Norovirus InfectionsViral gastroenteritis is a common illness. Noroviruses represent the most common cause of sporadic cases of gastroenteritis in the community and are the cause of one third to one half of all food borne outbreaks (Turcios et al., 2006). Noroviruses account for 54% gastrointestinal outbreaks in hospitals in England and Wales (Meakins et al., 2003). It is estimated that there are 23 million infections per year in the USA affecting people of all ages (reviewed in Atmar and Estes). Since 2002, the Public Health Agency of Canada (PHAC) has received approximately 300-400 reported outbreaks related to noroviruses each year (PHAC, 2005). With the well publicized outbreaks on university campuses and in acute care hospitals in Nova Scotia, there has been a lot of media attention focused on noroviruses recently. This is a brief review outlining the salient features of norovirus infection.The VirusNorovirus belongs to the non-enveloped RNA virus family caliciviridae. In the past they had been referred to as small round structured viruses (SRSV) based on their characteristic appearance on electron microscopy. However, most people know noroviruses as "Norwalk virus" which actually represents only one of the many strains of noroviruses. The term Norwalk refers to the town in Ohio where the CDC investigated a gastroenteritis outbreak in 1968. It was not until the early 1970's that noroviruses were identified as the cause of this outbreak. Volunteers who were fed a bacteria-free filtrate prepared from a rectal swab from a child in the Norwalk outbreak developed gastroenteritis and had the characteristic small round viruses identified in their stool by electron microscopy (reviewed in Atmar and Estes). Since that time naming norovirus strains according to the geographic region where they were first identified has become standard procedure (e.g. Snow Mountain virus, Toronto virus etc.). Although this naming scheme provides an identity it does not describe how the strains are related. Using sophisticated molecular techniques and phylogenetic analysis noroviruses can classified into "genogroups" based on their genetic similarity. Although there are 5 different genogroups of noroviruses, only genogroups I, II and IV infect humans. Each of these genogroups can be further divided into clusters (8 clusters in GI, 17 clusters in GII, one cluster in GIV), each of which may contain many distinct strains, demonstrating how genetically diverse this group of viruses is. Norwalk virus for example belongs to genogroup I.1. (Zheng et al., 2006). Although infections with genogroup IV have only been rarely described to date both genogroup I and II cause sporadic infections. Genogroup II has been the principle strain associated with acute outbreaks of gastroenteritis in the US. Interestingly strains belonging to one particular cluster (genogroup II.4) have been described as an epidemic strain associated with multiple outbreaks worldwide. Compared to other strains genogroup II.4 viruses are more frequently associated with outbreaks in closed or semi-closed settings such as cruise ships and is more commonly associated with outbreaks were confirmed person-to-person transmission has occurred; suggesting that there may be a significant biological difference with these strain (Blanton et al., 2006). The virus itself is quite hardy. It can survive at 60°C for 30 minutes and the PHAC web site suggests noroviruses can survive on non-porous surfaces for 12 hours and up to 12 days in contaminated carpets (PHAC, 2005). As Noroviruses cannot be cultured, experiments examining viral persistence after environmental contamination are often done using a feline calicivirus. A recent article used this feline calicivirus as a surrogate marker for human norovirus to demonstrate that the virus can survive for variable lengths of time on surfaces such as, telephone buttons, receivers and computer keys. Although the time for a 90% reduction of virus on these items was 4 - 24 hours the virus could still be detected up to three days on telephone buttons and receivers, illustrating the potential for spread via fomites and the need for disinfection (Clay et al., 2006). Transmission: Noroviruses are shed in high numbers from infected patients and as little as 10 to 100 virus particles are all that's reported to be necessary to cause infection (reviewed in Atmar and Estes). The virus is primarily transmitted by the fecal oral route by direct contact with infected individuals or by touching surfaces or objects that have been contaminated by patients. Noroviruses are also responsible for a significant portion of food related gastroenteritis each year. These may result from contamination of food by an infected food handler or during cultivation. Shellfish, a classic example, may concentrate the virus when grown in waters exposed to sewage. Water may also be the source of contamination of fruits and vegetables or ice in beverages. Due to it's infectious nature, the secondary attack rates associated with these outbreaks can be over 50%. Thus when norovirus is introduced into closed settings with shared exposures such as long-term care facilities, day care, or hospitals, large numbers of cases can occur (Atmar and Estes, 2006). There are well documented outbreaks of norovirus infection on cruise ships (Cramer et al., 2002) and it likely a more common cause of travelers diarrhea than previously recognized with one study placing it second only to toxigenic E. coli (Ko et al., 2005). The virus can also be found in vomit, which can be the source of direct or indirect infection through oral inoculation. Although there is also some evidence for airborne transmission from droplets generated during the act of vomiting, it can be difficult to differentiate acquisition from aerosols from exposure to contaminated fomites in the same environment. In addition to transmission from symptomatic patients, there is evidence of asymptomatic infection and shedding which may facilitate the propagating of the virus in the community (reviewed in Radford et al., 2004). SymptomsThe clinical presentation of norovirus infection had been described as early as 1929 when the name "winter vomiting disease" was proposed to describe outbreaks of non-bacterial gastroenteritis. Norovirus infections tend to predominate in the winter months in temperate climates but illness can occur throughout the year (Blanton et al., 2006). Although the vomiting may be explosive or projectile, symptoms can vary from one patient to another. Some patients may have predominately vomiting, while others have diarrhea or a combination of both. Some studies suggest vomiting is more common in children and diarrhea is more common in adults (Gotz et al., 2001) where as others have found that vomiting is less common in children < 1 year of age (Rockx et al., 2002). Also, people may have abdominal cramps and more systemic like features such as malaise, myalgias, and low grade fever. Clinical criteria established by Kaplan and colleagues (1982) suggests that outbreaks of noroviruses are characterized by an illness with a short incubation period (24-48 hours), a short symptomatic illness (12-60 hours), and a high frequency of vomiting (greater than 50%) in the absence of bacterial pathogens. A recent review of norovirus outbreaks in the US suggested that the Kaplan criteria are moderately sensitive (68%) but are highly specific (99%) for discriminating food borne outbreaks of gastroenteritis due to norovirus infection from bacterial causes (Turcios et al., 2006). Norovirus infection does not cause bloody diarrhea and if a patient presents with blood in their stools an alternative diagnosis should be sought. PathologyAlthough there are histopathologic changes in the small intestine such as broadening and flattening of the villi, the "mechanisms that lead to symptomatic infection is unknown" (Atmar and Estes, 2006).Infectious periodGenerally people are infectious from the time they feel ill for up to three days after their symptoms resolve. However, some studies have shown viral shedding can persist up to three weeks after infection in up to 26% of infected individuals reinforcing the need for good hygiene in the post symptomatic period (Rockx et al. 2002). Immunity to infection: Immunity to norovirus infection is a complex topic. Noroviruses are genetically and antigenically diverse. Since multiple strains of norovirus exist, infection with one strain will not protect from infection against other strains. Interestingly, there are individuals who can be exposed to norovirus repeatedly in large doses and never get infected, while others can have recurrent infections. Studies examining the genetic basis for this phenomenon suggest that susceptibility to norovirus infection correlates with blood group antigen expression. These individuals cannot produce the norovirus receptor and are thus resistant to infection. This may explain the paradoxical association in some studies where a lack of an antibody response was associated with resistance to infection: If someone cannot get infected by the virus they will not generate an antibody response where as those who generate antibody responses are obviously susceptible to the virus and may be susceptible to a different strain (Atmar and Estes, 2006). DiagnosisHuman caliciviruses cannot be cultured. In the past, at the QEII we diagnosed noroviruses by examining stools with electron microscopy (EM) and identifying the characteristic small round gastrointestinal viruses. However, EM requires 106 virus /ml of stool to be able to identify a positive specimen. There are rapid antigen tests such as dipsticks which can detect smaller amounts of viruses from infected stools (104 viral particles/ml) which may be used in other facilities. However these tests can have poor sensitivity against some norovirus strains. Here at the QEII we use reverse transcriptase PCR (RT-PCR) as the method of choice for diagnosing norovirus infection. It is very sensitive and can detect as little as 102 virus particles/ml of stool. In patients with suspect norovirus infection we suggest submitting a liquid stool. Ideally the specimen should be collected as close to the acute phase of illness as possible. However, the sensitivity of RT-PCR allows for the possibility of detecting virus after the symptomatic period which may be important in certain circumstances during an outbreak investigation. Specimens should be kept refrigerated at 4°C until processed and freezing should be avoided. Although the virus can be identified in vomit, this specimen is generally not processed due to the presence of inhibitors which can affect the sensitivity of the assay. Once a norovirus outbreak is confirmed, we suspend testing from that facility (or from the nursing unit in that facility) for two weeks as the clinical presentation should be sufficient to diagnose infection. If patients have persistent symptoms after this period of time we will repeat test to see if the virus continues to circulate or if there is a new problem. A request for more frequent testing or the testing of vomit would need to be discussed with the Medical Microbiologist. Although our RT-PCR method can detect noroviruses, other viruses capable of causing outbreaks of gastrointestinal illness such as rotavirus, adenovirus or Sapporo-like viruses will not be detected. Therefore if norovirus RT-PCR is negative in an outbreak situation RT-PCR directed at Sapporo-like viruses or further examination of stools with EM may reveal alternative causes.TreatmentAlthough infected individuals can be very unwell during their symptomatic period the illness is generally self-limiting and treatment is supportive. In the elderly and those who are immune suppressed or have other underlying medical conditions, more severe disease can occur. They may be at risk for complications including aspiration of vomit, dehydration and electrolyte abnormalities leading to renal dysfunction and death. Case fatality rates in one study from England and Wales was 7.5/10000 cases (Lopman et al., 2003). However a recent review of illness and death caused by gastroenteritis due to food borne illness in the US estimates that 310 of the 23 million cases of norovirus infection will die each year compared with 553 of the 1.4 million cases of salmonella infection (Mead et al., 1999). Others suggest that the methods used in this study to generate this estimation are flawed and that the actual mortality rates are lower. Since data suggests that the majority of food borne outbreaks of gastroenteritis with no determined cause are due to noroviruses, Frenzen (2004) argues that the mortality rate may actually be 0-3.7 cases/ year based on fact that only one death was recorded from all of the cases in 1900 food borne outbreaks that did not have a determined pathogen reported to the CDC from 1993 to 1997. PreventionThe cornerstone for preventing norovirus infection is good infection control practices, the most important of which is good hand washing technique. Hands should be washed thoroughly with soap and water after using the bathroom, changing diapers or cleaning up after a norovirus patient. Discard any stool or vomit into a toilet and keep the surrounding area clean. Although the virus is hardy it can be successfully inactivated using common household cleaners that contain sodium hypochlorite (eg. bleach). It is important to remember that the area must be cleaned prior to disinfection as organics (diarrhea and vomit) can inactivate the chlorine in bleach. For facilities with workers who are sensitized to the strong bleach odor, other options such as hydrogen peroxide based compounds can be used for disinfection. To prevent foodbourne transmission, hands should be washed before eating or preparing food. Fruits and vegetables should be cleaned thoroughly and food should be well cooked and served hot. Infected patients should not return to work for until 48-72 hours after their symptoms resolve. However, given that shedding can persist in some individuals for up to three weeks, vigilant hand hygiene is paramount in the post symptomatic period. Norovirus infection occurs every year. Why some years seem to have more severe or pronounced outbreaks is not clear. There is some suggestion that certain strains have a greater propensity to cause infection. The ultimate goal of a virus is not to kill its host but to find a new host to infect so that it can replicate its genetic material. What better way to do this than to induce explosive vomiting and diarrhea. This in combination with its low infectious dose essentially guarantees self perpetuation of the norovirus, which from an evolutionary perspective is quite clever. Todd F. Hatchette, MD, FRCPC Thanks to Kim Trigg and Janice Pettipas for their assistance in the preparation and review of this manuscript. References:
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