Atopic dermatitis and the 'hygiene hypothesis': too clean to be true?

BACKGROUND: The so-called 'hygiene hypothesis' postulates an inverse relationship between atopic dermatitis (AD) and an environment that leads to increased pathogen exposure. OBJECTIVES: We sought to systematically identify, summarize and critically appraise: (i) the epidemiological evidence to suggest that environmental exposures that lead to an increase in microbial burden reduce the risk of AD; (ii) whether any specific infections have been shown to reduce AD risk; (iii) whether there is a link between immunizations, use of antibiotics and AD risk; and (iv) to comment on the new therapeutic approaches in AD that have evolved out of the 'hygiene hypothesis'. METHODS: We searched Medline from 1966 until August 2004 to identify relevant studies for inclusion. Differences in study design and populations did not allow formal meta-analysis. Studies were therefore described qualitatively. RESULTS: We identified 64 studies that were relevant to our review, 27 (42%) of which were of prospective design. There was prospective evidence to support an inverse relationship between AD and endotoxins, early day care and animal exposure. Two well-designed cohort studies have found a positive association between infections in early life and AD, and measles vaccination and AD. Antibiotic use was consistently associated with an increase in AD risk even into the antenatal period, although a few studies did not reach conventional statistical significance. A few small randomized controlled trials have suggested that probiotics can reduce AD severity and that probiotics may also be able to prevent AD to some degree. CONCLUSIONS: Although population-based studies have suggested a consistent inverse relationship between AD and increasing family size, this does not seem to be explained by a straightforward increased exposure to a single environmental pathogen. The effect seen with early day care, endotoxin and animal exposure may be due to a nonpathogenic microbial stimulus of a chronic or recurrent nature. This would also explain the risk increase associated with antibiotic use. Caution should prevail in the prescribing of antibiotics early in life, especially in children with a family history of AD. Larger well-designed pragmatic trials on probiotics and the prevention and treatment of AD are now needed to inform whether such interventions should be used in routine clinical practice.