Summary Background Despite substantial decreases in recent decades, acute gastroenteritis causes the second greatest burden of all infectious diseases worldwide. Noroviruses are a leading cause of sporadic cases and outbreaks of acute gastroenteritis across all age groups. We aimed to assess the role of norovirus as a cause of endemic acute gastroenteritis worldwide. Methods We searched Embase, Medline, and Global Health databases from Jan 1, 2008, to March 8, 2014, for studies that used PCR diagnostics to assess the prevalence of norovirus in individuals with acute gastroenteritis. We included studies that were done continuously for 1 year or more from a specified catchment area (geographical area or group of people), enrolled patients who presented with symptoms of acute gastroenteritis, and used PCR-based diagnostics for norovirus on all stool specimens from patients with acute gastroenteritis. The primary outcome was prevalence of norovirus among all cases of gastroenteritis. We generated pooled estimates of prevalence by fitting linear mixed-effect meta-regression models. Findings Of 175 articles included, the pooled prevalence of norovirus in 187 336 patients with acute gastroenteritis was 18% (95% CI 17–20). Norovirus prevalence tended to be higher in cases of acute gastroenteritis in community (24%, 18–30) and outpatient (20%, 16–24) settings compared with inpatient (17%, 15–19, p=0·066) settings. Prevalence was also higher in low-mortality developing (19%, 16–22) and developed countries (20%, 17–22) compared with high-mortality developing countries (14%, 11–16; p=0·058). Patient age and whether the study included years of novel strain emergence were not associated with norovirus prevalence. Interpretation Norovirus is a key gastroenteritis pathogen associated with almost a fifth of all cases of acute gastroenteritis, and targeted intervention to reduce norovirus burden, such as vaccines, should be considered. Funding The Foodborne Disease Burden Epidemiology Reference Group (FERG) of WHO and the Government of the Netherlands on behalf of FERG.

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Global prevalence of norovirus in cases of gastroenteritis: a systematic review and meta-analysis.

Noroviruses: a comprehensive review.

Background Noroviruses (NoVs) are the most common cause of viral gastroenteritis Their high incidence and importance in health care facilities result in a great impact on public health Studies from around the world describing increasing prevalence have been difficult to compare because of differing nomenclatures for variants of the dominant genotype, GII4 We studied the global patterns of GII4 epidemiology in relation to its genetic diversity Methods Data from NoV outbreaks with dates of onset from January 2001 through March 2007 were collected from 15 institutions on 5 continents Partial genome sequences (n = 775) were collected, allowing phylogenetic comparison of data from different countries Results The 15 institutions reported 3098 GII4 outbreaks, 62% of all reported NoV outbreaks Eight GII4 variants were identified Four had a global distribution-the 1996, 2002, 2004, and 2006b variants The 2003Asia and 2006a variants caused epidemics, but they were geographically limited Finally, the 2001 Japan and 2001Henry variants were found across the world but at low frequencies Conclusions NoV epidemics resulted from the global spread of GII4 strains that evolved under the influence of population immunity Lineages show notable (and currently unexplained) differences in geographic prevalence Establishing a global NoV network by which data on strains with the potential to cause pandemics can be rapidly exchanged may lead to improved prevention and intervention strategies

Norovirus Illness Is a Global Problem: Emergence and Spread of Norovirus GII.4 Variants, 2001–2007

Background Noroviruses are the leading cause of viral acute gastroenteritis in humans, noted for causing epidemic outbreaks in communities, the military, cruise ships, hospitals, and assisted living communities. The evolutionary mechanisms governing the persistence and emergence of new norovirus strains in human populations are unknown. Primarily organized by sequence homology into two major human genogroups defined by multiple genoclusters, the majority of norovirus outbreaks are caused by viruses from the GII.4 genocluster, which was first recognized as the major epidemic strain in the mid-1990s. Previous studies by our laboratory and others indicate that some noroviruses readily infect individuals who carry a gene encoding a functional alpha-1,2-fucosyltransferase (FUT2) and are designated “secretor-positive” to indicate that they express ABH histo-blood group antigens (HBGAs), a highly heterogeneous group of related carbohydrates on mucosal surfaces. Individuals with defects in the FUT2 gene are termed secretor-negative, do not express the appropriate HBGA necessary for docking, and are resistant to Norwalk infection. These data argue that FUT2 and other genes encoding enzymes that regulate processing of the HBGA carbohydrates function as susceptibility alleles. However, secretor-negative individuals can be infected with other norovirus strains, and reinfection with the GII.4 strains is common in human populations. In this article, we analyze molecular mechanisms governing GII.4 epidemiology, susceptibility, and persistence in human populations. Methods and Findings Phylogenetic analyses of the GII.4 capsid sequences suggested an epochal evolution over the last 20 y with periods of stasis followed by rapid evolution of novel epidemic strains. The epidemic strains show a linear relationship in time, whereby serial replacements emerge from the previous cluster. Five major evolutionary clusters were identified, and representative ORF2 capsid genes for each cluster were expressed as virus-like particles (VLPs). Using salivary and carbohydrate-binding assays, we showed that GII.4 VLP-carbohydrate ligand binding patterns have changed over time and include carbohydrates regulated by the human FUT2 and FUT3 pathways, suggesting that strain sensitivity to human susceptibility alleles will vary. Variation in surface-exposed residues and in residues that surround the fucose ligand interaction domain suggests that antigenic drift may promote GII.4 persistence in human populations. Evidence supporting antigenic drift was obtained by measuring the antigenic relatedness of GII.4 VLPs using murine and human sera and demonstrating strain-specific serologic and carbohydrate-binding blockade responses. These data suggest that the GII.4 noroviruses persist by altering their HBGA carbohydrate-binding targets over time, which not only allows for escape from highly penetrant host susceptibility alleles, but simultaneously allows for immune-driven selection in the receptor-binding region to facilitate escape from protective herd immunity. Conclusions Our data suggest that the surface-exposed carbohydrate ligand binding domain in the norovirus capsid is under heavy immune selection and likely evolves by antigenic drift in the face of human herd immunity. Variation in the capsid carbohydrate-binding domain is tolerated because of the large repertoire of similar, yet distinct HBGA carbohydrate receptors available on mucosal surfaces that could interface with the remodeled architecture of the capsid ligand-binding pocket. The continuing evolution of new replacement strains suggests that, as with influenza viruses, vaccines could be targeted that protect against norovirus infections, and that continued epidemiologic surveillance and reformulations of norovirus vaccines will be essential in the control of future outbreaks.

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Mechanisms of GII.4 Norovirus Persistence in Human Populations

Factors involved in the aerosol transmission of infection and control of ventilation in healthcare premises

Increase in viral gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant

From May through June 2001, an outbreak of acute gastroenteritis that affected at least 200 persons occurred in a combined activity camp and conference center in Stockholm County. The source of illness was contaminated drinking water obtained from private wells. The outbreak appears to have started with sewage pipeline problems near the kitchen, which caused overflow of the sewage system and contaminated the environment. While no pathogenic bacteria were found in water or stools specimens, norovirus was detected in 8 of 11 stool specimens and 2 of 3 water samples by polymerase chain reaction. Nucleotide sequencing of amplicons from two patients and two water samples identified an emerging genotype designated GGIIb, which was circulating throughout several European countries during 2000 and 2001. This investigation documents the first waterborne outbreak of viral gastroenteritis in Sweden, where nucleotide sequencing showed a direct link between contaminated water and illness.

https://stacks.cdc.gov/view/cdc/14265/cdc_14265_DS1.pdf

Emerging genotype (GGIIb) of norovirus in drinking water, Sweden.

An outbreak of gastroenteritis affecting 158 of 219 (72%) guests and employees at a hotel is described. Food served at the hotel restaurant is believed to have been the source of the outbreak and to have been contaminated by sick employees working in the restaurant. A secondary attack rate of 22% was seen involving 43 persons in all. In stool specimens from seven of eight patients, Norwalk-like viruses (NLVs) were detected by electron microscopy. While NLV-specific PCR using primers JV12 and JV13 were negative, all specimens examined with primers NVp69 and NVp110 were positive. The failure of primers JV12 and JV13 was attributed to several mismatches in the JV12 primer. Genotyping and sequence analysis revealed that all samples had identical sequences and clustered with genogroup I, and the most closely related well-characterized genotype is Desert Shield. This is the first described food-borne outbreak associated with genogroup I virus in Sweden.

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Food-Borne Outbreak of Gastroenteritis Associated with Genogroup I Calicivirus

In March 1999, an outbreak of gastroenteritis occurred affecting 30 day-care centres served by the same caterer. A retrospective cohort study was performed in 13 randomly selected day-care centres to determine the source and mode of transmission. Electron microscopy and PCR were used to verify the diagnosis. The overall attack rate (AR) was 37% (195/524): 30% in children and 62% in adults. Modified by the age of the patient, eating pumpkin salad served on 1 March was associated with becoming an early case (odds ratio = 3.9; 95% confidence interval 1.8-8.8). No significant association was found between food consumption and becoming a late case. The primary food-borne AR was 27% and the secondary AR was 14%. The same genotype of Norwalk-like virus was found in 5 cases and in 1 ill and 1 asymptomatic food-handler. Contamination by 1 of the food-handlers seems the most likely route of spread of the virus and underlines the importance of strict hygienic routines.

Maria Torvén

Papers

Increase in viral gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant

Emerging genotype (GGIIb) of norovirus in drinking water, Sweden.

Food-Borne Outbreak of Gastroenteritis Associated with Genogroup I Calicivirus

Epidemiological investigation of a food-borne gastroenteritis outbreak caused by Norwalk-like virus in 30 day-care centres.