Norovirus Outbreaks in Long-term Care Facilities in the United States, 2009-2018: A Decade of Surveillance.

BACKGROUND: In the United States, norovirus is the leading cause of healthcare-associated gastroenteritis outbreaks. To inform prevention efforts, we describe the epidemiology of norovirus outbreaks in long-term care facilities (LTCFs). METHODS: The Centers for Disease Control and Prevention (CDC) collect epidemiologic and laboratory data on norovirus outbreaks from US health departments through the National Outbreak Reporting System (NORS) and CaliciNet. Reports from both systems were merged, and norovirus outbreaks in nursing homes, assisted living, and other LTCFs occurring in 2009-2018 were analyzed. Data from the Centers for Medicare and Medicaid Services and the National Center for Health Statistics were used to estimate state LTCF counts. RESULTS: During 2009-2018, 50 states, Washington D.C., and Puerto Rico reported 13 092 norovirus outbreaks and 416 284 outbreak-associated cases in LTCFs. Participation in NORS and CaliciNet increased from 2009 to 2014 and median reporting of LTCF norovirus outbreaks stabilized at 4.1 outbreaks per 100 LTCFs (interquartile range [IQR]: 1.0-7.1) annually since 2014. Most outbreaks were spread via person-to-person transmission (90.4%), and 75% occurred during December-March. Genogroup was reported for 7292 outbreaks with 862 (11.8%) positive for GI and 6370 (87.3%) for GII. Among 4425 GII outbreaks with typing data, 3618 (81.8%) were GII.4. LTCF residents had higher attack rates than staff (median 29.0% vs 10.9%; P < .001). For every 1000 cases, there were 21.6 hospitalizations and 2.3 deaths. CONCLUSIONS: LTCFs have a high burden of norovirus outbreaks. Most LTCF norovirus outbreaks occurred during winter months and were spread person-to-person. Outbreak surveillance can inform development of interventions for this vulnerable population, such as vaccines targeting GII.4 norovirus strains.

The economic burden of rotavirus hospitalization among children < 5 years of age in selected hospitals in Bangladesh.

BACKGROUND: Rotavirus is a common cause of severe acute gastroenteritis among young children. Estimation of the economic burden would provide informed decision about investment on prevention strategies (e.g., vaccine and/or behavior change), which has been a potential policy discussion in Bangladesh for several years. METHODS: We estimated the societal costs of children <5 years for hospitalization from rotavirus gastroenteritis (RVGE) and incidences of catastrophic health expenditure. A total of 360 children with stool specimens positive for rotavirus were included in this study from 6 tertiary hospitals (3 public and 3 private). We interviewed the caregiver of the patient and hospital staff to collect cost from patient and health facility perspectives. We estimated the economic cost considering 2015 as the reference year. RESULTS: The total societal per-patient costs to treat RVGE in the public hospital were 126 USD (95% CI: 116-136) and total household costs were 161 USD (95% CI: 145-177) in private facilities. Direct costs constituted 38.1% of total household costs. The out-of-pocket payments for RVGE hospitalization was 23% of monthly income and 76% of households faced catastrophic healthcare expenditures due to this expense. The estimated total annual household treatment cost for the country was 10 million USD. CONCLUSIONS: A substantial economic burden of RVGE in Bangladesh was observed in this study. Any prevention of RVGE through cost-effective vaccination or/and behavioural change would contribute to substantial economic benefits to Bangladesh.

Rotavirus Vaccination Likely to Be Cost Saving to Society in the United States.

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 <5 years of age using healthcare utilization data from 2001 to 2015 inclusive. We calculated the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained from both a healthcare system and societal perspective. 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.

Evaluating the potential economic and health impact of rotavirus vaccination in 63 middle-income countries not eligible for Gavi funding: a modelling study.

BACKGROUND: Middle-income countries (MICs) that are not eligible for funding from Gavi, the Vaccine Alliance, have been slow to adopt rotavirus vaccines. Few studies have evaluated the cost-effectiveness and benefit-risk of rotavirus vaccination in these settings. We aimed to assess the potential economic and health impact of rotavirus vaccination in 63 MICs not eligible for funding from Gavi. METHODS: In this modelling study, we estimated the cost-effectiveness and benefit-risk of rotavirus vaccination in 63 MICs not eligible to Gavi funding. We used an Excel-based proportionate outcomes model with a finely disaggregated age structure to estimate the number of rotavirus gastroenteritis cases, clinic visits, hospitalisations, and deaths averted by vaccination in children younger than 5 years over a 10-year period. We calculated cost-effectiveness ratios (costs per disability-adjusted life-years averted compared with no vaccination) and benefit-risk ratios (number of hospitalisations due to rotavirus gastroenteritis averted per excess hospitalisations due to intussusception). We evaluated three alternative vaccines available globally (Rotarix, Rotavac, and Rotasiil) and used information from vaccine manufacturers regarding anticipated vaccine prices. We ran deterministic and probabilistic uncertainty analyses. FINDINGS: Over the period 2020-29, rotavirus vaccines could avert 77 million (95% uncertainty interval [UI] 51-103) cases of rotavirus gastroenteritis and 21 million (12-36) clinic visits, 3 million (1·4-5·6) hospitalisations, and 37 900 (25 900-55 900) deaths due to rotavirus gastroenteritis in 63 MICs not eligible for Gavi support. From a government perspective, rotavirus vaccination would be cost-effective in 48 (77%) of 62 MICs considered. The benefit-risk ratio for hospitalisations prevented versus those potentially caused by vaccination exceeded 250:1 in all countries. INTERPRETATION: In most MICs not eligible for Gavi funding, rotavirus vaccination has high probability to be cost-effective with a favourable benefit-risk profile. Policy makers should consider this new evidence when making or revisiting decisions on the use of rotavirus vaccines in their respective countries. FUNDING: Bill & Melinda Gates Foundation.

Burden of Norovirus in the United States, as Estimated Based on Administrative Data: Updates for Medically Attended Illness and Mortality, 2001-2015.

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.

Diarrhea hospitalization costs among children <5 years old in Madagascar.

BACKGROUND: Following a recommendation by the World Health Organization, Madagascar introduced rotavirus vaccine in 2014. Though national rotavirus vaccine coverage has remained <80%, rotavirus hospitalizations declined by 78%. Gavi, the Vaccine Alliance, has provided financial support for rotavirus vaccine, however the Malagasy government has increasing responsibility for the financial cost. METHODS: In this evaluation, we describe the direct medical, direct non-medical, and indirect cost of illness due to diarrhea among children <5 years old at a public pediatric referral hospital. A 3-part structured questionnaire was administered during and following the hospitalization and the child's hospital record was reviewed. RESULTS: In total, 96 children were included in this analysis. The median total cost of the illness was $156.00 (IQR: 104.00, 210.86) and the median direct medical cost was $107.22. Service delivery costs represented a median of 44% of the inpatient costs; medications and diagnostic tests represented a median of 28% and 20% of the total costs of the hospitalization, respectively. The median percentage of the total illness costs paid by the household was 67%. Among households with income of <$61/month, the median costs of the illness paid by the household were $78.55, representing a median of 168% of the household's monthly expenses. Among households earning >$303/month, the median costs paid by the household were $147.30, representing a median of 53% of the household's monthly expenses. Among all household income levels, caregivers commonly paid these bills from savings, borrowed money, and donations. CONCLUSIONS: Our findings will be useful in assessing the cost-effectiveness of rotavirus vaccine by decisionmakers. These results may also help hospital administrators and healthcare providers better understand the financial constraints of families.

Cost estimates of diarrhea hospitalizations among children <5 years old in Zimbabwe.

INTRODUCTION: Diarrhoea is a leading killer of children <5 years old, accounting for 480,000 deaths in 2017. Zimbabwe introduced Rotarix into its vaccination program in 2014. In this evaluation, we estimate direct medical, direct non-medical, and indirect costs attributable to a diarrhea hospitalization in Zimbabwe after rotavirus vaccine introduction. METHODS: Children <5 years old admitted to Harare Central Hospital from June 2018 to April 2019 with acute watery diarrhea were eligible for this evaluation. A 3-part structured questionnaire was used to collect data by interview from the child's family and by review of the medical record. A stool specimen was also collected and tested for rotavirus. Direct medical costs were the sum of medications, consumables, diagnostic tests, and service delivery costs. Direct non-medical costs were the sum of transportation, meals and lodging for caregivers. Indirect costs are the lost income for household members. RESULTS: A total of 202 children were enrolled with a median age of 12 months (IQR: 7-21) and 48 (24%) had malnutrition. Children were sick for a median of 2 days and most had received outpatient medical care prior to admission. The median monthly household income was higher for well-nourished children compared to malnourished children (p < 0.001). The median total cost of a diarrhea illness resulting in hospitalization was $293.74 (IQR: 188.42, 427.89). Direct medical costs, with a median of $251.74 (IQR: 155.42, 390.96), comprised the majority of the total cost. Among children who tested positive for rotavirus, the median total illness cost was $243.78 (IQR: 160.92, 323.84). The median direct medical costs were higher for malnourished than well-nourished children (p < 0.001). CONCLUSION: Direct medical costs are the primary determinant of diarrhea illness costs in Zimbabwe. The descriptive findings from this evaluation are an important first step in calculating the cost effectiveness of rotavirus vaccine.

Cost of pediatric hospitalizations in Burkina Faso: A cross-sectional study of children aged <5 years enrolled through an acute gastroenteritis surveillance program.

INTRODUCTION: Diarrheal illness is a leading cause of hospitalizations among children <5 years. We estimated the costs of inpatient care for rotavirus and all-cause acute gastroenteritis (AGE) in two Burkina Faso hospitals. METHODS: We conducted a cross-sectional study among children <5 years from December 2017 to June 2018 in one urban and one rural pediatric hospital. Costs were ascertained through caregiver interview and chart abstraction. Direct medical, non-medical, and indirect costs per child incurred are reported. Costs were stratified by rotavirus results. RESULTS: 211 children <5 years were included. AGE hospitalizations cost 161USD (IQR 117-239); 180USD (IQR 121-242) at the urban and 154USD (IQR 116-235) at the rural site. Direct medical costs were higher in the urban compared to the rural site (140USD (IQR 102-182) vs. 90USD (IQR 71-108), respectively). Direct non-medical costs were higher at the rural versus urban site (15USD (IQR 10, 15) vs. 11USD (IQR 5-20), respectively). Indirect costs were higher at the rural versus urban site (35USD (IQR 8-91) vs. 0USD (IQR 0-26), respectively). Rotavirus hospitalizations incurred less direct medical costs as compared to non-rotavirus hospitalizations at the rural site (79USD (IQR 64-103) vs. 95USD (IQR 80-118)). No other differences by rotavirus testing status were observed. The total median cost of a hospitalization incurred by households was 24USD (IQR 12-49) compared to 75USD for government (IQR 59-97). Direct medical costs for households were higher in the urban site (median 49USD (IQR 31-81) versus rural (median 14USD (IQR 8-25)). Households in the lowest wealth quintiles at the urban site expended 149% of their monthly income on the child's hospitalization, compared to 96% at the rural site. CONCLUSIONS: AGE hospitalization costs differed between the urban and rural hospitals and were most burdensome to the lowest income households. Rotavirus positivity was not associated with greater household costs.

An overview of rotavirus vaccination programs in developing countries.

INTRODUCTION: Rotavirus is the leading cause of acute diarrhea among children <5 years worldwide. As all children are equally susceptible to infection and disease development, rotavirus vaccination programs are the best upstream approach to preventing rotavirus disease, and the subsequent risk of hospitalization or death. AREAS COVERED: We provide an overview of global rotavirus vaccine policy, summarize the burden of rotavirus disease in developing countries, review data on the effectiveness, impact, safety, and the cost-effectiveness of rotavirus vaccination programs, and identify areas for further research and improvement. EXPERT OPINION: Rotavirus vaccines continue to be an effective, safe, and cost-effective solution to preventing rotavirus disease. As two new rotavirus vaccines enter the market (Rotasiil and Rotavac) and Asian countries continue to introduce rotavirus vaccines into their national immunization programs, documenting vaccine safety, effectiveness, and impact in these settings will be paramount.

Evidence for Household Transmission of Rotavirus in the United States, 2011-2016.

BACKGROUND: Rotavirus is a leading cause of acute gastroenteritis (AGE) in children and is highly transmissible. In this study, we assessed the presence of AGE in household contacts (HHCs) of pediatric patients with laboratory-confirmed rotavirus. METHODS: Between December 2011 and June 2016, children aged 14 days to 11 years with AGE were enrolled at 1 of 7 hospitals or emergency departments as part of the New Vaccine Surveillance Network. Parental interviews, medical and vaccination records, and stool specimens were collected at enrollment. Stool was tested for rotavirus by an enzyme immunoassay and confirmed by real-time or conventional reverse transcription-polymerase chain reaction assay or repeated enzyme immunoassay. Follow-up telephone interviews were conducted to assess AGE in HHCs the week after the enrolled child's illness. A mixed-effects multivariate model was used to calculate odds ratios. RESULTS: Overall, 829 rotavirus-positive subjects and 8858 rotavirus-negative subjects were enrolled. Households of rotavirus-positive subjects were more likely to report AGE illness in ≥1 HHC than were rotavirus-negative households (35% vs 20%, respectively; P < .0001). A total of 466 (16%) HHCs of rotavirus-positive subjects reported AGE illness. Of the 466 ill HHCs, 107 (23%) sought healthcare; 6 (6%) of these encounters resulted in hospitalization. HHCs who were <5 years old (odds ratio, 2.2 [P = .004]) were more likely to report AGE illness than those in other age groups. In addition, 144 households reported out-of-pocket expenses (median, $20; range, $2-$640) necessary to care for an ill HHC. CONCLUSIONS: Rotavirus-associated AGE in children can lead to significant disease burden in HHCs, especially in children aged <5 years. Prevention of pediatric rotavirus illness, notably through vaccination, can prevent additional illnesses in HHCs.

Validation of Acute Gastroenteritis-related International Classification of Diseases, Clinical Modification Codes in Pediatric and Adult US Populations.

International Classification of Diseases diagnostic codes are used to estimate acute gastroenteritis (AGE) disease burden. We validated AGE-related codes in pediatric and adult populations using 2 multiregional active surveillance platforms. The sensitivity of AGE codes was similar (54% and 58%) in both populations and increased with addition of vomiting-specific codes.

Re-evaluating the potential impact and cost-effectiveness of rotavirus vaccination in 73 Gavi countries: a modelling study.

BACKGROUND: Previous studies have found rotavirus vaccination to be highly cost-effective in low-income countries. However, updated evidence is now available for several inputs (ie, rotavirus disease mortality rates, rotavirus age distributions, vaccine timeliness, and vaccine efficacy by duration of follow-up), new rotavirus vaccines have entered the market, vaccine prices have decreased, and cost-effectiveness thresholds have been re-examined. We aimed to provide updated cost-effectiveness estimates to inform national decisions about the new introduction and current use of rotavirus vaccines in Gavi countries. METHODS: We calculated the potential costs and effects of rotavirus vaccination for ten successive birth cohorts in 73 countries previously and currently eligible for Gavi support, compared with no vaccination. We used a deterministic cohort model to calculate numbers of rotavirus gastroenteritis cases, outpatient visits, hospitalisations, and deaths between birth and 5 years, with and without rotavirus vaccination. We calculated treatment costs from the government and societal perspectives. The primary outcome measure was the incremental cost-effectiveness ratio (discounted US$ per disability-adjusted life-year averted). Country-specific model input parameters were based on the scientific literature, published meta-analyses, and international databases. We ran deterministic and probabilistic uncertainty analyses. FINDINGS: Over the period 2018-27, rotavirus vaccination has the potential to prevent nearly 600 000 deaths in Gavi countries. Averted outpatient visits and hospitalisations could lead to treatment savings of approximately $484·1 million from the government perspective and $878·0 million from the societal perspective. The discounted dollars per disability-adjusted life-year averted has a very high probability (>90%) of being less than 0·5 times the gross domestic product per capita in 54 countries, and less than 1·0 times gross domestic product per capita in 63 countries. INTERPRETATION: Rotavirus vaccination continues to represent good value for money across most Gavi countries despite lower rotavirus mortality estimates and more stringent willingness-to-pay thresholds. FUNDING: Bill & Melinda Gates Foundation.

Effect of propensity of seeking medical care on the bias of the estimated effectiveness of rotavirus vaccines from studies using a test-negative case-control design.

BACKGROUND: Rotavirus is the leading cause of severe diarrhea among children worldwide, and vaccines can reduce morbidity and mortality by 50-98%. The test-negative control (TNC) study design is increasingly used for evaluating the effectiveness of vaccines against rotavirus and other vaccine-preventable diseases. In this study design, symptomatic patients who seek medical care are tested for the pathogen of interest. Those who test positive (negative) are classified as cases (controls). METHODS: We use a probability model to evaluate the bias of estimates of rotavirus vaccine effectiveness (VE) against rotavirus diarrhea resulting in hospitalization in the presence of possible confounding and selection biases due to differences in the propensity of seeking medical care (PSMC) between vaccinated and unvaccinated children. RESULTS: The TNC-based VE estimate corrects for confounding bias when the confounder's effects on the probabilities of rotavirus and non-rotavirus related hospitalizations are equal. If this condition is not met, then the estimated VE may be substantially biased. The bias is more severe in low-income countries, where VE is known to be lower. Under our model, differences in PSMC between vaccinated and unvaccinated children do not result in selection bias when the TNC study design is used. CONCLUSIONS: In practice, one can expect the association of PSMC (or other potential confounders) with the probabilities of rotavirus and non-rotavirus related hospitalization to be similar, in which case the confounding effects will only result in small bias in the VE estimate from TNC studies. The results of this work, along with those of our previous paper, confirm the TNC design can be expected to provide reliable estimates of rotavirus VE in both high- and low-income countries.

Rotavirus vaccine impact assessment surveillance in India: protocol and methods.

INTRODUCTION: Rotavirus infection accounts for 39% of under-five diarrhoeal deaths globally and 22% of these deaths occur in India. Introduction of rotavirus vaccine in a national immunisation programme is considered to be the most effective intervention in preventing severe rotavirus disease. In 2016, India introduced an indigenous rotavirus vaccine (Rotavac) into the Universal Immunisation Programme in a phased manner. This paper describes the protocol for surveillance to monitor the performance of rotavirus vaccine following its introduction into the routine childhood immunisation programme. METHODS: An active surveillance system was established to identify acute gastroenteritis cases among children less than 5 years of age. For all children enrolled at sentinel sites, case reporting forms are completed and a copy of vaccination record and a stool specimen obtained. The forms and specimens are sent to the referral laboratory for data entry, analysis, testing and storage. Data from sentinel sites in states that have introduced rotavirus vaccine into their routine immunisation schedule will be used to determine rotavirus vaccine impact and effectiveness. ETHICS AND DISSEMINATION: The Institutional Review Board of Christian Medical College, Vellore, and all the site institutional ethics committees approved the project. Results will be disseminated in peer-reviewed journals and with stakeholders of the universal immunisation programme in India.

Epidemiologic challenges in norovirus vaccine development.

Norovirus is the leading cause of acute gastroenteritis (AGE) worldwide. In the United States norovirus is estimated to cause 19-21 million illnesses, 1.7-1.9 million outpatient visits, 56,000-71,000 hospitalizations, and 570-800 deaths annually. Through direct costs and loss of productivity, norovirus disease cost the US economy more than $5.5 billion annually. Due to the lack of available therapies to treat norovirus infections and their highly infectious nature, preventing norovirus illness through vaccination is an appealing strategy. Currently, several norovirus vaccines are in development, including five vaccines in preclinical trials, an oral monovalent vaccine (Vaxart, Inc.) that recently completed a phase IB clinical trial, and a bivalent intramuscular vaccine (Takeda Pharmaceutical Company Limited) in a phase IIB clinical trial. However, no norovirus vaccines are currently available on the market. In this commentary we aim to describe some of the barriers faced in norovirus vaccine development, particularly focusing on vaccine effectiveness and defining the target population.

Preparing for safety monitoring after rotavirus vaccine introduction - Assessment of baseline epidemiology of intussusception among children <2 years of age in four Asian countries.

Intussusception is the invagination of one segment of the bowel into a distal segment, characterized by symptoms of bloody stool, vomiting, and abdominal pain. Previous studies have found regional differences in incidence but the etiology of most intussusception cases is unknown. Rotavirus vaccines were associated with a slightly of increased risk of intussusception in post-licensure evaluations in high- and middle-income countries, but not in low income African countries. To describe the baseline epidemiology of intussusception in young children prior to rotavirus vaccine implementation, active sentinel hospital surveillance for intussusception in children < 2 years of age was conducted in 4 low income Asian countries (Bangladesh, Nepal, Pakistan and Vietnam). Over a 24-month period, 15 sites enrolled 1,415 intussusception cases, of which 70% were enrolled in Vietnam. Overall, 61% of cases were male and 1% (n = 16) died, ranging from 8% in Pakistan to 0% in Vietnam. The median age of cases enrolled ranged from 6 months in Bangladesh and Pakistan to 12 months in Vietnam. The proportion of cases receiving surgical management was 100% in Bangladesh, 88% in Pakistan, 61% in Nepal, and 1% in Vietnam. The high proportion of males and median age of cases around 6 months of age found in this regional surveillance network are consistent with previous descriptions of the epidemiology of intussusception in these countries and elsewhere. Differences in management and the fatality rate of cases between the countries likely reflect differences in access to healthcare and availability of diagnostic modalities. These baseline data will be useful for post-rotavirus vaccine introduction safety monitoring.

Using surveillance and economic data to make informed decisions about rotavirus vaccine introduction.

While rotavirus vaccines are available, safe, and effective, many countries are not yet widely using these vaccines. Surveillance for rotavirus disease and potential vaccine adverse events is critical for country decision making about rotavirus vaccine. This special issue shares rotavirus and intussusception disease surveillance data and rotavirus vaccine cost-effectiveness analyses from countries that have yet to introduce rotavirus vaccines into their routine infant immunization programs. The studies highlight the substantial burden of rotavirus disease and the cost-effectiveness of rotavirus vaccine in a broad set of countries without rotavirus vaccine in their routine immunization programs.

Burden of Severe Norovirus Disease in Taiwan, 2003-2013.

Background: Despite the increasingly recognized role of norovirus in global acute gastroenteritis (AGE), specific estimates of the associated disease burden remain sparse, primarily due to limited availability of sensitive norovirus diagnostics in the clinical setting. We sought to estimate the incidence of norovirus-associated hospitalizations by age group in Taiwan using a previously developed indirect regression method. Methods: AGE-related hospitalizations in Taiwan were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes abstracted from a national database; population data were provided from the Department of Household Registration Affairs. Population and hospitalizations were aggregated by month and year (July 2003-June 2013) and grouped by age: <5 years, 5-19 years, 20-64 years, and ≥65 years. Monthly counts of cause-unspecified AGE hospitalizations were modeled as a function of counts of known causes, and the residuals were then analyzed to estimate norovirus-associated hospitalizations. Results: Over the study period, an annual mean of 101400 gastroenteritis-associated hospitalizations occurred in Taiwan (44 per 10000 person-years), most of which (83%) had no specified cause. The overall estimated rate of norovirus-associated hospitalizations was 6.7 per 10000 person-years, with the highest rates in children aged <5 years (63.7/10000 person-years). Predicted norovirus peaked in 2006-2007 and 2012-2013. Conclusions: Our study is one of the first to generate a population-based estimate of severe norovirus disease incidence in Asia, and highlights the large burden of norovirus in Taiwan, particularly in children. Predicted peak norovirus seasons coincided with the emergence of new strains and resulting pandemics, supporting the validity of the estimates.