Exposure to Toxocara spp. and Ascaris lumbricoides infections and risk of allergic rhinitis in children

Allergic rhinitis (AR) is one of the most prevalent and increasing inflammatory allergic disorders, affecting about 40% of the world population in all ages, with a great peak in the childhood [1, 2]. It is a global health problem, and although isn’t life-threatening but can cause significant adverse impacts on quality of life and emotional well-being, including poor sleep quality, poor performance in work or school, impaired cognitive function, poor social life, fatigue, and depression and anxiety [3]. AR is caused by IgE-mediated early- and late-phase hypersensitivity responses and characterized by pruritus, sneezing, nasal obstruction and blockage, nasal itching and rhinorrhea [4]. AR is strongly linked to other atopic respiratory diseases, such as asthma, and therefore have common environmental and genetic origin [5]. Studies indicated that AR is associated with many genetic loci on chromosomes 2, 5, 6, 7, 11, 13, 16, and 20 [6]. Other predictors to development of AR in children are including environmental pollution, birth during a pollen season, high socioeconomic status, ethnic origin, heavy maternal smoking during the first year of life, exposure to indoor allergens such as animal dander and dust mites, high concentrations in serum of IgE (> 100 IU/mL before age 6 years), positive allergen skin prick tests and early introduction of foods or formula [1, 7]. Moreover although some epidemiologic studies have shown that environmental exposure to products (e.g., endotoxins and lipopolysaccharides) of infectious agents such as Mycobacterium spp, hepatitis A, and Toxoplasma gondii, have a protective effect against development of AR, but infection with soil transmitted helminthes (such as Enterobius vermicularis, Toxocara spp. and Ascaris lumbricoides) have yielded different results and most of epidemiologic studies and meta-analyses indicated that these infections are risk factors for development of allergic disorders.

Both Toxocara spp. and A. lumbricoides are ascarid nematodes with worldwide distribution [8, 9]. It is estimated that, around the world, about 1.4 billion people are seropositive for Toxocara infection [10‐12] and 700 million people are infected with Ascaris infection [9, 13]. These parasites have a fecal–oral transmission and poor sanitation status, contact with soil and animals, drinking untreated water, eating unwashed vegetables and crowded or high-density living conditions, as found in tropical developing countries are major risk factors of these infections [10, 13]. Elevated levels of serum IgE and eosinophilia are the common indicators for both allergic disorders and helminthic infections, therefore it is hypothesized that intestinal or tissue helminthic infections may also play an etiological role in development of allergic disorders [9, 14‐17]. Two comprehensive meta-analyses have showed that Toxocara spp. and A. lumbricoides infections have a positive association to development of asthma [14, 18], but studies evaluating the association between these infection and allergic rhinitis are very rare. To our knowledge there are four studies evaluating association between Toxocara infection and AR [17, 19‐21], showing conflict results, although we have found only two relevant studies with respect to A. lumbricoides infection [21, 22].

Northern Iran is an endemic area for many parasitic infections including Toxocara and A. lumbricoides infection [9, 23‐25]. Also prevalence of AR is high in this area [26, 27]. Therefore the main objective of this study was to evaluate the association between Toxocara and A. lumbricoides infection and development of AR in children in this area.

There were 81 children with rhinitis and 101 matched controls. The median age of the cases and controls was 7.04 ± 2.69 and 6.52 ± 3.57 years, respectively. There were 44 (54.3%) boys in the case- and 57 (56.4%) boys in control- groups. The proportions of rural children of the case and control groups 71.6% and 51.5%, respectively. Thirty-five (43.2%) of children had family atopic history. More demographic features for both cases and controls are shown in Table 1. Univariate analysis revealed that children with rhinitis were more likely to have parents with high levels of education (OR, 4.53; 95% CI 2.37–8.68; P value < 0.001), working mothers (OR, 4.70; 95% CI 1.88–11.73; P value < 0.001), family atopic history (OR, 14.6; 95% CI 5.37–39.7; P value < 0.001) and smoker parents (OR, 3.52; 95% CI 1.65–7.5; P value < 0.001) (Table 1).

Overall, A. lumbricoides seropositivity was higher in children with rhinitis (12.34%, 9.92–14.75%) than in healthy controls (3.96%, 95% CI 3.26–4.65%). Statistical analyses revealed that, however, seropositivity to Ascaris infection was significantly associated with childhood rhinitis in univariate analysis (OR, 3.42; 95% CI 1.03–11.3; P value = 0.035), but this association was no longer significant after adjustment for potential confounders (OR, 1.85; 95% CI 0.42–8.18; AUC = 86.6; 95% CI 81.3–91.9) (Table 2 and Fig. 1). In addition, there were 3/81 (3.7%, 95% CI 2.97–4.42) anti-Toxocara IgG seropositive children identified among the cases and 1/101 (0.99%, 95% CI 0.81–1.16%) among the rhinitis-free controls, indicating no significant association between Toxocara seropoitivity and rhinitis in both univariate analysis (OR, 3.84; 95% CI 0.39–37.7) and multivariate analysis after adjustment (OR, 0.8; 95% CI 0.04–15.44) (Table 2).

To our present knowledge, the association of helminthes infection in development of allergic disorders is controversial. Besides that, epidemiological studies evaluating the role of A. lumbricoides and Toxocara infections in development of AR are very rare. Therefore, we designed and did a case–control study to further understanding this association. Our results demonstrated that, however, children with AR had a more exposure to A. lumbricoides (12.3% vs. 3.9%) and Toxocara spp. (3.7% vs. 0.99%) in comparison with healthy subjects, but a non-significant association was observed after adjustment for both of these parasitic infections.

In regard to A. lumbricoides infection, to our knowledge, this study is first to assess of a relationship between anti-Ascaris IgG and increased morbidity of AR. Two previous studies used specific IgE antibodies against A. lumbricoides to evaluate this association [21, 22]. In accordance with these studies, our univariate analysis showed a significant association between exposure to A. lumbricoides and development of AR in children, but when confounders were adjusted, in contrast with previous studies, this association was non-significant. With respect to Toxocara infection, previous studies showed contradictory results [19, 21, 30]. In accordance with our results, Arshi et al. [20] in Iran reported that although patients with AR had a higher seroprevalence rate of Toxocara infection in comparison with healthy controls, but difference was statistically non-significant. Mohammed Abdalla et al. in Egypt [21] and Yariktas et al. [17] in Turkey demonstrated a significant higher toxocariasis seropositivity rate in the patients with AR compared to controls. In contrast with above-mentioned studies, Manuel et al. [19] in Malaysia reported a significant higher seropositive rate of Toxocara infection in the controls as compared to allergic patients. More details for previous studies are presented in Table 3. The different results in studies could be due to difference in sample size and diagnostic criteria, difference in the genetic and immunological reactions, severity and susceptibility of recruited population to Ascaris infection from one to another setting.

The mechanism of pathogenesis, linking helminthes infections to allergic diseases is not clear, although it is assumed that immune response against these infections plays important role in development of allergic symptoms. It is hypothesized that these infections can influence allergic diseases by either stimulating or suppressing the allergic response, probably depending on the severity of the infection, host genetic susceptibility and the degree of exposure [16]. Immune responses raised against Toxocara and Ascaris infections are mediated by TH2 cell activation, which leads to a high concentration of IgE and eosinophil activation [16]. TH2 cells are associated with the high secretory level of IL-4, IL-13, and IL-5 cytokines. IL-4 and IL-13 stimulate polyclonal IgE production that binds to FcR on mucosal mast cells located in intestinal and alveoli tissue. IL-5 is also a potential factor for the development and activation of eosinophil [16, 31]. Besides, TH2 cells recruited in the site of allergic rhinitis also produce the same cytokine network. The pathological pathway involved in allergic rhinitis is probably started via mast cell activation and degranulation. Mast cells are activated through cross-linking of FcεRI, which occurs by binding of multivalent antigen to IgE [19, 32]. Moreover, some experimental studies have shown that infections with nematodes whose life cycle includes migration across different tissues (e.g. Toxocara spp. and Ascaris suum) could be associated with allergic disorders [33, 34]. On the other hand, because of inadequate innate immune response and parasite resistance to acquired immune response, most helminth infections are chronic. Chronic infections are associated with immune homeostasis. To modify the TH2 cell’s immune response, the basic level of IL-10 and TGF-β cytokines is produced by T regulatory (Treg) cells. Recent studies have shown that Treg cells in allergic diseases are dysfunctional, while Tregs of helminthic infections like Toxocara and Ascaris are more sufficient and functional [35]. So children who had exposure to Toxocara and Ascaris have more sufficient Tregs, which can compensate defects of allergic Treg cells. Hence the risk of AR in the face of helminth infection decreases with these justifications.

This study has some limitations. Low sample size is an important limitation, affection the significance of our results. We did not perform stool examination to determine whether there was evidence of chronic or active ascariasis. We also performed only a single ELISA on available sera without additional confirmative examinations, such as Western Blot or determination of IgE sensitization. Moreover, there is no supporting data on blood eosinophils or complete blood count (CBC) for our recruited population. Most of these limitations were related to our financial constraints.

In conclusion, our results showed that, although non-significant, Iranian children with AR had more exposure to A. lumbricoides and Toxocara infection. These results suggest more experimental and epidemiological investigations to further elucidate this relationship.