Commentary: use of antibiotics and risk of asthma.

Abstract

According to the hygiene hypothesis, infections in early life protect from atopy and asthma.1 Therefore, antibiotics have been hypothesized to cause increased risk of asthma by reducing the protective effect of infections or by interfering with normal gut flora.2 There are, however, several caveats in studying the association between antibiotic use and risk of asthma at the individual level, so the ecological study by Foliaki et al.3 is a welcome addition to the literature. The possibility of ‘reverse causation’, i.e. asthma causing increased risk of infections, is the major concern in studies on antibiotic use and risk of asthma. Infections, especially rhinovirus infections, are the main triggers of asthma attacks.4 Asthmatics, when infected, are also more likely to develop severe symptoms, especially in the lower respiratory tract.5 There is also some evidence that asthmatics have defective interferon (IFN)gamma or Th1 response to rhinovirus making them potentially more vulnerable to rhinovirus infection.6,7 Thereby asthmatics or subjects that will later develop asthma are likely to have more often symptomatic and more severe respiratory illnesses that are then treated with antibiotics. Results from two recent cohort studies support the suggestion that the association between antibiotic use in early life and asthma is due to ‘reverse causation’.8,9 In a prospective birth cohort study, the positive association between antibiotic use in the first year of life and wheezing disappeared after excluding subjects who had received antibiotics for wheezing-associated illness.8 There was no association with asthma. In a carefully performed retrospective cohort study, antibiotic use during the first 5 years of life was collected from contemporary medical records.9 There was no association with atopy, and the observed positive association between antibiotic use and asthma was largely confined to antibiotics prescribed for lower respiratory symptoms. The hygiene hypothesis started with the epidemiological observation that younger siblings have less atopy, possibly due to increased exposure to common infections.1 Epidemiological studies have later shown the protective effect of microbial exposure in general, either through gut microbial flora10 or through contact with farm animals.11 In contrast, the epidemiological evidence on the protective effect of clinical infections has been conflicting.1 This could be partly explained by the suggestion that only selected microbes, like measles, tuberculosis, and hepatatis A, have a protective effect.12 On the other hand, these infections explain only a minor proportion of antibiotic use, which makes it less likely that antibiotics act by reducing the protective effect of infections. In general, the evidence for the protective effect of microbes is stronger for atopy than for asthma.12 This fits with the theory that microbes affect primarily the Th1/Th2 balance13 as the Th1/Th2 balance is closely associated with atopy, but less than 50% of asthma is associated with atopy.14 If antibiotic use also affects the Th1/Th2 balance, possibly through an effect on gut microbial flora,2 one would expect stronger associations with atopy than with asthma. However, past studies on antibiotic use have generally observed stronger associations with asthma than with atopy.9 Taken together, the most likely explanation for the past epidemiological associations between antibiotic use and asthma is ‘reverse causation’. This does not necessarily exclude some effect of excessive antibiotic use leading to severe disturbance of gut microbial flora, which would resemble more the treatments used in animal experiments.2 Another possible exception is the large birth cohort study by McKeever et al.15 who observed a strong association between mother’s use of antibiotics during pregnancy and asthma. The association was clearly weaker for hay fever. If this finding indicates causality, it is not easily explained by the ‘hygiene hypotheses’. Infections and other complications during pregnancy have also been associated with increased risk of asthma.15,16 Possibly there is some common mechanism, such as increased maternal stress,17 that explains these associations. Given the problems of studying the association between use of antibiotics and risk of asthma at the individual level, the ecological study in the current issue of the International Journal of Epidemiology3 is interesting. The conclusion from this ecological analysis is the same as from the best individual-level studies, suggesting that sometimes ecological comparison can be less biased than individual-level studies. The results of the study suggest that the amount of antibiotic use does not explain the geographical differences in the prevalence of asthma and thereby they are not likely to be the major causes of the increase in asthma in developed world. Although interpreting ecological analysis at the individual level is problematic, the analysis by Foliaki et al.3 gives additional support to the above suggestion that the observed associations between antibiotic use in early life and asthma are mostly explained by ‘reverse causation’. In future, it will probably be more fruitful to focus on microbial exposure in general and less on symptomatic infections and their treatment, when searching for clues on the aetiology of atopy and asthma.