European Journal of Clinical Nutrition (2002) 56, Suppl 4, S39–S43 ß 2002 Nature Publishing Group All rights reserved 0954–3007/02 $25.00 www.nature.com/ejcn Asthma and allergic diseases: is there a downside to cleanliness and can we exploit it?{ J Crane* Department of Medicine, Wellington School of Medicine and Health Sciences, Wellington, New Zealand When hay fever was first described in the early 19th century it was an uncommon disorder. Since then asthma, allergic rhinitis and eczema, have become common conditions particularly in industrialised western economies. International prevalence studies reveal wide variation in the prevalence of asthma, and allergic disease, but confirm this view although the studies also show these diseases to be by no means rare in most countries. The reasons remain unclear but the ‘‘hygiene hypthesis’’ postulating an inverse relationship between hygiene, in its broadest sense, and allergic disease, fits some of the epidemiology of these diseases and has an associated immunological hypthesis to support it. Recent studies suggest that many hygiene related factors may influence immune development in favour of an allergic phenotype. Antibiotics in the first of life have been associated with increased risks of allergic disease in later childgood, and farming exposures to protection. Interest in hte role of bowel flora in modifying immune development has been suggested as an explanation for the risk associated with antibiotic exposure and has led to studies exploring the effects of modifying bowel flora with probiotics both to influence established allergic disease and to prevent it. The challenge is to continue to reap the enormous benefits that accrued from modifying infectious disease by both public and individual health strategies but at the same time convincing the immune system that it has been exposed to them. European Journal of Clinical Nutrition (2002) 56, Suppl 4, S39 – S43. doi:10.1038/sj.ejcn.1601660 Descriptors: asthma; atopy; antibiotics; endotoxin Introduction 1819, John Bostock gave the first detailed description of the The last two decades has seen an unprecedented increase in signs and symptoms of hay fever, describing his own disease, the reporting of asthma symptoms and in the diagnosis of in a paper read to the medical society in London (Bostock, allergic diseases in many countries around the world amongst 1819). Nine years later, in 1828, he read a second paper to both adults and children. A recent review of this pheno- the same society, in which he documented the disease in a menon described these changes as an epidemic (Holgate, further 18 cases that had been brought to his attention 1999). The cause, or causes, of this increase in asthma and (Bostock, 1828). At the beginning of the twenty first century, allergic disease prevalence is unknown. A number of hypo- some 170 years after these initial descriptions, the prevalence theses have been suggested, and have recently been the of hay fever in many developed countries is self reported at subject of considerable debate (von Mutius et al, 2001). between 20 and 30%. While there are many reasons why a While the symptoms of asthma have been described since relatively minor disorder such as hay fever might have gone antiquity (Cohen, 1992) and the allergic basis suggested as unnoticed amidst the everyday mortality and morbidity early as the sixteenth century (van Helmont, 1662), until the from major infectious diseases of the early nineteenth early part of the eighteenth century such diseases appear to century, it seems unlikely that a physician such as Bostock, have been more of curiosity than a significant health pro- already on the lookout for the signs and symptoms of hay blem. This pattern of disease development is typified by the fever, would have taken 9 y to recruit 18 cases if the development of hay fever or seasonal allergic rhinitis. In prevalence was in any way approaching that found today. These historical perspectives suggest that environmental *Correspondence: J Crane, Department of Medicine, Wellington School of change in its broadest sense is the major determinant of Medicine and Health Science, PO Box 7343, Wellington, New Zealand. these allergic diseases. E-mail: [email protected] However, their study has not proved straightforward. One {Based on a presentation to the symposium: Fermented food, fermentation and intestinal flora, National Institute of Nutrition, Mexico reason is that there are no universally agreed definitions, and City, Mexico, 17 – 18 May 2001. studies of their prevalence relies largely on the individual’s Asthma and allergic diseases J Crane S40 description of symptoms with the attendant problems of ferences. A striking feature of the study was that English- interpretation, increasing community awareness, combined speaking countries, in particular the UK, Australia, New with a reduced willingness to tolerate symptoms (Magnus & Zealand, and to a lesser extent the United States and Jaakkola, 1997). Similarly the criteria applied to these symp- Canada, had much higher rates than equally developed toms by health professionals have been changing. Some countries in continental Europe. Nevertheless there are authors have suggested that the evidence for this increase important differences in prevalence related to socio- in prevalence is far from conclusive and will require studies economic gradient. Broadly, with some important excep- that incorporate objective markers associated with allergic tions, these trends for asthma were mirrored by allergic disease before we can be certain that the prevalence has rhinitis and allergic dermatitis. indeed risen (Magnus & Jaakkola, 1997). It seems likely that at least a significant proportion of the increased prevalence can be attributed to an increased awareness of the symptoms The hygiene hypothesis of allergic diseases by a better informed public, particularly The rise in the prevalence of atopic diseases has been linked in developed countries. The symptoms that are used to to the decline in infectious disease. Gerrard et al (1976) define asthma, allergic rhinitis and eczema are non-specific. examined serum IgE amongst 275 individuals from 58 Thus wheezing and coughing and nasal discharge are symp- Metis families, descendants of Cree Indians in Northern toms that may arise in relation to colds or influenza. In the Saskatchewan. They compared total IgE and the prevalence case of eczema or allergic dermatitis, skin rashes particularly of atopic disease with 819 individuals from 176 white in infancy and early childhood from a wide variety of causes families living in the same region. The prevalence of are very common. Each of the symptoms may arise entirely eczema was 7-fold higher and asthma almost 3-fold higher in the absence of any allergic phenomenon and yet be in the white community compared with the Metis commu- indistinguishable from the same symptoms caused by nity. In contrast, geometric mean total IgE, was 3-fold higher allergy. Despite these obvious caveats, the prevalence at in the Metis community compared with the white commu- least since the nineteenth century almost certainly has nity. In their concluding statement these authors spelled out increased and a better understanding of the factors asso- what was to be termed the hygiene hypothesis a decade later. ciated with this increase might lead to preventative measures that could reduce the incidence. The prevalence of asthma, eczema and urticaria was greater in the white than in the Metis community and contrasted with the increased prevalence of helminth Geographical variation in the prevalence of infestation as well as of other untreated viral and asthma and allergic disease bacterial diseases in the Metis community. It is suggested International comparisons of asthma prevalence have only that atopic disease is the price paid by some members of recently been undertaken (Leung & Ho, 1994; Robertson et al, the white community for their relative freedom from 1993; Burr et al, 1994). Burr et al (1994) compared symptoms diseases due to viruses, bacteria and helminths. and exercise fall in peak flow, as a marker of airway hyperre- sponsiveness, in 12-y-old children in Wales, New Zealand, In noting this inverse relationship between infection and South Africa and Sweden. Asthma prevalence and a fall in atopic disease they raised, as others had previously in rural PEFR with exercise were reasonably similar in New Zealand and urban Gambia (Godfrey, 1975) and elsewhere, the para- and Wales but less prevalent in South Africa and Sweden. dox, that in communities exposed to more infection and Asher et al (1998) in ISAAC used simple written and video helminth infestation in particular, total IgE was elevated but questionnaires in the first large-scale international study of atopic disease infrequent. asthma and allergic disease prevalence in children. Almost In 1989 Strachan noted a strong inverse relationship 258 000 6 – 7-y-olds, from 91 centres in 38 countries, and between birth order and hay fever in cohort data in the UK 464 000 13 – 14-y-olds from 155 centres in 56 countries took (Strachan, 1989). He first articulated and coined the phrase part. There was a 15-fold variation in asthma symptoms ‘hygiene hypothesis’ to explain these associations, suggest- between countries, with economically developed countries ing that a greater exposure to infection in early childhood tending to have higher rates of asthma symptoms than less- might arise from contact with siblings. Subsequently a developed countries. This socio-economic gradient was number of studies have identified inverse prevalence rela- apparent within Europe, with Western European countries tionships between atopy or atopic disease and specific infec- tending to have higher prevalence than Eastern European tions (Matricardi et al, 1997; Shaheen et al, 1996; Shirakawa countries. Very high rates were found in some, but not all, et al, 1997). In Italy, with high rates of hepatitis A infection, South American countries, often higher than in Spain or a clear positive relationship has been established between Portugal.