Human noroviruses are globally important pathogens, contributing substantially to the burden of acute gastroenteritis across all age groups. The World Health Organization recently estimated that noroviruses caused 684 million illnesses and over 200,000 deaths globally in 2010 [1••]. Ahmed et al. conducted a systematic review of the scientific literature published from January 1,2008, to March 8,2014, and found that noroviruses were associated with almost one fifth of all cases of acute gastroenteritis, and the prevalence was higher in high income countries compared to low- and middle-income countries [2••].

Long-term care facilities (LTCFs) are common settings for outbreaks of norovirus infection, where they are responsible for 30–80% of acute gastroenteritis outbreaks [3, 4, 5, 6•]. While noroviruses can cause both sporadic infections and outbreaks in all age groups, older people are at higher risks of hospitalization and death [3], owing to intrinsic factors, such as age-related immunosenescence or the presence of comorbid conditions, which result in more extended symptoms [7]. Additionally, elderly residents of LTCFs are at elevated risks of infection as a result of institutionalized confinement that promotes transmission by sharing rooms and touching common surfaces [8]. This review summarizes the most up-to-date knowledge on norovirus infection in LTCF residents with the aim of identifying potential strategies for management.

Norovirus infection generally manifests as a relatively brief, self-limited illness in healthy immunocompetent individuals, although it can cause significant morbidity and mortality in frail elderly adults. Lindasay et al. reviewed 39 studies on risk estimates of norovirus infection and found a high burden of the infection in all ages with the highest rates of hospitalization and death among the elderly [3]. Older people are at higher risk of norovirus-associated hospitalization, resulting in excess hospital stays and greater costs compared to young adults [3]. The overall estimates of disease burden suggest that noroviruses are responsible for approximately 10–20% of gastroenteritis hospitalizations, 10–15% of gastroenteritis deaths, and ≥0.2% of all-cause mortality among older adults in upper-middle-income and high-income countries [9, 10, 11•, 12,13]. Additional data also suggest that noroviruses may trigger severe clinical complications, including acute renal failure, arrhythmia, chronic diarrhea, and severe enteropathy [14, 15].

Noroviruses are the most common cause of gastroenteritis outbreaks in LTCFs [16]. Review of US outbreak surveillance data show that over 60% of all norovirus outbreaks occur in LTCFs [17], while in other high-income countries norovirus outbreaks occur with roughly equal frequency in both acute-care hospitals and LTCFs. The definition of LTCFs differs between studies, but LTCFs generally refer to facilities that provide prolonged care for individuals who required daily living and/or nursing care support. Whereas most community cases of norovirus are self-limiting within 12–60 h, outbreaks of norovirus can significantly impact the institutionalized elderly and cause more severe or prolonged illness [18•, 19,20]. Several factors contribute to the enhanced risk of severe norovirus infection among older adults living in LTCFs, including nutritional status, immunodeficiency or senescence, chronic inflammation, microbiome alterations, and the use of certain medications [21]. Decreased ability to maintain adequate personal hygiene may also increase individual risk among LTCF residents. Environmental factors, such as residence in close, shared quarters, use of shared facilities, and limited ability to isolate infected residents, may contribute to virus transmission in LTCFs. Shared dining facilities may also increase risk for foodborne exposures.

Noroviruses, divided into at least six genogroups (GI-GVI) and more than 40 different genotypes (e.g., GII.4), are a genetically diverse group of non-enveloped single-stranded positive-sense RNA viruses [33]. The prevalence of infecting genogroups and genotypes differ between populations and route of transmission [22]. Genogroup I viruses are generally associated with foodborne or waterborne outbreaks [24, 34], while GII.4 viruses are strongly associated with person-to-person transmission and occur predominantly in healthcare and institutional settings [5, 6•, 35, 36]. Infections with GII.4 viruses are more likely to cause severe infections, leading to more hospitalization and deaths than those caused by other GII or GI viruses [37]. Multiple strains of noroviruses can cause human reinfection. Protective immunity to specific types of noroviruses has been reported, but with a limited duration [38].

Despite the extensive genetic diversity, previous data suggest that GII.4 viruses are responsible for the majority of norovirus outbreaks worldwide [39], with a new GII.4 variant strain emerging every 2–4 years [40]. Several mechanisms may enhance GII.4 evolution, including the host herd immunity that drives antigenic drift in the hypervariable P2 domain [41••]. This domain of the viral capsid binds with human histo-blood group antigens (HBGAs), which serve as a point for initial viral attachment [42]. GII.4 viruses can bind a wider range of HBGAs than other genotypes, causing infections to a larger susceptible population [33]. Another explanation for the emergence of novel GII.4 variants is related to homologous recombination, which contributes to the emergence of the recent pandemic GII.4 variants, such as GII.4 New Orleans 2009, and GII.4 Sydney 2012 [43]. The emergence of epidemic strains of noroviruses has contributed to the changing epidemiology of norovirus infection worldwide [44, 45].

Noroviruses are highly contagious. Ingestion of a small number of viral particles can lead to infection [27]. The onset of norovirus infection occurs after an average incubation period of 1.2 (range 1–2) days [46]. Vomiting is a cardinal sign of norovirus infection, along with acute onset of other gastrointestinal symptoms including nausea, watery and non-bloody diarrhea, and abdominal cramps. Symptoms often last for 24– 72 h with complete recovery in immunocompetent individuals [19], although older frail people may present with prolonged symptoms and develop complications. One study describing the clinical characteristics of nosocomial outbreaks found that elderly hospitalized patients had prolonged symptoms with norovirus infection, and almost one third of the patients experienced dehydration [47]. Notably, the majority of those study participants (83.9%) had underlying chronic conditions, suggesting that the impact of norovirus infection is more pronounced among older adults with comorbid conditions.

It is difficult to diagnose norovirus gastroenteritis in individual patients on the basis of clinical features alone. The definition for norovirus infection in LTCFs requires the presence of both a compatible clinical presentation and a laboratory confirmation [48]. Historically, human noroviruses could not be cultured in vitro. However, Jones et al. recently published a protocol describing methods for culturing the GII.4-Sydney human norovirus strain directly in human B lymphocytes [49••]. This is a breakthrough research, as for the first time, a human norovirus can be grown in a culture dish. It enables research into the development of antiviral drugs, as well as opens a door to definitively evaluate the efficacy of infection control and prevention options.

Diagnostic methods of norovirus infection have focused on detecting viral RNA or antigen. In recent years, real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays have become the gold standard for the rapid and sensitive detection of noroviruses in stool, vomitus, foods, water, and environmental specimens [33]. However, virus detection by RT-qPCR does not always correlate with the disease. Infected persons can shed virus for weeks after recovery from clinical symptoms, and noroviruses are also frequently detected in stool samples from asymptomatic patients. Chan et al. analyzed data collected from sporadic cases and speculated a correlation between viral load and virus transmission from infected persons to susceptible hosts through fecal-oral route [50]. This finding indicates that assessment of a possible difference in viral load in samples may be a useful tool to aid clinical interpretation and to assess causal relationship.

Given the rapid spread of noroviruses, especially during outbreaks, timely diagnosis is essential to assist management and implementation of appropriate control measures. Rapid commercial assays, such as enzyme immunoassays (EIAs) have been cleared by the US Food and Drug Administration to detect norovirus antigen in stool samples during outbreaks. However, due to the poor sensitivity of EIAs [51], samples with negative results should be confirmed by a second technique, such as RT-qPCR [52]. Consequently, EIA kits should not replace molecular methods during outbreak investigations, and caution should be used when interpreting test results from sporadic cases [52].

In the absence of laboratory diagnostic tests or delays in obtaining laboratory results, outbreaks of norovirus infection can be identified according to Kaplan criteria [53]. These criteria are based on the clinical and epidemiological profile of illness, which include (1) vomiting in >50% of patients, (2) a mean incubation period of 24–48 h, (3) a mean duration of illness of 12–60 h, and (4) lack of bacterial pathogens in stool culture. The set of Kaplan criteria is highly specific (99%), although with moderate sensitivity (68%) in discriminating outbreaks due to bacteria from those due to norovirus [54]. In LTCF, outbreaks satisfying Kaplan's criteria may justify rapid institution of control measures to limit spread of infection.

The highly infectious nature of noroviruses and their environmental persistence pose multiple challenges to infection management in LTCFs. In 2011, the Centers for Disease Control and Prevention published guidelines providing recommendations for the prevention and control of norovirus gastroenteritis outbreaks in healthcare facilities [60]. Table 1 summarizes the risk-based approach for norovirus infection prevention and management in LTCFs, based on these guidelines and other published recommendations [52, 60, 62, 63, 73•]. The major strategies have included measures for timely diagnosis and implementation of infection control interventions to limit virus transmission.

The key means of managing norovirus infection in LTCFs are well-functioning infection control programs. Current guidelines for prevention and control are generally based on infection control principles, although the efficacy of those control measures is poorly quantified due to the inability to culture the virus. With the recent breakthroughs of human norovirus in vitro culture, doors are now opened to, for example, definitively evaluate the efficacy of environmental disinfectants and hand hygiene options. In addition, there is no specific antiviral therapy available to treat norovirus infection. Therefore, development of licensed vaccines against noroviruses may provide another important tool for infection prevention among high-risk individuals.