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.

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.

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.

Uptake of hepatitis C virus screening and treatment in persons under opioid substitution therapy between 2008 and 2013 in Belgium.

BACKGROUND: Hepatitis C is a viral infection caused by the hepatitis C virus (HCV) with people who inject drugs as the main group at risk worldwide. AIM: This study investigated the differences in uptake for HCV screening and treatment between persons in opioid substitution therapy (OST) and the other members of the Christian Health Insurance Fund in Belgium. METHODS: Invoice data were retrospectively collected from the Christian Health Insurance Fund, representing 42% of the healthcare users. Information on demographics, screening, diagnostic tests, treatment and disease progression was obtained from 2008 till 2013. All people in this study were aged 20-65 year. Persons in the OST group were identified as having at least one prescription reimbursed for methadone. This group was compared to the other members of the Insurance Fund not on OST (NOST). RESULTS: The Insurance Fund registered 8,409 unique OST and 3,525,190 members in the general group. HCV RNA screening rate was higher in the OST group after correction for age and gender (4.3% vs. 0.2%). Ribavirin reimbursement, did not differ between the OST and NOST group screened for HCV RNA (16.9% vs. 14.4%), though the probability of having ribavirin reimbursed was smaller for females than for males. Procedures concerning disease progression were reimbursed less frequently in the HCV RNA screened OST group compared to the NOST group (0.3% vs. 1.2%). CONCLUSION: People on OST were screened more often for HCV RNA. However, the general uptake for HCV screening and treatment in both populations remained suboptimal.

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.

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.

Author Correction: Multidisciplinary study of the secondary immune response in grandparents re-exposed to chickenpox.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

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.

Amoxicillin for acute lower respiratory tract infection in primary care: subgroup analysis by bacterial and viral aetiology.

OBJECTIVE: We aimed to assess the effects of amoxicillin treatment in adult patients presenting to primary care with a lower respiratory tract infection (LRTI) who were infected with a potential bacterial, viral, or mixed bacterial/viral infection. METHODS: This multicentre randomized controlled trial focused on adults with LRTI not suspected for pneumonia. Patients were randomized to receive either antibiotic (amoxicillin 1 g) or placebo three times daily for 7 consecutive days using computer-generated random numbers (follow-up 28 days). In this secondary analysis of the trial, symptom duration (primary outcome), symptom severity (scored 0-6), and illness deterioration (reconsultation with new or worsening symptoms, or hospital admission) were analysed in pre-specified subgroups using regression models. Subgroups of interest were patients with a (strictly) bacterial, (strictly) viral, or combined infection, and patients with elevated values of procalcitonin, C-reactive protein, or blood urea nitrogen. RESULTS: 2058 patients (amoxicillin n = 1036; placebo n = 1022) were randomized. Treatment did not affect symptom duration (n = 1793). Patients from whom a bacterial pathogen only was isolated (n = 207) benefited from amoxicillin in that symptom severity (n = 804) was reduced by 0.26 points (95% CI -0.48 to -0.03). The odds of illness deterioration (n = 2024) was 0.24 (95% CI 0.11 to 0.53) times lower from treatment with amoxicillin when both a bacterial and a viral pathogen were isolated (combined infection; n = 198). CONCLUSIONS: Amoxicillin may reduce the risk of illness deterioration in patients with a combined bacterial and viral infection. We found no clinically meaningful benefit from amoxicillin treatment in other subgroups.

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.

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.

Multidisciplinary study of the secondary immune response in grandparents re-exposed to chickenpox.

Re-exposure to chickenpox may boost varicella-zoster virus (VZV) immunity in the elderly. This secondary immune response is hypothesized to confer protection against herpes zoster. We longitudinally sampled 36 adults over the course of one year after re-exposure to chickenpox. The resulting 183 samples and those of 14 controls were assessed for VZV-specific T-cell immunity and antibody titres. The percentages of VZV-specific CD4+ IL-2-producing T-cells were increased in re-exposed grandparents compared to control participants up to 9 months after re-exposure. Using a longitudinal mixture modelling approach, we found that 25% and 17% of re-exposed grandparents showed a boosting of VZV-specific CD4+ IL-2-producing T-cells and VZV-specific antibodies, respectively. The antibody boosting occurred exclusively in cytomegalovirus (CMV) IgG-positive participants. CMV IgG-positive participants also had higher VZV IE62-specific CD4+ IFN-γ-producing T-cell percentages and VZV-specific antibody titres. The protective effect of re-exposure to chickenpox is likely limited, as boosting only occurred in 17-25% of the VZV re-exposed grandparents and for less than one year.

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.

Model-based inference for small area estimation with sampling weights.

Obtaining reliable estimates about health outcomes for areas or domains where only few to no samples are available is the goal of small area estimation (SAE). Often, we rely on health surveys to obtain information about health outcomes. Such surveys are often characterised by a complex design, stratification, and unequal sampling weights as common features. Hierarchical Bayesian models are well recognised in SAE as a spatial smoothing method, but often ignore the sampling weights that reflect the complex sampling design. In this paper, we focus on data obtained from a health survey where the sampling weights of the sampled individuals are the only information available about the design. We develop a predictive model-based approach to estimate the prevalence of a binary outcome for both the sampled and non-sampled individuals, using hierarchical Bayesian models that take into account the sampling weights. A simulation study is carried out to compare the performance of our proposed method with other established methods. The results indicate that our proposed method achieves great reductions in mean squared error when compared with standard approaches. It performs equally well or better when compared with more elaborate methods when there is a relationship between the responses and the sampling weights. The proposed method is applied to estimate asthma prevalence across districts.

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.

Impact of high intensity exercise on muscle morphology in EAE rats.

The impact of high-intensity exercise on disease progression and muscle contractile properties in experimental autoimmune encephalomyelitis (EAE) remains unclear. Control (CON) and EAE rats were divided into sedentary and exercise groups. Before onset (experiment 1, n=40) and after hindquarter paralysis (experiment 2, n=40), isokinetic foot extensor strength, cross sectional area (CSA) of tibialis anterior (TA), extensor digitorum longus (EDL) and soleus (SOL) and brain-derived neurotrophic factor (BDNF) levels were assessed. EAE reduced muscle fiber CSA of TA, EDL and SOL. In general, exercise was not able to affect CSA, whereas it delayed hindquarter paralysis peak. CON muscle work peaked and declined, while it remained stable in EAE. BDNF-responses were not affected by EAE or exercise. In conclusion, EAE affected CSA-properties of TA, EDL and SOL, which could, partly, explain the absence of peak work during isokinetic muscle performance in EAE-animals. However, exercise was not able to prevent muscle fiber atrophy.

The social contact hypothesis under the assumption of endemic equilibrium: Elucidating the transmission potential of VZV in Europe.

The basic reproduction number R0 and the effective reproduction number R are pivotal parameters in infectious disease epidemiology, quantifying the transmission potential of an infection in a population. We estimate both parameters from 13 pre-vaccination serological data sets on varicella zoster virus (VZV) in 12 European countries and from population-based social contact surveys under the commonly made assumptions of endemic and demographic equilibrium. The fit to the serology is evaluated using the inferred effective reproduction number R as a model eligibility criterion combined with AIC as a model selection criterion. For only 2 out of 12 countries, the common choice of a constant proportionality factor is sufficient to provide a good fit to the seroprevalence data. For the other countries, an age-specific proportionality factor provides a better fit, assuming physical contacts lasting longer than 15 min are a good proxy for potential varicella transmission events. In all countries, primary infection with VZV most often occurs in early childhood, but there is substantial variation in transmission potential with R0 ranging from 2.8 in England and Wales to 7.6 in The Netherlands. Two non-parametric methods, the maximal information coefficient (MIC) and a random forest approach, are used to explain these differences in R0 in terms of relevant country-specific characteristics. Our results suggest an association with three general factors: inequality in wealth, infant vaccination coverage and child care attendance. This illustrates the need to consider fundamental differences between European countries when formulating and parameterizing infectious disease models.

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.