The Increase in Asthma Cannot Be Ascribed to Cleanliness

Thomas A. E. Platts-Mills, Judith A. Woodfolk, and Richard B. Sporik

University of Virginia, Charlottesville, Virginia

	ARTICLE

TOP ARTICLE REFERENCES

Several different hypotheses have been proposed to explain the rise in allergic diseases and asthma. In 1976, Gerrard and coworkers speculated that the virtual absence of allergy and asthma among Canadian Indians was due to a protective effect of environmental or infectious factors (1). Subsequently, Strachan and colleagues presented the "cleanliness hypothesis" as an explanation for the protective effect of large families against allergy and asthma (2). Cookson and Moffat proposed, as a mechanism for the protective effect of infections, that activation of helper T cell type 1 (Th1) responses by mycobacteria could control or reduce Th2 responses (3). The idea was that a milieu rich in cytokines such as interferon  (IFN-) and interleukin 12 (IL-12) could nonspecifically suppress the induction of Th2 responses. However, the data on BCG vaccination do not show an effect on the prevalence of allergy, and adoptive transfer experiments in mice do not show that Th1 cells can influence Th2 responses to other antigens (4, 5). More recently, Rook and colleagues have refined the hypothesis, suggesting that products of mycobacteria that used to be common in the environment activated T cells that could regulate both Th1 and Th2 responses (6).

Over the last 100 years both hay fever and allergic asthma have increased in developed countries. By contrast, in the rural villages of many underdeveloped countries asthma remains rare (7). However, it is not clear whether the rise in allergy as judged by skin tests or symptoms occurred at the same time as the increase in asthma. Hay fever was recognized before 1900 and was becoming common when Noon invented immunotherapy in 1911 (8). By 1960, seasonal hay fever was present in 16% of a population survey in Michigan, and there has been little evidence of an increase in the United States since that time (9). Indeed, much of the evidence used to support a recent increase in "allergy" is based on questionnaires about nonspecific nasal symptoms. In contrast, the objective evidence about an increase in asthma comes from studies of emergency room use, hospitalization, and mortality, as well as population studies of the prevalence of symptoms and treatment. Crane would argue that wheezing as a symptom was common before 1960 (Reference 10 and personal communication, Dr. Julian Crane). However, all other aspects of asthma have increased dramatically. In one study we found that admissions of African American children in Charleston, South Carolina had increased 20-fold on a population-at-risk basis over the period 1967-1997 (11). Strikingly, the increase in this town parallels the time course of increases seen in many other countries (12).

To consider the relevance of the hypothesis to the increase in asthma, it is important to consider when major changes in public health occurred. Taking New York City as a model: eradication of malaria (1910), chlorinated water supplies (~ 1920), universal wearing of shoes (before 1900), minimal contact with farm animals, and the cure of major infectious diseases, occurred before 1946 (13). That year coincided with the start of the ragweed eradication plan to combat hay fever in New York (14). By contrast, the rise in asthma did not start before 1960. By 1982, asthma was recognized as a health problem secondary only to acquired immunodeficiency syndrome (AIDS), on the basis of hospital data. In New York, as elsewhere in the United States, the increase in asthma was a special problem for minority populations living in poverty. Given that the major increases in asthma occurred between 1970 and 2000, what changes relevant to "cleanliness" occurred during that period? Housing conditions have not improved; the major allergens (i.e., cockroach and rodent urine) do not suggest overly hygienic conditions; family size may have decreased, but the protective effects of large families have not been confirmed among African Americans. There have been increases in vaccination, but overall, we would argue that the major changes in "cleanliness" occurred long before the increase in asthma.

In more recent versions of the hypothesis, increased allergic or Th2 responses are considered to reflect a change in the form of allergen-specific immune responses as opposed to decreased suppression of allergic responses in general. Increases in early day care, in numbers of older siblings, higher endotoxin exposure, and close association with farm animals have each been interpreted as favoring Th1 responses to common allergens (15). However, there is little evidence that the common inhaled allergens can induce a specific Th1 response. Pollen, dust mite, and cat allergens do not give rise to delayed hypersensitivity and have not been incriminated as causes of hypersensitivity pneumonitis or any lung disease that could be related to Th1 responses. Is there any evidence of an alternative immune response to common allergens? Several studies have shown a protective effect against asthma from having a cat in the house. Detailed evaluation of children with high exposure to cat allergen, that is,  20 µg of Fel d 1 per gram of dust, confirmed a significantly decreased risk of sensitization, but also found evidence of a "modified Th2" response. This response includes IgG and IgG4 antibodies without IgE antibody and without an increased risk of asthma (18). Thus, the highest allergen exposure that we are aware of produces a modified Th2 response rather than a Th1 response.

There are a select number of chronic diseases that have increased during the last half of the 20th Century. Rook and coworkers would point to chronic inflammatory bowel disease, arthritis, and type 1 diabetes as diseases of immunodysregulation (6). However, the other group of diseases that have increased are obesity, hypertension, and type 2 diabetes, that is, diseases related to modern sedentary lifestyle. Of these, the only one that has been associated with asthma epidemiologically is obesity. Evidence from New York, from the Nurses Health Study, and from the United Kingdom has shown highly significant associations between body mass index (BMI) and the risk of asthma (19, 20). The indoor lifestyle includes at least three elements relevant to asthma: increased time exposed to indoor allergens, overeating, and decreased physical activity. The close association between these factors in the United States makes it difficult to analyze them separately. It is possible to argue that overeating increases inflammation in the lungs. Alternatively, we could argue that the decline in physical activity (particularly in normal outdoor play) has removed a form of protection that previously acted to control wheezing.

During the last 40 years of the 20th century, asthma as a condition requiring treatment or hospitalization has become epidemic. Attempts to explain this increase on the basis of increased cleanliness are unconvincing because (1) increases in asthma in African towns have occurred under conditions that could not possibly be considered as "clean"; (2) there are few data concerning humans to document the supposed changes in allergen-specific immune responsiveness; and (3) the increase in asthma between 1970 and 2000 does not coincide with any consistent changes in cleanliness.

	References

TOP ARTICLE REFERENCES

1. Gerrard J, Geddes C, Reggin P, Gerrard C, Horne S. Serum IgE levels in white and Metis communities in Saskatchewan. Ann Allergy 1976; 37: 91-100 [Medline].

2. Strachan DP, Taylor EM, Carpenter RG. Family structure, neonatal infection, and hay fever in adolescence. Arch Dis Child 1996; 74: 422-426 [Abstract].

3. Cookson WOCM, Moffat MF. Asthma: an epidemic in the absence of infection? Science 1997; 275: 41-42 [Free Full Text].

4. Strannegard IL, Larsson LO, Wennergren G, Strannegard O. Prevalence of allergy in children in relation to prior BCG vaccination and infection with atypical mycobacteria. Allergy 1998; 53: 249-254 [Medline].

5. Hansen G, Berry G, DeKruyff RH, Umetsu DT. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 1999; 103: 175-183 [Medline].

6. Rook GAW, Rosa-Brunet L, Hunt J. Cat allergen and sensitization. (Letter). Lancet 2001; 357: 2137-2138 [Medline].

7. Weinberg EG. Urbanization and childhood asthma: an African perspective. J Allergy Clin Immunol 2000; 105: 224-231 [Medline].

8. Noon L. Prophylactic innoculation for hay fever. Lancet 1911;I:1572.

9. Broder I, Higgins NW, Mathews KP, Keller JB. Epidemiology of asthma and allergic rhinitis in a total community. Tecumseh, Michigan. IV. Natural history. J Allergy 1974; 54: 100 .

10. Williams H, McNicol KN. Prevalence, natural history, and relationship of wheezy bronchitis and asthma in children. An epidemiological study. Br Med J 1969; 4: 321-325 .

11. Crater D, Heisse S, Morse KG, Herbett R, Perzanowski M, Platts-Mills TAE. Asthma admissions in Charleston, South Carolina, 1956-1997; twenty fold increase in admissions of African American children over 30 year period. Pediatrics (in press)

12. Beasley R, Crane J, Lai CKW, Pearce N. Prevalence and etiology of asthma. J Allergy Clin Immunol 2000; 105: S466-S472 [Medline].

13. Armstrong GL, Conn LA, Pinner RW. Trends in infectious disease mortality in the United States during the 20th century. JAMA 1999; 281: 61-66 [Abstract/Free Full Text].

14. Walzer M, Siegel BB. The effectiveness of the ragweed eradication compaigns in New York City: a nine-year study (1946-1954). J Allergy 1956; 27: 113-125 [Medline].

15. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright L. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000; 343: 538-543 [Abstract/Free Full Text].

16. Gereda JE, Leung DYM, Thatayatikom A, Streib JE, Price MR, Klinnert MD, Liu AH. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitization in infants at high risk of asthma. Lancet 2000; 355: 1680-1683 [Medline].

17. Von Mutius E. The environmental predictors of allergic disease. J Allergy Clin Immunol 2000; 105: 9-19 [Medline].

18. Platts-Mills TAE, Vaughan J, Squillace S, Woodfolk J, Sporik R. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 2001; 357: 752-756 [Medline].

19. Luder E, Melnik TA, DiMaio M. Association of being overweight with greater asthma symptoms in inner city Black and Hispanic children. J Pediatr 1998; 132: 699-703 [Medline].

20. Camago CA Jr,, Field AE, Coldritz GA, Speizer FE. Body mass index and asthma in children age 9-14. Am J Respir Crit Care Med 1999; 159: A150 .