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IntroductionPrevious randomised controlled trials (RCTs) suggest antibiotics for treating episodes of asthma-like symptoms in preschool children. Further, high-dose vitamin D supplementation has been shown to reduce the rate of asthma exacerbations among adults with asthma, while RCTs in preschool children are lacking. The aims of this combined RCT are to evaluate treatment effect of azithromycin on episode duration and the preventive effect of high-dose vitamin D supplementation on subsequent episodes of asthma-like symptoms among hospitalised preschoolers.Methods and analysisEligible participants, 1–5 years old children with a history of recurrent asthma-like symptoms hospitalised due to an acute episode, will be randomly allocated 1:1 to azithromycin (10 mg/kg/day) or placebo for 3 days (n=250). Further, independent of the azithromycin intervention participants will be randomly allocated 1:1 to high-dose vitamin D (2000 IU/day+ standard dose 400 IU/day) or standard dose (400 IU/day) for 1 year (n=320). Participants are monitored with electronic diaries for asthma-like symptoms, asthma medication, adverse events and sick-leave. The primary outcome for the azithromycin intervention is duration of asthma-like symptoms after treatment. Secondary outcomes include duration of hospitalisation and antiasthmatic treatment. The primary outcome for the vitamin D intervention is the number of exacerbations during the treatment period. Secondary outcomes include time to first exacerbation, symptom burden, asthma medication and safety.Ethics and disseminationThe RCTs are approved by the Danish local ethical committee and conducted in accordance with the guiding principles of the Declaration of Helsinki. The Danish Medicines Agency has approved the azithromycin RCT, which is monitored by the local Unit for Good Clinical Practice. The vitamin D RCT has been reviewed and is not considered a medical intervention. Results will be published in peer-reviewed journals and presented at international conferences.Trial registration numbersNCT05028153,NCT05043116.

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.

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.