Estimating age-stratified influenza-associated invasive pneumococcal disease in England: A time-series model based on population surveillance data.

BACKGROUND: Measures of the contribution of influenza to Streptococcus pneumoniae infections, both in the seasonal and pandemic setting, are needed to predict the burden of secondary bacterial infections in future pandemics to inform stockpiling. The magnitude of the interaction between these two pathogens has been difficult to quantify because both infections are mainly clinically diagnosed based on signs and symptoms; a combined viral-bacterial testing is rarely performed in routine clinical practice; and surveillance data suffer from confounding problems common to all ecological studies. We proposed a novel multivariate model for age-stratified disease incidence, incorporating contact patterns and estimating disease transmission within and across groups. METHODS AND FINDINGS: We used surveillance data from England over the years 2009 to 2017. Influenza infections were identified through the virological testing of samples taken from patients diagnosed with influenza-like illness (ILI) within the sentinel scheme run by the Royal College of General Practitioners (RCGP). Invasive pneumococcal disease (IPD) cases were routinely reported to Public Health England (PHE) by all the microbiology laboratories included in the national surveillance system. IPD counts at week t, conditional on the previous time point t-1, were assumed to be negative binomially distributed. Influenza counts were linearly included in the model for the mean IPD counts along with an endemic component describing some seasonal background and an autoregressive component mimicking pneumococcal transmission. Using age-specific counts, Akaike information criterion (AIC)-based model selection suggested that the best fit was obtained when the endemic component was expressed as a function of observed temperature and rainfall. Pneumococcal transmission within the same age group was estimated to explain 33.0% (confidence interval [CI] 24.9%-39.9%) of new cases in the elderly, whereas 50.7% (CI 38.8%-63.2%) of incidence in adults aged 15-44 years was attributed to transmission from another age group. The contribution of influenza on IPD during the 2009 pandemic also appeared to vary greatly across subgroups, being highest in school-age children and adults (18.3%, CI 9.4%-28.2%, and 6.07%, CI 2.83%-9.76%, respectively). Other viral infections, such as respiratory syncytial virus (RSV) and rhinovirus, also seemed to have an impact on IPD: RSV contributed 1.87% (CI 0.89%-3.08%) to pneumococcal infections in the 65+ group, whereas 2.14% (CI 0.87%-3.57%) of cases in the group of 45- to 64-year-olds were attributed to rhinovirus. The validity of this modelling strategy relies on the assumption that viral surveillance adequately represents the true incidence of influenza in the population, whereas the small numbers of IPD cases observed in the younger age groups led to significant uncertainty around some parameter estimates. CONCLUSIONS: Our estimates suggested that a pandemic wave of influenza A/H1N1 with comparable severity to the 2009 pandemic could have a modest impact on school-age children and adults in terms of IPD and a small to negligible impact on infants and the elderly. The seasonal impact of other viruses such as RSV and rhinovirus was instead more important in the older population groups

Efficient real-time monitoring of an emerging influenza epidemic: how feasible?

A prompt public health response to a new epidemic relies on the ability to monitor and predict its evolution in real time as data accumulate. The 2009 A/H1N1 outbreak in the UK revealed pandemic data as noisy, contaminated, potentially biased, and originating from multiple sources. This seriously challenges the capacity for real-time monitoring. Here we assess the feasibility of real-time inference based on such data by constructing an analytic tool combining an age-stratified SEIR transmission model with various observation models describing the data generation mechanisms. As batches of data become available, a sequential Monte Carlo (SMC) algorithm is developed to synthesise multiple imperfect data streams, iterate epidemic inferences and assess model adequacy amidst a rapidly evolving epidemic environment, substantially reducing computation time in comparison to standard MCMC, to ensure timely delivery of real-time epidemic assessments. In application to simulated data designed to mimic the 2009 A/H1N1 epidemic, SMC is shown to have additional benefits in terms of assessing predictive performance and coping with parameter non-identifiability.MRC, NIH

Exploiting routinely collected severe case data to monitor and predict influenza outbreaks

Abstract Background Influenza remains a significant burden on health systems. Effective responses rely on the timely understanding of the magnitude and the evolution of an outbreak. For monitoring purposes, data on severe cases of influenza in England are reported weekly to Public Health England. These data are both readily available and have the potential to provide valuable information to estimate and predict the key transmission features of seasonal and pandemic influenza. Methods We propose an epidemic model that links the underlying unobserved influenza transmission process to data on severe influenza cases. Within a Bayesian framework, we infer retrospectively the parameters of the epidemic model for each seasonal outbreak from 2012 to 2015, including: the effective reproduction number; the initial susceptibility; the probability of admission to intensive care given infection; and the effect of school closure on transmission. The model is also implemented in real time to assess whether early forecasting of the number of admissions to intensive care is possible. Results Our model of admissions data allows reconstruction of the underlying transmission dynamics revealing: increased transmission during the season 2013/14 and a noticeable effect of the Christmas school holiday on disease spread during seasons 2012/13 and 2014/15. When information on the initial immunity of the population is available, forecasts of the number of admissions to intensive care can be substantially improved. Conclusion Readily available severe case data can be effectively used to estimate epidemiological characteristics and to predict the evolution of an epidemic, crucially allowing real-time monitoring of the transmission and severity of the outbreak

Efficient real-time monitoring of an emerging influenza pandemic: How feasible?

A prompt public health response to a new epidemic relies on the ability to monitor and predict its evolution in real time as data accumulate. The 2009 A/H1N1 outbreak in the UK revealed pandemic data as noisy, contaminated, potentially biased and originating from multiple sources. This seriously challenges the capacity for real-time monitoring. Here, we assess the feasibility of real-time inference based on such data by constructing an analytic tool combining an age-stratified SEIR transmission model with various observation models describing the data generation mechanisms. As batches of data become available, a sequential Monte Carlo (SMC) algorithm is developed to synthesise multiple imperfect data streams, iterate epidemic inferences and assess model adequacy amidst a rapidly evolving epidemic environment, substantially reducing computation time in comparison to standard MCMC, to ensure timely delivery of real-time epidemic assessments. In application to simulated data designed to mimic the 2009 A/H1N1 epidemic, SMC is shown to have additional benefits in terms of assessing predictive performance and coping with parameter nonidentifiability

Effectiveness of Influenza Vaccination in Preventing Hospitalization Due to Influenza in Children: A Systematic Review and Meta-analysis.

This systematic review assesses the literature for estimates of influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza-associated hospitalization in children. Studies of any design to June 8, 2020, were included if the outcome was hospitalization, participants were 17 years or younger and influenza infection was laboratory-confirmed. A random-effects meta-analysis of 37 studies that used a test-negative design gave a pooled seasonal IVE against hospitalization of 53.3% (47.2-58.8) for any influenza. IVE was higher against influenza A/H1N1pdm09 (68.7%, 56.9-77.2) and lowest against influenza A/H3N2 (35.8%, 23.4-46.3). Estimates by vaccine type ranged from 44.3% (30.1-55.7) for live-attenuated influenza vaccines to 68.9% (53.6-79.2) for inactivated vaccines. IVE estimates were higher in seasons when the circulating influenza strains were antigenically matched to vaccine strains (59.3%, 48.3-68.0). Influenza vaccination gives moderate overall protection against influenza-associated hospitalization in children supporting annual vaccination. IVE varies by influenza subtype and vaccine type

Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study

Objective To establish mortality from pandemic A/H1N1 2009 influenza up to 8 November 2009

Real-time modelling of a pandemic influenza outbreak.

BACKGROUND: Real-time modelling is an essential component of the public health response to an outbreak of pandemic influenza in the UK. A model for epidemic reconstruction based on realistic epidemic surveillance data has been developed, but this model needs enhancing to provide spatially disaggregated epidemic estimates while ensuring that real-time implementation is feasible. OBJECTIVES: To advance state-of-the-art real-time pandemic modelling by (1) developing an existing epidemic model to capture spatial variation in transmission, (2) devising efficient computational algorithms for the provision of timely statistical analysis and (3) incorporating the above into freely available software. METHODS: Markov chain Monte Carlo (MCMC) sampling was used to derive Bayesian statistical inference using 2009 pandemic data from two candidate modelling approaches: (1) a parallel-region (PR) approach, splitting the pandemic into non-interacting epidemics occurring in spatially disjoint regions; and (2) a meta-region (MR) approach, treating the country as a single meta-population with long-range contact rates informed by census data on commuting. Model discrimination is performed through posterior mean deviance statistics alongside more practical considerations. In a real-time context, the use of sequential Monte Carlo (SMC) algorithms to carry out real-time analyses is investigated as an alternative to MCMC using simulated data designed to sternly test both algorithms. SMC-derived analyses are compared with 'gold-standard' MCMC-derived inferences in terms of estimation quality and computational burden. RESULTS: The PR approach provides a better and more timely fit to the epidemic data. Estimates of pandemic quantities of interest are consistent across approaches and, in the PR approach, across regions (e.g. R0 is consistently estimated to be 1.76-1.80, dropping by 43-50% during an over-summer school holiday). A SMC approach was developed, which required some tailoring to tackle a sudden 'shock' in the data resulting from a pandemic intervention. This semi-automated SMC algorithm outperforms MCMC, in terms of both precision of estimates and their timely provision. Software implementing all findings has been developed and installed within Public Health England (PHE), with key staff trained in its use. LIMITATIONS: The PR model lacks the predictive power to forecast the spread of infection in the early stages of a pandemic, whereas the MR model may be limited by its dependence on commuting data to describe transmission routes. As demand for resources increases in a severe pandemic, data from general practices and on hospitalisations may become unreliable or biased. The SMC algorithm developed is semi-automated; therefore, some statistical literacy is required to achieve optimal performance. CONCLUSIONS: Following the objectives, this study found that timely, spatially disaggregate, real-time pandemic inference is feasible, and a system that assumes data as per pandemic preparedness plans has been developed for rapid implementation. FUTURE WORK RECOMMENDATIONS: Modelling studies investigating the impact of pandemic interventions (e.g. vaccination and school closure); the utility of alternative data sources (e.g. internet searches) to augment traditional surveillance; and the correct handling of test sensitivity and specificity in serological data, propagating this uncertainty into the real-time modelling. TRIAL REGISTRATION: Current Controlled Trials ISRCTN40334843. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology programme and will be published in full in Health Technology Assessment; Vol. 21, No. 58. See the NIHR Journals Library website for further project information. Daniela De Angelis was supported by the UK Medical Research Council (Unit Programme Number U105260566) and by PHE. She received funding under the NIHR grant for 10% of her time. The rest of her salary was provided by the MRC and PHE jointly

Changes in characteristics and case-severity in patients hospitalised with influenza A (H1N1) pdm09 infection between two epidemic waves-England, 2009-2010.

BACKGROUND: During 2009-2010, pandemic influenza A (H1N1) pdm09 virus (pH1N1) infections in England occurred in two epidemic waves. Reasons for a reported increase in case-severity during the second wave are unclear. METHODS: We analysed hospital-based surveillance for patients with pH1N1 infections in England during 2009-2010 and linked national data sets to estimate ethnicity, socio-economic status and death within 28 days of admission. We used multivariable logistic regression to assess whether changes in demographic, clinical and management characteristics of patients could explain an increase in ICU admission or death, and accounted for missing values using multiple imputation. RESULTS: During the first wave, 54/960 (6%) hospitalised patients required intensive care and 21/960 (2%) died; during the second wave 143/1420 (10%) required intensive care and 55/1420 (4%) died. In a multivariable model, during the second wave patients were less likely to be from an ethnic minority (OR 0.33, 95% CI 0.26-0.42), have an elevated deprivation score (OR 0.75, 95% CI 0.68-0.83), have known comorbidity (OR 0.78, 95% CI 0.63-0.97) or receive antiviral therapy ≤2 days before onset (OR 0.72, 95% CI 0.56-0.92). Increased case-severity during the second wave was not explained by changes in demographic, clinical or management characteristics. CONCLUSIONS: Monitoring changes in patient characteristics could help target interventions during multiple waves of COVID-19 or a future influenza pandemic. To understand and respond to changes in case-severity, surveillance is needed that includes additional factors such as admission thresholds and seasonal coinfections