvement of the pericardium is usually caused by extension from a nearby draining focus of infection, such as hilar or mediastinal lymph nodes, the lung, spine, or sternum. Less commonly, it arises from hematogenous seeding. Tuberculous pericarditis usually responds well to antituberculous therapy, but drainage or surgical management may be required if there is tamponade or restriction. Adjunctive corticosteriod therapy is beneficial.
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Fig. 4.32 Abdominal computed tomography scan showing tuberculous involvement of the ileocecal region of the gastrointestinal tract (tuberculous typhlitis). This patient had been mistakenly treated for ulcerative colitis for 6 months. Gastrointestinal tuberculosis usually arises due to the swallowing of infected pulmonary secretions with secondary seeding of the gastrointestinal tract. Tuberculosis can involve any portion of the tract with the ileocecal region being most common. Symptoms are varied, most commonly diarrhea and abdominal pain. Cecal tuberculosis can be mistaken for inflammatory bowel disease, thereby delaying treatment and risking exacerbation by the use of corticosteroids or other immunosuppressive therapy without antituberculous treatment. Patients can also have tuberculous peritonitis due to spread from adjacent tuberculous foci into the peritoneum. Laparoscopic or open peritoneal biopsy is often required to make this diagnosis.
Fig. 4.34 Right lateral decubitus chest radiograph of same patient as in Fig. 4.33. Pleural tuberculosis can be due to direct extension, hematogenous seeding, or from rupture of a subpleural caseous focus into the pleural space. Thoracentesis and pleural biopsy with smears, cultures, and histologic examination of biopsy tissue are the most useful diagnostic tests.
Fig. 4.33 Chest radiograph of a 33-year-old male with a right-sided pleural effusion secondary to tuberculosis. He presented with right-sided pleuritic chest pain, nonproductive cough, and anorexia.
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Diagnosis Latent TB TST is used in epidemiological surveys to evaluate the prevalence of TB infection in populations, and for the diagnosis of latent tuberculous infection (Fig. 4.35). A positive tuberculin skin test indicates prior tuberculous infection. TST is recommended for groups at high risk of TB infection or for developing active TB (Table 4.1). The sensitivity and susceptibility of the TST varies according to the population being evaluated (Table 4.3). Most people with a TST greater than 10 mm are infected with M. tub erculo sis. In immunocompromised or HIV-infected persons and close contacts of infectious TB cases, a 5 mm cut-off is used. False-negative and false-positive tests occur, often influenced by host characteristics such as malnutrition, immunodeficiency, and environmental exposure to non-tuberculous mycobacteria. Prior Bacille Calmette–Guérin (BCG) vaccination in infancy generally has little effect on the size of TST reactions in adulthood. TST reactions in the BCG-vaccinated adult should be interpreted the same as in non-BCG vaccinated individuals. New in vitro tests based on production of interferon-γ by sensitized lymphocytes in the presence of specific mycobacterial antigens are now becoming clinically useful. These tests use mycobacterial antigens found in M. tuberculosis, but not in most other non-tuberculous bacteria or BCG, enhancing the specificity of these tests. They have the added advantages of being done during a single visit, having no boosted responses, and little intraobserver variability. The full role of these new tests, particularly in immunosuppressed patients such as those with HIV infection, needs to be further defined.
Table 4.3 Interpretation of positive results for the tuberculin skin test in at-risk populations
≥5 mm induration • HIV infected • Close contact with someone who has tuberculosis • Chest X-ray changes suggestive of previous tuberculosis (fibrotic changes, calcifications, apical scarring) • Organ transplant recipients, patients taking tumor necrosis factor-alpha inhibitors, patients receiving immunosuppressive agents (e.g. prednisone >15 mg/d or equivalent) ≥10 mm induration • Recent immigrant from high-prevalence country • Injection drug use • High-risk groups (silicosis, diabetes, chronic renal failure, or other chronic medical conditions) • Resident or employee of prison, nursing home, homeless shelter ≥15 mm induration • Persons not in any of the above high-risk groups
Fig. 4.35 This picture shows the proper placement of the Mantoux tuberculin skin test. Purified protein (PPD) is a commercially available mixture of tuberculin antigens whose potency is adjusted using an international standard. Skin testing is performed by the intradermal injection of 0.1 ml of PPD containing 5 tuberculin units of PPD-S or 2 tuberculin units of PPD RT-23 antigen into the skin of the flexor surface of the forearm. The injection should immediately raise a wheal. The test should be read 48–72 hours later. The greatest diameter of palpable induration of the skin should be recorded in millimeters. (Courtesy of CDC.)
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Laboratory diagnosis The diagnosis of TB is made by demonstrating the presence of tuberculi bacilli or their genomic products in smears, cultures, or from other sources of infected tissue. There is no accurate blood test for the diagnosis of TB. Sputum microscopy and culture are the most common diagnostic tests done worldwide. At least three sputum samples should be obtained, preferably in the morning when the sputum bacillary load is greatest. In those unable to produce adequate sputum samples, induced sputums with hypertonic saline, morning gastric aspirates, or bronchoscopy with lavage can be performed. When bronchoscopy is done, transbronchial biopsies can be performed for culture and histology. Other involved tissues such as lymph nodes can be sent for stains, culture, and histologic evaluation. In miliary TB, sputum smears and cultures are usually negative and diagnosis is made from culture and histology of liver, bone marrow, or transbronchial lung biopsy. Mycobacteria are notable for their acid-fastness. Staining may be performed by hot Ziehl–Neelsen stain or cold Kinyoun methods (Fig. 4.36). In the Ziehl–Neelsen method, a fixed smear covered with carbol-fuchsin is heated, rinsed, decolorized with acid-alcohol, and then counterstained with methylene blue. The Kinyoun stain is modified to make heating unnecessary. Tubercle bacilli appear as slightly bent, beaded rods 2–4 μm long. One to ten thousand tubercle bacilli per milliliter must be present in a sample for a consistently positive smear. Many large laboratories use fluorochrome stains with auramine and a counterstain (Fig. 4.37) resulting in fluorescence of the bacilli. Fluorochrome staining allows
rapid screening of large numbers of slides at lower magnification with good sensitivity. In the appropriate clinical setting, a positive smear makes TB highly likely, but culture is required for definitive diagnosis and drug susceptibility testing. Several media support the growth of tubercle bacilli. Eggbased Löwenstein–Jensen (Fig. 4.38) and clear agar-based Middlebrook media are two of the most popular. M. tuberculosis is a slow growing organism (dividing time 12–18 hours) and it may require several weeks before colonies are visible on solid media. Cultures should be examined weekly until positive or for a total of 8 weeks. Organisms from culture can then be speciated to identify them as M. tuberculosis or atypical mycobacteria using biochemical, morphologic, and genomic methods. Drug susceptibility requires an additional 2–4 weeks to complete using conventional methods. Enriched liquid culture systems such as the mycobacterial growth indicator tube (MGIT) system are becoming more widely used. These liquid culture systems are able to detect metabolically active mycobacteria more quickly than waiting for visible colonies to appear on solid media, and significantly shorten the time until cultures turn positive. Rapid tests based on nucleic acid amplification methods such as polymerase chain reaction (PCR) have been developed for diagnosis and speciation of mycobacteria. These methods are more expensive, require special equipment, and have decreased diagnostic sensitivity in patients with smear-negative disease.
Fig. 4.36 Photomicrograph of positive Kinyoun stain of a sputum smear showing numerous acid-fast bacilli. (Courtesy of Dr Rosana Eisenberg.)
Fig. 4.37 Positive sputum smear stained with fluorescent auramine with rhodamine counterstain. (Courtesy of Dr Rosana Eisenberg.)
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Fig. 4.38 Growth of bread crumb-like colonies of M. tuberculosis on Löwenstein–Jensen slant. This egg-based agar is the most common medium used worldwide for mycobacterial cultures.
Person with clinical or epidemiological risk factor for TB
No
Yes
Place tuberculin skin test
No tuberculin test recommended (if test is performed without indication, positive ≥15 mm)
Negative
Positive (by criteria, see Table 4.3)
High-risk exposure within 3 months
Chest radiograph Clinical evaluation
No
Treatment of latent infection not indicated
Yes
Normal chest radiograph
Evaluate patient for treatment of latent infection
Fig. 4.39 Algorithm for the evaluation of persons with suspected TB infection.
Abnormal chest radiograph or patient has symptoms (fever, cough, weight loss)
Evaluate patient for active TB
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Susceptibility testing of strains of TB can be performed conventionally by evaluating critical concentrations of drugs required for inhibition of growth on solid media. A drawback of these methods is that they take an additional 2–4 weeks to perform after a positive culture is obtained. This delay can be substantially reduced using enriched liquid culture systems. In addition, rapid PCR-based methods have been developed to detect rifampicin resistance, based on detection of frequent mutations of the bacterial RNA polymerase. Other rapid susceptibility tests are in development.
Fig. 4.40 Chest radiograph showing extensive tuberculosis of the left lung with a large upper lung field cavity in a 40-year-old male with smear-positive tuberculosis.
Fig. 4.41 The same patient as seen in Fig. 4.40 after completing antituberculous therapy. Note the healing of cavitary lesion and scarring and fibrosis, with retraction of the trachea to the left.
Radiographic diagnosis In addition to sputum microscopy and culture, chest radiography is commonly done in patients with suspected TB (Fig. 4.39). Active pulmonary TB classically presents with upper lobe involvement on one or both lungs. The apical and posterior segments of the upper lobes are most commonly affected. Active TB is suggested by consolidation, nodular infiltrates, and cavitation. These findings in the right clinical context are highly suggestive of TB although other diseases such as histoplasmosis, aspergillosis, sarcoidosis, and atypical mycobacterial infections can present with similar findings. Illustrative cases are shown in Figs. 4.40–4.43.
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Fig. 4.42 Extensive bilateral patchy infiltrates and a left upper lung cavitary lesion in an adult with tuberculosis infected with human immunodeficiency virus.
Fig. 4.43 Chest radiograph of the patient seen in Fig. 4.42 after completing antituberculous therapy.
Management Combination chemotherapy using the directly observed therapy, short course (DOTS) approach is the standard for TB treatment worldwide, and is highly successful and costeffective. Treatment of patients with drug-susceptible TB with 6 months of chemotherapy using isoniazid (INH), rifampicin, ethambutol, and pyrazinamide for 2 months followed by treatment with INH and rifampicin for 4 months is effective in over 95% of cases when fully administered using the DOTS approach. The DOTS approach (Fig. 4.44) is a comprehensive case management strategy including regular, supervised administration of antiTB drugs, a steady supply of high-quality drugs, systematic
recording of treatment outcomes, and commitment by governments, TB control programs, and caregivers to cure patients with TB. TB is treated with a combination of drugs with different mechanisms of action for a minimum of 6–9 months (Table 4.4). Active TB should never be treated with a single drug, and a single drug should never be added to a failing regimen because of the risk of emergence of drug resistance. Six months of treatment is recommended for patients with drug susceptible disease (Table 4.5). Patients with cavitary pulmonary TB whose sputum cultures are still positive after the first 2 months (intensive phase) of treatment should have
Table 4.4 Dosages of first-line antituberculosis drugs
Drug
Daily dose (maximum dose)
Thrice weekly dose (maximum dose)
Isoniazid
5 mg/kg (300 mg)
10 mg/kg (900 mg)
Rifampicin
10 mg/kg (600 mg)
10 mg/kg (600 mg)
Pyrazinamide
25 mg/kg (2000 mg)
35 mg/kg (3000 mg)
Ethambutol
15 mg/kg (1600 mg)
30 mg/kg (4000 mg)
(Adapted from WHO guidelines, 2004)
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DOTS population coverage (%) Not implementing <10 10–90 91–100
Fig. 4.44 Population coverage (%) of directly observed therapy, short course in 2001. (Adapted from WHO data.)
Table 4.5 Recommended 6 month short course chemotherapy regimen for patients with tuberculosis likely due to drug-susceptible tubercle bacilli
Intensive phase (2 months: kills rapidly dividing bacilli; daily treatment for first 2 weeks, then treatment may be given daily or thrice weekly) • Isoniazid • Rifampicin • Ethambutol • Pyrazinamide
Continuation phase (4 months: may be given daily or thrice weekly) • Isoniazid • Rifampicin • Pyridoxine 25–50 mg/d is frequently given to prevent the development of peripheral neuropathy secondary to isoniazid. This is particularly important in pregnant women and malnourished persons
(Adapted from WHO. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edition, 2003. Document no. WHO/CDS/TB/2003.313)
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their second phase of treatment with INH and rifampicin extended from 4 months to 7 months. Many authorities treat patients with tuberculous meningitis, tuberculous spondylitis, or tuberculous arthritis for 12 months.
Table 4.6 Second-line antituberculous drugs
• Cycloserine • Ethionamide
Multidrug resistant TB
• Para-amino salicylic acid
Multidrug resistant (MDR) -TB is defined as resistance to at least INH and rifampicin, the two most important first-line anti-TB drugs. Globally, MDR-TB is a significant public health issue and high-prevalence areas of MDR-TB occur in all regions of the world. The most important risk factors for MDR-TB are prior TB treatment or living in an area with a high prevalence of MDR-TB. When possible, drug susceptibility testing should be done on initial positive cultures from all patients with newly diagnosed TB and whenever there is evidence of treatment failure, based on lack of clinical response or positive culture after 3 months of treatment. The treatment of MDR-TB requires multiple second-line antituberculous agents (Table 4.6) for an extended period of time, usually 12–18 months after the sputum conversion. Second-line drugs are costly and have frequent side-effects. Suspected cases of MDR-TB should be referred to a specialist center for further management whenever possible.
• Fluoroquinolones (ofloxacin, levofloxacin)
Latent tuberculous infection Some countries and TB programs treat persons found to have latent TB infection (LTBI) (positive TST test without evidence of active TB) with anti-TB drugs to prevent the later development of active TB. Active TB must be excluded prior to beginning treatment of presumed LTBI to prevent the development of drug-resistant TB due to inadequate chemotherapy. Evaluation should include a medical history, physical examination, chest radiograph and, when appropriate, sputum examination and other tests. The recommended regimen for treating LTBI in most adults and children is 6–9 months of INH (5 mg/kg daily, up to 300 mg/day). In compliant patients, INH has been shown to be up to 90% effective for the treatment of latent TB infection. Daily rifampicin (10 mg/kg daily, up to 600 mg/day) for 4 months can be used in those intolerant to INH, or in those potentially infected with INH-resistant strains. Three months of daily INH and rifampicin is another alternative regimen recommended by some national programs. The main toxicity of these regimens is hepatotoxicity. Patients should be told to stop the medication and return to the clinic if they develop nausea, vomiting, abdominal pain, or jaundice.
• Kanamycin or amikacin • Capreomycin
Atypical mycobacteria Several species of pathogenic mycobacteria other than M. tub e rc ulo sis cause disease in humans. These include important human pathogens such as M. avium complex, M. kansasii, M. xenopi, and M. marinum that cause pulmonary disease, lymphadenitis and, less frequently, other extrapulmonary disease. The reader is referred to an excellent review by the British Thoracic Society on the management of atypical mycobacterial infections (Thorax 2000;55:210–218).
Conclusions • TB is a major global health problem. An estimated onethird of the world’s population is infected by M. tuberculosis. Nine million new TB cases and 2 million deaths due to TB occur annually worldwide. • Worldwide, TB is the most common serious opportunistic infection and one of the leading causes of death in persons with HIV/AIDS. • The most common manifestation of TB is pulmonary disease. TB classically presents as an upper lung field fibrocavitary pneumonia in patients with persistent cough for 3 or more weeks. • Sputum AFB smears and cultures are the best diagnostic tests for TB. • Standard 6 month short course chemotherapy with INH, rifampicin, ethambutol, and pyrazinamide given under direct supervision using the DOTS strategy is highly effective for the treatment of TB.
Tuberculosis 99
Further reading American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662. (http://www.thoracic.org/adobe/statements/rr5211.pdf) US national guidelines for TB treatment. Thorough review of the treatment of TB including drug dosing, side-effects, and treatment monitoring. Includes helpful information on the treatment of extrapulmonary TB and treatment of special groups such as children and pregnant women. Exhaustively referenced. Blumberg HM, Leonard MK, Jr., Jasmer RM. Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA 2005;293:2776–2784. Updated information on evolving issues in the treatment of latent TB infection and active tuberculosis. Centers for Disease Control and Prevention. Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitor or nonnucleoside reverse transcriptase inhibitors. Updated January 20, 2004. (http://www.cdc.gov/nchstp/tb/TB_HIV_Drugs/PDF/tbh iv.pdf) Current source of information about use of rifamycincontaining anti-TB treatment regimens in HIV-infected persons receiving highly active antiretroviral therapy (HAART). Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009–1021. Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet 2003;362:887–899. A thorough update on the global TB situation. Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 2004;363:474–481. Important article describing principles and programs needed for successful treatment of MDR-TB. Nachega JB, Chaisson RE. Tuberculosis drug resistance: a global threat. Clin Infect Dis 2003;36:S24–S30.
Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Management of opportunist mycobacterial infections: Joint Tuberculosis Committee Guidelines 1999. Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Thorax 2000;55:210–218. Describes treatment of disease due to nontuberculous mycobacteria. Aziz MA, Wright A, Lazlo A, et al. Epidemiology of antituberculosis drug resistance (the Global Project on Antituberculosis Drug Resistance Surveillance): an updated analysis. Lancet 2006;368:2142–2154. Includes data on the prevalence of drug resistant and MDR-TB from 76 countries and geographical areas. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. Geneva: World Health Organization; 2003. Report No.: WHO/CDS/TB/2003.313. (http://www.who.int/tb/publications/cds_tb_2003_ 313/en/index.html) WHO guidelines for TB treatment for national TB programs using the DOTS strategy. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing: WHO Report 2007. Geneva: World Health Organization; 2007. Report No.: WHO/HTM/TB/2007.376. (http://www.who.int/tb/publications/global_report/2007/ pdf/full.pdf) Report on global TB incidence reported by country and region.
Chapter 5
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Malaria Arlene Dent, MD, PhD and Charles H King, MD, MS, FACP, FRSTMH
Introduction
Etiology and pathogenesis
Malaria is a life-threatening infectious disease caused by apicomplexan protozoan parasites of the genus Plasmodium. Typically, infection is transmitted from person to person via the bite of an intermediate insect vector, i.e. the female Anopheles spp. mosquito. Globally, there are 300–500 million human cases of malaria each year. One to two million deaths result; the majority are among children under the age of 5 years. More children die of malaria than any other infection. These deaths are unwarranted, as malaria is both preventable and treatable. The majority of malaria infections and related deaths occur in sub-Saharan Africa, where the resultant economic burden is estimated to be at least US$12 billion per year in lost GDP. Malaria is frequently a disease of the poor, and its presence serves to perpetuate the cycle of poverty. On a global and national level, past programs to reduce transmission have met with some success, but efforts to eradicate malaria completely have proven unsuccessful. In 1998, The Roll Back Malaria (RBM) program was jointly initiated by the World Health Organization (WHO), the World Bank, the United Nations Development Program, UNICEF, and other agencies, with the goal of halving the world’s burden of malaria by 2010. The RBM program focuses on improving access to effective treatment, preventing malaria in pregnancy through intermittent prophylactic therapy, reducing human–mosquito contact through distribution of insecticide-treated bed nets, and improving access and distribution of antimalarial medications. Nonetheless, recent estimates of global malaria burden have shown increasing levels of malaria morbidity and mortality despite these efforts. Development of infrastructure and distribution of preventative and therapeutic interventions remain significant challenges.
Four species of Plasmodium cause human malarial disease. The four species are P. falciparum, P. vivax, P. ovale, and P. m alariae . P. falc iparum causes the most severe, lifethreatening form of malaria. Human infection with P. knowlesi, a recognized pathogen of non-human primates, has also been described. Plasmodium parasites enter the human host when an infected female Anopheles mosquito takes a blood meal, usually during the evening or nighttime. The sporozoites injected in the mosquito’s saliva enter the bloodstream and travel to the liver, where they infect host hepatocytes (Fig. 5.1). Over the next several weeks, the sporozoites mature into schizont forms. With P. vivax and P. ovale infections, schizonts may remain dormant in hepatocytes as hypnozoites for weeks to months before causing clinical relapses. The infected hepatocyte ruptures, releasing merozoites into the circulation. Merozoites then attach to and invade erythrocytes, where they grow as trophozoites (Fig. 5.2). During the next 48–72 hours, these trophozoites grow into schizonts, which, once mature, reproduce asexually by division. The infected red blood cells burst, releasing multiple daughter merozoites, which continue the erythrocytic infection cycle. A small proportion of infecting parasites differentiate into non-replicating sexual forms known as gametocytes. When gametocytes are ingested in a blood meal taken by a mosquito, the life cycle is completed: sexual reproduction occurs via gametocyte fusion in the mosquito midgut to form an ookinete, whence thousands of infective sporozoites result. These then migrate to the mosquito’s salivary glands, ready for transmission via its next bite (Fig. 5.3). Pathogenesis of the disease has been best described in P. falciparum infection. Malaria symptoms appear 7–14 days
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i
Infective stage
d
Diagnostic stage
Human liver stages Liver cell
Mosquito stages 1 Mosquito takes a blood meal (injects gametocytes)
12 Ruptured oocyst
11 Oocyst
2 Infected liver cell Exo-erythrocyte cycle 4 Ruptured schizont
i
Release of sporozoites
3 Schizont
i
Sporogenic cycle 10 Ookinete
9 Microgamete entering macrogamete
Human blood stages 5
8 Mosquito takes a blood meal (ingests gametocytes)
Immature trophozoite (ring stage) d
Erythrocyte cycle
P. falciparum
Mature trophozoite
6 Ruptured schizont
d d
Exflagellated microgametocyte
Schizont P. vivax P. ovale P. malariae
7 Gametocytes 7 Gametocytes d
Fig. 5.1 Schematic representation of the malaria life cycle. (Adapted from CDC data.)
Fig. 5.3 Female Anopheles mosquito taking a blood meal. (Courtesy of CDC.)
Fig. 5.2 Electron microscopy image of a merozoite attached to a host erythrocyte. (Courtesy of Dr R Salata.)
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after the infectious mosquito bite. The severity of disease is dependent on several factors: high parasite burdens, combined with the propensity of infected erythrocytes to adhere to host endothelium, lead to microvascular occlusion, cytokine release, metabolic derangement, and acidosis, resulting in the clinical manifestations of severe malaria. Common presentations include respiratory distress syndrome, renal insufficiency, severe anemia, and cerebral malaria. Host factors including sickle cell hemoglobin and glucose-6-phosphate dehydrogenase deficiency genetic polymorphisms can modify the severity of malaria, at the risk of host pathology caused by these traits.
Global epidemiology Malaria is one of the most prevalent infections worldwide, with 40% of the world’s population at risk for infection. In addition to children, it is pregnant women (especially primigravidae), and non-immune travelers and foreign workers who are at particular risk for developing severe disease. Political conflicts that cause mass displacement of populations can lead to movement of non-immune people into malaria-endemic regions, which can result in large numbers of cases of acute malaria. The risk of severe
malarial disease increases during malaria epidemics, which can occur with periodic climatic changes. Warm climates with high humidity and high rainfall create conditions favorable to mosquito breeding and survival (Fig. 5.4). Man-made environmental changes (such as agricultural projects and mining) can increase the breeding area of vector anopheline mosquitoes. Malaria has been eradicated from the US, Europe, and Australia. However, these areas remain at risk for reintroduction of the parasite. In non-endemic areas, most cases are attributed to persons returning from endemic areas (‘imported’ malaria). There is also the possibility of an imported case resulting in new, locally-transmitted mosquito-borne cases (‘airport transmission’), and persisting asymptomatic infection can result in congenital malaria or in transmission through blood transfusion or organ transplantation. In the past, chloroquine was a cheap and widely used antimalarial medication, and its prophylactic use was associated with significant declines in regional prevalence. Today, however, resistance to chloroquine is common throughout Africa, Asia, and most of South America. As a result, malaria is re-emerging in many of these areas. Currently, the remaining areas with chloroquine-sensitive malaria are limited to northern parts of Central America.
No malaria Countries with malaria risk
Fig. 5.4 Map of the global distribution of malaria (2003). (Adapted from WHO data.)
Malaria
Resistance to another inexpensive drug, sulfadoxinepyrimethamine (SP), is also increasing dramatically. P. vivax, which was universally chloroquine-sensitive in the past, is now showing emerging chloroquine resistance in Oceania, Myanmar, Guyana, Colombia, and Brazil. Multidrug resistant malaria is, therefore, an emerging problem that now threatens many countries.
Clinical manifestations Malaria symptoms appear 7–14 days after an infectious mosquito bite. In non-immune adults, malaria typically produces fever, shaking chills, headache, vomiting, and other flu-like symptoms. Any fever in a traveler who has visited a malaria-endemic area should be considered to be due to malaria until proven otherwise. Delay in diagnosis and treatment can have devastating consequences. At times, malaria may result in classic fever patterns: P. vivax and P. ovale infections are said to cause ‘tertian’ (every 48 hours) fevers (Fig. 5.5), whereas P. malariae causes quartan (every 72 hours) fevers. P. falciparum has been associated with ‘malignant tertian’ fevers where the pattern is hectic rather than consistent (Fig. 5.6). Paroxysms are associated with the fevers and typically occur in three stages. First, an individual will have ‘cold’ shaking chills, followed by fever to 40ºC or higher, along with systemic symptoms. As the fever resolves, an individual will experience diaphoresis and fatigue. Fever and splenomegaly are commonly found on physical exam. In addition, pallor from hemolytic anemia is noted along with hepatomegaly and abdominal tenderness. The
presence of a rash and lymphadenopathy are not consistent with malaria. Individuals living in malaria-endemic regions can develop partial immunity to malarial disease. Repeated infections produce cellular and humoral immune responses that limit the severity of disease in subsequent infections. Immunity is not fully protective, however. In an ‘immune’ host, the clinical presentation of malaria symptoms is typically less severe when compared to illness in a non-immune person. However, fever is almost always present and may be associated with headache, chilling, or arthralgias. Oftentimes, partially-immune individuals have lower levels of parasitemia and these are associated with fewer symptoms. Although severe acute disease may not occur, recurrent infection can result in severe and chronic anemia. In children, manifestations of clinical malaria are similar to those in adults, but they are not typically associated with classic fever patterns (Table 5.1). Malaria in children can be rapidly progressive or fatal if left untreated. Children who survive an episode of severe malaria may have persistent learning impairment or other neurologic damage. Pregnant women and their fetuses are especially vulnerable to malaria. Malaria in pregnancy can cause perinatal mortality, low birth weight, and severe maternal anemia. Severe malaria is defined by the WHO as malaria parasitemia (usually 5% or higher of circulating red blood cells infected), plus one of the following: prostration (inability to sit up without help), impaired consciousness, respiratory distress or pulmonary edema, seizures, vascular collapse, abnormal bleeding, jaundice, hemoglobinuria, or severe anemia (hemoglobin <50 g/l or hematocrit <15%).
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
am pm am pm am pm am pm am pm am pm am pm
am pm am pm am pm am pm am pm am pm am pm
44
44
43
43
42
42
41
41
40 39
Celsius
Celsius
104
40 39
38
38
37
37
36
36
Fig. 5.5 Pattern of Plasmodium vivax-induced fever. (Adapted from WHO data.)
Fig. 5.6 Pattern of Plasmodium falciparum-induced fever in a patient. (Adapted from WHO data.)
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Table 5.1 Clinical manifestations of malaria in children
Symptoms • General malaise, fatigue, listlessness • Fever, generally high (>40ºC) with no classic fever pattern • Headache • Cough, shortness of breath • Vomiting or loose stools
Physical findings • Mental status changes • Ill appearance, lethargy • Pallor • Tachycardia • Tachypnea, respiratory distress • Hepatosplenomegaly • Dehydration
Complications • Cerebral malaria • Severe anemia • Acute massive hemolysis with renal insufficiency (‘blackwater fever’) • Pulmonary edema/acute respiratory distress syndrome • Metabolic acidosis • Hypoglycemia • Vascular collapse/shock • Death
Fig. 5.7 Child being treated with quinine for severe malaria disease (A) and the same child the next day showing her recovery (B).
A
Mortality from severe malarial disease can exceed 20%, even with optimal management. Individuals with cerebral malaria present with altered consciousness, focal neurologic findings, and seizures, and mortality in these cases can reach 25%; survivors often have residual neurologic deficits. Malaria caused by P. vivax and P. ovale can make children very ill, but these infections rarely cause death in the absence of other disease (Fig. 5.7). Complications that are seen frequently include hepatosplenomegaly (Fig. 5.8), anemia, or late relapse (from liver hypnozoites). P. ovale infection may resolve without treatment. P. m alariae infection can remain asymptomatic for much longer than P. falciparum or P. vivax infections, but can cause nephrotic syndrome.
B
Fig. 5.8 Splenomegaly in a child with malaria in Papua New Guinea.
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Laboratory findings
Diagnosis
Anemia and thrombocytopenia are common in clinically symptomatic malaria. On presentation, the leukocyte count is usually normal or low. Liver function tests may be abnormal, with elevated transaminases and bilirubin. Electrolyte abnormalities including hyponatremia (especially with cerebral malaria) and elevated creatinine may be seen. Hypoglycemia is rare on presentation, but with severe disease and/or therapy with quinine, it may represent a grave complication. Metabolic acidosis is seen with severe disease.
In order to obtain a diagnosis, patients must attend a clinic where blood smears can be obtained. Thick and thin peripheral blood smears stained with Giemsa stain are the ‘gold standard’ for malaria diagnosis. Thick smears have high sensitivity for parasite-infected cells. Thin smears are used to identify the infective Plasmodium species (Figs. 5.9–5.11). Because parasitemia can vary within the host throughout the day, at least three negative blood smears, obtained over a period of 48 hours, are needed to exclude malaria as a diagnosis. Slide examination by a trained
A Fig. 5.9 Plasmodium falciparum ring stage in an erythrocyte. (Courtesy of CDC.)
B
Fig. 5.10 Plasmodium falciparum gametocyte (A) and schizont (B) in blood smears. (Courtesy of CDC.)
Fig. 5.11 Plasmodium vivax schizont in blood smear. (Courtesy of CDC.)
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microscopist is essential for accurate interpretation of blood smears (Fig. 5.12). Clinical laboratories outside of endemic areas may not have sufficiently trained personnel. In the face of negative smears but a positive travel history along with typical clinical symptoms, a high degree of suspicion of malaria needs to be maintained. Alternatives to blood smears include rapid antigen tests and nucleic acid-based diagnostic tests. Rapid antigen detection tests detect parasite proteins in finger-prick blood samples. They are limited by their inability to detect low level parasitemia, their inability to identify infecting Plasm o dium species, and their inability to quantify
parasitemia. Nucleic acid-based tests include polymerase chain reaction (PCR) (Fig. 5.13), ligase chain reaction (LCR), and real time quantitative PCR (Fig. 5.14). These tests have excellent sensitivity and specificity, including species-specific identification. However, they require several steps, including deoxyribonucleic acid (DNA) isolation from blood samples that take additional time to perform, thus eliminating them as ‘quick tests’. Automation may soon shorten the turnaround time for these tests. Nevertheless, antigen detection and nucleic acid-based tests are all expensive and will have little application in resource-poor countries where malaria frequently predominates.
A
B
C
D
E
Fig. 5.13 Polymerase chain reaction gel using Plasmodium falciparum specific primers. P. falciparumspecific DNA was amplified from 3 out of 4 patients with various levels of parasitemia. By blood smear, only 1 patient (lane B) was positive. Lane A is the negative control.
70
Fig. 5.12 Lab technician examining thick and thin blood smears for malaria parasites in a rural clinic.
Fig. 5.14 Comparison of blood smear (BS), polymerase chain reaction (PCR) and real time quantitative PCR (RTQ PCR) in blood samples taken from children of various ages. PCR was more sensitive than BS. Quantitative measurements with RTQ PCR demonstrate that high levels of parasitemia (>10,000 copies of the gene of interest) can be detected in children. (Data courtesy of I Malhotra and CL King.)
Percent positive
60 50 40 30 20 10 0
3–6
7–9
10–12 13–18 19–24 25–36
Age (months) % BS positive % PCR positive % RTQ-PCR >10,000
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Management Antimalarial drugs are the mainstay of treatment for malaria (Figs. 5.15, 5.16). Treatment depends on which Plasmodium species is causing the infection, the geographic area of acquisition (due to prevalence of drug resistance), and the severity of symptoms (requiring parenteral or oral therapy). Tables 5.2 and 5.3 outline the current guidelines for treatment of P. falciparum infection. Treatment for most P. vivax (except in parts of Asia) and P. ovale infection involves a course of chloroquine, followed by 14 days of
primaquine to eradicate liver hypnozoites that cause relapse. P. malariae is usually treated with chloroquine only. In cases of high-level parasitemia, rapid initiation of antimalaria medication is needed. In addition, exchange transfusion should be considered because infection-related progressive hemolytic anemia may be life threatening. The US Centers for Disease Control and Prevention (CDC) has a malaria hotline with recommendations for malaria treatment at (404)332-4555 or www.cdc.gov.
Table 5.2 Drug treatment of severe Plasmodium falciparum malaria
Drug Quinidine gluconate
Adult dosage 10 mg/kg loading dose IV over 1–2 hr followed by basal 0.02 mg/kg/min until oral therapy can be started
Pediatric dosage Same as adult
Comments Continuous EKG, blood pressure, and glucose monitoring are needed
Quinine dihydrochloride
20 mg/kg loading dose in 5% dextrose IV over 4 hr followed by 10 mg/kg over 2–4 hr q 8 hr (max 1800 mg/d) until oral therapy can be started
Same as adult
Not available in the US but common in other countries. Adverse effects include hypoglycemia, tinnitus, dizziness, and gastrointestinal disturbances
Artemether
3.2 mg/kg IM, then 1.6 mg/kg daily x5–7 d
Same as adult
Not available in the US
(Adapted from Drugs for Parasitic Infections. Med Lett Drugs Ther August 2004; Epub:1. Available online at www.medicalletter.org)
Fig. 5.15 Dispensing antimalarial medications during a treatment time-to-reinfection study among Papua New Guinean school children.
Fig. 5.16 Antimalarial medications in a rural Kenyan clinic. Less than optimal storage conditions may limit potency and efficacy of available drugs.
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Table 5.3 Oral drug treatment for uncomplicated Plasmodium falciparum malaria Drug
Adult dosage
Pediatric dosage
Comments
Quinine sulfate plus Doxycycline or Tetracycline or Pyrimethamine-sulfadoxine
650 mg q 8 hr x3-7 d 100 mg q 12 hr x7 d 250 mg q 6 hr x7 d 3 tablets on last day of quinine
30 mg/kg/d div q 8 hr x3-7 d 4 mg/kg/d div q 12 hr x7 d 6.25 mg/kg q 6 hr x7 d <1 yr: 1/4 tablet 1–3 yr: 1/2 tablet 4–8 yr: 1 tablet 9–14 yr: 2 tablets on last day of quinine
Doxycycline and tetracycline are not recommended in children under 8 years of age (because of tooth staining) unless alternatives are unavailable. Quinine not available in US
Mefloquine
750 mg then 500 mg 12 hr later
If <45 kg: 15 mg/kg followed by 10 mg/kg 12 hr later
Mefloquine resistance must be considered with travel to certain areas of southeast Asia
Artesunate plus Mefloquine
4 mg/kg/d x3 d 750 mg then 500 mg 12 hr later
Same as adult If <45 kg: 15 mg/kg followed by 10 mg/kg 12 hr later
Artesunate not available in US
Atovaquone/proguanil
4 tablets q d x3 d
11–20 kg: 1 tablet x3 d 21–30 kg: 2 tablets x3 d 31–40 kg: 3 tablets x3 d >40 kg: 4 tablets x3 d
All doses in adult tablet formulation (250 mg atovaquone/100 mg proguanil)
Artemether (20 mg)/ lumefantrine (120 mg)
4 tablets x 6 doses at times 0 then 8 hr, 24 hr, 36 hr, 48 hr, and 60 hr after
10–14 kg 1 tablet 15–24 kg 2 tablets 25–34 kg 3 tablets >34 kg 4 tablets
Not available in the US, but recommended by WHO
Chloroquine phosphate
1 g (600 mg base) then 500 mg 6–12 hr later, followed by 500 mg/d x2 d
10 mg base/kg (max 600 mg base) then 5 mg base/kg 6–12 hr later, followed by 5 mg base/kg/d x2 d
Only for infections acquired in chloroquine sensitive areas
Primaquine phosphate (for use with Plasmodium vivax, or P. ovale infections in addition to treating with above medications)
30 mg base/d x14 d
0.6 mg base/kg/d (max 30 mg base/d) x14 d
Screen for G6PD deficiency before giving primaquine
G6PD: glucose-6-phosphate dehydrogenase (Shortened and adapted from Drugs for Parasitic Infections. Med Lett Drugs Ther August 2004; Epub:1. Available online at www.medicalletter.org)
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Prevention Most malaria-carrying mosquitoes bite at night. Use of indoor spraying and bed nets impregnated with pyrethroid insecticide can dramatically reduce death and illness due to malaria (Figs. 5.17–5.20). Repeated insecticide treatment is needed every 6 months to maintain full efficacy. However, studies show that even under non-optimal conditions, bed nets are still beneficial even 6 years after their introduction. Researchers are working to make long-lasting treated nets. Campaigns to promote bed net use, manufacture, and distribution are critical to reducing the impact of malaria, but resources must be used wisely (Fig. 5.21). Malaria is a disease of great importance to public health. It affects primarily poor and rural populations; those who live in
developed regions have significantly decreased incidence of malaria. Research for malaria prevention is now focused on developing antimalarial vaccines. A number of malaria antigens are being investigated as potential vaccine candidates. Several are in clinical trials in endemic countries. These experimental vaccines target either the preerythrocytic or erythrocytic stage of the malaria life-cycle. Although results of some trials are promising, a commercially-available vaccine will take at least 10 years to develop. Vaccine-associated immunity may prove only partial, but could limit the severity of disease, especially in children. Non-immune individuals traveling to malaria-endemic
Table 5.4 Drug prophylaxis for prevention of Plasmodium falciparum malaria
Drug
Adult dosage
Pediatric dosage
Comments
Mefloquine
250 mg PO q wk
If <10 kg: 5 mg/kg 10–19 kg: 1/4 tablet 20–30 kg: 1/2 tablet 31–45 kg: 3/4 tablet >45 kg: 1 tablet
Beginning 1–2 weeks before travel, continuing through travel time and for 4 weeks after leaving malaria-endemic areas. Can have neuropsychiatric adverse effects
Atovaquone/proguanil
250 mg/100 mg (1 tablet) PO daily
11–20 kg: 1/4 tablet 21–30 kg: 1/2 tablet 31–40 kg: 3/4 tablet >40 kg: 1 tablet
Beginning 1–2 days before travel, continuing through travel time and for 7 days after leaving malaria-endemic areas. Pediatric tablets are available. 1 pediatric tablet = 1/4 adult tablet
Doxycycline
100 mg PO daily
2 mg/kg/d (max 100 mg)
Adverse effects include photosensitivity. Not for use in children <8 years of age
Chloroquine phosphate
500 mg (300 mg base) PO q wk
5 mg base/kg (up to 300 mg base) PO q wk
Only for travel to chloroquinesensitive areas, of which there are few
(Adapted from Drugs for Parasitic Infections. Med Lett Drugs Ther August 2004; Epub:1. Available online at www.medicalletter.org)
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areas should be instructed to take prophylactic medication (described in Table 5.4). They should also avoid mosquito bites by wearing topical insecticides containing 20–30% diethyltoluamide (DEET), wearing clothing with long sleeves, and sleeping under permethrin-treated bed nets. Without protection, in those areas holoendemic for malaria, a person may have one or more bites from a Plasmodiuminfected mosquito every night.
Fig. 5.17 Dipping bed nets in synthetic pyrethroid insecticide.
Fig. 5.18 Bed net recently treated with pyrethroid insecticide.
Fig. 5.20 Spraying a house with insecticide. It is more critical that inside walls are also sprayed.
Fig. 5.19 Kenyan women with recently treated insecticide bed nets drying in the shade. Sun exposure can detrimentally affect insecticide.
Fig. 5.21 As part of an NGO program to prevent mosquitoes from entering a dwelling, screens were placed on all the windows. However, the gap between the top of the wall and the ceiling was not addressed, resulting in ineffective preventative measures and waste of resources. (Courtesy of M Van Dyke.)
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Illustrative cases Case 1: In Uganda, a 6-year-old girl is carried into the clinic by her mother. Her mother states that the child was hot for the past two nights and has a cough. Last night, the child was more sleepy than usual and went to sleep early in the evening. This morning, she was difficult to arouse. This child has had malaria in the past but has been otherwise healthy. She does not go to school, but helps her mother take care of younger children at home. She has taken no medication. Table 5.5 shows the results of her exam. The patient was started on intravenous quinine, and after
1.5 days had improvement in her mental status (Fig. 5.22). On the second day, she began to eat, and her intravenous quinine was changed to oral quinine. No neurological deficits were apparent at this time. Comments: Cerebral malaria is a serious complication of P. falciparum infection. The course is often complicated by hypoglycemia. Aggressive therapy with close monitoring is essential, as cerebral inflammation can potentiate cerebral herniation and death.
Table 5.5 Results from examination of Case 1
Physical exam Temperature 40.2°C Heart rate 120/min Respiratory rate 30/min Blood pressure 102/67 mmHg Observations Patient is lying in her mother’s arms with eyes closed She withdraws to pain but does not open her eyes or talk Cardiac exam II/VI systolic flow murmur Lung exam normal Abdomen benign No lymphadenopathy or rash Laboratory studies Blood smear positive for many malarial forms Cerebrospinal fluid studies WBC 14 x 106/l RBC 2 x 106/l Glucose 35 mg/dl (1.94 mmol/l) Protein 40 mg/dl (0.4 g/l) 1+ Plasmodium on smear Spinal fluid bacterial cultures negative
Fig. 5.22 A 6-year-old Ugandan girl recovering from cerebral malaria.
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Case 2: A 20-year-old male college student from the midwestern US presents in early December with headache, fever, and malaise. His symptoms began after a basketball game, where he felt as if he had no energy. He has had fever and night sweats, and complains chiefly of a frontal headache. He traveled to India for 2 months over the summer but stated that he took his malarial prophylaxis. During that trip, he experienced two episodes of non-bloody diarrhea that spontaneously resolved after 4–6 days. His past medical history is insignificant. He takes no routine medications, but has been taking ibuprofen for his headache with little relief. Table 5.6 shows the results of his exam. After this initial evaluation, the patient was discharged with a diagnosis of viral infection. Two days later, he loses consciousness in class. Upon readmission to the hospital, his hemoglobin has dropped to 115 g/l. A thick and thin smear showed 5% Plasmodium parasitemia, with an appearance consistent with P. vivax. He was treated with intravenous quinidine followed by 14 days of primaquine, and makes a complete recovery.
Comments: Malaria prophylaxis is never 100% effective, and can be difficult to take consistently. For example, for its maximal effect, atovaquone/proguanil should be taken at the same time each day with a fatty meal. In addition, P. vivax has a medication-resistant liver hypnozoite form that can remain dormant for a number of months. Travel history (for at least the past year) is germane and should be included in the history. In addition, while it is important to treat this patient with antimalarial medications to eradicate the blood stage parasites, at the end of the treatment for acute malaria, it is also necessary to treat with 2 weeks of primaquine to eliminate any remaining hypnozoites.
Table 5.6 Results from examination of Case 2
Physical exam Temperature 37.2°C Heart rate 88/min Respiratory rate 20/min Blood pressure 110/70 mmHg Observations Patient appears mildly ill Cooperative with the examination Heart and lung exams are within normal limits No lymphadenopathy No hepatosplenomegaly, but mild abdominal pain Laboratory studies WBC 7.2 x 109/l Hemoglobin 145 g/l Platelet count 200 x 109/l Serologies are negative for HIV, EBV, CMV Blood culture negative
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Case 3: An 8-year-old Kenyan boy is brought to the clinic for evaluation. His aunt states that he has had fever every few days for the last week. He is more tired than usual, and is not eating as much as his younger siblings. When he was 3 years old, his mother died of tuberculosis. He was treated for bacterial pneumonia 1 year ago. Table 5.7 shows the results of his exam. Comments: This case represents the complex presentation of mixed symptoms and findings that is typical in a
developing country. Many malaria-endemic countries also have a high prevalence of human immunodeficiency virus (HIV) infection. Malaria is not considered an opportunistic infection for HIV-positive individuals. However, research shows that individuals with HIV may have more symptoms with their malaria infections. In children who have mild symptoms, or symptoms more likely related to another coinfection, malaria should still be treated if parasites are visualized on peripheral smear or malaria is clinically suspected.
Table 5.7 Results from examination of Case 3
Physical exam Temperature 37°C Heart rate 130/min Respiratory rate 24/min Blood pressure 107/70 mmHg Observations This mildly ill-appearing, thin child sits in his aunt’s lap Exam is remarkable for conjunctival and oropharyngeal pallor, angular stomatitis, and diffuse lymphadenopathy of the cervical and inguinal, but not axillary regions Heart exam II/VI systolic flow murmur Lung exam clear Abdominal exam significant for splenomegaly 3 cm below the left costal margin. Herpes zoster scars with keloid formation are noted along the left flank above his iliac crest in the distribution of the T10 dermatome. When asked, his aunt states that they had been there for at least the last 2 years but could not remember exactly when they occurred Laboratory examination WBC 3.6 x 109/l Hemoglobin 93 g/l Platelets 180 x 109/l Blood smear positive for Plasmodium forms HIV ELISA test positive
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Conclusions • 1–2 million people, mostly children, die from malaria each year. • High-risk groups include pregnant women, young children, non-immune travelers, refugees, and other persons displaced into malaria-endemic areas. • African countries have the greatest burden of malarial disease, resulting in enormous economic loss that perpetuates the cycle of poverty. • Malaria is transmitted through evening/night-biting female Anopheles mosquitoes. • Prevention is essential in reducing the malaria disease burden.
Further reading Armitage KB, King CH. Malaria. In: Expert Guide to Infectious Diseases. American College of Physicians, Philadelphia, 2002, pp. 803–817. Chotivanich K, Udomsangpetch R, Simpson JA, et al. Parasite multiplication potential and the severity of Falciparum malaria. J Infect Dis 2000;181:1206–1209. Documenting the link between parasite growth rate and risk for disease. Drugs for parasitic infections. Med Lett Drugs Ther, August 2004. Available online at www.medicalletter.org. Consensus recommendations from independent experts for drug choice and dosing in malaria therapy. Krogstad DJ. Malaria. In: Tropical Infectious Diseases: Principles, Pathogens & Practice. Guerrant RL, Walker DH, Weller PF (eds). Churchill Livingstone, Philadelphia, 1999, pp. 736–766.
Maitland K, Nadel S, Pollard AJ, Williams TN, Newton CR, Levin M. Management of severe malaria in children: proposed guidelines for the United Kingdom. BMJ 2005;331:337–343. Systematic approach to the diagnosis and treatment of severe childhood malaria. Mehlotra RK, Lorry K, Kastens W, e t al. Random distribution of mixed species malaria infections in Papua New Guinea. Am J Trop Med Hyg 2000;62:225–231. PCR te sting no w indic ate s an unsuspe c te d high pre vale nc e o f c o nc urre nt, m ultispe c ie s Plasmodium infections. Schlagenhauf-Lawlor P (ed). Travelers’ Malaria. 2001, BC Decker, London. Schofield L, Grau GE. Immunological processes in malaria pathogenesis. Nat Rev Immunol 2005;5:722–735. This article details the innate and adaptive immune mechanisms that either cause or prevent disease in malarial infections. White NJ. Malaria. In: Manson’s Tropical Diseases. Zumla A, Cook GC (eds). 2003, WB Saunders Co, Philadelphia, pp. 1205–1295. Whitty CJ, Edmonds S, Mutabingwa TK. Malaria in pregnancy. BJOG 2005;112:1189–1195. Detailed review of the complex features of malaria in pregnancy, including recommendations for treatment and prophylaxis.
Chapter 6
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Diarrheal disease Keith B Armitage, MD and Dalia El-Bejjani, MD
Introduction Infectious diarrhea is a disease of historical significance, and continues to be an important clinical problem in a variety of settings. Worldwide diarrhea accounts for more than 2 million deaths annually, and continues to be a significant contributor to childhood mortality in the developing world. In developed countries, new and emerging pathogens such as Escherichia coli 0157:H7 and large-scale outbreaks of viral gastroenteritis have focused media attention on diarrheal illnesses and have stimulated scientific inquiry. In the United States, an estimated 210 to 375 million episodes of acute diarrhea occur each year, and these episodes are associated with more than 900,000 hospitalizations and 6000 deaths annually. The cost for all food-borne illness in the United States is estimated at over 30 billion dollars. Diarrhea remains the most common illness in travelers from industrialized countries to the developing world. Recent developments include the recognition of new and emerging pathogens, a greater understanding of the pathogenesis of some conditions, and a changing epidemiology and prevalence of enteric pathogens. Clostridium difficile-associated diarrhea (CDAD) is epidemic in health care settings in many parts of the world, with an apparent increasing prevalence and lethality. Antibiotic resistance among enteric pathogens is a growing problem worldwide, limiting treatment options for bacterial pathogens for travelers and other patients. In the western world, epidemics of noroviruses (the newer name for the ‘Norwalk’ family of caliciviruses) are increasingly well documented, and our understanding of factors in susceptibility and pathogenesis of this family of viruses is growing. New and emerging protozoan pathogens such as Cyclospora and Cryptosporidium are increasingly recognized
in travelers and domestic outbreaks. In the United States, food-borne diarrheal illness continues to impose a significant burden of disease. In this chapter we will review significant recent literature that highlights these and other developments in infectious diarrhea.
Clostridium difficile Although Clostridium difficile has been recognized as the cause of CDAD for many years, recent evidence of a significantly increasing prevalence of illness due to C. difficile makes this truly an emerging infection. Antibiotic-associated colitis has been recognized since the advent of the antibiotic era, and C. difficile was originally reported as an agent of antibiotic-associated diarrhea in 1977. The gastrointestinal tract hosts a very complex ecosystem of microbes that act as a barrier against microbial pathogens. C. difficile diarrhea results from the suppression of the normal flora in the colon, which allows overgrowth of C. difficile and production of cytopathic toxins. C. dfficile is a Gram-positive, sporeforming rod (Figs. 6.1, 6.2). In the modern era, C. difficile is recognized as a major cause of antibiotic-associated diarrhea, the basis for >99% of pseudomembranous colitis (Figs. 6.3, 6.4), and the leading cause of diarrhea in hospitalized patients. In most cases, CDAD produces an inflammatory diarrhea, with the stool positive for fecal leukocytes (Fig. 6.5). Recent reports have provided evidence of an epidemic of CDAD in North America1. The study from Sherbrooke, Quebec is the most recent large study to examine the population-based incidence of CDAD. The authors demonstrate an increase in the incidence of
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Fig. 6.1 Gram stain of Clostridium difficile demonstrating Gram-positive, spore-forming rods. C. difficile-associated diarrhea is epidemic in hospitals in North America. (Courtesy of Dr D Bobak.)
Fig. 6.2 Spores of Clostridium difficile. The spores play an important role in hospital epidemics as they may exist for long periods of time in harsh environmental conditions in the hospital, and patients may become colonized. (Courtesy of Dr R Salata.)
Fig. 6.3 Endoscopic examination revealing psueodomembranes. Pseudomembraneous colitis occurs in a subset of patients with Clostridium difficile-associated diarrhea (CDAD). Lower endoscopy revealing pseudomembranes is pathognomonic for CDAD. (Courtesy of Dr R Salata.)
1
1
Fig. 6.4 CT scan showing dilated and thickened colon (arrow, colon wall; 1, pericolonic fat). Most patients with Clostridium difficile-associated diarrhea (CDAD) do not have pseudomembranes, but when they are seen on a CT in a patient with CDAD the appearance on the CT scan can establish the diagnosis. (Courtesy of Dr R Salata.)
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Fig. 6.5 Stool prep showing abundant fecal leukocytes from a patient with Clostridium difficile-associated diarrhea (CDAD). Fecal leukocytes are usually present in CDAD, and in patients with inflammatory colitis from bacterial pathogens such as Salmonella, Campylobacter and Shigella. Pathogens that produce illness without producing intestinal inflammation are not associated with fecal leukocytes. Pathogens that typically produce diarrheal illness without fecal leukocytes include viruses, enterotoxigenic Escherichia coli, cholera, Giardia, Cryptosporidium, and Cyclospora. (Courtesy of Dr R Salata.)
CDAD over the past decade, with a striking increase in the number of cases in elderly patients in 2003. Their report also provides evidence that the mortality associated with CDAD has increased, particularly among the elderly. Increasing nosocomial spread, changing patterns of antibiotic use, spread of more pathogenic C. difficile strains, and higher numbers of immunocompromised patients are cited as reasons for the increase. The authors also reported evidence that CDAD may be becoming a more lethal disease; in their study the proportion of patients who died within 30 days of the diagnosis increased to 13.8% in 2003 from 4.7% in 1991. Many experts believe that the incidence of more severe cases of CDAD represents clonal expansion of more lethal strains. We anticipate that publications addressing this issue will appear in the near future. These authors also found an association between a better outcome and vancomycin as the initial therapy in severe cases. Further studies specifically designed to address this issue are needed.
A final emerging issue with CDAD is the association with classes of antibiotics not previously associated with CDAD. Clindamycin was the classic antibiotic associated with illness due to C. difficile and, in recent years, beta-lactams, particularly advanced generation cephalosporins, and betalactam/beta-lactamase inhibitor combinations have been frequently implicated in CDAD. The common theme among antibiotics associated with CDAD is antimicrobial activity against intestinal anaerobes but no activity against C. difficile. Antibiotics whose antimicrobial spectrum does not include robust activity against gut anaerobes are much less frequently associated with CDAD. Ciprofloxacin was the first fluoroquinolone to gain widespread clinical use. There have been case reports associating ciprofloxacin with CDAD, but clinical experience and published data have not implicated ciprofloxacin as a frequent cause of CDAD. Beginning in the late 1990s, advanced generation quinolones, including levofloxacin, gatifloxacin, and moxyfloxacin, gained widespread use for a variety of infections. Unlike ciprofloxacin, the advanced generation fluoroquinolones have broader activity against anaerobes, and clinical experience and anecdotal reports associating the new quinolones with CDAD have been reported. Several recent papers have demonstrated that fluoroquinolone use was strongly associated with CDAD2. The advanced generation fluoroquinolones are active against anaerobes but lack activity against C. difficile.
Travelers’ diarrhea Between 20% and 50% of individuals traveling to developing countries will develop diarrhea during or shortly after their trip. The risk is highest when traveling to India, Latin America, Africa, the Middle East, and south Asia. The average duration of an episode of travelers’ diarrhea is 3–6 days. About 10% of episodes last longer than 1 week. Basic precautions, such as avoidance of unsafe water and uncooked food, can significantly decrease the risk of diarrhea in travelers. Water or food from street vendors, for instance, is among potential high-risk exposures (Fig. 6.6). An emerging issue with travelers’ diarrhea is the possible association with post-diarrhea irritable bowel syndrome (IBS), which could potentially alter the strategy for preventing and treating travelers’ diarrhea. The most commonly used strategy for short-term visitors to developing countries is to provide an antibiotic for
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Fig. 6.6 Street vendor in a developing country. The basic principle in avoiding travelers’ diarrhea is to drink only water that is bottled or boiled, and eat only cooked food except fruits with intact skin that the traveler peels. Ice, water, or uncooked food from street vendors is a high-risk for enteric pathogens. (Courtesy of Dr R Salata.)
Fig. 6.7 Gram stain of a stool from a patient with Campylobacter, demonstrating curved Gram-negative rods and inflammatory cells. In a stool specimen, Campylobacter has a similar appearance to Vibrio cholera; however, V. cholera does not produce an inflammatory diarrhea and fecal leukocytes are not seen in stool preparations in patients with cholera. (Courtesy of Dr D Bobak.)
‘presumptive therapy’, to be taken if diarrhea develops. Presumptive therapy has been shown to be effective in clinical trials in quickly attenuating and resolving the diarrhea. This strategy has the advantage of limiting antibiotic use to those travelers that develop diarrhea. Travelers’ diarrhea treated with this strategy is thought to be self-limited with no significant long-term consequences. In the past 20 years a number of studies have associated acute bacterial gastroenteritis with the subsequent development of IBS. It is hypothesized that infectious gastroenteritis might cause chronic low-grade inflammation of the gastrointestinal tract leading to IBS. IBS complicating otherwise self-limited travelers’ diarrhea has been reported, but the incidence and prevalence of IBS complicating travelers’ diarrhea are not known. A recent study looked prospectively at the incidence of IBS 6 months after an episode of travelers’ diarrhea3. The authors show that infectious gastroenteritis is a potential risk factor for IBS but fail to demonstrate an association with a specific pathogen. Further studies with longer duration of follow-up are needed to evaluate the natural course of postinfectious IBS. The authors do not want to overstate the potential association between IBS and travelers’ diarrhea, but include it as an emerging issue. The potential for post-travelers’ diarrhea IBS may cause
a re-evaluation of presumptive therapy. The availability of effective new luminal agents may make a preventive strategy more feasible. Rifaximin, a luminal, gastrointestinalselective oral antibiotic, was approved for the treatment of travelers’ diarrhea in 2004. Rifaximin is primarily indicated for enterotoxigenic E. coli (ETEC) in travelers to developing countries (Fig. 6.6). ETEC is the most frequent bacterial cause of travelers’ diarrhea worldwide and especially in Latin America. It usually causes a secretory-type diarrhea through its heat-labile toxin, which structurally resembles the cholera toxin. Diarrhea due to ETEC usually responds to treatment with quinolones, trimethoprim sulfa, and cephalosporins. Rifaximin is an alternative therapy for travelers’ diarrhea due to E. coli (the most common pathogen), but has limited activity against other common pathogens. A recent randomized, double-blind, placebocontrolled trial by DuPont et al. looked at efficacy of rifaximin in preventing travelers’ diarrhea in US students visiting Mexico5. This study showed that rifaximin significantly prevented diarrhea as compared to placebo; it was also found to be well tolerated with minimal effect on enteric flora. More studies are under way to evaluate the role of rifaximin in areas of the world where ETEC is not the most frequent isolate.
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Fig. 6.8 Micrograph of Salmonella, demonstrating flagella, which allow the organism motility. (Courtesy of Dr R Salata.)
Antimicrobial resistance has not become a major issue in ETEC, but is an emerging issue with Salmonella and Campylobacter, the second and third most common bacterial causes of travelers’ diarrhea. Travel is a risk factor for infection with quinolone-resistant Campylobacter. Illness due to Campylobacter usually produces a non-specific inflammatory diarrhea. Wet prep of stools from patients with Campylobacter may reveal bacteria resembling cholera, but can be differentiated from cholera by the presence of fecal leukocytes and a different clinical presentation (Fig. 6.7). Campylobacter is the most common antecedent infection in patients with Guillain–Barré syndrome (GBS); GBS is uncommon in patients with Campylobacter, but almost half of all GBS patients have serologic evidence of recent Campylobacter infection. Salmonella species (Fig. 6.8) are becoming increasingly resistant to quinolones and other antibiotics. Antimicrobial resistance is also an emerging issue with shigellosis; Shigella is a less common cause of travelers’ diarrhea, but may cause severe dysentery. Patients with classic dysentery have tenesmus and frequent small, bloody stools (Fig. 6.9). Shigella infection can also lead to a toxic megacolon, characterized by ileus and marked dilatation of the colon (Figs. 6.10, 6.11).
Fig. 6.9 Wet prep of stool from a patient with shigellosis. Note the presence of fecal leukocytes and red blood cells. Patients with dysentery produce stools with blood and mucus, reflecting marked colonic mucosal inflammation. (Courtesy of Dr R Salata.)
Fig. 6.10 Abdominal plain film showing marked distended colon, in a patient with toxic megacolon due to Shigella. Toxic megacolon can be seen in other conditions, including illness due to Entamoeba histolytica and Clostridium difficile-associated diarrhea. (Courtesy of Dr R Salata.)
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Fig. 6.11 Sigmoidoscopy revealing severe hemorrhagic colitis in a patient infected with shigellosis. Shigella are transmitted from human to human by fecal contamination, with no animal reservoir. In developing countries, most bacterial pathogens that produce gastroenteritis arise from agricultural sources, and shigellosis is uncommon. (Courtesy of Dr R Salata.)
Fig. 6.12 Wet prep of stool in a patient infected with Entamoeba histolytica, demonstrating E. histolytica cysts. The diagnosis of intestinal amebiasis is made by identification of E. histolytica in the stool. (Courtesy of Dr R Salata.)
Figs. 6.13, 6.14 Wet prep of stool in a patient infected with Giardia lamblia. Traditionally, the diagnosis of giardiasis was made by microscopic exam of stools. Recently, antigen tests have been introduced that are used to identify Giardia in stool. These tests are less reliant on the expertise of the individual examining the stool, have increased sensitivity, and can be done quickly. (6.13 courtesy of Dr R Salata; 6.14 courtesy of Dr D Bobak.)
Toxic megacolon can also be seen in infection with Entamoeba histolytica , a protozoan pathogen also seen in travelers, though much less often than bacterial pathogens or Giardia (see below). Infection by E. histolytica occurs by ingestion of mature cysts in fecally contaminated food, water, or hands. Because of the protection conferred by their walls, the cysts can survive days to weeks in the external
environment and are responsible for transmission. In industrialized countries, risk groups include male homosexuals, travelers and recent immigrants, and institutionalized populations. Infection with E. histolytica produces a wide range of clinical presentations, from asymptomatic infection, to invasive intestinal amebiasis (dysentery, colitis, appendicitis, toxic megacolon,
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amebomas), to invasive extraintestinal amebiasis (liver abscess, peritonitis, pleuropulmonary abscess, cutaneous and genital amebic lesions). The diagnosis can be made by examination of a wet prep of stool (Fig. 6.12), but caution must be taken to distinguish E. histolytica from other nonpathogenic protozoa. For asymptomatic infections, iodoquinol, paromomycin, or diloxanide furoate (not commercially available in the US) are the drugs of choice. For symptomatic intestinal disease or extraintestinal infections (e.g. hepatic abscess), the drugs of choice are metronidazole or tinidazole, immediately followed by treatment with iodoquinol, paromomycin, or diloxanide furoate. Nitazoxanide, discussed below, is a new agent recently approved for treating diarrhea due to E. histolytica.
Giardia Giardiasis is an emerging cause of persistent, non-bloody diarrhea in returning travelers. Giardia lamblia is prevalent throughout much of the developing world. Latin America is the most common site of Giardia acquisition, reflecting the relative frequency of American travelers. Homosexual men also have a high prevalence of infection because of specific sexual practices. The diagnosis can be made by a stool
Figs. 6.15, 6.16 Small-bowel biopsies from patients with cryptosporidiosis. Cryptosporidium infects small-bowel enterocytes, but does not cause cell death or invade the mucosa. The result of enterocyte infection is malabsorption of water and solutes, leading to voluminous watery diarrhea, with no inflammatory cells. (Courtesy of Dr R Salata.)
antigen test; examination of a stool may also demonstrate the organism (Figs. 6.13, 6.14). The drug of choice for adults is metronidazole, 500–750 mg three times a day for 7 days. Nitazoxanide (Alinia), approved for use in the United States in 2002, is an emerging new alternative for treating Giardia and Cryptosporidium parvum (500 mg every 12 hours for 3 days).
Cryptosporidium Cryptosporidium is a protozoan parasite that was first described in 1976 but became increasingly important in the 1980s with the advent of the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic, and in the last decade has become established as a cause of travelers’ diarrhea8. Cryptosporidium infects humans via ingestion of the robust oocysts shed in the environment from infected animals (human-to-human transmission occurs less often). Cryptosporidiosis is a smallbowel disease, producing a watery, non-inflammatory diarrhea (Figs. 6.15, 6.16). The diagnosis can be made by acid-fast examination of stool (Figs. 6.17, 6.18). This illness causes a self-limited gastroenteritis in immunocompetent hosts. In immunocompromised hosts or
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Figs. 6.17, 6.18 Acid-fast stain of stool revealing Cryptosporidium oocysts. Routine ova and parasite exams will miss Cryptosporidium, and acid-fast staining is usually required to make the diagnosis. Diagnostic tools using antigen tests are becoming available. (6.17 courtesy of Dr R Salata.)
patients receiving immunosuppressive therapy, infection with Cryptosporidium causes profuse and persistent/recurrent diarrhea leading to profound weight loss and wasting. Until recently no treatment was consistently effective as far as parasitological or even clinical response, especially in HIVinfected patients with CD4+
treatment of drinking water, which has been shown to prevent Cryptosporidium oocysts from retaining their infectivity potential.
Cyclospora Cyclospora cayetanensis is a unicellular coccidian parasite that has emerged in the past decade as a cause of diarrhea in developing countries and among travelers (Fig. 6.19). Outbreaks of cyclosporiasis have been reported in the United States and Canada, most often in association with food imported from Central and South America, particularly raspberries, but other fresh fruits and vegetables have been implicated10. Person-to-person transmission is very uncommon, as Cyclospora requires time to become infectious after a passed bowel movement. Like Giardia and Cryptosporidium, Cyclospora infects the small bowel and produces watery diarrhea. Other symptoms of Cyclospora infection include loss of appetite, substantial weight loss, bloating, increased gas, stomach cramps, nausea, vomiting, prolonged fatigue, muscle aches, and low-grade fever. Signs of systemic inflammation are absent, as are fecal leukocytes. The incubation period is about 1 week. Symptoms typically last for a few weeks, but may persist much longer in some individuals.
Diarrheal disease 125 Fig. 6.19 Diagram demonstrating the life cycle of Cyclospora, an emerging pathogen in travelers and in patients consuming imported fresh produce from Central and South America. (Courtesy of Dr R Salata.)
5 Ingestion of contaminated food/water Sporulated oocyst Infective stage
Raspberries
4 Sporulated oocysts enter the food chain Water
Basil
3 Oocyst sporulation in the environment
2 Environmental contamination
1 Unsporulated oocyst
Excretion of Diagnostic unsporulated stage oocysts in the stool 7 Unsporulated ocyst Sexual
Asexual 6 Excystation
Zygote
The diagnosis can be made by microscopic examination of stool, and may be aided by acid-fast staining (Figs. 6.20, 6.21). Infection with Cyclospora responds to therapy with trimethoprim–sulfamethoxizole; Alinia may be an alternative in sulfa intolerant individuals, but this is not certain, and there are no known alternatives. The risk to travelers varies by region and season. For instance, in Nepal, the risk is highest during the rainy season, when Cyclospora may be responsible for one-third of all cases of travelers’ diarrhea. Fig. 6.20 Wet prep of stool revealing Cyclospora. Infection with Cyclospora can produce prolonged diarrhea. (Courtesy of Dr R Salata.)
Meront Meront II I
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Cholera
Fig. 6.21 Acid-fast stain of stool revealing Cyclospora oocysts. Infection with Cyclospora can produce longlasting non-inflammatory diarrhea, and responds to therapy with trimethoprim–sulfamethoxizole. (Courtesy of Dr D Bobak.)
Cholera is endemic in parts of Asia and Africa, and has returned to South and Central America, where it is a major concern to travelers (Fig. 6.22). It still causes outbreaks mostly in developing countries and other areas of the world where public health structures are disrupted11. Vibrio cholera is the infecting agent and the illness is caused by serogroups Ol and O139. The El Tor biotype, of the Ol serogroup, is the most frequent worldwide (Fig. 6.22). Illness due to cholera is mediated by an enterotoxin, which leads to severe secretory diarrhea and rapid progression to dehydration and hypovolemic shock. Severely affected patients may have almost continuous watery diarrhea, leading to the use of the ‘cholera cot’ (Fig. 6.23). Diarrhea due to cholera is noninflammatory; examination of the stool reveals an absence of blood and leukocytes, with the presence of many curved Gram-negative rods. Treatment is supportive with aggressive volume repletion, ideally the oral rehydration
Countries with imported cholera cases Countries with reported cholera cases
Fig. 6.22 Map showing the distribution of cholera in 2004–2005. The epidemiology of cholera is continually evolving as new strains emerge and spread. There was no cholera in the western hemisphere for 100 years, but in the 1980s Vibrio cholera became re-established after being imported in contaminated water. The El tor biotype is the most frequent worldwide. (Courtesy of Dr R Salata.)
Diarrheal disease 127 therapy (Fig. 6.24). The currently available vaccine is not highly effective and is not routinely recommended for travel into endemic areas. Health education on likely sources of transmission is far more effective in preventing disease than vaccination. However, cholera vaccine is still an active research area. Garcia et al. recently published the results of a randomized, double-blind, placebo-controlled trial of the attenuated live cholera vaccine12. The study was performed in Cuba and involved a total of 45 volunteers. The results demonstrated that unlike the placebo group, the majority of the vaccine recipients (single oral dose) had a dramatic increase in their titers of antivibriocidal antibodies. Also most of the vaccinated subjects did not develop diarrhea when challenged with a virulent V. cholera strain 1 month after vaccination; most of the challenged in the placebo group developed the illness. Larger scale studies are obviously still needed, as the development of an effective cholera vaccine would be of paramount importance to developing countries and potentially to travelers from developed countries.
Escherichia coli 0157:H7 E. coli is the predominant Gram-negative aerobe in the colonic flora, and the vast majority of strains are nonpathogenic when present in the lumen of the colon. Strains of E. coli that produce diarrheal diseases include ETEC, the major cause of travelers’ diarrhea, discussed above. In developing countries, E. coli 0l57:H7 is an emerging cause of food-borne illness, causing an estimated 73,000 cases of infection and 61 deaths in the United States each year13. In most cases, E. coli 0l57:H7 infection causes severe bloody diarrhea and abdominal cramps. Milder cases may be indistinguishable clinically from other bacterial pathogens causing a dysentery syndrome, such as Shigella sp. Usually little or no fever is present, and the illness resolves in 5–10 days. In children and less often the elderly, E. coli 0157:H7 infection leads to hemolytic–uremic syndrome. Most persons recover without antibiotics or other specific treatment in 5–10 days. There is no evidence that antibiotics improve the course of disease, and it is thought that
Fig. 6.23 Cholera cot, with a hole allowing diarrhea to pass into a container below. Cholera produces voluminous, watery diarrhea. (Courtesy of Dr R Salata.) Fig. 6.24 Oral rehydration solutions were introduced for the treatment of cholera and other diarrheal illnesses 30 years ago, and represented a significant advance in therapy. They remain the mainstay of therapy in many rural developing countries. The solutions contain a mixture of salts and sugars that enhance water absorption and treat electrolyte imbalances. (Courtesy of Dr R Salata.)
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treatment with some antibiotics may precipitate kidney complications. Microscopically, pathogenic strains of E. coli are not distinguishable from those that produce disease (Fig. 6.25). Infection with E. coli 0l57:H7 is diagnosed by detecting the bacterium in the stool cultures using sorbitol–MacConkey and other methods. Many hospitalbased microbiology labs routinely test for E. coli 0l57:H7 when stools are submitted for any bacterial cultures. E. coli 0157:H7 infection is nationally reportable and is reportable in most US states. E. coli 0l57:H7 has become a major public health issue in the past 15 years, with several well-documented multistate outbreaks associated with contaminated beef. E. coli 0l57:H7 has been associated with a variety of foods14, 15, but most cases can be traced back to contamination of food products by cow feces. Human-to-human transmission can occur, with a well-documented outbreak in a children’s pool at a water park. The CDC website, FoodNet (http:i/www.cdc.gov/foodnet/), tracks cases of E. coli 0l57:H7, as well as other food-borne pathogens. Campylobacter and Salmonella continue to emerge as the most common causes of bacterial gastroenteritis in the US. Transmission of Campylobacter and Salmonella in developed countries occurs primarily from agricultural sources to food to humans.
Fig. 6.25 Micrograph of Escherichia coli 0157:H7. E. coli represent the predominant aerobic Gram-negative rod in the normal flora of the colon. Pathogenic and nonpathogenic strains have an identical appearance, and biochemical or molecular tests are required to identify pathogenic strains. (Courtesy of Dr D Bobak.)
Norovirus Noroviruses are a group of related, single-stranded ribonucleic acid (RNA), non-enveloped viruses that cause acute gastroenteritis in humans16 (Fig. 6.26). Noroviruses are named after the original strain ‘Norwalk virus’, which caused an outbreak of gastroenteritis in a school in Norwalk, Ohio, in 1968. In 2002 norovirus was approved as the official genus name for the group of viruses provisionally described as ‘Norwalk-like viruses’. The CDC estimates that there are 23 million cases per year in the United States, and that norovirus is the cause of up to one-half of all foodborne illness17. Most food-borne outbreaks of norovirus illness are likely to arise through direct contamination of food by a food handler. Strains of norovirus can be distinguished by molecular techniques, and the CDC maintains a molecular taxonomy tool (CaliciNet) to track strain types and outbreaks.
Fig. 6.26 Micrograph showing norovirus particles. Noroviruses are the most common cause of self-limited viral gastroenteritis, and have been associated with large outbreaks from raw oysters, and with outbreaks on cruise ships.
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Norovirus is the primary cause of self-limited ‘stomach flu’ in adults. Symptoms include nausea, vomiting, diarrhea, and stomach cramping. Sometimes patients have a lowgrade fever, chills, headache, muscle aches, and malaise. The incubation period for norovirus-associated gastroenteritis in humans is usually between 24 and 48 hours (median in outbreaks 33–36 hours), but cases can occur within 12 hours of exposure. The illness is usually brief, with symptoms lasting 1 or 2 days. Recovery is usually complete and there is no evidence of any serious long-term sequelae. There is no specific therapy. Noroviruses are very contagious and can spread easily from person to person18. Both stool and vomit are infectious, and as few as 10 viral particles may produce infection. In the past 5 years, norovirus has gained attention in the general media as a cause of large outbreaks on cruise ships. Contaminated environmental surfaces propagate the infection during outbreaks on ships, college dormitories, and nursing homes.
Conclusions • Clostridium difficile associated diarrhea is epidemic in North America and is a major cause of morbidity and mortality. The emergence of a more pathogenic strain that is resistant to quinolones appears to be an important factor in this epidemic. • Travelers’ diarrhea continues to be an important threat to those engaged in international travel. Emerging issues include the development of antimicrobial resistance, which complicates prevention and treatment, and the association of travelers’ diarrhea with IBS. • Giardiasis and Cryptosporidium are emerging causes of persistent, non-bloody diarrhea in returning travelers. Nitazoxanide offers promise for treating Cryptosporidium. • E. coli 0157:H7 has become a major health issue in the past 15 years, and is associated with hemolytic-uremic syndrome in children and the elderly.
References 1 Pepin J, Valiquette L, Alary ME, et al. Clostridium diffic ile -associated diarrhea in a region of Quebec 1991–2003: a changing pattern of disease severity. JAMC 2004;171(5):466–472. 2 Paterson DL. Collateral damage from cephalosporin or quinolone antibiotic therapy. Clin Infe c t Dis 2004;38(Suppl 4):5341–5345. 3 Okhuysen P, Jiang Z, Carlin L, Forbes C, Dupont H. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol 2004;99:1774–1778. 4 Iluang DB, DuPont HL. Rifaximin: a novel antimicrobial for enteric infections. J Infect 2005;50(2):97–106. 5 DuPont HL, Jiang ZD, Okhuysen PC, e t al. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Intern Med 2005;142(10):805–812. 6 Steffen R, Tornieporth N, Clemens SA, e t al. Epidemiology of travelers’ diarrhea: details of a global survey. J Travel Med 2004;11(4):231–237. 7 White CA Jr. Nitazoxanide: a new broad-spectrum antiparasitic agent. Exp Re v Antinfe c t T he r 2004;2(1):43–49. 8 Ribes JA, Seabolt JP, Overman SB. Point prevalence of Cryptosporidium, Cyclospora, and Isospora infections in patients being evaluated for diarrhea. Am J Clin Pathol 2004;122(l):28–32. 9 Zulu I, Kelly P, Njobvu L, et al. Nitazoxanide for persistent diarrhea in Zambian acquired immune deficiency syndrome patients: a randomized controlled trial. Aliment Pharmacol Therap 2005;21(6):757–763. 10 Kansouzidou A, Charitidou C, Varnis T, Vavatsi N, Kamaria F. Cyclospora cayetanensis in a patient with travelers’ diarrhea: case report and review. J Travel Med 2004;11(l):61–63. 11 O’Ryan M, Prado V, Pickering LK. A millennium update on pediatric diarrheal illness in the developing world. Sem Ped Infect Dis 2005;16(2):125–136. 12 Garcia L, Jidy MD, Garcia H, Rodriguez BL, Fernandez R.The vaccine candidate Vibrio cholera 638 is protective against cholera in healthy volunteers. Infect Immun 2005;73(5):3018–3024.
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13 Rangel JM, Sparling PH, Crowe C, Griffin PM, Swerdlow DL. Epidemiology of Escherichia coli 0l57:H7 outbreaks, United States, 1982–2002. Emerg Infect Dis 2005;11(4):603–609. 14 Garmendia J, Frankel C, Crepin VF. Enteropathogenic and enterohemorrhagic Esc he ric hia c o li infections: translocation, translocation, translocation. Infect Immun 2005;73(5):2573–2585. 15 Flint JA,Van Duynhoven YT, Angulo FJ, DeLong SM. Estimating the burden of acute gastroenteritis, foodborne disease, and pathogens commonly transmitted by food: an International Review. Clin Infe c t Dis 2005;41:698–704. 16 Atreya CD. Major foodborne illness causing viruses and current status of vaccines against the diseases. Foodborne Path Dis 2004;1(2):89–96. 17 Widdowson MA, Monroe SS, Glass RI. Are noroviruses emerging? Emerg Infect Dis 2005;11(5):735–737. 18 Hutson AM, Atmar RL, Estes MK. Norovirus disease: changing epidemiology and host susceptibility factors. Trends Microbiol 2004;12(6):279–287.
Further reading Aslam S, Musher DM. An update on diagnosis, treatment, and prevention of Clostridium difficile-associated disease. Gastroenterol Clin N Am 2006;35(2):315–335. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Eng J Med 2006;354(2):119–130. Nivatpumin P. Cases from the Osler Medical Service at John Hopkins University. Cryptosporidium parvum. Am J Med 2004;117(7):523–524. Riddle MS, Sanders JW, Putnam SD, et al. Incidence, etiology and impact of diarrhea among long-term travelers (US military and similar populations): a systemic review. Am J Tro p Me d & Hygie ne 2006;74(5);891–900. Starr J. Clostridium difficile associated diarrhea: diagnosis and treatment. BMJ 2005;331(7515):498–501.
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Note: Page references in italic refer to tables in the text abacavir 25 acetaminophen 41 acid-fast bacilli (AFB) smears 85, 85, 93 acidosis, metabolic 106 acute retroviral syndrome 5, 6 adenopathy, in TB 82, 83, 85, 85, 87, 88 adenoviruses 49 Africa, sub-Saharan 3 AIDS etiology and pathogenesis 1–2 first recognized 1 global epidemiology 3, 4 see also HIV infection AIDS dementia complex 12 alanine aminotransferase (ALT) levels 38, 41, 55 alcohol ingestion 41 Alinia, see nitazoxanide alpha fetoprotein (AFP) levels 41 alveolar damage, diffuse 58, 59 amantadine 75 anemia interferon/ribavirin therapy 43 malaria 106 animals avian influenza virus 68, 70, 71–2 coronaviruses 51 as SARS-CoV reservoirs 52 Anopheles mosquito control 110–11 life cycle 101–2 antibiotic-associated diarrhea 117–19 antibiotics E. coli 0157:H7 127–8 implicated in CDAD 119 prophylactic in HIV/AIDS 24, 26 resistance to 121 see also named agents antigenic drift 68, 69 antigenic shift 68, 70 antiretroviral agents currently approved in HIV/AIDS 24, 24 regiments for failing therapy 28
antiretroviral agents (continued) side effects 26 artemether 108 artesunate 109 arthralgia 38 Asia avian influenza 68, 72, 75 hepatitis C 34 SARS-CoV 52 aspartate aminotransferase (AST) 55 atazanavir 25 atovaquone 26 atovaquone/proguanil 109, 110 avian bronchitis virus 51 avian influenza 68–76 clinical features 73–4 diagnosis 75, 76 epidemiology 71–3 H7 strains 73 prevention 75 treatment 75 virology 68–70 azithromycin 26 Bacille Calmette-Guérin (BCG) vaccination 92 B cell lymphoma 38 bed nets 110, 111 beta-lactamase inhibitors 119 beta-lactams 119 ‘bird flu’, see avian influenza birds wild 68, 70, 71–2 see also poultry blood products 36, 66 blood smears, malaria 106–7 bone marrow function 2 bovine respiratory coronavirus 51 brain abscesses, AIDS patient 11 breast-feeding, and hepatitis C 37 bronchiolitis, viral 49, 65 bronchoalveolar lavage, SARS-CoV 58, 59, 60 bronchoscopy, TB 93 CaliciNet 128
Campylobacter 121, 128 Candida infections, HIV/AIDS 6, 7, 20 canine respiratory coronavirus 51 capreomycin 98 case histories hepatitis C 46 malaria 112–14 SARS 57–8 CD4+ T cells counts and AIDS complications 12–23 and AIDS prognosis 24 and TB risk 85, 85 destruction in HIV 1, 2, 3, 5 central nervous system (CNS) disease HIV/AIDS 5, 20, 22 malaria 112 tuberculosis 88–9 cephalosporins 119, 120 cerebrospinal fluid (CSF), HIV infection 5 cervical carcinoma 20 cervical intraepithelial neoplasia 10 chest radiography avian influenza 73, 74 HIV/AIDS 8, 9–13, 21–3 human metapneumovirus 65 SARS-CoV 56, 56, 57–8 tuberculosis 85–6, 87, 89–91, 95–6 children hepatitis C transmission 36, 37 human metapneumovirus 64–5 malaria 101, 104, 105, 108, 112, 114 treatment China, SARS-CoV 52 chloroquine 103, 108, 109, 110 resistance to 103 cholera 126–7 ‘cholera cot’ 126 chorioretinitis, Toxoplasma 18 ciprofloxacin 119 cirrhosis, hepatitis C 31, 32, 34, 38, 38, 41 civets 52 clarithromycin 26 clindamycin 119
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clinical syndromes, viral 49, 51 Clostridium difficile 117 Clostridium difficile-associated diarrhea (CDAD) 117–19, 129 coinfection HIV and hepatitis C 36 HIV and tuberculosis 81, 85–7, 85, 96 colitis, pseudomembranous 117 colon, dilatation 121 common cold 49, 51 computed tomography (CT) HIV/AIDS 9, 11, 14 human metapneumovirus 65–6 SARS-CoV 56, 56, 58 tuberculosis 91 condylomata acuminata 10, 12 coronaviruses clinical syndromes 49, 51 species and hosts 51 structure 51–2 see also severe acute respiratory syndrome-associated coronavirus (SARS-CoV) corticosteroids 62, 86 cotrimoxazole 26 creatine kinase 55 croup 49 cruise ships, norovirus infections 129 cryoglobulinemia 38, 46 cryptococcosis 20, 21, 22 cryptosporidiosis 20, 123–4, 129 Cryptosporidium 117, 123–4, 129 Cryptosporidium parvum 20 cycloserine 98 Cyclospora 117, 124–6 cytomegalovirus (CMV) infections 18–19, 49 encephalitis 18–19 retinitis 18 dapsone 26 dementia, AIDS complex 12 diabetes mellitus 54 diarrheal disease antibiotic-associated 117–19 immunocompromised host 20, 123–4 ‘presumptive therapy’ 119–20 travelers’ 119–28 didanosine 25 diethyltoluamide (DEET) 111 diloxanide furoate 123 directly observed therapy, short course (DOTS) 96, 97 doxycycline 109, 110 early virologic response (EVR) 42–3 economic burden food-borne illness 117 malaria 101 efavirenz 25 Egypt, hepatitis C 34 electrolyte abnormalities, malaria 106 emtricitabine 25
encephalitis cytomegalovirus 18–19 Toxoplasma 16–18, 16 encephalopathy, HIV (AIDS dementia complex) 12 Entamoeba histolytica 122–3 enterotoxins 126 enteroviruses 49 enzyme immunosorbent assay (EIA) 39 Epstein-Barr virus 8, 49 erythrocytes, Plasmodium invasion 101 erythropoietin therapy 43 Escherichia coli 0157:H7 127–8 enterotoxigenic (ETEC) 120 esophagitis, Candida 20 ethambutol 96, 96, 97 ethionamide 98 eye disease 18 fat wasting/redistribution, HIV/AIDS 26 feline enteric coronavirus 51 feline infectious peritonitis virus 51 fibrosis liver 34, 38 lung 83 fluorochrome staining 93 fluoroquinolones 98 food, street vendors 119 Food and Drugs Administration 75 FoodNet 128 fosamprenavir 25 fungal disease, HIV/AIDS 20 gametocytes 101 gastrointestinal tract tuberculous involvement 91 see also diarrheal disease gatifloxacin 119 genetic evolution, influenza viruses 68–70 genetic reassortment 72 genitourinary tuberculosis 90 Ghon focus 80, 82 giant cells 58 Giardia lamblia 122, 123 giardiasis 123, 129 Giemsa stain 106 glomerulonephritis, membranoproliferative 39 glucose-6-phoshate dehydrogenase deficiency 103 Guangdong province, China 52 Guillain–Barré syndrome (GBS) 121 H1N1 virus 71 H5N1 virus 68, 72 clinical symptoms 73 diagnosis of infection 75, 76 epidemiology 72, 75 treatment of infection 75 hemagglutinating encephalitis virus 51 hemolytic-uremic syndrome 127, 129 Hemophilus influenzae 10 hepatic fibrosis 34, 38
hepatitis C infection clinical manifestations 38–9 diagnosis 39–41 epidemiology 31, 34–7 etiology and pathogenesis 31–3 in HIV/AIDS 36 illustrative case 46 risk factors 36, 36 treatment 41–6 new agents 45–6, 46 non-response to 45, 45 hepatitis C virus (HCV) characteristics 31–2, 31 genotypes 34, 34, 35, 42 indications for testing 40 hepatocellular carcinoma (HCC) 20, 31, 32, 34, 38 hepatocytes, Plasmodium infection 101 hepatosplenomegaly 105 hepatotoxic drugs 41, 98 herpes simplex virus 49 herpes zoster (shingles) 6 highly active retroviral therapy (HAART) 1, 20, 24–8, 28 efficacy 3 IRIS reactions 86–7 hilar lymphadenopathy 82, 83, 85 Histoplasma capsulatum 20, 22 HIV-2 1 HIV (HIV-1) genomic organization 1, 2 plasma RNA levels 24 replication 2 structure 1, 2 HIV infection CDC staging system 6, 6 clinical manifestations 5–23 coinfection with hepatitis C 36 coinfection with tuberculosis 81, 85–7, 85, 96 diarrheal disease 20, 123–4 epidemiology 3, 4, 28 malaria infections 114 morbidity and mortality 3 sex distribution 3 in women 3, 4, 10 see also AIDS HIV resistance testing 26, 27 Hong Kong avian influenza 68, 72 SARS-CoV 52 human coronavirus-Netherlands 51 human laryngeal cancer cells (HEp-2) 67 human metapneumovirus (hMPV) 63–7 clinical features 64–7 epidemiology 64 laboratory diagnosis 67 prevention 67 treatment 67 virology 63 human papilloma virus (HPV) 10 human respiratory coronavirus 51 hypnozoite 113 hypoglycemia, malaria 106
Index 133
hypoglychorrhachia 89 immune reconstitution inflammatory syndrome (IRIS) reactions 86–7 immunocompromised persons diarrheal disease 20, 123–4 human metapneumovirus 65, 66 tuberculosis 85–7 see also HIV infection infant, hepatitis C transmission 36, 37 influenza viruses 49, 68 classification 68 genetic evolution 68–70 pandemics 71 see also avian influenza virus insecticides 110, 111 interferon α, recombinant human 42, 42, 46 adverse effects 43–5, 44 contraindications 44 non-response to 45, 45 iodoquinol 123 irritable bowel syndrome (IBS), postdiarrheal disease 119–20 isoniazid (INH) 26, 96, 96, 97, 98 Isospora bellii 20 jaundice 38 kanamycin 98 Kaposi’s sarcoma 8 Kinyoun stain 93 Koch’s pustulates 52, 53 lactate dehydrogenase 54, 55 lamivudine 25 leukemia, acute myeloid 66 leukocytes, fecal 117 levofloxacin 98, 119 lichen planus 38 ligase chain reaction (LCR) 107 lipodystrophy 26 liver function tests hepatitis C 38, 38, 41, 46 malaria 106 lopinavir 25, 62 Löwenstein–Jensen slant 93, 94 lumefantrine 109 lymphadenopathy HIV/AIDS 5, 6, 6 tuberculosis 82, 83, 85, 87 lymphocytopenia 55 lymphoma hepatitis C 38, 46 HIV/AIDS 16, 20, 23 non-Hodgkin’s 20, 23 primary CNS (PCNSL) 16 Madin–Darby Canine Kidney (MDCK) cell line 75 malaria cerebral 105, 112 in children 101, 104, 105, 108, 112, 114 clinical manifestations 104–5
malaria (continued) diagnosis 106–7 economic burden 101 epidemiology 103–4 eradication programs 101 etiology and pathogenesis 101–3 HIV-positive individuals 114 illustrative cases 112–14 management 108–9, 108, 109 non-endemic areas 103 partial immunity 104 prevention 110–11, 110 prophylaxis 110, 113 malignancies hepatocellular carcinoma 20, 31, 32, 34, 38 in HIV/AIDS 10, 20 Mantoux tuberculin skin test 92 measles virus 49 mefloquine 109, 110 megacolon, toxic 121–2 meningitis aseptic in HIV/AIDS 5 cryptococcal 20 tuberculous 89 merozoites 101 metapneumoviruses 49 see also human metapneumovirus (hMPV) metronidazole 123 Microsporidia 20 Middlebrook media 93 monoclonal antibodies 63 mosquitoes control 110–11 life cycle 101–2 mosquito nets 110, 111 moxyfloxacin 119 mucosal candidiasis 6, 7 murine hepatitis virus 51 mycobacteria, atypical 20, 26, 98 mycobacterial growth indicator tube (MGIT) system 93 Mycobacterium africanum 79 Mycobacterium avium-intracellulare 20, 26, 98 Mycobacterium bovis 79 Mycobacterium canetti 79 Mycobacterium kansasii 98 Mycobacterium marinum 98 Mycobacterium microti 79 Mycobacterium tuberculosis 79 prophylactic antibiotics 26 Mycobacterium xenopi 98 nets, mosquito 110, 111 neuroaminidase inhibitors 75 neurologic syndromes, HIV/AIDS 12 nevirapine 25 nitazoxanide (Alinia) 123, 124, 125, 129 Nocardia spp. 10 non-Hodgkin’s lymphoma (NHL) 20 non-nucleoside reverse transciptase inhibitors (NNRTIs) 24, 25, 26, 28
noroviruses 117, 128–9 nucleoside/nucleotide reverse transciptase inhibitors (NRTIs) 24, 26, 28 ofloxacin 98 oral hairy leukoplakia (OHL) 8 oral rehydration therapy 126 organ transplantation 36 orthomyxoviruses 49, 68 oseltamivir 75 palm civet 52 para-amino salicylic acid 98 parainfluenza viruses 49 paramyxoviruses 49 paromomycin 123 pentamidine 26 pericarditis, tuberculous 90 permethrin 111 persistent generalised lymphadenopathy (PGL) 6, 6 pharyngitis 49 picornovirus 49 Plasmodium spp., life cycle 101–3 Plasmodium falciparum 104, 105 drug prophylaxis 110, 113 treatment of infection 108, 108, 109 Plasmodium knowlesi 101 Plasmodium malariae 104, 105 Plasmodium ovale 101, 104, 105 treatment of infection 108, 109 Plasmodium vivax 101, 104, 105, 113 drug resistance 104 treatment of infection 108, 109 pleurisy, tuberculous 86–7, 91 Pneumocystis jirovecii disseminated infection 12 pneumonia 10–12 prophylactic antimicrobials 26 pneumocytes, atypical 58, 67 pneumonia cryptococcal 20 HIV 8, 10–12, 20 human metapneumovirus 64–6 Pneumocystis jirovecii 10–12 tuberculous 82 viral causes 49 pneumonitis, Toxoplasma 16–18 pneumothorax 12 polyarthritis 38 polymerase chain reaction (PCR) HCV diagnosis 41 malaria diagnosis 107 SARS diagnosis 58, 60, 60 TB diagnosis 93, 95 polymerase inhibitors 46 polyomavirus (JC) 12 porcine transmissible gastroenteritis virus 51 porphyria cutanea tarda 38 Pott’s disease 88, 89 poultry avian influenza virus 68, 70, 71–2, 75 coronaviruses 51
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poverty 79, 101 pregnancy hepatitis C infection 36, 37, 46 malaria 104 ‘presumptive therapy’ 120 primaquine 109, 113 primary CNS lymphoma (PCNSL) 16 progressive multifocal leukoencephalopathy (PML) 12, 15 proguanil 109, 110 prophylaxis HIV/AIDS 24, 26 malaria 110, 113 SARS-CoV 63 protease inhibitors (PI) 24, 25, 26, 28, 46, 62 pseudomembranous colitis 117 Pseudomonas aeruginosa 10 pulmonary cysts 12 pulmonary infiltrates 86 purified protein (PPD) 92 pyrazinamide 26, 96, 96, 97 pyrethroid insecticides 110, 111 pyridoxine 26, 97 pyrimethamine-sulfadoxine 104, 109 pyuria, sterile in tuberculosis 90 quinidine gluconate 108 quinine 106, 108, 109, 112 quinolones 119, 120, 121 rabbit coronavirus 51 raccoon dog 52 Ranke complex 80, 82 rapid antigen tests, malaria 107 rash, in HIV/AIDS 6, 7 rat coronavirus 51 reassortment, genetic 72 recombinant immunoblot assay-version two (RIBA-2) 39 rehydration therapy, oral 128 renal disease hepatitis C 39 tuberculous 90 respiratory syncytial virus 49 respiratory viral infections, clinical syndromes 49 retinal disease 18 reverse transcriptase polymerase chain reaction (RT-PCR) 58, 60, 60, 67, 75 rhesus monkey kidney cells (LLC-MK2) 58, 67 rhinovirus 49 Rhodococcus eq ui 10 ribavirin 42, 42, 46, 67 adverse effects 43, 45 contraindications 42, 44 non-response to 45, 45 rifampicin 26, 96, 96, 97, 98 rifaximin 120 rimantadine 75 ritonavir 25, 62 RNA assays, HCV 41 RNA disrupting agents 46
Roll Back Malaria (RBM) program 101 Salmonella 121, 128 scrofula 87, 88 serum markers, HCV infection 41 severe acute respiratory syndromeassociated coronavirus (SARS-CoV) 51–63 clinical features 54–8 epidemiology 52–4 illustrative cases 57–8 laboratory diagnosis 58–61 outcomes 62 pathology 58–9 prevention 62–3 risk factors for death/ICU admission 54, 54 treatment 62 sex distribution, HIV 3 sexual activity, and hepatitis C 36, 36 Shigella 121 shingles (herpes zoster) 6 ships, norovirus infections 129 sialodacryoadenitis virus 51 sickle cell hemoglobin 103 Simon’s foci 81 skin disorders hepatitis C 38, 46 HIV/AIDS 7, 8 sorbitol-MacConkey agar 128 ‘Spanish Flu’ 71 splenomegaly hepatitis C 46 malaria 104, 105, 114 spondylitis, tuberculous (Pott’s disease) 88, 89 sputum samples, TB 93 squamous intraepithelial lesions (SIL) 10, 12 stem cell transplant 66 ‘stomach flu’ 129 street vendors 119 Streptococcus pneumoniae 8 sub-Saharan Africa HIV/AIDS 3 malaria 101 TB 81 sulfadoxine-pyrimethamine 104, 109 sustained virological response (SVR) 42, 42 T cells, CD4+, see CD4+ T cells tenofovir 25 tetracycline 109 thrombocytopenia hepatitis C 46 malaria 106 SARS-CoV 55 thrush 6 thymocytes 2 thymus, function 2 toxic megacolon 121–2 Toxoplasma infections 16–18 prophylactic antimicrobials 26
transplants, organ/blood products 36, 66 travel malaria-endemic areas 111, 113 and SARS-CoV 52, 63 travelers’ diarrhea 119–23, 129 cholera 126–8 cryptosporidiosis 123–4 cyclosporiasis 124–5 E. coli 0157:H7 127–8 giardiasis 123 trimethoprim sulfamethoxizole 120, 125 trophozoites 101 tuberculin skin test (TST) 82, 85, 92, 92 tuberculoma 88–9 tuberculosis (TB) diagnosis 92–6, 93–6 epidemiology 81 etiology and pathogenesis 79–81 extrapulmonary manifestations 87–91 in HIV/AIDS 85–7, 96 latent infection 92, 98 management 96–8 miliary 84, 90 multidrug resistant (MDR) 98 primary 80–1, 82 reactivation 82 risk factors 80 turkey respiratory coronavirus 51 typhlitis, tuberculous 91 ultrasound examination 41 ultraviolet light water treatment 124 United Nations Development Program (UNICEF) 101 US Centers for Disease Control and Prevention (CDC) CaliciNet 128 FoodNet 128 HIV staging 6, 6 malaria hotline 108 SARS control guidelines 62 vaccines cholera 126–7 human metapneumovirus 67 malaria 110 SARS-CoV 63 vaginal candidiasis 6, 7 vancomycin 119 varicella-zoster virus 18, 49 ventriculoencephalitis, CMV 18 Vero-E6 cells 58, 59 Vibrio cholera 126–7 water treatment, UV light 124 women, HIV infection 3, 4, 10 World Bank 101 World Health Organization (WHO) 51, 81, 101 zanamivir 75 zidovudine 1, 25 Ziehl–Neelsen stain 80, 93
