The case of drug causation of childhood asthma: antibiotics and paracetamol

Abstract

AimThe rising prevalence of bronchial asthma has led to world-wide efforts to understand and stem this development. Cross-sectional studies appear to show that early childhood use of antibiotics may be an important contributory factor, with paracetamol as an additional suspected cause. However, mounting evidence, which is reviewed here, points to various confounding factors as the major reasons for these reported associations.MethodsPubMed and EMBASE were systematically searched for studies on associations between antibiotics and/or paracetamol with asthma and/or wheezing, published up to November 2012. A total of 64 pertinent studies were identified, 35 focusing on antibiotics, 19 on paracetamol, and ten addressing both antibiotics and paracetamol, bringing the number of relevant datasets to 74.ResultsNumerous studies were cross-sectional and made no adjustment for the indication of antibiotics or paracetamol; consequently, they were unable to dismiss possible confounding by indication. Where such adjustments could be performed (mostly in longitudinal studies), they substantially weakened or entirely eliminated the association with asthma or asthma surrogates present in the unadjusted data.ConclusionThe weight of evidence of the collected studies in our review strongly suggests that the association of antibiotics with childhood asthma reflects various forms of bias, the most prominent of which is confounding by indication. Recent studies and meta-analyses support the same conclusion for paracetamol. Truly indicated antibiotics should not be withheld from infants or young children for fears they might develop asthma. Likewise, there is no sound reason to replace paracetamol as the preferred pain relief and fever medication in this age group.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-012-1463-7) contains supplementary material, which is available to authorized users.

The gut microbiota and inflammatory noncommunicable diseases: Associations and potentials for gut microbiota therapies

“…Retrospective studies have reported antibiotic treatment in early life to be associated with increased risk of asthma, although the results may still be influenced by reverse causation or confounding by indication 42 .…”

Randomized controlled trials and real life studies. Approaches and methodologies: a clinical point of view.

“…An interesting example of this type of bias comes from pediatric studies suggesting that the development of asthma in children <5 years old is associated with the use of antibiotics [111,112]. This association was identified when antibiotics are prescribed for lower respiratory tract infections (LRTI) [113,114]. In this case, the increased risk of asthma could be associated with LTRI, rather than antibiotics.…”

Role of Antibiotics and Infection-Host Interactions in the Prevalence of Respiratory Atopy: Experience and Perspective

“…On the first hand, it is postulated that 'antibiotic-induced growth inhibition of enteric flora can suppress the "education" of Th1 profile immune response in children, leading to the induction of a Th2 allergic inflammatory predisposition' without changes of genome even after exposure to one course of antibiotics in the first year of life [2,12,13,[16][17][18][19][20]. On the other hand, different infectious agents can manipulate the host immunity through induction of Th2/Immunoglobulin (Ig) E response, in order to increase their surviving chances [2,15,21,22].…”

“…Prevalence antecedent decades [15]. Maybe in a few decades, antibiotics exposure will no longer be a risk factor for asthma and atopy among populations of recently-developed countries, 'including the important period between 0 and 1 year of age' [13]. This concept (in concert with other established risk factors) can explain the increased allergy prevalence in industrialized countries among autochthonous populations, as well as the actual divergent trends in prevalence of respiratory allergies between them and populations of recently-developed countries.…”

“…With respect to increased prevalence, the most important factors comprise improved hygienic conditions, decreased exposure to infections, massive use of antibiotics, exposure to pollution and traffic exhausts, etc. A consistent proportion of these factors are presumed to be components of "hygiene hypothesis", whereas more recently all risk factors are incorporated in "the changing world theory" [10][11][12][13].…”