Infectious Diseases

Rotaviruses

OVERVIEW: What every practitioner needs to know

Are you sure your patient has rotavirus infection? What should you expect to find?

Rotavirus gastroenteritis typically presents in children younger than 3 years of age within 1-3 days of infection. Clinical disease is initially marked by 2 days of low-grade fever and emesis followed by 4-5 days of profuse, non-bloody diarrhea. Although most cases are self-limited, 1-2% of children will develop severe volume depletion manifested by hypotension, tachycardia, and metabolic acidosis. Such severe disease is a hallmark of primary, rather than recurrent, infection. Adults present with a similar pattern of signs and symptoms but are far less likely to develop serious complications. Moreover, they are better able to communicate additional symptoms, such as nausea, abdominal cramping, and diminished appetite. Adult infection may also have a longer incubation period and shorter natural history.

How did the patient develop rotavirus infection? What was the primary source from which the infection spread?

Rotavirus has been identified in multiple species across avian and mammalian species worldwide. Despite some homology to veterinary strains, human pathogenic strains have no animal reservoir and are primarily transmitted among humans. The exact mode of transmission continues to be debated. Investigations of outbreaks have offered little help in discriminating the primary vehicle for transmission: fomites, feces, and respiratory droplets are all implicated.

Although fecal-oral contact is deemed most likely, the seasonality and universality of rotavirus disease raise the possibility of respiratory spread. In northern latitudes, particularly in the continental United States, incidence peaks in the autumn and winter months and spreads geographically from west to east. One hypothesis for these seasonal trends rests on evidence that rotavirus is less viable in humid conditions. The ubiquity of rotavirus is manifested in serologic studies that demonstrate near universality of exposure among children by 3 years of age. Infants between 6 months and 2 years of age are at greatest risk of developing severe disease—when passively acquired maternal immunity has waned and the host immune system has not yet matured.

The 140 million annual cases of rotavirus make it the leading cause of severe gastroenteritis globally. In the United States, three-quarters of children younger than 5 years of age are symptomatic from rotavirus infection. Despite causing 3 million domestic cases of diarrhea each year, no more than 50-100 children in the United States die from the disease. The overwhelming majority (about 85%) of the 600,000 annual case fatalities occur in low-income countries. Recent data indicate that disease incidence has fallen in developed nations where the rotavirus vaccine has become widely available, but symptomatic infection has remained stable throughout the rest of the world. Mortality, however, has fallen by approximately 30% since the 1980s, in large part, because of the adoption of cost-effect oral rehydration therapies.

Which individuals are of greater risk of developing rotavirus infection?

Infants are at greatest risk for infection and severe gastroenteritis between 6 months and 3 years of age—the period when passive maternal immunity has waned and active host immunity has not sufficiently matured. Although recurrent infections occur later in childhood and into adulthood, these episodes are successively milder. Both B and T lymphocyte immunodeficiency disorders—including X-linked agammaglobulinemia, DiGeorge syndrome, and severe combined immunodeficiency—are associated with chronic rotavirus infection and disseminated disease. Acquired immunodeficiencies that result from human immunodeficiency virus (HIV)-1 infection and stem-cell transplantation predispose individuals to symptomatic infection as well. However, other causes of diarrheal disease (i.e., coronavirus, adenovirus, Clostridium difficile) are more prevalent in these special populations.

Beware: there are other diseases that can mimic rotavirus infection:

Approximately 60-90% of individuals afflicted with rotavirus gastroenteritis present with fever, vomiting, and diarrhea. This constellation of signs and symptoms, however, is common to many infective gastroenteritides. Thus, rotavirus infection can be easily misdiagnosed, if based solely on clinical features. Acute, febrile, non-bloody diarrhea should trigger a broader differential than rotavirus alone to include infection with other viruses, such as coronavirus, enterovirus, adenovirus, hepatitis A, or bacteria, such as enterotoxigenic Escherichia coli, Salmonella species, and Campylobacter strains.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

There is little in the way of laboratory abnormalities to distinguish rotavirus from other diarrheal disease pathogens. Abnormal values are generally restricted to electrolyte disturbances and only in cases of severe volume depletion. Transaminase and uric acid levels can also be elevated during infection, but these findings are neither common nor specific to the disease. However, rotavirus infection is unique among many gastroenteritides, as it does not usually elicit a leukemoid reaction, either in the blood or stool.

Results that confirm the diagnosis

Although rotavirus gastroenteritis is often diagnosed presumptively, there are several rarely used, but widely available, laboratory diagnostics that enable confirmation of infection. Originally, electron microscopic examination of stool specimens was the standard way to make a definitive diagnosis. However, antigen detection kits have largely supplanted this process. Both enzyme immunoassay and latex agglutination, the most commonly employed methods, have a high sensitivity but require a viral burden of at least 10,000 virions to detect infection. Furthermore, gains made in the sensitivity of either approach are countered by a significant occurrence of false positives, particularly in neonatal populations.

What imaging studies will be helpful in making or excluding the diagnosis of rotavirus infection?

Radiography is generally not indicated in the routine diagnostic work-up of rotavirus gastroenteritis. In complicated cases in which there is a clinical suspicion of necrotizing enterocolitis, pneumatosis intestinalis, or intussusception, abdominal roentgenography or computed tomography may aid, although is not necessary, in confirming the diagnosis and justifying surgical intervention.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has rotavirus infection, what therapies should you initiate immediately?

A general practitioner can manage most cases of rotavirus infections, whether it is a pediatrician, family practitioner, or general internist. When the diagnosis is called into question or if the infection occurs in an immunosuppressed patient, an infectious disease specialist should be consulted. When bowel obstruction or perforation is suspected, a general surgeon should be consulted emergently.

Oral rehydration is the mainstay of therapy for rotavirus gastroenteritis, as the primary causes of morbidity and mortality are dehydration and electrolyte imbalance. The World Health Organization (WHO) currently recommends that individuals who can tolerate oral intake should be fed a rehydration formula of low osmolarity sodium, potassium, chloride, glucose, and bicarbonate or citrate. The success of oral rehydration solutions for rotavirus or any other diarrheal diseases operates on the basic concept that sodium-solute co-transport will reverse the osmotic gradient across the luminal surface of enterocytes. This physiologic mechanism remains intact even in the setting of intestinal villous atrophy. Although oral rehydration should be the first therapeutic option, in the case of severe gastroenteritis or circulatory collapse, intravenous rehydration should be favored over oral therapy.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Anti-infectives are not currently recommended for the treatment of rotavirus gastroenteritis. On establishing a diagnosis of rotavirus gastroenteritis, oral or intravenous rehydration—depending on the clinical severity—should be implemented immediately. In the case of diagnostic uncertainty, the most likely pathogens should be considered when selecting an antimicrobial. In most pediatric and adult patients, gastroenteritis is viral in etiology. Bacterial causes can often be discerned by historical cues even before ordering laboratory tests. In those instances in which there remains diagnostic uncertainty and there is need for empiric therapy, the patient’s history, exam, and risk factors should dictate antimicrobial selection. With regard to rotavirus specifically, only one agent, nitazoxanide, an anti-protozoal, has demonstrated some benefit.

In several small but controlled studies among pediatric cohorts, investigators found the administration of nitazoxanide to be associated with a shorter time to disease resolution. No other antibiotic has demonstrated such benefit, but some probiotics, such as those containing lactobacilli, have been shown to reduce the duration of diarrhea by just less than 1 day.

2. Other key therapeutic modalities.

When oral rehydration therapy is administered alongside zinc supplementation, randomized trials have shown the combined intervention to reduce persistent diarrhea by 15% per day compared to oral rehydration alone. Thus, the WHO recommends that oral rehydration therapy be coupled with 10-14 days of zinc supplementation dosed at 10mg/day in infants younger than 6 months of age or 20mg/day in children older than 6 months of age. Although no official recommendations are made on behalf of other therapeutics, the use of passive immunity for the treatment of more severe cases has become more common. Initially based on anecdotal evidence and case reports, there have been data emerging recently that support a clinical benefit from the oral administration of polyclonal antibodies to pediatric patients with symptomatic rotavirus infection. Prophylactic use of antibodies against rotavirus antigens has also shown some efficacy in neonates.

Other experimental adjunctive therapies have been investigated, but none have demonstrated enough benefit to be included in any official guidelines. Among the more extensively studied pharmacologic agents are acetorphan and bismuth salicylate. The former, known also by its trade name, Racecadotril, is an enkephalinase inhibitor that has anti-diarrheal properties by decreasing intestinal secretion and motility. Bismuth salicylate has had similar success, but the potential for salicylate absorption and risk of Reye’s syndrome raises concern for its use in pediatric populations. Anti-motility agents, on the whole, are still not favored in the treatment of rotavirus.

What complications could arise as a consequence of rotavirus infection?

What should you tell the family about the patient's prognosis?

The most common complications of rotaviral infection occur as a consequence of dehydration and associated electrolyte abnormalities (i.e., hyponatremia, hyperkalemia, and acidemia). These metabolic disturbances can have multiple, pathophysiologic effects that include seizure, renal failure, and cardiovascular collapse. Severe volume depletion may cause hypovolemic shock and subsequent multi-organ failure as well. Rotavirus gastroenteritis has also been reported to antecede acute gastrointestinal disorders, such as necrotizing enterocolitis, pneumatosis intestinalis, and intussusception.

A causal association, however, remains to be established. Lactose intolerance is commonly encountered in young children and may persist. This can exacerbate the nutritional needs of children and enhance super-infection with bacterial pathogens. Extra-intestinal infection (e.g., kidney, liver, lungs) has also been demonstrated but is of unclear clinical significance. Ultimately, recognition of the disease and prompt initiation of supportive therapy will prevent a majority of these complications.

The prognosis for rotavirus gastroenteritis is generally excellent in settings in which the infected have access to clean, potable water supplies and nutrients that can act as rehydration solutes. The geographic disparity in mortality statistics illustrates the importance of environment to the outcome of the disease. Globally, 600,000 children die from rotavirus every year; only a few dozen of those occur in the United States. Prognosis is also impacted by immune status. Immunocompromised individuals are more likely to suffer from prolonged disease and to shed virus for extended time periods. However, with continual rehydration therapy, outcomes are generally favorable in this group as well.

How do you contract rotavirus infection and how frequent is this disease?

Rotavirus has been identified in multiple species across avian and mammalian species worldwide. Despite some homology to veterinary strains, human pathogenic strains have no animal reservoir and are primarily transmitted among humans. The exact mode of transmission continues to be debated. Investigations of outbreaks have offered little help in discriminating the primary vehicle for transmission: fomites, feces, and respiratory droplets are all implicated.

Although fecal-oral contact is deemed most likely, the seasonality and universality of rotavirus disease raise the possibility of respiratory spread. In northern latitudes, particularly in the continental United States, incidence peaks in the autumn and winter months and spreads geographically from west to east. One hypothesis for these seasonal trends rests on evidence that rotavirus is less viable in humid conditions. The ubiquity of rotavirus is manifested in serologic studies that demonstrate near universality of exposure among children by the time they reach 3 years of age. However, infants between 6 months of age and 2 years of age are at greatest risk of developing severe disease—when passively acquired maternal immunity has waned and the host immune system has not yet matured.

The 140 million annual cases of rotavirus make it the leading cause of severe gastroenteritis globally. In the United States, three-quarters of children under 5 years of age are symptomatic from rotavirus infection. Despite causing 3 million domestic cases of diarrhea each year, no more than 50-100 children in the United States die from the disease. The overwhelming majority (about 85%) of the 600,000 annual case fatalities occur in low-income countries. Recent data indicate that disease incidence has fallen in developed nations where the rotavirus vaccine has become widely available, but symptomatic infection has remained stable throughout the rest of the world. Mortality, however, has fallen by approximately 30% since the 1980s in large part, because of the adoption of cost-effect oral rehydration therapies.

What pathogens are responsible for this disease?

Rotavirus—the cause of rotaviral gastroenteritis—is a non-enveloped, double-stranded, segmented RNA virus of the Reoviridae family. Although considered a single pathogen, the rotavirus genus includes a broad diversity of serologically and genetically distinct groups, each capable of causing diarrheal disease of varying clinical severity and demographic specificity. The virus’ 11 genomic segments encode 6 structural (VPs) and 6 nonstructural proteins (NSPs). Both classes of proteins play parts in viral infection and replication, but the viral capsid is largely responsible for eliciting immunity.

How do these pathogens cause rotavirus infection?

Infection begins when host intestinal trypsin cleaves VP4. This event exposes a domain on the structural protein that then binds an integrin on the surface of its target cells, which are confined to the villous epithelium of the small intestine. A conformational change of this protein then enables rotaviral fusion and entry. The virus’s mechanism of inducing diarrhea, however, is not as well understood. It is clear from pathologic specimens that rotavirus infection—independent of the immune response it elicits—causes significant damage to the intestinal mucosa. Clinical studies have demonstrated that the extent of this damage correlates with the severity of diarrhea. The destruction of intestinal villi reduces overall surface area and the total number of mature, functioning epithelial cells needed for adequate absorption of sodium, glucose, and water. It is also evident from histopathology, however, that the diarrhea of rotavirus infection can precede the destruction of intestinal villi.

Murine models suggest an alternative mechanism: that the diarrhea may be more secretory than osmotic. Experimental data have demonstrated that the exogenous administration of rotavirus nonstructural protein NSP4 induces a secretory state via calcium release and resultant activation of a surface chloride channel. This putative enterotoxin may also mediate secretion through its activation of the enteric nervous system. However, mutations in NSP4 have failed to demonstrate an impact on the natural history of the disease in animal models or humans. In reality, the pathway from rotavirus infection to diarrheal disease manifestation is complicated and likely multifactorial in etiology.

Host immunity to rotavirus echoes some of the mystery of its pathogenesis. Rotavirus immunization works by recruiting all arms of the adaptive immune response: antibodies, cytotoxic T lymphocytes, and helper T-cell responses. The hierarchy of these immune effectors, however, is not as well understood in the context of natural immunity. Although a number of studies have shown that immunization and natural infection elicit cross-reactive neutralizing antibodies against structural proteins, such as VP4 and VP7, other trials have failed to demonstrate the importance of neutralizing antibody titers in conferring immunity. It is well established, though, that intestinal mucosal IgA correlates with some protection against re-infection, but that this immunity is partial and wanes over the course of months to years.

What other clinical manifestations may help me to diagnose and manage rotavirus infection?

There are some cues that implicate rotavirus as the likely pathogen. Vomiting, for example, is more common and more prolonged in rotaviral disease as compared to other gastrointestinal virus infections. And bloody diarrhea almost always excludes rotavirus as the diagnosis.

What other additional laboratory findings may be ordered?

Newer polymerase chain reaction (PCR)-based assays are used with increasing frequency to capitalize on their enhanced sensitivity, near-complete specificity, and ability to discriminate viral strains. Viral culture, although possible, is neither feasible nor readily available in standard inpatient or outpatient laboratories.

How can rotavirus infection be prevented?

Rotavirus is a near ubiquitous pathogen. By the third year of life, almost all humans demonstrate serologic evidence of exposure to the virus, although this does not always correspond to broad or prolonged immunity. Host susceptibility is complicated by the existence of multiple viral serotypes and the virus’ capacity to reassort its genomic segments in a manner similar to influenza virus. Thus, prevention of infection poses unique problems that make eradication unlikely. Primary prevention of severe rotavirus gastroenteritis, however, is a goal made attainable within the past decade.

In the last century, there were no effective strategies to prevent rotavirus gastroenteritis. Although the virus was deemed transmissible via fecal-oral contact, public sanitation campaigns had little effect on the epidemiology of the disease. This may be, in part, because of an alternative route of transmission through the aerosolization of respiratory droplets, the pathogen’s environmental resilience and miniscule infectious dose, or its expansive host range. Despite the inability of hygienic measures to disrupt rotavirus transmission, the Centers for Disease Control and Prevention (CDC) still recommend that all hospitalized patients with documented or suspected rotavirus diarrhea be placed in contact isolation.

Given the global reach of rotavirus and the limited impact of public sanitation efforts on disease incidence, a new, more potent tool in the form of immunization was in dire need. In 1998, the US Food and Drug Administration (FDA) licensed the first rotavirus vaccine: RotaShield, a quadrivalent, attenuated, simian-human recombinant virus developed by Wyeth Ayerst. Although it reached 90% efficacy in some phase III trials and was recommended by the Advisory Committee on Immunization Practices (ACIP) for inclusion in the childhood immunization schedule, the vaccine was withdrawn from the market only 1 year after its licensure. A post-marketing surveillance study demonstrated a significantly increased risk of intestinal intussusception within 2 weeks of receiving the vaccine. However, a more in-depth analysis over an extended period following exposure revealed no excess risk of intussusception in vaccine recipients. Notwithstanding these data, the vaccine was discontinued, although not before 1 million doses were administered.

Since the withdrawal of RotaShield, two new live-attenuated rotavirus vaccines have reached licensure: RotaTeq and RotaRix, manufactured by Merck and GlaxoSmithKline, respectively. RotaTeq, like its predecessor RotaShield, is an oral live-attenuated vaccine that incorporates four serotypes of the immunogenic VP7 surface protein, although on a bovine and not simian rotavirus background. It is highly efficacious (>98%) in preventing severe gastroenteritis and has not been associated with intussusception since its release in 2006. RotaRix—also an oral live-attenuated vaccine as well—differs from the other two products, as it is monovalent and derived from a human rotavirus isolate. Its efficacy approximates the other two vaccine products (about 90%) in preventing severe gastroenteritis, prompting its FDA approval in 2008.

Both RotaTeq and RotaRix have been recommended by the ACIP as routine childhood immunizations. RotaTeq is approved for administration at 2, 4, and 6 months of age, whereas RotaRix only needs to be given at 2 and 4 months of age. Other rotavirus vaccines are being developed and administered in developing countries to overcome the cost of the aforementioned products. Data on the efficacy of these new products, however, are sparse. Although immunizations are the most effective means of preventing hospitalization and death from rotavirus diarrhea, secondary prevention strategies, such as oral rehydration, are still the mainstay of mortality reduction throughout most of the world.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Anderson, EJ, Weber, SG. "Rotavirus infection in adults". Lancet Infect Dis. vol. 4. 2004. pp. 91-9.

Desai, R, Curns, AT, Steiner, CA, Tate, JE, Patel, MM, Parashar, UD. "All-cause gastroenteritis and rotavirus-coded hospitalizations among US children, 2000-2009". Clin Infect Dis. vol. 55. 2012. pp. e28-34.

Dormitzer, PR, Mandell, GL, Bennett, JE, Dolin, R. "Retroviruses". Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Elsevier. 2010. pp. 2491-4.

Feigen, RD, Cherry, JD, Demmler-Harrison, GJ, Kaplan, SL, Ward, RL, Bernstein, DI, Staat, MA. "Retroviruses". Textbook of pediatric infectious diseases. Elsevier. 2009. pp. 2245-70.

King, CK, Glass, R, Bresee, JS, Duggan, C. "Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy". MMWR Recomm Rep. vol. 52(RR-16). 2003. pp. 1-16.

Pang, XL, Lee, B, Boroumand, N, Leblanc, B, Preiksaitis, JK, Yu Ip, CC. "Increased detection of rotavirus using a real time reverse transcription-polymerase chain reaction (RT-PCR) assay in stool specimens from children with diarrhea". J Med Virol. vol. 72. 2004. pp. 496-501.

Pitzer, VE, Viboud, C, Simonsen, L. "Demographic variability, vaccination, and the spatiotemporal dynamics of rotavirus epidemics". Sci. vol. 325. 2009. pp. 290-4.

Plotkin, SA, Orenstein, WA, Offit, PA, Clark, HF, Offitt, PA, Parashar, UD, Ward, RL. "Rotavirus vaccines". Vaccines. Elsevier. 2008. pp. 715-731.

Raboni, SM, Nogueira, MB, Hakim, VM, Torrecilha, VT, Lerner, H, Tsuchiya, LR. "Comparison of latex agglutination with enzyme immunoassay for detection of rotavirus in fecal specimens". Am J Clin Pathol. vol. 117. 2002. pp. 392-4.

Rossignol, JF, Abu-Zekry, M, Hussein, A, Santoro, MG. "Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial". Lancet. vol. 368. 2006. pp. 124-9.

"World Health Organization/United Nations Children’s Fund (WHO/UNICEF). Clinical management of acute diarrhoea". WHO/UNICEF Joint Statement. 2004.

DRG CODES and expected length of stay

008.61 - Enteritis due to rotavirus

1209 - Rotavirus vaccine dose

009.0 - Infectious colitis, enteritis, and gastroenteritis

009.3 - Diarrhea of presumed infectious origin

009.2 - Infectious diarrhea

The expected length of stay for those patients admitted for rotavirus gastroenteritis is 2-4 days. The occurrence in immunocompromised hosts or the development of a complication will extend this stay for a time period commensurate with the severity of immunosuppression or complication.

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