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Background It has been suggested that the transiently increased infection risk following childcare enrolment is compensated by decreased infection risk later in childhood and adolescence. We investigated how childcare enrolment affected rates of antimicrobial-treated infections during childhood and adolescence. Methods In a register-based cohort study of all children born in Denmark 1997–2014 with available exposure information (n = 1 007 448), we assessed the association between childcare enrolment before age 6 years and infection risks up to age 20 years, using antimicrobial exposure as proxy for infections. Nationwide childcare and prescription data were used. We estimated infection rates and the cumulative number of infections using adjusted Poisson regression models. Results We observed 4 599 993 independent episodes of infection (antimicrobial exposure) during follow-up. Childcare enrolment transiently increased infection rates; the younger the child, the greater the increase. The resulting increased cumulative number of infections associated with earlier age at childcare enrolment was not compensated by lower infection risk later in childhood or adolescence. Accordingly, children enrolled in childcare before age 12 months had experienced 0.5–0.7 more infections at age 6 years (in total 4.5–5.1 infections) than peers enrolled at age 3 years, differences that persisted throughout adolescence. The type of childcare had little impact on infection risks. Conclusions Early age at childcare enrolment is associated with a modest increase in the cumulative number of antimicrobial-treated infections at all ages through adolescence. Emphasis should be given to disrupting infectious disease transmission in childcare facilities through prevention strategies with particular focus on the youngest children.

Aim To assess the association between socioeconomic factors and mortality in Danish children diagnosed with different types of severe chronic disease, including cancer. Methods National cohort study 1994-2020 including Danish children with chronic disease. Inclusion was based on diagnoses in The National Patient Register, socioeconomic information was obtained from Statistics Denmark and mortality was ascertained from the Cause of Death Register. Hazard ratios (HR) with 95% confidence intervals (CIs) were based on Cox regression. The factors were combined in one common risk score and the association with disease-specific mortality was analysed overall and by ethnicity status. Results Overall, non-Danish ethnicity (HR = 1.96 (95% CI 1.69-2.28)) was associated with all-cause mortality in 128 129 children (69 435 male and 58 694 female) with chronic disease. Median age at first diagnosis was 1.42 years (range 0-18 years). Low family income was associated with mortality regardless of ethnicity status, and young maternal age was also a notable risk factor across ethnicities. The socioeconomic association was more pronounced in children with cancer. Conclusion In the high-income setting of Denmark, ethnicity and differences in socioeconomic background were associated with child mortality even among children with severe chronic disease. The pattern was more pronounced in paediatric cancer patients.

Declining levels and duration of passively acquired maternal antibodies prompted a Danish trial to test the feasibility of advancing administration of the first measles, mumps, and rubella vaccine (MMR1) from 15 to 6 months of age. A trial-embedded qualitative study aimed to understand parents’ (N = 24) and health professionals’ (N = 11) attitudes about the measles, mumps, and rubella vaccine (MMR) in general and about advancing MMR1 administration. Overly positive parent attitudes were contrasted by members of a vaccine-skeptical organization including parents considering that their child was seriously vaccine-injured long ago. Parents’ attitudes to advancing MMR1 mirrored their attitudes about the MMR vaccine in general, with four positions along a continuum of trust in the healthcare system: unquestioning trust, acceptance after careful consideration, challenging indecisiveness, and defensive rejection. Low tolerance was identified between vaccine supporters and vaccine opponents. Parents of children with perceived serious vaccine-related injuries described lifelong unresolved feelings of guilt. Supporters of advanced MMR1 saw it as a timely and convenient administration of a well-known vaccine, whereas opponents feared it would disturb the children’s immature immune systems and emphasized difficulties in recognizing side effects so early in life. Health professionals were supportive of advancing the MMR1 vaccine and they carefully challenged the parents. Current MMR vaccine supporters show readiness to advance MMR1 administration.

Objective To pave the way for universal or risk factor-based vaccination strategies, the present study aimed to describe the epidemiology and compare risk factors for hospitalization associated with respiratory syncytial virus (RSV) and influenza virus infections in Danish children. Methods National register-based cohort study among 403,422 Danish children born 2010–2016. Results Prior asthma hospitalization, number of children in the household, chronic disease and maternal history of asthma hospitalization were the most important risk factors for both RSV and influenza hospitalization. The incidence of influenza increased at school start. Conclusions Our findings enable targeted vaccination programs for high-risk children with asthma-like disease, chronic disease, siblings in the household, or maternal history of asthma hospitalization.

In this prospective nationwide multicenter study from Denmark, myopericarditis after Pfizer-BioNTech mRNA COVID-19 vaccination was identified in 13 males and 2 females between May 15 and September 15, 2021, among 133,477 vaccinated males and 127,857 vaccinated females 12-17 years of age, equaling 97 males and 16 females per million. In conclusion, the incidence of myopericarditis after COVID-19 vaccination among males appears higher than reports from the United States.

Viral pneumonia is a common cause of hospital admission among Danish children. However, it remains unknown how many admissions among Danish children may be ascribed to viral pneumonia overall.Based on data drawn from the National Patient Register and the Danish Microbiology Database, hospital admissions for viral pneumonia and asthma-like disease were investigated among Danish children and adolescents less than 18 years. Testing of admitted patients for respiratory syncytial virus (RSV) and influenza virus was also considered.A total of 5,218 admissions with a diagnosis of viral pneumonia were identified among Danish children and adolescents less than 18 years from 2012 to 2016. During the same period, 63,731 tests were conducted during hospital admission for RSV or influenza virus, which produced 9,933 positive tests for RSV and 3,287 for influenza. In addition, 43,213 admissions were due to asthma-like disease.The present study documented overlapping age and seasonal epidemiological patterns of different measures of viral pneumonia among Danish children and presented how the collection of data from different sources (diagnoses and diagnostic tests) yielded a more complete picture of the burden of hospital contacts among Danish children and adolescents caused by viral pneumonia. Viral pneumonia is a very common cause of hospital admission among Danish children and adolescents.No specific funding was available for the present project.not relevant.

BackgroundMeasles is a highly contagious and serious infection. Before the introduction of vaccination, measles caused yearly epidemics putting vulnerable children at risk of brain damage and death. Despite safe and cost-effective vaccines, measles remains a leading cause of death in children globally. Due to insufficient vaccine coverage and low levels of in utero transferred antibodies from vaccinated mothers, outbreaks of measles in Denmark and other high-income countries are observed at increasing frequency.The current vaccine was introduced in Denmark in 1987 as a one-shot measles-mumps-rubella vaccine at 15 months, a timing chosen to avoid inhibition of the infant’s immune response by maternal antibodies. One generation later, the MMR vaccinated mothers have lower antibody levels compared to the naturally infected, and their infants are already susceptible at 6 months of age or earlier, thus increasing the risk of epidemics.MethodsThe Danish MMR trial is a double-blind randomized clinical trial recruiting between March 2019 and December 2021 with last patient last visit in February 2022. AltogetherN = 6500 infants aged 6 months will be randomly assigned to intramuscular vaccination with routine MMR (M-M-R VaxPro) or placebo (solvent only). According to the Danish Childhood vaccination program, all infants will receive a routine MMR vaccination at 15 months of age. At randomization, 1 month later, and 1 month after routine MMR vaccination at 15 months of age, a blood sample is drawn from app. 10% (N = 600) of the population. Additionally, hair, saliva, and urine are sampled at randomization. The co-primary study outcomes are immunogenicity 1 month after MMR vaccination at 6 months of age assessed as plaque-reduction neutralization test, and incidence of infectious disease hospitalizations from randomization to 12 months of age. Six weeks post randomization, all participants are interviewed regarding adverse events.Trial registrationThe trial is registered in the EU Clinical Trials Registry. EudraCT registration number:2016-001901-18. Registered on 14 February 2017.

ObjectivesTo assess the risk of acute and post-acute adverse events after SARS-CoV-2 infection in children and adolescents in Denmark and to evaluate the real world effectiveness of the BNT162b2 mRNA vaccine (Pfizer-BioNTech) among adolescents.DesignCohort study.SettingNationwide Danish healthcare registers.ParticipantsAll Danish people younger than 18 years who were either tested for SARS-CoV-2 using reverse transcriptase polymerase chain reaction (RT-PCR) or vaccinated with BNT162b2 to 1 October 2021.Main outcome measuresRisk of hospital admissions (any hospital contact of ≥12 hours); intensive care unit (ICU) admissions; serious complications, including multisystem inflammatory syndrome in children (MIS-C), myocarditis, and neuroimmune disorders; and initiating drug treatment and health service use up to six months after being tested. Vaccine effectiveness in vaccine recipients compared with unvaccinated peers was evaluated as one minus the risk ratio at 20 days after the first dose and 60 days after the second dose.ResultsOf 991 682 children and adolescents tested for SARS-CoV-2 using RT-PCR in Denmark, 74 611 (7.5%) were positive. The risk of hospital admission with any variant for ≥12 hours was 0.49% (95% confidence interval 0.44% to 0.54%; 361/74 350), and 0.01% (0.01% to 0.03%; 10/73 187) of participants were admitted to an ICU within 30 days of testing positive. The risk of MIS-C within two months of SARS-CoV-2 infection was 0.05% (0.03% to 0.06%; 32/70 666), whereas no participants had myocarditis outside of MIS-C or encephalitis and fewer than five had Guillain-Barré syndrome. In the post-acute phase (1-6 months after infection), participants who tested positive for SARS-CoV-2 showed a 1.08-fold (95% confidence interval 1.06-fold to 1.10-fold) increase in rate of contacts with general practitioners compared with a reference cohort sampled among all children tested for SARS-CoV-2 during the study period. Overall, 278 649 adolescents received BNT162b2. Compared with unvaccinated adolescents, the estimated vaccine effectiveness among 229 799 adolescents vaccinated with one dose was 62% (95% confidence interval 59% to 65%) after 20 days, and among 175 176 vaccinated with two doses was 93% (92% to 94%) after 60 days during a period when delta was the dominant variant.ConclusionsThe absolute risks of adverse events after SARS-CoV-2 infection were generally low in Danish children and adolescents, although MIS-C occurred in 0.05% (32/70 666) of participants with RT-PCR confirmed SARS-CoV-2 infection. In adjusted analyses, rates of general practitioner visits were slightly increased in SARS-CoV-2 positive children and adolescents, which could indicate persisting symptoms. BNT162b2 appeared to be effective in reducing the risk of SARS-CoV-2 infection with the delta variant in adolescents.

Background The Bacille Calmette-Guerin (BCG) vaccine against tuberculosis (TB) may have beneficial non-specific effects (NSEs) beyond the protection against TB. This may be related to modifications of the innate immune system. We investigated the effect of BCG at birth on differential white blood cell (WBC) count in healthy, Danish infants. Method The Danish Calmette Study randomised newborns to BCG at birth (Danish strain 1331, Statens Serum Institut) or no intervention. A sub-group of infants had blood samples collected 4 days after randomisation (n = 161), and at age 3 months (n = 152) and 13 months (n = 300). We evaluated the effect of BCG on WBC differential count (total leucocytes, lymphocytes, monocytes, eosinophil, neutrophil and basophil granulocytes (109 cells/L)) measured in peripheral blood. Results Overall, we found no effect of BCG on differential WBC counts at any time point. Conclusion BCG at birth did not affect WBC count in our cohort of healthy, Danish infants.

Objective: To explore the informational needs of mothers with different levels of education in order to improve counselling about vaccination. Methods: In the setting of a large vaccination trial, mothers' assessments and yield of written information in combination with telephone consultations were evaluated in a survey. Furthermore, searching strategies for additional information were investigated. Mothers' perspectives on informational needs were explored in focus group discussions. Results: Out of 2025 mothers, 95% felt well-informed. Of the 4% not feeling well-informed, there were significantly more mothers with basic schooling and nontheoretical education. There was no correlation between searching for additional information and feeling well-informed. The telephone consultation was found to be very supportive for the decision. Conclusion: The written information was digestible over time. The telephone consultation ensured the mothers' understanding by tailoring and deriving meaning from the information to her special needs. Moreover, it helped the mothers gain an overview of risks and benefits and inspired confidence. These findings indicate that the telephone consultation improved health literacy. Practice implications: Individual counselling about vaccines is required in addition to information about side effects and accurate instructions on how to react upon them.

Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1β, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-γ and IL-22 response to BCG. Stratifying for 'age at randomization' we found a potentiating effect of BCG on cytokine production (TNF-α, IL-6, IL-10) in the 4 days post randomization stimulations, among children who were vaccinated at age 2-7 days versus age 0-1 days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4 days post randomization, BCG was associated with higher cytokine production in the later randomized children.

Introduction Prior studies found associations between respiratory syncytial virus (RSV) infection, wheezing, and asthma. The present study aimed to examine the risk of wheezing after RSV, by the history of wheezing. Methods We included 39 children hospitalized for RSV infection (cases) and 23 children hospitalized for nonrespiratory tract infection reasons (controls) and followed the children prospectively with regular standardized telephone interviews until 18 months, and again 5 years after inclusion. The risk of wheeze was estimated by odds ratios (OR), comparing children hospitalized for RSV with children hospitalized for other reasons and stratified by wheezing history. Results Eighteen months after hospitalization for RSV, the adjusted OR of wheezing was 3.16 (95% confidence interval: 0.75–13.3). The effect of hospitalization for RSV on the risk of wheeze was significantly present among children who did not wheeze already before inclusion (adjusted OR: 11.83; 95% confidence interval: 1.12–124.9), while the adjusted OR of wheeze was 0.95 (95% confidence interval: 0.10–9.00) among children who wheezed already before inclusion. The adjusted OR of wheeze after hospitalization for RSV among children who did not wheeze before inclusion was 8.50 (95% confidence interval: 0.79–91.6) 5 years after inclusion. Conclusion We conclude that the effect of severe RSV infection requiring hospitalization differs according to the history of wheezing, and wanes with time. We recommend that future studies on severe RSV infection and the risk of subsequent wheeze and asthma include information on prior wheeze and asthma.

Palivizumab is a humanized monoclonal antibody designed to provide passive immunity against respiratory syncytial virus. It is prescribed to children at high risk for severe infection with respiratory syncytial virus. However, little is known about the risk of the immune-mediated diseases atopic dermatitis, asthma, and allergic rhinoconjunctivitis after palivizumab exposure. Our objective was to investigate whether exposure to palivizumab was associated with atopic dermatitis, asthma, or allergic rhinoconjunctivitis in childhood. This was a cross-national population-based cohort study including data from 769,523 Danish children born 1 January 1999–31 December 2010 and 581,742 Swedish children born 1 July 2005–31 December 2010. Since palivizumab is only indicated for children at the highest risk, sub-cohorts of preterm children, children with bronchopulmonary dysplasia, and children with hemodynamic significant heart disease were defined. Of the 1,351,265 children included, 1192 (0.09%) were exposed to palivizumab. An increased risk of asthma after palivizumab exposure was observed in the total birth cohort (hazard ratio [HR] 1.49; 95% confidence interval [CI] 1.32–1.68) and in the sub-cohort of preterm children (HR 1.24; 95% CI 1.07–1.44). However, post hoc analyses using the propensity score to balance confounding factors found no increased risk of asthma in preterm children (HR 0.91; 95% CI 0.56–1.48). No increased risks of atopic dermatitis (HR 1.18; 95% CI 0.94–1.48) or allergic rhinoconjunctivitis (HR 1.14; 95% CI 0.92–1.42) were observed. Exposure to palivizumab neither increased the risk of atopic disease nor protected against asthma.

ObjectivesTo estimate the association between childhood vaccination and subsequent morbidity and mortality by adjusting for environmental and host factors. Further, to examine the degree of residual confounding in such observational studies.DesignRegister-based cohort study including 1 122 929 Danish children.ParticipantsAll children born in Denmark in the period 1999–2016 who survived until 16 months of age without prior migration followed from 16 months until the first of the following: event of interest, migration, 5 years of age or 31 December 2016.Main outcome measuresAdjusted HRs (aHRs) and absolute risks were calculated for the three outcomes: mortality, hospitalisation for infection and asthma using register data on deaths, specific hospital contacts and dispensed prescribed medication. The exposure was the combination of the routine vaccines against diphteria–tetanus–pertussis–polio–Haemophilus influenzaetype b and measles–mumps–rubella (DTP and MMR in short) administered in early childhood. Hospitalisation due to accidents was analysed as a negative control outcome to examine residual confounding.ResultsChildren with 3DTP+MMR had a lower hazard of mortality than the reference group with 3DTP, adjusted HR (aHR)=0.45 (95% CI: 0.35 to 0.57), whereas the children with 1 or 2 DTP had higher hazards of dying, aHR=1.55 (95% CI: 1.14 to 2.13) and aHR=1.96 (95% CI: 1.34 to 2.89). The vaccination group 3DTP+MMR was associated with a reduced hazard of asthma aHR=0.94 (95% CI: 0.92 to 0.96). Also, the vaccination group 3DTP+MMR was associated with a reduced hazard of hospitalisation due to accidents, aHR=0.83 (0.80 to 0.85) compared with the reference group with 3 DTP.ConclusionsThe results suggested a beneficial impact of MMR on under-five mortality but did not support the hypothesis that DTP is detrimental, since the group of children with fewer DTP vaccinations experienced increased mortality. The results of the study may to some degree be prone to residual confounding since an unexpected association between MMR vaccination and hospitalisation for accidents was observed.

Background The bacillus Calmette-Guérin (BCG) vaccine against tuberculosis might reduce the non–tuberculosis-related child mortality rate in low-income settings. We tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalization for infection in Denmark, a high-income setting. Hospitalization for infection was a secondary outcome in a randomized trial with the primary aim to estimate the potential non-specific effects of BCG vaccination at birth on all-cause hospitalization. Methods A total of 4262 children included in the Danish Calmette Study were assigned randomly to either receive the BCG vaccine or not and were followed through the Danish National Patient Register. The outcome was number of hospitalizations for infection until the age of 15 months. Data were analyzed by Cox regression in intention-to-treat (ITT) and per-protocol (PP) analyses. Results In the ITT analysis, we observed 588 hospitalizations for infection (mean, 0.28 hospitalization per child) among the 2129 children allocated to receive the BCG vaccine and 595 hospitalizations for infection (mean, 0.28 hospitalization per child) among the 2133 children allocated to the control group (hazard ratio [HR], 0.99 [95% confidence interval (CI), 0.85–1.15]). The PP analysis yielded an HR of 1.00 (95% CI, 0.86–1.16). Predefined interaction ITT analyses showed that among 740 children with a BCG-vaccinated mother, the HR for BCG-vaccinated children was 0.65 (95% CI, 0.45–0.94); the HR for children who had a non–BCG-vaccinated mother was 1.10 (95% CI, 0.93–1.29) (P = .01, test of no interaction). Cesarean delivery modified the effect of BCG vaccination (HRs, 0.73 [95% CI, 0.54–0.99] in children born by cesarean section vs 1.10 [95% CI, 0.92–1.30] in other children; P = .02). When the outcome was defined as time to first hospitalization, the HR for premature children after BCG vaccination was 1.81 (95% CI, 0.95–3.43), whereas the HR was 0.94 (95% CI, 0.82–1.08) for children born at term (P = .05). Conclusion BCG vaccination did not affect the rate of hospitalization for infection up to the age of 15 months in Danish children. In future studies, the role of maternal BCG-vaccination, premature birth, and cesarean delivery needs further exploration.

ObjectivesTo describe the temporal development of mortality and health service utilisation defined as in- and outpatient hospital contacts, contacts with general practitioner and specialists, and prescribed dispensed medication among Danish children 0-5 years of age from 1999 to 2016.DesignRegister-based descriptive study.ParticipantsAll children born in Denmark in the period 1994-2016 followed until 5 years of age.Main outcome measuresAnnual incidence rates of mortality and health service utilisation outcomes, and incidence rate ratios compared to the reference calendar year 1999. The new measure of post-discharge mortality is presented.ResultsPost-discharge mortality decreased from 1999 to 2016, IRR2016 = 0.49 (95% CI: 0.36 to 0.66). Total contacts did not change much over time, IRR2016 = 1.02 (1.02 to 1.03), but increased among neonates, IRR2016 = 3.69 (3.63 to 3.75), and decreased among children with chronic disease IRR2016 = 0.94 (0.93 to 0.94). In- and out-patient hospitalisations increased, IRR2016 = 1.26 (1.24-1.27) resp. IRR2016 = 1.62 (1.60-1.63), contacts with medical specialists increased, IRR2016 = 1.43 (1.42 to 1.43), whilst contacts with general practitioner decreased, IRR2016 = 0.91 (0.91 to 0.91). Medication use decreased, IRR2016 = 0.82 (0.82 to 0.82).ConclusionsOur measure of post-discharge mortality was halved during the study period indicating improved health. Overall health service utilisation did not change much, but the type of utilisation changed, and the development over time differed between subgroups defined by age and chronic disease status. Our findings call for considerations about the benefit of increased specialisation and increased use of health services among 'healthy' children not suffering from chronic disease.

Treatment with biologic pharmaceuticals may be associated with an increased risk of immune-mediated disease. Palivizumab is a humanized monoclonal antibody designed to provide passive immunity against respiratory syncytial virus infection. Palivizumab is primarily used in preterm children known to be immunologically immature. The long-term effect of palivizumab in terms of autoimmune diseases has not yet been investigated.Our objective was to investigate whether exposure to palivizumab was associated with the development of autoimmune diseases in children.This was a population-based cohort study including data from 769,523 Danish children born between 1 January 1999 and 31 December 2010 and data from 581,742 Swedish children born between 1 July 2005 and 31 December 2010.Of the 1,351,265 children included, 1192 (0.09 %) were exposed to palivizumab. Nine cases of autoimmune disease were diagnosed among palivizumab-exposed children during the period of observation. Among the children exposed to palivizumab, one child in Denmark developed inflammatory bowel disease; in Sweden, children developed juvenile arthritis (one child), diabetes mellitus (two children), celiac disease (four children), and inflammatory bowel disease (one child). The risk of autoimmune disease was not significantly increased after palivizumab exposure (hazard ratio adjusted for age and country: 1.54; 95 % confidence interval 0.80-2.95).The risk of autoimmune disease was not increased after palivizumab exposure. Given the small number of incident cases of autoimmune disease observed, this finding should be interpreted with caution.

Background Bacillus Calmette-Guerin vaccine (BCG) induces a complex, pro-inflammatory immune response. Obesity is associated with low-grade inflammation. Aims The purpose of the study was to test whether BCG at birth has effects on infant growth and body composition. Study design, subjects, and outcome measures The Danish Calmette Study is a randomized, clinical trial. The study was conducted at three university hospitals and randomized 4262 children of gestational age ≥ 32 weeks to receive BCG within seven days of birth or to a no-intervention control group. Follow-up consisted of clinical examinations. Outcome measures were weight and length at 3 months, and weight, length, mid upper-arm circumference, and triceps and subscapular skinfold at 13 months. Data collectors were blinded to allocation. Anthropometric measurements were converted to z-scores using WHO reference population. Results Follow-up was 94% complete at 3 and 13 months after birth. The children were bigger than the WHO reference population. There was no effect of BCG on weight z-score at 13 months (− 0.028 [95% confidence interval: − 0.085 to 0.029], p = 0.34). There was no effect on weight and length at 3 months, or length, mid-upper-arm circumference, or triceps and subscapular skinfold at 13 months. Conclusion In this study, vaccination with BCG at birth did not have effects on child growth or body composition at 13 months. Trial registration www.clinicaltrials.gov , registration number NCT01694108 .

BackgroundThe BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting.MethodsPregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age. Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per-protocol analyses.Results4184 pregnant women were randomised and their 4262 children allocated to BCG or no intervention. There was no difference in risk of hospitalisation up to 15 months of age; 2129 children randomised to BCG experienced 1047 hospitalisations with a mean of 0.49 hospitalisation per child compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0.94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics.ConclusionsBCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15 months of age in this Danish study population.Trial registration numberNCT01694108, results.

Background: Childhood infections are common and Bacillus Calmette-Guérin (BCG) vaccination at birth may prevent these via nonspecific effects. Methods: A randomized, clinical multicenter trial. All women planning to give birth (n = 16,521) at the three study sites were invited during the recruitment period. Participating children were randomized to receive BCG within 7 d of birth or to a no intervention control group. Parent-reported infections (events) were collected using telephone interviews at 3 and 13 mo. Data collectors were blinded to allocation. Results: The analyses included 4,224/4,262 (99%) and 4,192/4,262 (98%) children at 3 and 13 mo. From 0 to 3 mo, there were 291 events in the BCG group vs. 336 events in the control group, incidence rate ratio (IRR) = 0.87 (95% confidence interval (CI): 0.72 to 1.05). In this age group, the IRR was 0.62 (95% CI: 0.39 to 0.98) if the mother was BCG vaccinated. From 3 to 13 mo, there were 7,028 vs. 6,791 events, IRR = 1.02 (95% CI: 0.97 to 1.07). Conclusion: This study did not find a nonspecific public health benefit of BCG on parent-reported infections. BCG may have reduced the incidence of infections in children of BCG-vaccinated mothers during the first 3 mo.

Objectives Estimating associations between somatic and socioeconomic risk factors and post-discharge under-five mortality. Design Register-based national cohort study using multiple Cox regression. Participants The population of 1,263,795 Danish children live-born 1997-2016 who survived until date of first discharge to the home after birth was followed from that date until death, emigration, 5 years of age or 31 December 2016. Main outcome measures (A) Mortality hazard ratios (HRs) among all children, (B) mortality HRs among children without severe chronic disease, and (C) mortality HRs among children without severe chronic disease or asthma. Main results In the total population (1,947 deaths) severe chronic disease was associated with mortality HR = 15.28 (95% CI: 13.77-16.95). In children without severe chronic-disease (719 deaths) other somatic risk factors were immature birth HR = 3.40 (1.92-6.02), maternal smoking HR = 1.84 (1.55-2.18) and low birth weight HR = 1.74 (1.21-2.51). Socioeconomic risk factors for mortality included: maternal age < 25 years HR = 1.91 (1.38-2.64) compared to > 35 years (similar for 30-35 years and 25-29 years), lowest vs. highest family income tertile HR = 1.76 (1.23-2.51), not living with both parents HR = 1.63 (1.25-2.13), maternal unemployment HR = 1.54 (1.12-2.12), presence of siblings HR = 1.44 (1.20-1.71) and secondary vs. tertiary parental education HR = 1.33 (1.07-1.65) for fathers and HR = 1.23 (1.01-1.52) for mothers. Factors not found to be associated with child mortality in this population included presence of asthma HR = 1.29 (0.83-1.98) and non-Danish ethnicity HR = 0.98 (0.70-1.37). Conclusions Childhood death after discharge to the home after birth and before 5 years of age is a very rare event in Denmark. This 'post-discharge' mortality was heavily associated with severe chronic disease. In children without severe chronic disease, immature birth, maternal smoking and certain socioeconomic characteristics were noticeable risk factors. Mortality may possibly be decreased by focusing on vulnerable groups.

Highlights • MMR vaccination is given to protect against measles, mumps and rubella. • RSV is an important cause of acute lower respiratory infections in young children. • MMR vaccination was associated with 22% lower rate of RSV hospital contacts. • MMR vaccination may reduce the rate or severity of RSV infection., Background The live measles vaccine has been associated with lower non-measles mortality and admissions in low-income countries. The live measles–mumps–rubella vaccine has also been associated with lower rate of admissions with any type of infection in Danish children; the association was strongest for admissions with lower respiratory infections. Objective To examine whether measles, mumps, and rubella (MMR) vaccination was associated with reduced rate of hospital contact related to respiratory syncytial virus (RSV) in a high-income country. Methods Nationwide cohort study of laboratory-confirmed RSV hospital contacts at age 14–23 months in all children born in Denmark 1997–2002 who had already received the vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) at the recommended ages of 3, 5, and 12 months. Results The study included 888 RSV hospital contacts in 128,588 person years of follow up (rate 6.8/1000 person years). Having MMR as the most recent vaccine was associated with a reduced rate of RSV hospital contacts compared with having DTaP-IPV-Hib as the most recent vaccine (Incidence rate ratio (IRR), 0.75; 95% confidence interval (CI), 0.63–0.89). After adjustment for potential confounders including exact age in days the IRR was 0.78 (95% CI, 0.66–0.93). The adjusted IRR was 0.74 (95% CI, 0.60–0.92) in males and 0.84 (95% CI, 0.66–1.06) in females (P Interaction, 0.42). There was no association in the first month after MMR vaccination (adjusted IRR, 0.97; 95% CI, 0.76–1.24) but the adjusted IRR was 0.70 (95% CI, 0.58–0.85) from one month after MMR vaccination. Conclusions MMR vaccination was associated with reduced rate of hospital contacts related to laboratory-confirmed RSV infection. Further research on the association between MMR vaccination and other unrelated pathogens are warranted.

Background: Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. Methods: The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational age

Background Vaccination with Bacillus Calmette-Guerin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. Methods The Danish Calmette Study was conducted from 2012-2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age 0.35 kUA/l) was found in 55/743 (7.4%) children in the BCG group and 50/627 (8.0%) of the control group (risk ratio 0.94 (0.65 to 1.36)). Conclusion In this randomized clinical trial neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age. This article is protected by copyright. All rights reserved.

Background The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis is administered intradermally, and vaccination is often followed by a scar at the injection site. Among BCG-vaccinated individuals, having a scar has been associated with lower mortality. We aimed to examine the impact of vaccination technique for scarring in a high income setting, by assessing the associations between the post injection reaction, the wheal size, and the probability of developing a scar, and scar size. Methods This study was nested within a clinical multicenter study randomizing 4262 infants to either BCG vaccination (BCG 1331 SSI) or no intervention. In this substudy, including 492 vaccinated infants, the immediate post BCG vaccination reaction was registered as either wheal (a raised, blanched papule at the injection site), bulge (a palpable element at the injection site), or no reaction. The presence or absence of a BCG scar and the size the scar was measured at 13 months of age. Results Of 492 infants included, 87% had a wheal after vaccination, 11% had a bulge, and 2% had no reaction. The mean wheal size was 3.8 mm (95% confidence interval 3.7–3.9). Overall, 95% (442/466, 26 lost to follow-up) of BCG-vaccinated infants had a scar at 13 months of age. In infants with a wheal, the probability of developing a scar was 96%, declining to 87% in the case of a bulge, and to 56% in the case of no reaction (p for same probability = 0.03). Wheal size was positively correlated with the probability of getting a scar and scar size. Conclusion Scarring after BCG vaccination has been associated with lower infant mortality. In a high-income setting, we found that correct injection technique is highly important for the development of a BCG scar and that registration of the category of BCG skin reaction (as wheal, bulge, or no reaction) may be used to identify infants at risk of scar failure. Finally, the wheal size was positively associated with both the probability of getting a scar and scar size. Trial registration The study was registered at www.ClinicalTrials.gov with trial registration number NCT01694108. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2641-0) contains supplementary material, which is available to authorized users.

Background The incidence of atopic dermatitis, wheezing, asthma and allergic rhinoconjunctivitis have been increasing. Register-based studies are essential for research in subpopulations with specific diseases, and facilitate epidemiological studies to identify causes and evaluate interventions. Algorithms have been developed to identify children with atopic dermatitis, asthma or allergic rhinoconjunctivitis using register information on disease-specific dispensed prescribed medication and hospital contacts, but the validity of the algorithms has not been evaluated. The present study validated the algorithms versus gold standard deep telephone interviews with the caretaker about physician-diagnosed atopic dermatitis, wheezing, asthma, or allergic rhinoconjunctivitis in the child. Methods The algorithms defined each of the three atopic diseases using register-based information on disease specific hospital contacts and/or filled prescriptions of disease specific medication. Confirmative answers to questions about physician-diagnosed atopic disease were used as the gold standard for the comparison with the algorithms, resulting in sensitivities and specificities and 95% confidence intervals. The interviews with the caretaker of the included 454 Danish children born 1997-2003 were carried out May-September 2015; the mean age of the children at the time of the interview being 15.2 years (standard deviation 1.3 years). Results For the algorithm capturing children with atopic dermatitis, the sensitivity was 74.1% (95-% confidence interval: 66.9-80.2%) and the specificity 73.0% (67.3-78.0%). For the algorithm capturing children with asthma, both the sensitivity of 84.1% (78.0-88.8%) and the specificity of 81.6% (76.5-85.8%) were high compared with physician-diagnosed asthmatic bronchitis (recurrent wheezing). The sensitivity remained high when capturing physician-diagnosed asthma: 83.3% (74.3-89.6%), however, the specificity declined to 66.0% (60.9-70.8%). For allergic rhino-conjunctivitis, the sensitivity was 84.4% (78.0-89.2) and the specificity 81.6% (75.0-84.4). Conclusion The algorithms are valid and valuable tools to identify children with atopic dermatitis, wheezing, asthma or allergic rhinoconjunctivitis on a population level using register data. This article is protected by copyright. All rights reserved.

The Bacillus Calmette–Guérin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets, determined by flow cytometry. In 118 infants blood samples were obtained 4 (±2) days post randomization to BCG vaccination or no intervention, and at 3 and 13 months of age. No effects of BCG were found at 4 days. However, BCG increased proportions of effector memory cells at 3 months (Geometric mean ratio (GMR) 1.62, 95% confidence interval (CI) (1.20–2.21), p = 0.002 for CD4+ T cells and GMR 1.69, 95% CI (1.06–2.70), p = 0.03 for CD8+ T cells), and reduced proportions of late differentiated CD4+ T cells (GMR = 0.62, 95% CI (0.38–1.00), p = 0.05) and apoptotic CD4+ T cells at 13 months (GMR = 0.55, 95% CI (0.32–0.92), p = 0.03). In conclusion, limited overall impact of neonatal BCG vaccination on lymphocyte subsets was found in healthy Danish infants within the first 13 months of life. This is in line with the limited clinical effects of BCG observed in our setting.

Objectives To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A. Design Systematic review, including assessment of risk of bias, and meta-analyses of similar studies. Study eligibility criteria Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5. Data sources Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified. Results Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV. Conclusions Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.

Contains fulltext : 169904.pdf (Publisher’s version ) (Open Access) INTRODUCTION: BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guerin (BCG) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. METHODS: Within 7days after birth, children were randomised 1:1 to BCG vaccination or to the control group (no intervention). After three routine vaccinations given at age 3, 5 and 12months, antibodies against DiTeKiPol/Act-Hib and Prevenar 13 (Streptococcus pneumoniae serotype type 4, 6B, 9V, 14, 18C, 19F and 23F) were measured 4weeks after the third vaccine dose. RESULTS: Among the 300 included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by 'age at randomisation' we found a possible inducing effect of BCG on antibodies against B. pertussis and all pneumococcal serotypes, when BCG was given after the first day of life. Girls had significantly higher antibody levels for Haemophilus influenza type b and pneumococcus than boys. CONCLUSIONS AND RELEVANCE: Three routine vaccinations with DiTeKiPol/Act-Hib and Prevenar 13 induced sero-protective levels in almost all children. No overall effect of neonatal BCG vaccination was observed.

Background: Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. Objective: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. Methods: The Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age. Results: By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. Conclusion: Neonatal BCG had no effect on the development of RW before 13 months of age.

Background: The Bacillus Calmette-Guérin vaccine (BCG) has been associated with beneficial nonspecific effects on infant health. We aimed to examine the effect of BCG at birth on thymic size and the associations between thymic output, circulating lymphocytes, risk of infection, and thymic size. Methods: In infants randomized to BCG or no BCG, thymic index (TI), and thymic/weight index (TWI) were measured by ultrasound at birth and at the age of 3 mo. T cell subpopulations including CD4+ T cells, CD8+ T cells, and recent thymic emigrants (RTEs) were assessed by flow cytometry. Infections up to age 3 mo were parent-reported. Results: BCG vaccination did not affect thymic size at age 3 mo, measured as TI. At birth, the number of lymphocytes, CD4+ T cells, CD8+ T cells, and RTEs were positively associated with TI and TWI. Furthermore, a reduced risk of infections up to age 3 mo was associated with a large thymic size at birth. Conclusion: We found no effect of BCG vaccination on thymic size. The positive association between thymic output, lymphocytes, reduced risk of infections, and TI/TWI suggests that assessment of TI/TWI by ultrasound may be a predictor of the immunological capacity in the newborn.