IJE Advance Access originally published online on May 2, 2008
International Journal of Epidemiology 2008 37(3):570-572; doi:10.1093/ije/dyn077
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Commentary: The end of the hygiene hypothesis?
Centre for Public Health Research, Massey University Wellington Campus, Private Box 756, Wellington, New Zealand.
* Corresponding author. E-mail: j.douwes{at}massey.ac.nz
Accepted 1 April 2008
Three years ago, we published a commentary in the International Journal of Epidemiology, which concluded that the observed increases in asthma prevalence in Western countries had peaked or even begun to decline.1 Further evidence for this is presented in the paper by Ponsonby et al.2 that appears in the current issue of the journal. However, although there is now substantial evidence that the ‘epidemic’ of asthma in Western countries has begun to decline, the reasons for the decline remain as mysterious as the reasons for the epidemic itself. In recent years, it has become routine to attribute the epidemic to the ‘hygiene hypothesis’, particularly with regards to the protective effects of microbial exposure early in life, but there are many anomalies in the epidemiological evidence that raise questions about this interpretation of the global asthma prevalence time trends.1
The ‘hygiene hypothesis’ has been prompted by evidence that overcrowding, unhygienic conditions and larger family size were associated with a lower prevalence of atopy, eczema, hay-fever and asthma.3,4 An increase in infections as well as increased exposures to specific microbial agents with strong pro-inflammatory properties, such as bacterial endotoxin has been proposed as an explanation for these findings.5 Although the specific immune mechanisms are not clear, it is believed that microbial exposures may activate innate immune pathways through expression of Toll-like receptors (TLRs) and CD14.6 These exposures may thereby suppress T-helper-2 (TH2) cell expansion and the development of IgE-antibodies and TH2 dependent diseases, including allergic asthma, hay fever and eczema.5 It has, therefore, been hypothesized that increased cleanliness, reduced family size and subsequent decreased microbial pressure in the past few decades could explain the increase in global asthma prevalence.
This new paradigm has gained considerable support from asthma researchers worldwide, and has resulted in new aetiological theories, and inspired basic scientists to develop novel laboratory-based studies.5 However, despite great enthusiasm and rapid uptake of this new theory there is reason for caution, and the findings reported by Ponsonby et al.2 provide further reason for scepticism. They examined asthma trends in 22 882 Australian children aged 4–6 using annual questionnaires from 2000 to 2005 inclusive. In contrast to what would be expected based on the hygiene hypothesis, asthma symptom prevalence showed a steady decline. The prevalence of eczema symptoms on the other hand, significantly increased. Ponsonby et al.2 also found that immigrant and non-immigrant children showed similar asthma time trends, which argues against the suggestion that the immunological reactivity expressed in childhood is predominantly established within the first year of life or even in the prenatal period—a view often associated with the hygiene hypothesis.
These findings add to other contradictory evidence that warrants scepticism about the hygiene hypothesis as the primary explanation for global asthma prevalence time trends.
First, it has now been well established that the proportion of asthma cases that are attributable to atopy is usually less than one-half.7 Similarly, recent studies have demonstrated that < 50% of asthma cases are attributable to eosinophilic airway inflammation, the hallmark of allergic asthma.8 Thus, evidence from studies of eosinophilia and asthma is consistent with that from studies of atopy and asthma: in both instances, at most about one-half of asthma cases appear to be due to ‘allergic’ mechanisms. The hygiene hypothesis suggests that a decrease of exposure to microbes would—through enhanced atopic immune responses—increase the incidence of allergies and allergic asthma. If true, then the protective effects would be most pronounced for the atopic asthma phenotype as well as other atopic conditions such as eczema. Interestingly, in the study by Ponsonby et al.,2 a steady increase in eczema was observed, suggesting that some atopic conditions may indeed still be on the rise. If so, then the observed decrease in asthma may be explained by a decline in non-atopic asthma, potentially masking the (smaller) increase in atopic asthma. Similarly, the past increase in asthma may not have been exclusively attributable to an increase in allergic asthma. In fact, there is some evidence that non-atopic asthma may have increased more than atopic asthma.9 Furthermore, in a repeated population survey among pre-school children, an increase in asthma prevalence was not only found in children with the classic asthma pattern of wheeze, but also in all wheezing phenotypes including viral-induced wheezing.10 Thus, at least some of the time trends may be due to temporal variation in factors affecting non-allergic asthma. Ponsonby et al.2 also observed a decline in hay fever that may be seen as an argument against the hypothesis that the observed decline is due to non-allergic mechanisms, but we have previously shown that rhinitis, like asthma, is a heterogeneous condition with an important non-atopic component.11 Unfortunately, most time-trend studies have not included comparable measures of atopy, and differential time-trend patterns for different asthma/rhinitis phenotypes can, therefore, not be established at this time.
Second, as noted earlier, asthma prevalence has begun to decline in both children12,13 and adults14 in Western countries, but it appears unlikely that these countries have become less clean in recent decades5 and there is certainly no evidence that family size has increased. There are also a number of anomalies in the evidence from studies conducted within these countries. For example, although housing conditions are unlikely to have become more hygienic in United States inner city populations, asthma prevalence has increased significantly in those populations, particularly among African Americans living in poverty.15 Furthermore, studies of specific infections and asthma risk have not consistently demonstrated a protective effect.16
Third, a further anomaly is the high asthma prevalence in countries in Latin America, which appear unlikely to have lower infection rates than European countries such as Spain and Portugal, which have the same dominant languages—and to a large extent, culture—and lower asthma symptom prevalence.17
Fourth, although the hygiene hypothesis is generally explained as a protective effect of early life exposures resulting in long-lasting health benefits, recent studies suggest that exposures throughout life may be important and that long-term continual exposure to protective factors including microbial agents may be required to maintain optimal protection.18,19 These data are consistent with the data presented by Ponsonby et al.,2 which suggest that the immunological reactivity expressed in later life is not exclusively established in the prenatal period or first year of life.
On the other hand, none of these anomalies are fatal for the hygiene hypothesis in general, but only for the very ‘narrow’ version of it in which microbial pressure early in life protects against atopic asthma by suppressing TH2 immune responses. It is possible that this very specific form of the hygiene hypothesis may be invalid, or at least incomplete, but that a more general version of the hygiene hypothesis is still valid. In particular: (i) the hygiene hypothesis is a very useful model to explain the significant protective effects of farming on asthma and allergies observed in many studies worldwide20; (ii) the hygiene hypothesis is consistent with findings that pets in the home may protect against allergies and asthma21 and (iii) many aspects of the hygiene hypothesis can be reproduced in mice models of allergic asthma.22 However, although the hygiene hypothesis may be a valid explanation for some of the observed differences in asthma prevalence between populations, it is unlikely that the hygiene hypothesis on its own can explain the large asthma prevalence increases observed over the last decades or the decline in asthma prevalence observed more recently in western countries. Furthermore, it appears unlikely that the immunologic reactivity expressed in later life is exclusively established in early life as is often assumed in the hygiene hypothesis. As we have previously noted,5 it is important that we consider the ‘forest’ of changes that occur with westernization, as well as the specific ‘trees’, and that the package of changes that come with westernization and increased hygiene may increase asthma risk, but not necessarily exclusively through an imbalance of TH1/TH2 immunity. New aetiological theories of global asthma prevalence are, therefore, required that are more consistent with the epidemiological evidence and which take into account factors affecting the time trends for both allergic and non-allergic asthma.
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The Centre for Public Health Research is supported by a Programme Grant from the Health Research Council (HRC) of New Zealand. Jeroen Douwes is supported by an HRC funded Sir Charles Hercus Fellowship.
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TopAcknowledgementsReferences |
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1 Pearce N, Douwes J. Asthma time trends – mission accomplished? Int J Epidemiol (2005) 34:1018–19.
2 Ponsonby A-L, Glasgow N, Pezic A, Dwyer T, Ciszek K, Kljakovic M. A temporal decline in asthma but not eczema prevalence from 2000-2005 at school entry in the Australian Capital Territory with further consideration of country of birth. In: Int J Epidemiol (2008) 37:559–69.
3 Strachan DP. Hay fever, hygiene, and household size. Br Med J (1989) 299:1259–60.
4 Strachan DP. Allergy and family size: a riddle worth solving. Clin Exp Allerg (1997) 27:235–36.[CrossRef][Web of Science][Medline]
5 Douwes J, Pearce N. Asthma and the westernization ‘package’. Int J Epidemiol (2002) 31:1098–102.
6 Ege MJ, Bieli C, Frei R, et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J Allerg Clin Immunol (2006) 117:817–23.[CrossRef][Web of Science][Medline]
7 Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax (1999) 54:268–72.
8 Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms [comment]. Thorax (2002) 57:643–48.
9 Thomsen SF, Ulrik CS, Larsen K, Backer V. Change in prevalence of asthma in Danish children and adolescents. Ann Allerg Asthma Immunol (2004) 92:506–11.[Web of Science][Medline]
10 Kuehni CE, Davis A, Brooke AM, Silverman M. Are all wheezing disorders in very young: (preschool) children increasing in prevalence? Lancet (2001) 357:1821–25.[CrossRef][Web of Science][Medline]
11 Zacharasiewicz A, Douwes J, Pearse N. What proportion of rhinitis symptoms is attributable to atopy? J Clin Epidemiol (2003) 56:385–90.[CrossRef][Web of Science][Medline]
12 Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys. Lancet (2006) 368:733–43.[CrossRef][Web of Science][Medline]
13 Pearce N, Aït-Khaled N, Beasley R, et al. Worldwide trends in the prevalence of asthma symptoms: phase three of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax (2007) 62:757–65.
14 Chinn S, Jarvis D, Burney P, et al. Increase in diagnosed asthma but not in symptoms in the European Community Respiratory Health Survey. Thorax (2004) 59:646–51.
15 Crater DD, Heise S, Perzanowski M. Asthma hospitalization trends in Charleston, South Carolina, 1956 to 1997: twenty-fold increase among black children during a 30-year period. Paediatrics (2001) 108:E97.[CrossRef][Medline]
16 Pearce N, Douwes J, Beasley R. Asthma. In: Oxford Textbook of Public Health—Tanaka H, ed. (2002) 4th edn. Oxford: Oxford University Press. 1255–77.
17 Pearce N, Duwes JT. The Latin American exception: why is childhood asthma so prevalent in Brazil? J Paediatr (2006) 82:319–21.[CrossRef]
18 Douwes J, Le Gros G, Gibson P, Pearce N. Can bacterial endotoxin exposure reverse atopy and atopic disease? J Allerg Clin Immunol (2004) 114:1051–54.[CrossRef][Web of Science][Medline]
19 Douwes J, Travier N, Huang K, et al. Lifelong farm exposure may strongly reduce the risk of asthma in adults. Allergy (2007) 62:1158–65.[CrossRef][Web of Science][Medline]
20 Braun-Fahrlander C, Lauener R. Farming and protective agents against allergy and asthma. Clin Exp Allerg (2003) 33:409–11.[CrossRef][Web of Science][Medline]
21 Hesselmar B, Aberg N, Aberg B, Eriksson B, Bjorksten B. Does early exposure to cat or dog protect against later allergy development? Clin Exp Allerg (1999) 29:611–17.[CrossRef][Web of Science][Medline]
22 Lundy SK, Berlin AA, Lukacs NW. Interleukin-12-independent down-modulation of cockroach antigen-induced asthma in mice by intranasal exposure to bacterial lipopolysaccharide. Am J Pathol (2003) 163:1961–68.
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- A temporal decline in asthma but not eczema prevalence from 2000 to 2005 at school entry in the Australian Capital Territory with further consideration of country of birth
- Anne-Louise Ponsonby, Nicholas Glasgow, Angela Pezic, Terence Dwyer, Karen Ciszek, and Marjan Kljakovic
Int. J. Epidemiol. 2008 37: 559-569.[Abstract] [FREE Full Text]
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