US Pharm. 2016;41(4):45-48.
Human norovirus is a small virus that contains single-stranded RNA with a protein coating. This virus is a major cause of epidemic gastroenteritis. Noroviruses are responsible for at least 95% of viral outbreaks and over 50% of all outbreaks worldwide. Transmission of these highly infectious viruses occurs primarily through contaminated food or water, but also through person-to-person contact and exposure to clothes, utensils, and furniture. Norovirus infections are typically acute and self-limited. However, the disease can be much more severe and prolonged in infants, the elderly, and immunocompromised individuals. There are many different types of noroviruses, and most are named after the city where they were first identified. The first human norovirus was identified in Norwalk, Ohio: Nor-O-Virus. Currently, there are 25 different strains of norovirus that affect humans.1
Noroviruses are highly contagious, extremely stable in the environment, constantly evolving, resistant to common disinfectants, and associated with debilitating illness. These characteristics have enabled noroviruses to become the leading cause of endemic diarrheal diseases across all age groups. The number of reported norovirus outbreaks has risen sharply since 2002, suggesting the emergence of more infectious strains. There has also been increased recognition that noroviruses are important causes of childhood hospitalization. Moreover, noroviruses have recently been associated with multiple clinical outcomes other than gastroenteritis.2
In the United States alone, noroviruses are responsible for an estimated 21 million cases of acute gastroenteritis annually, including >70,000 hospitalizations and nearly 800 deaths. In developing countries, where the greatest burden of diarrheal disease occurs, noroviruses have been estimated to cause up to 200,000 deaths each year in children <5 years of age.2
Epidemiology
In 2002, a sharp rise in norovirus outbreaks worldwide occurred that correlated with the emergence of a new GII.4 norovirus strain. Interestingly, researchers have determined that GII.4 strains resulted in pandemics in 1995-1996 and 2002-2006. These GII.4 variants spread rapidly around the globe and are thought to account for 70% to 80% of all norovirus outbreaks since 2002. A recent study demonstrates that GII.4 strains associated with severe illness were circulating as early as 1974, and that the ancestral strain most likely emerged in the 1960s. It is unclear why the GII.4 norovirus strains are so predominant, but possibilities include increased environmental stability, transmissibility, and virulence.1
Because of the lack of a cell culture system and the historical lack of animal models of norovirus infection, the extent of our knowledge regarding pathogenesis of norovirus infection comes primarily from physical, histologic, and biochemical studies of infected human volunteers. In recent years, work in porcine, bovine, and murine models has also begun to contribute to our understanding of norovirus pathogenesis. Based on numerous studies around the world, it is now recognized that noroviruses are an important cause of illness in hospitalized children, second to or as prevalent as rotavirus infections.2
A global surveillance network called NoroNet (www.noronet.nl/noronet) was recently established that aims to monitor norovirus epidemics in an effort to limit their scope. Continued efforts of this kind will be critical in delineating the global burden of norovirus illness.2
Signs and Symptoms
In immunocompetent adults, the course of norovirus infection is rapid, with an incubation period of 24 to 48 hours, and resolution of symptoms within 12 to 72 hours. Symptoms include vomiting and diarrhea, with or without nausea, and abdominal cramps. Low-grade fever and malaise can also develop. While norovirus infection typically causes an acute bout of gastroenteritis that resolves within days of the onset of symptoms, norovirus-induced disease can be much more severe and prolonged in specific risk groups. For example, infants and young children can develop more severe gastroenteritis following norovirus infection, with symptoms lasting up to 6 weeks.3
Noroviruses have been reported to be second only to rotaviruses as a cause of severe childhood gastroenteritis. Considering the recent success in vaccinating infants against rotavirus infections, noroviruses will likely become the most common cause of childhood diarrheal disease in the foreseeable future. In addition, prolonged symptomatic infection has been well documented in transplant patients and other immunosuppressed individuals, with symptoms lasting over 2 years. Similarly, norovirus infection can be particularly severe in the elderly, even resulting in death.2
One recent study also reported that patients with inflammatory bowel disease may present with bloody diarrhea upon norovirus infection. While it has long been assumed that norovirus infection is confined to the intestine, there is no direct proof for this claim, and several recent findings suggest that this statement has to be reconsidered. A recent study detected norovirus RNA in the serum of 15% of infected individuals.3
Outbreaks
Most outbreaks of norovirus illness happen when infected people spread the virus to others (SIDEBAR 1). But consuming contaminated food or water can also spread it. Food can be contaminated with norovirus at any point when it is being grown, shipped, handled, or prepared. Outbreaks occur most commonly in semiclosed communities such as nursing homes, hospitals, cruise ships, schools, disaster relief/evacuation sites, and military settings.3 Nosocomial outbreaks are one of the most common causes of norovirus closures. The three main foods that are commonly contaminated are leafy greens, fresh fruits, and shellfish (such as oysters). In general, any food that is served raw or handled after being cooked can become contaminated.4
Over half of all norovirus outbreaks reported in the U.S. occur in long-term-care facilities. The virus can be introduced into healthcare facilities by infected patients—who may or may not be symptomatic—or by staff, visitors, or contaminated foods. Outbreaks in these settings can be quite long, sometimes lasting months. Illness can be severe, occasionally even fatal, in hospitalized or nursing home patients, as it generally is not in otherwise healthy people.3
Infected food workers in restaurants are frequently the source of these outbreaks. Norovirus outbreaks can also occur from fecal contamination of certain foods at their source. Examples include oysters harvested from contaminated water and raspberries irrigated with contaminated water.4
Over 90% of diarrheal disease outbreaks on cruise ships are caused by norovirus. This is partly due to shared dining areas and rapid turnover of passengers. Repeated outbreaks on consecutive cruises may also result from infected crew members and environmental contamination. This is because norovirus can persist on surfaces and is resistant to many common disinfectants.3
The outbreaks have also happened in institutional settings such as schools, child care centers, colleges, prisons, and military camps. Sometimes, it has led to institution closure. Norovirus was the most common cause of gastroenteritis among U.S. Marines during Operation Iraqi Freedom and a common cause of outbreaks among British troops deployed to Iraq from 2002 to 2007.3
The principle elements in preventing and controlling outbreaks are hand hygiene, exclusion and isolation, environmental disinfection, use of personal protective equipment, and reporting of outbreaks to the CDC.3
Pathophysiology
The success of noroviruses should come as no surprise once one considers how well adapted they are for transmission within human populations. First, noroviruses have an extremely low infectious dose (18 viral particles) coupled with copious viral shedding (105-1011 viral copies per gram of feces), even among asymptomatic infections; this suggests that up to 5 billion infectious doses may be shed by an infected individual in each gram of feces. Second, noroviruses are environmentally stable, able to survive both freezing and heat (although not thorough cooking), are resistant to many common chemical disinfectants, and can persist on surfaces for up to 2 weeks. Third, there are a number of ways in which noroviruses may be spread, including direct contact between hosts via fecal-oral transmission, ingestion of contaminated foods or water, and handling of contaminated utensils followed by hand-to-mouth contact via ingestion of aerosolized particles.2
Finally, noroviruses are a genetically diverse group of viruses that rapidly evolve, leading to an apparent lack of prolonged cross-protective immunity following infection. Clearly, public health efforts to prevent and control the spread of noroviruses face a big challenge.2
Diagnosis
Although recognition of this immense disease burden is relatively recent, it is unclear whether it has long been present but not been recognized because of lack of sensitive diagnostics or if, in fact, noroviruses represent a truly emergent public health issue. The complete scope of norovirus-induced morbidity worldwide, particularly in developing nations, has been challenging to ascertain due to several factors. First, norovirus detection is difficult because these viruses cannot be propagated in cell culture and are genetically variable, complicating reverse transcription polymerase chain reaction–based detection assays. Second, there is a lack of reporting to health officials because of the acute nature of the disease. Finally, national and international diagnostic/surveillance programs are not standardized, if present at all. Importantly though, there has recently been increased recognition of the burden of norovirus disease owing to significant improvements in norovirus diagnostic assays and an increased awareness of the need for surveillance standardization.3
As norovirus diagnostics have improved, there have been numerous reports of norovirus association with clinical outcomes other than gastroenteritis. For example, one case report detected norovirus RNA in the serum and cerebrospinal fluid of a child with encephalopathy. In addition, during a norovirus outbreak among military personnel in Afghanistan in May 2002, three infected patients presented with gastroenteritis, diminished alertness, headache, neck stiffness, and light sensitivity; one of these patients also displayed disseminated intravascular coagulation.3
Noroviruses have also been implicated in necrotizing enterocolitis in premature infants, postinfectious irritable bowel syndrome, and benign infantile seizures. While these case reports provide only anecdotal evidence that norovirus infection can have varied clinical outcomes, they do suggest that noroviruses should be considered as potential etiologic agents of diseases other than gastroenteritis.3
Treatment and Vaccine Development
The complex and varied ways through which noroviruses are spread make development of effective prevention and control measures difficult. The current methods of norovirus control rely on relatively generic measures, such as hand hygiene, environmental disinfection, and isolation of infected individuals. However, because of the difficulty in modifying human behaviors and the knowledge gaps resulting from our inability to cultivate human noroviruses in vitro, these steps are often inadequate.3
There is no specific medicine to treat people with norovirus illness. Norovirus infection cannot be treated with antibiotics because it is a viral (not a bacterial) infection.
People who have norovirus illness should drink plenty of liquids to replace fluid lost from vomiting and diarrhea. This will help prevent dehydration.3 Sports drinks and other drinks without caffeine or alcohol can help with mild dehydration. These drinks may not, however, replace important nutrients and minerals. Oral rehydration fluids that can be obtained as OTC are most helpful for mild dehydration.
Dehydration can lead to serious problems. Severe dehydration may require hospitalization for treatment with IV fluids. People with severe nausea and vomiting are often given medication (e.g., promethazine, prochlorperazine, or ondansetron) by IV to reduce or stop vomiting. If this is effective, patients may later receive oral or rectal preparations of these drugs and be monitored by their physicians. A few severely dehydrated patients may require hospitalization until their fluids and electrolytes are replenished.4
In February 2015, the Bill and Melinda Gates Foundation and the CDC brought together norovirus experts from around the world to discuss how to make the norovirus vaccine a reality. Participants were from 17 countries on six continents and included representatives from academia, industry, government, and private charitable foundations.3
Important questions remain regarding how humans develop immunity to norovirus, the duration of immunity, whether immunity to one norovirus strain protects against infection from other strains, the performance in high-risk groups (e.g., the elderly and young children), and whether protection is afforded against the full range of norovirus infections, including those that are asymptomatic. These are all critical questions for a vaccine, and this meeting was a step toward finding answers to these questions and making a norovirus vaccine a reality.3
Although a vaccine may one day serve as another critical tool, thorough epidemiological investigations and sound infection control practices will undoubtedly continue to be necessary in decreasing the spread of these well-adapted pathogens.
Conclusion
Outbreaks of norovirus present a significant challenge in virtually every state in the U.S. According to the CDC, people who are sick to their stomachs, vomiting, and experiencing diarrhea are likely infected with norovirus. The virus can be ingested from contaminated food or water or contact with an infected person. The virus can spread quickly, especially in big, contained spaces like a cruise ship. The CDC has a task force, the Vessel Sanitation Program (VSP), that requires any ship visiting foreign ports to submit to two random sanitation inspections per year. Following an outbreak, VSP experts come up with best practices to protect the cruise ship passengers from this unpleasant experience.
Recent studies in the area of norovirus have greatly helped our further understanding of how this emerging RNA virus family causes disease and persists worldwide. These advances include the identification and structural characterization of norovirus receptors, the development of animal models and a murine norovirus cell culture system, and the design of norovirus infectious clones. Studies in the murine norovirus model suggest that immunity to natural infection does indeed diminish over time but can be enhanced by repeat exposure.
While prevention of norovirus, especially in long-term-care facilities, may be virtually unachievable at least until a vaccine is developed, interventions following CDC guidelines and good public health practice can certainly limit the extent and severity of outbreaks.
REFERENCES
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2. Karst SM. Pathogenesis of noroviruses, emerging RNA viruses. Viruses. 2010;2(3):748-781.
3. Centers for Disease Control and Prevention. Setting of norovirus outbreaks. www.cdc.gov/norovirus/setting-outbreaks.html. Accessed December 2015.
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9. Alfano-Sobsey A, Sweat D, Hall A, Breedlove F, et al. Norovirus outbreak associated with undercooked oysters and secondary household transmission, Epidemiol Infect. 2012;140(2):276-282.
10. Desai R, Yen C, Wikswo ME, et al. Transmission of norovirus among NBA players and staff, winter 2010-2011, Clin Infect Dis. 2011;53(11):1115-1117.
11. Rhodin T. Virus sickens more than 50 at Lafayette College. PennLive LLC. www.lehighvalleylive.com/warren-county/index.ssf/2016/03/virus_sickens_more_than_50_at.html. Accessed March 10, 2016.
12. Snyder B, Baertlein L. Cleanup of Massachusetts Chipotle complete after norovirus scare. Reuters. www.reuters.com/article/us-chipotle-mexican-health-idUSKCN0WB22B. Accessed March 10, 2016.
