Rotavirus Still Ranks High as Cause of Acute Gastroenteritis in Children

Rotavirus may not be on the hot list of viruses dominating headlines, but globally, it still tops the charts as the leading cause of severe, dehydrating diarrhea in children younger than 5 years, resulting in an estimated 200,000 deaths annually in 2013.

In the U.S., widespread routine vaccination has vastly decreased the burden of disease. For the most part, rotavirus is now just one of the several enteric viruses that causes mild cases of acute gastroenteritis every year, particularly in the winter through early spring.

“Before there was a vaccine, which was introduced in the United States in 2006, every year rotavirus would cause several million cases, about 70,000 hospitalizations, because of severe dehydration,” Paul Offit, MD, of the Children’s Hospital of Philadelphia, told MedPage Today. “And it would cause in the U.S. about 60 deaths a year, so it was a common virus.”

Worldwide, the virus caused a staggering 500,000 deaths annually before the introduction of the vaccine, primarily due to challenges in rehydrating children in developing countries, Offit noted.

First identified as a major cause of gastroenteritis in children in 1973, rotavirus is a double-stranded RNA virus in the family Reoviridae. The viral particle is composed of three concentric layers that consists of 11 genome segments encoding for six structural viral proteins (VPs) and six non-structural viral proteins (NSPs). The outermost layer contains two important structural viral proteins VP7 and VP4, which stimulate neutralizing antibody production in infected individuals and are important in the development of protective immunity against the virus. At least 11 different VP7 antigens (G-types) and 11 different VP4 antigens (P-types) have been identified. In the U.S., the G12P[8] genotype has become the most common one in recent years.

Transmission of the virus occurs primarily by the fecal-oral route, directly from person-to-person or indirectly via fomites, though contaminated food or water can be uncommon sources of transmission. The virus is shed in high concentrations and for many days in the stool and vomit of infected individuals. Moreover, rotavirus is stable in the environment and can remain viable for weeks or months.

Following an incubation period of 1 to 3 days, the illness often begins abruptly. Vomiting usually precedes the onset of diarrhea, and up to one-third of patients have a temperature over 102°F. Rotavirus-associated gastroenteritis is generally short-lived, with symptoms resolving in 3 to 7 days. Children who are immunocompromised, as well as immunocompromised adults, are at higher risk for severe disease or prolonged gastroenteritis.

Severe rotavirus infections can lead to dehydration, electrolyte imbalance, and metabolic acidosis, and primarily occurs in unvaccinated children 3 to 35 months of age.

The rapid dehydration is why children frequently ended up hospitalized for rotavirus before the vaccine, Offit pointed out. “The reason is that you have three ways of being dehydrated: 1) you vomit up fluid, 2) you have diarrhea, and 3) you have fever, which essentially increases your metabolic rate.”

In developing countries, three-quarters of children have a first episode of rotavirus gastroenteritis before the age of 12 months, but in other countries the first episode is frequently delayed until 2 to 5 years of age. In the pre-vaccine era, rotavirus infection was nearly universal, Offit said. “Pretty much no one in the world gets to 5 years of age without having been exposed to this virus pre-vaccine.”

Rotavirus Effects on the Gut

“We don’t really understand why, of all the viruses that can infect the human small intestine, rotavirus is capable of causing such severe disease” in unvaccinated individuals or those at high risk, Sue Ellen Crawford, PhD, of the Baylor College of Medicine in Houston, told MedPage Today. “It’s almost like a bacterial infection in some ways, but it doesn’t induce any of the inflammatory response that bacterial infections do.”

Rotavirus causes both osmotic and secretory diarrhea, but until recently, the mechanisms on how that occurred were poorly understood, Crawford said. However, newer research is shedding light on the pathophysiology of rotavirus infection.

In addition to disruption of the duodenal mucosa, the virus appears to hijack several cellular pathways on the surface of enterocytes. Of note, NSP4, one of the nonstructural antigens on the virus, affects tight junction proteins and disrupts reabsorption pathways. Importantly, NSP4 also appears to activate calcium-dependent chloride channels, creating an osmotic gradient and leading to secretory diarrhea.

In two recent studies from Baylor, researchers found that not only do virus-infected cells display aberrant calcium signals, but infected cells may also trigger intercellular calcium waves in uninfected cells. Adenosine diphosphate appears to be a primary mediator of this effect, binding to its receptor, P2Y1, on uninfected neighboring cells.

But what causes all the vomiting? Rotavirus-associated nausea and vomiting might be a result of increased 5-hydroxytryptamine (5-HT), or serotonin, levels stimulated by the rise in intracellular calcium levels, Crawford explained. 5-HT can stimulate the vagus nerve and associated neurons that project from the gut to the brain and are associated with emesis, she said.

“We think it’s all of these multiple mechanisms that rotavirus induces to cause the diarrhea and the vomiting, because it really is severe,” Crawford said. In children who are unvaccinated, “it’s more severe than any other viral infection of the intestine.”

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