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. 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. 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. 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.
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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:
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.
Each year, more than 3.5 million infants develop acute viral gastroenteritis, resulting in more than 500,000 office visits, 55,000 hospitalizations, and 30 deaths. 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. The CDC estimates that viruses cause 9.2 million cases of food-related illness each year (out of a total of 13.8 million cases from all causes).
Noroviruses cause approximately 23 million cases of acute gastroenteritis each year and are the leading cause of outbreaks of gastroenteritis. They are responsible for 68-80% of all outbreaks in industrialized countries. 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 health care settings, cruise ships, in other travelers, and in immunocompromised patients. In 2010-2011, norovirus was transmitted among players and staff of the National Basketball Association.
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.
The frequency is seasonal. 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. However, a CDC study by Tate et al demonstrated a decline in the seasonality of rotavirus following the 2006 introduction of the rotavirus vaccine.
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). 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. 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.
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.
Noroviruses were attributed to 9 out of the 21 outbreaks of acute gastroenteritis on cruise ships reported to the CDC's Vessel Sanitation Program from January 1, 2002, to December 2, 2002. 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.
Severe cases are seen in the elderly, infant, and immunosuppressed populations, including transplant patients.
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.
The CDC reported enteritis deaths more than doubled in the United States, an increase to 17,000 in 2007 from about 7,000 in 1999. 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, though there were 50% more deaths in years when epidemics were caused by new strains of the virus.
Acute viral gastroenteritis occurs throughout life. Severe cases are seen in the very young and in the elderly. Etiology also varies with age.
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:
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
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.
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%).
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 (formerly Norwalk-like viruses), 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.
In most cases that fit the clinical features of viral gastroenteritis, lab tests are not indicated.
If bacterial or protozoal infection is suspected, stool studies for occult blood, WBC count, microscopy for protozoa, Clostridium 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, CBC count, and abdominal imaging studies.
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 the polymerase chain reaction has allowed many of the different 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.
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).
In 1996, the American Academy of Pediatrics formulated and published practice guidelines for the management of acute gastroenteritis in children. 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.
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.
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.
Until further data are available, only those organisms that have been clinically tested can be reasonably recommended, Lactobacillus casei GG and S boulardii being the most reported. Limited data and modest expected benefit must be explained to patients.
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.
On February 21, 2006, the CDC Advisory Committee on Immunization Practices (ACIP) recommended RotaTeq, an oral attenuated pentavalent rotavirus vaccine (PRV), for the vaccination of infants. Three doses should be given at 2, 4, and 6 months. The third dose should be given no later than 32 weeks.
In the REST trial, a double-blind placebo-controlled trial of over 60,000 infants, RotaTeq demonstrated a 74% reduction in all rotavirus cases. There was a 98% reduction in severe cases and a 96% reduction in hospitalized cases.
Of note, there was a 59% reduction in all-cause gastroenteritis admissions, highlighting rotavirus as a larger contributor to the cause of acute gastroenteritis than originally expected.
The oral live attenuated vaccine was not tested in immunocompromised patients and not approved for this use.
There was no association of RotaTeq with intussusceptions in this trial. The former RotaShield vaccine was pulled from the market for increased intussusceptions. However, this risk was only seen in older infants. The RotaTeq trial did not test older infants. For these reasons, the RotaTeq vaccine is not approved for infants older than 32 weeks, and a "catch-up" vaccination is not recommended.
There are some questions as to the efficacy in less developed countries where the vaccine was not tested and nonvaccine serotypes (VP4, VP6, and VP7) are more prevalent.
RotaShield is not approved for use, but it is being considered for reintroduction into the marketplace in limited use for early infant vaccination only.
In April 2008, the United States Food and Drug Administration (FDA) approved a new vaccine for rotavirus gastroenteritis. Rotarix is a monovalent vaccine derived from the most common human rotavirus strain that has been attenuated by serial passage and is administered in 2 oral doses, 1-2 months apart.
The phase 3 trial of Rotarix reported the following results:
Rotarix was highly protective against severe rotavirus gastroenteritis (85%) and hospitalization for severe rotavirus gastroenteritis (85%).
The vaccine was also protective against gastroenteritis of any cause (40%) and hospitalization for gastroenteritis of any cause (42%).
Infants vaccinated with Rotarix had fewer serious adverse events or required hospitalization because of gastrointestinal events.
The vaccine proved to be safe with respect to the risk of intussusceptions. The observed risk estimate was below the initial risk increase of 4 per 100,000 that led to the withdrawal of the RotaShield vaccine, and it was also below the subsequent consensus risk estimate of 1 per 100,000 for that vaccine.
The Rotarix vaccine strain replicates well in the gut after the first dose and provides cross-protection against most other serotypes. RotaTeq, on the other hand, 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.
Recommendations from the American Academy of Pediatrics and the CDC for the use of Rotarix are pending.
Research on a vaccine for calicivirus infection is proceeding rapidly. Baculovirus-produced antigens spontaneously form virus-like particles without RNA that are immunogenic and possibly protective. Genomes also can be inserted into edible foodstuffs (eg, potatoes, bananas).
Proper hygiene is still the first preventative step in viral gastroenteritis. 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.
Michael J Grupka, MD, Physician, Atlanta Center for Gastroenterology
Disclosure: Nothing to disclose.
John Gunn Lee, MD, Director of Pancreaticobiliary Service, Associate Professor, Department of Internal Medicine, Division of Gastroenterology, University of California at Irvine School of Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Noel Williams, MD, Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
Disclosure: Nothing to disclose.
Alex J Mechaber, MD, FACP, Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Disclosure: Nothing to disclose.
Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine