Unlike most of the conditions mentioned above, asthma and allergies have become increasingly frequent in the prosperous countries of Western Europe, although they remains much less common in the Eastern part of the continent. A number of genetic polymorphisms have been described (see section 4.2.1) as associated with the risk of asthma, but the change in prevalence over a short period of two or three decades and the variation from country to country within Europe and the wider world speaks for important environmental determinants. In the broadest sense, this appears to be something associated with increasing national prosperity (not "westernisation", since it has been observed, for example, in Saudi Arabia). Two plausible hypothetical explanations have been advanced for increasing population susceptibility to allergic disease - changes in patterns of exposure to micro-organisms (the hygiene hypothesis) and alterations in diet and energy output.
The Hygiene hypothesis
The hygiene hypothesis was originally based on an inverse relationship between infections and hayfever. leading the concept that protection of younger infants may be derived from infections passing round the family, altering their immune development from one primarily allergic (mediated by T helper 2 lymphocytes) to an anti-infective T helper 1 lymphocyte response. This concept has to answer two important objections. First, there has in fact also been an increase in T helper 1 associated diseases such as diabetes, and the two types of disease are not mutually exclusive. Secondly, the immunological features of the family size effect appear to be present in cord blood before the child is born, suggesting that the effect is unrelated to infections acquired in post-natal life, but is more likely due to the mother's increasing immune tolerance of her children in utero. Nevertheless, there is evidence that some infections early in childhood, including measles and hepatititis A and possibly tuberculosis, may protect against later allergies and perhaps asthma. Recent research along these lines has investigated the possibility of temporal changes in the species of micro-organisms colonising the gut as patterns of early diet change, altering immune programming in the infant - in fact, a variant of the dietary hypothesis.
Strachan (1989) first proposed the 'hygiene hypothesis' that infections in early childhood prevented the development of allergic diseases. An inverse relationship was observed between family size, particularly the presence of older siblings, and features of allergic disease, including hay fever and positive skin prick test responses, but not with asthma. Recent observations that the prevalence of allergy is reduced in farming communities [von Ehrenstein et al, 2000] might also be explained by increased exposure to infections in early life in this setting, although other differences in lifestyle between rural farming and urban communities are possible confounders of this relationship. T cell responses may be central to the mechanisms of these observed associations. Activated T lymphocytes are important in maintaining lung inflammation in adults with asthma and the demonstration of increased concentrations of soluble interleukin 2 receptors in children with asthma suggests that activated T cells are important in this context also. Atopy in children has been proposed to represent persistence of fetal Th2 responses [Prescott et al, 1999] with the production of type 2 cytokines (interleukins 4, 5, 6, 10, 13) in response to allergens. Infections may be important in early childhood by stimulating Th1 predominant responses (IL 2, interferon, TNF). Survivors of a measles epidemic in Guinea-Bissau were found to have decreased prevalence of atopy compared with immunised children [Shaheen et al, 1996], although the possibility that children with impaired Th1 responses were more susceptible to dying during the epidemic has been raised. Also, exposure to tuberculosis has been shown to result in lower prevalence of atopy, but not asthma, in a large Finnish study [Von Hertzen et al, 1999]. The potential for immune modulation of T helper response by bowel flora and the effect of antibiotics on bowel colonisation has also been studied. These clinical observations together with laboratory studies of T cell sensitisation have led to the development of strategies to modulate the switch from Th2 to Th1 predominant responses, either by allergen avoidance from early gestation [Jones et al, 1998] or by the development of vaccines, Th1 selective adjuvants or immunotherapy.
In addition to potential protective effects on later development of asthma, viral respiratory infections have also been proposed as contributors to the development of obstructive airways disease. A number of studies have reported persistent or recurrent wheezing after RSV bronchiolitis in infants . However, there is still debate about whether RSV causes asthma or whether severe RSV infection is a manifestation of pre- existing risk factors for both bronchiolitis and asthma [Sigurs, 2001]. It is hoped that randomised control trials of RSV prophylaxis will be able to address some of these questions but these are currently restricted to high-risk infants.”
The prenatal effects of maternal famine were studied in a Dutch population exposed to the famine of 1944-45. The prevalence of obstructive airways diseases in the offspring of famine-exposed mothers was higher, particularly when the exposure occurred in early gestation. This effect did not appear to be mediated through increased prevalence of atopic disease in this population, suggesting that impairment of fetal lung development was an important factor.
A number of dietary constituents have been examined in relation to their potential role in the aetiology of lung diseases, including fatty acids, anti-oxidants and sodium intake. The observation that Eskimos had a low prevalence of lung disease and a diet high in oily fish prompted speculation that n-3 fatty acids, which competitively inhibit the metabolism of arachidonic acid, may be protective against asthma [Schwartz, 2000]. However, there is only weak evidence for this and no intervention studies have yet been done.
Oxidative damage to the lungs, mediated through oxygen free radicals, is believed to be important in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Fruit is a major source of antioxidant vitamins and epidemiological associations between fruit intake and lung function in adults have been established. A positive association between fresh fruit consumption and lung function has also been demonstrated in children [Cook et al, 1997]. Selenium is essential to the activity of glutathione peroxidase enzymes that are involved in the lung's antioxidant defences. Low serum concentrations of selenium have been demonstrated in subjects with asthma but it is unclear whether selenium deficiency contributes to the development of asthma or if selenium consumption occurs as a consequence of oxidant injury. A recent ecological study of asthma and allergy (ISAAC) did not demonstrate an increased prevalence in countries in which selenium deficiency is endemic [Moreno-Reyes et al, 1998] compared with areas with abundant dietary selenium sources. Low dose vitamin A supplementation has been examined for its possible protective role in the development of lower respiratory infections in children. Two intervention studies in developing countries have suggested that this effect is strongly related to nutritional status with decreased acute lower respiratory infections observed in underweight children only [Sempertegui al, 1999; Fawzi et al, 2000] and adverse effects noted in children of normal nutritional status.
Regional differences in asthma mortality have been correlated with table salt purchase, leading to the possibility that dietary sodium may be an important factor in asthma pathogenesis. However, dietary salt intake in children has been associated with increased bronchial responsiveness to methacholine but not with a diagnosis of asthma or with exercise induced bronchospasm [Demissie et al, 1996].”
In utero and infant environment
There is evidence that intra-uterine factors influence risks of asthma and allergies, but not always in the same direction. The strongest associations are with allergic rhinitis, the risks of which are increased in the children of young mothers and decreased in premature and low birthweight children. In contrast, asthma is more likely in children of older mothers and less likely in high birthweight children. Maternal smoking in pregnancy is associated with lower birthweight, reduced lung function and increased respiratory symptoms in the infant, but the effects on longer-term risks of asthma and allergies are equivocal. Breast-feeding, if prolonged for about 6 months or more, appears to protect against early respiratory symptoms, possibly by transfer of immunity, but again effects on longer-term risks of asthma and allergy are equivocal.