Is asthma really linked to atopy?

In western societies questions about the role of atopy in asthma sound almost absurd. Many studies have consistently shown that atopy, i.e. the production of specific immunoglobulin (Ig)E antibodies to environmental allergens, is strongly associated with childhood and adult asthma. In cross-sectional and clinical studies atopic sensitization was related to an increased prevalence of asthma, airway hyper-responsiveness (AHR) and a greater severity of respiratory symptoms as compared to the absence of atopy [1]. Moreover, the strength of atopic sensitization as assessed by increasing numbers of positive skin prick test results [2, 3] or increasing weal sizes [4] was linearly related to the severity of childhood asthma and airway hyperresponsiveness. Early sensitization developing before the age of six to eight years was found to be a stronger predictor for asthma than sensitization being only detectable thereafter [4, 5]. Thus, factors enhancing the production of specific IgE antibodies or the lack of protective mechanisms to induce tolerance towards environmental allergens early in life may increase the risk of asthma in western societies. There is, however, increasing scepticism about this paradigm arising from the findings of population studies both in western and developing societies. Ann Woolcock pointed towards striking disparities when comparing the prevalence of asthma and atopy across populations world-wide [6]. There are populations, mostly in western cultures, where those with a high prevalence of asthma, e.g. in the UK, have corresponding increased rates of atopy (9.5% and 32.0%., respectively). Likewise, low rates of asthma have been found to be paralleled by a reduced prevalence of atopy, e.g. in Estonia (3.2% and 14.3%, respectively). From a more global perspective however, populations arising from developing societies such as China [7], Ethiopia [8] or The Gambia as reported in the current issue of Clinical and Experimental Allergy[9, 10] show discrepant relations. In these areas a high prevalence of atopy was associated with an exceedingly low rate of asthma, e.g. in China: 49.0% atopy vs. 1.9% asthma; or in The Gambia: 35.3% atopy and 3.6% asthma. In the Gambian population, Walraven and colleagues assessed asthma based on self-completed questionnaire information relating to wheeze and doctor-diagnosed asthma [10]. In addition, the authors performed airway challenges using the standard methacholine challenge procedure of the European Respiratory Society. Interestingly, only a very minor proportion of subjects with wheeze and asthma (3.0% and 4.3%, respectively) reacted to the bronchial challenge. These low rates are in marked contrast to figures from western countries where more than half of wheezing subjects challenged with methacholine showed a significant drop in FEV1[11]. Such discrepancies may be attributable to difficulties in adequately translating ‘wheeze’ and ‘asthma’ into local languages where such conditions have been exceedingly rare in the past. Yet, it seems unlikely that such linguistic issues should fully account for this large discrepancy since careful forward and backward translations had been performed. Rather, the low rate of AHR among symptomatic subjects may tell us that within the large pool of the ‘asthma syndrome’, a particular phenotype arises in developing countries which is dissociated from atopy and AHR. Since in western populations atopic sensitization is a very strong predictor for AHR, the lack of association between AHR and asthma in populations with an inverse relation between atopy and asthma may not be surprising. The high rates of atopy in countries such as The Gambia, China and Africa have been attributed to the endemic presence of parasitic infections. It is well recognized that helminth infections induce potent Th2-type immune responses which result in elevated serum IgE levels, eosinophilia and elevated interleukin (IL)-4 production by polyclonally-stimulated peripheral blood mononuclear cells [12]. These increased responses are in apparent contrast to the reduced prevalence of asthma and clinical allergies seen in countries with endemic parasitic infections [12]. Moreover, in a study enrolling children from Gabon, Africa, an apparent dissociation between elevated serum IgE levels in vitro and skin reactivity in vivo was found: less than one-third of serum IgE-positive children exhibited skin test reactions to a prevalent allergen. Similar results have been obtained by Nyan and colleagues in the Gambian population where skin test reactivity was inversely related to the presence of helminth infections, although total serum IgE levels were about 2.5 times the upper limit of the reference range in western populations [9]. Two potential mechanisms have been proposed to resolve these discrepancies. Firstly, investigators have speculated that high levels of polyclonal non-antigen-specific IgE may occupy IgE receptors on mast cells thereby blocking the mast cell degranulation response to allergen-specific IgE. Secondly, anti-inflammatory cytokines such as IL-10 or transforming growth factor (TGF)-β have been proposed to act as inhibitory signals for down-regulation of target tissue responses to allergens [13]. Thus, the findings suggest that while helminths may be permissive or even stimulatory towards Th2-mediated immune responses, they additionally trigger powerful anti-inflammatory mechanisms which limit the magnitude of ensuing in vivo responses to allergens [14]. What can be learned from such studies in developing countries in order to improve our understanding of asthma in western populations? Firstly, these findings may alert us to the fact that there is a component to the ‘asthma syndrome’ which is not related to atopy and which may therefore be determined by very different risk factors than the atopic part of the ‘asthma syndrome’. In fact, a recent review summarizing the available epidemiological evidence world-wide concluded that the population-based proportion of asthma cases that are attributable to atopy is usually less than one-half [15]. Mechanisms more pertinent to airway and lung structure potentially involving smooth muscle, the epithelial cell layer or mechanical properties of the respiratory tract may play a role. It is, however, also conceivable that it is the asthmatic condition which results in a certain pattern of atopic sensitization. In populations with a high prevalence of elevated IgE levels attributable to other causes and a low rate of asthma the link between asthma and atopy will most likely be missed. Recent findings from the German Multicentre Allergy Study in fact support this notion [5]. In this longitudinal survey asthma was found to be related only to a certain pattern of atopic sensitization. This specific association was, however, mainly seen in children with maternal risk factors. These findings suggested that it is not atopy which in a progressive march eventually results in the development of asthma, but it is a maternal factor which determines both asthma and concurrently a certain pattern of ongoing sensitization. Such reflections are not of purely philosophical interest, but may well help us to understand why current paradigms of, for example, allergen avoidance strategies aiming at reducing atopic sensitization have failed to prevent the development of asthma.