Asthma and the westernization ‘package’

Jeroen Douwesa,b and Neil Pearcea

a Centre for Public Health Research, Massey University Wellington Campus, Private Box 756, Wellington, New Zealand.
b Institute for Risk Assessment Sciences (IRAS), Division of Environmental and Occupational Health, Utrecht University, The Netherlands.

Correspondence: Jeroen Douwes, Centre for Public Health Research, Massey University Wellington Campus, Private Box 756, Wellington, New Zealand.E-mail: j.douwes{at}massey.ac.nz


    Introduction
 Top
 Introduction
 Westernization and asthma
 Fetal growth and asthma
 The westernization...
 Acknowledgements
 References
 
Ten years ago we knew what caused asthma, and we knew how to prevent it. Asthma was an atopic disease caused by allergen exposure. The fundamental aetiological mechanism was that allergen exposure, particularly in infancy, produced atopic sensitization and continued exposure resulted in asthma through the development of eosinophilic airways inflammation, bronchial hyper-responsiveness and reversible airflow obstruction. Asthma prevalence was increasing around the world because of changes in lifestyle and domestic building design that were increasing allergen exposure. The solution was therefore clear: to prevent asthma we needed to prevent exposure to allergens.1–3

In recent years it has become increasingly evident that this picture is, at best, too simplistic.4 Bronchial responsiveness is a poor surrogate measure of clinical asthma and the current evidence is that it has lower validity than standard symptom questionnaires.5 Less than one half of asthma cases are attributableto atopy and/or eosinophilic airways inflammation,6 and (non-allergic/non-atopic) neutrophilic airways inflammation may account for the other half.7 Furthermore, although there are some clear cases of allergen exposure causing asthma in adults in the occupational environment, overall there is little evidence that allergen exposure is a major primary cause of asthma,8 and even some evidence that allergen exposure early in life may have a protective effect (see below).

The ‘established’ risk factors for asthma, including allergen exposure, were ‘discovered’ primarily on the basis of clinical studies and case reports of exacerbations in asthma patients. It is natural for physicians and patients to assume that the factors involved in secondary causation may also be important for primary causation. Once the theory became established it was easy to find ‘verifications’ of the allergen hypothesis, and to dismiss ‘refutations’ as chance findings or as being due to inadequate measurements of exposure and outcome. Of course, there are well-documented instances where allergen exposure does act as a primary cause of asthma, particularly in adults. However, allergen exposure does not appear to be the major primary cause of asthma that it has been assumed to be, nor to account for global patterns of asthma prevalence, or the striking increases in asthma prevalence over time.9


    Westernization and asthma
 Top
 Introduction
 Westernization and asthma
 Fetal growth and asthma
 The westernization...
 Acknowledgements
 References
 
As the ‘established’ asthma risk factors are increasingly being called into question, epidemiological studies are playing a major role in the search for new theoretical paradigms which are more consistent with the epidemiological evidence and which have greater explanatory power. Recent research has therefore shifted attention from allergens that may cause sensitization and/or provoke asthma attacks, to factors that may ‘programme’ the initial susceptibility to asthma, through allergic or non-allergic mechanisms. This also in part involves a shift of attention from risk factors for asthma to protective factors, and the possible role of the loss of protective factors in the global increases in asthma prevalence.

Several studies have indicated that certain exposures (in particular of microbial origin) early in life may protect against atopy and asthma which has led to the ‘hygiene hypothesis’. Briefly, microbial exposure may affect T lymphocytes which have an important function in controlling immune responses including (amongst others) help for B cell production of antibodies (IgE, IgG, IgA, IgM). T-helper 2 (TH2) cells stimulate B-cells to produce IgE upon allergen stimulation whereas T helper 1 cells (TH1) inhibit this process. In these processes various cytokines are involved including TH1-associated interleukin 12 (IL-12) and interferon gamma (IFN-{gamma}), and IL-5 and IL-4 associated with TH2 immunity (Figure 1Go). The so called ‘hygiene hypothesis’ postulates that growing up in a more hygienic environment with less microbial exposure may enhance atopic (TH2) immune responses, whereas microbial pressure would drive the response of the immune system—which is known to be skewed in an atopic TH2 direction during fetal and perinatal life—into a TH1 direction and away from its tendency to develop atopic immune responses.10,11



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Figure 1 Potential protective effects of microbial exposure by enhancing TH1 and inhibiting TH2 immunity

APC: Antigen presenting cells; BMNC: Blood mononuclear cells; IL: interleukin; IFN-gamma; interferon-gamma; TH: T helper cell; IgE; Immunoglobulin E.

 
This ‘hygiene hypothesis’ has been prompted by the results of several epidemiological studies showing that overcrowding and unhygienic conditions were associated with a lower prevalence of atopy, eczema and hay-fever although the evidence for asthma is less consistent.12,13 A large number of siblings (especially older siblings) and attendance at day care centres were determined to be particularly protective.14,15 An increase in infections has been proposed as an explanation for these findings.16

Several studies have shown a direct association between infections (e.g. hepatitis A, measles) or immunization with BCG and a lower prevalence of atopy and allergies.17–20 However, the results for airborne viruses (measles, mumps, rubella and chickenpox) and BCG vaccination were inconsistent.21–24 The role of respiratory viral infections is also not very clear; respiratory tract infections are known to exacerbate pre-existing asthma,25 and lower respiratory tract infections may be a risk factor for asthma.26,27 On the other hand upper respiratory infections may protect against atopy and asthma.27 The type of infection (food-borne and oral-faecal versus airborne, and viral versus bacterial) and location (higher versus lower airways) may thus be important in determining the effect on atopy and asthma. Furthermore, exposure to specific microbial agents with strong pro-inflammatory properties such as bacterial endotoxin have been suggested to be protective.11,28–30 One study demonstrated in infants that endotoxin levels in house dust correlated with IFN-{gamma} producing T cells (TH1), but not with IL-4, IL-5 or IL-13 producing cell proportions (TH2). In addition, it was shown that allergen sensitized infants had significantly lower endotoxin levels in house dust than non-sensitized infants.31 However, the evidence for a protective effect of endotoxin is currently still weak.32

In addition to specific agents with potential protective effects, subpopulations have been identified with low atopy and asthma rates compared to the general populations. For instance, it has been documented that children with an anthroposophic lifestyle in Sweden33 and children raised on farms with livestock in Europe, Canada, and Australia34–41 have less atopy and asthma. However, it is currently not clear which specific factors confer protection but specific microbial exposures have been hypothesized to be involved either through ingestion (lactobacilli) or inhalation (endotoxin; see above). Ingestion of lactobacilli may be important since they have the ability to colonize the human gut42 and some (mostly experimental) evidence exists suggesting that they may modify the immune development into a non-atopic TH1 direction.43–50 However, various other microbes of the gut flora may play a role as well.51–53

Finally, several studies have shown that the presence of pets in the home early in life in Europe was negatively associated with atopy.54,55 This should, however, be interpreted with caution, since avoidance behaviour (removal of pets in the families with sensitized and/or symptomatic children) may have contributed to this inverse association.56 Recently, an explanation was offered for a potential protective effect by Platts-Mills et al.57,58 who suggested some form of tolerance involving a modified TH2 response characterized by the presence of high IgG4 antibody levels and suppressed IgE production. Alternatively, increased exposures to bacterial endotoxin may play a role since it is known that pets in the home are associated with higher endotoxin levels in house dust.59–62 In other parts of the world (Guinea-Bissau and Nepal) it has been shown that pigs and cattle in the home are associated with less atopy.20,63 This is in line with observations that animal contact in farmers’ children may confer protection, and as hypothesized for the farmers’ children, increased endotoxin exposures may play a role.32

Thus the current ‘hygiene hypothesis‘, may explain an increase in atopy and allergic asthma. However, with the large proportion of asthma that is not associated with atopy it is questionable whether the ‘hygiene hypothesis’ (as defined above) on its own can explain the large increase observed over the last decades. For instance, in a repeated population survey among preschool children an increase in asthma prevalence was not only found in children with the classic asthma pattern of wheeze but in all wheezing phenotypes including viral wheeze.64 However, this was not confirmed in another study among children and young adults that showed an increase in all wheezers but not in viral wheeze. In addition, some studies have suggested that only atopic asthma has increased, but in those studies poor markers of atopy were used with unknown validity.65,66 Studies in farmers’ children have indicated that protective effects of farming were independent from effects on atopic sensitization.36 Finally, although housing conditions have likely not become more hygienic in US inner city populations, asthma prevalence has increased significantly in those populations, and particularly among African Americans living in poverty,67,68 which is in contrast to previous findings showing a positive association between affluence and asthma prevalence. These studies thus further emphasize the potential limitations of the current hygiene hypothesis. However, whatever mechanism is involved, it is becoming increasingly clear that the ‘package’ of changes associated with westernization may be contributing to the global increases in asthma prevalence, and that this process involves an increase in asthma susceptibility rather than an increase in exposure to ‘established’ asthma risk factors.9


    Fetal growth and asthma
 Top
 Introduction
 Westernization and asthma
 Fetal growth and asthma
 The westernization...
 Acknowledgements
 References
 
In this context, it is of interest that some recent studies have identified a relatively large size at birth as a risk factor for the subsequent development of asthma in adolescence,69–72 and the findings of Yuan et al.73 in this issue of the International Journal of Epidemiology add to this evidence. These studies have examined the ‘other end’ of the ‘Barker hypothesis’ which had previously almost exclusively focussed on the ‘low end’ of the fetal growth spectrum which was found to be associated with an increased risk of disease in adult life. Now we are discovering that bigger is not always better, and that there are also health consequences of high fetal growth. The reasons for these associations are unclear, but fetal growth apparently reflects a number of intrauterine influences, particularly relating to maternal diet and placental function. This is potentially a finding of major importance since anthropometric measures at birth have increased during this century.

Nevertheless, it is important to place these findings in perspective. Firstly, the findings are, as usual, inconsistent. A large prospective birth cohort in Finland of 5192 subjects who were followed up to the age of 31 showed an inverse association between atopy and gestational age (excluding those infants that were born prematurely), but no association was found with length and weight at birth. In addition, no associations with any of the birth characteristics (including birthweight, length and gestational age) and asthma was found.74 The most consistent finding is that a large head circumference at birth is associated with an increased risk of atopy,69,71,72 but the association with asthma is much weaker71,72 with the exception of one study.70 On the other hand, birth length has been associated with asthma, but not with atopy in one study,71 while low birthweight has been associated with a reduced risk of asthma in some studies70,71 and an increased risk in others.75,76

Secondly, assuming that the findings reported by Yuan et al.,73 regarding high birthweight and/or ponderal index and subsequent hospitalization for asthma, are confirmed in further studies, they may not be due to the atopic aetiological mechanisms that they focus on in their discussion. As noted above, it appears that at most one half of asthma cases are attributable to atopy,6 which may explain in part the inconsistent findings for fetal growth, atopy, and asthma.

Finally, it should be noted that the population attributable risk of high fetal growth as a cause of asthma is relatively small. The strongest finding reported by Yuan et al.73 is for birthweight and hospitalization for asthma, but even in this instance the population attributable risk is around 1.5%. As countries become more ‘Western‘, babies are getting larger, and this is associated with an increased risk of atopy and/or asthma, but it cannot explain the striking increases in asthma prevalence over recent decades.

Currently little is known about other prenatal risk factors for atopy and asthma (with the possible exception of maternal smoking), and even less is known about potential protective factors, whereas prenatal events or exposures may be very important in the development of these conditions.77,78 The cytokine profile of the mother may affect the development of the fetal immune system.79,80 Prenatal allergen exposure may also play a role.81 It has been hypothesized, and some evidence has been presented,82–88 that the immune system may be primed through transamniotic or transplacental exposure to antigens or antigen-derived peptides, resulting in a decreased capacity of TH1 cytokine interferon {gamma} production, which may result in atopic TH2 immune responses in neonates.87 A recent study showed a positive association between allergen exposure (measured as allergen levels in the mother’s mattresses) and total IgE in cord blood suggesting that prenatal exposures may indeed affect the development of fetal immune responses.88 Moreover, in the same study an inverse association was shown for endotoxin. Interestingly, in a recent cross-sectional study among farmers’ children it was suggested that farm activity of the pregnant mother (associated with high endotoxin exposures) had a protective effect on atopy and asthma of her child.36 Thus, prenatal endotoxin exposure could confer protection for atopy and asthma. However, as with pre-natal allergen exposure as a potential risk factor, the evidence is currently weak and needs confirmation in larger prospective studies.


    The westernization ‘package’
 Top
 Introduction
 Westernization and asthma
 Fetal growth and asthma
 The westernization...
 Acknowledgements
 References
 
The striking increases in asthma prevalence globally cannot be primarily due to genetic factors, since they are occurring too rapidly, and therefore they must be occurring due to changes in environmental exposures. It seems that as a result of this ‘package’ of changes in the intrauterine and infant environment, we are seeing an increased susceptibility to the development of asthma and/or allergy. There are a number of elements of this ‘package’ including changes in maternal diet, increased fetal growth, smaller family size, reduced infant infections and increased use of antibiotics and immunization, all of which have been (inconsistently) associated with an increased risk of childhood asthma, but none of which can alone explain the increases in prevalence.9 Thus, it is important that we consider the ‘forest’ of changes that occur with westernization, as well as doing studies of specific ‘trees’. In particular, the inconsistent findings with regard to fetal growth and asthma suggest that studies of this issue alone are unlikely to yield major benefits, although they may be an important part of the process of understanding the bigger picture. It is likely that the ‘package’ is more than the sum of its parts, and that these social and environmental changes are all pushing infants’ immune systems in the same direction. To know what that direction is, and which components of the ‘package’ are responsible, requires that better aetiological theories of asthma are developed to replace the allergen theory, or to incorporate it as a special case.

Although have we focussed in this editorial on perinatal factors and early life exposures that may play a role in programming asthma susceptibility, later exposures (Western or otherwise) may be important too. However, currently little is known (with the exception of occupational asthma) on how exposures later in life may affect these processes. Similarly, most of the studies we have discussed relate to allergic mechanisms for asthma, because few studies have been done on non-allergic mechanisms for asthma and their potential contribution to population trends.

It is essential that in the future as much attention is paid to non-allergic (non-eosinophilic) mechanisms for asthma as has been paid to allergic (eosinophilic) mechanisms in the past. Furthermore, it requires that epidemiologists rigorously test these new theories systematically in population-based studies, rather than the ad hoc and anecdotal approach that has been adopted in the past with respect to studies of the allergen hypothesis. Epidemiology has played a major role in calling the ‘established’ theory of asthma causation into question. It also has a major role to play in developing and testing new aetiological theories of asthma causation.


    Acknowledgements
 Top
 Introduction
 Westernization and asthma
 Fetal growth and asthma
 The westernization...
 Acknowledgements
 References
 
The Centre for Public Health Research is supported by a Programme Grant from the Health Research Council of New Zealand. Jeroen Douwes is supported by a research fellowship from the Netherlands Organization for Scientific Research (NWO).


    References
 Top
 Introduction
 Westernization and asthma
 Fetal growth and asthma
 The westernization...
 Acknowledgements
 References
 
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