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Background Moderate acute malnutrition (MAM) affects millions of children, increasing their risk of dying from infections. Thymus atrophy may be a marker of malnutrition-associated immunodeficiency, but factors associated with thymus size in children with MAM are unknown, as is the effect of nutritional interventions on thymus size. Methods Thymus size was measured by ultrasound in 279 children in Burkina Faso with MAM, diagnosed by low mid-upper arm circumference (MUAC) and/or low weight-for-length z-score (WLZ), who received 12 weeks treatment with different food supplements as part of a randomized trial. Correlates of thymus size and of changes in thymus size after treatment, and after another 12 weeks of follow-up were identified. Results Thymus size correlated positively with age, anthropometry and blood haemoglobin, and was smaller in children with malaria. Children with malnutrition diagnosed using MUAC had a smaller thymus than children diagnosed based on WLZ. Thymus size increased during and after treatment, similarly across the different food supplement groups. Conclusions In children with MAM, the thymus is smaller in children with anaemia or malaria, and grows with recovery. Assuming that thymus size reflects vulnerability, low MUAC seems to identify more vulnerable children than low WLZ in children with MAM. Impact Thymus atrophy is known to be a marker of the immunodeficiency associated with malnutrition in children.In children with moderate malnutrition, we found the thymus to be smaller in children with anaemia or malaria.Assuming that thymus size reflects vulnerability, low MUAC seems to identify more vulnerable children than low weight for length.Thymus atrophy appears reversible with recovery from malnutrition, with similar growth seen in children randomized to treatment with different nutritional supplements.

AIM Hypertension has been reported in up to 4.0% of American children, but no national data exist in Europe. We studied the frequency of registered hypertension in Danish children and evaluated the data. METHODS This 2014-2015 study focused on patients under the age of 16 registered with hypertension in the Danish National Patient Register and 10 paediatric departments in central and eastern Denmark. The diagnoses were coded according to the International Classification of Diseases, 10th revision. All the subjects' medical records were reviewed, including any confirmed diagnoses. RESULTS There were 55 784 children under 16 in the study regions at 30 April 2014. By May 2015, 222 of those had been registered with hypertension: 200 in the Danish National Patient Register and 191 in the 10 paediatric departments. Their medical records confirmed hypertension in 187 and 185 cases, respectively. The prevalence of registered and confirmed hypertension was 222/553 784 (0.04%). The positive predictive values of hypertension were 187/200 (94%) and 185/191 (97%), and the completeness of diagnosed hypertension was 187/222 (84%) and 185/222 (83%). CONCLUSION The registers had high-quality positive predictive values and completeness, but only 0.04% of the Danish children were registered with a verified diagnosis of hypertension.

Background Studies in low-income countries have shown that among Bacille Calmette-Guérin (BCG) vaccinated children, those who develop a BCG-scar have significantly better survival than those who do not develop a scar. In a Danish multicenter randomized clinical trial we assessed determinants for developing a BCG-scar and for BCG scar size following neonatal BCG vaccination. Methods At three Danish hospitals, newborns were randomized 1:1 to BCG vaccination or no BCG vaccination. The infants were invited for a clinical examination at the ages of 3 and 13 months. At 13 months, the scar site was inspected and scar size measured. We investigated three groups of determinants; external, parental, and individual-level determinants on relative scar prevalence and differences in median scar sizes. Results Among 2118 BCG vaccinated infants, 2039 (96 %) were examined at 13 months; 1857 of these (91 %) had developed a BCG-scar. Compared with Copenhagen University Hospital, Hvidovre (85 %), Copenhagen University Hospital, Rigshospitalet had a scar prevalence of 95 % (adjusted Prevalence ratio (aPR) = 1.24 [CI 95 %: 1.18 to 1.30]); it was 93 % at Kolding Hospital (aPR 1.27 [CI 95 %: 1.19 to 1.35]). Increasing vaccine experience was positively associated with developing a scar and with scar size. Conclusion Across multiple potential determinants of BCG scaring and size, logistical factors dominated. The results support that injection technique is an important determinant of developing a scar. Given the strong link between having a BCG scar and subsequent health, improved BCG vaccination technique could play a major role for child health., BCG vaccine; BCG scar; Non-specific effects; Heterologous immunity.

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.

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.

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.

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.

Congenital heart diseases (CHDs) are reported in 0.8% of newborns. Numerous factors influence cardiovascular development and CHD prevalence, and possibly also development of cardiovascular disease later in life. However, known factors explain the probable etiology in only a fraction of patients. Past large-scale population-based studies have made invaluable contributions to the understanding of cardiac disease, but none recruited participants prenatally and focused on the neonatal period. The Copenhagen Baby Heart Study (CBHS) is a population-based study of the prevalence, spectrum, and prognosis of structural and functional cardiac abnormalities. The CBHS will also establish normal values for neonatal cardiac parameters and biomarkers, and study prenatal and early childhood factors potentially affecting later cardiovascular disease risk. The CBHS is an ongoing multicenter, prospective study recruiting from second trimester pregnancy (gestational weeks 18–20) (expected n = 25,000). Information on parents, pregnancy, and delivery are collected. After birth, umbilical cord blood is collected for biochemical analysis, DNA purification, and biobank storage. An echocardiographic examination, electrocardiography, and post-ductal pulse oximetry are performed shortly after birth. Infants diagnosed with significant CHD are referred to a specialist or admitted to hospital, depending on CHD severity. CBHS participants will be followed prospectively as part of specific research projects or regular clinical follow-up for CHD. CBHS design and methodology are described. The CBHS aims to identify new mechanisms underlying cardiovascular disease development and new targets for prevention, early detection, and management of CHD and other cardiac diseases presenting at birth or developing later in life.

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.

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.

BACKGROUND: The impairment of immune functions associated with malnutrition may be one reason for the high mortality in children with severe acute malnutrition (SAM), and thymus atrophy has been proposed as a marker of this immunodeficiency. The aim of this study was to identify nutritional and clinical correlates of thymus size in children with SAM, and predictors of change in thymus size with nutritional rehabilitation.METHODS: In an observational study among children aged 6-59 months admitted with SAM in Uganda, we measured thymus area by ultrasound on hospital admission to treatment with F75 and F100, on hospital discharge and after 8 weeks of nutritional rehabilitation with ready-to-use therapeutic food, as well as in well-nourished healthy children. We investigated anthropometric, clinical, biochemical and treatment-related correlates of area and growth of the thymus.RESULTS: Eighty-five children with SAM with a median age of 16.5 months were included. On admission 27% of the children had a thymus undetectable by ultrasound. Median thymus area was 1.3 cm(2) in malnourished children, and 3.5 cm(2) in healthy children (p 5 mg/L. At follow-up after 8 weeks, median thymus area had increased to 2.5 cm(2) (p CONCLUSION: Malnutrition and inflammation are associated with thymus atrophy, and thymus area seems positively associated with plasma phosphate. Substituting therapeutic formula with unfortified rice porridge with the aim of alleviating diarrhea may impair regain of thymus size with nutritional rehabilitation. This calls for research into possible effects of phosphate status on thymus size and other immunological markers.TRIAL REGISTRATION: The study is based on data from the FeedSAM study, ISRCTN55092738 .

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.

OBJECTIVE: To evaluate adverse reactions of the Bacillus Calmette-Guérin (BCG) Statens Serum Institut (SSI) (Danish strain 1331) used as intervention in a randomized clinical trial.DESIGN: A randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG or no intervention. Follow-up until 13 months of age.SETTING: Pediatric and maternity wards at three Danish university hospitals.PARTICIPANTS: All women planning to give birth at the three study sites (n=16,521) during the recruitment period were invited to participate in the study. Four thousand one hundred and eighty four families consented to participate and 4262 children, gestational age 32 weeks and above, were randomized: 2129 to BCG vaccine and 2133 to no vaccine. None of the participants withdrew because of adverse reactions.MAIN OUTCOME AND MEASURE: Trial-registered adverse reactions after BCG vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations.RESULTS: Among the 2118 BCG-vaccinated children we registered no cases of severe unexpected adverse reaction related to BCG vaccination and no cases of disseminated BCG disease. Two cases of regional lymphadenitis were hospitalized and thus classified as serious adverse reactions related to BCG. The most severe adverse reactions were 10 cases of suppurative lymphadenitis. This was nearly a fivefold increase compared to what was expected based on the summary of product characteristics of the vaccine. All cases were treated conservatively and recovered. Six of 10 (60%) families of children experiencing suppurative lymphadenitis compared to 117/2071 (6%) of those with no lymphadenitis indicated that the vaccine had more adverse effects than expected (p-value CONCLUSIONS AND RELEVANCE: BCG vaccination was associated with only mild morbidity and no mortality. A higher incidence of suppurative lymphadenitis than expected was observed. All children were treated conservatively without sequelae or complications.TRIAL REGISTRATION: Trial registration number NCT01694108 at www.clinicaltrials.gov.