The Increase in Asthma Can Be Ascribed to Cleanliness

Erika von Mutius

University Children's Hospital, Munich, Germany

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There is no doubt that an increase in the prevalence of asthma has occurred (1). Reports from Britain show that the prevalence of asthma is still on the rise (2). For preschool children aged 1-5 years, an approximately twofold increase in the prevalence of all types of wheezing has been documented for the years 1990 to 1998.

Before debating the role of any potential explanation, it is of key importance to understand the natural course of asthma. Only influences anticipating the onset of disease can have an effect on the incidence of the illness. Since the peak incidence of all asthma is in the first to fourth years of life (3), only exposures during pregnancy and early childhood will have a major impact on the development of asthma.

How could too much cleanliness affect infancy and/or pregnancy? There is little doubt that the vast array of products aimed at improving personal hygiene is ever increasing. Yet, there exist no data linking personal hygiene to the incidence of asthma. However, early in life unhygienic contact with other children or animals has been shown in numerous studies to decrease significantly the risk of asthma.

My grandparents, with the exception of one grandfather, all had at least 6 to 10 siblings. The one "lonely" grandfather came from a "small" family with only 4 children. Numerous children were not unique to my family, but were characteristic of most families at the beginning of the 20th century. There is abundant evidence that family size has decreased over more recent decades in affluent countries. Yet, sibship size has been shown to be a strong determinant of atopic conditions in children, adolescents, and adults (4). Most reports that were sufficiently large to allow a separate analysis of the influence of older and younger siblings have revealed a stronger relation between atopy and the presence of older versus younger siblings. These findings suggest that repeated infections in early childhood transmitted by contact with older siblings infected through peers in day care, kindergarten, and school may prevent the development of atopic immune responses. The consistency and strength of these associations over all age groups and different populations are intriguing and suggest a major underlying strong determinant of these responses.

The "sibling effect" has mostly been shown for atopy, and not for asthma. But only one longitudinal survey took the timing of exposure into account. In the Tucson Respiratory Study, exposure to older siblings and day care in the first 6 months of life was associated with a substantial reduction in the risk of asthma at school age and adolescence (adjusted odds ratio [OR] = 0.3; 95% confidence interval [CI], 0.2-0.5) (5). Day care attendance, and thereby increased exposure to infectious agents early in life, was characteristic of the former East German lifestyle, where the prevalence of asthma and bronchial hyperresponsiveness was significantly lower as compared with West Germany (5). Children from East German families entering day nursery in the first year of life were much less likely to develop asthma and atopy than children attending day care after their second birthday (6). Likewise, repeated episodes of runny nose in the first year of life were found to be associated with a significant reduction in the risk of asthma up to school age in a longitudinal birth cohort study in Germany (7).

Do unhygienic conditions result only from human contacts? There is certainly a lot more to hygiene then just infections of any kind. Pasteur hunted germs in the air and reported a large variability of exposure depending on the site of measurement, for example, few germs on the slopes of Mont Blanc but abundant exposure in the dusty yard of the Paris Observatory (8). Not only viable germs, but also microbial products, that is, immune system-activating bacterial cell wall components or DNA, are ubiquitous in nature, being present in normal indoor environments as a constituent of dust (9). The highest levels of microbial products can be found in farmhouses, where animals such as cattle, pigs, and poultry are kept (10). Yet, contact with such animals confers a strong protection against the development of asthma, as shown among children raised in farming environments. The odds of childhood asthma at school age was reduced to one third when children were exposed to farm yard animals in the crucial time window of the first year of life (adjusted OR = 0.27, 95% CI, 0.11-0.68) when compared with children with later or no such exposure (11).

These findings have prompted investigators to speculate that there are "good" and "bad" germs that must be identified to prevent bad ones from harming us, and to take advantage of the good ones to properly booster our immune responses. With the potential exception of respiratory syncytial virus (RSV) infections, surveys have, however, failed to identify microbial agents with one-sided qualities (12). Immunology further supports the notion that it is not particular germs that direct a maturing immune system toward tolerance, but the overall burden of infectious stimuli that shapes immune responses toward supporting or suppressing IgE responses to environmental stimuli (13). Thus, not one particular infection (e.g., measles) and the lack of one particular immunization (e.g., measles vaccination) will do the job, but repeated stimuli over the first decisive years of life encountered through older siblings, day care, or animals will be necessary to induce tolerance.

How can these findings be related to the increase in the prevalence of asthma? Increased exposure to microbial agents, either through the infecting pathway or exposure to its products, has convincingly been shown to substantially reduce the risk of atopic and nonatopic asthma. Because family and sibship size have dramatically decreased, the relevant protective exposures have become less. There may, however, also be a maternal influence on the temporal trend in asthma prevalence. Maternal transmission of asthma has repeatedly been shown to be stronger than paternal transmission (14), pointing toward independent effects of in utero exposure. If, in fact, the intrauterine environment must first be shifted toward an atopic phenotype to give rise to offspring with asthma, then environmental factors influencing the temporal rise in asthma prevalence must be sought in the maternal generation preceding that of the affected individuals. Then such factors as migration from rural farming-related exposures to urban areas, and the change from horse carriages to modern car traffic, may well affect the incidence of asthma.

	References

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1. von Mutius E, Martinez F. Epidemiology of childhood asthma. In: Pediatric asthma. New York: Marcel Dekker; 1999.

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8. de Kruif P. Microbe hunters. San Diego, CA: Harcourt Brace & Company; 1996.

9. Michel O, Ginanni R, Duchateau J, Vertongen F, Le Bon B, Sergysels R. Domestic endotoxin exposure and clinical severity of asthma. Clin Exp Allergy 1991; 21: 441-448 [Medline].

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12. von Mutius E. Infection: friend or foe. The epidemiological evidence. Eur Respir J 2001. (In press)

13. Holt P. Mucosal immunity in relation to the development of oral tolerance/sensitization. Allergy 1998;53(46 Suppl):16-19.

14. Litonjua A, Carey V, Burge H, Weiss ST, Gold D. Parental history and the risk for childhood asthma. Does mother confer more risk than father? Am J Respir Crit Care Med 1998; 158: 176-181 [Abstract/Free Full Text].