Gastrointestinal viruses

Epidemiology and risk factors

Norovirus is transmitted through the fecal-oral route by close person-to-person contact. It can also be transmitted through contaminated food or water, and environmental contamination has been implicated in outbreaks. In addition, because norovirus is present in the vomitus of infected individuals, it can be spread by droplets to those who are in close contact with or caring for individuals who are vomiting. Norovirus is very infectious and a low inoculum is needed to cause disease. Norovirus virions are quite stable in the environment and can remain infectious on fomites for at least 7 days. Norovirus can be detected in the stool of asymptomatic individuals; one meta-analysis found norovirus in the stools of 7% of healthy controls (3% to 10%). This is likely a consequence of asymptomatic infection and/or convalescent excretion after illness has resolved. The role of asymptomatic shedding in transmission is unknown.

Noroviruses are a leading cause of both sporadic cases and outbreaks of acute gastroenteritis in the community worldwide. Community outbreaks occur year-round but the majority occur in the winter. They are also important causes of institutional and nosocomial infection and outbreaks. A recent survey of U.S. hospitals revealed that noroviruses were among the most commonly detected nosocomial pathogens and caused the highest rate of hospital unit closures.

Norovirus affects all age groups. Globally, norovirus prevalence in acute gastroenteritis cases in children younger than 5 years was 18% (15% to 20%) and 19% (7% to 21%) in all age groups. In the United States, norovirus is associated with 19 million to 21 million episodes of gastroenteritis and up to 71,000 hospitalizations annually. Nearly 800 deaths are caused by norovirus each year, which is the second most common cause of gastroenteritis-related death in the United States. Deaths occur disproportionately among individuals with chronic and/or immunocompromising conditions, such as transplantation and/or chemotherapy. Norovirus has been detected in 22% to 32% of immunocompromised children with diarrhea. ^{, ,}

Clinical manifestations

Symptoms of norovirus infection are similar to other causes of acute viral gastroenteritis and include vomiting, abdominal pain, watery, nonbloody diarrhea, and low-grade fever after an incubation period of about 24 hours. Vomiting is common and may be the only symptom. Symptoms usually last 12 to 60 hours in immunocompetent individuals. In contrast, the immunocompromised can have more severe and prolonged symptoms. A study of pediatric oncology patients with diarrheal illness found that 44% of these patients with norovirus required hospitalization. The median duration of diarrhea was 6 days (interquartile range 3 to 10 days). Another study of immunocompromised pediatric patients found that the mean duration of symptoms was 10 days; the majority (70%) had symptoms for 4 days or longer and more than 20% had symptoms for longer than 14 days. In addition, nearly half of these children had seven or more diarrheal episodes daily.

Chronic norovirus diarrhea (lasting ≥4 weeks) has been well described, especially in solid organ transplant (SOT) recipients and other immunocompromised individuals. Illness can be associated with significant weight loss, failure to thrive, dehydration requiring hospitalization, renal dysfunction, and relapsing diarrhea. One study found that the strongest association with duration of diarrhea was having received induction immunosuppression with antithymocyte globulin and having received plasmapheresis, in addition to human antigen leukocyte– and/or ABO-incompatible kidney transplant status, suggesting that more significant immunosuppression could be associated with a more severe course. Another study of norovirus in SOT patients also found that CMV infection in the 90 days preceding norovirus diagnosis and nausea at presentation were two significant risk factors for diarrhea persisting more than 2 weeks.

Disease prophylaxis and prevention

No licensed norovirus vaccines exist. Five different norovirus vaccines are currently being developed. Two vaccines have been studied in humans with promising results. One safety and immunogenicity trial in children is ongoing (NCT02153112). All of these are virus-like particle vaccines targeting the major capsid protein. It is unclear whether candidate vaccines would be effective in patients with significant immunosuppression. However, an effective vaccine might still protect immunocompromised patients via herd effects.

Diagnosis

The genetic (and antigenic) diversity of noroviruses has led to low sensitivity for antigen detection tests, whereas polymerase chain reaction (PCR)-based detection has proven very sensitive. Multiple singleplex PCR-based tests that have high sensitivity are commercially available. Recently sensitive multiplex PCR-based tests for multiple gastrointestinal pathogens (including norovirus) have become increasingly available and used. None of the three commercially available multipathogen gastrointestinal panels can distinguish between norovirus GI and GII. Because norovirus can be shed by healthy and/or asymptomatic individuals and given the high sensitivity of many of the PCR-based assays, clinicians must interpret a positive test result in the context of the clinical situation and symptoms.

Treatment

Clinical management of norovirus is supportive and targeted at maintaining adequate hydration, nutrition, and electrolyte balance. The WHO recommends low-osmolarity oral rehydration solution as opposed to traditional oral rehydration solution, and it has been shown to decrease vomiting and stool output in children with acute gastroenteritis. Ondansetron reduces vomiting in children with acute gastroenteritis and decreases need for intravenous hydration.

Multiple potential therapies have been tried, with limited success in immunocompromised patients, to manage the more severe manifestations. Reduction of immunosuppression, when possible, often is helpful in immunocompromised patients with prolonged and/or severe symptoms but may be associated with the risk of graft rejection. One small study in kidney transplant patients described decreased immunosuppression associated with clinical improvement, but continued viral shedding in two-thirds of the patients.

No medications are currently approved for treatment of norovirus infection. Nitazoxanide is an antiparasitic drug licensed in the United States for treatment of Cryptosporidium parvum and Giardia lamblia in adults and children older than 12 months. However, nitazoxanide has been reported to have broad-spectrum antiviral activity as well through a variety of poorly understood mechanisms. A recent systematic review of five studies of nitazoxanide for the treatment of acute gastroenteritis caused by norovirus, rotavirus, or adenovirus showed use of this agent shortened duration of diarrhea by approximately 24 hours compared with placebo. Multiple published case reports describe the use of nitazoxanide for norovirus gastroenteritis in immunocompromised individuals with variable effect on clinical symptoms and/or viral shedding. ^, A multicenter, randomized, placebo-controlled trial of nitazoxanide for treatment of symptomatic norovirus infection in SOT and hematopoietic stem cell transplantation (HSCT) recipients is ongoing and will hopefully provide definitive evidence regarding the efficacy of this agent for norovirus disease (NCT03395405).

Both intravenous and enteral administration of immunoglobulin have been used in immunocompromised patients with norovirus, but published experience is limited to case reports. Two single case reports in heart and pancreas transplant recipients cited no difference in symptoms after intravenous immunoglobulin administration. Enteral administration of immunoglobulin has been described in case reports as well, with mixed results. Concern exists about protein degradation by the acidic environment, so jejunal administration has been used. A case-control study of pediatric oncology and transplant patients (primarily SOT) evaluated enteral immunoglobulin in 12 patients and found a trend toward resolution of diarrhea and stool output 7 days after treatment. However, the study did not find a difference in length of stay, hospitalization cost, or time to resolution of diarrhea. Because of the possible antiviral effects of mammalian target of rapamycin inhibitors, substituting rapamycin for other immunosuppressants is a theoretical strategy whose use has been reported in a few cases of chronic norovirus. Additional studies of potential therapeutics are clearly needed for immunocompromised pediatric patients.

Infection prevention and anticipatory guidance

Norovirus is relatively resistant to many available disinfectants, including alcohol-based hand sanitizers. It is also relatively resistant to many commonly used hospital disinfectants based on phenolic compounds (triclosan and quaternary ammonium). Bleach-based solutions are recommended for environmental cleaning. Handwashing with soap and water is effective at preventing transmission, including in institutional settings. Guidelines recommend standard precautions for viral gastroenteritis, including norovirus, with the use of contact precautions for diapered or incontinent patients for the duration of illness. Owing to the description of nosocomial outbreaks and the potential for serious consequences among transplant patients, we recommend contact precautions for all transplant patients with viral gastroenteritis, In addition, transmission has been described through aerosolized vomitus or fecal material ; thus droplet precautions are appropriate if a patient is actively vomiting. Ideally, these patients should be in private rooms. Given the infectiousness of symptomatic individuals, infected health care workers should be excluded from work for at least 48 hours after resolution of symptoms.

Epidemiology and risk factors

Young children 6 months to 2 years of age who are immunologically naïve are at highest risk for rotavirus infection. Most children have experienced an initial rotavirus infection by age 5. Older children and adults who are immunocompetent are usually asymptomatic or have mild disease with subsequent episodes of infection. Transmission occurs via a fecal-oral route, usually through direct contact between people, and a small inoculum, such as 100 virions per gram of stool can be contagious. Transmission also can occur via ingestion of contaminated water or food and contact with contaminated surfaces or objects. Family outbreaks are common, and up to 50% of exposed immunocompetent children within a household develop rotavirus gastroenteritis. Rotavirus is present in the stools of infected children several days before and after the onset of clinical symptoms. Asymptomatic excretion of rotavirus in stool is relatively common and likely plays a role in transmission. The virus is stable in the environment and can be found on toys or hard surfaces. The incubation period is short, usually less than 2 days. In the United States, incidence peaks during late winter and early spring with annual epidemics occurring from December through June.

Clinical manifestations

Rotavirus infections are characterized by watery nonbloody diarrhea, vomiting, fever, or abdominal pain. Vomiting usually lasts for 2 to 3 days and other symptoms resolve within a week. Gastroenteritis caused by rotavirus cannot be clinically distinguished from that caused by other viral enteric pathogens. Severe cases can result in dehydration with shock, electrolyte imbalance, and death. Central nervous system involvement with seizures and encephalopathy has been described and rotavirus has been detected in cerebrospinal fluid on occasion. Necrotizing enterocolitis, intussusception, biliary atresia, and diabetes mellitus have also been described in association with rotavirus infection. However, it is uncertain whether rotavirus is an etiologic factor for these clinical syndromes.

Among immunocompromised children, particularly those with T-cell immunodeficiency or those who have undergone HSCT, rotavirus infections can cause severe disease with prolonged diarrhea fever, dehydration, electrolyte imbalances, acidosis, and mortality. Among 183 pediatric patients who received an allogeneic HSCT at St. Jude Children’s Research Hospital, 36 (19.7%) had at least one episode of rotavirus infection over the first 3 years after transplant and the median duration of diarrhea was 17.5 days (range 4 to 122 days). In a retrospective case-control study among pediatric oncology patients, the median duration of rotavirus-related symptoms was 7 days (range 4 to 34 days) and the median duration of viral shedding was 17 days (range 4 to 73 days). Children with SOT usually have more severe disease compared with healthy children and may experience prolonged hospitalization; however, the infection usually resolves without treatment. In addition, rotavirus may promote acute cellular rejection, particularly among intestinal transplant patients.

In addition, rotavirus infection can lead to increased serum levels of particular immunosuppressive agents in organ transplant recipients, particularly in liver transplant recipients. Fruhwirth and colleagues described three pediatric SOT recipients in whom rotavirus infection caused increased trough levels of tacrolimus. Although exact mechanisms are uncertain, as tacrolimus is significantly metabolized in the intestine, increased intestinal permeability and decreased gastrointestinal transit time, which would enhance drug availability in areas with lower intestinal metabolism such as the colon, have been proposed as potential mechanisms for increasing trough levels of tacrolimus.