Viral Gastroenteritis

Back

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.

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]

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.

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.

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:

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.

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]

 

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.

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]

Physical Examination

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

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]

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.

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]

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.

Author

Brian Lin, New York College of Osteopathic Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

George Y Wu, MD, PhD, Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Noel Williams, MD, FRCPC, FACP, MACG, 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.

Chief Editor

Burt Cagir, MD, FACS, Clinical Professor of Surgery, The Commonwealth Medical College; Director, General Surgery Residency Program, Robert Packer Hospital; Attending Surgeon, Robert Packer Hospital and Corning Hospital

Disclosure: Nothing to disclose.

Additional Contributors

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.

Michael J Grupka, MD, Physician, Atlanta Center for Gastroenterology

Disclosure: Nothing to disclose.

Michael Vincent F Tablang, MD, Resident Physician, Department of Internal Medicine, University of Connecticut Health Center

Disclosure: Nothing to disclose.

References

  1. Chiejina M, Samant H. Diarrhea, viral. 2017 Jun. [View Abstract]
  2. Ramani S, Kang G. Viruses causing childhood diarrhoea in the developing world. Curr Opin Infect Dis. 2009 Oct. 22(5):477-82. [View Abstract]
  3. Scarcella C, Carasi S, Cadoria F, et al. An outbreak of viral gastroenteritis linked to municipal water supply, Lombardy, Italy, June 2009. Euro Surveill. 2009 Jul 23. 14(29):epub ahead of print. [View Abstract]
  4. Lorrot M, Vasseur M. How do the rotavirus NSP4 and bacterial enterotoxins lead differently to diarrhea?. Virol J. 2007 Mar 21. 4:31. [View Abstract]
  5. Olortegui MP, Rouhani S, Yori PP, et al, for the MAL-ED Network. Astrovirus infection and diarrhea in 8 countries. Pediatrics. 2018 Jan. 141 (1):[View Abstract]
  6. Chhabra P, Payne DC, Szilagyi PG, et al. Etiology of viral gastroenteritis in children J Infect Dis</i>. 2013 Sep 1. 208(5):790-800. [View Abstract]
  7. Glass RI, Kilgore PE, Holman RC, et al. The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden. J Infect Dis. 1996 Sep. 174 Suppl 1:S5-11. [View Abstract]
  8. Fischer TK, Viboud C, Parashar U, et al. Hospitalizations and deaths from diarrhea and rotavirus among children <5 years of age in the United States, 1993-2003. J Infect Dis. 2007 Apr 15. 195 (8):1117-25. [View Abstract]
  9. Tate JE, Panozzo CA, Payne DC, et al. Decline and change in seasonality of US rotavirus activity after the introduction of rotavirus vaccine. Pediatrics. 2009 Aug. 124(2):465-71. [View Abstract]
  10. Centers for Disease Control and Prevention. Norovirus worldwide: global trends. Available at https://www.cdc.gov/norovirus/worldwide.html. Updated: June 24, 2016; Accessed: January 9, 2018.
  11. Smith MJ, Clark HF, Lawley D, et al. The clinical and molecular epidemiology of community- and healthcare-acquired rotavirus gastroenteritis. Pediatr Infect Dis J. 2008 Jan. 27(1):54-8. [View Abstract]
  12. Centers for Disease Control and Prevention. Norovirus: US trends and outbreaks. Available at https://www.cdc.gov/norovirus/trends-outbreaks.html. Reviewed: June 24, 2016; Accessed: January 9, 2018.
  13. Centers for Disease Control and Prevention. Estimates of foodborne illness in the United States. Burden of foodborne illness: findings. Available at https://www.cdc.gov/foodborneburden/2011-foodborne-estimates.html. Updated July 15, 2016; Accessed: January 9, 2018.
  14. Estes MK, Prasad BV, Atmar RL. Noroviruses everywhere: has something changed?. Curr Opin Infect Dis. 2006 Oct. 19(5):467-74. [View Abstract]
  15. Desai R, Yen C, Wikswo M, Gregoricus NA, Provo JE, Parashar UD, et al. Transmission of norovirus among NBA players and staff, winter 2010-2011. Clin Infect Dis. 2011 Dec. 53(11):1115-7. [View Abstract]
  16. CDC research shows outbreaks linked to imported foods increasing. Available at http://www.cdc.gov/media/releases/2012/p0314_foodborne.html. Accessed: March 14, 2012.
  17. Wikswo ME, Kambhampati A, Shioda K, Walsh KA, Bowen A, Hall AJ, et al. Outbreaks of acute gastroenteritis transmitted by person-to-person contact, environmental contamination, and unknown modes of transmission--United States, 2009-2013. MMWR Surveill Summ. 2015 Dec 11. 64 (12):1-16. [View Abstract]
  18. Barreira DMPG, Fumian TM, Tonini MAL, et al. Detection and molecular characterization of the novel recombinant norovirus GII.P16-GII.4 Sydney in southeastern Brazil in 2016. PLoS One. 2017. 12 (12):e0189504. [View Abstract]
  19. Notes from the field: outbreaks of rotavirus gastroenteritis among elderly adults in two retirement communities--Illinois, 2011. MMWR Morb Mortal Wkly Rep. 2011 Oct 28. 60(42):1456. [View Abstract]
  20. Centers for Disease Control and Prevention (CDC). Deaths from gastroenteritis double. Available at http://www.cdc.gov/media/releases/2012/p0314_gastroenteritis.html
  21. Lindesmith LC, Brewer-Jensen PD, Mallory ML, et al. Antigenic characterization of a novel recombinant GII.P16-GII.4 Sydney norovirus strain with minor sequence variation leading to antibody escape. J Infect Dis. 2017 Dec 22. [View Abstract]
  22. Pogan R, Schneider C, Reimer R, Hansman G, Uetrecht C. Norovirus-like VP1 particles exhibit isolate dependent stability profiles. J Phys Condens Matter. 2017 Dec 28. [View Abstract]
  23. Turcios RM, Widdowson MA, Sulka AC, et al. Reevaluation of epidemiological criteria for identifying outbreaks of acute gastroenteritis due to norovirus: United States, 1998-2000. Clin Infect Dis. 2006 Apr 1. 42(7):964-9. [View Abstract]
  24. [Guideline] DuPont HL. Guidelines on acute infectious diarrhea in adults. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol. 1997 Nov. 92 (11):1962-75. [View Abstract]
  25. [Guideline] Guerrant RL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001 Feb 1. 32 (3):331-51. [View Abstract]
  26. Schierenberg A, Nipshagen MD, Broekhuizen BD, van de Pol AC, Bruijning-Verhagen PC, Kusters JG, et al. Design of the PROUD study: PCR faeces testing in outpatients with diarrhoea. BMC Infect Dis. 2016 Jan 30. 16:39. [View Abstract]
  27. Kowada K, Takeuchi K, Hirano E, Toho M, Sada K. Development of a multiplex real-time PCR assay for detection of human enteric viruses other than norovirus using samples collected from gastroenteritis patients in Fukui Prefecture, Japan. J Med Virol. 2018 Jan. 90 (1):67-75. [View Abstract]
  28. Lee RM, Lessler J, Lee RA, et al. Incubation periods of viral gastroenteritis: a systematic review. BMC Infect Dis. 2013 Sep 25. 13:446. [View Abstract]
  29. Lee N, Chan MC, Wong B, et al. Fecal viral concentration and diarrhea in norovirus gastroenteritis. Emerg Infect Dis. 2007 Sep. 13(9):1399-401. [View Abstract]
  30. [Guideline] American Academy of Pediatrics. Practice parameter: the management of acute gastroenteritis in young children. American Academy of Pediatrics, Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Pediatrics. 1996 Mar. 97 (3):424-35. [View Abstract]
  31. [Guideline] American Academy of Pediatrics Provisional Committee on Quality Improvement. Practice parameter: the management of acute gastroenteritis in young children. American Academy of Pediatrics, Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Pediatrics. 1996 Mar. 97 (3):424-35. [View Abstract]
  32. [Guideline] King CK, Glass R, Bresee JS, Duggan C, Centers for Disease Control and Prevention. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR Recomm Rep. 2003 Nov 21. 52 (RR-16):1-16. [View Abstract]
  33. Vandenplas Y, Salvatore S, Vieira M, et al. Probiotics in infectious diarrhoea in children: are they indicated?. Eur J Pediatr. 2007 Dec. 166(12):1211-8. [View Abstract]
  34. Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004 May. 126(6):1620-33. [View Abstract]
  35. Centers for Disease Control and Prevention. Vaccines and preventable diseases. Rotavirus vaccination: information for health care professionals). Available at https://www.cdc.gov/vaccines/vpd/rotavirus/hcp/index.html. Updated: November 22, 2016; Accessed: January 8, 2018.
  36. Glass RI, Parashar UD. The promise of new rotavirus vaccines. N Engl J Med. 2006 Jan 5. 354(1):75-7. [View Abstract]
  37. Centers for Disease Control and Prevention. Vaccines & immunizations. Rotavirus vaccine (RotaShield) and intussusception (archived document). Available at https://www.cdc.gov/vaccines/vpd-vac/rotavirus/vac-rotashield-historical.htm. Reviewed: April 22, 2011; Accessed: January 8, 2018.
  38. Marsh ZA, Grytdal SP, Beggs JC, et al. The unwelcome houseguest: secondary household transmission of norovirus. Epidemiol Infect. 2017 Dec 12. 1-9. [View Abstract]
  39. US Food and Drug Administration. FDA Approves New Vaccine to Prevent Gastroenteritis Caused by Rotavirus. Available at http://www.fda.gov/bbs/topics/NEWS/2008/NEW01814.html
  40. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006 Jan 5. 354(1):11-22. [View Abstract]
  41. American Academy of Pediatrics. Red Book® Online Table - NEWStatus of Licensure and Recommendations for New Vaccines*. Available at http://aapredbook.aappublications.org/news/vaccstatus.shtml
  42. Ball JM, Graham DY, Opekun AR, et al. Recombinant Norwalk virus-like particles given orally to volunteers: phase I study. Gastroenterology. 1999 Jul. 117(1):40-8. [View Abstract]
  43. Belhorn T. Rotavirus diarrhea. Curr Probl Pediatr. 1999 Aug. 29(7):198-207. [View Abstract]
  44. Bon F, Fascia P, Dauvergne M, et al. Prevalence of group A rotavirus, human calicivirus, astrovirus, and adenovirus type 40 and 41 infections among children with acute gastroenteritis in Dijon, France. J Clin Microbiol. 1999 Sep. 37(9):3055-8. [View Abstract]
  45. Burkhart DM. Management of acute gastroenteritis in children. Am Fam Physician. 1999 Dec. 60(9):2555-63, 2565-6. [View Abstract]
  46. Caeiro JP, Mathewson JJ, Smith MA, et al. Etiology of outpatient pediatric nondysenteric diarrhea: a multicenter study in the United States. Pediatr Infect Dis J. 1999 Feb. 18(2):94-7. [View Abstract]
  47. Centers for Disease Control and Prevention. Advisory Committee Recommends New Vaccine to Prevent Rotavirus.
  48. Centers for Disease Control and Prevention. Outbreak of Gastroenteritis Associated with Noroviruses on Cruise Ships --- United States, 2002. MMWR Morb Mortal Wkly Rep. 2002 Dec 13. 51(49):1112-1115.
  49. Centers for Disease Control and Prevention. Withdrawal of rotavirus vaccine recommendation. JAMA. 1999 Dec 8. 282(22):2113-4. [View Abstract]
  50. Clark B, McKendrick M. A review of viral gastroenteritis. Curr Opin Infect Dis. 2004 Oct. 17(5):461-9. [View Abstract]
  51. Estes MK, Morris AP. A viral enterotoxin. A new mechanism of virus-induced pathogenesis. Adv Exp Med Biol. 1999. 473:73-82. [View Abstract]
  52. Fankhauser RL, Noel JS, Monroe SS, et al. Molecular epidemiology of "Norwalk-like viruses" in outbreaks of gastroenteritis in the United States. J Infect Dis. 1998 Dec. 178(6):1571-8. [View Abstract]
  53. Flem E, Vainio K, Dollner H, et al. Rotavirus gastroenteritis in Norway: Analysis of prospective surveillance and hospital registry data. Scand J Infect Dis. 2009. 41(10):753-9. [View Abstract]
  54. Ford T. Emerging issues in water and health research. J Water Health. 2006. 4 Suppl 1:59-65. [View Abstract]
  55. Gaggero A, O'Ryan M, Noel JS, et al. Prevalence of astrovirus infection among Chilean children with acute gastroenteritis. J Clin Microbiol. 1998 Dec. 36(12):3691-3. [View Abstract]
  56. Green J, Gallimore CI, Norcott JP, et al. Broadly reactive reverse transcriptase polymerase chain reaction for the diagnosis of SRSV-associated gastroenteritis. J Med Virol. 1995 Dec. 47(4):392-8. [View Abstract]
  57. ICTVdb. The Universal Virus Database of the International Committee on Taxonomy of Viruses Web site. Available at: http://ictvdb.bio2.columbia.edu/Ictv/index.htm. Accessed on December 27, 2002.
  58. Johnsen CK, Midgley S, Bottiger B. Genetic diversity of sapovirus infections in Danish children 2005-2007. J Clin Virol. 2009 Nov. 46(3):265-9. [View Abstract]
  59. Maldonado Y, Cantwell M, Old M, et al. Population-based prevalence of symptomatic and asymptomatic astrovirus infection in rural Mayan infants. J Infect Dis. 1998 Aug. 178(2):334-9. [View Abstract]
  60. Mead PS, Slutsker L, Dietz V, et al. Food-related illness and death in the United States. Emerg Infect Dis. 1999 Sep-Oct. 5(5):607-25. [View Abstract]
  61. Pang XL, Joensuu J, Vesikari T. Human calicivirus-associated sporadic gastroenteritis in Finnish children less than two years of age followed prospectively during a rotavirus vaccine trial. Pediatr Infect Dis J. 1999 May. 18(5):420-6. [View Abstract]
  62. Pang XL, Koskenniemi E, Joensuu J, et al. Effect of rhesus rotavirus vaccine on enteric adenovirus--associated diarrhea in children. J Pediatr Gastroenterol Nutr. 1999 Sep. 29(3):366-9. [View Abstract]
  63. Pang XL, Vesikari T. Human astrovirus-associated gastroenteritis in children under 2 years of age followed prospectively during a rotavirus vaccine trial. Acta Paediatr. 1999 May. 88(5):532-6. [View Abstract]
  64. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006 Jan 5. 354(1):11-22. [View Abstract]
  65. Saps M, Pensabene L, Turco R, et al. Rotavirus gastroenteritis: precursor of functional gastrointestinal disorders?. J Pediatr Gastroenterol Nutr. 2009 Nov. 49(5):580-3. [View Abstract]
  66. Shornikova AV, Isolauri E, Burkanova L, et al. A trial in the Karelian Republic of oral rehydration and Lactobacillus GG for treatment of acute diarrhoea. Acta Paediatr. 1997 May. 86(5):460-5. [View Abstract]
  67. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med. 2006 Jan 5. 354(1):23-33. [View Abstract]
  68. Wang X, Wang S, Zhang C, et al. Development of a surrogate neutralization assay for norovirus vaccine evaluation at the cellular level. Viruses. 2018 Jan 5. 10 (1):785-808. [View Abstract]
  69. Gaythorpe KAM, Trotter CL, Lopman B, Steele M, Conlan AJK. Norovirus transmission dynamics: a modelling review. Epidemiol Infect. 2017 Dec 22. 1-12. [View Abstract]
  70. Centers for Disease Control and Prevention. Rotavirus: rotavirus in the US. Available at https://www.cdc.gov/rotavirus/surveillance.html. Reviewed: August 12, 2016; Accessed: January 9, 2018.