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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.

The existing vaccine paradigm assumes that vaccines only protect against the target infection, that effective vaccines reduce mortality corresponding to the target infection's share of total mortality, and that the effects of vaccines are similar for males and females. However, epidemiological vaccine research has generated observations that contradict these assumptions and suggest that vaccines have important non-specific effects on overall health in populations. These include the observations that several live vaccines reduce the incidence of all-cause mortality in vaccinated compared with unvaccinated populations far more than can be explained by protection against the target infections, and that several non-live vaccines are associated with increased all-cause mortality in females. In this Personal View we describe current observations and contradictions and define six emerging principles that might explain them. First, that live vaccines enhance resistance towards unrelated infections. Second, non-live vaccines enhance the susceptibility of girls to unrelated infections. Third, the most recently administered vaccination has the strongest non-specific effects. Fourth, combinations of live and non-live vaccines given together have variable non-specific health effects. Fifth, vaccinating children with live vaccines in the presence of maternal immunity enhances beneficial non-specific effects and reduces mortality. Finally, vaccines might interact with other co-administered health interventions, for example vitamin A supplementation. The potential implications for child health are substantial. For example, if BCG vaccination was given to children at birth, if higher measles vaccination coverage could be obtained, if diphtheria, tetanus, and pertussis-containing vaccines were not given with or after measles vaccine, or if the BCG strain with the best non-specific effects could be used consistently, then child mortality could be considerably lower. Pursuing these emerging principles could improve our understanding and use of vaccines globally.

To compare the use of antibiotics in children in four Northern European countries. We conducted a register-based study based on individual-level prescription data from national prescription registers. We identified all redeemed outpatient prescriptions for systemic antibiotics in children aged 0-14 years from July 2006 to June 2017 in Denmark, Finland, Norway, and Sweden. We computed incidence rates and incidence rate ratios of treatment episodes with any antibiotic and different antibiotic classes. In 2016/2017, the rates of antibiotic treatment episodes per 1000 person-years in children aged 0-14 years were 429, 284, 219, and 184 in Finland, Denmark, Sweden, and Norway, respectively, and the rate ratios (95% confidence intervals) compared with Norway were 2.33 (2.33-2.34), 1.54 (1.54-1.55), and 1.19 (1.19-1.20) in Finland, Denmark, and Sweden, respectively. The rate of antibiotic treatment episodes declined over time in all countries. The relative reductions in 2016/2017 compared with 2006/2007 were 36% in Finland, 40% in Denmark, 49% in Sweden, and 29% in Norway. Treatment episodes peaked between age 12 and 18 months. The most used antibiotic class was beta-lactamase sensitive penicillins among all children in Norway and Sweden and among children above two years in Denmark, while penicillins with extended spectrum were most used in Finland and among the youngest children in Denmark. In all countries, the use of antibiotics in children declined between 2006 and 2017. However, there were still considerable differences in antibiotic use between otherwise quite similar Nordic countries, with a more than 2-fold difference between the countries with the lowest and highest rates. Interventions to reduce the number of antibiotic treatment episodes in the countries with higher rates could reduce the total antibiotic use.

High‐dose corticosteroids have been associated with increased risk of serious infection in patients with metastatic melanoma treated with immune checkpoint inhibitors targeting cytotoxic T‐lymphocyte antigen 4. This potential association needs to be examined further among patients with other cancer types and for other immune checkpoint inhibitors. We examined whether receipt of high‐dose corticosteroids was associated with increased rates of hospitalization for infection among 981 Danish renal, urothelial, and lung cancer patients followed from first administration of programmed death receptor 1 (PD‐1)/programmed death ligand 1 (PD‐L1) immune checkpoint inhibitors. Our cohort analysis was based on the information from national medical registries. During follow‐up, 522 patients (53.2%) initiated treatment with high‐dose corticosteroids and 317 patients (32.3%) experienced at least one hospitalization for infection. In analyses adjusted for age, sex, and previous use of chemotherapy/targeted therapy, initiation of high‐dose systemic corticosteroids was associated with increased rate of hospitalization for infections (hazard ratio (HR) = 2.96, 95% confidence interval (CI) = 2.41–3.65) even in patients not receiving any chemotherapy/targeted therapy (HR = 3.66, 95% CI = 2.25–5.96). Our findings showed that high‐dose corticosteroid initiation is associated with hospitalization for infection in patients treated with PD‐1/PD‐L1 immune checkpoint inhibitors. Clinicians and patients should be aware of this risk of infection when initiating treatment with high‐dose corticosteroids. High‐dose corticosteroids have been associated with increased risk of serious infection in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs) targeting cytotoxic T‐lymphocyte antigen 4. The present study adds that use of high‐dose corticosteroids is also associated with increased rate of hospitalization for infection among lung, kidney, and urothelial cancer patients treated with ICIs targeting programmed death receptor 1 or programmed death ligand 1 even in patients who did not receive chemotherapy/targeted therapy.

Comparing rates of childhood infectious disease hospitalisations across countries may uncover areas for improvement in the prevention of severe childhood infections. We compared rates of childhood infectious disease hospital contacts across Denmark, Finland, Norway, and Sweden with the overall objective to elucidate potential differences in burden of disease and in organisational and registration practices. Using national registries, we estimated incidence rates for infectious disease hospital contacts between 2008 and 2017 among children aged 0-14 years. We investigated the rates for different types of contacts (inpatient or outpatient including emergency room), duration of admission, and by sex. During the study period, the rate of all hospital contacts per 1000 person-years was highest in Sweden (125.2) followed by Finland (87.1), Denmark (79.0), and Norway (62.1). The rates aligned for inpatient contacts with overnight stays; 19.3 (Denmark), 16.6 (Finland), 16.3 (Norway), and 13.0 (Sweden); these were highest in early infancy in all countries. A peak around 1 year of age was seen in all countries except in Sweden. The rates were higher among boys compared with girls in early childhood, after 13 years of age the rates among girls surpassed the boys. Large cross-country differences were observed for outpatient and short-term hospital contacts for infectious diseases, affected by differences in organisational structures and coding practices across and within countries over time. Inpatient contacts requiring overnight stays reflected more comparable levels of severe infections across countries. Childhood infectious disease morbidity was greatest among boys and before 2 years of age.

To develop algorithms to identify number of lines of anti-neoplastic therapy per patient based on the Danish National Patient Registry (DNPR) and identify which algorithm has the highest percentage agreement with a reference standard of documentation in medical records. We included 179 patients diagnosed between January 1, 2012, and December 31, 2016, with stage II, III, or IV urothelial cell carcinoma or stage III or IV epithelial ovarian cancer, gastric adenocarcinoma, renal cell carcinoma, or non-small cell lung cancer (NSCLC). We developed two algorithms for number of lines of anti-neoplastic therapy based on dates and treatment codes (eg, \"treatment with cisplatin\" or \"cytostatic treatment\") in the DNPR. First, to denote a change in line of therapy the \"Time-based algorithm\" used the number of days between consecutive administrations. Second, the \"Drug-based algorithm\" used information on drug names if available or the number of days between consecutive administrations if no drug names were specified. We calculated the percentage agreement between the algorithms setting the number of allowed days between consecutive administrations from 28 to 50 and the reference standard - information on anti-neoplastic therapy drugs abstracted from medical records and subsequently coded according to lines of anti-neoplastic therapy. For the \"Time-based algorithm\", the highest percentage agreement with the reference standard was found when using <45 days between consecutive administrations (67.6%; 95% CI: 60.1-73.8%). However, the percentage agreement was higher for the \"Drug-based algorithm\" using <45 days between consecutive administrations for registrations where the drug name was unspecified (90.5%; 95% CI: 85.0-93.7%). The algorithm for number of lines of anti-neoplastic therapy that had the highest percentage agreement with the reference standard (medical records) incorporated both registration of specific drug names and <45 days between consecutive administrations if the drug name was unspecified in routinely recorded data from DNPR.

BackgroundThe live smallpox and Bacillus Calmette-Guérin (BCG) vaccinations have been associated with better adult survival in both Guinea-Bissau and Denmark. In Guinea-Bissau, human immunodeficiency virus (HIV)-1 became an important cause of death after smallpox vaccination was phased out globally in 1980. We hypothesised that smallpox and BCG vaccinations were associated with a lower prevalence of HIV-1 infection, and we tested this hypothesis in both Guinea-Bissau and Denmark.MethodsWe conducted 2 studies: (1) a cross-sectional study of HIV infection and vaccination scars in Guinea-Bissau including 1751 individuals and (2) a case-base study with a background population of 46239 individuals in Denmark. In Guinea-Bissau, HIV-1 transmission was almost exclusively sexually transmitted. In Denmark, we excluded intravenous drug users. Data were analyzed using logistic regression.ResultsBacillus Calmette-Guérin and/or smallpox vaccination compared with neither of these vaccines was associated with an adjusted odds ratio (aOR) for HIV-1 of 0.62 (95% confidence interval [CI], 0.36–1.07) in Guinea-Bissau and 0.70 (95% CI, 0.43–1.15) in Denmark. We combined the results from both settings in a meta-analysis (aOR = 0.66; 95% CI, 0.46–0.96). Data from Guinea-Bissau indicated a stronger effect of multiple smallpox vaccination scars (aOR = 0.27; 95% CI, 0.10–0.75) as follows: women, aOR = 0.18 (95% CI, 0.05–0.64); men, aOR = 0.52 (95% CI, 0.12–2.33); sex-differential effect, P = .29.ConclusionsThe studies from Guinea-Bissau and Denmark, 2 very different settings, both suggest that the BCG and smallpox vaccines could be associated with a decreased risk of sexually transmitted HIV-1. It might be informative to pursue this observation and explore possible protective mechanisms as part of the search for an HIV-1 vaccine.

Few studies have described real-world treatment patterns and survival before the widespread use of immune checkpoint inhibitors (ICIs). We aimed to describe anti-cancer treatment including the use of programmed cell death-1 and ligand-1 (PD-1/PD-L1) ICIs and overall survival (OS) in advanced cancer patients as a benchmarking real-world standard before widespread use of ICIs. Using nationwide Danish medical registries, we assembled cohorts of Danish patients with advanced non-small cell lung cancer (NSCLC) (n=12,283), urothelial carcinoma (n=2504), epithelial ovarian cancer (n=1466), gastric adenocarcinoma (n=1457), and renal cell carcinoma (RCC) (n=1261) diagnosed between 1/1/2013 and 31/12/2017. We describe anti-cancer treatment and OS using proportions, medians, and Kaplan-Meier methods. Between 9% (ovarian cancer) and 25% (gastric adenocarcinoma) of patients did not receive anti-cancer treatment. The remaining patients received surgery, radiation therapy, and/or medical therapy. Chemotherapy was the most frequent medical therapy in all cohorts except for RCC (tyrosine kinase inhibitors). PD-L1/PD-1 ICIs were used in 7-8% of the NSCLC and RCC cohorts-mainly as second or higher line treatments. OS was longest in patients starting treatment with surgery (eg 25.6 months [95%-confidence interval (CI)=21.9-29.4] for NSCLC and 21.4 months [95%-CI=19.8-23.5] for urothelial carcinoma) and shortest for radiation therapy (eg 3.9 months [95%-CI=3.6-4.2] for NSCLC and 12.6 months [95%-CI=9.2-17.5] for urothelial carcinoma). NSCLC patients starting with medical therapy had OS between these limits. Median OS for NSCLC patients starting treatment with PD-L1/PD-1 ICIs was 21.4 months (95%-CI=13.9-not estimable). Most patients with advanced NSCLC, urothelial carcinoma, epithelial ovarian cancer, gastric adenocarcinoma and RCC had poor OS in an era where only a minority received PD-L1/PD-1 ICIs. This information on treatment patterns and survival is important as a benchmarking real-world standard before widespread use of ICIs.

It has been suggested that non-live vaccines may increase susceptibility to non-targeted infections and that such deleterious non-specific effects are more pronounced in girls. We investigated whether receipt of non-live vaccine against human papillomavirus (HPV) was associated with increased risk of infectious disease hospitalization. A nationwide cohort study based on detailed individual-level data from national registries was performed in Denmark, Finland, Norway, and Sweden. The cohort consisted of girls aged 11–14 years in Denmark, Finland, and Norway, and 10–14 years in Sweden. Cox regression, with extensive control for potential confounders, was used to assess whether risk of infectious disease hospitalization with at least one overnight stay differed according to time-varying HPV vaccination status. In total, 754 458 girls were included in the analysis. The infectious disease hospitalization rate (per 10 000 person years) was 44.1 in Denmark, 35.7 in Finland, 37.1 in Norway, and 28.5 in Sweden. Comparing HPV-vaccinated with HPV-unvaccinated person time, the adjusted hazard ratio (95% confidence interval) was 0.81 (0.72, 0.90) in Denmark, 0.69 (0.60, 0.80) in Finland, 0.76 (0.66, 0.88) in Norway, and 0.59 (0.49, 0.71) in Sweden. Decreased risk was observed regardless of number of doses, except in Norway, where risk among girls with only one dose did not differ from risk among unvaccinated girls. Receipt of HPV vaccine was consistently associated with decreased risk of infectious disease hospitalization among girls in the Nordic countries. Our study does not support that HPV vaccines have deleterious non-specific effects.