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Allergy and family size: a riddle worth solving

George Bernard Shaw urged his readers to choose their parents wisely. When it comes to allergy, it appears prudent also to choose the number, and perhaps the age, of one's siblings. Children from large families are at reduced risk of developing hay fever [1-3], eczema [1,2], and allergic sensitization to common aeroallergens [3-5]. This observation, first ptiblished lOyr ago [1] was subsequently elaborated into an aetiological hypothesis [2] which attributed the emergence of allergic disease as a 'post-industrial revolution epidemic' [6] to the decline in cross-infection within young families. This 'hygiene' hypothesis [2] challenged the immunological opinion prevailing at the time, which proposed that early infection might promote, rather than protect against, allergic sensitization [7]. However, more recent advances in our understanding of T-lymphocyte differentiation [8,9] have suggested a possible mechanism for such a protective effect. The 'natural' inimune response to infections occurring in early life, perhaps specifically at the time of first exposure to the relevant allergen, may inhibit the proliferation of Th2-cell clones, and thereby prevent allergy [10]. An alternative hypothesis is that a stable state of Thl-type or Th2-type predominance is not reached for some 5-7 yr after birth [11], and may be influenced by the cytokine environment prevailing at each of multiple exposures to a specific allergen [9]. Despite these immunological advances, epidemiological evidence directly relating early infection to the subsequent development of allergy is sparse and far from convincing [3,12-14]. The relationship of family size to allergy thus remains unexplained, but is it a riddle worth solving? Before addressing this question, it is timely to review the evidence in more detail, considering not only the size but also the structure of the household in childhood. An inverse association between manifestations of allergy and sibship size has been consistently found from an early age [1,2] through childhood [4] and adolescence [3]. In this issue of the journal, Jarvis et al. [15] provide further evidence, this time in adults. Two other recent studies of adults corroborate these findings [5,16]. Four studies [3-5,15] have reported inverse correlations between objective measures of allergic sensitization and sibship size, arguing strongly against a spurious relationship attributable to differential recognition, reporting or diagnosis of allergic symptoms in smaller and larger families. Jarvis et al. [15] report that some symptoms of asthma were inversely related to family size. The incidence and prevalence of all forms of wheezing illnesses throughout childhood varies little with birth order or family size [17,18]. A possible explanation for this discrepancy is that an inverse correlation between sibship size and the prevalence of allergic asthma is counterbalanced, particularly in younger age groups, by the tendency of children from larger families to experience viral infections triggering wheeze by non-allergic mechanisms [7]. The structure as well as the size of the family may be influential. After adjustment for family size, position within the sibship [1-3,5], birth spacing [3], sibhng gender [16] and maternal age [3,19] have been related to hay fever or allergic sensitization. These associations are less consistent than for total sibship size and require further confirmation. Nevertheless, they may offer useful clues to a solution of the conundrum. Jarvis etal. [15] found slightly stronger associations of hay fever and specific IgE with sibship size than with birth order, suggesting that family size is of greater importance than position within the household. However, large sample sizes are required to distinguish with confidence the effects of older and younger siblings, and two studies of over 10000 subjects [2,3] are consistent in finding a significantly steeper decline in prevalence of hay fever with the number of older brothers and sisters than with the number of younger siblings. This is confirmed by skin prick tests to common aeroallergens at age 35 in one study [5]. In contrast, another large study of selfreported allergy among adult women [16] found no independent effect of birth order, after adjustment for matemal age and total sibship size. The intriguing finding in the latter study was that the number of brothers was much more influential than the number of sisters. Whether this reflects a protective effect of brotherly love, or exposure to siblings of the opposite sex, remains to be resolved. Taken individually, these effects of family size and structure are subtle and are detected at a high level of statistical significance only in large datasets. Nevertheless, they are of considerable epidemiological and scientific importance, for two reasons. Firstly, they are unlikely to arise from genetic variation. In theory, the inverse association between allergy and family size could reflect a genetic link between fertility and atopy, but such a link could not explain the associations with birth order within families of similar size. If parents deliberately limited their family size as a result of bearing a child with allergic disease, it would tend to be the last bom, rather than the first bom, who would experience the highest prevalence. Thus, although genetic factors are undoubtedly important in determining the risk of allergy, we have a