Viral Gastroenteritis

Etiologic Agents

A small group of viruses account for most cases of acute gastroenteritis among children. These include: human caliciviruses (including noroviruses and sapoviruses), group A rotaviruses, enteric adenoviruses (types 40 and 41), human astroviruses, and coronaviruses. ^, Other viruses are frequently detected in children suffering from diarrheal illnesses; however, the prevalence of many of these other viruses in healthy controls has not been determined, and therefore a causal association with diarrhea has not been established. A key method of establishing a causal association between a virus and a disease is observing a higher prevalence among children with gastroenteritis compared with asymptomatic children ( Table 56.1 ), though even this case-control approach may be problematic because enteropathogens frequently cause asymptomatic reinfection. ^,

Caliciviruses are nonenveloped, 27–40-nm single-stranded RNA viruses in the family Caliciviridae . Human caliciviruses are divided into two genera, norovirus and sapovirus. Noroviruses include a number of genetically related viruses, further divided into 10 genogroups and 49 genotypes. ^, Despite this extensive genetic diversity among noroviruses, genogroup II genotype 4 (GII.4) viruses are the most common cause of norovirus outbreaks worldwide; the emergence of new GII.4 strains, which occurs every 2–4 years, can be associated with global increases of gastroenteritis outbreaks. Several norovirus vaccine candidates are currently in development, utilizing virus-like particles. ^,

Rotaviruses (family Reoviridae ) are 100-nm particles comprised of an outer capsid, inner capsid, and core. The double-stranded RNA genome is composed of 11 segments which code for 6 structural proteins and 6 nonstructural proteins. The outer capsid is composed of 2 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 account for the classification scheme for rotavirus strains.

Adenoviruses are 70- to 100-nm, nonenveloped, double-stranded DNA viruses in the family Adenoviridae . While seven species of adenoviruses (classified HAdV A-G) containing over 60 different genotypes can cause human infection, species F (genotypes 40 and 41) adenoviruses typically cause gastroenteritis.

Astroviruses are nonenveloped, 28-nm single-stranded RNA viruses in the family Astroviridae . Until 2008, human astroviruses were thought to be limited to eight closely related genotypes (serotypes), now referred to as the “classic” human astroviruses (HAstV 1–8). HAstV genotype 1 is most commonly detected, followed by types 2–5; however, >1 serotype usually circulates in communities during each season. Non-type 1 viruses can predominate in a season, and greater serotype diversity may be found in low to middle income countries.

Coronavirus infections, including severe acute respiratory syndrome-coronavirus (SARS), Middle East respiratory syndrome (MERS-CoV), and SARS-CoV-2 (which causes COVID-19 disease), cause diarrhea in 13%–25% of cases. ^{, , ,}

In some reports of viral gastroenteritis etiology, up to 50% of cases do not have an identifiable causative agent. Pathogen discovery efforts using broad-range polymerase chain reaction (PCR) assays, pan-viral microarrays, and unbiased viral metagenomics led to identification of Picornaviridae (salivirus, cosavirus, Saffold virus), Astroviridae (VA-like and MLB-like) and Parvoviridae (bocavirus, tusavirus, bufavirus) in patients with viral gastroenteritis; however, the data are inconclusive regarding the pathogenicity for many of these viruses and the causal association with clinical gastroenteritis in these patients.

Epidemiology

All the major enteric viruses are transmitted primarily through close person-to-person contact via the fecal-oral route. In addition, noroviruses are easily spread through contaminated food and water, and therefore are a major cause of foodborne disease. Noroviruses are present in the vomitus of ill people, and droplet spread through exposure to vomitus is a demonstrated mechanism of spread both in healthcare and public settings. Contact with a symptomatic child is a major determinant in norovirus infection. Children <5 years of age seem to be more infectious than older children and adults and therefore play a key role in norovirus transmission to all age groups. The modes of transmission of adenovirus are less well-understood, but they are presumed to be primarily through close contact by fecal-oral spread and possibly through droplet and aerosol spread. Adenovirus infections are prevalent in childcare centers and households with young children, and nosocomial outbreaks have been described. Spread through fomites may play an important role in disease acquired through institutional settings and group childcare.

Common viral gastroenteritis viruses are globally distributed. While traditionally temperate climates are associated with a strong winter peak of rotavirus, a meta-analysis showed that the level of country development was a stronger predictor of seasonality than geographic location or climate. Since the introduction of rotavirus vaccines, the rotavirus season has diminished substantially in magnitude and has also been delayed in some years. ^, A biennial pattern of lower, delayed rotavirus seasons followed by slightly higher peaks has emerged in the US ( Fig. 56.1 ). ^{, ,} In low-income and tropical settings, rotaviruses typically circulate year-round. ^{, ,} Noroviruses circulate year-round in most areas, but there is clear winter-time seasonality to outbreaks, particularly in healthcare settings. ^{, ,} Astroviruses typically peak during winter, and sapoviruses peak during early spring months in temperate countries. ^, The seasonality of adenoviruses is less distinct, and transmission has been described year-round with summertime epidemics. ^,

The highest rates of severe rotavirus infections occur in the first 2 years of life, with most hospitalizations and severe dehydrating disease occurring between 4 and 23 months of age. Infections in the first 3 months are less common and often asymptomatic, probably because of protection from maternally-acquired antibodies. ^, Rotaviruses can infect children more than once, with each subsequent infection becoming less severe as a result of immunity that develops following infection. Severe rotavirus disease among older children and adults is less common, but infection can occur in people exposed to younger children in childcare and schools. Outbreaks can occur in long-term care facilities.

Prior to the introduction of rotavirus vaccines, rotaviruses accounted for 25%–50% of gastroenteritis hospitalizations among children <5 years of age and 5%–20% of milder cases in people who seek care in clinics. ^, Following vaccine introduction, the rates of rotavirus-associated healthcare utilization have substantially decreased ( Fig. 56.1 ). ^{, , ,} Population-based surveillance in the US detected rotavirus in 13% of children hospitalized due to gastroenteritis and in 6% of pediatric outpatient gastroenteritis visits. Globally, 200,000 annual deaths were attributed to rotavirus in children <5 years of age, with deaths among children in the poorest countries accounting for >90% of the total. ^, Since the introduction of rotavirus vaccines in 2006, worldwide rotavirus deaths and acute gastroenteritis hospitalizations had each declined by 36% as of 2019. Rotavirus-associated mortality is rare in high-income countries. In middle-income countries (e.g., Mexico and Brazil) where rotavirus vaccines were introduced in 2006, sustained reductions were documented in diarrhea-associated pediatric mortality ( Fig. 56.2 ). Important reductions in disease burden have also been observed in low-income settings, despite lower vaccine efficacy in these regions.

Noroviruses are now recognized as the most common cause of both endemic disease and outbreaks of gastroenteritis. ^{, ,} Noroviruses are estimated to cause 19–21 million illnesses a year in the US. The annual burden of medically-attended norovirus illnesses in the US is 2.3 million outpatient visits, 465,000 emergency department visits, 109,000 hospitalizations, and 900 deaths. Globally, norovirus is estimated to cause 18% of severe diarrheal disease in children <5 years of age (17% of inpatient cases and 24% of community episodes) and approximately 70,000–200,000 deaths. ^, Following the introduction of rotavirus vaccines and subsequent decline in rotavirus disease burden, noroviruses have overtaken rotavirus to become the predominant cause of severe gastroenteritis in the pediatric population. ^{, , ,} The incidence of norovirus is greatest among young children. In England, the incidence of norovirus gastroenteritis-associated medical consultation was 34 episodes per 1000 person-years and the incidence of norovirus-associated hospitalization was 3.3 episodes per 1000 person-years among children <5 years of age. In the US, norovirus accounted for 21% of gastroenteritis requiring medical attention—17% among inpatient cases and 28% in community episodes.

Noroviruses are the most commonly reported cause of foodborne disease in the US, while internationally estimates vary widely. ^, Common foods associated with outbreaks include those that are uncooked or handled after cooking (which may be contaminated by ill food handlers) and shellfish harvested from contaminated water. Healthcare facilities, including nursing homes and hospitals, are the most common settings of norovirus outbreaks; other environments such as childcare facilities and cruise ships are frequently affected.

Sapoviruses are most commonly associated with sporadic gastroenteritis, usually among young children. ^, Sapoviruses were detected in approximately 10% of all gastroenteritis episodes in England and Finland and 4% of hospitalized cases in Finland among children <2 years of age. ^, In the US, sapoviruses were detected in 7% of pediatric diarrhea cases compared with 3% among healthy controls ( Table 56.1 ). ^, Sapovirus infections tend to be less severe than norovirus; vomiting is common and diarrhea may not be present ( Table 56.2 ). ^{, ,} More recent studies using sensitive molecular diagnostics in lower-income settings suggest a larger etiological role for sapoviruses. ^,

Although astroviruses have been detected in all age groups, most infections are in children <2 years of age and tend to be less severe than rotavirus. Serosurveys in the US have shown that >90% of children have antibodies to human astroviruses by 6–9 years of age. Disease in adults is uncommon, but can occur in outbreak settings. Astroviruses are usually detected in <10% of young children treated for gastroenteritis in outpatient clinics or hospitals, but are occasionally found at higher frequencies. ^{, ,} While astroviruses primarily cause sporadic disease, outbreaks have been reported in a range of settings and may be a common cause of nosocomial gastroenteritis in children’s hospitals.

Adenoviruses 40 and 41 cause a substantial proportion of viral gastroenteritis year-round, especially in children <2 years of age. ^{, ,} Enteric adenoviruses were shown to account for 5%–22% of hospitalizations for acute gastroenteritis in children and may be a common cause of healthcare-associated diarrhea. ^{, ,} Enteric adenoviruses are detected in 1%–12% of children with community-associated diarrhea. ^{, ,}

Coronavirus infections may cause gastrointestinal symptoms in infected children. Gastrointestinal symptoms were reported in 14%–30% of children infected with SARS-CoV-2. Children suffering from gastrointestinal symptoms were younger and had a higher prevalence of fever.

Pathogenesis

After oral inoculation, viruses infect cells of the small intestine villi. Infection of the mature villous enterocytes, which have both digestive and absorptive functions, leads to cell death and sloughing of the villus cells, resulting in villus blunting. 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. Viruses are shed in large quantities in the stool during the acute illness. Rotaviruses, noroviruses, and astroviruses can also be shed for 1–2 days prior to illness and for several days following resolution of symptoms. ^, While viral gastrointestinal infections generally are confined to the intestine, rotavirus and norovirus infections can result in antigenemia and presence of nucleic acid in the blood of ill patients; however, extraintestinal disease is rare. ^, Asymptomatic infection is common, especially for norovirus, and is thought to play a role in viral transmission.

Immunity to rotavirus is acquired and multiple infections are typically required until the child is fully protected against disease. ^{, ,} After a primary infection, homotypic immunity is stronger, but immunity seems to broaden to other serotypes with subsequent infections. Estimates of the duration of immunity to norovirus range from ∼6 months to 4–9 years after natural infection occurs; however, heterotypic immunity may be limited. ^, Because diarrheal disease caused by astrovirus, adenovirus, and sapoviruses is largely restricted to children, immunity is believed to be long-lasting.

Norovirus and rotavirus are known to recognize and bind to histo-blood group antigens (HBGAs). HBGAs are a diverse family of carbohydrates expressed on the mucosal epithelia of the respiratory, genitourinary, and digestive tracts, which are recognized as receptors allowing norovirus attachment and cellular entry. The expression of HBGAs is determined by three gene families expressing the ABO (A/B enzymes) genes, secretor (FUT2) gene, and Lewis-type (FUT3) gene. Single nucleotide gene polymorphisms (SNPs) can inactivate the expression of these gene products, breaking a link in the norovirus binding and infection process. Mutations in the FUT2 gene leading to the absence of HBGA expression (non-secretor phenotype) have been associated with resistance to infection ^, ; moreover, HGBA expression appears to be highly variable by ethnicity, with non-secretors comprising a higher proportion of Caucasian populations compared with individuals of Meso-American/Hispanic ancestry in the US. A systematic review assessed FUT2 secretors as 9.9 times as likely to be infected with genogroup II.4 noroviruses, 2.2 times as likely to be infected with genogroup II non-4 noroviruses, and 26.6 times more susceptible to P[8] type rotaviruses compared with non-secretors.

Clinical Manifestations and Differential Diagnosis

Characteristic presentation of viral gastroenteritis in children consists of diarrhea (≥3 loose/watery stools in 24 hours or an increase in the number of loose/watery stools by ≥2 compared with the child’s usual number of daily bowel movements) with or without vomiting, fever, and abdominal pain. Older age, presence of gross blood or mucus, and leukocytosis may be indicative of dysentery from bacterial causes. Other nonviral causes include parasitic gastroenteritis or noninfectious causes of diarrhea ( Table 56.3 ).

While viral agents causing acute gastroenteritis widely differ genetically and structurally, the clinical presentations are indistinguishable. After a short incubation period, infection with any of the viruses leads to an acute onset of gastroenteritis ( Table 56.2 ). Vomiting is often an early sign common in rotavirus and particularly pronounced in norovirus and sapovirus infections. ^, Typically, diarrhea is watery and without blood or visible mucus. Fever occurs in approximately half of children suffering from rotavirus and a quarter of children suffering from non-rotavirus viral gastroenteritis, and is often an early sign. Vomiting and fever often cease within 1–3 days, whereas diarrhea can persist longer, especially in rotavirus infections. Other symptoms include abdominal cramps, malaise, and seizures. ^, Stools generally do not contain blood or fecal leukocytes.

The most important and common complication of viral gastroenteritis is dehydration, often with electrolyte abnormalities. Malabsorption and chronic diarrhea can occur during the acute illness and can persist for weeks following infection. Risk of chronic diarrhea is increased in children with malnutrition or congenital or acquired immunodeficiencies. Extraintestinal complications associated with viral gastroenteritis include necrotizing enterocolitis (in pre-term infants) and benign infantile convulsions with gastroenteritis. Rare extraintestinal complications, including encephalitis, acute myositis, hemophagocytic lymphohistiocytosis, acute flaccid paralysis, and sudden infant death syndrome, have been described in children with rotavirus infections, but causal association was not established. ^{, ,}

While viral etiologies 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. An analysis of >10,000 outbreaks reported the following classification and regression tree (CART) modeling-based criteria for distinguishing viral from non-viral gastroenteritis outbreaks: ratio of proportion of cases with fever to the proportion of cases with vomiting <1; proportion of cases with bloody stool <0.1; and proportion of cases with vomiting ≥0.26.