Modeling Respiratory Syncytial Virus Adult Vaccination in the United States With a Dynamic Transmission Model.

BACKGROUND: Respiratory syncytial virus (RSV) is shown to cause substantial morbidity, hospitalization, and mortality in infants and older adults. Population-level modeling of RSV allows to estimate the full burden of disease and the potential epidemiological impact of novel prophylactics. METHODS: We modeled the RSV epidemiology in the United States across all ages using a deterministic compartmental transmission model. Population-level symptomatic RSV acute respiratory tract infection (ARI) cases were projected across different natural history scenarios with and without vaccination of adults aged ≥60 years. The impact of vaccine efficacy against ARIs, infectiousness and vaccine coverage on ARI incidence were assessed. The impact on medical attendance, hospitalization, complications, death, and other outcomes was also derived. RESULTS: Without a vaccine, we project 17.5-22.6 million symptomatic RSV ARI cases annually in adults aged ≥18 years in the US, with 3.6-4.8 million/year occurring in adults aged ≥60 years. Modeling indicates that up to 2.0 million symptomatic RSV-ARI cases could be prevented annually in ≥60-year-olds with a hypothetical vaccine (70% vaccine efficacy against symptomatic ARI and 60% vaccine coverage) and that up to 0.69 million/year could be prevented in the nonvaccinated population, assuming 50% vaccine impact on infectiousness. CONCLUSIONS: The model provides estimated burden of RSV in the US across all age groups, with substantial burden projected specifically in older adults. Vaccination of adults aged ≥60 years could significantly reduce the burden of disease in this population, with additional indirect effect in adults aged <60 years due to reduced transmissibility.

Optimising the case-crossover design for use in shared exposure settings.

With a case-crossover design, a case's exposure during a risk period is compared to the case's exposures at referent periods. The selection of referents for this self-controlled design is determined by the referent selection strategy (RSS). Previous research mainly focused on systematic bias associated with the RSS. We additionally focused on how RSS determines the number of referents per risk, sensitivity to overdispersion and time-varying confounding.We illustrated the consequences of different RSS using a simulation study informed by data on meteorological variables and Legionnaires' disease. By randomising the events and exposure time series, we explored statistical power associated with time-stratified and fixed bidirectional RSS and their susceptibility to systematic bias and confounding bias. In addition, we investigated how a high number of events on the same date (e.g. outbreaks) affected coefficient estimation. As illustrated by our work, referent selection alone can be insufficient to control for a time-varying confounding bias. In contrast to systematic bias, confounding bias can be hard to detect. We studied potential solutions: varying the model parameters and link-function, outlier-removal and aggregating the input-data over smaller areas. Our simulation study offers a framework for researchers looking to detect and to avoid bias in case-crossover studies.

Short-term associations between Legionnaires' disease incidence and meteorological variables in Belgium, 2011-2019.

The number of reported cases with Legionnaires' disease (LD) is increasing in Belgium. Previous studies have investigated the associations between LD incidence and meteorological factors, but the Belgian data remained unexplored. We investigated data collected between 2011 and 2019. Daily exposure data on temperature, relative humidity, precipitation and wind speed was obtained from the Royal Meteorological Institute for 29 weather stations. Case data were collected from the national reference centre and through mandatory notification. Daily case and exposure data were aggregated by province. We conducted a time-stratified case-crossover study. The 'at risk' period was defined as 10 to 2 days prior to disease onset. The corresponding days in the other study years were selected as referents. We fitted separate conditional Poisson models for each day in the 'at risk' period and a distributed lag non-linear model (DLNM) which fitted all data in one model. LD incidence showed a yearly peak in August and September. A total of 614 cases were included. Given seasonality, a sequence of precipitation, followed by high relative humidity and low wind speed showed a statistically significant association with the number of cases 6 to 4 days later. We discussed the advantages of DLNM in this context.

The seroprevalence of cytomegalovirus infection in Belgium anno 2002 and 2006: a comparative analysis with hepatitis A virus seroprevalence.

Cytomegalovirus (CMV) infection is endemic worldwide but its seroprevalence varies widely. The goal of this study was to estimate the age-specific seroprevalence of CMV infection in Belgium based on two cross-sectional serological datasets from 2002 and 2006. The seroprevalence was estimated relying on diagnostic test results based on cut-off values pre-specified by the manufacturers of the tests as well as relying on mixture models applied to continuous pathogen-specific immunoglobulin G antibody titre concentrations. The age-specific seroprevalence of hepatitis A virus (HAV), based on three Belgian cross-sectional serological datasets from 1993, 2002 and 2006, was used as a comparator since individuals acquire lifelong immunity upon recovery, implying an increasing seroprevalence with age. The age group weighted overall CMV seroprevalence derived from the mixture model was 32% (95% confidence interval (CI) 31-34%) in 2002 and 31% (95% CI 30-32%) in 2006. We demonstrated that CMV epidemiology differs from the immunizing infection HAV. This was the first large-scale study of CMV and HAV serial datasets in Belgium, estimating seroprevalence specified by age and birth cohort.

Current levels of gonorrhoea screening in MSM in Belgium may have little effect on prevalence: a modelling study.

There is considerable uncertainty as to the effectiveness of Neisseria gonorrhoeae (NG) screening in men who have sex with men. It is important to ensure that screening has benefits that outweigh the risks of increased antibiotics resistance. We develop a mathematical model to estimate the effectiveness of screening on prevalence. Separable Temporal Exponential family Random Graph Models are used to model the sexual relationships network, both with main and casual partners. Next, the transmission of Gonorrhoea is simulated on this network. The models are implemented using the R package 'statnet', which we adapted among other things to incorporate infection status at the pharynx, urethra and rectum separately and to distinguish between anal sex, oral sex and rimming. The different screening programmes compared are no screening, 3.5% of the population screened, 32% screened and 50% screened. The model simulates day-by-day evolution for 10 years of a population of 10 000. If half of the population would be screened, the prevalence in the pharynx decreases from 11.9% to 10.2%. We conclude that the limited impact of screening on NG prevalence may not outweigh the increased risk of antibiotic resistance.

Estimating age-time-dependent malaria force of infection accounting for unobserved heterogeneity.

Despite well-recognized heterogeneity in malaria transmission, key parameters such as the force of infection (FOI) are generally estimated ignoring the intrinsic variability in individual infection risks. Given the potential impact of heterogeneity on the estimation of the FOI, we estimate this quantity accounting for both observed and unobserved heterogeneity. We used cohort data of children aged 0·5-10 years evaluated for the presence of malaria parasites at three sites in Uganda. Assuming a Susceptible-Infected-Susceptible model, we show how the FOI relates to the point prevalence, enabling the estimation of the FOI by modelling the prevalence using a generalized linear mixed model. We derive bounds for varying parasite clearance distributions. The resulting FOI varies significantly with age and is estimated to be highest among children aged 5-10 years in areas of high and medium malaria transmission and highest in children aged below 1 year in a low transmission setting. Heterogeneity is greater between than within households and it increases with decreasing risk of malaria infection. This suggests that next to the individual's age, heterogeneity in malaria FOI may be attributed to household conditions. When estimating the FOI, accounting for both observed and unobserved heterogeneity in malaria acquisition is important for refining malaria spread models.

A systematic review of varicella seroprevalence in European countries before universal childhood immunization: deriving incidence from seroprevalence data.

Surveillance systems for varicella in Europe are highly heterogeneous or completely absent. We estimated the varicella incidence based on seroprevalence data, as these data are largely available and not biased by under-reporting or underascertainment. We conducted a systematic literature search for varicella serological data in Europe prior to introduction of universal varicella immunization. Age-specific serological data were pooled by country and serological profiles estimated using the catalytic model with piecewise constant force of infection. From the estimated profiles, we derived the annual incidence of varicella infection (/100·000) for six age groups (<5, 5-9, 10-14, 15-19, 20-39 and 40-65 years). In total, 43 studies from 16 countries were identified. By the age of 15 years, over 90% of the population has been infected by varicella in all countries except for Greece (86·6%) and Italy (85·3%). Substantial variability across countries exists in the age-specific annual incidence of varicella primary infection among the <5 years old (from 7052 to 16 122 per 100 000) and 5-9 years old (from 3292 to 11 798 per 100 000). The apparent validity and robustness of our estimates highlight the importance of serological data for the characterization of varicella epidemiology, even in the absence of sampling or assay standardization.

Community-acquired pneumonia (CAP) hospitalizations and deaths: is there a role for quality improvement through inter-hospital comparisons?

OBJECTIVE: To assess between-hospital variations in standardized in-hospital mortality ratios of community-acquired pneumonia (CAP), and identify possible leads for quality improvement. DESIGN: We used an administrative database to estimate standardized in-hospital mortality ratios for 111 Belgian hospitals, by carrying out a set of hierarchical logistic regression models, intended to disentangle therapeutic attitudes and biases. To facilitate the detection of false-negative/positive results, we added an inconclusive zone to the funnel plots, derived from the results of the study. Data quality was validated by comparison with (i) alternative data from the largest Belgian Sickness Fund, (ii) published German hospital data and (iii) the results of an on-site audit. SETTING: All Belgian hospital discharge records from 2004 to 2007. STUDY PARTICIPANTS: A total of 111 776 adult patients were admitted for CAP. MAIN OUTCOME MEASURE: Risk-adjusted standardized in-hospital mortality ratios. RESULTS: Out of the 111 hospitals, we identified five and six outlying hospitals, with standardized mortality ratios of CAP consistently on the extremes of the distribution, as providing possibly better or worse care, respectively, and 18 other hospitals as having possible quality weaknesses/strengths. At the individuals' level of the analysis, adjusted odds ratios showed the paramount importance of old age, comorbidity and mechanical ventilation. The data compared well with the different validation sources. CONCLUSIONS: Despite the limitations inherent to administrative data, it seemed possible to establish inter-hospital differences in standardized in-hospital mortality ratios of CAP and to identify leads for quality improvement. Monitoring is needed to assess progress in quality.

Assessing the risk of measles resurgence in a highly vaccinated population: Belgium anno 2013.

Despite long-standing two-dose measles-mumps-rubella (MMR) vaccination, measles outbreaks still occur in highly vaccinated European populations. For instance, large measles outbreaks occurred in France (2008­13), the United Kingdom (2012­13) and the Netherlands (2012). Based on a multicohort model approach, using spatial serological survey data, MMR vaccination coverage data and data on social contacts, we found effective reproduction numbers significantly higher than 1 for measles in Belgium. This indicates that at one of the expected re-introductions, a measles outbreak is likely to spread, especially when it occurs during school term. The predicted average effective reproduction number increased over a 30-year time span from 1.3 to 2.2 and from 1.9 to 3.2 for basic reproduction numbers of 12 and 18, respectively. The expected relative measles incidence was highest in infants under one year of age, in adolescents and young adults. In conclusion, gradually increasing proportions of susceptible adolescents and young adults provide through their highly active social life an avenue for measles to resurge in large outbreaks upon re-introduction in Belgium, especially during school terms. Infants form an important vulnerable group during future measles outbreaks.

INDIVIDUAL-BASED MODELS: POWERFUL OR POWER STRUGGLE?

Individual-based models (IBMs) offer endless possibilities to explore various research questions but come with high model complexity and computational burden. Large-scale IBMs have become feasible but the novel hardware architectures require adapted software. The increased model complexity also requires systematic exploration to gain thorough system understanding. We elaborate on the development of IBMs for vaccine-preventable infectious diseases and model exploration with active learning. Investment in IBM simulator code can lead to significant runtime reductions. We found large performance differences due to data locality. Sorting the population once, reduced simulation time by a factor two. Storing person attributes separately instead of using person objects also seemed more efficient. Next, we improved model performance up to 70% by structuring potential contacts based on health status before processing disease transmission. The active learning approach we present is based on iterative surrogate modelling and model-guided experimentation. Symbolic regression is used for nonlinear response surface modelling with automatic feature selection. We illustrate our approach using an IBM for influenza vaccination. After optimizing the parameter spade, we observed an inverse relationship between vaccination coverage and the clinical attack rate reinforced by herd immunity. These insights can be used to focus and optimise research activities, and to reduce both dimensionality and decision uncertainty.

Determinants of between-country differences in ambulatory antibiotic use and antibiotic resistance in Europe: a longitudinal observational study.

OBJECTIVES: To identify key determinants explaining country-year variations in antibiotic use and resistance. METHODS: Ambulatory antibiotic use data [in defined daily doses per 1000 inhabitants per day (DIDs)] for 19 European countries from 1999 to 2007 were collected, along with 181 variables describing countries in terms of their agriculture, culture, demography, disease burden, education, healthcare organization and socioeconomics. After assessing data availability, overlap and relevance, multiple imputation generalized estimating equations were applied with a stepwise selection procedure to select significant determinants of global antibiotic use (expressed in DIDs), relative use of subgroups (amoxicillin and co-amoxiclav) and resistance of Escherichia coli and Streptococcus pneumoniae. RESULTS: Relative humidity, healthcare expenditure proportional to gross domestic product, feelings of distrust, proportion of population aged >65 years and availability of treatment guidelines were associated with higher total antibiotic use expressed in DIDs. Restrictions on marketing activities towards prescribers, population density, number of antibiotics, educational attainment and degree of atheism were associated with a lower number of total DIDs used. Relative prescribing of amoxicillin and co-amoxiclav was mainly determined by healthcare system choices [e.g. general practitioner (GP) registration and restricted marketing]. Specific antibiotic use was found to be a significant determinant of resistance for some but not all drug/organism combinations. Incentives to stimulate GP gatekeeping were associated with lower levels of resistance, and life expectancy at age 65+ and atheism were associated with more resistance. CONCLUSIONS: Myriad factors influence antibiotic use and resistance at the country level and an important part of these can be modified by policy choices.

A systematic review and meta-regression analysis of mivacurium for tracheal intubation.

We systematically reviewed factors associated with intubation conditions in randomised controlled trials of mivacurium, using random-effects meta-regression analysis. We included 29 studies of 1050 healthy participants. Four factors explained 72.9% of the variation in the probability of excellent intubation conditions: mivacurium dose, 24.4%; opioid use, 29.9%; time to intubation and age together, 18.6%. The odds ratio (95% CI) for excellent intubation was 3.14 (1.65-5.73) for doubling the mivacurium dose, 5.99 (2.14-15.18) for adding opioids to the intubation sequence, and 6.55 (6.01-7.74) for increasing the delay between mivacurium injection and airway insertion from 1 to 2 min in subjects aged 25 years and 2.17 (2.01-2.69) for subjects aged 70 years, p < 0.001 for all. We conclude that good conditions for tracheal intubation are more likely by delaying laryngoscopy after injecting a higher dose of mivacurium with an opioid, particularly in older people.

Rotavirus vaccination coverage and adherence to recommended age among infants in Flanders (Belgium) in 2012.

In Belgium, rotavirus vaccination has been recommended and partially reimbursed since October 2006. Through a retrospective survey in 2012, we estimated the coverage rate of the rotavirus vaccination in Flanders among infants born in 2010. Using a standardised questionnaire, 874 families were interviewed at home, collecting information on demographic characteristics, socio-economic background and documented vaccination history (updated from medical files and vaccination database, if needed). Adherence to the recommended age for vaccination (8, 12 and 16 weeks) was also assessed. The coverage rate for two doses of rotavirus vaccination was 92.2% (95% confidence interval: 90.2-93.8). Respectively 31.7% and 10.1% of the children received their first and second dose at the recommended age. Incomplete vaccination was often a deliberate choice of the parents. Only eight children (1%) were vaccinated after the maximum age of 26 weeks. Factors identified by multiple logistic regression as related to incomplete vaccination were: living in the province of Antwerp, unemployed mother, and three or more older siblings in the household. Four years after introduction, the coverage rates were surprisingly high for a vaccine that is not fully reimbursed and not readily available in the vaccinator's fridge, which is the case for the other recommended infant vaccines.

Chronic disease patients have fewer social contacts: A pilot survey with implications for transmission dynamics.

Non-communicable diseases (NCD) are the most important cause of death in the world. The socio-economic costs associated with NCDs makes it imperative to prevent and control them in the 21st century. The severe toll that the COVID-19 pandemic has taken worldwide is an unfortunate illustration of our limited insight into the infectious risk for the global population. Co-incidence between NCD and infection offers an underexplored opportunity to design preventive policies. In a pilot survey, we observed that the NCD population displays a substantial reduction in their social contacting behavior as compared to the general population. This indicates that existing mathematical models based on contact surveys in the general population are not applicable to the NCD population and that the risk of acquiring an infection following a contact is probably underestimated. Our demonstration of reduced social mixing in several chronic conditions, raises the question to what extent the social mixing is influenced by the burden of disease. We advocate the design of disease-specific contact surveys to address how the burden of disease associates with social contact behavior and the risk of infection. The SARS-CoV-2 pandemic offers an unprecedented opportunity to gain insight into the importance of infection in the NCD population and to find ways to improve healthcare procedures.

Contribution of respiratory pathogens to influenza-like illness consultations.

Influenza-like illnesses (ILIs) are caused by several respiratory pathogens. These pathogens show weak to strong seasonal activity implying seasonality in ILI consultations. In this paper, the contribution of pathogens to seasonality of ILI consultations was statistically modelled. Virological count data were first smoothed using modulation models for seasonal time series. Second, Poisson regression was used regressing ILI consultation counts on the smoothed time series. Using ratios of the estimated regression parameters, relative measures of the underreporting of pathogens were obtained. Influenza viruses A and B, parainfluenza virus and respiratory syncytial virus (RSV) significantly contributed to explain the seasonal variation in ILI consultations. We also found that RSV was the least and influenza virus A is the most underreported pathogen in Belgian laboratory surveillance. The proposed methods and results are helpful in interpreting the data of clinical and laboratory surveillance, which are the essential parts of influenza surveillance.

Estimating the force of infection for HCV in injecting drug users using interval-censored data.

Injecting drug users (IDUs) account for most new HCV infections. The objectives of this study were: to estimate the force of infection for hepatitis C virus in IDUs within the interval-censoring framework and to determine the impact of risk factors such as frequency of injection, drug injected, sharing of syringes and time of first injection on the time to HCV infection. We used data from the Amsterdam Cohort Study collected in The Netherlands and focused on those individuals who were HCV negative upon entry into the study. Based on the results, the force of infection was found to vary with time of first injection. The risk of infection was higher in the first 3 years of an IDU's career, implying estimates based on single cross-sectional studies could be biased. Frequency of injection and type of drug injected were found to be highly significant predictors, whereas sharing syringes was not.

Maternal mumps antibodies in a cohort of children up to the age of 1 year.

UNLABELLED: The duration of the presence of maternal mumps antibodies in a prospective cohort study is presented. Immunoglobulin G against mumps was portioned with a commercial ELISA test (Euroimmun® anti-mumps Virus AT ELISA, Germany) on samples from 213 mother-child pairs at seven time points between pregnancy and 12 months of age. Non-linear mixed models were used to model maternal antibody decay in infants. The model-based median time to loss of antibodies was 3.6 months. The median child-specific time to loss of antibodies in children of naturally immune women (3.8 months) and children of vaccinated women (2.4 months) differed significantly (p = 0.025). The log antibody level of the mother and the log birth weight were correlated with the duration of maternal antibodies in infants (p < 0.0001). CONCLUSION: Children of vaccinated women loose maternal mumps antibodies significantly earlier in life compared to children of naturally infected women. If early administration (<12 months) of the combined measles, mumps, and rubella vaccine is needed, maternal mumps antibodies are not expected to interfere with infant humoral vaccine responses.

Geographical variation of COVID-19 vaccination coverage, ethnic diversity and population composition in Flanders.

The vaccination coverage in Flanders is high, but some regions show lower vaccination willingness as compared to the overall vaccination coverage. Beginning November of 2021, the vaccination rate in Flanders was above 93% in age groups above 45 years, and around 85% in the age groups 12 to 44 years. Apart from Flanders as a whole, focus here is on the health sector Maasland, which has a slightly lower vaccination rate, especially in the age groups 12 to 44 years. In the Maasland region, located on the eastern border of Flanders, there are between 1% and 10% less vaccinated individuals than expected according to the vaccination rate in the whole of Flanders, with lowest vaccination rates in the south of the Maasland region. We study the impact of ethnic diversity in the population, population composition with respect to the ethnicity of individuals (in the sense of how the local population composition differs from the Flemish average), and socio-economic status on the vaccination rate at the level of the statistical sector, apart from the effect of age. We explain the statistical methods to investigate geographical differences and illustrate how one can deal with incomplete information in vaccination registries. Ethnic diversity in a region is associated with lower vaccination rates, as is a lower regional socio-economic status. The composition of the population in Maasland is associated with a 35% reduction in the odds to get vaccinated as compared to the overall Flemish population.

Are we hitting immunity targets? The 2006 age-specific seroprevalence of measles, mumps, rubella, diphtheria and tetanus in Belgium.

Susceptibility to vaccine-preventable diseases in Belgium in 2006 was estimated from a serum survey. Immunoglobulins against measles, mumps, rubella (MMR) and diphtheria at all available ages (1-65 years), and against tetanus in >40-year-olds, were measured by ELISA. Age-standardized overall seronegativity for MMR was low (3·9%, 8·0%, 10·4%, respectively). However, the World Health Organization's targets for measles elimination were not met in 5- to 24-year-olds and about 1 in 7 women at childbearing age (15-39 years) were seronegative for rubella. In adults >40 years, tetanus immunity (87·2%, >0·16 IU/ml) largely exceeded diphtheria immunity (20-45%, >0·1 IU/ml). Despite free universal vaccination against MMR for more than 20 years and against diphtheria and tetanus for almost 60 years, our study revealed specific age groups remaining at risk for infection with these pathogens.

Antibiotic use and resistance in Belgium: the impact of two decades of multi-faceted campaigning.

Objective: To present an overview of almost two decades of multi-faceted campaigning by the Belgian Antibiotic Policy Coordination Committee (BAPCOC) and partners, and its impact on public and prescribers' awareness, outpatient antibiotic use, its cost and antimicrobial resistance in Belgium.Methods: Awareness of both public and prescribers was assessed through pre- and post-campaign interviews and surveys. Outpatient antibiotic use was evaluated using national reimbursement data expressed in number of defined daily doses and packages (a good proxy for treatments) per 1000 inhabitants per day (DID and PID, respectively) from July 1997 to June 2018. Its cost was studied using the same data expressed in number of euros per 1000 inhabitants per day. Antimicrobial resistance was evaluated between 1986 and 2017 using national data on the proportion of Streptococcus pneumoniae isolates not susceptible to penicillins, macrolides and tetracyclines.Results: Antibiotic awareness improved significantly, with general practitioners preferred by 87.5% of respondents as source of information. The Belgian outpatient antibiotic use has decreased by 12.8% in DID and by 42.8% in PID in the 2017-2018 winter compared to the winter before the start of its public awareness campaigns (1999-2000). This evolution coincided with decreasing costs for antibiotics and decreasing antimicrobial resistance. Despite multi-faceted campaigning, outpatient antibiotic use and use of broad-spectrum antibiotics, especially fluoroquinolones and amoxicillin with clavulanic acid, are still high in Belgium.Conclusion: Almost two decades of multi-faceted campaigning coincide with improvements in antibiotic awareness among the public and prescribers, outpatient antibiotic use and resistance. Nevertheless, additional efforts are needed to reach the targets set in BAPCOC's national action plan 2014-2019. Therefore, a new national action plan was developed for 2020-2024 using a One Health approach.