Interleukin-10 and soil-transmitted helminth infections in Honduran children

Growing research evidence underscores the paramount importance of investigating the role of IL-10 during soil-transmitted helminthiases as it may increase susceptibility for these infections [27]. Further, it has been argued that large-scale deworming programs as currently implemented by recommendation of the World Health Organization [1], will have an impact on the Th1/Th2 immune profile of target populations, which may increase the risk for inflammatory diseases and allergies [40].

The present study is, to our knowledge, the first examining an association between STH infections and IL-10, not only in Honduras but in the Central American region, an area endemic for many parasitic infections including STH [41].

Our data reveals some interesting points. First of all, we detected a wide range of serum IL-10 concentrations among the studied children, from 0 pg/mL (non-detectable) to 105 pg/mL. Similarly, a study by Malla et al. in India reported ranges from 0 to 60 pg/mL in infected patients and from 0 to 5 in the control groups [29]. In the Ecuadorian study, IL-10 mean concentrations in cord blood ranged from 0 to 5 pg/mL, with a few outlying values of < 20 pg/mL [27]. In contrast, a study in Nigeria found much higher serum concentrations in children 6–10 years of age (152.5 ± 93.6 pg/mL) or older (177.5 ± 51.9 pg/mL) [28]. Considering that there is no expert agreement on what the healthy values for serum or plasma IL-10 are in the human population [42], the disparity of data suggests that each study must attain its own interpretation depending on their comparison group. In our view, this highlights the need for researchers to present a detailed methodological approach so the knowledge generated can be analyzed and compared appropriately.

We also found that serum IL-10 levels and age were negatively correlated; i.e., as children’s age increased, IL-10 levels tended to decrease. This finding seems unexpected for an endemic country where STH exposure -and therefore immune tolerance to helminths- is likely to increase with age. However, in populations where deworming treatment is offered through school-based programs, the natural patterns of infection are altered. It is worth mentioning that in the larger study originating the present investigation, age was not found significantly associated with STH infection. However, we observed that a one year increment in children’s age reduced their odds for ascariasis by 20% and increased their odds for T. trichiura and hookworm infections by 15% and 20%, respectively [36]. We proposed that such variations might have been linked to children receiving annual single-dose albendazole treatment, as this regimen is more efficacious for A. lumbricoides than for the other two species [43]. The inverse association between IL-10 and age reported in this study might also be confounded by deworming treatment. Albendazole shortens the duration of infections and/or reduces worm burden, depending on the infecting species [44]. Repeated albendazole treatments have a significant effect in the way children respond to immune stimulus [45], and an immune modulatory effect by IL-10 is likely more evident in chronic or high-intensity infections [46]. In fact, significant differences between chronic STH infections and elevated levels of IL-10 were observed in a study conducted in Ecuador [34]. We were not able to ascertain chronicity of infection in the present study, so this question remains an interesting challenge for future research.

In line with our findings, a study investigating IL-10 serum levels in Nigerian schoolchildren also found that age and intensity of A. lumbricoides infection were inverse correlated with IL-10, but a potential explanation for this correlation was not proposed by the authors [28]. Some in vitro studies have too explored this association. In a cross-sectional study in Cameroonian children in which a negative correlation between T. trichiura-specific IL-10 production and age was found; the authors concluded that IL-10 regulatory effects might be more likely in younger persons [30]. Nevertheless, observations from cross-sectional studies are unlikely to clarify this issue. Empirical evidence from longitudinal studies would help elucidating the effects of deworming and age on children’s immune response to parasitic infections.

No evidence for an association was found between parasitism by individual STH species and IL-10 levels. That these findings are in concordance with some studies [30,31] but in disagreement with others [28,29] is not entirely surprising. In the particular case of A. lumbricoides infections, contrasting results are reported throughout the literature [47,48].

In terms of mono- and polyparasitism, we observed, in congruence with other studies [27,28], that as the number of species parasitizing increased, IL-10 levels tended to increase. We could speculate that once parasitized with one species, children who build tolerance through higher levels of IL-10 could be more susceptible to infection with another species. Notwithstanding, it is necessary to be cautious when interpreting data from populations where polyparasitism is common, as very little is known about the immune interactions taking place in a host harbouring multiple parasite species. Moreover, as recently proposed, helminths may steer the host’s immune system not just directly but also indirectly by influencing the composition of the gut microbiome, which in turn may participate in the modulation of inflammatory processes [49].

We also investigated a potential association between intensity of infection (worm burden) and IL-10 levels, but none was found. Several reasons may explain this finding. Although Kato-Katz is the standard method for categorizing infection intensity [1], its sensitivity for a single-stool sample examination varies according to the STH species: >90% for both A. lumbricoides and T. trichiura, but <70% for hookworm infections [50]. Also, the number of eggs laid by female worms is subject to great variations [51].These two aspects suggest that misclassification of infection cannot be ruled out. In addition, variations in IL-10 levels may be caused not only by ongoing or past infections [21,24], but by host-related factors as well [52]. Undoubtedly, IL-10 regulation is extremely complex and many questions are yet to be answered [24].

In sum, given that IL-10 production and its modulatory effects during STH infection are likely determined by a combination of factors [30,45,53], it is crucial that future studies collect precise information on the deworming history of research participants, and that efforts are made to obtain accurate estimations of worm burden and length of infections. As well, future investigations should strive to analyze research participants’ socio-economic and environmental data as there is evidence that a number of environmental exposures [33] including the presence of a household latrine [52] have a modulatory effect on serum IL-10 levels. Furthermore, emerging evidence suggests that there is significant genetic component to susceptibility or resistance to STH infection [52], and that there may IL-10 genetic polymorphisms that protect against helminthic infections [54].

It is important to acknowledge the limitations of the present investigation. Firstly, we tested a small sample size from a cross-sectional study, which limits our ability to reach firm conclusions. Secondly, other parasitic infections that may shift the Th1/Th2 balance (e.g., with intestinal protozoa or other helminths such Strongyloides stercoralis) were not assessed. Thirdly, a detailed medical history was not obtained from the participating children, thus other condition causing increased IL-10 levels such as asthma [55], bacterial infections [56,57], viral infections, and autoimmune diseases [58], cannot be excluded. Finally, a complete immune profile of the studied children (including IL-10 to IFN-γ ratio) was not determined. We recommend future studies accounting for these limitations.