Do only European cattle protect from allergies?
Authors: C. Braun‐Fahrländer
Journal: Allergy (2002)

Since the first publication of papers on the reduced risk of hay fever, asthma, and the expression of atopy in children from farming families compared to their peers from nonfarming families (1, 2) the role of the farm environment in influencing the development of asthma and allergies has prompted much scientific interest. The original observations have been confirmed in a number of child studies in central and northern European countries, and also in Canada and Australia 3-7). Growing up on a farm—more specifically having contact with farm animals—is associated with a substantial decrease in risk for the development of hay fever and asthma, when children from farming families are compared with rural nonfarm children. Recent studies provided additional evidence that living on a farm in childhood is associated with a decreased risk of allergy in young adulthood, suggesting that environmental factors encountered in the farm environment may have a lifelong protective effect against the development of IgE-mediated diseases 8-12). The role of timing of the exposure to farm characteristics has further been investigated by the ALEX study group (ALlergy and EndotoXin)—an international cooperation of research teams from Switzerland, Austria and Germany (13). A cross-sectional study of more than 800 children showed that the timing of exposure to farm factors during or before the first year of life, and the amount and duration of exposure from the first year to the fifth year of life, were crucial for the protective effect on asthma and allergies. The “farm effect” may result at least partially from elevated exposure to bacterial compounds encountered in the microbial environment of stables where cattle are kept. Endotoxin is an intrinsic part of the outer membrane of gram-negative bacteria that is found in high concentrations in animal stables, and also in indoor environments. In rural areas of southern Germany and Switzerland, environmental endotoxin exposure was higher in the homes of farmers' children and children with regular contact with livestock as compared with nonfarm children without animal contact (14). In the ALEX study (13) dust samples were also obtained from the homes of all enrolled children and endotoxin concentrations were assessed using standardized methods. A strong inverse association was found between endotoxin exposure and prevalence of allergic asthma and other allergies among farm and nonfarm children, indicating that relatively lower levels of endotoxin exposure as seen in nonfarm environments can also favorably influence the development of IgE-mediated diseases in childhood (15). The mechanisms by which endotoxin exposure may protect against the development of IgE sensitization and diseases are not fully understood. However, mechanisms relating to the recognition of microbial compounds through innate immunity and the regulation of the resulting inflammatory responses through adaptive immunity are likely to be key factors in the development of illnesses associated with atopy, such as hay fever and childhood asthma and wheeze. In the present issue of Allergy, however, Wickens et al. (16) present the results of a study among 300 New Zealand farm and nonfarm children, giving evidence of an increased risk of hay fever symptoms associated with farm living. Atopy, assessed as a positive skin prick test (SPT) to a panel of common allergens, was not associated with farm living. In a larger sample of about 1000 New Zealand adults, aged 20–44, participating in the European Community Respiratory Health Survey (ECRHS), there was a similar (nonsignificant) increase in nasal symptoms in the presence of pollen, but a reduced risk of IgE antibody sensitization against at least one of five specific allergens (9), suggesting that the “farm effect” might indeed differ between New Zealand and Europe. In contrast to central European farms where cattle are usually kept during the winter in stables built near to the farmhouse, the temperate climate of New Zealand allows animals on large farm holdings to stay outdoors throughout the year. Children's exposure to microbial products from farm animals might therefore be very different on a New Zealand farm as compared to a central European farm. Indeed, the present study reports that endotoxin levels measured in the house-dust samples of New Zealand farm families were lower than those of nonfarm families (7438.3 EU/g vs. 11 058.2 EU/g, P = 0.02) Wickens et al. (16). Interestingly, Wickens et al. (16) found that endotoxin levels in the homes of children suffering from hay fever were lower than in families without sufferers (7407 EU/g vs. 10 340 EU/g, P = 0.09), supporting a protective role of high endotoxin levels against the development of IgE sensitization, as suggested by the ALEX data (15). Important differences also exist between farms in central and southern Europe (Crete) where animals are kept outdoors all year. In a study on childhood allergy performed in an urban area and in rural communities of Crete atopy was twice as common among urban children compared to rural. However, among rural children there was no gradient between intensity of animal contact and expression of atopy (17). When animals are kept outdoors, exposure to higher loads of microbial products might be more ubiquitously distributed. The relevant exposure of children is therefore not captured by assessing contact with specific farm animals. A more general description of the farm environment, such as dairy farming or crop farming, might be more appropriate. This might explain why Wickens et al. (16) found an inverse association between allergic rhinitis, wheeze, and SPT positivity, and dairy farming during the first year of life, but no such association with contact to specific farm animals. However, questions have been raised by the results of the New Zealand study. Exposure to poultry in early life are associated with increased risk of expression of the atopic constitution, although it is known from occupational studies that high endotoxin levels are found in poultry houses. Interestingly, a similar observation was reported in a case-control study on indoor exposures and childhood asthma in Nepal, where keeping cattle within the family home was associated with risk reduction for asthma, whereas poultry within the home increased the risk for asthma (18). Exposure to microbial compounds is not limited to the indoor and outdoor environment of rural children. Confrontation between microbes and their antigens occurs in the gastrointestinal tract immediately after birth. Consequently, commensal gastrointestinal microbes are the earliest and biggest stimulus for development of gut-associated lymphoid tissue. Recently, the beneficial effect of probiotics (Lactobacillus GG) in preventing (what was claimed to be) early atopic disease in children at high risk has been demonstrated in a randomized placebo-controlled trial (19). However, the benefit was limited to skin symptoms and no effect was seen on immunological parameters such as IgE sensitization. Another study from Finland (20) failed to document any effect (discussed in an editorial by Matricardi (21)). Further studies are needed on the potential (if any) of probiotics such as Lactobacilli and Bifidobacteria, found in yoghurt and fermented vegetables, to reduce the risk of allergic diseases, seen in the present study by Wickens et al. (16), in rural Crete (17), and among children from anthroposophic families (22). Whether consuming unpasteurized farm milk reduces the risk for developing allergic diseases through similar mechanisms remains to be shown. The role of allergen exposure encountered in the farm environment and its association with IgE sensitization and allergic symptoms is not yet well established. Several occupational studies of the farm environment have shown consistently that barns and the indoor environment of farm houses, have high concentrations of mite, cat, and dog allergens 23-25). Higher levels of mite allergens were also measured in dust samples of farm households in New Zealand (16). Despite high environmental allergen levels, most occupational studies found low degrees of sensitization to cat and dog allergens among farmers (24). However, in farmers sensitized to cat or dog allergens, a significant correlation was noted between environmental exposure to the allergen and the respective level of IgE antibodies. Similar results were found in an occupational study investigating exposure to mite allergens (25). Although most of the farm studies investigating children (1, 7, 17) or young adults 9-12) found a decreased risk for sensitization to common allergens, there are important exceptions. Klintberg et al. (5) reported that for children raised on the Island of Gotland the number of positive SPT did not differ between farm and nonfarm children, and Austrian farm children only had a decreased risk of being sensitized to pollen, not to cat or mite allergen (3). In this issue of Allergy, Kilpeläinen et al. (26) present the results of a detailed clinical investigation of 296 Finnish first-year university students sampled from a large population of over 10 000 students who responded to a questionnaire on asthma and atopic diseases (8). Subjects with childhood farm environment had a decreased risk for current asthma and were less likely to be sensitized to birch and timothy pollen, and to cat allergen. However, an increased risk for sensitization to house-dust mites was observed, which was more pronounced when low levels of IgE antibodies to house-dust mite were considered. These results suggest that exposure to farm characteristics during childhood does not suppress the process of IgE sensitization per se but protects from the development of clinically relevant symptoms. In line with this interpretation are the analyses of Gassner-Bachmann et al. (2) who investigated more than 1000 serum samples of farm and nonfarm children collected over a 15-year period. The protective effect of a farm environment increased with increasing levels of IgE antibodies to grass and birch pollen, and to cat allergen. However, for IgE antibodies to mite allergen the protective effect of farm-living was only seen when RAST class 4 or higher levels were considered. The immunological mechanisms behind these findings are presently not understood and need to be elucidated.