Benjamin A. Lopman

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

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.

Norovirus and Medically Attended Gastroenteritis in U.S. Children

BACKGROUND Cases of rotavirus-associated acute gastroenteritis have declined since the introduction of rotavirus vaccines, but the burden of norovirus-associated acute gastroenteritis in children remains to be assessed. METHODS We conducted active surveillance for laboratory-confirmed cases of norovirus among children younger than 5 years of age with acute gastroenteritis in hospitals, emergency departments, and outpatient clinical settings. The children resided in one of three U.S. counties during the years 2009 and 2010. Fecal specimens were tested for norovirus and rotavirus. We calculated population-based rates of norovirus-associated acute gastroenteritis and reviewed billing records to determine medical costs; these data were extrapolated to the U.S. population of children younger than 5 years of age. RESULTS Norovirus was detected in 21% of young children (278 of 1295) seeking medical attention for acute gastroenteritis in 2009 and 2010, with norovirus detected in 22% (165 of 742) in 2009 and 20% (113 of 553) in 2010 (P=0.43). The virus was also detected in 4% of healthy controls (19 of 493) in 2009. Rotavirus was identified in 12% of children with acute gastroenteritis (152 of 1295) in 2009 and 2010. The respective rates of hospitalization, emergency department visits, and outpatient visits for the norovirus were 8.6, 146.7, and 367.7 per 10,000 children younger than 5 years of age in 2009 and 5.8, 134.3, and 260.1 per 10,000 in 2010, with an estimated cost per episode of

Direct and Indirect Effects of Rotavirus Vaccination Upon Childhood Hospitalizations in 3 US Counties, 2006–2009

3,918,

Uptake, impact, and effectiveness of rotavirus vaccination in the United States: review of the first 3 years of postlicensure data.

435, and

Sustained decline in rotavirus detections in the United States following the introduction of rotavirus vaccine in 2006.

151, respectively, in 2009. Nationally, we estimate that the average numbers of annual hospitalizations, emergency department visits, and outpatient visits due to norovirus infection in 2009 and 2010 among U.S. children in this age group exceeded 14,000, 281,000, and 627,000, respectively, with more than

A Systematic Review and Meta-Analysis of the Global Seasonality of Norovirus

273 million in treatment costs each year. CONCLUSIONS Since the introduction of rotavirus vaccines, norovirus has become the leading cause of medically attended acute gastroenteritis in U.S. children and is associated with nearly 1 million health care visits annually. (Funded by the Centers for Disease Control and Prevention.).

Global Economic Burden of Norovirus Gastroenteritis

BACKGROUND Routine rotavirus vaccination of US infants began in 2006. We conducted active, population-based surveillance for rotavirus gastroenteritis hospitalizations in 3 US counties to assess vaccine impact. METHODS Children <36 months old hospitalized with diarrhea and/or vomiting were enrolled from January through June each year during the period 2006-2009 and tested for rotavirus. Age-stratified rates of hospitalization for rotavirus infection were compared with corresponding vaccination coverage among a control group of children with acute respiratory illness. To assess direct and indirect benefits, vaccination coverage rates in the control group were multiplied by vaccine effectiveness estimates to calculate expected reductions in the rate of hospitalization for rotavirus infection. Rotavirus serotypes were compared across years. RESULTS Compared with 2006, a significant reduction in rates of hospitalization for rotavirus infection (P < .001) was observed in 2008 among all age groups. There was an 87% reduction in the 6-11-month-old age group (coverage, 77%), a 96% reduction in the 12-23-months-old age group (coverage, 46%), and a 92% reduction in the 24-35-month-old age group (coverage, 1%), which exceeded reductions expected on the basis of coverage and vaccine effectiveness estimates. Age-specific rate reductions were nearly equivalent to those expected on the basis of age-specific vaccine coverage in 2009. Predominant strains varied annually: G1P[8] (91%) in 2006; G1P[8] (45%) and G12P[8] (36%) in 2007; G1P[8] (89%) in 2008; and G3P[8] (43%), G2P[4] (34%), and G9P[8] (27%) in 2009. CONCLUSIONS Rotavirus vaccination has dramatically decreased rates of hospitalization for rotavirus infection among children in these US counties. In 2008, reductions were prominent among both vaccine-eligible age groups and older, largely unvaccinated children; the latter likely resulted from indirect protection. Although rates among age groups eligible for vaccination remained low in 2009, indirect benefits disappeared.

The Potential Economic Value of a Human Norovirus Vaccine for the United States

Background: Rotavirus vaccine was recommended for routine use in US infants in 2006. Before the introduction of vaccine, rotavirus was the most common cause of severe gastroenteritis in children <5 years of age in the United States. Methods: We reviewed published data to summarize the US experience during the first 3 years of its rotavirus vaccination program. Results: Rotavirus seasons have been delayed and diminished in magnitude during the postvaccine era compared with the prevaccine era. Hospitalizations, emergency department visits, and outpatient visits due to gastroenteritis have declined dramatically in children <5 years of age including in children age-ineligible to have received vaccine, suggesting indirect benefits of vaccination. Rotavirus vaccine has been widely accepted by pediatricians. Vaccine coverage is steadily increasing but remains lower than coverage levels of other routine infant immunizations. Conclusions: The implementation of routine childhood immunization against rotavirus has rapidly and dramatically reduced the large health burden of rotavirus gastroenteritis in US children. Continued monitoring of rotavirus diarrhea is needed to determine if immunity wanes as vaccinated children get older and to better quantify the indirect benefits of vaccination. Ongoing surveillance will also enable monitoring of the long-term impact of vaccination on rotavirus epidemiology.

Rotavirus Vaccines and Health Care Utilization for Diarrhea in the United States (2007–2011)

Background: Following implementation of the rotavirus vaccination program in 2006, rotavirus activity in the United States declined dramatically in 2007–2008 but increased slightly in 2008–2009, despite greater vaccine uptake. To further evaluate impact of the vaccine program, we assessed trends in rotavirus testing and detection during 2009–2010. Methods: We examined rotavirus testing data from July 2000 to June 2010 from the National Respiratory and Enteric Viruses Surveillance System to compare rotavirus season timing and peak activity in the pre- and postvaccine introduction eras. Rotavirus season onset was defined as the first of 2 consecutive weeks during which the percentage of specimens testing positive for rotavirus was ≥10%. To assess trends in rotavirus testing and detection, we restricted the analyses to 25 laboratories that reported for ≥26 weeks per season from 2000 to 2010. Results: During 2009–2010, the threshold for the start of the rotavirus season was never achieved nationally or in the North, Midwest, or West. Activity in the South met this threshold but the season duration was substantially shorter and of lower magnitude than in all previous pre- and postvaccine introduction seasons. Nationally and within each region, the peak week was more delayed and the peak proportion of positive tests was substantially lower than all previous seasons. The total number of tests performed declined by 23%, and the number of positive tests declined by 86%. Conclusions: Rotavirus activity was substantially diminished during the 2009–2010 rotavirus season compared with the prevaccine baseline and the 2 previous postvaccine introduction seasons. These sustained declines over 3 rotavirus seasons reaffirm the health benefits of the US rotavirus vaccination program.

Burden of Norovirus Gastroenteritis in the Ambulatory Setting—United States, 2001–2009

Background Noroviruses are the most common cause of acute gastroenteritis across all ages worldwide. These pathogens are generally understood to exhibit a wintertime seasonality, though a systematic assessment of seasonal patterns has not been conducted in the era of modern diagnostics. Methods We conducted a systematic review of the Pubmed Medline database for articles published between 1997 and 2011 to identify and extract data from articles reporting on monthly counts of norovirus. We conducted a descriptive analysis to document seasonal patterns of norovirus disease, and we also constructed multivariate linear models to identify factors associated with the strength of norovirus seasonality. Results The searched identified 293 unique articles, yielding 38 case and 29 outbreak data series. Within these data series, 52.7% of cases and 41.2% of outbreaks occurred in winter months, and 78.9% of cases and 71.0% of outbreaks occurred in cool months. Both case and outbreak studies showed an earlier peak in season-year 2002-03, but not in season-year 2006-07, years when new genogroup II type 4 variants emerged. For outbreaks, norovirus season strength was positively associated with average rainfall in the wettest month, and inversely associated with crude birth rate in both bivariate and multivariate analyses. For cases, none of the covariates examined was associated with season strength. When case and outbreaks were combined, average rainfall in the wettest month was positively associated with season strength. Conclusions Norovirus is a wintertime phenomenon, at least in the temperate northern hemisphere where most data are available. Our results point to possible associations of season strength with rain in the wettest month and crude birth rate.