Genome-Wide Association study of susceptibility to respiratory syncytial virus hospitalization in young children < 5 years of age.

BACKGROUND: Worldwide, respiratory syncytial virus (RSV) infections are among the most common causes of infant hospitalization. Host genetic factors influencing the risk and severity of RSV infection are not well known. METHODS: We conducted a genome-wide association study (GWAS) to investigate single nucleotide polymorphisms (SNPs) associated with severe RSV infections using a nested case-control design based on two Danish cohorts. We compared SNPs from 1786 children hospitalized with RSV to 45,060 controls without a RSV-coded hospitalization. We performed gene-based testing, tissue-enrichment, gene-set enrichment, and a meta-analysis of the two cohorts. Finally, an analysis of potential associations between the severity of RSV infection and genetic markers was performed. RESULTS: We did not detect any significant genome-wide associations between SNPs and RSV infection, or the severity of RSV. We did find potential loci associated with RSV infections on chromosome 5 in one cohort, however, we failed to replicate any signals in both cohorts. CONCLUSION: Despite being the largest GWAS of severe RSV infection, we did not detect any genome-wide significant loci. This may be an indication of a lack of power, or an absence of signal. Future studies might include mild illness and need to be larger to detect any significant associations.

A Retrospective Cohort Study on Infant Respiratory Tract Infection Hospitalizations and Recurrent Wheeze and Asthma Risk: Impact of Respiratory Syncytial Virus.

BACKGROUND: Infant respiratory syncytial virus infection (RSV) has been associated with asthma later in life. We explored the risk of recurrent wheeze or asthma in children with infant RSV-associated hospitalization compared to other respiratory infections. METHODS: We performed a retrospective cohort study using Danish national hospital discharge registers. Infants younger than 6 months, born between January 1995 and October 2018, and with a RSV hospital admission were compared to infants hospitalized for injuries, non-RSV acute upper respiratory tract infection (AURTI), pneumonia and other respiratory pathogens, nonpathogen-coded lower respiratory tract infections (LRTI), pertussis, or nonspecific respiratory infections. Infants were followed until recurrent wheeze or asthma diagnosis, death, migration, age 10 years, or study end. We estimated cumulative incidence rate ratios (CIRR) and hazard ratios (HR) adjusted for sex, age at inclusion, hospital length of stay (LOS), maternal smoking, 5-minute APGAR score (APGAR5), prematurity, and congenital risk factors (CRF). RESULTS: We included 68 130 infants, of whom 20 920 (30.7%) had RSV hospitalization. The cumulative incidence rate of recurrent wheeze or asthma was 16.6 per 1000 person-years after RSV hospitalization, higher than after injury (CIRR, 2.69; 95% confidence interval [CI], 2.48-2.92), AURTI (CIRR, 1.48; 95% CI, 1.34-1.58), or pertussis (CIRR, 2.32; 95% CI, 1.85-2.91), similar to pneumonia and other respiratory pathogens (CIRR, 1.15; 95% CI, .99-1.34) and LRTI (CIRR, 0.79; 95% CI, .60-1.04), but lower than nonspecific respiratory infections (CIRR, 0.79; 95% CI, .73-.87). Adjusted HRs for recurrent wheeze or asthma after RSV hospitalization compared to injuries decreased from 2.37 (95% CI, 2.08-2.70) for 0 to <1 year to 1.23 (95% CI, .88-1.73) for 6 to <10 years for term-born children, and from 1.48 (95% CI, 1.09-2.00) to 0.60 (95% CI, .25-1.43) for preterm-born children. Sex, maternal smoking, LOS, CRF, and APGAR5 were independent risk factors. CONCLUSIONS: Infant RSV hospitalization is associated with recurrent wheeze and asthma hospitalization, predominantly at preschool age. If causal, RSV prophylaxis, including vaccines, may significantly reduce disease burden of wheeze and asthma.

Age-Specific Estimates of Respiratory Syncytial Virus-Associated Hospitalizations in 6 European Countries: A Time Series Analysis.

BACKGROUND: Knowledge on age-specific hospitalizations associated with RSV infection is limited due to limited testing, especially in older children and adults in whom RSV infections are not expected to be severe. Burden estimates based on RSV coding of hospital admissions are known to underestimate the burden of RSV. We aimed to provide robust and reliable age-specific burden estimates of RSV-associated hospital admissions based on data on respiratory infections from national health registers and laboratory-confirmed cases of RSV. METHODS: We conducted multiseason regression analysis of weekly hospitalizations with respiratory infection and weekly laboratory-confirmed cases of RSV and influenza as covariates, based on national health registers and laboratory databases across 6 European countries. The burden of RSV-associated hospitalizations was estimated by age group, clinical diagnosis, and presence of underlying medical conditions. RESULTS: Across the 6 European countries, hospitalizations of children with respiratory infections were clearly associated with RSV, with associated proportions ranging from 28% to 60% in children younger than 3 months and we found substantial proportions of admissions to hospital with respiratory infections associated with RSV in children younger than 3 years. Associated proportions were highest among hospitalizations with ICD-10 codes of "bronchitis and bronchiolitis." In all 6 countries, annual incidence of RSV-associated hospitalizations was >40 per 1000 persons in the age group 0-2 months. In age group 1-2 years the incidence rate ranged from 1.3 to 10.5 hospitalizations per 1000. Adults older than 85 years had hospitalizations with respiratory infection associated to RSV in all 6 countries although incidence rates were low. CONCLUSIONS: Our findings highlight the substantial proportion of RSV infections among hospital admissions across different ages and may help public health professionals and policy makers when planning prevention and control strategies. In addition, our findings provide valuable insights for health care professionals attending to both children and adults presenting with symptoms of viral respiratory infections.

Respiratory Syncytial Virus-Associated Hospital Admissions and Bed Days in Children <5 Years of Age in 7 European Countries.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections (RTIs) in young children. High-quality country-specific estimates of bed days and length of stay (LOS) show the population burden of RSV-RTI on secondary care services and the burden among patients, and can be used to inform RSV immunization implementation decisions. METHODS: We estimated the hospital burden of RSV-associated RTI (RSV-RTI) in children under 5 years in 7 European countries (Finland, Denmark, Norway, Scotland, England, the Netherlands, and Italy) using routinely collected hospital databases during 2001-2018. We described RSV-RTI admission rates during the first year of life by birth month and assessed their correlation with RSV seasonality in 5 of the countries (except for England and Italy). We estimated average annual numbers and rates of bed days for RSV-RTI and other-pathogen RTI, as well as the hospital LOS. RESULTS: We found that infants born 2 months before the peak month of RSV epidemics more frequently had the highest RSV-RTI hospital admission rate. RSV-RTI hospital episodes accounted for 9.9-21.2 bed days per 1000 children aged <5 years annually, with the median (interquartile range) LOS ranging from 2 days (0.5-4 days) to 4 days (2-6 days) between countries. Between 70% and 89% of these bed days were in infants aged <1 year, representing 40.3 (95% confidence interval [CI], 40.1-40.4) to 91.2 (95% CI, 90.6-91.8) bed days per 1000 infants annually. The number of bed days for RSV-RTI was higher than that for RTIs associated with other pathogens in infants aged <1 year, especially in those <6 months. CONCLUSIONS: RSV disease prevention therapies (monoclonal antibodies and maternal vaccines) for infants could help prevent a substantial number of bed days due to RSV-RTI. "High-risk" birth months should be considered when developing RSV immunization schedules. Variation in LOS between countries might reflect differences in hospital care practices.

A Systematic Review of European Clinical Practice Guidelines for Respiratory Syncytial Virus Prophylaxis.

BACKGROUND: Since the widespread adoption of palivizumab prophylaxis in Europe, there have been a number of clinical practice guidelines (CPGs) published for the prevention of respiratory syncytial virus (RSV) infection in children. The aim of this systematic review was to identify CPGs for the prevention of RSV infection across Europe. METHODS: We performed a systematic literature search and contacted European influenza and respiratory virus networks and public health institutions, to identify national CPGs for the prevention of RSV infection. The Reporting Items for practice Guidelines in Healthcare (RIGHT) Statement checklist was applied to extract data and review the quality of reporting. RESULTS: A total of 20 national CPGs were identified, all published between 2000 and 2018. The greatest discrepancy between guidelines was the recommendations for palivizumab prophylaxis for premature infants, with recommendations varying by gestational age. All guidelines recommended or considered the use of palivizumab in infants with bronchopulmonary dysplasia, 85% (n = 17) in children with congenital heart disease (CHD), and 60% (n = 12) in children with severe combined immunodeficiency. CONCLUSIONS: We recommend that agencies publishing RSV prevention guidelines adopt the RIGHT reporting requirements when updating these guidelines to improve the presentation of the evidence-base for decisions.

Public Preferences for Policies to Promote COVID-19 Vaccination Uptake: A Discrete Choice Experiment in The Netherlands.

OBJECTIVES: The COVID-19 pandemic forms an unprecedented public health, economic, and social crisis. Uptake of vaccination is critical for controlling the pandemic. Nevertheless, vaccination hesitancy is considerable, requiring policies to promote uptake. We investigate Dutch citizens' preferences for policies that aim to promote vaccination through facilitating choice of vaccination, profiling it as the norm, making vaccination more attractive through rewards, or punishing people who reject vaccination. METHODS: We conducted a discrete choice experiment in which 747 respondents were asked to choose between policies to promote vaccination uptake and their impacts on the number of deaths, people with permanent health problems, households with income loss, and a tax increase. RESULTS: Respondents generally had a negative preference for policies that promote vaccination. They particularly disliked policies that punish those who reject the vaccine and were more favorable toward policies that reward vaccination, such as awarding additional rights to vaccinated individuals through vaccination passports. Respondents who reject vaccination were in general much more negative about the policy options than respondents who consider accepting the vaccine. Nevertheless, vaccination passports are supported by both respondents who accept the vaccine, those who reject vaccination, and those who are unsure about vaccination. CONCLUSIONS: This study provides concrete directions for governments attempting to increase the vaccination uptake in ways that are supported by the public. Our results could encourage policy makers to focus on policy options that make vaccination easier and reward people who take the vaccine, as especially the implementation of vaccination passports was supported.

First wave of COVID-19 hospital admissions in Denmark: a Nationwide population-based cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease coronavirus disease 2019 (COVID-19), is a worldwide emergency. Demographic, comorbidity and laboratory determinants of death and of ICU admission were explored in all Danish hospitalised patients. METHODS: National health registries were used to identify all hospitalized patients with a COVID-19 diagnosis. We obtained demographics, Charlson Comorbidity Index (CCI), and laboratory results on admission and explored prognostic factors for death using multivariate Cox proportional hazard regression and competing risk survival analysis. RESULTS: Among 2431 hospitalised patients with COVID-19 between February 27 and July 8 (median age 69 years [IQR 53-80], 54.1% males), 359 (14.8%) needed admission to an intensive care unit (ICU) and 455 (18.7%) died within 30 days of follow-up. The seven-day cumulative incidence of ICU admission was lower for females (7.9%) than for males (16.7%), (p < 0.001). Age, high CCI, elevated C-reactive protein (CRP), ferritin, D-dimer, lactate dehydrogenase (LDH), urea, creatinine, lymphopenia, neutrophilia and thrombocytopenia within ±24-h of admission were independently associated with death within the first week in the multivariate analysis. Conditional upon surviving the first week, male sex, age, high CCI, elevated CRP, LDH, creatinine, urea and neutrophil count were independently associated with death within 30 days. Males presented with more pronounced laboratory abnormalities on admission. CONCLUSIONS: Advanced age, male sex, comorbidity, higher levels of systemic inflammation and cell-turnover were independent factors for mortality. Age was the strongest predictor for death, moderate to high level of comorbidity were associated with a nearly two-fold increase in mortality. Mortality was significantly higher in males after surviving the first week.

Identification of risk factors associated with national transmission and late presentation of HIV-1, Denmark, 2009 to 2017.

BackgroundDespite availability of pre-exposure prophylaxis (PrEP), the incidence of HIV-1 in Europe remained stable the past decade. Reduction of new HIV-1 infections requires more knowledge about the profiles of high-risk transmitters and late presenters (LP).AimWe aimed to investigate risk factors associated with HIV-1 transmission clusters and late presentation with HIV-1 in Denmark.MethodsBlood samples and epidemiological information were collected from newly diagnosed HIV-1 patients between 2009 and 2017. We genotyped pol genes and performed phylogenetic analyses to identify clusters. Risk factors for clustering and LP were investigated with partial proportional odds and logistic regression. Covariates included transmission mode, HIV-1 subtype, age, origin and cluster activity.ResultsWe included 1,040 individuals in the analysis, 59.6% identified with subtype B and 48.4% in a cluster. Risk factors for clustering included Danish origin (odds ratio (OR): 2.95; 95% confidence interval (CI): 2.21-3.96), non-LP (OR: 1.44; 95% CI: 1.12-1.86), and men who have sex with men (MSM). Increasing age and non-B subtype infection decreased risk (OR: 0.69; 95% CI: 0.50-0.94). Risk for late presentation was lower for active clusters (OR: 0.60; 95% CI: 0.44-0.82) and Danish origin (OR: 0.43; 95% CI: 0.27-0.67). Non-Danish MSM had a lower risk than non-Danish heterosexuals (OR: 0.34; 95% CI: 0.21-0.55).ConclusionHIV-1 transmission in Denmark is driven by early diagnosed, young, subtype B infected MSM. These may benefit most from PrEP. Non-Danish heterosexual HIV-1 patients could benefit from improved communication to achieve earlier diagnosis and treatment.

Respiratory Syncytial Virus-Associated Hospital Admissions in Children Younger Than 5 Years in 7 European Countries Using Routinely Collected Datasets.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection (RTI) in young children. Registries provide opportunities to explore RSV epidemiology and burden. METHODS: We explored routinely collected hospital data on RSV in children aged < 5 years in 7 European countries. We compare RSV-associated admission rates, age, seasonality, and time trends between countries. RESULTS: We found similar age distributions of RSV-associated hospital admissions in each country, with the highest burden in children < 1 years old and peak at age 1 month. Average annual rates of RTI admission were 41.3-112.0 per 1000 children aged < 1 year and 8.6-22.3 per 1000 children aged < 1 year. In children aged < 5 years, 57%-72% of RTI admissions with specified causal pathogen were coded as RSV, with 62%-87% of pathogen-coded admissions in children < 1 year coded as RSV. CONCLUSIONS: Our results demonstrate the benefits and limitations of using linked routinely collected data to explore epidemiology and burden of RSV. Our future work will use these data to generate estimates of RSV burden using time-series modelling methodology, to inform policymaking and regulatory decisions regarding RSV immunization strategy and monitor the impact of future vaccines.

Disease burden of varicella versus other vaccine-preventable diseases before introduction of vaccination into the national immunisation programme in the Netherlands.

IntroductionEstimating burden of disease (BoD) is an essential first step in the decision-making process on introducing new vaccines into national immunisation programmes (NIPs). For varicella, a common vaccine-preventable disease, BoD in the Netherlands was unknown.AimTo assess national varicella BoD and compare it to BoD of other vaccine-preventable diseases before their introduction in the NIP.MethodsIn this health estimates reporting study, BoD was expressed in disability-adjusted life years (DALYs) using methodology from the Burden of Communicable Diseases in Europe (BCoDE)-project. As no parameters/disease model for varicella (including herpes zoster) were available in the BCoDE toolkit, incidence, disease progression model and parameters were derived from seroprevalence, healthcare registries and published data. For most other diseases, BoD was estimated with existing BCoDE-parameters, adapted to the Netherlands if needed.ResultsIn 2017, the estimated BoD of varicella in the Netherlands was 1,800 (95% uncertainty interval (UI): 1,800-1,900) DALYs. Herpes zoster mainly contributed to this BoD (1,600 DALYs; 91%), which was generally lower than the BoD of most current NIP diseases in the year before their introduction into the NIP. However, BoD for varicella was higher than for rotavirus gastroenteritis (1,100; 95%UI: 440-2,200 DALYs) and meningococcal B disease (620; 95%UI: 490-770 DALYs), two other potential NIP candidates.ConclusionsWhen considering the introduction of a new vaccine in the NIP, BoD is usually estimated in isolation. The current approach assesses BoD in relation to other vaccine-preventable diseases' BoD, which may help national advisory committees on immunisation and policymakers to set vaccination priorities.

Loose Ends in the Epidemiology of the 1918 Pandemic: Explaining the Extreme Mortality Risk in Young Adults.

In the century since the 1918 influenza pandemic, insights have been sought to explain the pandemic's signature pattern of high death rates in young adults and low death rates in the elderly and infants. Our understanding of the origin and evolution of the pandemic has shifted considerably. We review evidence of the characteristic age-related pattern of death during the 1918 pandemic relative to the "original antigenic sin" hypothesis. We analyze age-stratified mortality data from Copenhagen around 1918 to identify break points associated with unusual death risk. Whereas infants had no meaningful risk elevation, death risk gradually increased, peaking for young adults 20-34 years of age before dropping sharply for adults ages 35-44 years, suggesting break points for birth cohorts around 1908 and 1878. Taken together with data from previous studies, there is strong evidence that those born before 1878 or after 1908 were not at increased risk of dying of 1918 pandemic influenza. Although the peak death risk coincided with the 1889-1892 pandemic, the 1908 and 1878 break points do not correspond with known pandemics. An increasing number of interdisciplinary studies covering fields such as virology, phylogenetics, death, and serology offer exciting insights into patterns and reasons for the unusual extreme 1918 pandemic mortality risk in young adults.

Years of Life Lost Due to Influenza-Attributable Mortality in Older Adults in the Netherlands: A Competing-Risks Approach.

We estimated the influenza mortality burden in adults aged 60 years or older in the Netherlands in terms of years of life lost, taking into account competing mortality risks. Weekly laboratory surveillance data for influenza and other respiratory pathogens and weekly extreme temperature served as covariates in Poisson regression models fitted to weekly mortality data, specific to age group, for the period 1999-2000 through 2012-2013. Burden for age groups 60-64 years through 85-89 years was computed as years of life lost before age 90 (YLL90), using restricted mean lifetime survival analysis and accounting for competing risks. Influenza-attributable mortality burden was greatest for persons aged 80-84 years, at 914 YLL90 per 100,000 persons (95% uncertainty interval: 867, 963), followed by persons aged 85-89 years (787 YLL90/100,000; 95% uncertainty interval: 741, 834). Ignoring competing mortality risks in the computation of influenza-attributable YLL90 would lead to substantial overestimation of burden, from 3.5% for persons aged 60-64 years to 82% for those aged 80-89 years at death. Failure to account for competing mortality risks has implications for the accuracy of disease-burden estimates, especially among persons aged 80 years or older. Because the mortality burden borne by the elderly is notably high, prevention initiatives may benefit from being redesigned to more effectively prevent infection in the oldest age groups.

Estimating the Population-Level Effectiveness of Vaccination Programs in the Netherlands.

BACKGROUND: There are few estimates of the effectiveness of long-standing vaccination programs in developed countries. To fill this gap, we investigate the direct and indirect effectiveness of childhood vaccination programs on mortality at the population level in the Netherlands. METHODS: We focused on three communicable infectious diseases, diphtheria, pertussis, and poliomyelitis, for which we expect both direct and indirect effects. As a negative control, we used tetanus, a noncommunicable infectious disease for which only direct effects are anticipated. Mortality data from 1903 to 2012 were obtained from Statistics Netherlands. Vaccination coverage data were obtained from various official reports. For the birth cohorts 1903 through 1975, all-cause and cause-specific childhood mortality burden was estimated using restricted mean lifetime survival methods, and a model was used to describe the prevaccination decline in burden. By projecting model results into the vaccination era, we obtained the expected burden without vaccination. Program effectiveness was estimated as the difference between observed and expected mortality burden. RESULTS: Each vaccination program showed a high overall effectiveness, increasing to nearly 100% within 10 birth cohorts. For diphtheria, 14.9% (95% uncertainty interval [UI] = 12.3%, 17.6%) of mortality burden averted by vaccination was due to indirect protection. For pertussis, this was 32.1% (95% UI = 31.3%, 32.8%). No indirect effects were observed for poliomyelitis or tetanus with -2.4% (UI = -16.7%, 7.1%) and 0.6% (UI = -17.9%, 10.7%), respectively. CONCLUSION: Vaccination programs for diphtheria and pertussis showed substantial indirect effects, providing evidence for herd protection.

The 1919-21 influenza pandemic in Greenland.

In Alaska, the 1918-20 influenza pandemic was devastating, with mortality rates up to 90% of the population, while in other arctic regions in northern Sweden and Norway mortality was considerably lower. We investigated the timing and age-patterns in excess mortality in Greenland during the period 1918-21 and compare these to other epidemics and the 1889-92 pandemic. We accessed the Greenlandic National Archives and transcribed all deaths from 1880 to 1921 by age, geography, and cause of death. We estimated monthly excess mortality and studied the spatial-temporal patterns of the pandemics and compared them to other mortality crises in the 40-year period. The 1918-21 influenza pandemic arrived in Greenland in the summer of 1919, one year delayed due to ship traffic interruptions during the winter months. We found that 5.2% of the Greenland population died of the pandemic with substantial variability between counties (range, 0.1% to 11%). We did not see the typical pandemic age-pattern of high young-adult mortality, possibly due to high baseline mortality in this age-group or remoteness. However, despite substantial mortality, the mortality impact was not standing out relative to other mortality crises, or of similar devastation reported in Alaskan populations.

Regional differences in historical diphtheria and scarlet fever notification rates in The Netherlands, 1905-1925: a spatial-temporal analysis.

BACKGROUND: We describe how rates of two frequently occurring notifiable diseases-diphtheria and scarlet fever-varied between regions of The Netherlands in the early twentieth century, and identify potential factors underlying this variation. METHODS: Digitized weekly mandatory notification data for 1905-1925, municipality level, were aggregated into 27 'spatial units' defined by unique combinations of province and population density category (high: more than 4500; mid : 1250-4500; low: less than 1250 inhabitants km-2). Generalized additive regression models were fitted to estimate the associations between notification rates and population density, infant mortality rate and household income, while adjusting for temporal trends per spatial unit. RESULTS: Annual per capita notification rates for both diphtheria and scarlet fever tended to rise from the beginning of the period 1905-1925 until peaking around 1918/1919. Adjusted diphtheria notification rates were higher for high- and mid- compared with low-density municipalities (by 71.6 cases per 100 000, 95% confidence interval (CI) : 52.7-90.5; 39.0/100 k, 95% CI : 24.7-53.3, respectively). Scarlet fever showed similar associations with population density (35.7 cases per 100 000, 95% CI : 9.4-62.0; 21.4/100 k, 95% CI: 1.5-41.3). CONCLUSIONS: There was considerable spatial variation in notification rates for both diseases in early twentieth century Netherlands, which could partly be explained by factors capturing variation in living conditions and socio-economic circumstances. These findings aid understanding of contemporary respiratory infection transmission.

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

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

Persistent Symptoms and Sequelae After Severe Acute Respiratory Syndrome Coronavirus 2 Infection Not Requiring Hospitalization: Results From Testing Denmark, a Danish Cross-sectional Survey.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with persistent symptoms ("long COVID"). We assessed the burden of long COVID among nonhospitalized adults with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Methods: In the fall of 2020, a cross-sectional survey was performed in the adult Danish general population. This included a self-administered point-of-care test for SARS-CoV-2 antibodies, the Short Form Health Survey (SF-12), and coronavirus disease 2019 (COVID-19)-associated symptom questions. Nonhospitalized respondents with a positive SARS-CoV-2 PCR test ≥12 weeks before the survey (cases) were matched (1:10) to seronegative controls on age, sex, and body mass index. Propensity score-weighted odds ratios (ORs) and ORs for risk factors were estimated for each health outcome. Results: In total, 742 cases and 7420 controls were included. The attributable risk of at least 1 long-COVID symptom was 25.0 per 100 cases (95% confidence interval [CI], 22.2-27.4). Compared to controls, cases reported worse general health (OR, 5.9 [95% CI, 5.0-7.0]) and had higher odds for a broad range of symptoms, particularly loss of taste (OR, 11.8 [95% CI, 9.5-14.6]) and smell (OR, 11.2 [95% CI, 9.1-13.9]). Physical and Mental Component Summary scores were also significantly reduced with differences of -2.5 (95% CI, -3.1 to -1.8) and -2.0 (95% CI, -2.7 to -1.2), respectively. Female sex and severity of initial infection were major risk factors for long COVID. Conclusions: Nonhospitalized SARS-CoV-2 PCR-positive individuals had significantly reduced physical and mental health, and 1 in 4 reported persistence of at least 1 long-COVID symptom.

The dynamics of scarlet fever in The Netherlands, 1906-1920: a historical analysis.

Background. Scarlet fever, an infectious disease caused by Streptococcus pyogenes, largely disappeared in developed countries during the twentieth century. In recent years, scarlet fever is on the rise again, and there is a need for a better understanding of possible factors driving transmission. Methods. Using historical case notification data from the three largest cities in The Netherlands (Amsterdam, Rotterdam and The Hague) from 1906 to 1920, we inferred the transmission rate for scarlet fever using time-series susceptible-infected-recovered (TSIR) methods. Through additive regression modelling, we investigated the contributions of meteorological variables and school term times to transmission rates. Results. Estimated transmission rates varied by city, and were highest overall for Rotterdam, the most densely populated city at that time. High temperature, seasonal precipitation levels and school term timing were associated with transmission rates, but the roles of these factors were limited and not consistent over all three cities. Conclusions. While weather factors alone can only explain a small portion of the variability in transmission rates, these results help understand the historical dynamics of scarlet fever infection in an era with less advanced sanitation and no antibiotic treatment and may offer insights into the driving factors associated with its recent resurgence.

"Please, you go first!" preferences for a COVID-19 vaccine among adults in the Netherlands.

BACKGROUND: Vaccination is generally considered the most direct way to restoring normal life after the outbreak of COVID-19, but the available COVID-19 vaccines are simultaneously embraced and dismissed. Mapping factors for vaccine hesitancy may help the roll-out of COVID-19 vaccines and provide valuable insights for future pandemics. OBJECTIVES: We investigate how characteristics of a COVID-19 vaccine affect the preferences of adult citizens in the Netherlands to take the vaccine directly, to refuse it outright, or to wait a few months and first look at the experiences of others. METHODS: An online sample of 895 respondents participated between November 4th and November 10th, 2020 in a discrete choice experiment including the attributes: percentage of vaccinated individuals protected against COVID-19, month in which the vaccine would become available and the number of cases of mild and severe side effects. The data was analysed by means of panel mixed logit models. RESULTS: Respondents found it important that a safe and effective COVID-19 vaccine becomes available as soon as possible. However, the majority did not want to be the first in line and would rather wait for the experiences of others. The predicted uptake of a vaccine with the optimal combination of attributes was 87%, of whom 55% preferred to take the vaccine after a waiting period. This latter group tends to be lower-educated. Older respondents gave more weight to vaccine effectiveness than younger respondents. CONCLUSIONS: The willingness to take a COVID-19 vaccine is high among adults in the Netherlands, but a considerable proportion prefers to delay their decision to vaccinate until experiences of others are known. Offering this wait-and-see group the opportunity to accept the invitation at a later moment may stimulate vaccination uptake. Our results further suggest that vaccination campaigns targeted at older citizens should focus on the effectiveness of the vaccine.

Trends in governmental expenditure on vaccination programmes in the Netherlands, a historical analysis.

BACKGROUND: Health economic evaluations are often required before implementing a vaccination programme. Such evaluations rarely consider the historical context of a vaccination programme. We review the financial history of vaccination programmes in the Netherlands, and compare these to demographic and macroeconomic developments as well as avoided mortality burden. METHODS: Previously uncatalogued historical expenditures on the Dutch National Immunisation Programme (NIP) and influenza vaccination were obtained from official reports. Costs were adjusted for inflation using Consumer Price Indices and expressed in Euro of 2016. Estimates on mortality burden averted were obtained from previous research and used to calculate the ratio of expenses to averted mortality burden for vaccinations against diphtheria, tetanus, pertussis, polio, measles, mumps and rubella for birth cohorts 1953-1992. RESULTS: Developments towards a uniform government funded NIP started early 1950s with vaccinations against diphtheria, pertussis and tetanus, culminating in its official launch in 1957 together with polio vaccinations. Since the 1980s, expenditure increased nearly five-fold mostly due to the addition of new vaccines, while spending on already implemented vaccinations tended to decline. Overall, expenditure increased from € 5 million in 1957 to € 93 million in 2014. Relative to total healthcare expenditure, the NIP contributed little, ranging between 0.05% and 0.14%. Spending on influenza vaccination increased from € 37 million in 1996 to € 52 million in 2014, while relative to total healthcare expenditure it decreased from 0.069% to 0.055%. In 2014, 0.15% of healthcare expenditure and € 533 per birth was spent on vaccination programmes. Overall, for birth cohorts 1953-1992, € 5.4 thousand (95% confidence interval: 4.0-7.3) was expended per year-of-life-lost averted. CONCLUSION: The actual costs per year-of-life gained are more favorable than estimated here since averted medical costs were not included. Although expenditure on vaccination programmes increased substantially, the contribution to overall healthcare expenditure remained small.