Norovirus outbreaks in healthcare settings affect vulnerable populations (eg, elderly persons), but because these outbreaks are predominantly spread by person-to-person transmission and are caused by GII.4 viruses [1
], it has not previously been possible to determine if the outbreak setting, transmission route, or virus strain was the cause of severe outcomes including hospitalization and death. Our review of over 800 outbreaks has highlighted that, indeed, hospitalizations and deaths were much more likely in healthcare outbreaks and, somewhat surprisingly, in GII.4 virus–associated outbreaks, independent of those factors for which we were able to control.
Among published NoV outbreak reports, we estimate an overall pooled NoV case hospitalization rate of 0.7% and mortality rate of 0.07%. However, these figures may overestimate the rate of severe outcomes because outbreaks with hospitalizations and/or deaths may also be more likely to be investigated and subsequently published in the peer-reviewed literature. Indeed, passive surveillance systems have estimated lower hospitalization and mortality rates [6
]. Many NoV outbreaks likely go unrecognized, and among those that get reported to local public health authorities, the majority are not systematically investigated or well documented [7
]. Additionally, the only outbreaks in this analysis that were reported from a low- (Afghanistan) or low-middle–income income (Iraq) setting occurred among US and UK military forces; however, it is thought that the burden of NoV disease is highest in developing regions [3
]. Given that poorer outcomes are related to inadequate access to medical care, our figures may represent an underestimate of the true hospitalization and mortality rate attributable to NoV disease in some international settings.
The high hospitalization rates in long-term care facilities and mortality in all healthcare settings underscores the vulnerability of populations affected by outbreaks in these settings. Norovirus infection often causes prolonged symptoms in frail, elderly patients with limited mobility [8
]. Due to limitations in the published outbreak data, it was not possible to assess whether healthcare settings may have been a proxy for intrinsic factors for patient vulnerability, such as age or comorbid conditions, which may have made residents and patients more likely to develop complications of NoV disease than staff or visitors. Unfortunately, only a minority of studies in our review discriminated between the NoV cases among staff and hospital patients/nursing home residents. If more studies had reported hospitalization and mortality rates separately for staff and patients/residents, we expect that estimates of severe disease frequency in these specific populations would have been even higher. Studies have demonstrated that rates of severe NoV disease are highest among the elderly [9
], whereas overall NoV rates are highest in younger age groups [10
], making advanced age a risk factor for higher NoV-associated hospitalization and fatality rates. Because age was not reported in the many outbreak reports, this unmeasured covariate could have confounded our results. However, because most patients in hospital and long-term care facility settings are elderly, setting of outbreak is likely a very strong proxy for age.
Route of transmission was identified as being foodborne, waterborne, person-to-person, or a combination of these routes in 63% of the outbreaks. Prolonged outbreaks that occurred in long-term care facility or hospital settings—where large groups of individuals typically live in close proximity–were often categorized as person-to-person. Foodborne and waterborne transmission were the most frequent type of transmission identified in our data. However, broad-based surveillance studies as well as expert elicitation suggest that the majority of NoV outbreaks primarily involve person-to-person transmission [1
], suggesting a publication bias favoring reports of foodborne and waterborne transmission. Fortunately, this bias would not affect our estimates of the association between mode of transmission and severe outcomes. In addition, this may be due to outbreak reports that concluded that outbreaks occurring over many days in community settings were the result of foodborne or waterborne transmission, even when a specific source was not identified. It is possible that transmission route may have been misclassified in some of these outbreaks.
Clinical and epidemiologic criteria can help attribute gastroenteritis outbreaks to NoV disease [13
]. However, commercial NoV PCR testing has become more widely available in recent years [14
], and there is now a Food and Drug Administration–cleared enzyme immunoassay for outbreak investigation in the United States. All of the published outbreaks evaluated in this study used confirmatory laboratory testing. Comparing outbreaks known to be due to GII.4 with those known to be due to a strain other than GII.4, we found a striking difference in mortality rate and hospitalization rate, suggesting that this genotype may be responsible for severe disease. Previous observations that GII strains are shed at higher levels [15
], are more likely to induce vomiting, and cause more severe disease in children [16
], when taken in the context of this study, demonstrate a consistent pattern. Noroviruses rapidly evolve and distinct strains have emerged every 2–4 years over the last decade [18
]. At least 2 GII.4 variants have escaped population immunity and were associated with large global outbreaks of disease [19
Currently there is no licensed NoV vaccine. Efforts to reduce NoV disease burden have been focused on effective disease surveillance and limiting disease transmission. We have again highlighted the importance of outbreak prevention and control of outbreaks in healthcare settings, where hospitalization and death are more likely to occur. In addition, NoV vaccines are under development, and it has been demonstrated that, in principle at least, it is possible to immunize using a GI.1 vaccine against a homotypic challenge [21
]. Our analysis highlights the importance of developing vaccines against GII.4 viruses that are safe and effective, particularly for vulnerable populations who suffer severe disease outcomes, including death.