BackgroundAsthma has a significant impact worldwide, but prevention strategies remain limited. We aimed to evaluate the efficacy of neonatal BCG vaccination in preventing asthma by modulating early‐life immunity.MethodsThe Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) was a phase 3 multicentre randomized controlled trial in Victoria, Australia. Infants were randomly assigned to receive the BCG‐Denmark vaccine or no intervention within 10 days of birth. The incidence of asthma at 5 years of age was estimated using the International Study of Asthma and Allergies in Childhood questions. ClinicalTrial.gov (NCT01906853).ResultsA total of 1272 infants were randomized. The adjusted incidence of asthma was 14.4% in the BCG group compared to 16.0% in the control group (adjusted risk difference [aRD] −1.7 percentage points; 95%CI −7.4, 3.9). Secondary outcomes, including severe asthma and use of preventer medication, showed similar trends, with an aRD of −3.9 (95%CI −7.7, 0.0), and −5.6 (95%CI −10.9, −0.4), respectively, favoring the BCG group. Among participants with one or both parents asthmatic, the rate of asthma was also lower in the BCG group (17.6%) compared with the control group (24.7%; aRD −7.2; 95%CI −15.9, 1.5), although a test for interaction was not significant (p = .07).ConclusionsWhile the point estimates suggested BCG vaccination might protect against asthma, the wide uncertainty around the estimates means further studies with larger sample sizes are needed to evaluate the long‐term benefits of BCG vaccination beyond its primary indication.

BackgroundPrevious evidence on season‐of‐birth differences in atopic diseases is partially mixed, and the etiology behind them is not well understood. For example, outdoor temperature may be an important modifier of the association but has been previously neglected.MethodsWe assess how the month of birth is associated with medication use for atopic diseases at ages 0–15 and how outdoor temperatures after birth modify these associations for 0.55 million Finns born during 1995–2004. We used Finnish register data on purchases of medications used for allergic rhinitis, eczema, asthma, and food allergies. We predicted month‐of‐birth associations with medication use using extensive controls for observed and unobserved confounders and assessed effect modification by 3‐month mean outdoor temperature after birth.ResultsApproximately half of the children had at least one purchase of medication used for atopic diseases. For children born in spring or summer, the probability of medication use was moderately lower than for children born in the autumn or winter. Among children born in the autumn or winter, exposure to the coldest outdoor temperatures in the first 3 months of life was associated with a nearly 10‐percentage‐point increase in the risk for medication use compared with the warmest temperatures.ConclusionsBehind the moderate overall associations between month of birth and childhood atopic diseases, there was notable variation by environmental conditions after birth, with cold weather after birth being particularly harmful. Future studies should assess what specific exposures do the outdoor temperatures affect, and in turn how they affect the development of atopic diseases.

BackgroundLong‐acting β2‐agonists (LABA) are commonly used to treat asthma. Some children do not respond well to LABA, which may be due to +46G>A−/rs1042713 (Arg16 amino acid) in the ADRB2 gene encoding the β2 receptor. Arg16Gly ADRB2 genotyping to guide treatment step‐up decisions in children with uncontrolled asthma despite inhaled corticosteroids (ICS) has been shown to reduce asthma exacerbations. We investigated whether ADRB2 genotype‐guided treatment is cost‐saving.MethodsTotal semi‐annual healthcare and indirect costs for children with and without exacerbations were calculated using PUFFIN trial data. One hundred and two Dutch and Swiss children were randomised to a genotype‐guided treatment arm (adding LABA [Gly16Gly] or double dose ICS [Arg16Arg/Arg16Gly]) or a control arm, where children were again randomised to LABA or double dose ICS. We used exacerbation rates of the PUFFIN and the PACT trials to calculate asthma‐related healthcare costs per treatment arm, as PACT closely matches the PUFFIN design. The PACT trial randomised 91 children from England and Scotland with uncontrolled asthma to the genotype‐guided treatment arm (LABA [Gly16Gly] or montelukast [Arg16Arg/Arg16Gly]) or the control arm (routine care as per British Thoracic Society guidelines).ResultsOverall mean semi‐annual costs per child were €56.24 lower in the genotype‐guided treatment arm compared to the control arm (€771.07 [range €616.86–€925.28, 23 of 90 children experienced exacerbations] and €827.31 [range €661.85–€992.77, 40 of 103 experienced exacerbations], respectively).ConclusionA treatment strategy that includes ADRB2 genotype‐guided treatment is potentially cost‐saving compared to usual care. The decreased healthcare costs associated with a reduction in asthma exacerbations more than offset the incurred genotyping costs.

BackgroundAllergic sensitization and respiratory infections commonly occur in childhood. Interplay between them in asthma development is known as the ‘two‐hit’ hypothesis. There has been no previous investigation of this hypothesis on adult lung function.ObjectiveIn a birth cohort at high risk for allergic diseases, we investigated interactions between these two factors and lung function outcomes into adulthood.MethodsAllergic sensitization was assessed at age 24 months by skin prick testing to aero and food allergens. Respiratory infection was defined as cough, rattle or wheeze measured by frequent questionnaires up to age 24 months. Regression models were utilized to identify interactions between these exposures and associations with lung function at ages 12, 18 and 25 years.ResultsAt age 25 years, those sensitized at age 2 years(n = 118) demonstrated reductions in pre‐bronchodilator FEV1 of 0.06(95% CI: −0.12, 0.00, z‐score units, p = .055) for each additional month of respiratory infections. Those not sensitized (n = 120) had increases in pre‐bronchodilator FEV1 of 0.07 (95% CI: 0.02, 0.13, z‐score units, p = .012) for each additional month of respiratory infection(pinteraction = .012). Similar findings were noted for FEV1/FVC ratio(pinteraction = .011), FEF25–75(pinteraction = .007) and absolute change in pre and post bronchodilator lung function. At 18 years, findings were similar; however, there was less evidence for interactions at 12 years.ConclusionOur study findings support the ‘two‐hit’ hypothesis of interactions between early‐life allergic sensitization and increasing respiratory infections, and impairment in lung function up to age 25 years. Early childhood respiratory infections however had different impacts on lung function depending upon the presence or absence of allergic sensitization.