Norovirus is a leading cause of acute gastroenteritis in the United States¹ and globally². Although norovirus infection causes illness in all age groups, incidence rates are highest among young children.^1,3 In several countries that have introduced national rotavirus vaccination programs, norovirus has replaced rotavirus as the leading cause of medically attended^4–8 and community^8,9 pediatric gastroenteritis. Approximately 99% of the 212,000 annual deaths caused by norovirus occur in developing countries.¹⁰ Although deaths are rare in the United States, norovirus is responsible for approximately 24,000 hospitalizations; 132,000 emergency room visits; and 925,000 outpatient visits in children less than 18 years, at an estimated cost of more than $200 million.^11,12 With norovirus vaccines under development,¹³ a review of the virology, epidemiology, clinical presentation, diagnosis, treatment, and prevention of pediatric norovirus is described herein.

Noroviruses are a genetically diverse group of viruses in the Caliciviridae family that cause acute gastroenteritis.¹⁴ The first norovirus was described when a viral particle was observed by electron microscopy in a stool sample derived from a 1968 outbreak in Norwalk, Ohio, leading to the initial name of Norwalk virus.¹⁵ Norwalk virus was the first virus shown to cause gastroenteritis. Since then, other Norwalk-like viruses have been discovered; currently, noroviruses are classified into genogroups GI to GVII.¹⁶ Genogroups GI, GII, and, to a lesser extent, GIV, are known to cause human disease. Globally, viruses of the GII.4 genotype are the leading cause of norovirus disease,¹⁷ include new variants that emerge every 2 years to 4 years,^18,19 and are associated with greater symptom severity and health care burden.²⁰

Norovirus infections cause acute gastroenteritis, presenting as acute-onset vomiting and/or diarrhea. When present, diarrhea is typically watery and nonbloody and may be accompanied by abdominal cramps, nausea, and fever.²¹ Constitutional symptoms, including low-grade fever, generalized myalgias, malaise, headache, and chills, frequently occur. The incubation period lasts 12 hours to 48 hours, and the duration of clinical symptoms is typically 12 hours to 72 hours. Asymptomatic norovirus infection, identified through stool shedding of norovirus in patients without gastroenteritis, has been found in 3% to 10% of children and adults.²² Although most infections result in full recovery,²³ severe outcomes, such as hospitalization and death, occur, particularly among children ages less than 5 years, adults ages greater than 65 years, and immunocompromised hosts.^1,24–26

Norovirus is highly contagious, and the infectious dose can be as few as 20 viral particles.⁴³ The most common route for transmission is person to person, either directly through the fecal-oral route, by ingestion of aerosolized vomitus, or by indirect exposure via fomites or contaminated environmental surfaces.⁴⁴ Norovirus is also the leading known cause of both sporadic cases^2,45 and outbreaks of foodborne disease, with contamination occurring either from infected food handlers or directly from foods.⁴⁶ Foods often implicated in norovirus outbreaks include leafy greens, fresh fruits, and shellfish, but any food that is served raw or handled after being cooked can be contaminated. Waterborne transmission is less common but possible when drinking or recreational water is not chlorinated.⁴⁷

Peak viral shedding occurs 2 days to 5 days after infection⁴⁴ and occurs primarily in stool but can also be present in vomitus. Although norovirus RNA has been detected in stool samples for up to 4 weeks to 8 weeks after symptom resolution in otherwise healthy individuals,⁴⁸ the infectivity of the virus beyond the symptomatic period is not well established.

Immunity to norovirus is an ongoing field of research relevant to prospects for vaccination. Acquired immunity after infection is likely of limited duration, with protection after volunteer challenge studies lasting for weeks up to 2 years,^49,50 whereas modeling studies suggest protection for up to 9 years.⁵¹ Evidence to support a limited duration of immunity in children is the identification of multiple norovirus infections in children monitored in birth cohort studies, with 25% to 40% of children followed from birth to 3 years in various settings having at least 2 episodes of norovirus gastroenteritis.^52–55 When immunity is acquired, protection may be limited to the initial genotype, because repeat infections by other genotypes do occur.^54,56

In addition to acquired immunity, innate immunity may be conferred by homozygous mutations in the alpha(1,2) fucosyltransferase (FUT2) gene, which control the expression of histo-blood group antigens on the gut surface epithelium that bind to norovirus.^52,57 These mutations vary by ethnicity and occur in approximately 5% to 50% of different populations worldwide.⁵⁸

Although norovirus gastroenteritis can be suspected by clinical symptoms, confirmatory testing requires laboratory testing of stool specimens (Table 1). Molecular tests, including conventional reverse-transcriptase polymerase chain reaction (RT-PCR) and quantitative, real-time RT-PCR (RT-qPCR), are most sensitive and the gold standard for norovirus detection but are usually only available in public health laboratories and research facilities. RT-qPCR affords several advantages, because it is the most sensitive assay available, can detect GI and GII strains simultaneously, and can limit false-negative results. Interpretation of RT-qPCR results may be complicated by norovirus frequently detected in stool samples of healthy and asymptomatic individuals.^9,59,60 Detection of norovirus in asymptomatic individuals seems more common in developing countries.²²

Laboratory diagnostics in the clinical setting have recently become more widely available. Molecular-based assays for multiple enteric pathogens, such as xTAG GPP (Luminex Corporation, Toronto, Canada),^61,62 FilmArray gastrointestinal panel (BioFire Diagnostics, Salt Lake City, Utah),^61,63 and Verigene Enteric Pathogens Test (Nanosphere, Northbrook, Illinois)⁶⁴ can detect multiple viral, bacterial, and parasitic pathogens simultaneously within a few hours. The equipment and testing can be expensive, however, and interpretation of positive results with mixed infections can pose challenges for appropriate treatment and management of patients. Norovirus-specific nucleic acid amplification tests are promising for having a short turn-around time for point-of-care testing and have recently received Food and Drug Administration clearance⁶⁵ but are not yet commonly used in practice. Other diagnostic tests include electron microscopy, enzyme immunoassay, and immunochromatographic lateral flow assays, although these tests are limited by moderate sensitivity or high cost.¹⁶

The assessment and treatment of gastroenteritis caused by norovirus are similar to those of other causes of viral gastroenteritis. Treatment of diarrhea usually begins at home, with a focus on replacing fluid losses and maintaining adequate nutrition intake.⁶⁶ Medical evaluation of children is indicated with young age (eg, age <6 months or weight <8 kg), history of premature birth, chronic medical conditions or concurrent illness, fever, bloody stool, high volume and frequency of diarrhea, persistent vomiting, change in mental status, caregiver concern for dehydration, or poor response to home treatment.⁶⁶ At the time of medical evaluation, clinicians should conduct a thorough history and physical examination to assess the level of dehydration and loss of body weight.

Treatment should be based on the degree of dehydration and include 2 phases: rehydration and maintenance (Box 1).⁶⁶ The rehydration phase should occur in the first 3 hours to 4 hours of treatment with the goal of replacing the fluid deficit. The maintenance phase should focus on realimentation and returning the patient to an age-appropriate diet. Breastfed infants should continue to nurse throughout treatment. Oral-rehydration solutions (ORS), whose practical use was first studied during cholera outbreaks in Bangladesh and India,^67,68 should be the mainstay of rehydration treatment.⁶⁶ Although several ORS formulations are commercially available, all are composed of a balance of carbohydrates, sodium, potassium, chloride, and bicarbonate to encourage rapid rehydration, electrolyte balance, and appropriate osmolarity, and glucose support.⁶⁹ Patients with minimal or no dehydration (<3% loss of body weight) may be managed conservatively with ORS provided at home. Patients with mild to moderate dehydration (3%–9%) should be initially medically supervised. Patients with severe dehydration (>9%) should be treated with ORS but may also require intravenous fluids to maintain fluid status. Intravenous fluids may also be required in cases of severe vomiting that precludes oral rehydration.

Aside from general supportive treatment of gastroenteritis, no specific antinorovirus therapy is recommended at this time. Research to identify antiviral treatment strategies is in progress^70,71 and should be bolstered by the recent discovery of human intestinal enteroid cultures to support norovirus replication in vitro.⁷² Adjunctive treatments for diarrhea, including use of analgesic, antimotility, antiemetic, antisecretory, and probiotic agents, are commonly used but often without robust supportive evidence.⁷³

The global prevalence of norovirus among cases of acute gastroenteritis is estimated at 17% in hospitalized patients and 24% in the community.²² A World Health Organization–commissioned analysis estimated 685 million annual norovirus infections (95% uncertainty interval 491 million–1.1 billion) and 212,000 (95% uncertainty interval 161,00–278,000) annual norovirus deaths worldwide.¹⁰ The wide uncertainty intervals reflect current gaps in country-level data, especially from low-income, high-mortality countries. More than half of global cases occur in winter months.⁷⁴ One factor in the seasonality of norovirus in high-income countries may be the start of the school year, with evidence to suggest that outbreaks in children begin with the school year and then spread to outbreaks in adults.⁷⁵ A systematic review found GII.4 the most common genotype in endemic norovirus gastroenteritis in children, identified in approximately two-thirds of cases.⁷⁶

Estimated rates of norovirus disease in the community, outpatient, emergency, and inpatient settings and for deaths from norovirus in children in high-income countries are summarized in Table 2. Applying rates for studies conducted in the United States to 2016 population estimates from the US Census,⁷⁷ the authors estimate the burden from norovirus illness in children aged <18 years to be approximately 4.2 million total illnesses; 815,000 outpatient visits; 130,000 emergency department visits; 24,600 hospitalizations; and 38 deaths (Fig. 1).

Norovirus is the leading etiology of gastroenteritis outbreaks reported to the National Outbreak Reporting System in the United States, accounting for 68% of out-breaks in which a single etiology is identified.⁴⁷ Norovirus is most commonly transmitted by person-to-person contact, reported in 66% to 77% of outbreaks, although can also be transmitted by food, water, and environmental routes.^47,78 Although long-term care facilities caring for adults are the most frequently reported setting, schools and day care centers have been reported in 2% to 5% of all norovirus outbreaks.^47,78 Periodic increases in norovirus outbreaks occur in association with the emergence of new GII.4 strains, observed every 2 to 4 years in the past 2 decades.¹⁸

The ubiquity of norovirus in the environment and the high burden of norovirus infection make vaccination against norovirus an appealing prevention strategy. Norovirus vaccines in development have been based on virus-like particles (VLPs), which contain the major capsid antigen but lack genetic material for viral replication.⁸⁶ VLPs have been shown to induce humoral, mucosal, and cellular immune responses after oral and intranasal administration.⁸⁷ Several norovirus vaccines are currently under development in preclinical and clinical trials using VLPs and involving intranasal, oral, and intramuscular routes of administration.^13,88

A norovirus vaccination strategy needs to address biological and programmatic challenges.⁸⁹ Biologically, norovirus vaccines need to protect against the diversity of norovirus strains that affect humans and the presence of emerging GII.4 strains. Immunity is currently thought to be of limited duration, estimated from 6 months to 9 years and to confer little protection across genogroups.^49,50 Programmatically, young children bear the highest overall incidence of disease and likely drive community transmission⁹⁰ and are thus an ideal target for vaccination. It is unknown, however, how norovirus vaccination might interact with other routine childhood vaccinations, and trials of norovirus vaccines have been mostly conducted in adults. Given prior exposure and underlying conditions, the immune response is likely to differ in young children, adolescents, adults, the elderly, and the immunocompromised.

Despite these challenges, norovirus vaccination has the potential to be highly beneficial to society. A simulation model estimated that vaccination could prevent 1 million to 2.2 million annual cases of norovirus gastroenteritis in the United States, resulting in savings of $2 billion over 4 years.⁹¹ Given the high burden and higher mortality in low-income countries, norovirus vaccination would be of even greater benefit if adopted broadly by national immunization programs.

Norovirus is the leading cause of acute gastroenteritis in the United States and globally, with higher incidence in children than in other age groups. In the United States, an estimated 4.2 million annual norovirus illnesses in children result in a high burden of medical care and hospitalization. Although deaths from norovirus in US children are rare, norovirus is a leading cause of death from childhood diarrhea in developing countries. Early assessment of dehydration status from diarrhea and appropriate treatment are advised to prevent complications, including death. Norovirus outbreaks should be managed with hand hygiene, exclusion of ill persons, and environmental control. Future prospects for prevention of norovirus include vaccination.