Commentary: The end of the hygiene hypothesis?

Three years ago, we published a commentary in the International Journal of Epidemiology, which concluded that the observed increases in asthma prevalence in Western countries had peaked or even begun to decline. Further evidence for this is presented in the paper by Ponsonby et al. that appears in the current issue of the journal. However, although there is now substantial evidence that the ‘epidemic’ of asthma in Western countries has begun to decline, the reasons for the decline remain as mysterious as the reasons for the epidemic itself. In recent years, it has become routine to attribute the epidemic to the ‘hygiene hypothesis’, particularly with regards to the protective effects of microbial exposure early in life, but there are many anomalies in the epidemiological evidence that raise questions about this interpretation of the global asthma prevalence time trends. The ‘hygiene hypothesis’ has been prompted by evidence that overcrowding, unhygienic conditions and larger family size were associated with a lower prevalence of atopy, eczema, hay-fever and asthma. An increase in infections as well as increased exposures to specific microbial agents with strong proinflammatory properties, such as bacterial endotoxin has been proposed as an explanation for these findings. Although the specific immune mechanisms are not clear, it is believed that microbial exposures may activate innate immune pathways through expression of Toll-like receptors (TLRs) and CD14. These exposures may thereby suppress T-helper-2 (TH2) cell expansion and the development of IgE-antibodies and TH2 dependent diseases, including allergic asthma, hay fever and eczema. It has, therefore, been hypothesized that increased cleanliness, reduced family size and subsequent decreased microbial pressure in the past few decades could explain the increase in global asthma prevalence. This new paradigm has gained considerable support from asthma researchers worldwide, and has resulted in new aetiological theories, and inspired basic scientists to develop novel laboratory-based studies. However, despite great enthusiasm and rapid uptake of this new theory there is reason for caution, and the findings reported by Ponsonby et al. provide further reason for scepticism. They examined asthma trends in 22 882 Australian children aged 4–6 using annual questionnaires from 2000 to 2005 inclusive. In contrast to what would be expected based on the hygiene hypothesis, asthma symptom prevalence showed a steady decline. The prevalence of eczema symptoms on the other hand, significantly increased. Ponsonby et al. also found that immigrant and non-immigrant children showed similar asthma time trends, which argues against the suggestion that the immunological reactivity expressed in childhood is predominantly established within the first year of life or even in the prenatal period—a view often associated with the hygiene hypothesis. These findings add to other contradictory evidence that warrants scepticism about the hygiene hypothesis as the primary explanation for global asthma prevalence time trends. First, it has now been well established that the proportion of asthma cases that are attributable to atopy is usually less than one-half. Similarly, recent studies have demonstrated that < 50% of asthma cases are attributable to eosinophilic airway inflammation, the hallmark of allergic asthma. Thus, evidence from studies of eosinophilia and asthma is consistent with that from studies of atopy and asthma: in both instances, at most about one-half of asthma cases appear to be due to ‘allergic’ mechanisms. The hygiene hypothesis suggests that a decrease of exposure to microbes would—through enhanced atopic immune responses—increase the incidence of allergies and allergic asthma. If true, then the protective effects would be most pronounced for the atopic asthma phenotype as well as other atopic conditions such as eczema. Interestingly, in the study by Ponsonby et al., a steady increase in eczema was observed, suggesting that some atopic conditions may indeed still be on the rise. If so, then the observed decrease in asthma may be explained by a decline in non-atopic asthma, potentially masking the (smaller) increase in atopic asthma. Similarly, the past increase in asthma may not have been exclusively attributable to an increase * Corresponding author. E-mail: j.douwes@massey.ac.nz Centre for Public Health Research, Massey University Wellington Campus, Private Box 756, Wellington, New Zealand. Published by Oxford University Press on behalf of the International Epidemiological Association