Dear Editor

Cullinan et al. [1] present interesting data on the association between antibiotic exposure in early life and the subsequent expression of atopy and asthma. In keeping with other studies they report a positive association between antibiotic receipt over the first 5 years of life and asthma. The association was however largely accounted for by prescriptions issued for respiratory illnesses, and the authors conclude that reverse causation was the likely explanation for this association.

The inappropriate use of antibiotics for respiratory symptoms caused by unrecognised asthma is the main potential confounding factor in observational studies attempting to demonstrate a causal link between antibiotic receipt and atopic illnesses. It is certainly plausible that GPs may prescribe antibiotic in children with symptoms such as cough and wheeze in early life. Suggestions of a casual link are strengthened by demonstration of an association when antibiotics were used for symptoms not associated with asthma. The earlier study by Farooqui and Hopkins [2] did indeed observe an association with non-respiratory use of antibiotics and asthma; in Cullinan et al’s study the association between non- respiratory indicated antibiotics and atopic asthma narrowly failed to reach statistical significance. The authors acknowledge that the study was only powered to show a doubling of odds ratio for the association between early-life antibiotic use and asthma, so an association remains possible in this cohort.

The most important limitation of the study however is in the timing of the observed early-life events in relation to secular changes in asthma prevalence and antibiotic prescribing, and hence the applicability of the results to modern-day settings. This study observes events occurring 30 or more years ago in the parents of the Ashford birth cohort. As is well described, the prevalence of asthma has increased greatly over the last 30 years.[3] There may also have been significant increases in antibiotic prescribing over this time; the subjects in this study received an average of 3.1 and a median of 3 antibiotic prescriptions over 5 years, while we have found that in a recent case-control study [4] comparing antibiotic exposure over the first 5 years of life in 37 children with atopy and wheezing with 37 children without either, the average and median number of antibiotic courses received was and 9.9 and 7 for wheezers, and was 6.3 and 5 for non-wheezers. There is also evidence of earlier prescribing of antibiotics in recent times; in our study group, 89% of wheezers and 68% of non-wheezers received one or more courses of antibiotics in the first year, while in the Ashford study only 396 prescriptions were issued to 746 subjects in the first year, so a maximum of 53% children received any antibiotics.

It seems likely from the data presented that at a point in time 30 years ago, when both asthma prevalence and antibiotic prescribing to young children were significantly less than they are now, that the antibiotic exposure did not play a major causal role in promoting the asthma phenotype, but the question of whether it may now be a significant and potentially modifiable factor remains unanswered.

References

1. Cullinan P, Harris J, Mills P, Moffat S, White C, Figg J et al. Early prescription of antibiotics and the risk of allergic disease in adults: a cohort study. Thorax 2004;59:11-5.

2. Farooqui IS,.Hopkin JM. Early childhood infection and atopic disorder. Thorax 1998;53:927-32.

3. Holgate ST. The epidemic of allergy and asthma. Nature 1999;402:B2-B4.

4. Thomas M, Murray CS, Simpson B, Custovic A, Woodcock A. Early life antibiotic exposure and subsequent risk of asthma: a case control study. Thorax 2003;58:iii67.