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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 rotavirus–based vaccines.
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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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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.
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In tropical settings, rotavirus disease occurs year-round, with less pronounced seasonal peaks than in temperate settings, where rotavirus 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. rotavirus 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 annual proportion of rotavirus tests that were positive was below 10% in both seasons (compared with a prevaccine baseline median of 26%). A pattern of biennial increases in rotavirus activity has emerged during the five postvaccine seasons (2007–2012), but activity has remained substantially below prevaccine levels in each season.
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During episodes of rotavirus-associated diarrhea, virus is shed in large quantities in stool (107–1012/g). Viral shedding detectable by EIA usually subsides within 1 week but may persist for >30 days in immunocompromised individuals; it may be detected for longer periods by sensitive molecular assays, such as PCR. The virus is transmitted predominantly through the fecal-oral route. Spread through respiratory secretions, person-to-person contact, or contaminated environmental surfaces has been postulated to explain the rapid acquisition of antibody in the first 3 years of life, regardless of sanitary conditions.
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At least 10 different G serotypes of group A rotavirus have been identified in humans, but only 5 types (G1 through G4 and G9) are 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.
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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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Rotaviruses infect and ultimately destroy mature enterocytes in the villous epithelium of the proximal small intestine. The loss of absorptive villous epithelium, coupled with the proliferation of secretory crypt cells, results in secretory diarrhea. Brush-border enzymes characteristic of differentiated cells are reduced, and this change leads to the accumulation of unmetabolized disaccharides and consequent osmotic diarrhea. Studies in mice indicate that a nonstructural rotavirus protein, NSP4, functions as an enterotoxin and contributes to secretory diarrhea by altering epithelial cell function and permeability. In addition, rotavirus may evoke fluid secretion through activation of the enteric nervous system in the intestinal wall. Data indicate that rotavirus antigenemia and viremia are common among children with acute rotavirus infection, although the antigen and RNA levels in serum are substantially lower than those in stool.
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Clinical Manifestations
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The clinical spectrum of rotavirus infection ranges from subclinical infection to severe gastroenteritis leading to life-threatening dehydration. After an incubation period of 1–3 days, 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 resolve in 3–7 days.
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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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Rotavirus does not appear to be a major opportunistic pathogen in children with HIV infection. In severely immunodeficient children, 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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Protection against rotavirus disease is correlated with the presence of virus-specific secretory IgA antibodies in the intestine and, to some extent, the serum. Because 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.
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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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TREATMENT Rotavirus Infections
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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Efforts to develop rotavirus vaccines were pursued 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.
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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 rotavirus 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 intussusception in some countries; however, the benefits of vaccination exceed the risks, and no changes in vaccine administration policy have been implemented.
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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 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.