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Background While rotavirus causes severe diarrheal disease in children aged Methods In the Vaccine Impact on Diarrhea in Africa study (2015–2018), we analyzed stool from children aged 0–59 months with moderate-to-severe diarrhea (MSD) and without diarrhea (controls) in Kenya, Mali, and The Gambia using quantitative polymerase chain reaction. We derived the attributable fraction (AFe) based on the association between MSD and the pathogen, accounting for other pathogens, site, and age. A pathogen was attributable if the AFe was ≥0.5. The severity of attributable MSD was defined by a modified Vesikari score (mVS). Monthly cases were plotted against temperature and rainfall to assess seasonality. Results Among 4840 MSD cases, proportions attributed to rotavirus, adenovirus 40/41, astrovirus, and sapovirus were 12.6%, 2.7%, 2.9%, and 1.9%, respectively. Attributable rotavirus, adenovirus 40/41, and astrovirus MSD cases occurred at all sites, with mVS of 11, 10, and 7, respectively. MSD cases attributable to sapovirus occurred in Kenya, with mVS of 9. Astrovirus and adenovirus 40/41 peaked during the rainy season in The Gambia, while rotavirus peaked during the dry season in Mali and The Gambia. Conclusions In sub-Saharan Africa, rotavirus was the most common cause of MSD; adenovirus 40/41, astrovirus, and sapovirus contributed to a lesser extent among children aged

Background Previously studied risk factors for rotavirus vaccine failure have not fully explained reduced rotavirus vaccine effectiveness in low-income settings. We assessed the relationship between histo-blood group antigen (HBGA) phenotypes and clinical rotavirus vaccine failure among children Methods Saliva was collected and tested for HBGA phenotype in children who received rotavirus vaccine. The association between secretor and Lewis phenotypes and rotavirus vaccine failure was examined overall and by infecting rotavirus genotype using conditional logistic regression in 218 rotavirus-positive cases with moderate-to-severe diarrhea and 297 matched healthy controls. Results Both nonsecretor and Lewis-negative phenotypes (null phenotypes) were associated with decreased rotavirus vaccine failure across all sites (matched odds ratio, 0.30 [95% confidence interval: 0.16–0.56] or 0.39 [0.25–0.62], respectively]. A similar decrease in risk against rotavirus vaccine failure among null HBGA phenotypes was observed for cases with P[8] and P[4] infection and their matched controls. While we found no statistically significant association between null HBGA phenotypes and vaccine failure among P[6] infections, the matched odds ratio point estimate for Lewis-negative individuals was >4. Conclusions Our study demonstrated a significant relationship between null HBGA phenotypes and decreased rotavirus vaccine failure in a population with P[8] as the most common infecting genotype. Further studies are needed in populations with a large burden of P[6] rotavirus diarrhea to understand the role of host genetics in reduced rotavirus vaccine effectiveness.

Background Human adenoviruses (HAdV) are a common cause of respiratory and gastrointestinal infections but rarely cause end-organ disease in children. From October 2021 to February 2022, several previously healthy children admitted to a single center for significant hepatitis also tested positive for HAdV. The aim of this investigation is to describe characteristics of these children. Methods Children admitted to Children’s of Alabama (COA) from October 2021 to February 2022 with hepatitis who tested positive for HAdV by whole blood RT-PCR were included. Demographic, clinical, laboratory and treatment data were collected from medical records. Residual blood specimens were sent for adenovirus typing. Results Nine pediatric patients with hepatitis and HAdV infection were identified (78% female; median age 3.0 years; IQR 1.7-3.0). Before admission, six reported diarrhea and three had respiratory symptoms. At presentation, eight had scleral icterus, six had jaundice, seven had hepatomegaly, and one was encephalopathic. All patients had elevated transaminases (AST range: 447-4000 U/L, ALT range: 784-4695 U/L); initial total bilirubin varied [range 0.23-13.5 mg/dL]). All had confirmed HAdV by RT-PCR on whole blood (initial qPCR range: 991-70,680 copies/mL). Notably, two children who transferred to another facility were negative for HAdV by RT-PCR when plasma was tested (instead of whole blood). Six children underwent liver biopsy showing varying degrees of hepatitis with no adenovirus detected on immunohistochemistry stains. Five children had HAdV type 41 confirmed. Three children presented or progressed to acute liver failure, two children were treated with cidofovir, and two underwent successful liver transplantation. No known epidemiologic links between patients were identified and all were from geographically distinct parts of Alabama. Conclusion HAdV is a potentially underrecognized cause of hepatitis. Whole blood specimens may be preferred over plasma for HAdV RT-PCR testing. HAdV type 41 was identified in all patients with typing results available. Improved type-based surveillance may help determine HAdV patterns of circulation and inform future diagnostic testing. Disclosures William Britt, MD, First Energy Corporation: Stocks/Bonds|Hookipa Pharma: Advisor/Consultant|Kroger Care: Stocks/Bonds|MDU Resources Group: Stocks/Bonds|PG&E Corporation: Stocks/Bonds.

Background Viruses are a leading cause of pediatric diarrheal illness, resulting in over 200,000 childhood deaths annually worldwide. Rotavirus is the most common viral cause of moderate-to-severe diarrhea in low to middle-income countries, but adenovirus 40/41, norovirus, sapovirus, and astrovirus are increasingly recognized as important contributors to the global viral gastroenteritis burden. Comparisons of clinical severity between these five viruses among infants and young children are currently limited. Methods The objective of this analysis was to describe the clinical severity of rotavirus, adenovirus 40/41, norovirus, sapovirus, and astrovirus among children enrolled in the Global Enteric Multicenter Study (GEMS). Stool samples from children younger than 5 years of age with moderate-to-severe diarrhea at four sites in Africa and three in Asia were tested by enzyme immunoassays (rotavirus, adenovirus) and multiplex reverse transcriptase polymerase chain reaction (norovirus, sapovirus, astrovirus). A modified Vesikari score (MVS) to assess clinical severity was calculated based on symptoms and clinical characteristics. Results Among 3,305 viral diarrhea cases, rotavirus had the highest median MVS (9 [interquartile range [IQR: 7,11]) followed by adenovirus 40/41 (8 [IQR]: 6,10]); sapovirus and astrovirus had a similar MVS distribution to norovirus (7 [IQR: 6, 9]). The proportion of patients experiencing > 3 episodes of vomiting was high for those with rotavirus (66.3%) and adenovirus 40/41 (55.7%); astrovirus (40.8%), sapovirus (40.0%), and norovirus (35.9%) patients also experienced substantial episodes of vomiting. A high proportion of cases with adenovirus 40/41 (54.0%) and rotavirus (46.3%) experienced ≥ 7 episodes of diarrhea within 24 hours. While hospitalization or intravenous fluids were required most frequently for patients with rotavirus (42.1%), the proportion was also high in those with adenovirus 40/41 (30.6%). Conclusion These findings demonstrate the clinical severity of viral diarrheal pathogens besides rotavirus, in particular adenovirus 40/41, warranting the continued development of vaccines and therapeutics to prevent morbidity and mortality due to viral enteric pathogens. Disclosures All Authors: No reported disclosures.

Worldwide, rotavirus is the leading pathogen causing severe diarrhea in children and a major cause of under 5 years mortality. In 1998, the first rotavirus vaccine, RotaShield, was licensed in the United States but a rare adverse event, intussusception, led to its withdrawal. Seven years passed before the next generation of vaccines became available, Rotarix (GSK) and Rotateq (Merck), and 11 years later, 2 additional vaccines from India, Rotavac (Bharat) and Rotasiil (Serum Institute), were recommended by World Health Organization for all children. Today, these vaccines are used in more than 100 countries and have contributed to marked decreases in hospitalizations and deaths from diarrhea. However, these live oral vaccines are less effective in low-income countries with high under 5 years mortality for reasons that are not understood. Efforts to develop new vaccines that avoid the oral route are in progress and will likely be needed to ultimately control rotavirus disease.

Background Following the introduction of rotavirus immunization in 2006 in the United States, there were substantial declines in the domestic rotavirus disease burden. In this study, we assess the value for money achieved by the program in the decade following vaccine introduction. Methods We applied an age-specific, static, multicohort compartmental model to examine the impact and cost-effectiveness of the US rotavirus immunization program in children Results Declines in healthcare use associated with the rotavirus and acute gastroenteritis occurred from 2006 and continued to grow before stabilizing from 2010 through 2011. From 2011 to 2015, an estimated annual average of approximately 118 000 hospitalizations, 86 000 emergency department presentations, and 460 000 outpatient and physician office visits were prevented. From a societal perspective during this same period, the program was estimated to be cost saving in the base case model and in >90% of probabilistic sensitivity analysis simulations and from a healthcare system perspective >98% of simulations found an ICER below $100 000 per QALY gained. Conclusions After the program stabilized, we found the rotavirus immunization in the United States was likely to have been cost saving to society. The greater than expected healthcare and productivity savings reflect the success of the rotavirus immunization program in the United States.

Background Following the implementation of rotavirus vaccination in 2006, severe acute gastroenteritis (AGE) due to group A rotavirus (RVA) has substantially declined in US children. We report the RVA genotype prevalence as well as coinfection data from 7 US New Vaccine Surveillance Network sites during 3 consecutive RVA seasons, 2014–2016 Methods A total of 1041 stool samples that tested positive for RVA by Rotaclone enzyme immunoassay were submitted to the Centers for Disease Control and Prevention (CDC) for RVA genotyping and multipathogen testing. Results A total of 795 (76%) samples contained detectable RVA when tested at the CDC. Rotavirus disease was highest in children < 3 years of age. Four G types (G1, G2, G9, and G12) accounted for 94.6% of strains while 2 P types (P[4] and P[8]) accounted for 94.7% of the strains. Overall, G12P[8] was the most common genotype detected in all 3 seasons. Stepwise conditional logistic analysis found year and study site were significant predictors of genotype. Twenty-four percent of RVA-positive specimens contained other AGE pathogens. Conclusions G12P[8] predominated over 3 seasons, but strain predominance varied by year and study site. Ongoing surveillance provides continuous tracking and monitoring of US genotypes during the postvaccine era.

Background Rotavirus vaccine (Rotarix [RV1]) has reduced diarrhea-associated hospitalizations and deaths in Malawi. We examined the trends in circulating rotavirus genotypes in Malawi over a 22-year period to assess the impact of RV1 introduction on strain distribution. Methods Data on rotavirus-positive stool specimens among children aged Results A rich rotavirus strain diversity circulated throughout the 22-year period; Shannon (H′) and Simpson diversity (D′) indices did not differ between the pre- and postvaccine periods (H′ P < .149; D′ P < .287). Overall, G1 (n = 268/924 [28.7%]), G2 (n = 308/924 [33.0%]), G3 (n = 72/924 [7.7%]), and G12 (n = 109/924 [11.8%]) were the most prevalent genotypes identified following RV1 introduction. The prevalence of G1P[8] and G2P[4] genotypes declined each successive year following RV1 introduction, and were not detected after 2018. Genotype G3 reemerged and became the predominant genotype from 2017 onward. No evidence of genotype selection was observed 7 years post–RV1 introduction. Conclusions Rotavirus strain diversity and genotype variation in Malawi are likely driven by natural mechanisms rather than vaccine pressure.

Although the etiology of type 1 diabetes (T1D) is not well understood, it is believed to comprise both genetic and environmental factors. Viruses are the most well studied environmental trigger, and there is a small but growing body of research on the potential influence of rotavirus on T1D. Rotavirus infections were initially identified as possible triggers of T1D given similarities between viral peptide sequences and T1D autoantigen peptide sequences. Furthermore, rotavirus infection has been shown to modify T1D risk in T1D-prone mice. However, research into associations of rotavirus infections with T1D development in humans have yielded mixed findings and suggested interactions with age and diet. As global availability of rotavirus vaccines increases, recent studies have assessed whether rotavirus vaccination modifies T1D development, finding null or protective associations. Overall, evidence to date suggests a possible triggering relationship between some wild-type rotavirus infections and T1D, but the potential effect of rotavirus vaccination remains unclear.

Background Acute gastroenteritis (AGE) is a common reason for children to receive medical care. However, the viral etiology of AGE illness is not well described in the post–rotavirus vaccine era, particularly in the outpatient (OP) setting. Methods Between 2012 and 2015, children 15 days through 17 years old presenting to Vanderbilt Children’s Hospital, Nashville, Tennessee, with AGE were enrolled prospectively from the inpatient, emergency department, and OP settings, and stool specimens were collected. Healthy controls (HCs) were enrolled and frequency matched for period, age group, race, and ethnicity. Stool specimens were tested by means of reverse-transcription real-time quantitative polymerase chain reaction for norovirus, sapovirus, and astrovirus RNA and by Rotaclone enzyme immunoassay for rotavirus antigen, followed by polymerase chain reaction verification of antigen detection. Results A total of 3705 AGE case patients and 1563 HCs were enrolled, among whom 2885 case patients (78%) and 1110 HCs (71%) provided stool specimens that were tested. All 4 viruses were more frequently detected in AGE case patients than in HCs (norovirus, 22% vs 8%, respectively; rotavirus, 10% vs 1%; sapovirus, 10% vs 5%; and astrovirus, 5% vs 2%; P Conclusions Norovirus remains the most common virus detected in all settings, occurring nearly twice as frequently as the next most common pathogens, sapovirus and rotavirus. Combined, norovirus, sapovirus, rotavirus, and astrovirus were associated with almost half of all AGE visits and therefore are an important reason for children to receive medical care.

Background The etiology of intussusception, the leading cause of bowel obstruction in infants, is unknown in most cases. Adenovirus has been associated with intussusception and slightly increased risk of intussusception with rotavirus vaccination has been found. We conducted a case-control study among children Methods From 2015 to 2017, we enrolled 1-to-1 matched intussusception cases and hospital controls; 249 pairs were included. Stool specimens were tested for 37 infectious agents using TaqMan Array technology. We used conditional logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) of each pathogen associated with intussusception in a pooled analysis and quantitative subanalyses. Results Adenovirus (OR, 2.67; 95% CI, 1.75–4.36) and human herpes virus 6 (OR, 3.50; 95% CI, 1.15–10.63) were detected more frequently in cases than controls. Adenovirus C detection Conclusions In this comprehensive evaluation, adenovirus and HHV-6 were associated with intussusception. Future research is needed to better understand mechanisms leading to intussusception, particularly after rotavirus vaccination.

Background The introduction of rotavirus vaccine in the United States has reduced rotavirus disease burden, but outbreaks still occur. Complete-series rotavirus vaccination coverage is Methods Clinical history, signs and symptoms, and vaccination history were abstracted for the 26 patients residing in the facility during the time of the outbreak. A case-patient was defined as one who experienced 3 or more loose stools in a period of 24 hours with onset between April 17 and May 17, 2017. Stool samples from 14 resident patients were tested for rotavirus with reverse-transcription polymerase chain reaction. Results The median patient age at the facility was 2.9 years. Of the 26 resident patients, 22 (85%) met the case definition. One child died. Stool samples from 11 case-patients were positive according to reverse-transcription polymerase chain reaction for rotavirus. Fifteen case-patients were unvaccinated against rotavirus; 3 were partially vaccinated, and 2 were fully vaccinated. Vaccination status could not be completely determined in 2 cases. Conclusions An outbreak of rotavirus affected nearly all resident patients of a subacute care facility and caused 1 death. Because of recommendations against giving rotavirus vaccine in an intensive care setting, infants who require a prolonged intensive care stay might age out of rotavirus vaccine eligibility (the first dose must be given before 15 weeks of age according to Advisory Committee on Immunization Practices recommendations). The result is a vulnerable population of unvaccinated infants who might later congregate in another care setting.

Rotavirus vaccination has been associated with a short-term increased risk of intussusception. Our analysis of insurance claims for 1 858 827 US children with 544 recorded cases of intussusception found a nonsignificant decrease in intussusception (hazard ratio, 0.79 [95% confidence interval, 0.57–1.09]) in fully rotavirus-vaccinated children followed up to the age of 2 years.

Background Norovirus is an important cause of epidemic acute gastroenteritis (AGE), yet the burden of endemic disease in adults has not been well documented. We estimated the prevalence and incidence of outpatient and community-acquired inpatient norovirus AGE at 4 Veterans Affairs Medical Centers (VAMC) (Atlanta, Georgia; Bronx, New York; Houston, Texas; and Los Angeles, California) and examined trends over 4 surveillance years. Methods From November 2011 to September 2015, stool specimens collected within 7 days of AGE symptom onset for clinician-requested diagnostic testing were tested for norovirus, and positive samples were genotyped. Incidence was calculated by multiplying norovirus prevalence among tested specimens by AGE-coded outpatient encounters and inpatient discharges, and dividing by the number of unique patients served. Results Of 1603 stool specimens, 6% tested were positive for norovirus; GII.4 viruses (GII.4 New Orleans [17%] and GII.4 Sydney [47%]) were the most common genotypes. Overall prevalence and outpatient and inpatient community-acquired incidence followed a seasonal pattern, with higher median rates during November–April (9.2%, 376/100 000, and 45/100 000, respectively) compared to May–October (3.0%, 131/100 000, and 13/100 000, respectively). An alternate-year pattern was also detected, with highest peak prevalence and outpatient and inpatient community-acquired norovirus incidence rates in the first and third years of surveillance (14%–25%, 349–613/100 000, and 43–46/100 000, respectively). Conclusions This multiyear analysis of laboratory-confirmed AGE surveillance from 4 VAMCs demonstrates dynamic intra- and interannual variability in prevalence and incidence of outpatient and inpatient community-acquired norovirus in US Veterans, highlighting the burden of norovirus disease in this adult population.

Background Up-to-date estimates of the burden of norovirus, a leading cause of acute gastroenteritis (AGE) in the United States, are needed to assess the potential value of norovirus vaccines in development. We aimed to estimate the rates, annual counts, and healthcare charges of norovirus-associated ambulatory clinic encounters, emergency department (ED) visits, hospitalizations, and deaths in the United States. Methods We analyzed administrative data on AGE outcomes from 1 July 2001 through 30 June 2015. Data were sourced from IBM MarketScan Commercial and Medicare Supplemental Databases (ambulatory clinic and ED visits), the Healthcare Utilization Project National Inpatient Sample (hospitalizations), and the National Center for Health Statistics multiple-cause-of-mortality data (deaths). Outcome data (ambulatory clinic and ED visits, hospitalizations, or deaths) were summarized by month, age group, and setting. Healthcare charges were estimated based on insurance claims. Monthly counts of cause-unspecified gastroenteritis-associated outcomes were modeled as functions of cause-specified outcomes, and model residuals were analyzed to estimate norovirus-associated outcomes. Healthcare charges were estimated by applying average charges per cause-unspecified gastroenteritis encounter to the estimated number of norovirus encounters. Results We estimate 900 deaths (95% confidence interval [CI], 650–1100), 109 000 hospitalizations (95% CI, 80 000–145 000), 465 000 ED visits (95% CI, 348 000–610 000), and 2.3 million ambulatory clinic encounters (95% CI, 1.7–2.9 million) annually due to norovirus, with an associated $430–$740 million in healthcare charges. Conclusions Norovirus causes a substantial health burden in the United States each year, and an effective vaccine could have important public health impact.

Background Noroviruses are the leading cause of acute gastroenteritis outbreaks worldwide. Clarifying the viral, host, and environmental factors (epidemiologic triad) associated with severe outcomes can help target public health interventions. Methods Acute norovirus outbreaks reported to the National Outbreak Reporting System (NORS) in 2009-2016 were linked to laboratory-confirmed norovirus outbreaks reported to CaliciNet. Outbreaks were analyzed for differences in genotype (GII.4 vs non-GII.4), hospitalization, and mortality rates by timing, setting, transmission mode, demographics, clinical symptoms, and health outcomes. Results A total of 3747 norovirus outbreaks were matched from NORS and CaliciNet. Multivariable models showed that GII.4 outbreaks (n = 2353) were associated with healthcare settings (odds ratio [OR], 3.94 [95% confidence interval {CI}, 2.99-5.23]), winter months (November-April; 1.55 [95% CI, 1.24-1.93]), and older age of cases (≥50% aged ≥75 years; 1.37 [95% CI, 1.04-1.79]). Severe outcomes were more likely among GII.4 outbreaks (hospitalization rate ratio [RR], 1.54 [95% CI, 1.23-1.96]; mortality RR, 2.77 [95% CI, 1.04-5.78]). Outbreaks in healthcare settings were also associated with higher hospitalization (RR, 3.22 [95% CI, 2.34-4.44]) and mortality rates (RR, 5.65 [95% CI, 1.92-18.70]). Conclusions Severe outcomes more frequently occurred in norovirus outbreaks caused by GII.4 and those in healthcare settings. These results should help guide preventive interventions for targeted populations, including vaccine development.

Rotaviruses bind to enterocytes in a genotype-specific manner via histo-blood group antigens (HBGAs), which are also detectable in saliva. We evaluated antirotavirus immunoglobulin A seroconversion ('vaccine take") among 166 Ghanaian infants after 2-3 doses of G1P[8] rotavirus vaccine during a vaccine trial, by HBGA status from saliva collected at age 4.1 years. Only secretor status was associated with seroconversion: 41% seroconversion for secretors vs 13% for nonsecretors; relative risk, 3.2 (95% confidence interval, 1.2-8.1; P = .016). Neither Lewis antigen nor salivary antigen blood type was associated with seroconversion. Likelihood of "take" for any particular rotavirus vaccine may differ across populations based on HBGAs.

Rotavirus vaccines were introduced in the United States in 2006, and in the years since they have fundamentally altered the seasonality of rotavirus infection and have shifted disease outbreaks from annual epidemics to biennial epidemics. We investigated whether season and year of birth have emerged as risk factors for rotavirus or have affected vaccine performance. We constructed a retrospective birth cohort of US children under age 5 years using the 2001–2014 MarketScan database (Truven Health Analytics, Chicago, Illinois). We evaluated the associations of season of birth, even/odd year of birth, and interactions with vaccination. We fitted Cox proportional hazards models to estimate the hazard of rotavirus hospitalization according to calendar year of birth and season of birth assessed for interaction with vaccination. After the introduction of rotavirus vaccine, we observed monotonically decreasing rates of rotavirus hospitalization for each subsequent birth cohort but a biennial incidence pattern by calendar year. In the postvaccine period, children born in odd calendar years had a higher hazard of rotavirus hospitalization than those born in even years. Children born in winter had the highest hazard of hospitalization but also had greater vaccine effectiveness than children born in spring, summer, or fall. With the emergence of a strong biennial pattern of disease following vaccine introduction, the timing of a child’s birth has become a risk factor for rotavirus infection.

BACKGROUND. Rotavirus is a common cause of acute gastroenteritis and has also been associated with generalized tonic-clonic afebrile seizures. Since rotavirus vaccine introduction, hospitalizations for treatment of acute gastroenteritis have decreased. We assess whether there has been an associated decrease in seizure-associated hospitalizations. METHODS. We used discharge codes to abstract data on seizure hospitalizations among children

Background In the United States, an estimated 179 million acute gastroenteritis (AGE) episodes occur each year. Identifying factors contributing to AGE susceptibility and severity is important to address the high disease burden of AGE among adults. The primary objective of this analysis was to identify risk factors for all-cause AGE, norovirus-associated AGE and severe AGE among hospitalized adults. Methods We analyzed data from 1029 inpatient AGE cases and 624 non-AGE controls enrolled prospectively from December 1, 2016 – November 30, 2019 from 5 Veterans Affairs Medical Centers (Atlanta, Bronx, Houston, Los Angeles, Palo Alto). Standardized patient interviews and medical chart abstractions were conducted to collect demographics, exposure history, and underlying medical conditions. Stool samples from participants were tested for 22 pathogens using the BioFire Gastrointestinal Panel. Severity of AGE was determined using a 20-point modified Vesikari score (MVS) and severe AGE was defined as a MVS score of ≥ 11. Multivariate logistic regression was performed to assess associations between potential risk factors and outcomes. Results Of the total AGE cases, 551 (54%) had severe AGE; 44 (4%) were norovirus positive. Risk factors for all-cause AGE vs. non-AGE controls included household contact with a person with AGE in the past 7 days (aOR=2.9, 95% CI:1.3-6.7), severe renal disease (aOR=3.1, 95% CI:1.8-5.2), human immunodeficiency virus (HIV) (aOR=3.9, 95% CI:1.8-8.5), and immunosuppressive therapy (aOR=5.6, 95% CI:2.7-11.7). Factors associated with norovirus positivity by univariate analysis were contact with a person with AGE outside (OR=4.4, 95% CI:1.6-12.0) and within (OR=5.0, 95% CI:2.2-11.5) the household in the past 7 days. Detection of any viral pathogen (aOR=4.0, 95% CI:1.7-9.5) was a risk factor for severe AGE. Conclusion Our findings suggest that inpatients with HIV or severe renal disease, on immunosuppressive therapy, or in contact with a person with AGE within household are at higher risk for all-cause AGE. Patients with these medical conditions should be monitored for AGE related hospitalizations and may benefit from targeted AGE prevention messaging. Disclosures Vincent Marconi, MD, Bayer (Consultant, Scientific Research Study Investigator)Eli Lilly (Consultant, Scientific Research Study Investigator)Gilead Sciences (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator)

We compared acute gastroenteritis (AGE)-related hospitalization rates among children

Two rotavirus vaccines, Rotarix (RV1) and RotaTeq (RV5), were licensed for global use in 2006. A systematic review of 48 peer- reviewed articles with postlicensure data from 24 countries showed a median RV1 vaccine effectiveness (VE) of 84%, 75%, and 57% in countries with low, medium, and high child mortality, respectively, and RV5 VE of 90% and 45% in countries with low and high child mortality, respectively. A partial vaccine series provided considerable protection, but not to the same level as a full series. VE tended to decline in the second year of life, particularly in medium- and high-mortality settings, and tended to be greater against more severe rotavirus disease. Postlicensure data from countries across geographic regions and with different child mortality levels demonstrate that under routine use, both RV1 and RV5 are effective against rotavirus disease, supporting the World Health Organization recommendation that all countries introduce rotavirus vaccine into their national immunization program.

Histo-blood group antigens (HBGAs) expressed on enterocytes are proposed receptors for rotaviruses and can be measured in saliva. Among 181 Pakistani infants in a G1P[8] rotavirus vaccine trial who were seronegative at baseline, anti-rotavirus immunoglobulin A seroconversion rates after 3 vaccine doses differed significantly by salivary HBGA phenotype, with the lowest rate (19%) among infants who were nonsecretors (ie, who did not express the carbohydrate synthesized by FUT2), an intermediate rate (30%) among secretors with non-blood group O, and the highest rate (51%) among secretors with O blood group. Differences in HBGA expression may be responsible for some of the discrepancy in the level of protection detected for the current rotavirus vaccines in low-income versus high-income settings.

BACKGROUND: Diarrhea is the third leading cause of child death in Zambia. Up to one-third of diarrhea cases resulting in hospitalization and/or death are caused by vaccine-preventable rotavirus. In January 2012, Zambia initiated a pilot introduction of the Rotarix live, oral rotavirus vaccine in all public health facilities in Lusaka Province. METHODS: Between July 2012 and October 2013, we conducted a case-control study at 6 public sector sites to estimate rotavirus vaccine effectiveness (VE) in age-eligible children presenting with diarrhea. We computed the odds of having received at least 1 dose of Rotarix among children whose stool was positive for rotavirus antigen (cases) and children whose stool was negative (controls). We adjusted the resulting odds ratio (OR) for patient age, calendar month of presentation, and clinical site, and expressed VE as (1 - adjusted OR) × 100. RESULTS: A total of 91 rotavirus-positive cases and 298 rotavirus-negative controls who had under-5 card-confirmed vaccination status and were ≥6 months of age were included in the case-control analysis. Among rotavirus-positive children who were age-eligible to be vaccinated, 20% were hospitalized. Against rotavirus diarrhea of all severity, the adjusted 2-dose VE was 26% (95% confidence interval [CI], -30% to 58%) among children ≥6 months of age. VE against hospitalized children ≥6 months of age was 56% (95% CI, -34% to 86%). CONCLUSIONS: We observed a higher point estimate for VE against increased severity of illness compared with milder disease, but were not powered to detect a low level of VE against milder disease.

Togo introduced monovalent rotavirus vaccine starting 19 June 2014. We compared all-cause acute gastroenteritis (AGE) hospitalizations and rotavirus-associated hospitalizations during the prevaccine period (July 2008-June 2014) to 1 year after vaccine introduction (July 2014-June 2015). The proportion of children with AGE who tested positive for rotavirus declined from 53% (645/1223) in prevaccine years to 36% (68/187) in the postvaccine year (P< .01). The decline only occurred in children

Background. Rotavirus vaccines have been introduced in many low-income African countries including Malawi in 2012. Despite early evidence of vaccine impact, determining persistence of protection beyond infancy, the utility of the vaccine against specific rotavirus genotypes, and effectiveness in vulnerable subgroups is important. Methods. We compared rotavirus prevalence in diarrheal stool and hospitalization incidence before and following rotavirus vaccine introduction in Malawi. Using case-control analysis, we derived vaccine effectiveness (VE) in the second year of life and for human immunodeficiency virus (HIV)–exposed and stunted children. Results. Rotavirus prevalence declined concurrent with increasing vaccine coverage, and in 2015 was 24% compared with prevaccine mean baseline in 1997–2011 of 32%. Since vaccine introduction, population rotavirus hospitalization incidence declined in infants by 54.2% (95% confidence interval [CI], 32.8–68.8), but did not fall in older children. Comparing 241 rotavirus cases with 692 test-negative controls, VE was 70.6% (95% CI, 33.6%–87.0%) and 31.7% (95% CI, −140.6% to 80.6%) in the first and second year of life, respectively, whereas mean age of rotavirus cases increased from 9.3 to 11.8 months. Despite higher VE against G1P[8] than against other genotypes, no resurgence of nonvaccine genotypes has occurred. VE did not differ significantly by nutritional status (78.1% [95% CI, 5.6%–94.9%] in 257 well-nourished and 27.8% [95% CI, −99.5% to 73.9%] in 205 stunted children; P = .12), or by HIV exposure (60.5% [95% CI, 13.3%–82.0%] in 745 HIV-unexposed and 42.2% [95% CI, −106.9% to 83.8%] in 174 exposed children; P = .91). Conclusions. Rotavirus vaccination in Malawi has resulted in reductions in disease burden in infants

BACKGROUND The Republic of Armenia was 1 of the 2 earliest countries in the Newly Independent States to introduce rotavirus vaccine into its national immunization program to reduce the burden of rotavirus disease (documented to cause 38% of acute gastroenteritis hospitalizations [AGE] among children aged

BACKGROUND: The public health impact of rotavirus vaccination in African settings with a high human immunodeficiency virus (HIV) infection prevalence is yet to be established. We evaluated trends in all-cause diarrheal hospitalizations in Soweto Johannesburg before and after the introduction of rotavirus vaccine into South Africas national immunization program in August 2009. METHODS: Hospitalizations in children

BACKGROUND: Rotavirus vaccine efficacy is lower in low-income countries than in high-income countries. Rwanda was one of the first low-income countries in sub-Saharan Africa to introduce rotavirus vaccine into its national immunization program. We sought to evaluate rotavirus vaccine effectiveness (VE) in this setting. METHODS: VE was assessed using a case-control design. Cases and test-negative controls were children who presented with a diarrheal illness to 1 of 8 sentinel district hospitals and 10 associated health centers and had a stool specimen that tested positive (cases) or negative (controls) for rotavirus by enzyme immunoassay. Due to high vaccine coverage almost immediately after vaccine introduction the analysis was restricted to children 7-18 weeks of age at time of rotavirus vaccine introduction. VE was calculated as (1 - odds ratio) x 100 where the odds ratio was the adjusted odds ratio for the rotavirus vaccination rate among case-patients compared with controls. RESULTS: Forty-eight rotavirus-positive and 152 rotavirus-negative children were enrolled. Rotavirus-positive children were significantly less likely to have received rotavirus vaccine (33/44 [73%] unvaccinated) compared with rotavirus-negative children (81/136 [59%] unvaccinated) (P= .002). A full 3-dose series was 75% (95% confidence interval [CI] 31%-91%) effective against rotavirus gastroenteritis requiring hospitalization or a health center visit and was 65% (95% CI -80% to 93%) in children 6-11 months of age and 81% (95% CI 25%-95%) in children >/=12 months of age. CONCLUSIONS: Rotavirus vaccine is effective in preventing rotavirus disease in Rwandan children who began their rotavirus vaccine series from 7 to 18 weeks of age. Protection from vaccination was sustained after the first year of life. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

BACKGROUND Because >60 rotavirus strains have been reported worldwide, concerns exist about strain replacement after the introduction of rotavirus vaccines, particularly in developing countries with diverse strains and lower efficacy. METHODS We used the case-control design in 4 hospitals in Nicaragua to assess strain-specific vaccine effectiveness (VE) of a pentavalent rotavirus vaccine (RotaTeq) against rotavirus diarrhea. Cases were identified through prospective strain surveillance with reverse transcription-polymerase chain reaction for 3 years among children hospitalized for diarrhea, and controls were children negative for rotavirus. RESULTS We enrolled 1178 case-patients, 1082 (92%) with G and P typing, and 4927 controls. A different strain predominated each year with increasing age of the vaccine-eligible cohort during the study period: G2P[4] in 2008 (97%; mean age, 11.9 months), G1P[8] in 2009 (55%; mean age, 17.0 months), and G3P[8] in 2010 (78%; mean age, 17.3 months). Overall VE was 45% (95% confidence interval, 25%-59%). Regardless of the strain, VE estimates were 12%-79% lower among children aged ≥12 months relative to those 6-11 months of age. The lower VE for G3P[8] was related to the higher mean age of cases (17.3 months) compared with the G2P[4] strains (11.9 months), with a significant trend (R(2)= 0.819;P< .001) of declining effectiveness with increasing mean age of the cases. CONCLUSIONS Introduction of RotaTeq did not result in sustained emergence of any particular strain in Nicaragua. Variation in strain-specific effectiveness was due to an age-related decline in effectiveness rather than differences in protection against the observed strains.

Two rotavirus vaccines have been licensed in >100 countries worldwide since 2006. As of October 2105 these vaccines have been implemented in the national immunization programs of 79 countries including 36 low-income countries that are eligible for support for vaccine purchase from Gavi the Vaccine Alliance. Rotavirus vaccines were initially introduced in Australia and countries of the Americas and Europe after completion of successful clinical trials in these regions and the impact of routine vaccination in reducing the health burden of severe childhood gastroenteritis in these regions has been well documented. Because of concerns around the performance of orally administered rotavirus vaccines in developing countries vaccine implementation in these settings only began after additional clinical trials were completed and the World Health Organization issued a global recommendation for use of rotavirus vaccines in 2009. This supplementary issue of Clinical Infectious Diseases includes a collection of articles describing the impact and effectiveness of routine rotavirus vaccination in developing countries that were among the early adopters of rotavirus vaccine. The data highlight the benefits of vaccination and should provide valuable evidence to sustain vaccine use in these countries and encourage other countries to adopt routine rotavirus vaccination to reduce the health burden of severe childhood gastroenteritis. (c) The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions e-mail journals.permissions@oup.com.

BACKGROUND Botswana introduced monovalent G1P rotavirus vaccine (RV1) in July 2012, providing one of the first opportunities to assess the effectiveness of routine RV1 vaccination in a high-burden setting in Africa. We sought to determine the effectiveness of RV1 against rotavirus diarrhea hospitalization using a case-control evaluation. METHODS Vaccine age-eligible children

BACKGROUND. In Bolivia, monovalent rotavirus vaccine was introduced in 2008 and a previous evaluation reported a vaccine effectiveness (VE) of 77% with 2 doses of vaccine in children aged 5 years after its introduction in Bolivia. Although VE appears to wane in children aged ≥1 year, it still provides significant protection, and does not wane against severe disease.

A monovalent human rotavirus vaccine (RV1) was introduced in Botswana in July 2012. We assessed the impact of RV1 vaccination on childhood gastroenteritis-related hospitalizations and deaths in 2013 and 2014.We obtained data from registers of 4 hospitals in Botswana on hospitalizations and deaths from gastroenteritis, regardless of cause, among children5 years of age. Gastroenteritis hospitalizations and deaths during the prevaccine period (January 2009-December 2012) were compared to the postvaccine period (January 2013-December 2014). Vaccine coverage was estimated from data collected through a concurrent vaccine effectiveness study at the same hospitals.By December 2014, coverage with ≥1 dose of RV1 was an estimated 90% among infants1 year of age and 76% among children 12-23 months of age. In the prevaccine period, the annual median number of gastroenteritis-related hospitalizations in children5 years of age was 1212, and of gastroenteritis-related deaths in children2 years of age was 77. In the postvaccine period, gastroenteritis-related hospitalizations decreased by 23% (95% confidence interval [CI], 16%-29%) to 937, and gastroenteritis-related deaths decreased by 22% (95% CI, -9% to 44%) to 60. Declines were most prominent during the rotavirus season (May-October) and among infants1 year of age, with reductions of 43% (95% CI, 34%-51%) in gastroenteritis hospitalizations and 48% (95% CI, 11%-69%) in gastroenteritis deaths.Following introduction of RV1 into the national immunization program, significant declines in hospitalizations and deaths from gastroenteritis were observed among children in Botswana, suggestive of the beneficial public health impact of rotavirus vaccination.

We examined the uptake of rotavirus vaccine and compared trends in acute gastroenteritis (AGE)-associated hospitalizations and outpatient visits among American Indian and Alaska Native (AI/AN) children aged

To describe the epidemiology of intussusception before introduction of the rotavirus vaccine, we reviewed the records of 280 patients younger than 5 years who were hospitalized in Kenya between 2002 and 2013. The patients who died (18 [6.4%]) had sought care later after symptom onset than the patients who survived (median, 5 vs 3 days, respectively; P = .04). Seeking prompt care may improve therapeutic outcomes.

Using data from rotavirus vaccine effectiveness (VE) studies, we assessed whether rotavirus season modifies rotavirus VE in infants. In the first year of life, adjusted VE was 72% for children born during rotavirus season and 84% for children born in other months (P = .01). Seasonal factors may interfere with vaccine performance.

We used Truven Health Marketscan claims database (2008-2011) to compare gastroenteritis rates during January-June among households whose child had received rotavirus vaccine with those whose child did not receive vaccine. Statistically significantly lower rates of hospitalization with a rotavirus gastroenteritis or unspecified-gastroenteritis discharge code occurred in vaccinated households among persons 20-29 years and females 20-29 years (2008/2009), and males 30-39 years (2009/2010). Lower emergency department gastroenteritis rates occurred in vaccinated households among females 20-29 years (2009/2010) and individuals 5-19 years (2010/2011). These data suggest rotavirus vaccination of infants provides indirect protection against moderate-to-severe rotavirus disease in young parents and older siblings.

Background Current oral rotavirus vaccines perform suboptimally in resource-poor settings. We investigated the effect of an additional dose and later schedule on the immunogenicity of monovalent rotavirus vaccine (RV1) in a developing country. Methods Infants received RV1 at 6 and 10, 10 and 14, or 6, 10, and 14 weeks of age. The primary objective was to compare antirotavirus immunoglobulin A (IgA) seroconversion at 18 weeks in the 6/10/14 arm to the cumulative seroconversion (highest result at 14 or 18 weeks) in the 6/10 arm. Results Overall, 480 (76.2%) of 630 randomized infants completed the trial per protocol. Seroconversion in the 6/10/14 arm was 36.7% (95% CI, 29.8, 44.2) compared to 36.1% (CI, 29.0, 43.9) in the 6/10 arm, (P=1.0); the result from the 10/14 arm was 38.5% (CI, 31.2, 46.3). Seroconversion in the 6/10 arm at 14 weeks (post hoc) was lower at 29.7% (CI, 23.1, 37.3). Conclusions In Pakistani infants, the immunogenicity of RV1 did not increase significantly with 3 doses at 6, 10, and 14 weeks compared to 2 doses at 6 and 10 weeks. Additional strategies should be evaluated for improving rotavirus vaccine immunogenicity in high burden countries.

Background. We assessed vaccine effectiveness (VE) for RotaTeq (RV5; 3 doses) and Rotarix (RV1; 2 doses) at reducing rotavirus acute gastroenteritis (AGE) inpatient and emergency department (ED) visits in US children. Methods. We enrolled children

Background. Gastroenteritis remains an important cause of morbidity in the United States. The burden ofnorovirus gastroenteritis in ambulatory US patients is not well understood.Methods. Cause-specified and cause-unspecified gastroenteritis emergency department (ED) and outpatientvisits during July 2001–June 2009 were extracted from MarketScan insurance claim databases. By using cause-specified encounters, time-series regression models were fitted to predict the number of unspecified gastroenteritisvisitsdue tospecificpathogensother thannorovirus.Model residuals wereused toestimatenorovirusvisits.Market-Scan rates were extrapolated to the US population to estimate national ambulatory visits.Results. During 2001–2009, the estimated annual mean rates of norovirus-associated ED and outpatient visitswere 14 and 57 cases per 10000 persons, respectively, across all ages. Rates for ages 0–4, 5–17, 18–64, and ≥65years were 38, 10, 12, and 15 ED visits per 10000 persons, respectively, and 233, 85, 35, and 54 outpatientvisits per 10000 persons, respectively. Norovirus was estimated to cause 13% of all gastroenteritis-associated am-bulatory visits, with ∼50% of such visits occurring during November–February. Nationally, norovirus contributedto approximately 400000 ED visits and 1.7 million office visits annually, resulting in $284 million in healthcarecharges.Conclusions. Norovirus is a substantial cause of gastroenteritis in the ambulatory setting.Keywords. norovirus; gastroenteritis; ambulatory care; United States.Noroviruses are the leading cause of acute gastroenter-itis (ie, diarrhea or vomiting) worldwide. The adventof molecular assays have shown that noroviruses arethe leading cause of foodborne disease [1], are respon-sible for approximately half of all gastroenteritis out-breaks [2], and are the leading cause of sporadicgastroenteritis across all ages [3,4].In the United States, noroviruses are estimated to cause21 million episodes of gastroenteritis every year [1 ]andare increasingly recognized as a cause of severe disease,leading to an estimated 71000 hospitalizations [ 5] and800 deaths annually [6].However, the absence of sensi-tive diagnostic tests in clinical settings has precluded acomprehensive description of the US norovirus diseaseburden. Notably, the contribution of norovirus to gas-troenteritis in the ambulatory setting is sparsely char-acterized. The few studies estimating the incidence ofnorovirus-associated outpatient visits across all ages inEurope and the United States have yielded rates of 40–640 cases per 10000 persons [3,7–9].An improved understanding of the role of norovirusamong healthcare encounters for gastroenteritis hasimportant implications for the practice and develop-ment of preventive strategies (eg, infection controlmeasures and vaccines) and could help guide clinicalmanagement (eg, antibiotics vs rehydration therapy).Our objective was to assess the contribution of norovi-rus to gastroenteritis-associated ambulatory visits inthe United States, including both ED and outpatientvisits, across all ages and to provide estimates of thenational burden.

Google Internet query share (IQS) data for gastroenteritis-related search terms correlated strongly with contemporaneous national (R(2) = 0.70) and regional (R(2) = 0.74) norovirus surveillance data in the United States. IQS data may facilitate rapid identification of norovirus season onset, elevated peak activity, and potential emergence of novel strains.

Background. Rotavirus vaccine was recommended for US infants in 2006. We estimated baseline prevaccine burden and monitored postvaccine trends in gastroenteritis-coded and rotavirus-coded hospitalizations among US children. Methods. We analyzed data from the State Inpatient Databases (SID) for 29–44 US states over a 10-year period (2000–2009) to calculate gastroenteritis and rotavirus-coded hospitalization rates by age group, sex, and region, among children

Background. Globally, gastroenteritis is recognized as an important contributor to mortality among children, but population-based data on gastroenteritis deaths among adults and the contributions of specific pathogens are limited. We aimed to describe trends in gastroenteritis deaths across all ages in the United States and specifically estimate the contributions of Clostridium difficile and norovirus. Methods. Gastroenteritis-associated deaths in the United States during 1999–2007 were identified from the National Center for Health Statistics multiple-cause-of-death mortality data. All deaths in which the underlying cause or any of the contributing causes listed gastroenteritis were included. Time-series regression models were used to identify cause-unspecified gastroenteritis deaths that were probably due to specific causes; seasonality of model residuals was analyzed to estimate norovirus-associated deaths. Results. Gastroenteritis mortality averaged 39/1 000 000 person-years (11 255 deaths per year) during the study period, increasing from 25/1 000 000 person-years in 1999–2000 to 57/1 000 000 person-years in 2006–2007 (P< .001). Adults aged ≥65 years accounted for 83% of gastroenteritis deaths (258/1 000 000 person-years). C. difficile mortality increased 5-fold from 10/1 000 000 person-years in 1999–2000 to 48/1 000 000 person-years in 2006–2007 (P< .001). Norovirus contributed to an estimated 797 deaths annually (3/1 000 000 person-years), with surges by up to 50% during epidemic seasons associated with emergent viral strains. Conclusions. Gastroenteritis-associated mortality has more than doubled during the past decade, primarily affecting the elderly. C. difficile is the main contributor to gastroenteritis-associated deaths, largely accounting for the increasing trend, and norovirus is probably the second leading infectious cause. These findings can help guide appropriate clinical management strategies and vaccine development.

Background. Noroviruses (NoVs) are the most common cause of epidemic gastroenteritis; however, the relative impacts of individual factors underlying severe illness are poorly understood. This report reviews published NoV outbreak reports to quantify hospitalization and mortality rates and assess their relationship with outbreak setting, transmission route, and strain. Methods. Using a string of terms related to “norovirus” and “outbreak,” we 2435 nonduplicate articles identified in PubMed, EMBASE, and Web of Knowledge published between January 1993 and June 2011. Inclusion criteria included outbreaks with a minimum of 2 ill persons with a common exposure and at least 1 reversetranscription polymerase chain reaction–confirmed case of NoV disease. Univariate analyses were performed, and multivariable models were fitted to estimate the independent effect of each factor. Results. We analyzed 843 NoV outbreaks reported in 233 published articles from 45 countries. Based upon 71 724 illnesses, 501 hospitalizations, and 45 deaths, overall hospitalization and mortality rates were 0.54% and 0.06%, respectively. In multivariate analysis, genogroup 2 genotype 4 (GII.4) NoV strains were associated with higher hospitalization (incidence rate ratio [IRR], 9.4; 95% confidence interval [CI], 6.1–14.4; P< .001) and mortality rates (IRR, 3.1; 95% CI, 1.3–7.6; P= .01). Deaths were much more likely to occur in outbreaks occurring in healthcare facilities (IRR, 60; 95% CI, 6–109; P= .01). Conclusions. Our review suggests that hospitalizations and deaths were more likely in outbreaks associated with GII.4 viruses, independent of other factors, and underscores the importance of developing vaccines against GII.4 viruses to prevent severe disease outcomes.

Background. With the recent postlicensure identification of an increased risk of intussusception with rotavirus vaccine, the 14 Latin American countries currently using rotavirus vaccine must now weigh the health benefits versus risks to assess whether to continue vaccination. To inform policy considerations, we estimated excess intussusception cases and mortality potentially caused by rotavirus vaccine for each of the 14 countries and compared these estimates to hospitalizations and deaths expected to be averted through vaccination. Methods. We used regional rotavirus disease burden and rotavirus vaccine efficacy data, global natural intussusception and regional rotavirus vaccine-related risk estimates, and country-specific diphtheria, tetanus, and pertussus vaccination coverage rates to estimate rotavirus vaccine coverage rates. We performed a probabilistic sensitivity analysis to account for uncertainty in these parameters. Results. For an aggregate hypothetical birth cohort of 9.5 million infants in these 14 countries, rotavirus vaccine would annually prevent 144 746 (90% confidence interval [CI], 128 821-156 707) hospitalizations and 4124 deaths (90% CI, 3740-4239) due to rotavirus in their first 5 years of life but could cause an additional 172 hospitalizations (90% CI, 126-293) and 10 deaths (90% CI, 6-17) due to intussusception, yielding benefit-risk ratios for hospitalization and death of 841:1 (90% CI, 479:1 to 1142:1) and 395:1 (90% CI, 207:1 to 526:1), respectively. In an uncertainty analysis using 10 000 simulations of our probabilistic parameters, in comparing rotavirus disease averted to intussusception events caused, the hospitalization ratio was never below 100:1, and our death ratio fell below 100:1 only once. Conclusions. The health benefits of vaccination far outweigh the short-term risks and support continued rotavirus vaccination in Latin America.

Google-based Internet query share (IQS) for rotavirus search terms correlated well with US rotavirus laboratory detections from 2004 to 2010 (r = 0.88; P < .001), capturing the reduction observed during postvaccine years (2008-2010). IQS analysis could become an inexpensive and reliable supplement for monitoring the impact of rotavirus vaccination in the United States.

Following the introduction of rotavirus vaccination in the United States, rotavirus and cause-unspecified gastroenteritis discharges significantly decreased in 2008 in the 0-4, 5-14, and 15-24-year age groups, with significant reductions observed in March, the historic peak rotavirus month, in all age groups. We estimate that 15% of the total 66 000 averted hospitalizations and 20% of the $204 million in averted direct medical costs attributable to the vaccination program were among unvaccinated 5-24 year-olds. This study demonstrates a previously unrecognized burden of severe rotavirus in the population >5 years and the primacy of very young children in the transmission of rotavirus.

Background Diarrhea remains an important cause of morbidity, but until the mid 1990s, hospital admissions for diarrhea in the US adult population were declining. We aimed to describe recent trends in gastroenteritis hospitalizations and to determine the contribution of norovirus. Methods We analyzed all gastroenteritis-associated hospital discharges during 1996-2007 from a nationally representative data set of hospital inpatient stays. Annual rates of discharges by age were calculated. Time-series regression models were fitted using cause-specified discharges as explanatory variables; model residuals were analyzed to estimate norovirus- and rotavirus-associated discharges. We then calculated the annual hospital charges for norovirus-associated discharges. Results Sixty-nine percent of all gastroenteritis discharges were cause-unspecified and rates increased by ≥ 50% in all adult and elderly age groups (≥ 18 years of age) from 1996 through 2007. We estimate an annual mean of 71,000 norovirus-associated hospitalizations, costing $493 million per year, with surges to nearly 110,000 hospitalizations per year in epidemic seasons. We also estimate 24,000 rotavirus hospitalizations annually among individuals aged ≥ 5 years. Conclusions Gastroenteritis hospitalizations are increasing, and we estimate that norovirus is the cause of 10% of cause-unspecified and 7% of all-cause gastroenteritis discharges. Norovirus should be routinely considered as a cause of gastroenteritis hospitalization.