Lisbeth Marianne Thøstesen 2017

Jensen, Lisbeth Marianne Thøstesen. 2017. Bacillus Calmette-Guérin vaccination at birth and the development of atopic dermatitis, recurrent wheeze and sensitisation in Danish infants. A randomised clinical trial. The Danish Calmette Study, CVIVA, Peadiatric Department Kolding.

Background

As one of the most used vaccines globally, the Bacillus Calmette Guérin (BCG) vaccine is administered in ≥100 countries to infants at birth to decrease the incidence of severe tuberculosis. Due to the low incidence of tuberculosis in Denmark, the BCG vaccine was withdrawn from the Danish Child Immunisation Program in the 1980’ies. Meanwhile, studies from West Africa have shown positive non-specific effects of early BCG immunisation on childhood morbidity and mortality. 

For about 30 years there has been an un-explained global increase in the incidence of the atopic diseases eczema, wheezing, asthma and allergy. Eczema and asthma have become the most common chronic diseases among children in high-income countries. Several smaller, retrospective, non-randomised studies and one small randomised clinical trial have already examined the effect of BCG immunisation on atopic disease, finding either no effect or a protective effect. 

Aims

A large prospective randomised clinical trial in Denmark (the Danish Calmette Study) was planned to test the hypothesis that compared to non-BCG-vaccinated infants, infants who are BCG vaccinated at birth experience less hospitalisations, use less antibiotics, and develop less atopic disease (eczema, recurrent wheeze, and allergy) in early childhood. The study included new-borns from Rigshospitalet, Hvidovre Hospital and Kolding Hospital. Each of the centres collected the same data, but had a specific scientific focus. 

The present PhD project focused on the development of atopic diseases. The specific aims (research questions) were 1) Does neonatal BCG immunisation protect against eczema during the 1st year of life? 2) Do BCG-immunised infants have less recurrent wheeze during the 1st year of life? 3) Is the parents’ experience of the infant having food allergy diminished by neonatal BCG immunisation? And does neonatal BCG vaccination diminish sensitisation measured as specific IgE in blood samples?

Results

All main results were measured by age 13 months.

Atopic dermatitis: Atopic dermatitis was diagnosed in 466/2,052 (22.7%) children in the BCG group and 495/1,952 (25.4%) children in the control group (Risk Ratio (RR) =0.90 (95% confidence intervals 0.80 to 1.00)). Two-thirds of the participants had atopic predisposition. The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74 to 0.95)) and children without atopic predisposition (RR 1.09 (0.88 to 1.37)) (test of no interaction, p=0.04). Among children with atopic predisposition, the number needed to treat with BCG to prevent one case of atopic dermatitis was 21 (12 to 76). 

Recurrent wheeze: By 13 months 211/2100 (10.0%) children in the BCG group and 195/2071 (9.4%) children in the control group had been diagnosed by a medical doctor with recurrent wheeze and had received anti-asthmatic treatment (RR 1.07 (0.89-1.28)). 

Suspicion of food allergy / sensitisation: The parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in an RR comparing BCG-vaccinated children with control children of 0.91 (0.71 to 1.16). Among the 1370 blood samples sensitisation (Phadiatop Infant > 0.35 kUA/l) was found in 55/743 (7.4%) children in the BCG group and 50/627 (8.0%) children in the control group (RR 0.94 (0.65 to 1.36)). 

Conclusion

In this randomised clinical trial neonatal BCG had no effect on the development of recurrent wheeze, on the suspicion of food allergy or on sensitisation at 13 months of age. There was no overall effect on atopic dermatitis, although BCG slightly reduced the incidence of atopic dermatitis among new-borns with atopic predisposition.