The age profile of respiratory syncytial virus burden in preschool children of low- and middle-income countries: A semi-parametric, meta-regression approach.

BACKGROUND: Respiratory syncytial virus (RSV) infections are among the primary causes of death for children under 5 years of age worldwide. A notable challenge with many of the upcoming prophylactic interventions against RSV is their short duration of protection, making the age profile of key interest to the design of prevention strategies. METHODS AND FINDINGS: We leverage the RSV data collected on cases, hospitalizations, and deaths in a systematic review in combination with flexible generalized additive mixed models (GAMMs) to characterize the age burden of RSV incidence, hospitalization, and hospital-based case fatality rate (hCFR). Due to the flexible nature of GAMMs, we estimate the peak, median, and mean incidence of infection to inform discussions on the ideal "window of protection" of prophylactic interventions. In a secondary analysis, we reestimate the burden of RSV in all low- and middle-income countries. The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively. Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths. On an average year, we estimate 28.23 to 31.34 million cases of RSV, between 2.95 to 3.35 million hospitalizations, and 16,835 to 19,909 in-hospital deaths in low, lower- and upper middle-income countries. In addition, we estimate 17,254 to 23,875 deaths in the community, for a total of 34,114 to 46,485 deaths. Globally, evidence shows that community-based incidence may differ by World Bank Income Group, but not hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p ≤ 0.01, p = 1, p = 0.86, 0.63, respectively). Our study is limited mainly due to the sparsity of the data, especially for low-income countries (LICs). The lack of information for some populations makes detecting heterogeneity between income groups difficult, and differences in access to care may impact the reported burden. CONCLUSIONS: We have demonstrated an approach to synthesize information on RSV outcomes in a statistically principled manner, and we estimate that the age profile of RSV burden depends on whether information on incidence is collected in hospitals or in the community. Our results suggest that the ideal prophylactic strategy may require multiple products to avert the risk among preschool children.

Estimating the cost-effectiveness of maternal vaccination and monoclonal antibodies for respiratory syncytial virus in Kenya and South Africa.

BACKGROUND: Respiratory syncytial virus (RSV) causes a substantial burden of acute lower respiratory infection in children under 5 years, particularly in low- and middle-income countries (LMICs). Maternal vaccine (MV) and next-generation monoclonal antibody (mAb) candidates have been shown to reduce RSV disease in infants in phase 3 clinical trials. The cost-effectiveness of these biologics has been estimated using disease burden data from global meta-analyses, but these are sensitive to the detailed age breakdown of paediatric RSV disease, for which there have previously been limited data. METHODS: We use original hospital-based incidence data from South Africa (ZAF) and Kenya (KEN) collected between 2010 and 2018 of RSV-associated acute respiratory infection (ARI), influenza-like illness (ILI), and severe acute respiratory infection (SARI) as well as deaths with monthly age-stratification, supplemented with data on healthcare-seeking behaviour and costs to the healthcare system and households. We estimated the incremental cost per DALY averted (incremental cost-effectiveness ratio or ICER) of public health interventions by MV or mAb for a plausible range of prices (5-50 USD for MV, 10-125 USD for mAb), using an adjusted version of a previously published health economic model of RSV immunisation. RESULTS: Our data show higher disease incidence for infants younger than 6 months of age in the case of Kenya and South Africa than suggested by earlier projections from community incidence-based meta-analyses of LMIC data. Since MV and mAb provide protection for these youngest age groups, this leads to a substantially larger reduction of disease burden and, therefore, more favourable cost-effectiveness of both interventions in both countries. Using the latest efficacy data and inferred coverage levels based on antenatal care (ANC-3) coverage (KEN: 61.7%, ZAF: 75.2%), our median estimate of the reduction in RSV-associated deaths in children under 5 years in Kenya is 10.5% (95% CI: 7.9, 13.3) for MV and 13.5% (10.7, 16.4) for mAb, while in South Africa, it is 27.4% (21.6, 32.3) and 37.9% (32.3, 43.0), respectively. Starting from a dose price of 5 USD, in Kenya, net cost (for the healthcare system) per (undiscounted) DALY averted for MV is 179 (126, 267) USD, rising to 1512 (1166, 2070) USD at 30 USD per dose; for mAb, it is 684 (543, 895) USD at 20 USD per dose and 1496 (1203, 1934) USD at 40 USD per dose. In South Africa, a MV at 5 USD per dose would be net cost-saving for the healthcare system and net cost per DALY averted is still below the ZAF's GDP per capita at 40 USD dose price (median: 2350, 95% CI: 1720, 3346). For mAb in ZAF, net cost per DALY averted is 247 (46, 510) USD at 20 USD per dose, rising to 2028 (1565, 2638) USD at 50 USD per dose and to 6481 (5364, 7959) USD at 125 USD per dose. CONCLUSIONS: Incorporation of new data indicating the disease burden is highly concentrated in the first 6 months of life in two African settings suggests that interventions against RSV disease may be more cost-effective than previously estimated.

Cost-Effectiveness of Respiratory Syncytial Virus Preventive Interventions in Children: A Model Comparison Study.

OBJECTIVES: Model-based cost-effectiveness analyses on maternal vaccine (MV) and monoclonal antibody (mAb) interventions against respiratory syncytial virus (RSV) use context-specific data and produce varied results. Through model comparison, we aim to characterize RSV cost-effectiveness models and examine drivers for their outputs. METHODS: We compared 3 static and 2 dynamic models using a common input parameter set for a hypothetical birth cohort of 100 000 infants. Year-round and seasonal programs were evaluated for MV and mAb interventions, using available evidence during the study period (eg, phase III MV and phase IIb mAb efficacy). RESULTS: Three static models estimated comparable medically attended (MA) cases averted versus no intervention (MV, 1019-1073; mAb, 5075-5487), with the year-round MV directly saving ∼€1 million medical and €0.3 million nonmedical costs, while gaining 4 to 5 discounted quality-adjusted life years (QALYs) annually in <1-year-olds, and mAb resulting in €4 million medical and €1.5 million nonmedical cost savings, and 21 to 25 discounted QALYs gained. In contrast, both dynamic models estimated fewer MA cases averted (MV, 402-752; mAb, 3362-4622); one showed an age shift of RSV cases, whereas the other one reported many non-MA symptomatic cases averted, especially by MV (2014). These differences can be explained by model types, assumptions on non-MA burden, and interventions' effectiveness over time. CONCLUSIONS: Our static and dynamic models produced overall similar hospitalization and death estimates, but also important differences, especially in non-MA cases averted. Despite the small QALY decrement per non-MA case, their larger number makes them influential for the costs per QALY gained of RSV interventions.

Cost-effectiveness analysis of typhoid conjugate vaccines in an outbreak setting: a modeling study.

BACKGROUND: Several prolonged typhoid fever epidemics have been reported since 2010 throughout eastern and southern Africa, including Malawi, caused by multidrug-resistant Salmonella Typhi. The World Health Organization recommends the use of typhoid conjugate vaccines (TCVs) in outbreak settings; however, current data are limited on how and when TCVs might be introduced in response to outbreaks. METHODOLOGY: We developed a stochastic model of typhoid transmission fitted to data from Queen Elizabeth Central Hospital in Blantyre, Malawi from January 1996 to February 2015. We used the model to evaluate the cost-effectiveness of vaccination strategies over a 10-year time horizon in three scenarios: (1) when an outbreak is likely to occur; (2) when an outbreak is unlikely to occur within the next ten years; and (3) when an outbreak has already occurred and is unlikely to occur again. We considered three vaccination strategies compared to the status quo of no vaccination: (a) preventative routine vaccination at 9 months of age; (b) preventative routine vaccination plus a catch-up campaign to 15 years of age; and (c) reactive vaccination with a catch-up campaign to age 15 (for Scenario 1). We also explored variations in outbreak definitions, delays in implementation of reactive vaccination, and the timing of preventive vaccination relative to the outbreak. RESULTS: Assuming an outbreak occurs within 10 years, we estimated that the various vaccination strategies would prevent a median of 15-60% of disability-adjusted life-years (DALYs). Reactive vaccination was the preferred strategy for WTP values of $0-300 per DALY averted. For WTP values > $300, introduction of preventative routine TCV immunization with a catch-up campaign was the preferred strategy. Routine vaccination with a catch-up campaign was cost-effective for WTP values above $890 per DALY averted if no outbreak occurs and > $140 per DALY averted if implemented after the outbreak has already occurred. CONCLUSIONS: Countries for which the spread of antimicrobial resistance is likely to lead to outbreaks of typhoid fever should consider TCV introduction. Reactive vaccination can be a cost-effective strategy, but only if delays in vaccine deployment are minimal; otherwise, introduction of preventive routine immunization with a catch-up campaign is the preferred strategy.

Cost-effectiveness of Respiratory Syncytial Virus Disease Prevention Strategies: Maternal Vaccine Versus Seasonal or Year-Round Monoclonal Antibody Program in Norwegian Children.

BACKGROUND: Every winter, respiratory syncytial virus (RSV) disease results in thousands of cases in Norwegian children under 5 years of age. We aim to assess the RSV-related economic burden and the cost-effectiveness of upcoming RSV disease prevention strategies including year-round maternal immunization and year-round and seasonal monoclonal antibody (mAb) programs. METHODS: Epidemiological and cost data were obtained from Norwegian national registries, while quality-adjusted life-years (QALYs) lost and intervention characteristics were extracted from literature and phase 3 clinical trials. A static model was used and uncertainty was accounted for probabilistically. Value of information was used to assess decision uncertainty. Extensive scenario analyses were conducted, including accounting for long-term consequences of RSV disease. RESULTS: We estimate an annual average of 13 517 RSV cases and 1572 hospitalizations in children under 5, resulting in 79.6 million Norwegian kroner (~€8 million) treatment costs. At €51 per dose for all programs, a 4-month mAb program for neonates born in November to February is the cost-effective strategy for willingness to pay (WTP) values up to €40 000 per QALY gained. For higher WTP values, the longer 6-month mAb program that immunizes neonates from October to March becomes cost-effective. Sensitivity analyses show that year-round maternal immunization can become a cost-effective strategy if priced lower than mAb. CONCLUSIONS: Assuming the same pricing, seasonal mAb programs are cost-effective over year-round programs in Norway. The timing and duration of the cost-effective seasonal program are sensitive to the pattern of the RSV season in a country, so continued RSV surveillance data are essential.

Economic Burden and Health-Related Quality of Life of Respiratory Syncytial Virus and Influenza Infection in European Community-Dwelling Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) and influenza virus infections result in a considerable mortality and morbidity among the aging population globally. Influenza vaccination for older adults before the seasonal influenza epidemic has been evaluated to be cost-effective in many countries. Interventions against RSV in older adults are in the pipeline, and evaluating their cost-effectiveness is crucial for decision making. To inform such evaluations, our aim was to estimate average costs and health-related quality of life (HRQoL) in older adults with RSV and influenza infection. METHODS: The European RESCEU observational cohort study followed 1040 relatively healthy community-dwelling older adults aged 60 years and older during 2 consecutive winter seasons. Health care resource use and HRQoL were collected and analyzed during RSV episodes, and also during influenza episodes. Country-specific unit cost data were mainly obtained from national databases. Direct costs were estimated from a patient, health care provider, and health care payers' perspective, whereas indirect costs were estimated from a societal perspective. Due to small sample size, no formal statistical comparisons were made. RESULTS: Thirty-six RSV and 60 influenza episodes were reported, including 1 hospitalization. Means (median; first-third quartile) of €26.4 (€5.5; 0-47.3) direct and €4.4 (€0; 0-0) indirect costs were reported per nonhospitalized RSV episode, and €42.5 (€36; 3.3-66.7) direct and €32.1 (€0; 0-0) indirect costs per nonhospitalized influenza episode. For RSV episodes, the utility value decreased from 0.896 (0.928; 0.854-0.953) to 0.801 (0.854; 0.712-0.937) from preseason to 1 week after symptom onset; for influenza, the change was from 0.872 (0.895; 0.828-0.953) to 0.664 (0.686; 0.574-0.797). CONCLUSIONS: The average costs and HRQoL estimates of older adults treated outside the hospital can be used to inform the design of future studies and the decision making regarding interventions to prevent RSV infection in older adults. Larger studies are needed to provide better country-specific and complementary cost estimates and to allow for formal statistical comparison of costs between RSV and influenza. CLINICAL TRIALS REGISTRATION: NCT03621930.

Impact of Adding Oseltamivir to Usual Care on Quality-Adjusted Life-Years During Influenza-Like Illness.

OBJECTIVES: The ALIC4E trial has shown that oseltamivir reduces recovery time while increasing the risk of nausea. This secondary analysis of the ALIC4E trial aimed to determine the gain in quality-adjusted life-years (QALYs) associated with adding oseltamivir to usual primary care in patients presenting with influenza-like illness (ILI). METHODS: Patients with ILI were recruited during the influenza season (2015-2018) in 15 European countries. Patients were assigned to usual care with or without oseltamivir through stratified randomization (age, severity, comorbidities, and symptom onset). Patients' health status was valued with the EQ-5D and visual analog scale (VAS) for up to 28 days. Average EQ-5D and VAS scores over time were estimated for both treatment groups using one-inflated beta regression in children (<13 years old) and adults (≥13 years old). QALY gain was calculated as the difference between the groups. Sensitivity analysis considered the value set to convert EQ-5D answers to summary scores and the follow-up period. RESULTS: In adults, oseltamivir gained 0.0006 (95% confidence interval 0.0002-0.0010) QALYs, whereas no statistically significant gain was found in children (14-day follow-up, EQ-5D). QALY gains were statistically significant in patients aged ≥65 years, patients without relevant comorbidities, or patients experiencing symptoms for ≤48 hours. Using VAS and accounting for 28-day follow-up resulted in higher QALY gain. CONCLUSIONS: QALY gain owing to oseltamivir is limited compared with other diseases, and its clinical meaningfulness remains to be determined. Further analysis is needed to evaluate whether QALY gain and its impact on ILI treatment cost render oseltamivir cost-effective.

Belgian population norms for the EQ-5D-5L, 2018.

PURPOSE: Health-related quality of life outcomes are increasingly used to monitor population health and health inequalities and to assess the (cost-) effectiveness of health interventions. The EQ-5D-5L has been included in the Belgian Health Interview Survey, providing a new source of population-based self-perceived health status information. This study aims to estimate Belgian population norms for the EQ-5D-5L by sex, age, and region and to analyze its association with educational attainment. METHODS: The BHIS 2018 provided EQ-5D-5L data for a nationally representative sample of the Belgian population. The dimension scores and index values were analyzed using logistic and linear regressions, respectively, accounting for the survey design. RESULTS: More than half of respondents reported problems of pain/discomfort, while over a quarter reported problems of anxiety/depression. The average index value was 0.84. Women reported more problems on all dimensions, but particularly on anxiety/depression and pain/discomfort, resulting in significantly lower index values. Problems with mobility, self-care, and usual activities showed a sharp increase after the age of 80 years. Consequently, index values decreased significantly by age. Lower education was associated with a higher prevalence of problems for all dimensions except anxiety/depression and with a significantly lower index value. CONCLUSION: This paper presents the first nationally representative Belgian population norms using the EQ-5D-5L. Inclusion of the EQ-5D in future surveys will allow monitoring over time of self-reported health, disease burden, and health inequalities.

Health and economic burden of respiratory syncytial virus (RSV) disease and the cost-effectiveness of potential interventions against RSV among children under 5 years in 72 Gavi-eligible countries.

BACKGROUND: Respiratory syncytial virus (RSV) frequently causes acute lower respiratory infection in children under 5, representing a high burden in Gavi-eligible countries (mostly low-income and lower-middle-income). Since multiple RSV interventions, including vaccines and monoclonal antibody (mAb) candidates, are under development, we aim to evaluate the key drivers of the cost-effectiveness of maternal vaccination and infant mAb for 72 Gavi countries. METHODS: A static Multi-Country Model Application for RSV Cost-Effectiveness poLicy (MCMARCEL) was developed to follow RSV-related events monthly from birth until 5 years of age. MCMARCEL was parameterised using country- and age-specific demographic, epidemiological, and cost data. The interventions' level and duration of effectiveness were guided by the World Health Organization's preferred product characteristics and other literature. Maternal vaccination and mAb were assumed to require single-dose administration at prices assumed to align with other Gavi-subsidised technologies. The effectiveness and the prices of the interventions were simultaneously varied in extensive scenario analyses. Disability-adjusted life years (DALYs) were the primary health outcomes for cost-effectiveness, integrated with probabilistic sensitivity analyses and Expected Value of Partially Perfect Information analysis. RESULTS: The RSV-associated disease burden among children in these 72 countries is estimated at an average of 20.8 million cases, 1.8 million hospital admissions, 40 thousand deaths, 1.2 million discounted DALYs, and US$611 million discounted direct costs. Strategy 'mAb' is more effective due to its assumed longer duration of protection versus maternal vaccination, but it was also assumed to be more expensive. Given all parameterised uncertainty, the optimal strategy of choice tends to change for increasing willingness to pay (WTP) values per DALY averted from the current situation to maternal vaccination (at WTP > US$1000) to mAB (at WTP > US$3500). The age-specific proportions of cases that are hospitalised and/or die cause most of the uncertainty in the choice of optimal strategy. Results are broadly similar across countries. CONCLUSIONS: Both the maternal and mAb strategies need to be competitively priced to be judged as relatively cost-effective. Information on the level and duration of protection is crucial, but also more and better disease burden evidence-especially on RSV-attributable hospitalisation and death rates-is needed to support policy choices when novel RSV products become available.

Economic costs analysis of uncomplicated malaria case management in the Peruvian Amazon.

BACKGROUND: Case management is one of the principal strategies for malaria control. This study aimed to estimate the economic costs of uncomplicated malaria case management and explore the influence of health-seeking behaviours on those costs. METHODS: A knowledge, attitudes and practices (KAP) survey was applied to 680 households of fifteen communities in Mazan-Loreto in March 2017, then a socio-economic survey was conducted in September 2017 among 161 individuals with confirmed uncomplicated malaria in the past 3 months. Total costs per episode were estimated from both provider (Ministry of Health, MoH) and patient perspectives. Direct costs were estimated using a standard costing estimation procedure, while the indirect costs considered the loss of incomes among patients, substitute labourers and companions due to illness in terms of the monthly minimum wage. Sensitivity analysis evaluated the uncertainty of the average cost per episode. RESULTS: The KAP survey showed that most individuals (79.3%) that had malaria went to a health facility for a diagnosis and treatment, 2.7% received those services from community health workers, and 8% went to a drugstore or were self-treated at home. The average total cost per episode in the Mazan district was US$ 161. The cost from the provider's perspective was US$ 30.85 per episode while from the patient's perspective the estimated cost was US$ 131 per episode. The average costs per Plasmodium falciparum episode (US$ 180) were higher than those per Plasmodium vivax episode (US$ 156) due to longer time lost from work by patients with P. falciparum infections (22.2 days) than by patients with P. vivax infections (17.0 days). The delayed malaria diagnosis (after 48 h of the onset of symptoms) was associated with the time lost from work due to illness (adjusted mean ratio 1.8; 95% CI 1.3, 2.6). The average cost per malaria episode was most sensitive to the uncertainty around the lost productivity cost due to malaria. CONCLUSIONS: Despite the provision of free malaria case management by MoH, there is delay in seeking care and the costs of uncomplicated malaria are mainly borne by the families. These costs are not well perceived by the society and the substantial financial impact of the disease can be frequently undervalued in public policy planning.

Case Fatality Rate of Enteric Fever in Endemic Countries: A Systematic Review and Meta-analysis.

Enteric fever is a febrile illness, occurring mostly in Asia and Africa, which can present as a severe and possibly fatal disease. Currently, a case fatality rate (CFR) of 1% is assumed when evaluating the global burden of enteric fever. Until now, no meta-analysis has been conducted to summarize mortality from enteric fever. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence. We estimated an overall CFR of 2.49% (95% confidence interval, 1.65%-3.75%; n = 44), and a CFR in hospitalized patients of 4.45% (2.85%-6.88%; n = 21 of 44). There was considerably heterogeneity in estimates of the CFR from individual studies. Neither age nor antimicrobial resistance were significant prognostic factors, but limited data were available for these analyses. The combined estimate of the CFR for enteric fever is higher than previously estimated, and the evaluation of prognostic factors, including antimicrobial resistance, urgently requires more data.

Lessons from a decade of individual-based models for infectious disease transmission: a systematic review (2006-2015).

BACKGROUND: Individual-based models (IBMs) are useful to simulate events subject to stochasticity and/or heterogeneity, and have become well established to model the potential (re)emergence of pathogens (e.g., pandemic influenza, bioterrorism). Individual heterogeneity at the host and pathogen level is increasingly documented to influence transmission of endemic diseases and it is well understood that the final stages of elimination strategies for vaccine-preventable childhood diseases (e.g., polio, measles) are subject to stochasticity. Even so it appears IBMs for both these phenomena are not well established. We review a decade of IBM publications aiming to obtain insights in their advantages, pitfalls and rationale for use and to make recommendations facilitating knowledge transfer within and across disciplines. METHODS: We systematically identified publications in Web of Science and PubMed from 2006-2015 based on title/abstract/keywords screening (and full-text if necessary) to retrieve topics, modeling purposes and general specifications. We extracted detailed modeling features from papers on established vaccine-preventable childhood diseases based on full-text screening. RESULTS: We identified 698 papers, which applied an IBM for infectious disease transmission, and listed these in a reference database, describing their general characteristics. The diversity of disease-topics and overall publication frequency have increased over time (38 to 115 annual publications from 2006 to 2015). The inclusion of intervention strategies (8 to 52) and economic consequences (1 to 20) are increasing, to the detriment of purely theoretical explorations. Unfortunately, terminology used to describe IBMs is inconsistent and ambiguous. We retrieved 24 studies on a vaccine-preventable childhood disease (covering 7 different diseases), with publication frequency increasing from the first such study published in 2008. IBMs have been useful to explore heterogeneous between- and within-host interactions, but combined applications are still sparse. The amount of missing information on model characteristics and study design is remarkable. CONCLUSIONS: IBMs are suited to combine heterogeneous within- and between-host interactions, which offers many opportunities, especially to analyze targeted interventions for endemic infections. We advocate the exchange of (open-source) platforms and stress the need for consistent "branding". Using (existing) conventions and reporting protocols would stimulate cross-fertilization between research groups and fields, and ultimately policy making in decades to come.

Quality-of-life: a many-splendored thing? Belgian population norms and 34 potential determinants explored by beta regression.

PURPOSE: To identify determinants of health-related quality-of-life in the Belgian population and to provide age-specific population norms of health-related quality-of-life. METHODS: Between September 2010 and February 2011, a representative sample of 1774 persons (age 0-99) was surveyed using the standard Euroqol questionnaire (EQ-5D-3L) with a Visual Analogue Scale (VAS). Significant determinants were identified using multivariate beta (VAS) and one-inflated beta (EQ-5D) regression, the latter modelling the probability to be in perfect health separately from the average EQ-5D score if not in perfect health. RESULTS: Health-related quality-of-life depends largely on age and experience with severe disease. The probability to be in perfect health is highest for children. For 0-2 years children who are not in perfect health, proxies report EQ-5D and VAS scores as low as that of the elderly. Also smoking behaviour, educational attainment, pet ownership, working or having worked in health care, and potentially household size and 60+ living on their own (yes/no) are associated with health-related quality-of-life, whereas no association was found with gender, living in a single-parent home, educational attainment of mothers, alcohol consumption of 60+, having (grand-) children and the frequency of seeing them. The same determinants are significant for VAS and the probability to be in perfect health, but not for the average EQ-5D score if not in perfect health. CONCLUSIONS: The population norms provided can be used directly as input in health economic evaluations. Estimating health-related quality-of-life in children and developing statistical tools capturing the particular features of health-related quality-of-life measures are important areas for future research.

Sustained low rotavirus activity and hospitalisation rates in the post-vaccination era in Belgium, 2007 to 2014.

In 2006, Belgium was the first country in the European Union to recommend rotavirus vaccination in the routine infant vaccination schedule and rapidly achieved high vaccine uptake (86-89% in 2007). We used regional and national data sources up to 7 years post-vaccination to study the impact of vaccination on laboratory-confirmed rotavirus cases and rotavirus-related hospitalisations and deaths. We showed that (i) from 2007 until 2013, vaccination coverage remained at 79-88% for a complete course, (ii) in children 0-2 years, rotavirus cases decreased by 79% (95% confidence intervals (CI): 68--89%) in 2008-2014 compared to the pre-vaccination period (1999--2006) and by 50% (95% CI: 14-82%) in the age group ≥ 10 years, (iii) hospitalisations for rotavirus gastroenteritis decreased by 87% (95% CI: 84-90%) in 2008--2012 compared to the pre-vaccination period (2002--2006), (iv) median age of rotavirus cases increased from 12 months to 17 months and (v) the rotavirus seasonal peak was reduced and delayed in all post-vaccination years. The substantial decline in rotavirus gastroenteritis requiring hospitalisations and in rotavirus activity following introduction of rotavirus vaccination is sustained over time and more pronounced in the target age group, but with evidence of herd immunity.

Environmental triggers of acute myocardial infarction: results of a nationwide multiple-factorial population study.

OBJECTIVE: The objective of this study was to study the independent environmental triggers of ST-elevation myocardial infarction (STEMI) in a multifactorial environmental population model. METHODS AND RESULTS: Daily counts of all STEMI patients who underwent urgent percutaneous coronary intervention over the period 2006-2009 in Belgium were associated with average daily meteorological data and influenza-like illness incidence data. The following meteorological measures were investigated: particulate matter less than 10 µM (PM10) and less than 2.5 µM (PM(2.5)), ozone, black smoke, temperature and relative humidity. During the study period a total of 15,964 STEMI patients (mean age 63, 75% male) were admitted with a daily average admission rate of 11 ± 4 patients. A multivariate Poisson regression analysis showed that only the temperature was significantly correlated with STEMI, with an 8% increase in the risk of STEMI for each 10°C decrease in temperature (adjusted incidence risk ratio (IRR) 0.92, 95% CI 0.89-0.96). The effects of temperature were consistent among several subpopulations but the strongest effect was seen in diabetic patients (IRR 0.85, 95% CI 0.78 -0.95). There was a trend for an incremental risk of STEMI for each 10 µg/m³ PM(2.5) increase and during influenza epidemics with IRR of 1.02 (95% CI 1.00-1.04) and 1.07 (95% CI 0.98-1.16), respectively. CONCLUSION: In a global environmental model, low temperature is the most important environmental trigger for STEMI, whereas air pollution and influenza epidemics only seem to have a modest effect.

Cost per episode of diarrhea and respiratory syncytial virus (RSV) in 128 low- and middle-income countries: how well do disease-specific and WHO-CHOICE estimates align?

Objective: Non-disease-specific WHO-CHOICE unit costs are often used in cost and cost-effectiveness studies in the absence of country-specific data. This study aims to compare reported country-specific disease costs and the corresponding WHO-CHOICE estimates. We use generically defined "diarrhea" (including rotavirus diarrhea) and pathogen-specific "respiratory syncytial virus (RSV)" disease as examples. Methods: We updated systematic reviews for both diseases in low-income (LICs), lower-middle-income (LMICs) and upper-middle-income (UMICs) countries. Diarrheal (including a sub-analysis of rotavirus-specific) and RSV-specific outpatient and inpatient costs per episode were extracted and compared with WHO-CHOICE estimates in the same countries. If a consistent pattern of under- or over-estimation was identified, we quantified the magnitude of the discrepancy. All costs were updated to 2022 international dollar values. Results: Out of 1975 new records identified, 23 new cost studies were included. Including previous reviews, we retained 31 diarrhea and 16 RSV studies for comparison. WHO-CHOICE based direct medical costs were similar for diarrheal disease including rotavirus diarrhea, but lower for RSV-related disease. We estimated the cost per episode of diarrhea and RSV in 128 countries. RSV outpatient cost were adjusted by multiplying WHO-CHOICE costs by 6.89 (95% uncertainty interval: 5.58-8.58) in LICs and LMICs and 5.87 (4.95-6.96) in UMICs; RSV inpatient costs were multiplied by 1.43 (1.01-2.01) and 1.36 (0.82-2.27), respectively. Conclusion: WHO-CHOICE based costs should be used cautiously. They aligned well with studies for diarrheal disease, but underestimate costs of RSV-related disease. More country- and disease-specific cost data are needed, especially for RSV in LICs.

Cost-effectiveness of monoclonal antibody and maternal immunization against respiratory syncytial virus (RSV) in infants: Evaluation for six European countries.

BACKGROUND: Respiratory syncytial virus (RSV) imposes a substantial burden on pediatric hospital capacity in Europe. Promising prophylactic interventions against RSV including monoclonal antibodies (mAb) and maternal immunizations (MI) are close to licensure. Therefore, we aimed to evaluate the cost-effectiveness of potential mAb and MI interventions against RSV in infants, for six European countries. METHODS: We used a static cohort model to compare costs and health effects of four intervention programs to no program and to each other: year-round MI, year-round mAb, seasonal mAb (October to April), and seasonal mAb plus a catch-up program in October. Input parameters were obtained from national registries and literature. Influential input parameters were identified with the expected value of partial perfect information and extensive scenario analyses (including the impact of interventions on wheezing and asthma). RESULTS: From the health care payer perspective, and at a price of €50 per dose (mAb and MI), seasonal mAb plus catch-up was cost-saving in Scotland, and cost-effective for willingness-to-pay (WTP) values ≥€20,000 (England, Finland) or €30,000 (Denmark) per quality adjusted life-year (QALY) gained for all scenarios considered, except when using ICD-10 based hospitalization data. For the Netherlands, seasonal mAb was preferred (WTP value: €30,000-€90,000) for most scenarios. For Veneto region (Italy), either seasonal mAb with or without catch-up or MI was preferred, depending on the scenario and WTP value. From a full societal perspective (including leisure time lost), the seasonal mAb plus catch-up program was cost-saving for all countries except the Netherlands. CONCLUSION: The choice between a MI or mAb program depends on the level and duration of protection, price, availability, and feasibility of such programs, which should be based on the latest available evidence. Future research should focus on measuring accurately age-specific RSV-attributable hospitalizations in very young children.

Economic burden and health-related quality-of-life among infants with respiratory syncytial virus infection: A multi-country prospective cohort study in Europe.

BACKGROUND: Respiratory syncytial virus (RSV) causes a considerable disease burden in young children globally, but reliable estimates of RSV-related costs and health-related quality-of-life (HRQoL) are scarce. This study aimed to evaluate the RSV-associated costs and HRQoL effects in infants and their caregivers in four European countries. METHODS: Healthy term-born infants were recruited at birth and actively followed up in four European countries. Symptomatic infants were systematically tested for RSV. Caregivers recorded the daily HRQoL of their child and themselves, measured by a modified EQ-5D with Visual Analogue Scale, for 14 consecutive days or until symptoms resolved. At the end of each RSV episode, caregivers reported healthcare resource use and work absenteeism. Direct medical costs per RSV episode were estimated from a healthcare payer's perspective and indirect costs were estimated from a societal perspective. Means and 95% confidence intervals (CI) of direct medical costs, total costs (direct costs + productivity loss) and quality-adjusted life-day (QALD) loss per RSV episode were estimated per RSV episode, as well as per subgroup (medical attendance, country). RESULTS: Our cohort of 1041 infants experienced 265 RSV episodes with a mean symptom duration of 12.5 days. The mean (95% CI) cost per RSV episode was €399.5 (242.3, 584.2) and €494.3 (317.7, 696.1) from the healthcare payer's and societal perspective, respectively. The mean QALD loss per RSV episode of 1.9 (1.7, 2.1) was independent of medical attendance (in contrast to costs, which also differed by country). Caregiver and infant HRQoL evolved similarly. CONCLUSION: This study fills essential gaps for future economic evaluations by prospectively estimating direct and indirect costs and HRQoL effects on healthy term infants and caregivers separately, for both medically attended (MA) and non-MA laboratory-confirmed RSV episodes. We generally observed greater HRQoL losses than in previous studies which used non-community and/or non-prospective designs.

Cost-effectiveness of adding oseltamivir to primary care for influenza-like-illness: economic evaluation alongside the randomised controlled ALIC4E trial in 15 European countries.

BACKGROUND: Oseltamivir is usually not often prescribed (or reimbursed) for non-high-risk patients consulting for influenza-like-illness (ILI) in primary care in Europe. We aimed to evaluate the cost-effectiveness of adding oseltamivir to usual primary care in adults/adolescents (13 years +) and children with ILI during seasonal influenza epidemics, using data collected in an open-label, multi-season, randomised controlled trial of oseltamivir in 15 European countries. METHODS: Direct and indirect cost estimates were based on patient reported resource use and official country-specific unit costs. Health-Related Quality of Life was assessed by EQ-5D questionnaires. Costs and quality adjusted life-years (QALY) were bootstrapped (N = 10,000) to estimate incremental cost-effectiveness ratios (ICER), from both the healthcare payers' and the societal perspectives, with uncertainty expressed through probabilistic sensitivity analysis and expected value for perfect information (EVPI) analysis. Additionally, scenario (self-reported spending), comorbidities subgroup and country-specific analyses were performed. RESULTS: The healthcare payers' expected ICERs of oseltamivir were €22,459 per QALY gained in adults/adolescents and €13,001 in children. From the societal perspective, oseltamivir was cost-saving in adults/adolescents, but the ICER is €8,344 in children. Large uncertainties were observed in subgroups with comorbidities, especially for children. The expected ICERs and extent of decision uncertainty varied between countries (EVPI ranged €1-€35 per patient). CONCLUSION: Adding oseltamivir to primary usual care in Europe is likely to be cost-effective for treating adults/adolescents and children with ILI from the healthcare payers' perspective (if willingness-to-pay per QALY gained > €22,459) and cost-saving in adults/adolescents from a societal perspective.

Generating, Presenting, and Interpreting Cost-Effectiveness Results in the Context of Uncertainty: A Tutorial for Deeper Knowledge and Better Practice.

This tutorial aims to help make the best available methods for generating and presenting cost-effectiveness results with uncertainty common practice. We believe there is a need for such type of tutorial because some erroneous practices persist (e.g., identifying the cost-effective intervention as the one with the highest probability to be cost-effective), while some of the more advanced methods are hardly used (e.g., the net loss statistic 'NL', expected net loss curves and frontier). The tutorial explains with simple examples the pros and cons of using ICER, incremental net benefit and NL to identify the cost-effective intervention, both with and without uncertainty accounted for probabilistically. A flowchart provides practical guidance on when and how to use ICER, incremental net benefit or NL. Different ways to express and present uncertainty in the results are described, including confidence and credible intervals, the probability that a strategy is cost-effective (as usually shown with cost-effectiveness acceptability curves (CEACs)) and the expected value of perfect information (EVPI). The tutorial clarifies and illustrates why EVPI is the only measure accounting fully for decision uncertainty, and why NL curves and the NL frontier may be preferred over CEACs and other plots for presenting cost-effectiveness results in the context of uncertainty. The easy calculations and a worked-out real-life example will help users to thoroughly understand and correctly interpret key cost-effectiveness results. Examples with mathematical calculations, interpretation, plots and R code are provided.