In the present study, although 39% of the 283 studied children for IgE antibodies experienced at least one episode of severe wheezing over the past 12 months, only 10% possessed IgE antibodies against common allergens ≥3.5 kU/L. This IgE level is considered as the threshold for developing the clinical symptoms of allergic asthma . Furthermore, no association was found of wheezing with anti-allergen IgE antibody levels ≥0.35 kU/L (Table 5). Thus, most of the reported wheezing episodes were not atopy-related. Further support for this observation comes from the finding that the absence of a household connection to the sewer system increased the odds of wheezing in the multivariate analyses. This finding seems contrary to the hygiene hypothesis but reinforces the possibility of an infectious aetiology for the reported wheezing. The current study is in agreement with previous reports that most early-childhood wheezing is not related to allergy, based on data from developed countries, where this condition is mainly described associated with virus infection [16, 17]. The finding that wheezing is more common in boys than in girls is also in accordance with previous studies .
Both A. lumbricoides and T. trichiura infections were positively associated with wheezing in the present study (in the case of A. lumbricoides, only when the infection was serologically defined by the presence of specific IgE antibodies). The associations were robust, even after adjustment for confounding variables in the multiple logistic regression analysis. The finding that anti-A. lumbricoides IgE antibodies increases the risk for atopy and wheezing has been reported previously in regions of low, medium, and high endemicity [18–20]. On the other hand, T. trichiura infection has not been described as positively associated with asthma or atopy in the literature, although an association of this parasite with atopic eczema has been reported . Intestinal helminths induce IgE-producing, Th2 immune responses . The A. lumbricoides infection that leads to high levels of anti-Ascaris antibodies could also promote, by a non-specific effect, higher levels of allergen-specific antibodies [23, 24]. This could explain the association between this parasite specific IgE antibodies and atopic wheezing, but not with non-atopic wheezing. An explanation for this last association could be the sensitization of lung mast cells with anti-A. lumbricoides IgE antibodies and their eventual degranulation by antigens released by migrating A. lumbricoides larvae.
The presence of high levels of anti-A. lumbricoides IgE antibodies would reflect at least a partial immunity to infection, which would explain the association of wheezing with IgE antibodies and not with A. lumbricoides eggs in the stool. This immunity would therefore explain the absence of correlation between A. lumbricoides eggs in the stool and this parasite specific serum IgE antibodies, observed in this and in a previously reported study . The frequency of antibody-eliciting larvae invasion should be directly proportional to poor sanitation, such as a lack of a sewage system, which was also associated with more frequent wheezing in the studied population.
In addition to association with wheezing, we identified a clear association between the presence of anti-A. lumbricoides IgE antibodies and atopy. However, as mentioned earlier, there are conflicting reports on intestinal helminthic infections decreasing, not affecting or increasing atopy and allergic symptoms [2–7], although a systematic review and meta-analysis found that A. lumbricoides infection was associated with a significantly increased risk of asthma . The fact that A. lumbricoides eggs were not associated with wheezing and atopy, while there were strong associations of anti-A. lumbricoides IgE antibodies with these two outcomes, may explain why some previous studies relying only on the detection of helminthic eggs did not identify these associations [4, 5]. In addition, one widely accepted hypothesis that has been put forward to explain these discrepant findings is that high worm burden and chronic helminthic infections would lead to the production of immunoregulatory cytokines and to protection against atopy and asthma, while low worm burden or recent infection would promote atopy and allergy [5, 8]. The present data corroborate this hypothesis, since the studied children are very young and probably had been infected recently. Moreover, these children had low to moderate A. lumbricoides and T. trichiura egg burdens. It is possible that several months or years in the future, with repeated or chronic T. trichiura infections, the tendency would be for infection-associated regulatory cells [27, 28] reducing atopy. This phenomenon would account for the findings of an investigation carried out recently in Salvador by our research group , which showed that early infection by T. trichiura protected against the development of aeroallergen skin test reactivity in later childhood. This finding in older children, and the demonstration in the present report of a positive association between T. trichiura infection and wheezing in infants, is consistent with the acute-chronic infection hypothesis explaining different types of association between helminth infection and atopy, mentioned above.
In the present work, we have quantified parasitic eggs in faecal samples and analysed the association of worm burden with wheezing and atopy (data not shown). The absence of association between worm burden with wheezing and atopy was attributed to a low variability of parasite burdens, since all children had low to moderate egg intensity.
Unfortunatelly, anti-T. trichiura IgE antibodies could not be measured in this work, so it was not possible to study the association of IgE antibodies against this parasite with the studied outcomes, as was done for anti-A. lumbricoides IgE levels. The hypothesis proposed above, however, predicts that the association of wheezing and atopy with anti-T. trichiura IgE antibodies should be stronger than their association with T. trichiura egg burden. The presence of a statistically significant association of T. trichiura infection with atopic wheezing and not with atopy, in the multivariate analysis, is not easily explained. However, it may indicate that T. trichiura infection would enhance the development of wheezing more easily in children who are more susceptible to develop lung inflammation, perhaps by stimulating on-going allergic responses. In addition, another intriguing question remains. Since anti-A. lumbricoides IgE antibodies, but not A. lumbricoides eggs, are associated with wheezing and atopy in the studied children, why is the presence of T. trichiura eggs in the stool robustly associated with wheezing in the same children? One potential explanation is that helminths may differ in their susceptibility to IgE antibodies. More specifically, T. trichiura may be more resistant than A. lumbricoides to IgE-dependent effector mechanisms. Thus, the effect of T. trichiura on the immune system would enhance IgE responses in a whole, accounting for its association with atopic wheezing, without concomitantly leading to self-elimination.