Viral Gastroenteritis

Viral gastroenteritis is the most common disease associated with acute vomiting and diarrhea among children, and remains a leading cause of pediatric morbidity and mortality worldwide. With discovery of both Norwalk virus¹ and rotavirus² in the early 1970s, and subsequent development of improved diagnostic strategies for these and other enteric viruses,^{3, 4} the importance of viral agents as causes of diarrheal disease increasingly has been appreciated. The most important viral agents associated with gastroenteritis in children include rotaviruses, caliciviruses, adenoviruses, and astroviruses (Table 60-1 ). Many other viruses have occasionally been associated with acute vomiting and diarrhea, such as parvovirus B19, enteroviruses, coronaviruses, toroviruses, and picobirnaviruses, but none is likely to be a common cause. Although the pathogens that cause viral gastroenteritis are diverse, they share similar clinical presentations, modes of transmission, and treatment, so that they often remain undiagnosed clinically.

TABLE 60-1.

Relative Distribution of Viral Pathogens as Causes of Acute Gastroenteritis among Children

Agent	Hospitalizationsa (%)	Community diseasea (%)
Rotaviruses	25–50	5–20
Noroviruses	5–30	10–25
Sapoviruses	< 5	5–10
Astroviruses	5–10	10–25
Adenoviruses 40/41	5–12	10–15

^a(% of all viruses detected). Other viruses often found in stool samples account for the remainder, including coronaviruses, toroviruses, picornaviruses, enteroviruses, and others.

ETIOLOGY AGENTS

A small group of viruses account for most cases of acute gastroenteritis among children. These include rotaviruses, caliciviruses, astroviruses, and adenoviruses.

Rotaviruses (family Reoviridae) are 100-nm, triple-layered particles comprised of an outer capsid, inner capsid, and core.⁵ The double-stranded RNA genome is composed of 11 segments which code for six structural proteins (VP1 to VP4, VP6, and VP7) and six nonstructural proteins (NSP1 to NSP6). The outer capsid is composed of two proteins, VP7 (G protein, for glycoprotein) and VP4 (P protein, for protease-cleaved protein). These proteins are the principal antigens to which neutralizing antibodies are directed and are the proteins that account for the classification scheme for rotavirus strains. The middle layer is made up of the VP6 protein, which is the most abundant protein in the virus and is the protein to which common immune diagnostics are directed. Rotaviruses are commonly classified according to group and serotype. Six groups of rotavirus have been described (A to F), and are based on differences in the VP6 protein. Only viruses in groups A, B, and C are known to cause disease in humans. Group A rotaviruses are the principal cause of human disease. Group B and C rotaviruses also cause gastroenteritis but are uncommon, and covered elsewhere (see Chapter 216, Rotaviruses).^6–8 Group A rotaviruses are further classified by serotype based on their VP7 (G) and VP4 (P) proteins.^{9, 10} While 12 P types and 11 G types have been described,¹⁰ five G types (G1 to G4 and G9) and three P types (P[4], P[6], and P[8]) predominate globally.^9–11 In addition, five combinations of these common types generally account for more than 90% of circulating viruses: P[8],G1; P[4],G2; P[8],G3; P[8],G4, and P[8],G9. P[8],G1 strains are the dominant strain worldwide, accounting for 50% to 90% of seasonal strains characterized in most large reviews.^{9, 10, 12} Even so, less common strains, such as G8, G12, and G5 strains, may be of public health importance and even predominate in any given season, potentially complicating vaccine effectiveness.^12–14

Caliciviruses are nonenveloped, 27- to 40-nm viruses in the family Caliciviridae, containing single-stranded RNA.¹⁵ Human caliciviruses are divided into two genera, Norovirus and Sapovirus. Noroviruses include a number of genetically related viruses, of which Norwalk virus is the prototype. Noroviruses have been previously referred to by a variety of names, including small round-structured viruses and “Norwalk-like viruses.” Sapoviruses were first described in 1976 when detected in stools of patients with gastroenteritis. This group of viruses has been referred to as classical caliciviruses and “Sapporo-like viruses” in reference to the location of first detection of Sapporo virus, the prototype strain. By electron microscopy, caliciviruses have characteristic cup-shaped depressions over the surface of the virion (Greek, calyx = cup), but often these viruses, especially Norviruses, have rough, nondistinct borders (Figure 60-1 ). Noroviruses are further divided into five genogroups (I, II, III, IV, V); only three (I, II, and IV) cause human disease. These three are then subdivided into at least 29 genetic clusters or subgroups.¹⁶ The number of viruses in each genogroup continues to increase with the increased use of molecular techniques for characterization.

Figure 60-1.

Electron micrograph of four viruses known to cause childhood gastroenteritis, visualized by negative staining in diarrheal stool specimens from children. (A) Rotaviruses are 70-nm particles with a double shell and a characteristic “wheel-and-spoke” appearance. (B) Enteric adenoviruses are 70- to 90-nm particles with a characteristic icosahedral structure. (C) Astroviruses (in this instance located around the head of a bacteriophage) are 26 to 28 nm, have a smooth edge, and have five- to six-pointed stars in some particles. (D) Caliciviruses are typically 30 to 35 nm and have either a distinctive “star-of-David” appearance or 10 surface spikes apparent in some particles, depending on the orientation. Scale bar = 50 nm.

(Courtesy of W. David Cubitt, Ph.D., Institute of Child Health, London.)

Astroviruses, first discovered in 1975,^{17, 18} are nonenveloped, single-stranded RNA viruses in the family Astroviridae.¹⁹ Astroviruses are 28 to 30 nm with a smooth edge, while 10% have a characteristic star-like appearance in the center (Greek, astron = star).²⁰ Eight distinct serotypes (HastV 1 to 8) of human astroviruses have been described. Serotype 1 is most commonly detected, but more than one serotype usually circulates in communities during each season. Nonserotype 1 viruses can predominate in a season, and greater serotype diversity may be found in developing countries.^{21, 22}

Adenoviruses are 70- to 80-nm, nonenveloped, double-stranded DNA viruses in the family Adenoviridae.²³ While six subgroups of adenoviruses, containing at least 51 different serotypes, can cause human infection, subgroup F (serotypes 40 and 41) adenoviruses are the most clearly associated with gastroenteritis.²⁴ Serotype 31 adenoviruses occasionally have been associated with gastroenteritis in some studies and serotypes 42 and 29 have been reported as causes of diarrhea in human immunodeficiency virus (HIV)-infected patients.²⁵ Adenoviruses 40 and 41 are referred to as enteric adenoviruses.²⁶

Other viruses are also associated with gastroenteritis, including human coronaviruses and toroviruses within the virus family Coronaviridae, and picobirnavirus. Human coronaviruses and toroviruses have been detected in studies in several countries, but their association with gastroenteritis remains unclear.²⁷ Recent reports of the clinical characteristics of patients infected with the severe acute respiratory syndrome–coronavirus have described diarrhea in approximately one-fourth of cases.²⁸ Picobirnaviruses have been associated with disease in a study of HIV-infected adults.²⁹ Other viruses, such as pestiviruses, some picornaviruses, parvoviruses, and parvo-like viruses, reoviruses, enteroviruses, and other unclassified small round viruses, have been found in fecal specimens and implicated in gastroenteritis.³⁰ However, many of these viruses have been reported sporadically or have been associated with single outbreaks of illness, and the data are inconclusive regarding the relative importance and features for many of these viruses.

PATHOGENESIS

Rotaviruses and astroviruses are transmitted primarily through close person-to-person contact via the fecal–oral route.^{5, 31} While, noroviruses are also spread through close contact, they are the only one of these agents that is easily spread through contaminated food and water, and therefore is a major cause of foodborne disease.^32–34 In addition, noroviruses are present in vomitus of ill people,³⁵ and droplet spread through exposure to vomitus has been demonstrated.³⁶ The modes of transmission of adenovirus are not well understood, but are presumed to be through close contact by fecal–oral spread. Spread through fomites is possible for each of the agents, and may play an important role in disease acquired in institutional settings and group childcare.^{31, 37}

After oral inoculation, viruses infect cells in villi of the small intestine.^{5, 38–43} Infection of the mature villous enterocytes of the small intestine, which have both digestive and absorptive functions, leads to cell death and sloughing of the villus cells and resulting villus blunting. Diarrhea that occurs as a result of rotavirus infection is likely due to osmotic diarrhea, caused by loss of absorptive function due to destruction of mature enterocytes. Rotavirus infections have also been shown to produce secretory diarrhea, due to the opening of calcium channels, which results in an influx of calcium and efflux of sodium and water (associated with a nonstructural viral protein, NSP4).^{44, 45} The intraenterocyte calcium concentration also leads to cell death. In a normal host, infection resolves as the number of susceptible mature enterocytes decreases due to cell death and as the host generates an immune response. While viral gastrointestinal tract infections are generally confined to the intestine, data have indicated that rotavirus infections can result in antigenemia and presence of nucleic acid in blood of ill patients.⁴⁶ Even so, extraintestinal disease (e.g., encephalitis) is rare in rotavirus infections.

Following infection, viruses are shed in the stool during the acute illness in large amounts. However, rotaviruses, noroviruses, and astroviruses can be shed for 1 to 2 days prior to illness and for several days following resolution of symptoms, facilitating transmission.^{31, 47, 48} Asymptomatic infection is common and asymptomatic people can be sources of transmission.

EPIDEMIOLOGY

Two distinct epidemiologic patterns are associated with viral gastroenteritis – endemic and epidemic disease. Rotavirus, astrovirus, enteric adenovirus, and sapovirus infections occur primarily as endemic disease, while norovirus infections are commonly seen both as sporadic illnesses and in outbreaks (Table 60-1). All common viral gastroenteritis viruses have no geographic limits. Rotavirus, astrovirus, and sapovirus infections occur in clear wintertime seasonal peaks in temperate countries,^{22, 49–52} while they often circulate year-round in tropical settings, with peaks during dry seasons.^53–56 Seasonality of adenoviruses is less distinct,^{51, 57, 58} and noroviruses likely circulate year-round in most areas.³⁴ Rotaviruses have the distinct feature in the United States of occurring in peaks, first in the southwest, with migration of the peaks towards the northeast each season.⁵⁹ In the United States, summertime rotavirus infections are rare and often found among immunocompromised children or associated with false-positive test results.⁶⁰

The highest rates of rotavirus infection occur in the first 2 years of life, with most hospitalizations and severe dehydrating disease occurring between 4 and 23 months of age.^{61, 62} Infections in the first 3 months are less common and often asymptomatic because of protection from maternally acquired antibodies.⁶³ Rotavirus infections can occur more than once, with each subsequent infection becoming less severe as a result of immunity that develops following early infections.⁶¹ Illness among older children and adults is less common, but can occur in people exposed to younger children in group childcare and schools.⁶⁴ Rotaviruses account for 25% to 50% of gastroenteritis hospitalizations among children <5 years of age and 5% to 20% of milder cases in people who seek care in clinics.^65–68 Globally, rotavirus causes approximately 600,000 deaths per year in children less than 5 years of age, with deaths among children in the poorest countries accounting for more than 85% of the total.⁶⁵ In the United States, rotavirus causes 45,000 to 70,000 hospitalizations annually,^{49, 69} but generally, fewer than 40 deaths.⁷⁰

Like rotaviruses, sapoviruses are most commonly associated with sporadic gastroenteritis, usually among young children.^{71, 72} Sapoviruses were detected in 9% of all gastroenteritis episodes and 4% of hospitalized cases of gastroenteritis among children <2 years of age in Finland.^{71, 73} Outbreaks due to sapoviruses are less common, but can occur among children and the elderly.³²

Although astroviruses have been detected in all age groups, most infections are in children <2 years of age.^{56, 74} Serosurveys in the United States have shown that >90% of children have antibody to human astroviruses by 6 to 9 years of age.⁷⁵ Disease in adults is uncommon, but can occur in outbreak settings.⁷⁶ Astroviruses have usually been detected in <10% of young children treated for gastroenteritis in outpatient clinics or in hospitals, but are the most common virus detected in a few studies.^{4, 51, 77} While astroviruses primarily cause sporadic disease, outbreaks have been reported in closed settings such as schools,⁷⁶ childcare centers,^{31, 47} hospitals,⁷⁸ nursing homes,⁷⁹ and households.⁸⁰ Astroviruses have been reported to be responsible for 5% to 16% of nosocomial gastroenteritis in children's hospitals, second only to rotavirus.⁸¹

Most adenovirus infections occur in children < 2 years of age, and they appear to be less important causes of gastroenteritis among adults.^{82, 83} Enteric adenoviruses account for 5% to 10% of hospitalizations for acute gastroenteritis in children and may be a common cause of healthcare-associated diarrhea.^82–85 Enteric adenoviruses are generally detected in 1% to 4% of children with community-associated diarrhea.^{57, 86} In economically developing countries, enteric adenoviruses, compared with other viral agents, appear to account for a smaller proportion of diarrheal disease than in developed countries, although they are occasionally detected in rates similar to rotavirus.⁵⁸

All age groups are infected by noroviruses, but serosurveys document that antibody is acquired at an early age, indicating that first exposure to these viruses occurs early in life.⁸⁷ Noroviruses are the most common cause of foodborne illness in the United States.³³ They are estimated to cause 23 million illnesses a year in the United States and 93% of all nonbacterial outbreaks reported by the Centers for Disease Control and Prevention between 1997 and 2000. Common foods associated with outbreaks include uncooked foods contaminated by ill foodhandlers who are shedding virus, and shellfish harvested from contaminated water.⁸⁸ Approximately half of norovirus-associated outbreaks occur through person-to-person spread in closed populations, such as nursing homes, childcare centers, hospitals, and cruise ships. Norovirus outbreaks in institutions can require closing of patient-care units or suspension of cruises. In addition, noroviruses are increasingly appreciated to cause sporadic community-associated gastroenteritis among children.⁷² In a Finnish cohort of children between 2 months and 2 years of age, noroviruses were detected in 20% of stool specimens from episodes of gastroenteritis and 13% of hospitalized cases, second only to that of rotaviruses.^{71, 73}

CLINICAL MANIFESTATIONS

After a short incubation period, infections with any of the viruses lead to an acute onset of gastroenteritis (Table 60-2 ). The clinical characteristics of illnesses caused by the different viruses are generally indistinguishable.^{85, 89–91} Vomiting is often an early sign, and particularly pronounced in norovirus infections. Diarrhea is frequent, watery, and without blood or visible mucus. Fever occurs in approximately half of children and is often an early sign. Vomiting and fever often cease within 1 to 3 days, whereas diarrhea can persist for additional days. Other symptoms include abdominal cramps and malaise. Stools generally do not contain blood or fecal leukocytes.

TABLE 60-2.

Epidemiologic Features of Viral Agents of Gastroenteritis

Rights were not granted to include this table in electronic media. Please refer to the printed book.

Modified from Peck AJ, Bresee JS. Viral gastroenteritis. McMillan JA, In: Feigin RD, De Angelis CD, Jones MD (eds) Oski's Pediatrics, 4th ed. Philadelphia, PA, Lippincott, Williams and Wilkins, 2006, pp 1288–1294.; Reprinted from CDC. Managing acute gastroenteritis among children. MMWR 2003;52:1–16.

© 2008

The most important and common complication of viral gastroenteritis is dehydration, often with electrolyte abnormalities. Malabsorption can occur during the illness and persist for weeks following infection. Simultaneous respiratory tract symptoms may occur but are likely due to concurrent wintertime respiratory tract viral infections. Extraintestinal complications are rare, but encephalitis, acute myositis, hemophagocytic lymphohistiocytosis, polio-like paralysis, and sudden infant death syndrome have been described rarely in children with rotavirus infections.⁵ Their relationship to rotavirus infection remains unclear. Long-term complications are not associated with viral gastroenteritis. Prolonged diarrhea associated with each agent has been reported among children with malnutrition and among immunocompromised patients.

While viral etiologies of cases of gastroenteritis are not distinguishable by clinical signs and symptoms, clinical characteristics of cases in outbreak settings have been helpful in predicting the presence of noroviruses. Kaplan and colleagues found that outbreaks that met simple epidemiologic and clinical criteria were likely to have been caused by noroviruses.⁹² These criteria included: (1) failure to detect a bacterial or parasitic pathogen in stool specimens; (2) the occurrence of vomiting in >50% of patients; (3) mean duration of illness of 12 to 60 hours; and (4) mean incubation period of 24 to 48 hours. The “Kaplan criteria” have been widely used by local health departments for the diagnosis of outbreaks in the absence of laboratory testing.

DIAGNOSIS

Laboratory diagnosis of viral gastroenteritis is best made by detection of viral antigen or nucleic acid in fresh, whole stool samples obtained during the acute illness. Commercially available assays to detect rotavirus antigen in stools offer an easy and inexpensive method to diagnose infection in children. These tests are available as either enzyme immunoassay (EIA) or latex particle agglutination test for group A rotaviruses, designed to detect the VP6 protein.⁵ Antigen detection tests generally have a high (90% to 95%) sensitivity and specificity.⁹³ Other methods for rotavirus detection, including electron microscopy, viral isolation, polyacrylamide gel electrophoresis (PAGE) of RNA extracted directly from stool, and reverse transcription-polymerase chain reaction (RT-PCR), are available in research settings, but are rarely used in clinical practice.⁹³ Serologic testing for rotavirus infection is possible but impractical, thus is not widely available in clinical care settings. Immunohistochemical stains have been developed that identify rotavirus antigen in pathologic tissues, and are available in some research and public health settings.

Commercial antigen detection kits are available for caliciviruses, but are not available in the United States. Commercial EIA tests for caliciviruses have poor sensitivity but may be useful in outbreak investigations.⁹⁴ RT-PCR has become the standard diagnostic assay used for caliciviruses, but is seldom used clinically. RT-PCR has become widely available in public health laboratories for outbreak investigations, where sequencing of the PCR product from clinical samples may allow for linking cases to each other and to a common source.⁸⁸ Caliciviruses have not been reproducibly propagated in cell cultures.

Commercial EIAs for detection of astrovirus viral antigen in stool are available in Europe, but not in the United States.⁴ Similarly, RT-PCR is a sensitive and specific method for detection of astroviruses. RT-PCR, serologic assays, and electron microscopy are primarily used in research settings. Similarly, EIA and latex particle agglutination kits are available commercially and provide highly sensitive and specific antigen detection of enteric adenoviruses.⁹⁵ All viral gastroenteritis agents are detectable by electron microscopy and immune electron microscopy, but these tests are seldom used because of relatively low sensitivity and specificity, expense, and required expertise.

TREATMENT

No specific therapies are available for viral gastroenteritis. Case management depends on accurate and rapid assessment, correction of fluid loss and electrolyte disturbances, and maintenance of adequate hydration and nutrition.⁹⁶ Oral rehydration therapy with appropriate glucose-electrolyte solutions is sufficient for most patients (Table 60-3 ). Intravenous rehydration may be required for children with severe dehydration with shock or intractable vomiting. Breastfed infants should continue to nurse on demand. Infants receiving formula should continue their usual formula upon rehydration. Children taking solid foods should continue to receive their usual diet during episodes of diarrhea, although substantial amounts of foods high in simple sugars should be avoided because the osmotic content might worsen diarrhea. Because viral agents account for the large majority of infectious gastroenteritis in children, appropriate use of antimicrobial agents in patients with acute gastroenteritis should be stressed.

TABLE 60-3.

Composition of Commercial Oral Rehydration Solutions and Commonly Consumed Beverages

Solution	CHO (g/L)	Na (mmol/L)	K (mmol/L)	Cl (mmol/L)	Basea (mmol/L)	Osmolarity (mosmol/kgH2O)
ORAL REHYDRATION SOLUTIONS
WHO-ORS (2002)	13.5	75	20	65	10	245
WHO-ORS (1975)	20	90	20	80	10	311
ESPGHAN ORS	16	60	20	60	10	240
Enfalyteb	30	50	25	45	34	200
Pedialytec	25	45	20	35	30	250
Rehydralytec	25	75	20	65	30	305
Ceralyted	40	50–90	20	40–80	30	220
COMMONLY USED BEVERAGES
Apple juicee	120	0.4	44	45	−	730
Coca-Colaf	112	1.6	−	−	13.4	650
Gatoradeg	46	23.5	2.5	17	3	330
Chicken brothe	8	260	0.5	260	−	450
Teae	−	6	−	−	−	6

WHO-ORS, World Health Organization oral rehydration solution.

^aActual or potential bicarbonate, such as lactate, citrate, or acetate.

^bMead-Johnson Laboratories, Princeton, NJ.

^cRoss Laboratories, Columbus, OH (data for Flavored and Freezer Pop Pedialyte are identical).

^dwww.ceralyte.com/index.htm, accessed April 25, 2003.

^eUnited States Department of Agriculture.

^fCoca-Cola Corporation, Atlanta, GA (figures do not include electrolytes, which may be present in local water used for bottling; base = phosphate).

^gThe Gatorade Company, Chicago, IL.

Some evidence exists to support the use of oral probiotics, such as Lactobacillus species, that reduce the duration of diarrhea caused by rotavirus.⁹⁷ Human or bovine colostrums and human serum immunoglobulin that contain antibodies to rotavirus may be beneficial in decreasing or preventing rotavirus diarrhea, but are not used in routine practice.^98–101

PREVENTION

Except for rotavirus, prevention of viral gastroenteritis is limited to nonspecific strategies. Breastfeeding confers some protection against rotavirus infection, and probably astrovirus infections, in young infants; it is likely mediated through rotavirus antibodies and other nonimmunologic factors in the milk. Good hygiene, including hand hygiene practices, is an effective prevention strategy and should be encouraged, particularly in institutional settings, such as childcare centers and hospitals.¹⁰² Noroviruses are relatively resistant to environmental disinfection, but cleaning contaminated surfaces and food preparation areas with household chlorine bleach-based cleaners can decrease spread of infection with these viral agents and is likely effective in settings where rotavirus and astrovirus outbreaks occur.¹⁰³

However, significantly reducing transmission of viral agents of gastroenteritis is difficult because the disease generally requires a low infectious dose, high quantity of viruses are excreted in stool (and often vomitus) from infected persons, and the agents are quite stable in the environment.

The best option for preventing rotavirus morbidity and mortality is the use of live, oral rotavirus vaccines in routine immunization programs. Rotavirus vaccines are attenuated strains given in multiple doses designed to replace a child's first exposure to wild-type rotavirus with strains that will not cause disease but will generate an adequate immune response to confer protection.^{104, 105} Two rotavirus vaccines are licensed in the world. One was licensed in the United States in 2006 and recommended for use universally.^{106, 107} Additional vaccines are in late stages of FDA submission or development and are expected to be available within the next several years.¹⁰⁵ While most vaccines in clinical development are live, orally administered vaccines, parenterally administered vaccines are also being investigated.¹⁰⁴ Neither of the licensed vaccines, nor any vaccine in development, has yet been tested in countries with high mortality rates. Because past rotavirus vaccines have shown little efficacy in these settings,^{68, 108–112} trials of rotavirus vaccines are under way; decisions about use of these vaccines in countries where mortality is high will await the results of these trials.⁶⁸

While experimental vaccines against noroviruses are in early stages of development, proof that these vaccines could be protective remains to be established.¹¹³ No vaccines against other caliciviruses, astroviruses, or enteric adenoviruses are yet in human trials.