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- Materials and methods
Background: Respiratory allergies are inversely related to early acquisition of food-borne and fecal-oral infections, consumption of unpasteurized milk, early exposure to stables and high endotoxin concentrations in a farming environment. We tested therefore if infection by Salmonella in early life can protect from development of respiratory allergies later in life.
Methods: During 2003, we studied two groups of Sardinian children (age 6–18 years) who had been hospitalized before 4 years of age (during 1989–2001) with non-typhoid salmonellosis (n = 148) or acute enteritis of nonbacterial etiology (NB-enteritis) (n = 167). Allergic rhinoconjunctivitis (AR) and asthma were evaluated by telephonic interview with a ISAAC questionnaire; participants reporting AR and/or asthma were further examined through a complete diagnostic work-up to objectively confirm or exclude current disease. Kaplan–Meier curves and Cox proportional hazard models were used to analyze the role of different types of enteritis on the risk of developing allergic rhinoconjunctivitis or asthma over time.
Results: Children who had been hospitalized with salmonellosis had a lower prevalence of allergic rhinoconjunctivitis (eight of 148, 5.4%vs 23 of 167, 13.8%; P = 0.019) or asthma (five of 148, 3.4%vs 21 of 167, 12.6%; P = 0.006) than those who had been hospitalized with NB-enteritis. The proportional hazard of salmonellosis for asthma was 0.23 (95% CI: 0.08–0.67; P < 0.01) and for allergic rhinoconjunctivitis was 0.40 (95% CI: 0.17–0.95; P = 0.04), after adjusting for confounders.
Discussion: The strength of the observed associations suggests that Salmonella may contribute to shape the natural history of respiratory allergies. However, further studies are needed to test in other settings the association observed in Sardinian children. We speculate that clinical or subclinical infection by Salmonella may contribute to the atopy protective influence of a traditional farming environment or of areas endemic for food-borne and fecal-oral infections. Food hygiene and prevention of salmonellosis must remain however a public health priority.
The reasons why allergic disorders have been increasing in westernized countries are still unknown and are probably multifactorial (1). A popular theory proposes that children can develop allergy more frequently if they are less exposed to microbes early in life (2–4). This ‘hygiene hypothesis’ has not been formally demonstrated yet (5, 6). Although many infections may contribute to prevent atopic sensitization and allergic inflammation through a range of different mechanisms (2, 4, 7–9), no specific infection has been demonstrated to prevent atopy (10). Nonetheless, atopy is less frequent among subjects who acquire food-borne and fecal-oral infections (11), in those exposed to stables and to high endotoxin concentrations, or consuming unpasteurized milk in a farming environment (12–14).
Therefore, an example of atopy-preventing infection may be found among gram-negative bacteria transmitted by contaminated food and the fecal-oral route, and by animals typical of farming environment. A number of infectious agents share these properties; among them, Salmonella can be better studied since they cause diseases that can be easily diagnosed even in early childhood.
We tested the hypothesis that acquisition of an infection by Salmonella in early childhood may counteract the development of respiratory allergies later in life. To this end, we compared the incidence of hay fever and asthma in a group of Sardinian school-aged children who had been hospitalized at preschool-age with salmonellosis to that observed in children who had been hospitalized with acute enteritis of nonbacterial etiology.
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- Materials and methods
We found that Sardinian children hospitalized for salmonellosis in preschool-age developed allergic asthma less frequently than children hospitalized for acute enteritis of nonbacterial etiology. Given the rationale of our study and the strength of the observed associations, it is tempting to speculate that acquisition of infection early in life by Salmonella may inhibit the development of atopic diseases and in particular of allergic asthma. Salmonella may contribute to prevent the development of respiratory allergies through a range of mechanisms acting on the innate immune system, in a critical period for the maturation of immune response against ubiquitous allergens (4).
The comprehension of the mechanisms of such a putative protective influence falls beyond the objectives of the present study. However, Salmonella, as mycobacteria, grow into the endosomes of macrophages and induce a strong activation of CD4+ T helper-1 lymphocytes, which is required to enhance intracellular killing and clearance (17, 18). This process is highly dependent on production of γ-interferon and interleukin-12, so that patients with selective deficiencies of these cytokines or their receptors develop fatal infections by Salmonella as well as mycobacteria (19). In addition, Salmonella play a transient regulatory role on adaptive immunity (20). Finally, the immune response to Salmonella is controlled by the natural resistance-associated macrophage protein 1 (Nramp-1) gene (21), which plays also a major role in regulation of atopic responses and airways allergic inflammation in rodents (22). These properties or other unknown mechanisms may provide biologic plausibility to the hypothesis that salmonellosis contributed to protect from allergic asthma and rhinoconjunctivitis the children we examined.
Alternative explanations of the observed associations must be considered. First, we cannot totally exclude that early acquisition of Salmonella may be related in our study area to acquisition of many other food-borne and fecal-oral infections (11, 16), to a different gut microflora composition (23) or to nonmicrobial dietary factors that may have partially or totally determined the observed associations (24). On the contrary, our results may be an additional example of gene-by-environment interaction in the hygiene hypothesis (25, 26): it could be argued that a genetic predisposition to develop atopic responses protects from developing an enteritis severe enough to require hospitalization after infection by Salmonella (reverse causation). However, a family history of allergy was equally distributed between participants hospitalized with salmonellosis and those hospitalized with NB-enteritis. Finally, the prevalence of respiratory allergies among subjects with NB-enteritis may have been sustained by infections facilitating atopy; however, the prevalence of allergic asthma and rhinoconjunctivitis among controls felt in the range of values measured in the 1990s with the same questionnaire in 13 Italian cities (15).
The finding that the predictive role of asthma for allergic rhinitis is more important than that of salmonellosis is not surprising as in the majority of patients rhinitis was associated with asthma, in keeping with the concept ‘one airway, one disease’ (27).
Our observations highlight that Salmonella deserve attention in future investigations on the hygiene hypothesis. In particular, further longitudinal studies in different geographic areas and settings (traditional farming environment, developing countries) are necessary to discriminate if and how salmonellosis occurred before 4 years of age contribute to prevent respiratory allergies or if the associations we observed in Sardinia are made spurious by local factors. Anyway, food hygiene and prevention of salmonellosis must continue to be a public health priority.
It has been previously proposed that we may learn from microbes how to prevent or treat allergy without causing infectious diseases (28). Interestingly, molecules derived by Salmonella have been already examined as adjuvants in specific immunotherapy for respiratory allergies (29). Our results encourage further efforts to find new strategies to identify microbial products to prevent or treat allergic diseases (30).