Viral Gastroenteritis

Background

Acute gastroenteritis is a common cause of morbidity and mortality worldwide. Conservative estimates put diarrhea in the top 5 causes of deaths worldwide, with most occurring in young children in nonindustrialized countries. In industrialized countries, diarrheal diseases are a significant cause for morbidity across all age groups. Etiologies include bacteria, viruses, parasites, toxins, and drugs. Viruses are responsible for a significant percentage of cases affecting patients of all ages; in the United States, viruses are the leading cause of acute gastroenteritis.^[1] Viral gastroenteritis ranges from a self-limited watery diarrheal illness (usually <1 wk) associated with symptoms of nausea, vomiting, anorexia, malaise, or fever, to severe dehydration resulting in hospitalization or even death.

The clinician encounters acute viral gastroenteritis in 3 settings. The first is sporadic gastroenteritis in infants, which most frequently is caused by rotavirus.^[2] The second is epidemic gastroenteritis, which occurs either in semiclosed communities (eg, families, institutions, ships, vacation spots) or as a result of classic food-borne or water-borne pathogens.^[3] Most of these infections are caused by caliciviruses. The third is sporadic acute gastroenteritis of adults, which most likely is caused by caliciviruses, rotaviruses, astroviruses, or adenoviruses.

For patient education resources, see Digestive Disorders Center, as well as Gastroenteritis (Stomach Flu), Norovirus Infection, and Diarrhea.

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Pathophysiology

Viral spread from person to person occurs by fecal-oral transmission of contaminated food and water. Some viruses, like noroviruses, may be transmitted by an airborne route. Clinical manifestations are related to intestinal infection, but the exact mechanism of the induction of diarrhea is not clear.

The most extensive studies have been done with rotavirus. Rotaviruses attach and enter mature enterocytes at the tips of small intestinal villi. They cause structural changes to the small bowel mucosa, including villus shortening and mononuclear inflammatory infiltrate in the lamina propria.

The current knowledge on the mechanisms leading to diarrheal disease by rotavirus is as follows:^[4]

• Rotavirus infections induce maldigestion of carbohydrates, and their accumulation in the intestinal lumen, as well as a malabsorption of nutrients and a concomitant inhibition of water reabsorption, can lead to a malabsorption component of diarrhea.
• Rotavirus secretes an enterotoxin, NSP4, which leads to a Ca²⁺ -dependent Cl^- secretory mechanism. Mobilization of intracellular calcium associated with NSP4 expressed endogenously or added exogenously is known to induce transient chloride secretion.

Morphologic abnormalities can be minimal, and studies demonstrate that rotavirus can be released from infected epithelial cells without destroying them. Viral attachment and entry into the epithelial cell without cell death may be enough to initiate diarrhea. The epithelial cell synthesizes and secretes numerous cytokines and chemokines, which can direct the host immune response and potentially regulate cell morphology and function. Studies also suggest that one of the nonstructural viral proteins may act as an enterotoxin, promoting active chloride secretion mediated through increases in intracellular calcium concentration. Toxin-mediated diarrhea would explain the observation that villus injury is not necessarily linked to diarrhea.

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Etiology

Sporadic infantile viral gastroenteritis

Group A rotavirus causes 25-65% of severe infantile gastroenteritis worldwide. Acute infections with group C are quite frequent in the United States and worldwide.

After rotavirus, the most important cause of acute infantile gastroenteritis probably is calicivirus infection. Seroepidemiologic studies have shown that antibodies to caliciviruses are present in 50-90% of children younger than 2 years in Kuwait, Italy, Kenya, China, London, and South Africa. Using broadly reactive reverse-transcription polymerase chain reaction for calicivirus to study stool specimens from children with acute gastroenteritis, studies have found these viruses in 7-22% of cases.

Astrovirus infection is associated with 2-9% of cases of infantile gastroenteritis worldwide, making it the third most frequent cause after rotavirus and calicivirus. The burden of astrovirus disease in developing countries might be especially high. In a study comprising pediatric data from 82,082 children in 8 countries, using 25,898 surveillance stools and 7,077 diarrheal stools, investigators found 35% of children had astrovirus infections, with an astrovirus prevalence of 5.6% in diarrheal stools.^[5] Children with astrovirus infection were 2.3 times more likely to experience diarrhea, with undernutrition a risk factor.^[5]

Researchers have recognized for a long time that certain enteric adenoviruses are an important cause of infantile gastroenteritis. Studies confirm that they cause 2-6% of cases.

A study by Chhabra et al indicated that in addition to rotavirus and norovirus, frequent causes of acute gastroenteritis in US children include adenovirus, sapovirus, and astrovirus. The study, which included patients from hospitals, emergency departments, and primary care clinics in three US counties, found that stool specimens from 22.1% of children under age 5 years who presented with acute gastroenteritis and who tested negative for rotavirus and norovirus, tested positive for adenovirus (11.8%), sapovirus (5.4%), and astrovirus (4.9%).^[6]

Epidemic viral gastroenteritis

Most cases of epidemic viral gastroenteritis in adults and children are caused by the caliciviruses. Some examples include Norovirus (formerly called Norwalk-like viruses), genogroup I (eg, Norwalk, Southampton, Desert Shield, Cruise Ship); norovirus, genogroup II (eg, Snow Mountain, Mexico, White River, Lordsdale, Bristol, Camberwell, Toronto, Hawaii, Melksham); and sapovirus (formerly Sapporo-like viruses), which sometimes are referred to as genogroup III, although they are not like Norwalk (eg, Sapporo, Parkville, Manchester, Houston, London).

Modern molecular diagnostic techniques, such as broadly reactive reverse-transcription polymerase chain reaction, have linked these viruses to epidemics associated with oysters, contaminated community water supplies, restaurant food, hospital patients and staff, day care facilities, nursing homes, college dormitories, military ships, cruise ships, and vacation spots. Rotavirus and astrovirus also may cause epidemics of viral gastroenteritis.

Sporadic adult viral gastroenteritis

Few studies have examined the causes of sporadic cases of adult viral gastroenteritis. Seroepidemiologic evidence suggests that the etiologies are (in descending order of frequency) caliciviruses, non–group A rotavirus, astrovirus, and adenovirus.

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Epidemiology

United States data

Before the advent of rotavirus vaccine, more than 3.5 million infants developed acute viral gastroenteritis, resulting in more than 500,000 office visits, 55,000 hospitalizations, and 30 deaths.^{[7, 8]} However, a CDC study by Tate et al demonstrated a decline in the seasonality of rotavirus following the 2006 introduction of the rotavirus vaccine.^[9]

The investigators evaluated data for July 2000 through June 2008 to assess national, regional, and local trends in rotavirus testing and detection and found not only was the onset of the 2007-2008 rotavirus season delayed 15 weeks and the peak delayed 8 weeks relative to the prevaccine rotavirus season from 2000 to 2006, but the 2007-2008 season also lasted a little over half (14 wk) of the median prevaccine seasons (26 weeks).^[9]  Moreover, there was a 67% decline in the number and a 69% decline in the proportion of 2007-2008 rotavirus-positive test results compared with the median in 2000-2006.

Rotavirus is the most common etiologic agent of health care–acquired diarrhea in pediatric patients.^[10]  Community- and health care–acquired infections have similar temporal distributions; they are caused by the same viral subtypes; and they affect children of the same age groups. All of the health care–acquired infections with known viral subtypes occurred while the same subtype was still active in the community, suggesting that health care–acquired infections arise from repeated introduction of the community-acquired rotavirus into the hospital setting.^[11]

Statistics on sporadic cases of adult viral gastroenteritis are not known; however, food- and water-borne epidemics of viral gastroenteritis are monitored by the US Centers for Disease Control and Prevention (CDC) surveillance programs. 

Norovirus causes an annual 19-21 million cases of acute gastroenteritis occur in the United States, resulting in 1.7-1.9 million outpatient visits and 400,000 emergency department visits, primarily in young children.^[12] It is the leading cause of gastroenteritis outbreaks and contributes to an estimated 56,000-71,000 hospitalizations and 570-800 deaths, mainly affecting children and the elderly.^[12]  The CDC estimates that norovirus alone causes nearly 5.5 million cases of food-related illness each year (of a total of 48 million cases from all causes).^[13]  The genus Norovirus, formerly called the Norwalk-like virus, is a member of the family Caliciviridae.

Noroviruses are now recognized to be a common cause of gastroenteritis in new settings, including nursing homes and other healthcare settings, cruise ships, in other travelers, and in immunocompromised patients.^[14] In 2010-2011, norovirus was transmitted among players and staff of the National Basketball Association.^[15]

In March 2012, the CDC reported a rise in foodborne disease outbreaks caused by imported food in 2009 and 2011. Nearly 50% of the outbreaks implicated food that was imported from regions not previously associated with outbreaks (mostly fish and peppers). Approximately 45% percent of the imported foods causing outbreaks came from Asia.^[16]

In 2015, the CDC published its first National Outbreak Reporting System (NORS) results on data on acute gastroenteritis outbreaks spread through person-to-person contact, environmental contamination, and unknown modes of transmission in all 50 US states, the District of Columbia (DC), and Puerto Rico between 2009 and 2013.^[17]  The following were among the NORS findings:

• A total of 10,756 outbreaks of acute gastroenteritis over the study period resulted in 356,532 reported illnesses, 5,394 hospitalizations, and 459 deaths.
• In any given year, there was an increase in the median outbreak reporting rate for all sites, from 2.7 outbreaks per million population in 2009 to 11.8 outbreaks in 2013, with almost one third (31%) of these outbreaks having an unknown cause, whereas of the outbreaks with a suspected or confirmed cause, norovirus was reported in 84%.

The frequency is seasonal. Acute gastroenteritis outbreaks most frequently occurring during the winter (December-February).^[17] The highest incidence of rotavirus cases occurs during the months from November to April. Cruise ship outbreaks of noroviruses are more common during the summer months.^[10]

International data

Acute viral gastroenteritis is a leading cause of infant mortality throughout the world. By age 3 years, virtually all children become infected with the most common agents. Rotavirus causes 2 million hospitalizations and 600,000-875,000 deaths per year.

Globally, Norovirus causes an estimated 20% of cases of acute gastroenteritis and is considered the most common of this condition (most common strain: genogroup II genotype 4^[18] ).^[10]  It is responsible for 685 million cases annually, with 200 million cases involving children younger than 5 years and resulting in an estimated 50,000 child deaths every year, primarily in developing countries.^[10]

The occurrence of noroviruses on cruise ships has led to the use of the term "the cruise ship virus" as another name for these viruses. Some illnesses previously attributed to sea sickness are now recognized to be caused by norovirus infections.^[14]

Age-related demographics

Acute viral gastroenteritis occurs throughout life. Severe cases are seen in the very young and in the elderly.^[19]  The etiology also varies with age. In infants, most cases are due to rotavirus; in adults, the most common cause is norovirus.

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Prognosis

Acute viral gastroenteritis is generally self-limited and has a good prognosis.^[1]

Morbidity/mortality

Severe cases are seen in the elderly, infant, and immunosuppressed populations, including transplant patients.^[1]

Rotavirus infantile gastroenteritis is an important cause of infant mortality in the developing world.

In the United States, elderly persons have the highest risk of death from gastroenteritis.

Caliciviruses may kill more people in the United States than do rotaviruses.

Noroviruses are the most common cause of gastroenteritis in nursing homes, and several such outbreaks have resulted in deaths due to aspiration or exacerbation of another chronic disease. Norovirus infections in hospitalized patients are more severe than those seen in otherwise healthy persons.^[14]

In a 2012 report, the CDC revealed enteritis deaths more than doubled in the United States, an increase to 17,000 in 2007 from about 7,000 in 1999.^[20]  Adults over 65 years old accounted for 83% of deaths. Clostridium difficile (C difficile) and norovirus were the most common infectious causes of gastroenteritis-associated deaths. Norovirus was associated with about 800 deaths annually, although there were 50% more deaths in years when epidemics were caused by new strains of the virus.^[20]  New norovirus strains continue to emerge.^{[18, 21, 22]}

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History

The clinical spectrum of acute viral gastroenteritis ranges from asymptomatic infection to severe dehydration and death. Viral gastroenteritis typically presents with short prodrome, with mild fever and vomiting, followed by 1-4 days of nonbloody, watery diarrhea. Viral gastroenteritis is usually self-limited.

• The history should focus on severity and dehydration. The onset, frequency, quantity, and duration of diarrhea and vomiting are important factors in assessing the status. Oral intake, urine output, and weight loss are important considerations. Viruses are the suspected cause of acute gastroenteritis when vomiting is prominent, when the incubation period is longer than 14 hours, and when the entire illness is over in less than 3 days. Travel history (including cruise ships), eating history, and daycare history are important epidemiological factors.
• A viral cause should be suspected when the warning signs of bacterial infection (ie, high fever, bloody diarrhea, severe abdominal pain, >6 stools/24 h) are absent and an alternative diagnosis is not suggested by epidemiologic clues from the history (eg, travel, sexual practices, antibiotic use).
• Factors associated with severe and prolonged disease are immunodeficiency and immune suppression, comorbid disease, and malnutrition.
• Death results from dehydration and acidosis.
• Ruling out other diagnoses is important. Mucus or overt blood in the stool almost always indicates bacterial or parasitic infection.

In 1982, the Kaplan criteria were established to distinguish outbreaks due to norovirus from outbreaks of bacterial etiology. The criteria are highly specific (99%) and moderately sensitive (68%). The 4 criteria indicative of an outbreak due to norovirus are as follows:^[23]

• Vomiting in 50% of affected persons in the outbreak
• Mean incubation period of 24-48 hours
• Mean duration of illness of 12-60 hours
• Lack of identification of a bacterial pathogen in stool culture

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Physical Examination

The physical examination can be helpful in determining the etiology of gastroenteritis and in assessing the presence and degree of dehydration.

• Temperature, blood pressure and pulse, and body weight can provide evidence of severity of the condition.
• Temperature may be slightly elevated. High fever suggests bacterial infection. Tachycardia, thready pulse, and hypotension suggest severe dehydration.
• Inflammatory signs associated with bowel infection (fever, bloody or mucoid stools) suggest invasive bacteria (eg, salmonella, shigella, or campylobacter), enteric viruses (eg, cytomegalovirus [CMV] or adenovirus), Entamoeba histolytica, or a cytotoxic organism such as C difficile.^[24]
• The degree of weight loss may be related to dehydration and the duration of the diarrhea.
• The mucous membranes and the skin should be examined carefully. Dry mouth, no tears, skin tenting, dry skin, and capillary refill are all signs of dehydration.
• The mental status in elderly patients and infants may be abnormal, especially when blood pressure and circulation are compromised.
• The abdominal examination may demonstrate mild tenderness. Severe abdominal pain and tenderness suggest bacterial infection or an abdominal emergency.

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Laboratory Studies

General laboratory evaluation

In most cases that fit the clinical features of viral gastroenteritis, laboratory tests are not indicated.

If bacterial or protozoal infection is suspected, stool studies for occult blood, white blood cell (WBC) count, microscopy for protozoa, C difficile toxin, Giardia lamblia by enzyme immunoassay (EIA), or bacterial culture may be indicated.

Consider investigating patients with low-grade fever, nausea, vomiting, abdominal pain, and extreme dehydration by evaluating serum electrolytes, urea, creatinine, amylase, complete blood cell (CBC) count, and abdominal imaging studies.

Blood cultures should be obtained in patients with high fevers or who appear systemically ill.

Stool cultures are not performed for most patients who do not have severe illness or high-risk comorbidities, because most infectious cases of acute diarrhea are self-limited and of viral etiology, and the rate of positive stool cultures in all-comers with acute diarrhea is generally low.^[25]  When stool cultures are obtained in patients with acute diarrhea, it is to identify a potential bacterial pathogen and determine the potential for complications and treatment decisions.

Polymerase chain reaction (PCR) for enteropathogen detection in stool of patients with diarrhea is available. Cost effectiveness in specific communities remains to be determined.^[26]

Japanese researchers have developed a multiplex real-time PCR assay to detect human enteric viruses other than norovirus ("non-NoV" gastroenteritis viruses) conducted separately from norovirus testing that have the potential to deal with two types of epidemiologic investigations: regular surveillance of infectious gastroenteritis and urgent testing when gastroenteritis outbreaks occur.^[27]

In a systematic literature review, Lee et al used pooled data to calculate median incubation periods for astrovirus (4.5 days), norovirus genogroups I and II (1.2 days), sapovirus (1.7 days), and rotavirus (2.0 days).^[28]

Diagnosis of rotavirus infection

Rapid antigen testing of the stool, either by EIA (>98% sensitivity and specificity) or latex agglutination tests (less sensitive and specific as compared to EIA), is used to aid in the diagnosis of rotavirus infection.

Expect antirotavirus antibodies (ie, immunoglobulin M, immunoglobulin A) to be excreted in the stool after the first day of illness. Antibody tests can remain positive for 10 days after primary infection and longer after reinfection; therefore, they can be used as an adjunct to diagnosis.

Diagnosis of calicivirus infection

In epidemics, save stool and emesis specimens for evaluation by public health officials. Polymerase chain reaction is valuable in both the outbreak setting and the sporadic case setting.

Researchers have cloned several of the caliciviruses and placed the genome in a baculovirus that produces unlimited amounts of recombinant calicivirus capsid protein. Enzyme immunoassays for serum antibody and stool antigen have been developed using this antigen source.

A modification to PCR has allowed many of the various strains of caliciviruses to be recognized with just a few primers (broadly reactive reverse-transcription polymerase chain reaction). These primers are directed at a region of the genome that is common to many of the strains of calicivirus. This has been an important tool for identifying caliciviruses as the most common cause of epidemic viral gastroenteritis.

Fecal viral concentration of norovirus correlates with duration of illness. As in most viral infections, active viral replication determines clinical disease. High fecal viral concentrations suggest the need for both aggressive fluid replacement and stringent infection control measures.^[29]

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Medical Care

In 1996, the American Academy of Pediatrics (AAP) formulated and published practice guidelines for the management of acute gastroenteritis in children.^[30] The AAP continues to update these guidelines^[31] and/or endorses those from other health organizations, including the Centers for Disease Control and Prevention.^[32] Use the following parameters to assess the degree of dehydration: blood pressure, pulse, heart rate, skin turgor, fontanelle, mucous membranes, eyes, extremities, mental status, urine output, and thirst.

• The treatment of rotavirus diarrhea is based primarily on replacing fluids and electrolytes, as directed by the estimated degree of dehydration.
• Oral rehydration therapy is recommended for preventing and treating early dehydration and continued replacement therapy for ongoing loses.
• Shock, severe dehydration, and decreased consciousness require intravenous therapy.
• Age-appropriate diets should be continued in children with diarrhea who are not dehydrated. When mild-to-moderately dehydrated children are rehydrated, resume age-appropriate diet.
• Administering antiemetics and antidiarrheal agents to small children is not recommended.
• Several studies have shown that antirotavirus immunoglobulin, as pooled gamma globulin, bovine colostrum, or human milk, may decrease frequency and duration of diarrhea.
• Small studies have suggested that zinc supplements may reduce the severity and duration of illness.

Probiotics are nonpathogenic live microorganisms that provide beneficial effects on the health of the host. In recent years, probiotics have entered mainstream medical practice, as a decrease in the severity and duration of infectious gastroenteritis has been shown in some strains.^[33]

• Probiotics help to improve the balance of the intestinal microflora, although the exact mechanism of action is incompletely understood. Hypothesized mechanisms include suppression of growth or invasion by pathogenic bacteria, improvement of intestinal barrier function, and effects on immune function.^[34]
• Literature shows a statistically significant, but clinically moderate, benefit for some strains, mainly in infants and young children, in the treatment of acute watery diarrhea, especially in rotavirus gastroenteritis.^[33]
• Until further data are available, only those organisms that have been clinically tested can be reasonably recommended, Lactobacillus casei GG and Saccharomyces boulardii being the most reported. Limited data and modest expected benefit must be explained to patients.^[33]

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Prevention

Natural infection with rotavirus does not afford complete immunity, and multiple infections in the first few years of life probably are common; however, immune response to these infections reduces the frequency and severity of subsequent rotavirus infection.

The Centers for Disease Control and Prevention (CDC) recommend administering rotavirus vaccine in infants. There are two licensed rotavirus vaccines for use in infants in the United States: RotaTeq (RV5), an oral attenuated pentavalent rotavirus vaccine (PRV), is given in three doses at age 2, 4, and 6 months, and Rotarix (RV1), an oral attenuated monovalent rotavirus vaccine, is given in two doses, at age 2 and 4 months.^[35]

The Rotarix vaccine strain replicates well in the gut after the first dose and provides cross-protection against most other serotypes. RotaTeq, however, is not so broadly cross-protective and grows less well in human intestines. In addition, the vaccine strains are infrequently shed in the stool, and 3 doses are required.^[36]

RotaShield was removed from the market in the United States in 1999 owing to an association between this vaccine and intussception.^[37]

Proper hygiene is still the first essential preventative step in viral gastroenteritis,^[1] particularly in households with two or more primary cases of norovirus and at least one primary case with diarrhea.^[38] Hand washing to prevent fecal-oral transmission is very important. It also includes properly handling food and using clean water supplies.

On a community level, proper sanitation, clean water supplies, and surveillance programs for outbreaks are important steps in prevention.

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