InternalMed_Harrison

InternalMed_Harrison. Several enteric viruses have been recognized as important etiologic agents of acute infectious gastroenteritis (Table 227-1, Fig. 227-1). Although most viral gastroenteritis is caused by RNA viruses, the DNA viruses that are occasionally involved (e.g., adenovirus types 40 and 41) are included in this chapter. Illness caused by these viruses is characterized by the acute onset of vomiting and/or diarrhea, which may be accompanied by fever, nausea, abdominal cramps, anorexia, and malaise. As shown in Table 227-2, several features can help distinguish gastroenteritis caused by viruses from that caused by bacterial agents. However, the distinction based on clinical and epidemiologic parameters alone is often difficult, and laboratory tests are required to confirm the diagnosis.


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InternalMed_Harrison. HuMAN CALICIVIRuSES Etiologic Agent The Norwalk virus is the prototype strain of a group of small (27–40 nm), nonenveloped, round, icosahedral viruses with relatively amorphous surface features on visualization by electron microscopy. These viruses have been difficult to classify because they have not been adapted to growth in cell culture and no animal models are available. Molecular cloning and characterization have demonstrated that the viruses have a single, positive-strand RNA genome ~7.5 kb in length and possess a single virion-associated protein—similar to that of typical caliciviruses—with a molecular mass of 60 kDa. On the basis of these molecular characteristics, these viruses are presently classified in two genera belonging to the family Caliciviridae: the noroviruses and the sapoviruses (previously called Norwalk-like viruses and Sapporo-like viruses, respectively).


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InternalMed_Harrison. Epidemiology Infections with the Norwalk and related human caliciviruses are common worldwide, and most adults have antibodies to these viruses. Antibody is acquired at an earlier age in developing countries—a pattern consistent with the presumed fecal-oral mode of transmission. Infections occur year-round, although, in temperate climates, a distinct increase has been noted in cold-weather months. Noroviruses may be the most common infectious agents of mild gastroenteritis in the community and affect all age groups, whereas sapoviruses primarily cause gastroenteritis in children. Noroviruses also cause traveler’s diarrhea, and outbreaks have occurred among military personnel deployed to various parts of the world. The limited data available indicate that norovirus may be the second most common viral agent (after rotavirus) among young Norovirus Caliciviridae Positive-sense All ages + + EM, RT-PCR single-strand RNA


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InternalMed_Harrison. Norovirus Caliciviridae Positive-sense All ages + + EM, RT-PCR single-strand RNA Sapovirus Caliciviridae Positive-sense Children <5 years + EM, RT-PCR single-strand RNA Astrovirus Astroviridae Positive-sense Children <5 years + EM, EIA, RT-PCR single-strand RNA Adenovirus (mainly types Adenoviridae Double-strand DNA Children <5 years +/+ + EM, EIA (commercial), PCR 40 and 41) Abbreviations: EIA, enzyme immunoassay; EM, electron microscopy; PAGE, polyacrylamide gel electrophoresis; PCR, polymerase chain reaction; RT-PCR, reverse-transcription PCR.


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InternalMed_Harrison. Abbreviations: EIA, enzyme immunoassay; EM, electron microscopy; PAGE, polyacrylamide gel electrophoresis; PCR, polymerase chain reaction; RT-PCR, reverse-transcription PCR. children and the most common agent among older children and adults. In the United States, with the decline in severe rotavirus disease following implementation of rotavirus vaccines, norovirus has become the leading cause of medically attended gastroenteritis in young children. Noroviruses are also recognized as the major cause of epidemics of gastroenteritis worldwide. In the United States, >90% of outbreaks of nonbacterial gastroenteritis are caused by noroviruses.


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InternalMed_Harrison. Virus is transmitted predominantly by the fecal-oral route but is also present in vomitus. Because an inoculum with very few viruses can be infectious, transmission can occur by aerosolization, by contact with contaminated fomites, and by person-to-person contact. Viral shedding and infectivity are greatest during the acute illness, but challenge studies with Norwalk virus in volunteers indicate that viral antigen may be shed by asymptomatically infected persons and also by symptomatic persons before the onset of symptoms and for several weeks after the resolution of illness. Viral shedding can be prolonged in immunocompromised individuals.


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InternalMed_Harrison. Pathogenesis The exact sites and cellular receptors for attachment of viral particles have not been determined. Data suggest that carbohydrates that are similar to human histo-blood group antigens and are present on the gastroduodenal epithelium of individuals with the secretor phenotype may serve as ligands for the attachment of Norwalk virus. Additional studies must more fully elucidate norovirus-carbohydrate interactions, including potential strain-specific variations. After the infection of volunteers, reversible lesions are noted in the upper jejunum, with broadening and blunting of the villi, shortening of the microvilli, vacuolization of the lining epithelium, crypt hyperplasia, and infiltration of the lamina propria by polymorphonuclear neutrophils and lymphocytes. The lesions persist for at least 4 days after the resolution of symptoms and are associated with malabsorption of carbohydrates and fats and a decreased level of brush-border enzymes.


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InternalMed_Harrison. FIGuRE 227-1 Viral agents of gastroenteritis. NV, norovirus; SV, sapovirus. Adenylate cyclase activity is not altered. No histopathologic changes are seen in the stomach or colon, but gastric motor function is delayed, and this alteration is believed to contribute to the nausea and vomiting that are typical of this illness.


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InternalMed_Harrison. Clinical Manifestations Gastroenteritis caused by Norwalk and related human caliciviruses has a sudden onset following an average incubation period of 24 h (range, 12–72 h). The illness generally lasts 12–60 h and is characterized by one or more of the following symptoms: nausea, vomiting, abdominal cramps, and diarrhea. Vomiting is more prevalent among children, whereas a greater proportion of adults develop diarrhea. Constitutional symptoms are common, including headache, fever, chills, and myalgias. The stools are characteristically loose and watery, without blood, mucus, or leukocytes. White cell counts are generally normal; rarely, leukocytosis with relative lymphopenia may be observed. Death is a rare outcome and usually results from severe dehydration in vulnerable persons (e.g., elderly patients with debilitating health conditions).


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InternalMed_Harrison. Immunity Approximately 50% of persons challenged with Norwalk virus become ill and acquire short-term immunity against the infecting strain. Immunity to Norwalk virus appears to correlate inversely with level of antibody; i.e., persons with higher levels of preexisting antibody to Norwalk virus are more susceptible to illness. This observation suggests that some individuals have a genetic predisposition to illness. Specific ABO, Lewis, and secretor blood group phenotypes may influence susceptibility to norovirus infection.


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InternalMed_Harrison. Diagnosis Cloning and sequencing of the genomes of Norwalk and several other human caliciviruses have allowed the development of assays based on polymerase chain reaction (PCR) for detection of virus in stool and vomitus. Virus-like particles produced by expression of capsid proteins in a recombinant baculovirus vector have been used to develop enzyme immunoassays (EIAs) for detection of virus in stool or a serologic response to a specific viral antigen. These newer diagnostic techniques are considerably more sensitive than previous detection methods, such as electron microscopy, immune electron microscopy, and EIAs based on reagents derived from humans. However, no currently available single assay can detect all human caliciviruses because of their great genetic and antigenic diversity. In addition, the assays are still cumbersome and are available primarily in research laboratories, although they are increasingly being adopted by public health laboratories for routine screening of


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InternalMed_Harrison. In addition, the assays are still cumbersome and are available primarily in research laboratories, although they are increasingly being adopted by public health laboratories for routine screening of fecal specimens from patients affected by outbreaks of gastroenteritis. Commercial EIA kits have limited sensitivity and usefulness in clinical practice and are of greatest utility in outbreaks, in which many specimens are tested and only a few need be positive to identify norovirus as the cause.


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InternalMed_Harrison. The disease is self-limited, and oral rehydration therapy is generally adequate. If severe dehydration develops, IV fluid therapy is indicated. No specific antiviral therapy is available. Prevention Epidemic prevention relies on situation-specific measures, such as control of contamination of food and water, exclusion of ill food handlers, and reduction of person-to-person spread through good personal hygiene and disinfection of contaminated fomites. The role of immunoprophylaxis is not clear, given the lack of long-term immunity from natural disease, but efforts to develop norovirus vaccines are ongoing. In a clinical study, a candidate virus-like particle norovirus vaccine was shown to protect against homologous viral challenge.


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InternalMed_Harrison. ROTAVIRuS Etiologic Agent Rotaviruses are members of the family Reoviridae. The viral genome consists of 11 segments of double-strand RNA that are enclosed in a triple-layered, nonenveloped, icosahedral capsid 75 nm in diameter. Viral protein 6 (VP6), the major structural protein, is the target of commercial immunoassays and determines the group specificity of rotaviruses. There are seven major groups of rotavirus (A through G); human illness is caused primarily by group A and, to a much lesser extent, by groups B and C. Two outer-capsid proteins, VP7 (G-protein) and VP4 (P-protein), determine serotype specificity, induce neutralizing antibodies, and form the basis for binary classification of rotaviruses (G and P types). The segmented genome of rotavirus allows genetic reassortment (i.e., exchange of genome segments between viruses) during co-infection—a property that may play a role in viral evolution and that has been utilized in the development of reassortant animal-human


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InternalMed_Harrison. (i.e., exchange of genome segments between viruses) during co-infection—a property that may play a role in viral evolution and that has been utilized in the development of reassortant animal-human rotavirus–based vaccines.


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InternalMed_Harrison. Epidemiology Worldwide, nearly all children are infected with rotavirus by 3–5 years of age. Neonatal infections are common but are often asymptomatic or mild, presumably because of protection by maternal antibody or breast milk. Compared with rotavirus disease in industrialized countries, disease in developing countries occurs at a younger age, is less seasonal, and is more frequently caused by uncommon rotavirus strains. Moreover, because of suboptimal access to hydration therapy, rotavirus is a leading cause of diarrheal death among children in the developing world, with the highest mortality rates among children in sub-Saharan Africa and South Asia (Fig. 227-2).


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InternalMed_Harrison. First infections after 3 months of age are likely to be symptomatic, and the incidence of disease peaks among children 4–23 months of age. Reinfections are common, but the severity of disease decreases with each repeat infection. Therefore, severe rotavirus infections are less common among older children and adults than among younger individuals. Nevertheless, rotavirus can cause illness in parents and caretakers of children with rotavirus diarrhea, immunocompromised persons, travelers, and elderly individuals and should be considered in the differential diagnosis of gastroenteritis among adults.


InternalMed_Harrison

InternalMed_Harrison. In tropical settings, rotavirus disease occurs year-round, with less pronounced seasonal peaks than in temperate settings, where rota-virus disease occurs predominantly during the cooler fall and winter months. Before the introduction of rotavirus vaccine in the United States, the rotavirus season each year began in the Southwest during the autumn and early winter (October through December) and migrated across the continent, peaking in the Northeast during late winter and spring (March through May). The reasons for this characteristic pattern are not clear but may be correlated with state-specific differences in birth rates, which could influence the rate of accumulation of susceptible infants after each rotavirus season. After the implementation of routine vaccination of U.S. infants against rotavirus in 2006, the characteristic prevaccine geotemporal pattern of U.S. rota-virus was dramatically altered, and these changes were accompanied by substantial declines in rotavirus


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InternalMed_Harrison. against rotavirus in 2006, the characteristic prevaccine geotemporal pattern of U.S. rota-virus was dramatically altered, and these changes were accompanied by substantial declines in rotavirus detections by a national network of sentinel laboratories (Fig. 227-3). During the latest two seasons with available data (spanning 2010–2012), the number of rotavirus detections declined by 74–90% from the prevaccine baseline, and the common. While human rotavirus strains that possess a high degree of genetic homology with animal strains have been identified, animal-to-human transmission appears to be uncommon. Group B rotaviruses have been associated with several large epidemics of severe gastroenteritis among adults in China since 1982 and have also been identified in India. Group C rotaviruses have been associated with a small proportion of pediatric gastroenteritis cases in several countries worldwide.


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InternalMed_Harrison. <10 deaths per 100,000 10 to 50 deaths per 100,000 and ultimately destroy mature enterocytes in the villous epithe 50 to 100 deaths per 100,000 100 to 500 deaths per 100,000 lium of the proximal small intes-FIGuRE 227-2 Rotavirus mortality rates by country, per 100,000 children <5 years of age. (Reproduced tine. The loss of absorptive villous with permission from UD Parashar et al: J Infect Dis 200:S9, 2009.) epithelium, coupled with the pro liferation of secretory crypt cells, results in secretory diarrhea. Brush-annual proportion of rotavirus tests that were positive was below 10% border enzymes characteristic of differentiated cells are reduced, in both seasons (compared with a prevaccine baseline median of 26%). and this change leads to the accumulation of unmetabolized disac-A pattern of biennial increases in rotavirus activity has emerged during charides and consequent osmotic diarrhea. Studies in mice indithe five postvaccine seasons (2007–2012), but activity has remained cate


InternalMed_Harrison

InternalMed_Harrison. of biennial increases in rotavirus activity has emerged during charides and consequent osmotic diarrhea. Studies in mice indithe five postvaccine seasons (2007–2012), but activity has remained cate that a nonstructural rotavirus protein, NSP4, functions as an substantially below prevaccine levels in each season. enterotoxin and contributes to secretory diarrhea by altering epi-


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InternalMed_Harrison. During episodes of rotavirus-associated diarrhea, virus is shed in thelial cell function and permeability. In addition, rotavirus may large quantities in stool (107–1012/g). Viral shedding detectable by EIA evoke fluid secretion through activation of the enteric nervous usually subsides within 1 week but may persist for >30 days in immu-system in the intestinal wall. Data indicate that rotavirus antigennocompromised individuals; it may be detected for longer periods by emia and viremia are common among children with acute rotavirus sensitive molecular assays, such as PCR. The virus is transmitted pre-infection, although the antigen and RNA levels in serum are substandominantly through the fecal-oral route. Spread through respiratory tially lower than those in stool. secretions, person-to-person contact, or contaminated environmental surfaces has been postulated to explain the rapid acquisition of anti-Clinical Manifestations The clinical spectrum of rotavirus infection body in the


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InternalMed_Harrison. contact, or contaminated environmental surfaces has been postulated to explain the rapid acquisition of anti-Clinical Manifestations The clinical spectrum of rotavirus infection body in the first 3 years of life, regardless of sanitary conditions. ranges from subclinical infection to severe gastroenteritis leading to


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InternalMed_Harrison. At least 10 different G serotypes of group A rotavirus have been life-threatening dehydration. After an incubation period of 1–3 days, identified in humans, but only 5 types (G1 through G4 and G9) are the illness has an abrupt onset, with vomiting frequently preceding the onset of diarrhea. Up to one-third of patients may have a temperature of >39°C. The stools are characteristically loose and watery and only infrequently contain red or white cells. Gastrointestinal symptoms generally resolve60 in 3–7 days. Respiratory and neurologic features in children with rotavirus infection have been reported, but causal associations have not been proven. Moreover, rotavirus infection has been associated with a variety of other clinical conditions (e.g., sudden infant death syndrome, necrotizing enterocolitis, intussusception, Kawasaki’s disease, and type 1 diabetes), but no causal relationship has been confirmed with any of these syndromes.


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InternalMed_Harrison. Kawasaki’s disease, and type 1 diabetes), but no causal relationship has been confirmed with any of these syndromes. Rotavirus does not appear to be a major opportunistic pathogen in children with HIV infection. In severely immunodeficient chil dren, rotavirus can cause protracted diarrhea with prolonged viral excretion and, in rare instances, can disseminate systemically. Persons who are immunosuppressed for bone marrow transplantation also are at risk for severe or even fatal rotavirus disease.


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InternalMed_Harrison. FIGuRE 227-3 Percentage of rotavirus tests with positive results, by week of year, July– June, 2000–2012. The maximal or minimal percentage of rotavirus-positive tests for 2000– Immunity Protection against rotavirus disease 2006 may have occurred during any of the six baseline seasons. Data are from the National is correlated with the presence of virus-specific Respiratory and Enteric Virus Surveillance System. (Adapted from Centers for Disease Control and secretory IgA antibodies in the intestine Prevention, 2012.) and, to some extent, the serum. Because


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InternalMed_Harrison. Percent of tests rotavirus positive virus-specific IgA production at the intestinal surface is short lived, complete protection against disease is only temporary. However, each infection and subsequent reinfection confers progressively greater immunity; thus severe disease is most common among young children with first or second infections. Immunologic memory is believed to be important in the attenuation of disease severity upon reinfection. Diagnosis Illness caused by rotavirus is difficult to distinguish clinically from that caused by other enteric viruses. Because large quantities of virus are shed in feces, the diagnosis can usually be confirmed by a wide variety of commercially available EIAs or by techniques for detecting viral RNA, such as gel electrophoresis, probe hybridization, or PCR.


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InternalMed_Harrison. Rotavirus gastroenteritis can lead to severe dehydration. Thus appropriate treatment should be instituted early. Standard oral rehydration therapy is successful for most children who can take fluids by mouth, but IV fluid replacement may be required for patients who are severely dehydrated or are unable to tolerate oral therapy because of frequent vomiting. The therapeutic roles of probiotics, bismuth subsalicylate, enkephalinase inhibitors, and nitazoxanide have been evaluated in clinical studies but are not clearly defined. Antibiotics and antimotility agents should be avoided. In immunocompromised children with chronic symptomatic rotavirus disease, orally administered immunoglobulins or colostrum may result in the resolution of symptoms, but the best choices regarding agents and their doses have not been well studied, and treatment decisions are often empirical.


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InternalMed_Harrison. Prevention Efforts to develop rotavirus vaccines were pur sued because it was apparent—given the similar rates in less developed and industrialized nations—that improvements in hygiene and sanitation were unlikely to reduce disease incidence. The first rotavirus vaccine licensed in the United States in 1998 was withdrawn from the market within 1 year because it was linked with a low incidence of intussusception, a severe bowel obstruction.


InternalMed_Harrison

InternalMed_Harrison. In 2006, promising safety and efficacy results for two new rotavirus vaccines were reported from large clinical trials conducted in North America, Europe, and Latin America. Both vaccines are now recommended for routine immunization of all U.S. infants, and their use has rapidly led to a >70–80% decline in rotavirus hospitalizations and emergency department visits at hospitals across the United States. Indirect benefits from vaccination (i.e., herd immunity) have also been documented in many settings. In April 2009, the World Health Organization recommended the use of rotavirus vaccines in all countries worldwide. As of May 2013, a total of 42 countries, including 5 low-income countries in Africa and Asia, have incorporated rota-virus vaccine into their national childhood immunization programs. In Mexico and in Brazil, a decline in deaths from childhood diarrhea following introduction of rotavirus vaccines has been documented. Postmarketing surveillance has identified a low risk of


InternalMed_Harrison

InternalMed_Harrison. In Mexico and in Brazil, a decline in deaths from childhood diarrhea following introduction of rotavirus vaccines has been documented. Postmarketing surveillance has identified a low risk of intussusception in some countries; however, the benefits of vaccination exceed the risks, and no changes in vaccine administration policy have been implemented. The different epidemiology of rotavirus disease and the greater prevalence of co-infection with other enteric pathogens, of comorbidities, and of malnutrition in developing countries may adversely affect the performance of oral rotavirus vaccines, as is the case with oral vaccines against poliomyelitis, cholera, and typhoid in these regions. Therefore, evaluation of the efficacy of rotavirus vaccines in resource-poor settings of Africa and Asia was specifically recommended, and these trials have now been completed. As anticipated, the efficacy of rotavirus vaccines was moderate (50– 65%) in these settings when compared with that in


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InternalMed_Harrison. and Asia was specifically recommended, and these trials have now been completed. As anticipated, the efficacy of rotavirus vaccines was moderate (50– 65%) in these settings when compared with that in industrialized countries. Nevertheless, even a moderately efficacious rotavirus vaccine would be likely to have substantial public health benefits in these areas with a high disease burden.


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InternalMed_Harrison. Enteric adenoviruses of serotypes 40 and 41 belonging to subgroup F are 70to 80-nm viruses with double-strand DNA that cause ~2–12% of all diarrhea episodes in young children. Unlike adenoviruses that cause respiratory illness, enteric adenoviruses are difficult to cultivate in cell lines, but they can be detected with commercially available EIAs. Adenovirus types 31 and 42–49 have been linked to diarrhea in HIV-infected and other immunocompromised persons.


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InternalMed_Harrison. Astroviruses are 28to 30-nm viruses with a characteristic icosahedral structure and a positive-sense, single-strand RNA. At least seven serotypes have been identified, of which serotype 1 is most common. Astroviruses are primarily pediatric pathogens, causing ~2–10% of cases of mild to moderate gastroenteritis in children. The availability of simple immunoassays to detect virus in fecal specimens and of molecular methods to confirm and characterize strains will permit more comprehensive assessment of the etiologic role of these agents. Toroviruses are 100to 140-nm, enveloped, positive-strand RNA viruses that are recognized as causes of gastroenteritis in horses (Berne virus) and cattle (Breda virus). Their role as a cause of diarrhea in humans is still unclear, but studies from Canada have demonstrated associations between torovirus excretion and both nosocomial gastroenteritis and necrotizing enterocolitis in neonates. These associations require further evaluation.


InternalMed_Harrison

InternalMed_Harrison. Picobirnaviruses are small, bisegmented, double-strand RNA viruses that cause gastroenteritis in a variety of animals. Their role as primary causes of gastroenteritis in humans remains unclear, but several studies have found an association between picobirnaviruses and gastroen teritis in HIV-infected adults. Several other viruses (e.g., enteroviruses, reoviruses, pestiviruses, and parvovirus B) have been identified in the feces of patients with diarrhea, but their etiologic role in gastroenteritis has not been proven. Diarrhea has also been noted as a manifestation of infection with recently recognized viruses that primarily cause severe respiratory illness: the severe acute respiratory syndrome–associated coronavirus (SARS-CoV), influenza A/H5N1 virus, and the current pandemic strain of influenza A/H1N1 virus. Enterovirus, Parechovirus, and Jeffrey I. Cohen


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InternalMed_Harrison. Enteroviruses, members of the family Picornaviridae, are so designated because of their ability to multiply in the gastrointestinal tract. Despite their name, these viruses are not a prominent cause of gastroenteritis. Enteroviruses encompass more than 100 human serotypes: 3 serotypes of poliovirus, 21 serotypes of coxsackievirus A, 6 serotypes of coxsackievirus B, 28 serotypes of echovirus, enteroviruses 68–71, and multiple new enteroviruses (beginning with enterovirus 73) that have been identified by molecular techniques. Human enteroviruses have been reclassified into four species designated A–D. Echoviruses 22 and 23 have been reclassified as parechoviruses 1 and 2 on the basis of low nucleotide homology and differences in viral proteins. Enterovirus surveillance conducted in the United States by the Centers for Disease Control and Prevention (CDC) in 2007–2008 showed that the most common enterovirus serotype, coxsackievirus B1, was followed in frequency by echoviruses 18, 9, and


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InternalMed_Harrison. States by the Centers for Disease Control and Prevention (CDC) in 2007–2008 showed that the most common enterovirus serotype, coxsackievirus B1, was followed in frequency by echoviruses 18, 9, and 6; together, these four viruses accounted for 52% of all isolates.


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InternalMed_Harrison. Human enteroviruses contain a single-stranded RNA genome surrounded by an icosahedral capsid comprising four viral proteins. These viruses have no lipid envelope and are stable in acidic environments, Enterovirus, Parechovirus, and Reovirus Infections 1290 including the stomach. They are susceptible to chlorine-containing cleansers but resistant to inactivation by standard disinfectants (e.g., alcohol, detergents) and can persist for days at room temperature.


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InternalMed_Harrison. Much of what is known about the pathogenesis of enteroviruses has been derived from studies of poliovirus infection. After ingestion, poliovirus is thought to infect epithelial cells in the mucosa of the gastrointestinal tract and then to spread to and replicate in the submucosal lymphoid tissue of the tonsils and Peyer’s patches. The virus next spreads to the regional lymph nodes, a viremic phase ensues, and the virus replicates in organs of the reticuloendothelial system. In some cases, a second episode of viremia occurs and the virus replicates further in various tissues, sometimes causing symptomatic disease.


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InternalMed_Harrison. It is uncertain whether poliovirus reaches the central nervous system (CNS) during viremia or whether it also spreads via peripheral nerves. Since viremia precedes the onset of neurologic disease in humans, it has been assumed that the virus enters the CNS via the bloodstream. The poliovirus receptor is a member of the immunoglobulin super-family. Poliovirus infection is limited to primates, largely because their cells express the viral receptor. Studies demonstrating the poliovirus receptor in the end-plate region of muscle at the neuromuscular junction suggest that, if the virus enters the muscle during viremia, it could travel across the neuromuscular junction up the axon to the anterior horn cells. Studies of monkeys and of transgenic mice expressing the poliovirus receptor show that, after IM injection, poliovirus does not reach the spinal cord if the sciatic nerve is cut. Taken together, these findings suggest that poliovirus can spread directly from muscle to the CNS by neural


InternalMed_Harrison

InternalMed_Harrison. after IM injection, poliovirus does not reach the spinal cord if the sciatic nerve is cut. Taken together, these findings suggest that poliovirus can spread directly from muscle to the CNS by neural pathways.


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InternalMed_Harrison. Poliovirus can usually be cultured from the blood 3–5 days after infection, before the development of neutralizing antibodies. While viral replication at secondary sites begins to slow 1 week after infection, it continues in the gastrointestinal tract. Poliovirus is shed from the oropharynx for up to 3 weeks after infection and from the gastrointestinal tract for as long as 12 weeks; hypogammaglobulinemic patients can shed poliovirus for >20 years. During replication in the gastrointestinal tract, attenuated oral poliovirus can mutate, reverting to a more neurovirulent phenotype within a few days; however, additional mutations are probably required for full neurovirulence. One patient with hypogammaglobulinemia who had been infected 12 years earlier and was receiving IV immune globulin suddenly developed quadriplegia and respiratory muscle paralysis and died; analysis showed that the virus had reverted to a more wild-type sequence.


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InternalMed_Harrison. Humoral and secretory immunity in the gastrointestinal tract is important for the control of enterovirus infections. Enteroviruses induce specific IgM, which usually persists for <6 months, and specific IgG, which persists for life. Capsid protein VP1 is the predominant target of neutralizing antibody, which generally confers lifelong protection against subsequent disease caused by the same serotype but does not prevent infection or virus shedding. Enteroviruses also induce cellular immunity whose significance is uncertain. Patients with impaired cellular immunity are not known to develop unusually severe disease when infected with enteroviruses. In contrast, the severe infections in patients with agammaglobulinemia emphasize the importance of humoral immunity in controlling enterovirus infections. Disseminated enterovirus infections have occurred in hematopoietic cell transplant recipients. IgA antibodies are instrumental in reducing poliovirus replication in and shedding from the


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InternalMed_Harrison. infections. Disseminated enterovirus infections have occurred in hematopoietic cell transplant recipients. IgA antibodies are instrumental in reducing poliovirus replication in and shedding from the gastrointestinal tract. Breast milk contains IgA specific for enteroviruses and can protect humans from infection.


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InternalMed_Harrison. Enteroviruses have a worldwide distribution. More than 50% of nonpoliovirus enterovirus infections and more than 90% of poliovirus infections are subclinical. When symptoms do develop, they are usually nonspecific and occur in conjunction with fever; only a minority of infections are associated with specific clinical syndromes. The incubation period for most enterovirus infections ranges from 2 to 14 days but usually is <1 week.


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InternalMed_Harrison. Enterovirus infection is more common in socioeconomically disadvantaged areas, especially in those where conditions are crowded and in tropical areas where hygiene is poor. Infection is most common among infants and young children; serious illness develops most often during the first few days of life and in older children and adults. In developing countries, where children are infected at an early age, poliovirus infection has less often been associated with paralysis; in countries with better hygiene, older children and adults are more likely to be seronegative, become infected, and develop paralysis. Passively acquired maternal antibody reduces the risk of symptomatic infection in neonates. Young children are the most frequent shedders of enteroviruses and are usually the index cases in family outbreaks. In temperate climates, enterovirus infections occur most often in the summer and fall; no seasonal pattern is apparent in the tropics.


InternalMed_Harrison

InternalMed_Harrison. Most enteroviruses are transmitted primarily by the fecal-oral or oral-oral route. Patients are most infectious shortly before and after the onset of symptomatic disease, when virus is present in the stool and throat. The ingestion of virus-contaminated food or water also can cause disease. Certain enteroviruses (such as enterovirus 70, which causes acute hemorrhagic conjunctivitis) can be transmitted by direct inoculation from the fingers to the eye. Airborne transmission is important for some viruses that cause respiratory tract disease, such as coxsackievirus A21. Enteroviruses can be transmitted across the placenta from mother to fetus, causing severe disease in the newborn. The transmission of enteroviruses through blood transfusions or insect bites has not been documented. Nosocomial spread of coxsackievirus and echovirus has taken place in hospital nurseries.


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InternalMed_Harrison. CLINICAL FEATuRES Poliovirus Infection Most infections with poliovirus are asymptomatic. After an incubation period of 3–6 days, ~5% of patients present with a minor illness (abortive poliomyelitis) manifested by fever, malaise, sore throat, anorexia, myalgias, and headache. This condition usually resolves in 3 days. About 1% of patients present with aseptic meningitis (nonparalytic poliomyelitis). Examination of cerebrospinal fluid (CSF) reveals lymphocytic pleocytosis, a normal glucose level, and a normal or slightly elevated protein level; CSF polymorphonuclear leukocytes may be present early. In some patients, especially children, malaise and fever precede the onset of aseptic meningitis.


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InternalMed_Harrison. paralytic poliomyelitis The least common presentation is that of paralytic disease. After one or several days, signs of aseptic meningitis are followed by severe back, neck, and muscle pain and by the rapid or gradual development of motor weakness. In some cases the disease appears to be biphasic, with aseptic meningitis followed first by apparent recovery but then (1–2 days later) by the return of fever and the development of paralysis; this form is more common among children than among adults. Weakness is generally asymmetric, is proximal more than distal, and may involve the legs (most commonly); the arms; or the abdominal, thoracic, or bulbar muscles. Paralysis develops during the febrile phase of the illness and usually does not progress after defervescence. Urinary retention may also occur. Examination reveals weakness, fasciculations, decreased muscle tone, and reduced or absent reflexes in affected areas. Transient hyperreflexia sometimes precedes the loss of reflexes.


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InternalMed_Harrison. may also occur. Examination reveals weakness, fasciculations, decreased muscle tone, and reduced or absent reflexes in affected areas. Transient hyperreflexia sometimes precedes the loss of reflexes. Patients frequently report sensory symptoms, but objective sensory testing usually yields normal results. Bulbar paralysis may lead to dysphagia, difficulty in handling secretions, or dysphonia. Respiratory insufficiency due to aspiration, involvement of the respiratory center in the medulla, or paralysis of the phrenic or intercostal nerves may develop, and severe medullary involvement may lead to circulatory collapse. Most patients with paralysis recover some function weeks to months after infection. About two-thirds of patients have residual neurologic sequelae.


InternalMed_Harrison

InternalMed_Harrison. Paralytic disease is more common among older individuals, pregnant women, and persons exercising strenuously or undergoing trauma at the time of CNS symptoms. Tonsillectomy predisposes to bulbar poliomyelitis, and IM injections increase the risk of paralysis in the involved limb(s).


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InternalMed_Harrison. vaccine-associated poliomyelitis The risk of developing poliomyelitis after oral vaccination is estimated at 1 case per 2.5 million doses. The risk is ~2000 times higher among immunodeficient persons, especially in persons with hypoor agammaglobulinemia. Before 1997, an average of eight cases of vaccine-associated poliomyelitis occurred—in both vaccinees and their contacts—in the United States each year. With the change in recommendations first to a sequential regimen of inactivated poliovirus vaccine (IPV) and oral poliovirus vaccine (OPV) in 1997 and then to an all-IPV regimen in 2000, the number of cases of vaccine-associated polio declined. From 1997 to 1999, six such cases were reported in the United States; no cases have been reported since 1999.


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InternalMed_Harrison. postpolio syndrome The postpolio syndrome presents as a new onset of weakness, fatigue, fasciculations, and pain with additional atrophy of the muscle group involved during the initial paralytic disease 20–40 years earlier. The syndrome is more common among women and with increasing time after acute disease. The onset is usually insidious, and weakness occasionally extends to muscles that were not involved during the initial illness. The prognosis is generally good; progression to further weakness is usually slow, with plateau periods of 1–10 years. The postpolio syndrome is thought to be due to progressive dysfunction and loss of motor neurons that compensated for the neurons lost during the original infection and not to persistent or reactivated poliovirus infection.


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InternalMed_Harrison. Other Enteroviruses An estimated 5–10 million cases of symptomatic disease due to enteroviruses other than poliovirus occur in the United States each year. Among neonates, enteroviruses are the most common cause of aseptic meningitis and nonspecific febrile illnesses. Certain clinical syndromes are more likely to be caused by certain serotypes (Table 228-1). nonspecific febrile illness (sUmmer grippe) The most common clinical manifestation of enterovirus infection is a nonspecific febrile illness. After an incubation period of 3–6 days, patients present with an acute onset of fever, malaise, and headache. Occasional cases are associated with upper respiratory symptoms, and some cases include nausea and vomiting. Symptoms often last for 3–4 days, and most cases resolve in a week. While infections with other respiratory viruses occur more often from late fall to early spring, febrile illness due to enteroviruses frequently occurs in the summer and early fall.


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InternalMed_Harrison. Serotype(s) of Indicated Virus generalized disease of tHe newborn Most serious enterovirus infections 1291 in infants develop during the first week of life, although severe disease can occur up to 3 months of age. Neonates often present with an illness resembling bacterial sepsis, with fever, irritability, and lethargy. Laboratory abnormalities include leukocytosis with a left shift, thrombocytopenia, elevated values in liver function tests, and CSF pleocytosis. The illness can be complicated by myocarditis and hypotension, fulminant hepatitis and disseminated intravascular coagulation, meningitis or meningoencephalitis, or pneumonia. It may be difficult to distinguish neonatal enterovirus infection from bacterial sepsis, although a history of a recent virus-like illness in the mother provides a clue.


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InternalMed_Harrison. aseptic meningitis and encepHalitis In children and young adults, enteroviruses are the cause of up to 90% of cases of aseptic meningitis in which an etiologic agent can be identified. Patients with aseptic meningitis typically present with an acute onset of fever, chills, headache, photophobia, and pain on eye movement. Nausea and vomiting also are common. Examination reveals meningismus without localizing neurologic signs; drowsiness or irritability may also be apparent. In some cases, a febrile illness may be reported that remits but returns several days later in conjunction with signs of meningitis. Other systemic manifestations may provide clues to an enteroviral cause, including diarrhea, myalgias, rash, pleurodynia, myocarditis, and herpangina. Examination of the CSF invariably reveals pleocytosis; the CSF cell count shows a shift from neutrophil to lymphocyte predominance within 1 day of presentation, and the total cell count does not exceed 1000/μL. The CSF glucose level is


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InternalMed_Harrison. pleocytosis; the CSF cell count shows a shift from neutrophil to lymphocyte predominance within 1 day of presentation, and the total cell count does not exceed 1000/μL. The CSF glucose level is usually normal (in contrast to the low CSF glucose level in mumps), with a normal or slightly elevated protein concentration. Partially treated bacterial meningitis may be particularly difficult to exclude in some instances. Enteroviral meningitis is more common in summer and fall in temperate climates, while viral meningitis of other etiologies is more common in winter and spring. Symptoms ordinarily resolve within a week, although CSF abnormalities can persist for several weeks. Enteroviral meningitis is often more severe in adults than in children. Neurologic sequelae are rare, and most patients have an excellent prognosis.


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InternalMed_Harrison. Enteroviral encephalitis is much less common than enteroviral aseptic meningitis. Occasional highly inflammatory cases of enteroviral meningitis may be complicated by a mild form of encephalitis that is recognized on the basis of progressive lethargy, disorientation, and sometimes seizures. Less commonly, severe primary encephalitis may develop. An estimated 10–35% of cases of viral encephalitis are due to enteroviruses. Immunocompetent patients generally have a good prognosis. Patients with hypogammaglobulinemia, agammaglobulinemia, or severe combined immunodeficiency may develop chronic meningitis or encephalitis; about half of these patients have a dermatomyositis-like syndrome, with peripheral edema, rash, and myositis. They may also have chronic hepatitis. Patients may develop neurologic disease while receiving immunoglobulin replacement therapy. Echoviruses (especially echovirus 11) are the most common pathogens in this situation.


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InternalMed_Harrison. Paralytic disease due to enteroviruses other than poliovirus occurs sporadically and is usually less severe than poliomyelitis. Most cases are due to enterovirus 70 or 71 or to coxsackievirus A7 or A9. Guillain-Barré syndrome is also associated with enterovirus infection. While earlier studies suggested a link between enteroviruses and chronic fatigue syndrome, most recent studies have not demonstrated such an association.


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InternalMed_Harrison. pleUrodynia (bornHolm disease) Patients with pleurodynia present with an acute onset of fever and spasms of pleuritic chest or upper abdominal pain. Chest pain is more common in adults, and abdominal pain is more common in children. Paroxysms of severe, knifelike pain usually last 15–30 min and are associated with diaphoresis and tachypnea. Fever peaks within an hour after the onset of paroxysms and subsides when pain resolves. The involved muscles are tender to palpation, and a pleural rub may be detected. The white blood cell count and chest x-ray results are usually normal. Most cases are due to coxsackievirus B and occur during epidemics. Symptoms resolve in a few days, and recurrences are rare. Treatment includes the administration of nonsteroidal anti-inflammatory agents or the application of heat to the affected muscles.


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InternalMed_Harrison. Enterovirus, Parechovirus, and Reovirus Infections 1292 myocarditis and pericarditis Enteroviruses are estimated to cause up to one-third of cases of acute myocarditis. Coxsackievirus B and its RNA have been detected in pericardial fluid and myocardial tissue in some cases of acute myocarditis and pericarditis. Most cases of enteroviral myocarditis or pericarditis occur in newborns, adolescents, or young adults. More than two-thirds of patients are male. Patients often present with an upper respiratory tract infection that is followed by fever, chest pain, dyspnea, arrhythmias, and occasionally heart failure. A pericardial friction rub is documented in half of cases, and the electrocardiogram shows ST-segment elevations or STand T-wave abnormalities. Serum levels of myocardial enzymes are often elevated. Neonates commonly have severe disease, while most older children and adults recover completely. Up to 10% of cases progress to chronic dilated cardiomyopathy. Chronic constrictive


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InternalMed_Harrison. are often elevated. Neonates commonly have severe disease, while most older children and adults recover completely. Up to 10% of cases progress to chronic dilated cardiomyopathy. Chronic constrictive pericarditis may also be a sequela.


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InternalMed_Harrison. eXantHems Enterovirus infection is the leading cause of exanthems in children in the summer and fall. While exanthems are associated with many enteroviruses, certain types have been linked to specific syndromes. Echoviruses 9 and 16 have frequently been associated with exanthem and fever. Rashes may be discrete or confluent, beginning on the face and spreading to the trunk and extremities. Echovirus 9 is the most common cause of a rubelliform (discrete) rash. Unlike the rash of rubella, the enteroviral rash occurs in the summer and is not associated with lymphadenopathy. Roseola-like rashes develop after defervescence, with macules and papules on the face and trunk. The Boston exanthem, caused by echovirus 16, is a roseola-like rash. A variety of other rashes have been associated with enteroviruses, including erythema multiforme (see Fig. 25e-25) and vesicular, urticarial, petechial, or purpuric lesions. Enanthems also occur, including lesions that resemble the Koplik’s spots seen


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InternalMed_Harrison. enteroviruses, including erythema multiforme (see Fig. 25e-25) and vesicular, urticarial, petechial, or purpuric lesions. Enanthems also occur, including lesions that resemble the Koplik’s spots seen with measles (see Fig. 25e-2).


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InternalMed_Harrison. Hand-foot-and-moUtH disease (Fig. 228-1) After an incubation period of 4–6 days, patients with hand-foot-and-mouth disease present with fever, anorexia, and malaise; these manifestations are followed by the development of sore throat and vesicles (see Fig. 25e-23) on the buccal mucosa and often on the tongue and then by the appearance of tender vesicular lesions on the dorsum of the hands, sometimes with involvement of the palms. The vesicles may form bullae and quickly ulcerate. About one-third of patients also have lesions on the palate, uvula, or tonsillar pillars, and one-third have a rash on the feet (including the soles) or on the buttocks. The disease is highly infectious, with attack rates of close to 100% among young children. The lesions usually resolve in 1 week. Most cases are due to coxsackievirus A16 or enterovirus 71.


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InternalMed_Harrison. An epidemic of enterovirus 71 infection in Taiwan in 1998 resulted in thousands of cases of hand-foot-and-mouth dis ease or herpangina (see below). Severe complications included CNS disease, myocarditis, and pulmonary hemorrhage. About 90% of those who died were children ≤5 years old, and death was associated with pulmonary edema or pulmonary hemorrhage. CNS disease included aseptic meningitis, flaccid paralysis (similar to that seen in poliomyelitis), and rhombencephalitis with myoclonus and tremor or ataxia. The mean age of patients with CNS complications was 2.5 years, and MRI in cases with encephalitis usually showed brain-stem lesions. Follow-up of children at 6 months showed persistent dysphagia, cranial nerve palsies, hypoventilation, limb weakness, and atrophy; at 3 years, persistent neurologic sequelae were documented, with delayed development and impaired cognitive function.


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InternalMed_Harrison. Another epidemic of enterovirus 71 infection occurred in China in 2008–2010, with nearly 500,000 infections and 126 deaths. Infections were associated with fever, rash, brain-stem encephalitis with myoclonic jerks, and limb trembling; some cases progressed to seizures and coma. Lung findings included pulmonary edema and hemorrhage; while the level of creatine kinase MB was sometimes elevated, myocardial necrosis was generally not found. Cyclic epidemics occur every 2–3 years in other Asian countries. However, the virus circulates at lower rates in the United States, Europe, and Africa. In the United States, hand-foot-and-mouth disease is most commonly associated with coxsackievirus A16. Between November 2011 and February 2012, outbreaks of hand-foot-and-mouth disease


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InternalMed_Harrison. FIGuRE 228-1 Vesicular eruptions of the hand (A), foot (B), and mouth (C) of a 6-year-old boy with coxsackievirus A6 infection. (Images reprinted courtesy of Centers for Disease Control and Prevention/Emerging Infectious Diseases.) due to coxsackievirus A6 occurred in several U.S. states, and 19% of the affected persons were hospitalized. Herpangina Herpangina is usually caused by coxsackievirus A and presents as acute-onset fever, sore throat, odynophagia, and grayish-white papulovesicular lesions on an erythematous base that ulcerate. The lesions can persist for weeks; are present on the soft palate, anterior pillars of the tonsils, and uvula; and are concentrated in the posterior portion of the mouth. In contrast to herpes stomatitis, enteroviral herpangina is not associated with gingivitis. Acute lymphonodular pharyngitis associated with coxsackievirus A10 presents as white or yellow nodules surrounded by erythema in the posterior oropharynx. The lesions do not ulcerate.


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InternalMed_Harrison. acUte HemorrHagic conjUnctivitis Patients with acute hemorrhagic conjunctivitis present with an acute onset of severe eye pain, blurred vision, photophobia, and watery discharge from the eye. Examination reveals edema, chemosis, and subconjunctival hemorrhage and often shows punctate keratitis and conjunctival follicles as well (Fig. 228-2). Preauricular adenopathy is often found. Epidemics and nosocomial spread have been associated with enterovirus 70 and coxsackievirus A24. Systemic symptoms, including headache and fever, develop in 20% of cases, and recovery is usually complete in 10 days. The sudden onset and short duration of the illness help to distinguish acute hemorrhagic conjunctivitis from other ocular infections, such as those due to adenovirus and Chlamydia trachomatis. Paralysis has been associated with some cases of acute hemorrhagic conjunctivitis due to enterovirus 70 during epidemics.


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InternalMed_Harrison. otHer manifestations Enteroviruses are an infrequent cause of childhood pneumonia and the common cold. In the fall of 2014, enterovirus D68 infection was confirmed in more than 500 persons with mild to severe respiratory illnesses in 43 U.S. states. Nearly all reported cases were in children, many of whom had asthma. Enterovirus D68 was detected in upper respiratory tract specimens from some patients with unexplained acute neurologic disease during outbreaks of infection with this virus; however, the virus was not detected in the CSF, and at present the link between the virus and neurologic disease is uncertain. Coxsackievirus B has been isolated at autopsy from the pancreas of a few children presenting with type 1 diabetes mellitus; however, most attempts to isolate the virus have been unsuccessful. Other diseases that have been associated with enterovirus infection include parotitis, bronchitis, bronchiolitis, croup, infectious lymphocytosis, polymyositis, acute arthritis, and acute


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InternalMed_Harrison. Other diseases that have been associated with enterovirus infection include parotitis, bronchitis, bronchiolitis, croup, infectious lymphocytosis, polymyositis, acute arthritis, and acute nephritis.


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InternalMed_Harrison. Isolation of enterovirus in cell culture is the traditional diagnostic procedure. While cultures of stool, nasopharyngeal, or throat samples from patients with enterovirus diseases are often positive, isolation of the virus from these sites does not prove that it is directly associated with disease because these sites are frequently colonized for weeks in


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InternalMed_Harrison. FIGuRE 228-2 Acute hemorrhagic conjunctivitis due to enterovirus 70. (Image reprinted with permission from Red Book 2012: Committee on Infectious Diseases, 29th ed. Used with permission of the American Academy of Pediatrics.) patients with subclinical infections. Isolation of virus from the throat is 1293 more likely to be associated with disease than is isolation from the stool since virus is shed for shorter periods from the throat. Cultures of CSF, serum, fluid from body cavities, or tissues are positive less frequently, but a positive result is indicative of disease caused by enterovirus. In some cases, the virus is isolated only from the blood or only from the CSF; therefore, it is important to culture multiple sites. Cultures are more likely to be positive earlier than later in the course of infection. Most human enteroviruses can be detected within a week after inoculation of cell cultures. Cultures may be negative because of the presence of neutralizing antibody, lack of


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InternalMed_Harrison. the course of infection. Most human enteroviruses can be detected within a week after inoculation of cell cultures. Cultures may be negative because of the presence of neutralizing antibody, lack of susceptibility of the cells used, or inappropriate handling of the specimen. Coxsackievirus A may require inoculation into special cell-culture lines or into suckling mice.


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InternalMed_Harrison. Identification of the enterovirus serotype is useful primarily for epidemiologic studies and, with a few exceptions, has little clinical utility. It is important to identify serious infections with enterovirus during epidemics and to distinguish the vaccine strain of poliovirus from the other enteroviruses in the throat or in the feces. Stool and throat samples for culture as well as acute-and convalescent-phase serum specimens should be obtained from all patients with suspected poliomyelitis. In the absence of a positive CSF culture, a positive culture of stool obtained within the first 2 weeks after the onset of symptoms is most often used to confirm the diagnosis of poliomyelitis. If polio-virus infection is suspected, two or more fecal and throat swab samples should be obtained at least 1 day apart and cultured for enterovirus as soon as possible. If poliovirus is isolated, it should be sent to the CDC for identification as either wild-type or vaccine virus.


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InternalMed_Harrison. Reverse-transcriptase polymerase chain reaction (PCR) has been used to amplify viral nucleic acid from CSF, serum, urine, stool, conjunctiva, throat swabs, and tissues. A pan-enterovirus PCR assay can detect all human enteroviruses. With the proper controls, PCR of the CSF is highly sensitive (70–100%) and specific (>80%) and is more rapid than culture. PCR of the CSF is less likely to be positive when patients present ≥3 days after the onset of meningitis or with enterovirus 71 infection; in these cases, PCR of throat or rectal swabs— although less specific than PCR of CSF—should be considered. PCR of serum is also highly sensitive and specific in the diagnosis of disseminated disease. PCR may be particularly helpful for the diagnosis and follow-up of enterovirus disease in immunodeficient patients receiving immunoglobulin therapy, whose viral cultures may be negative. Antigen detection is less sensitive than PCR.


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InternalMed_Harrison. Serologic diagnosis of enterovirus infection is limited by the large number of serotypes and the lack of a common antigen. Demonstration of seroconversion may be useful in rare cases for confirmation of culture results, but serologic testing is usually limited to epidemiologic studies. Serum should be collected and frozen soon after the onset of disease and again ~4 weeks later. Measurement of neutralizing titers is the most accurate method for antibody determination; measurement of complement-fixation titers is usually less sensitive. Titers of virus-specific IgM are elevated in both acute and chronic infection.


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InternalMed_Harrison. Most enterovirus infections are mild and resolve spontaneously; however, intensive supportive care may be needed for cardiac, hepatic, or CNS disease. IV, intrathecal, or intraventricular immunoglobulin has been used with apparent success in some cases for the treatment of chronic enterovirus meningoencephalitis and dermatomyositis in patients with hypogammaglobulinemia or agammaglobulinemia. The disease may stabilize or resolve during therapy; however, some patients decline inexorably despite therapy. IV immunoglobulin often prevents severe enterovirus disease in these patients. IV administration of immunoglobulin with high titers of antibody to the infecting virus has been used in some cases of life-threatening infection in neonates, who may not have maternally acquired antibody. In one trial involving neonates with enterovirus infections, immunoglobulin containing very high titers of antibody to the infecting virus reduced rates of viremia; however, the study was too small to show


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InternalMed_Harrison. trial involving neonates with enterovirus infections, immunoglobulin containing very high titers of antibody to the infecting virus reduced rates of viremia; however, the study was too small to show a substantial clinical benefit. The level of


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InternalMed_Harrison. Enterovirus, Parechovirus, and Reovirus Infections 1294 enteroviral antibodies varies with the immunoglobulin preparation. A phase 2 trial of pleconaril for severe neonatal enterovirus disease has been completed; however, as of this writing, the results have not been reported and the drug is not available on a compassionate-use basis. Glucocorticoids are contraindicated. Good hand-washing practices and the use of gowns and gloves are important in limiting nosocomial transmission of enteroviruses during epidemics. Enteric precautions are indicated for 7 days after the onset of enterovirus infections. Enterovirus 71 vaccine candidates are under development.


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InternalMed_Harrison. (See also Chap. 148) After a peak of 57,879 cases of poliomy elitis in the United States in 1952, the introduction of IPV in 1955 and of OPV in 1961 ultimately eradicated disease due to wild-type poliovirus in the Western Hemisphere. Such disease has not been documented in the United States since 1979, when cases occurred among religious groups who had declined immunization. In the Western Hemisphere, paralysis due to wild-type poliovirus was last documented in 1991.


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InternalMed_Harrison. In 1988, the World Health Organization adopted a resolution to eradicate poliomyelitis by the year 2000. From 1988 to 2001, the number of cases worldwide decreased by >99%, with only 496 confirmed cases reported in 2001. Wild-type poliovirus type 2 has not been detected in the world since 1999. The Americas were certified free of indigenous wild-type poliovirus transmission in 1994, the Western Pacific Region in 2000, and the European Region in 2002. However, in 2002, there were 1922 cases of polio, with 1600 cases reported in India. In fact, after the nadir of 496 cases in 2001, 21 countries that had previously been free of polio reported cases imported from 6 polio-endemic countries in 2002–2005. By 2006, polio transmission had been reduced in most of these 21 countries. In 2012, 293 cases of polio were reported (the lowest number ever in a 1-year period); 85% were from Nigeria, Pakistan, and Afghanistan, the only countries where polio remains endemic (Table 228-2). As of November


InternalMed_Harrison

InternalMed_Harrison. of polio were reported (the lowest number ever in a 1-year period); 85% were from Nigeria, Pakistan, and Afghanistan, the only countries where polio remains endemic (Table 228-2). As of November 2013, there had been 390 cases of polio in 2013 compared with 293 cases in 2012. The increase was associated with a marked rise in imported cases, including more than 180 cases in Somalia, more than 10 cases each in Kenya and Syria, and cases in Cameroon and Ethiopia. Also in 2013, wild-type poliovirus was detected in sewage in Israel, prompting a massive vaccination campaign with OPV. As of November 2013, India had not reported a case of polio since January 2011. Polio is a source of concern for unimmunized or partially immunized travelers. Importation of polio-virus accounted for ~50% of cases in 2013. Clearly, global eradication of polio is necessary to eliminate the risk of importation of wild-type virus. Outbreaks are thought to have been facilitated by suboptimal rates of vaccination,


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InternalMed_Harrison. in 2013. Clearly, global eradication of polio is necessary to eliminate the risk of importation of wild-type virus. Outbreaks are thought to have been facilitated by suboptimal rates of vaccination, isolated pockets of unvaccinated children, poor sanitation and crowding, improper vaccine-storage conditions, and a reduced level of response to one of the serotypes in the vaccine.


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InternalMed_Harrison. Country Type of Transmission No. of Cases aOf these cases, 8 were vaccine-derived. bOf these cases, 16 were vaccine-derived. cOf these cases, 9 were vaccine-derived. dOf these cases, 12 were vaccine-derived. Source: World Health Organization. While the global eradication campaign has markedly reduced the number of cases of endemic polio, doubts have been raised as to whether eradication is a realistic goal, given the large number of asymptomatic infections and the political instability in developing countries.


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InternalMed_Harrison. The occurrence of outbreaks of poliomyelitis due to circulating vaccine-derived poliovirus of all three types has been increasing, especially in areas with low vaccination rates. In Egypt, 32 cases of vaccine-derived polio occurred in 1983–1993; in the Dominican Republic and Haiti, 21 cases occurred in 2000–2001; in Indonesia, 46 cases were reported in 2005; in Nigeria, 385 cases occurred in 2005–2012; in the Democratic Republic of the Congo, 64 cases were reported in 2008–2012; in Pakistan, 16 cases occurred in 2012, and at least 30 cases occurred in 2013. These OPV-derived viruses reverted to a more neurovirulent phenotype after undetected circulation (probably for >2 years). The epidemic in Hispaniola was rapidly terminated after intensive vaccination with OPV. In 2005, a case of vaccine-derived polio occurred in an unvaccinated U.S. woman returning from a visit to Central and South America. In the same year, an unvaccinated immunocompromised infant in Minnesota was found to be


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InternalMed_Harrison. polio occurred in an unvaccinated U.S. woman returning from a visit to Central and South America. In the same year, an unvaccinated immunocompromised infant in Minnesota was found to be shedding vaccine-derived poliovirus; further investigation identified 4 of 22 infants in the same community who were shedding the virus. All 5 infants were asymptomatic. These outbreaks emphasize the need for maintaining high levels of vaccine coverage and continued surveillance for circulating virus.


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InternalMed_Harrison. IPV is used in most industrialized countries and OPV in most developing countries, including those in which polio still is or recently was endemic. While IM injections of other vaccines (live or attenuated) can be given concurrently with OPV, unnecessary IM injections should be avoided during the first month after OPV vaccination because they increase the risk of vaccine-associated paralysis. Since 1988, an enhanced-potency inactivated poliovirus vaccine has been available in the United States.


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InternalMed_Harrison. After several doses of OPV alone, the seropositivity rate for individual poliovirus serotypes may still be suboptimal for children in developing countries; one or more supplemental doses of IPV can increase the rate of seropositivity for these serotypes. Against a given serotype, monovalent OPV containing only that serotype is more immunogenic than trivalent vaccine because of a lack of interference from other serotypes. With eradication of wild-type poliovirus type 2, bivalent OPV (types 1 and 3), which was shown to be superior to trivalent OPV, has been the vaccine of choice to eliminate polio and has markedly reduced rates of polio in Nigeria. As the frequency of wild-type polio declines and reports of polio associated with circulating vaccine-derived viruses increase, the World Health Organization is investigating whether IPV can be produced from OPV strains that require less biocontainment, ultimately replacing OPV.


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InternalMed_Harrison. OPV and IPV induce antibodies that persist for at least 5 years. Both vaccines induce IgG and IgA antibodies. Compared with recipients of IPV, recipients of OPV shed less virus and less frequently develop reinfection with wild-type virus after exposure to poliovirus. Although IPV is safe and efficacious, OPV offers the advantages of ease of administration, lower cost, and induction of intestinal immunity resulting in a reduction in the risk of community transmission of wild-type virus. Because of progress toward global eradication of polio and the continued occurrence of cases of vaccine-associated polio, an all-IPV regimen was recommended in 2000 for childhood poliovirus vaccination in the United States, with vaccine administration at 2, 4, and 6–18 months and 4–6 years of age. The risk of vaccine-associated polio should be discussed before OPV is administered. Recommendations for vaccination of adults are listed in Table 228-3.


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InternalMed_Harrison. There are concerns about discontinuing vaccination in the event that endemic spread of poliovirus is eliminated. Among the reasons for these concerns are that poliovirus is shed from some immunocompromised persons for >10 years, that vaccine-derived poliovirus can circulate and cause disease, and that wild-type poliovirus is present in research laboratories. Human parechoviruses (HPeVs), like enteroviruses, are members of the family Picornaviridae. The 16 serotypes of HPeV commonly cause 1. Most adults in the United States have been vaccinated during childhood and are at little risk of exposure to wild-type virus in the United States. Immunization is recommended for those with a higher risk of exposure than the general population, including: a. travelers to areas where poliovirus is or may be epidemic or endemic; b. members of communities or population groups with disease caused by wild-type polioviruses; c. d.


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InternalMed_Harrison. travelers to areas where poliovirus is or may be epidemic or endemic; b. members of communities or population groups with disease caused by wild-type polioviruses; c. d. health care workers in close contact with patients who may be excreting wild-type polioviruses. 2. Three doses of IPV are recommended for adults who need to be immunized. The second dose should be given 1–2 months after the first dose; the third dose should be given 6–12 months after the second dose. 3. Adults who are at increased risk of exposure to wild-type poliovirus and who have previously completed primary immunization should receive a single dose of IPV. Adults who did not complete primary immunization should receive the remaining required doses of IPV. Abbreviation: IPV, inactivated poliovirus vaccine. Source: Modified from Pickering LK, ed. Red Book 2012: Committee on Infectious Diseases, 29th ed.


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InternalMed_Harrison. Source: Modified from Pickering LK, ed. Red Book 2012: Committee on Infectious Diseases, 29th ed. infections in early childhood. HPeV-1 infections occur throughout the year, while other parechovirus infections occur more commonly in summer and fall. Infections with HPeVs present similarly to those due to enteroviruses and may cause generalized disease of the newborn, aseptic meningitis, encephalitis, transient paralysis, exanthems, respiratory tract disease, and gastroenteritis. While HPeV-1 is the most common serotype and generally causes mild disease, deaths of infants in the United States have been associated with HPeV-1, HPeV-3, and HPeV-6. HPeVs can be isolated from the same sites as enteroviruses, including the nasopharynx, stool, and respiratory tract secretions. PCR using pan-enterovirus primers does not detect HPeVs, and while PCR assays are performed by the CDC and research laboratories, many commercial laboratories do not perform the test.


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InternalMed_Harrison. Reoviruses are double-stranded RNA viruses encompassing three serotypes. Serologic studies indicate that most humans are infected with reoviruses during childhood. Most infections either are asymptomatic or cause mild upper respiratory tract symptoms. Reovirus is considered a rare cause of mild gastroenteritis or meningitis in infants and children. Speculation regarding an association of reovirus type 3 with idiopathic neonatal hepatitis and extrahepatic biliary atresia is based on an elevated prevalence of antibody to reovirus in some affected patients and the detection of viral RNA by PCR in hepatobiliary tissues in some studies. New orthoreoviruses have been associated with human disease—e.g., Melaka and Kampar viruses with fever and acute respiratory disease in Malaysia, and Nelson Bay virus with acute respiratory disease in a traveler from Bali.


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InternalMed_Harrison. Measles (Rubeola) Kaitlin Rainwater-Lovett, William J. Moss DEFINITION Measles is a highly contagious viral disease that is characterized by a prodromal illness of fever, cough, coryza, and conjunctivitis followed by the appearance of a generalized maculopapular rash. 229 Before the widespread use of measles vaccines, it was estimated that measles caused between 5 million and 8 million deaths worldwide each year.


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InternalMed_Harrison. Before the widespread use of measles vaccines, it was estimated that measles caused between 5 million and 8 million deaths worldwide each year. tion. In the Americas, intensive vaccination and surveillance efforts—based in part on the successful Pan American Health Organization strategy of periodic nationwide measles vaccination campaigns (supplementary immunization activities, or SIAs)—and high levels of routine measles vaccine coverage interrupted endemic transmission of measles virus. In the United States, high-level coverage with two doses of measles vaccine eliminated endemic measles virus transmission in 2000. More recently, progress has been made in reducing measles incidence and mortality rates in sub-Saharan Africa and Asia as a consequence of increasing routine measles vaccine coverage and provision of a second dose of measles vaccine through mass measles vaccination campaigns and childhood immunization programs.


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InternalMed_Harrison. In 2003, the World Health Assembly endorsed a resolution urging member countries to reduce the number of deaths attributed to measles by 50% (compared with 1999 estimates) by the end of 2005. This target was met. Global measles mortality rates were further reduced in 2008; during that year, there were an estimated 164,000 deaths due to measles (uncertainty bounds: 115,000 and 222,000 deaths). These achievements attest to the enormous public-health significance of measles vaccination. However, recent large outbreaks of measles in Europe and Africa illustrate the challenges faced in sustaining measles control: in these outbreaks, measles was imported into countries that had eliminated indigenous transmission of measles virus.


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InternalMed_Harrison. The Measles and Rubella Initiative, a partnership led by the American Red Cross, the United Nations Foundation, UNICEF, the U.S. Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO), is playing an important role in reducing global measles incidence and mortality rates. Since its inception in 2001, the Initiative has provided governments and communities in more than 80 countries with technical and financial support for routine immunization activities, mass vaccination campaigns, and disease surveillance systems. Through its 2012–2020 Global Measles and Rubella Strategic Plan, the Initiative aims to reduce measles deaths by 95% (compared with year 2000 estimates) by 2015 and to eliminate measles from at least five of the six WHO regions by 2020. As regional goals for measles elimination are set, global measles eradication is likely to become a public health goal in the near future.


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InternalMed_Harrison. Measles virus is a spherical, nonsegmented, single-stranded, negative-sense RNA virus and a member of the Morbillivirus genus in the family Paramyxoviridae. Measles was originally a zoonotic infection, arising from animal-to-human transmission of an ancestral morbillivirus ~10,000 years ago, when human populations had attained sufficient size to sustain virus transmission. Although RNA viruses typically have high mutation rates, measles virus is considered to be an antigenically monotypic virus; i.e., the surface proteins responsible for inducing protective immunity have retained their antigenic structure across time and distance. The public health significance of this stability is that measles vaccines developed decades ago from a single strain of measles virus remain protective worldwide. Measles virus is killed by ultraviolet light and heat, and attenuated measles vaccine viruses retain these characteristics, necessitating a cold chain for vaccine transport and storage.


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InternalMed_Harrison. Measles virus is one of the most highly contagious directly transmitted pathogens. Outbreaks can occur in populations in which <10% of persons are susceptible. Chains of transmission are common among household contacts, school-age children, and health care workers. There are no latent or persistent measles virus infections that result in prolonged contagiousness, nor are there animal reservoirs for the virus. Thus, measles virus can be maintained in human populations only by an unbroken chain of acute infections, which requires 1296 a continuous supply of susceptible individuals. Newborns become susceptible to measles virus infection when passively acquired maternal antibody is lost; when not vaccinated, these infants account for the bulk of new susceptible individuals. Endemic measles has a typical temporal pattern characterized by yearly seasonal epidemics superimposed on longer epidemic cycles of 2–5 years or more. In temperate climates, annual measles outbreaks typically occur in


InternalMed_Harrison

InternalMed_Harrison. a typical temporal pattern characterized by yearly seasonal epidemics superimposed on longer epidemic cycles of 2–5 years or more. In temperate climates, annual measles outbreaks typically occur in the late winter and early spring. These annual outbreaks are probably attributable to social networks facilitating transmission (e.g., congregation of children at school) and environmental factors favoring the viability and transmission of measles virus. Measles cases continue to occur during interepidemic periods in large populations, but at low incidence. The longer epidemic cycles occurring every several years result from the accumulation of susceptible persons over successive birth cohorts and the subsequent decline in the number of susceptibles following an outbreak. Secondary attack rates among susceptible household and institutional contacts generally exceed 90%. The average age at which measles occurs depends on rates of contact with infected persons, protective maternal antibody


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InternalMed_Harrison. among susceptible household and institutional contacts generally exceed 90%. The average age at which measles occurs depends on rates of contact with infected persons, protective maternal antibody decline, and vaccine coverage. In densely populated urban settings with low-level vaccination coverage, measles is a disease of infants and young children. The cumulative distribution can reach 50% by 1 year of age, with a significant proportion of chil dren acquiring measles before 9 months—the age of routine vaccina tion in many countries, in line with the schedule recommended by the


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InternalMed_Harrison. WHO’s Expanded Programme on Immunization. As measles vaccine coverage increases or population density decreases, the age distribu tion shifts toward older children. In such situations, measles cases predominate in school-age children. Infants and young children, although susceptible if not protected by vaccination, are not exposed transmitted by direct contact with infected secretions but does not survive for long on fomites.


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InternalMed_Harrison. The incubation period for measles is ~10 days to fever onset and 14 days to rash onset. This period may be shorter in infants and longer (up to 3 weeks) in adults. Infection is initiated when measles virus is deposited on epithelial cells in the respiratory tract, oropharynx, or conjunctivae (Fig. 229-1A). During the first 2–4 days after infection, measles virus proliferates locally in the respiratory mucosa and spreads to draining lymph nodes. Virus then enters the bloodstream in infected leukocytes (primarily monocytes), producing the primary viremia that disseminates infection throughout the reticuloendothelial system. Further replication results in secondary viremia that begins 5–7 days after infection and disseminates measles virus throughout the body. Replication of measles virus in these target organs, together with the host’s immune response, is responsible for the signs and symptoms of measles that occur 8–12 days after infection and mark the end of the incubation period


InternalMed_Harrison

InternalMed_Harrison. in these target organs, together with the host’s immune response, is responsible for the signs and symptoms of measles that occur 8–12 days after infection and mark the end of the incubation period (Fig. 229-1B).


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InternalMed_Harrison. to measles virus at a rate sufficient to cause a large disease burden in this age group. As vaccination coverage increases further, the age distribution of cases may be shifted into adolescence and adulthood; this distribution is seen in measles outbreaks in the United States and age groups. Persons with measles are infectious for several days before and after the onset of rash, when levels of measles virus in blood and body fluids are highest and when cough, coryza, and sneezing, which facilitate virus spread, are most severe. The contagiousness of measles before the onset of recognizable disease hinders the effectiveness of quarantine measures. Viral shedding by children with impaired cell-mediated immunity can be prolonged.


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InternalMed_Harrison. Medical settings are well-recognized sites of measles virus transmission. Children may present to health care facilities during the prodrome, when the diagnosis is not obvious although the child is Days after infection infectious and is likely to infect susceptible contacts. Health care workers can acquire measles from infected children and transmit measles virus to others. Nosocomial transmission can be reduced by maintenance of a high index of clinical suspicion, use of appropriate isolation precautions when measles is suspected, administration of measles vaccine to susceptible children and health care workers, and documentation of health care workers’ immunity to measles (i.e., proof of receipt of two doses of measles vaccine or detection of antibodies to measles virus).


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InternalMed_Harrison. As efforts at measles control are increasingly successful, public perceptions of the risk of measles as a disease diminish and are replaced by concerns about possible adverse events associated with measles vaccine. As a consequence, numerous measles outbreaks have occurred because of opposition to vaccination on religious or philosophical grounds or unfounded fears of serious adverse events (see “Active Immunization,” below). Measles virus is transmitted primarily by respiratory droplets over short distances and, less commonly, by small-particle aerosols that remain suspended in the air for long periods. Airborne transmission appears to be important in certain settings, including schools, physicians’ offices, hospitals, and enclosed public places. The virus can be FIGuRE 229-1 Measles virus infection: pathogenesis, clinical features, and immune responses. A. Spread of measles virus, from initial infection of the respiratory tract through dissemination to the skin.


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InternalMed_Harrison. B. Appearance of clinical signs and symptoms, including Koplik’s spots and rash. C. Antibody and T cell responses to measles virus. The signs and symptoms of measles arise coincident with the host immune response. (Source: Modified from WJ Moss, DE Griffin: Nat Rev Microbiol 4:900, 2006.)


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InternalMed_Harrison. Host immune responses to measles virus are essential for viral clearance, clinical recovery, and the establishment of long-term immunity (Fig. 229-1C). Early nonspecific (innate) immune responses during the prodromal phase include activation of natural killer cells and increased production of antiviral proteins. The adaptive immune responses consist of measles virus–specific antibody and cellular responses. The protective efficacy of antibodies to measles virus is illustrated by the immunity conferred to infants from passively acquired maternal antibodies and the protection of exposed, susceptible individuals after administration of anti–measles virus immunoglobulin. The first measles virus–specific antibodies produced after infection are of the IgM subtype, with a subsequent switch to predominantly IgG1 and IgG4 isotypes. The IgM antibody response is typically absent following reexposure or revaccination and serves as a marker of primary infection.


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InternalMed_Harrison. The importance of cellular immunity to measles virus is demonstrated by the ability of children with agammaglobulinemia (congenital inability to produce antibodies) to recover fully from measles and the contrasting picture for children with severe defects in T lymphocyte function, who often develop severe or fatal disease (Chap. 374). The initial predominant TH1 response (characterized by interferon γ) is essential for viral clearance, and the later TH2 response (characterized by interleukin 4) promotes the development of measles virus–specific antibodies that are critical for protection against reinfection. The duration of protective immunity following wild-type measles virus infection is generally thought to be lifelong. Immunologic memory to measles virus includes both continued production of measles virus–specific antibodies and circulation of measles virus–specific CD4+ and CD8+ T lymphocytes.


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InternalMed_Harrison. However, the intense immune responses induced by measles virus infection are paradoxically associated with depressed responses to unrelated (non–measles virus) antigens, which persist for several weeks to months beyond resolution of the acute illness. This state of immune suppression enhances susceptibility to secondary infections with bacteria and viruses that cause pneumonia and diarrhea and is responsible for a substantial proportion of measles-related morbidity and deaths. Delayed-type hypersensitivity responses to recall antigens, such as tuberculin, are suppressed, and cellular and humoral responses to new antigens are impaired. Reactivation of tuberculosis and remission of autoimmune diseases after measles have been described and are attributed to this period of immune suppression. APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: Clinicians should consider measles in persons presenting with fever and generalized erythematous rash, particularly when measles virus is known to be circulating or the patient has a history of travel to endemic areas. Appropriate precautions must be taken to prevent nosocomial transmission. The diagnosis requires laboratory confirmation except during large outbreaks in which an epidemiologic link to a confirmed case can be established. Care is largely supportive and consists of the administration of vitamin A and antibiotics (see “Treatment,” below). Complications of measles, including secondary bacterial infections and encephalitis, may occur after acute illness and require careful monitoring, particularly in immunocompromised persons.


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InternalMed_Harrison. In most persons, the signs and symptoms of measles are highly characteristic (Fig. 229-1B). Fever and malaise beginning ~10 days after exposure are followed by cough, coryza, and conjunctivitis. These signs and symptoms increase in severity over 4 days. Koplik’s spots (see Fig. 25e-2) develop on the buccal mucosa ~2 days before the rash appears. The characteristic rash of measles (see Fig. 25e-3) begins 2 weeks after infection, when the clinical manifestations are most severe, and signal the host’s immune response to the replicating virus. 1297 Headache, abdominal pain, vomiting, diarrhea, and myalgia may be present. Koplik’s spots (see Fig. 25e-2) are pathognomonic of measles and consist of bluish white dots ~1 mm in diameter surrounded by erythema. The lesions appear first on the buccal mucosa opposite the lower molars but rapidly increase in number to involve the entire buccal mucosa. They fade with the onset of rash.


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InternalMed_Harrison. The rash of measles begins as erythematous macules behind the ears and on the neck and hairline. The rash progresses to involve the face, trunk, and arms (see Fig. 25e-3), with involvement of the legs and feet by the end of the second day. Areas of confluent rash appear on the trunk and extremities, and petechiae may be present. The rash fades slowly in the same order of progression as it appeared, usually beginning on the third or fourth day after onset. Resolution of the rash may be followed by desquamation, particularly in undernourished children.


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InternalMed_Harrison. Because the characteristic rash of measles is a consequence of the cellular immune response, it may not develop in persons with impaired cellular immunity (e.g., those with AIDS; Chap. 226). These persons have a high case-fatality rate and frequently develop giant-cell pneumonitis caused by measles virus. T lymphocyte defects due to causes other than HIV-1 infection (e.g., cancer chemotherapy) also are associated with increased severity of measles. A severe atypical measles syndrome was observed in recipients of a formalin-inactivated measles vaccine (used in the United States from 1963 to 1967 and in Canada until 1970) who were subsequently exposed to wild-type measles virus. The atypical rash began on the palms and soles and spread centripetally to the proximal extremities and trunk, sparing the face. The rash was initially erythematous and maculopapular but frequently progressed to vesicular, petechial, or purpuric lesions (see Fig. 25e-22).


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InternalMed_Harrison. The differential diagnosis of measles includes other causes of fever, rash, and conjunctivitis, including rubella, Kawasaki disease, infectious mononucleosis, roseola, scarlet fever, Rocky Mountain spotted fever, entero virus or adenovirus infection, and drug sensitivity. Rubella is a milder illness without cough and with distinctive lymphadenopathy. The rash of roseola (exanthem subitum) (see Fig. 25e-5) appears after fever has subsided. The atypical lymphocytosis in infectious mononucleosis contrasts with the leukopenia commonly observed in children with measles.


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InternalMed_Harrison. Measles is readily diagnosed on clinical grounds by clinicians familiar with the disease, particularly during outbreaks. Koplik’s spots (see Fig. 25e-2) are especially helpful because they appear early and are pathognomonic. Clinical diagnosis is more difficult (1) during the prodromal illness; (2) when the rash is attenuated by passively acquired antibodies or prior immunization; (3) when the rash is absent or delayed in immunocompromised children or severely undernourished children with impaired cellular immunity; and (4) in regions where the incidence of measles is low and other pathogens are responsible for the majority of illnesses with fever and rash. The CDC case definition for measles requires (1) a generalized maculopapular rash of at least 3 days’ duration; (2) fever of at least 38.3°C (101°F); and (3) cough, coryza, or conjunctivitis.


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InternalMed_Harrison. Serology is the most common method of laboratory diagnosis. The detection of measles virus–specific IgM in a single specimen of serum or oral fluid is considered diagnostic of acute infection, as is a fourfold or greater increase in measles virus–specific IgG antibody levels between acuteand convalescent-phase serum specimens. Primary infection in the immunocompetent host results in antibodies that are detectable within 1–3 days of rash onset and reach peak levels in 2–4 weeks. Measles virus–specific IgM antibodies may not be detectable until 4–5 days or more after rash onset and usually fall to undetectable levels within 4–8 weeks of rash onset.


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InternalMed_Harrison. Several methods for measurement of antibodies to measles virus are available. Neutralization tests are sensitive and specific, and the results are highly correlated with protective immunity; however, these tests 1298 require propagation of measles virus in cell culture and thus are expensive and laborious. Commercially available enzyme immunoassays are most frequently used. Measles can also be diagnosed by isolation of the virus in cell culture from respiratory secretions, nasopharyngeal or conjunctival swabs, blood, or urine. Direct detection of giant cells in respiratory secretions, urine, or tissue obtained by biopsy provides another method of diagnosis. For detection of measles virus RNA by reverse-transcriptase polymerase chain reaction amplification of RNA extracted from clinical specimens, primers targeted to highly conserved regions of measles virus genes are used. Extremely sensitive and specific, this assay may also permit identification and characterization of measles virus


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InternalMed_Harrison. primers targeted to highly conserved regions of measles virus genes are used. Extremely sensitive and specific, this assay may also permit identification and characterization of measles virus genotypes for molecular epidemiologic studies and can distinguish wild-type from vaccine virus strains.


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InternalMed_Harrison. There is no specific antiviral therapy for measles. Treatment consists of general supportive measures, such as hydration and administration of antipyretic agents. Because secondary bacterial infections are a major cause of morbidity and death attributable to measles, effective case management involves prompt antibiotic treatment for patients who have clinical evidence of bacterial infection, including pneumonia and otitis media. Streptococcus pneumoniae and Haemophilus influenzae type b are common causes of bacterial pneumonia following measles; vaccines against these pathogens probably lower the incidence of secondary bacterial infections following measles.


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InternalMed_Harrison. Vitamin A is effective for the treatment of measles and can markedly reduce rates of morbidity and mortality. The WHO recommends administration of once-daily doses of 200,000 IU of vitamin A for 2 consecutive days to all children with measles who are ≥12 months of age. Lower doses are recommended for younger children: 100,000 IU per day for children 6–12 months of age and 50,000 IU per day for children <6 months old. A third dose is recommended 2–4 weeks later for children with evidence of vitamin A deficiency. While such deficiency is not a widely recognized problem in the United States, many American children with measles do, in fact, have low serum levels of vitamin A, and these children experience increased measles-associated morbidity. The Committee on Infectious Diseases of the American Academy of Pediatrics recommends that the administration of two consecutive daily doses of vitamin A be considered for children who are hospitalized with measles and its complications as well as


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InternalMed_Harrison. Academy of Pediatrics recommends that the administration of two consecutive daily doses of vitamin A be considered for children who are hospitalized with measles and its complications as well as for children with measles who are immunodeficient; who have ophthalmologic evidence of vitamin A deficiency, impaired intestinal absorption, or moderate to severe malnutrition; or who have recently immigrated from areas with high measles mortality rates. Parenteral and oral formulations of vitamin A are available.


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InternalMed_Harrison. Anecdotal reports have described the recovery of previously healthy pregnant and immunocompromised patients with measles pneumonia and of immunocompromised patients with measles encephalitis after treatment with aerosolized and IV ribavirin. However, the clinical benefits of ribavirin in measles have not been conclusively demonstrated in clinical trials. Most complications of measles involve the respiratory tract and include the effects of measles virus replication itself and secondary bacterial infections. Acute laryngotracheobronchitis (croup) can occur during measles and may result in airway obstruction, particularly in young children. Giant-cell pneumonitis due to replication of measles virus in the lungs can develop in immunocompromised children, including those with HIV-1 infection. Many children with measles develop diarrhea, which contributes to undernutrition.


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InternalMed_Harrison. Most complications of measles result from secondary bacterial infections of the respiratory tract that are attributable to a state of immune suppression lasting for several weeks to months after acute measles. Otitis media and bronchopneumonia are most common and may be caused by S. pneumoniae, H. influenzae type b, or staphylococci. Recurrence of fever or failure of fever to subside with the rash suggests secondary bacterial infection.


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InternalMed_Harrison. Rare but serious complications of measles involve the central nervous system (CNS). Postmeasles encephalomyelitis complicates ~1 in 1000 cases, affecting mainly older children and adults. Encephalomyelitis occurs within 2 weeks of rash onset and is characterized by fever, seizures, and a variety of neurologic abnormalities. The finding of periventricular demyelination, the induction of immune responses to myelin basic protein, and the absence of measles virus in the brain suggest that postmeasles encephalomyelitis is an autoimmune disorder triggered by measles virus infection. Other CNS complications that occur months to years after acute infection are measles inclusion body encephalitis (MIBE) and subacute sclerosing panencephalitis (SSPE). In contrast to postmeasles encephalomyelitis, MIBE and SSPE are caused by persistent measles virus infection. MIBE is a rare but fatal complication that affects individuals with defective cellular immunity and typically occurs months after


InternalMed_Harrison

InternalMed_Harrison. MIBE and SSPE are caused by persistent measles virus infection. MIBE is a rare but fatal complication that affects individuals with defective cellular immunity and typically occurs months after infection. SSPE is a slowly progressive disease characterized by seizures and progressive deterioration of cognitive and motor functions, with death occurring 5–15 years after measles virus infection. SSPE most often develops in persons infected with measles virus at <2 years of age.