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Seasonal influenza is responsible for a large disease and economic burden. Despite the expanding recommendation of influenza vaccination, influenza has continued to be a major public health concern in the United States (U.S.). To evaluate influenza prevention strategies it is important that policy makers have current estimates of the economic burden of influenza. To provide an updated estimate of the average annual economic burden of seasonal influenza in the U.S. population in the presence of vaccination efforts. We evaluated estimates of age-specific influenza-attributable outcomes (ill-non medically attended, office-based outpatient visit, emergency department visits, hospitalizations and death) and associated productivity loss. Health outcome rates were applied to the 2015 U.S. population and multiplied by the relevant estimated unit costs for each outcome. We evaluated both direct healthcare costs and indirect costs (absenteeism from paid employment) reporting results from both a healthcare system and societal perspective. Results were presented in five age groups (<5 years, 5–17 years, 18–49 years, 50–64 years and ≥65 years of age). The estimated average annual total economic burden of influenza to the healthcare system and society was $11.2 billion ($6.3–$25.3 billion). Direct medical costs were estimated to be $3.2 billion ($1.5–$11.7 billion) and indirect costs $8.0 billion ($4.8–$13.6 billion). These total costs were based on the estimated average numbers of (1) ill-non medically attended patients (21.6 million), (2) office-based outpatient visits (3.7 million), (3) emergency department visit (0.65 million) (4) hospitalizations (247.0 thousand), (5) deaths (36.3 thousand) and (6) days of productivity lost (20.1 million). This study provides an updated estimate of the total economic burden of influenza in the U.S. Although we found a lower total cost than previously estimated, our results confirm that influenza is responsible for a substantial economic burden in the U.S.

•Annual seasonal vaccine production capacity is estimated at 1.48 billion doses.•Best-case annual production for pandemic vaccine is estimated at 8.31 billion doses.•Modest growth in pandemic influenza vaccine production capacity since 2015.•The majority of production is occurring in High Income Countries.•Challenges remain regarding maintenance of capacity and equitable distribution. Vaccines will be an important element in mitigating the impact of an influenza pandemic. While research towards developing universal influenza vaccines is ongoing, the current strategy for vaccine supply in a pandemic relies on seasonal influenza vaccine production to be switched over to pandemic vaccines. Understanding how much vaccine could be produced, in which regions of the world and in what timeframe is critical to informing influenza pandemic preparedness. Through the Global Action Plan for Influenza Vaccines, 2006–2016, WHO promoted an increase in vaccine production capacity and monitors the landscape through periodically surveying influenza vaccine manufacturers. This study compares global capacity for production of influenza vaccines in 2019 with estimates from previous surveys; provides an overview of countries with established production facilities; presents vaccine production by type and manufacturing process; and discusses limitations to these estimates. Results of the current survey show that estimated annual seasonal influenza vaccine production capacity changed little since 2015 increasing from 1.47 billion to 1.48 billion doses with potential maximum annual influenza pandemic vaccine production capacity increasing from 6.37 billion to 8.31 billion doses. However, this figure should be interpreted with caution as it presents a best-case scenario with several assumptions which may impact supply. Further, pandemic vaccines would not be immediately available and could take four to six months for first supplies with several more months needed to reach maximum capacity. A moderate-case scenario is also presented of 4.15 billion doses of pandemic vaccine in 12 months. It is important to note that two doses of pandemic vaccine are likely to be required to elicit an adequate immune response. Continued efforts are needed to ensure the sustainability of this production and to conduct research for vaccines that are faster to produce and more broadly protective taking into account lessons learned from COVID-19 vaccine development.

ObjectiveAcute myocardial infarction (AMI) is the leading cause of death and disability globally. There is increasing evidence from observational studies that influenza infection is associated with AMI. In patients with known coronary disease, influenza vaccination is associated with a lower risk of cardiovascular events. However, the effect of influenza vaccination on incident AMI across the entire population is less well established.MethodThe purpose of our systematic review of case–control studies is twofold: (1) to estimate the association between influenza infection and AMI and (2) to estimate the association between influenza vaccination and AMI. Cases included those conducted with first-time AMI or any AMI cases. Studies were appraised for quality and meta-analyses using random effects models for the influenza exposures of infection, and vaccination were conducted.Results16 studies (8 on influenza vaccination, 10 on influenza infection and AMI) met the eligibility criteria, and were included in the review and meta-analysis. Recent influenza infection, influenza-like illness or respiratory tract infection was significantly more likely in AMI cases, with a pooled OR 2.01 (95% CI 1.47 to 2.76). Influenza vaccination was significantly associated with AMI, with a pooled OR of 0.71 (95% CI 0.56 to 0.91), equating to an estimated vaccine effectiveness of 29% (95% CI 9% to 44%) against AMI.ConclusionsOur meta-analysis of case–control studies found a significant association between recent respiratory infection and AMI. The estimated vaccine effectiveness against AMI was comparable with the efficacy of currently accepted therapies for secondary prevention of AMI from clinical trial data. A large-scale randomised controlled trial is needed to provide robust evidence of the protective effect of influenza vaccination on AMI, including as primary prevention.

Seasonal influenza affects millions of people globally each year, causing significant morbidity and mortality. However, there remains substantial uncertainty about the attack rate (incidence) of influenza, particularly in unvaccinated individuals. We undertook a systematic review of vaccine randomised controlled trials (RCTs) that reported on laboratory-confirmed seasonal influenza in the placebo arm. We calculated the influenza attack rate from included studies as the number of laboratory-confirmed positive seasonal influenza cases in the placebo arm divided by the total number of subjects in this arm. A random effects meta-analysis was conducted to estimate the influenza attack rate among unvaccinated individuals (both symptomatic only as well as symptomatic and asymptomatic combined). We included 32 RCTs that had a total of 13,329 participants. The pooled estimates for symptomatic influenza were 12.7% (95%CI 8.5%, 18.6%) for children (<18 years), 4.4% (95%CI 3.0%, 6.3%) for adults, and 7.2% (95%CI 4.3%, 12.0%) for older people (65 years and above). The pooled estimates for symptomatic and asymptomatic influenza combined for all influenza were 22.5% (95%CI 9.0%, 46.0%) for children and 10.7% (95%CI 4.5%, 23.2%) for adults. Only one study was identified for symptomatic and asymptomatic combined in older people which had a rate of 8.8% (95%CI 7.0%, 10.8%). There was substantial heterogeneity between studies. Overall, we found that approximately 1 in 5 unvaccinated children and 1 in 10 unvaccinated adults were estimated to be infected by seasonal influenza annually, with rates of symptomatic influenza roughly half of these estimates. Our findings help to establish the background risk of seasonal influenza infection in unvaccinated individuals.

The aetiological role of human papillomavirus (HPV) in oesophageal squamous cell carcinoma (OSCC) has been widely researched for more than three decades, with conflicting findings. In the absence of a large, adequately powered single case-control study, a meta-analysis of all available case-control studies is the most rigorous way of identifying any potential association between HPV and OSCC. We present the first global meta-analysis of case-control studies investigating the role of HPV in OSCC. Case-control studies investigating OSCC tissue for presence of HPV DNA were identified. 21 case-control studies analyzing a total of 1223 cases and 1415 controls, met our inclusion criteria. HPV detection rates were tabulated for each study and all studies were assessed for quality. The random effects method was used to pool the odds ratios (OR). From all OSCC specimens included in this meta-analysis, 35% (426/1223) were positive for HPV DNA. The pooled OR for an HPV-OSCC association was 3.04 (95% CI 2.20 to 4.20). Meta-regression analysis did not find a significant association between OR and any of the quality domains. Influence analysis was non-significant for the effect of individual studies on the pooled estimate. Studies conducted in countries with low to medium OSCC incidence showed a stronger relationship (OR 4.65, 95% CI 2.47 to 8.76) than regions of high OSCC incidence (OR 2.65, 95% CI 1.80 to 3.91). Uncertainty around the aetiological role of HPV in OSCC is due largely to the small number and scale of appropriately designed studies. Our meta-analysis of these studies suggests that HPV increases the risk of OSCC three-fold. This study provides the strongest evidence to date of an HPV-OSCC association. The importance of these findings is that prophylactic vaccination could be of public health benefit in prevention of OSCC in countries with high OSCC incidence.

Official statistics under-estimate influenza deaths. Time series methods allow the estimation of influenza-attributable mortality. The methods often model background, non-influenza mortality using a cyclic, harmonic regression model based on the Serfling approach. This approach assumes that the seasonal pattern of non-influenza mortality is the same each year, which may not always be accurate. To estimate Australian seasonal and pandemic influenza-attributable mortality from 2003 to 2009, and to assess a more flexible influenza mortality estimation approach. We used a semi-parametric generalized additive model (GAM) to replace the conventional seasonal harmonic terms with a smoothing spline of time ('spline model') to estimate influenza-attributable respiratory, respiratory and circulatory, and all-cause mortality in persons aged <65 and ≥ 65 years. Influenza A(H1N1)pdm09, seasonal influenza A and B virus laboratory detection time series were used as independent variables. Model fit and estimates were compared with those of a harmonic model. Compared with the harmonic model, the spline model improved model fit by up to 20%. In <65 year-olds, the estimated respiratory mortality attributable to pandemic influenza A(H1N1)pdm09 was 0.5 (95% confidence interval (CI), 0.3, 0.7) per 100,000; similar to that of the years with the highest seasonal influenza A mortality, 2003 and 2007 (A/H3N2 years). In ≥ 65 year-olds, the highest annual seasonal influenza A mortality estimate was 25.8 (95% CI 22.2, 29.5) per 100,000 in 2003, five-fold higher than the non-statistically significant 2009 pandemic influenza estimate in that age group. Seasonal influenza B mortality estimates were negligible. The spline model achieved a better model fit. The study provides additional evidence that seasonal influenza, particularly A/H3N2, remains an important cause of mortality in Australia and that the epidemic of pandemic influenza A (H1N1)pdm09 virus in 2009 did not result in mortality greater than seasonal A/H3N2 influenza mortality, even in younger age groups.

The WHO recommended intervention of Directly Observed Treatment, Short-course (DOTS) appears to have been less successful than expected in reducing the burden of TB in some high prevalence settings. One strategy for enhancing DOTS is incorporating active case-finding through screening contacts of TB patients as widely used in low-prevalence settings. Predictive models that incorporate population-level effects on transmission provide one means of predicting impacts of such interventions. We aim to identify all TB transmission modelling studies addressing contact tracing and to describe and critically assess their modelling assumptions, parameter choices and relevance to policy. We searched MEDLINE, SCOPUS, COMPENDEX, Google Scholar and Web of Science databases for relevant English language publications up to February 2012. Of the 1285 studies identified, only 5 studies met our inclusion criteria of models of TB transmission dynamics in human populations designed to incorporate contact tracing as an intervention. Detailed implementation of contact processes was only present in two studies, while only one study presented a model for a high prevalence, developing world setting. Some use of relevant data for parameter estimation was made in each study however validation of the predicted impact of interventions was not attempted in any of the studies. Despite a large body of literature on TB transmission modelling, few published studies incorporate contact tracing. There is considerable scope for future analyses to make better use of data and to apply individual based models to facilitate more realistic patterns of infectious contact. Combined with a focus on high burden settings this would greatly increase the potential for models to inform the use of contract tracing as a TB control policy. Our findings highlight the potential for collaborative work between clinicians, epidemiologists and modellers to gather data required to enhance model development and validation and hence better inform future public health policy.

Background There are substantial differences between the costs of medical masks and N95 respirators. Cost-effectiveness analysis is required to assist decision-makers evaluating alternative healthcare worker (HCW) mask/respirator strategies. This study aims to compare the cost-effectiveness of N95 respirators and medical masks for protecting HCWs in Beijing, China. Methods We developed a cost-effectiveness analysis model utilising efficacy and resource use data from two cluster randomised clinical trials assessing various mask/respirator strategies conducted in HCWs in Level 2 and 3 Beijing hospitals for the 2008–09 and 2009–10 influenza seasons. The main outcome measure was the incremental cost-effectiveness ratio (ICER) per clinical respiratory illness (CRI) case prevented. We used a societal perspective which included intervention costs, the healthcare costs of CRI in HCWs and absenteeism costs. Results The incremental cost to prevent a CRI case with continuous use of N95 respirators when compared to medical masks ranged from US $490–$1230 (approx. 3000-7600 RMB). One-way sensitivity analysis indicated that the CRI attack rate and intervention effectiveness had the greatest impact on cost-effectiveness. Conclusions The determination of cost-effectiveness for mask/respirator strategies will depend on the willingness to pay to prevent a CRI case in a HCW, which will vary between countries. In the case of a highly pathogenic pandemic, respirator use in HCWs would likely be a cost-effective intervention.

Historically, counting influenza recorded in administrative health outcome databases has been considered insufficient to estimate influenza attributable morbidity and mortality in populations. We used database record linkage to evaluate whether modern databases have similar limitations. Person-level records were linked across databases of laboratory notified influenza, emergency department (ED) presentations, hospital admissions and death registrations, from the population (∼6.9 million) of New South Wales (NSW), Australia, 2005 to 2008. There were 2568 virologically diagnosed influenza infections notified. Among those, 25% of 40 who died, 49% of 1451 with a hospital admission and 7% of 1742 with an ED presentation had influenza recorded on the respective database record. Compared with persons aged ≥65 years and residents of regional and remote areas, respectively, children and residents of major cities were more likely to have influenza coded on their admission record. Compared with older persons and admitted patients, respectively, working age persons and non-admitted persons were more likely to have influenza coded on their ED record. On both ED and admission records, persons with influenza type A infection were more likely than those with type B infection to have influenza coded. Among death registrations, hospital admissions and ED presentations with influenza recorded as a cause of illness, 15%, 28% and 1.4%, respectively, also had laboratory notified influenza. Time trends in counts of influenza recorded on the ED, admission and death databases reflected the trend in counts of virologically diagnosed influenza. A minority of the death, hospital admission and ED records for persons with a virologically diagnosed influenza infection identified influenza as a cause of illness. Few database records with influenza recorded as a cause had laboratory confirmation. The databases have limited value for estimating incidence of influenza outcomes, but can be used for monitoring variation in incidence over time.

Herpes zoster (HZ) is a common condition that increases in incidence with older age but vaccines are available to prevent the disease. However, there are limited data estimating the health system burden attributable to herpes zoster by age. In this study, we quantified excess healthcare resource usage associated with HZ during the acute/sub-acute period of disease (21days before to 90 days after onset) in 5952 cases and an equal number of controls matched on age, sex, and prior healthcare resource usage. Estimates were adjusted for potential confounders in multivariable regression models. Using population-based estimates of HZ incidence, we calculated the age-specific excess number of health service usage events attributable to HZ in the population. Per HZ case, there was an average of 0.06 (95% CI 0.04-0.08) excess hospitalisations, 1.61 (95% CI 1.51-1.69) excess general practitioner visits, 1.96 (95% CI 1.86-2.15) excess prescriptions filled and 0.11 (95% CI 0.09-0.13) excess emergency department visits. The average number of healthcare resource use events, and the estimated excess per 100,000 population increased with increasing age but were similar for men and women, except for higher rates of hospitalisation in men. The excess annual HZ associated burden of hospitalisations was highest in adults ≥80 years (N = 2244, 95%CI 1719-2767); GP visits was highest in those 60-69 years (N = 50567, 95%CI 39958-61105), prescriptions and ED visits were highest in 70-79 years (N = 50524, 95%CI 40634-60471 and N = 2891, 95%CI 2319-3449 respectively). This study provides important data to establish the healthcare utilisation associated with HZ against which detailed cost-effectiveness analyses of HZ immunisation in older adults can be conducted.