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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.

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.

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

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.

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 There is increasing evidence that vaccines have an effect on general mortality which goes beyond specific disease protection. Oral polio vaccine (OPV) is widely used in low-income countries, but in observational studies in Guinea-Bissau we observed that not receiving OPV at birth was associated with reduced overall male infant mortality and enhanced immune response to BCG vaccine. We therefore initiated a randomized trial to test the overall effect of OPV at birth (OPV0). Objective A small thymic gland is a predictor of mortality in high-mortality settings. Within the trial we aimed to test whether no-OPV0 was associated with increased thymic size. Methods In 511 normal birth weight infants who were randomized to receive or not receive OPV0, thymic index and thymus/weight index were measured before randomization and after 2 weeks ( N = 49), 4 weeks ( N = 308) or 6 weeks ( N = 27). The association between OPV0 and the log transformed thymic size indicators were analyzed in ANCOVA models with thymic size at follow-up as the outcome and adjusting for thymic size at enrollment and age at follow-up. Estimates were reported as geometric mean ratios (GMR) with 95% confidence intervals, comparing no-OPV0 to OPV0. Results No-OPV0 was not associated with thymic index after 2 weeks (GMR: 1.14 (0.99–1.30)), after 4 weeks (GMR: 0.98 (0.93–1.05)) or after 6 weeks (GMR: 1.00 (0.81–1.23)). However, no-OPV0 was associated with increased thymus/weight index after 2 weeks (GMR: 1.22 (1.06–1.40)), but the effect was not seen after 4 weeks (GMR: 0.97 (0.92–1.03)) and 6 weeks (GMR: 0.99 (0.82–1.19)). There were no strong sex-differences. Discussion Overall there was no effect on thymic size of OPV0 when administered with BCG. The results could indicate that if an effect occurs, it is only within the first weeks after vaccination.

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.

Background: Maternal smoking during pregnancy is known to be associated with perinatal complications such as preterm delivery, low birth weight, and sudden infant death syndrome. Objective: The purpose of this study was to evaluate the influence of smoking during pregnancy on the risk of postnatal infections in preterm neonates. Method: We examined 80 preterm infants (gestational age 24–36 weeks), of whom 40% had been exposed to tobacco smoking during pregnancy. Results: Infections occurred in 31 infants. Gestational age and maternal smoking had a significant effect on the occurrence of infections (p < 0.001 and p = 0.015, respectively). An increase in maternal tobacco consumption by 10 cigarettes/day showed an odds ratio of 2.7 (95% confidence interval 1.1–6.4) for occurrence of infections. Conclusions: A significant association between maternal use of tobacco and the occurrence of infections in preterm neonates was found. Thus, campaigns about the damaging effects of tobacco are still warranted.

Infants with bronchopulmonary dysplasia (BPD) are at high risk of developing cardiovascular sequelae in the form of pulmonary hypertension (PH) which significantly increases morbidity and mortality. The aim of this study was to evaluate the incidence of BPD, to identify characteristics associated with BPD and to identify characteristics associated with PH in infants with BPD.A retrospective study was performed. Data were obtained from a regional neonatal database and by reviewing medical records of infants admitted during the 2002-2010 period. A total of 400 infants with a birth weight (BW)1,500 g were identified. Eight were excluded and 74 infants met the criteria for BPD. A total of 17 infants with BPD had PH.We found that the incidence of BPD at the Neonatal Department at Hvidovre Hospital between January 2002 and December 2010 was 18%. Infants with BPD differed significantly from infants without BPD with regard to the following characteristics: Infants with BPD more frequently had a lower gestational age and BW, intubation at birth, mechanical ventilation within 24 hours of birth, a lower Apgar score at one minute and five minutes. The incidence of PH was 23% among infants with BPD. Furthermore, we found a significantly larger frequency of intubation at birth, postnatal infection, longer duration of continuous positive airway pressure treatment and use of oxygen therapy among infants with PH and BPD than among the remaining infants.The incidence of BPD was 18%. Low gestational age was found to be the most important factor associated with development of BPD. Among BPD infants, postnatal infection was significantly associated with PH. Further prospective studies including routine echocardiography are needed to evaluate risk factors for PH.not relevant.not relevant.

INTRODUCTION: A previous study found that 0.04% of Danish children were registered with hypertension, among whom 54% were treated pharmacologically. Our study describes pharmacologically treated cases at the onset of antihypertensive therapy, noting whether the evaluation of target-organ damage could be improved.METHODS: Our review of the medical records of children under 16 years living in Central and Eastern Denmark from April 2014 to May 2015 found that 119 children were registered with an International Classification of Diseases, tenth edition diagnosis of hypertension and treated with antihypertensive medicine.RESULTS: The cohort consisted of 61% boys and 39% girls (p = 0.01). The majority of patients (80%) had secondary hypertension. Renal aetiology was found in 52%. Echocardiography, retinal examination and examination for proteinuria were undertaken in 77%, 74% and 100%, respectively. Both echocardiography and retinal examination were undertaken in 61% of patients with renal aetiology. Among the remaining patients, 95% and 89% underwent these examinations, respectively (p less than 0.001 and p less than 0.001). Abnormal echocardiography, abnormal retinal examination and proteinuria were found in 39%, 16% and 66%, respectively, of patients with renal aetiology and in 30%, 24% and 35% of the remaining patients (p = 0.3, p = 0.4 and p less than 0.001).CONCLUSIONS: Examination for target-organ damage was performed less often in patients with hypertension of renal aetiology than in the remaining patients. Examination for target-organ damage is recommended in all hypertensive children to determine whether treatment is indicated to reduce long-term morbidity.FUNDING: The study received funding from the Novo Nordisk Foundation, grant number NNF15OC0015702 and from Amager-Hvidovre Hospital Foundation.TRIAL REGISTRATION: not relevant.