Wang and hygiene standard, especially in developed countries. The so-called hygiene hypothesis of allergy was first suggested by Strachan (1989), who noted that the risk of developing allergies and asthma is inversely related to the number of children in the family. This effect has since been confirmed using various markers of infectious burden such as number of older siblings (von Mutius et al 1994a; Jarvis et al 1997; Bodner et al 1998), attendance at day care facilities (Krämer et al 1998), positive serology to orofecal infections (Matricardi et al 1997, 2000), and regular contact with farm animals before the age of 7 years (Radon et al 2004). To explain the hygiene hypothesis requires an appreciation of the developing immune system. T helper cell (Th2)-like cytokines (eg, IL-4, IL-5, and IL-13) produced in the uterine environment induce similar Th2- like responses in the immature immune system of the newborn, which increases the likelihood that postnatal (and possibly even prenatal) exposure to allergens leading to production of allergen-specific IgE and eosinophilic inflammation (Warner et al 1998). According to the hygiene hypothesis, infections with viruses and perhaps other intracellular organisms also influence the developing immune system: the T-cell responses to these infections generate Th1-like cytokines such as IL-12 and IFN-γ that down-regulate Th2 responses. Thus, the core of the hygiene hypothesis is based on the observations that Th1 responses induced by microbial stimulation can counterbalance allergen-induced Th2 responses. According to the hypothesis of “endotoxin switch”, a dose-dependent relationship exists between environmental exposure to bacterial products and the outcome of the immune response. The quantity of environmental endotoxin may also affect the balance of the Th1/Th2 cytokine level. It has been suggested that repeated viral infections other than lower respiratory tract infections early in life may stimulate the immature immune system towards the Th1 phenotype, thereby reducing the risk for the development of asthma up to school age (Illi et al 2001). The underlying mechanisms of these protective immuno- logic effects are still unclear. Which environmental or microbial factors are the culprits for atopic manifestation? It should not be assumed that all infectious diseases have the same effects on the development or clinical manifestation of allergic diseases. It is known that lower respiratory tract infections including respiratory syncytial virus bronchiolitis, pneumonia, perhaps pertussis, and measles in childhood may increase the subsequent risk of childhood asthma without modifying the likelihood of sensitization to allergens (Gern and Weiss 2000). A larger Finish population study (n = 517 910) showed a strong positive association between measles and atopic mani- festations, which does not support the hypothesis that experiencing natural measles infection offers protection against atopic diseases (Paunio et al 2000). More work is needed in the area of longitudinal epidemiologic studies to evaluate the effects of childhood infections (eg, viral and bacterial infections) on the development of the immune system and pathophysiology of allergic diseases. The challenges for future studies include identification of those factors that confer the protection proposed by the hygiene hypothesis, and, if possible, to find strategies to modify the environment without causing harm to susceptible individuals (Eder and von Mutius 2004). Air pollution In addition to previously described allergens, exposure to high levels of pollutants including oxides of nitrogen, ozone, sulfur dioxide, black smoke– large particulate matter, small particulates, carbon monoxide, and volatile organic compounds have been considered as important contributing factors in both exacerbation and etiology of allergic airway diseases (Utell and Samet 1993; Devalia et al 1994; Krishna et al 1995). It is still not clear whether the increasing prevalence of allergic diseases is distinctly different between the areas with higher or lower degrees of air pollution. The quantity and types of pollutants also influence the development of allergic disease. This has already been explained by an epidemio- logical study performed in two cities of Germany. Von Mutius et al (1994b) have studied a total of 7653 children in Munich (n = 5030) and Leipzig (n = 2623). In Leipzig, there was a considerably higher degree of air pollution, with sulfur dioxide produced by coal, while an “automobile type” of pollution was found in Munich. The prevalence rates of allergic rhinitis, asthma, and positive skin tests to aeroallergens were significantly lower in Leipzig (2.7%, 3.9%, and 18.2%) than in Munich (8.6%, 5.9%, and 36.7%). Therefore, it was suggested that an effective pollution control policy will require an understanding of how measures to alter emissions from different sources influence personal exposure, and hence health outcomes (Ashmore 1995). Air pollution certainly plays an important part, if not a pivotal role, in the pathogenesis of allergic and respiratory diseases. Some pollutants can either impair defense mechanisms in the airways rendering them more susceptible 118 Therapeutics and Clinical Risk Management 2005:1(2)