Decline in Total Serum IgE and Soluble CD30 in the Context of Soil-Transmitted Helminth Decline in Bolivia

INTRODUCTION

It is estimated that soil-transmitted helminthes (STHs), namely, the roundworm Ascaris lumbricoides, the whipworm Trichuris trichiura, and the hookworms Necator americanus and Ancylostoma duodenale, infect approximately one-fourth to one-fifth of the world’s population. Children are particularly exposed: approximately 270 million preschool-age children (pre-SAC) and more than 550 million school-age children (SAC) are affected, mostly living in resource-deprived areas, where these parasites are extensively transmitted because of the low socio-sanitary conditions.¹ Moreover, 370 million persons are now estimated to be infected worldwide with another intestinal nematode, Strongyloides stercoralis, but the global prevalence of this parasite has long been underestimated, as it has been based on studies using poorly sensitive diagnostics.²

In 2001, the WHO endorsed a resolution to control STH infections through improved sanitation, health education, and preventive chemotherapy (PC), whereby anthelmintic drugs such as albendazole or mebendazole should be periodically administered to high-risk groups, such as preSAC, SAC, and women of reproductive age.³ The global target is to eliminate morbidity due to soil-transmitted helminthiases in children by 2020, by regularly treating at least 75% of the children in endemic areas¹; in 2017, the coverage has reached more than 69% of the SAC and preSAC groups.⁴

In Bolivia, PC based on 6-monthly single-dose mebendazole delivery to SAC has been implemented since 1985 and achieved impressive results, at least in the Chaco region, in the southeastern part of the country. Parasitological surveys conducted 26 years apart in rural areas of the Bolivian Chaco documented a dramatic decrease in STH prevalence between 1987 and 2013: the prevalence of hookworm dropped from up to 50% to 0.4–1.3%, A. lumbricoides from 19% to 0.9–1.5%, and T. trichiura from 19% to 0%.^5–7 Based on these findings, and according to WHO recommendations, in September 2016, local authorities interrupted PC delivery in this area and started a program of STH surveillance through annual cross-sectional parasitological surveys at sentinel sites. Two years later, surveillance confirmed the sustained STH reduction (< 1%) in the entire ecological zone.⁸

Concomitantly, a serosurvey evidenced a drop of anti–S. stercoralis antibody prevalence from 1987 to 2013 (from 16% to 6%), although PC is not effective against this parasite.⁹ Conversely, protozoan parasitic infections did not show any substantial decreasing.⁷

Parasitic infections are associated with type 2 immune responses, characterized by T helper (Th)-2 cells activity, eosinophilia, and elevated IgE levels.¹⁰ The release by Th-2 cells of high amounts of soluble CD30 (sCD30), belonging to the tumor necrosis factor/nerve growth factor receptor superfamily, is also associated with type 2 response.¹¹ Type 2 immune response is also involved in allergic diseases, which can lead to debilitating or even fatal disorders. Studies in animals provide evidence that helminth infections downregulate parasitic-specific immune responses and protect against allergic airway inflammation.¹² According to the so-called hygiene hypothesis, the increase in allergic disorders observed in western countries in recent times would be related to the low exposure in childhood to microbes and parasites, which would modulate the human immune system growth.¹³

Taking advantage of the preferential expression of IgE and sCD30 as Th2 activation markers,¹⁴ we investigated whether a change in serum concentration of IgE and sCD30, as a proxy for Th2 activation markers, had occurred over a 26-year period (from 1987 to 2013), among people living in two rural communities of the Bolivian Chaco area at the same time of the progressive disappearance of STH infections.

MATERIALS AND METHODS

RESULTS

Overall, 151 sera were collected from people living in two rural communities (age 4–70 years): Javillo (65 serum samples, collected in 1987) and Ivamirapinta (86 serum samples, collected in 2013). Table 1 summarizes the characteristics of the participants in the surveys. No significant difference in sex distribution was observed between 1987 and 2013 population; participants were significantly older in 2013 (P < 0.0001).

The mean serum total IgE concentrations were 205.4 kU/L (SD 55.8 kU/L, median 186.0 kU/L) and 77.9 kU/L (SD 21.3 kU/L, median 81.5 kU/L) in 2013 and 1987, respectively. The mean serum total sCD30 concentrations were 46.0 U/mL (SD 19.2 U/mL, median 41.0 U/mL) and 18.4 U/mL (SD 10.6 U/mL, median 15.0 U/mL) in 1987 and 2013, respectively. The difference was statistically significant for both total IgE and sCD30 (P < 0.0001) (Figure 1), both overall and in each of the age categories (SAC, and subjects aged < 26 and ≥ 26 years) (Table 2). By linear models, both IgE and sCD30 confirmed a significant decline from 1987 to 2013 (P < 0.0001), independent of age (Supplemental Table). No significant differences were found in serum concentration of either markers between SAC and between subjects aged < 26 and ≥ 26 years, both in 1987 and in 2013 (Table 2).

View Full Size

Box-plot of serum median IgE (left panel) and sCD30 (right panel) concentration distributions in patients from Javillo (1987) and Ivamirapinta (2013) communities.

Citation: The American Journal of Tropical Medicine and Hygiene 102, 4; 10.4269/ajtmh.19-0180

• Download Figure
• Download figure as PowerPoint slide

DISCUSSION

Our study shows a significant decrease in IgE and sCD30 concentrations (P < 0.0001) between sera collected 26 years apart in two rural communities of the Bolivian Chaco. These changes paralleled an impressive drop in STH prevalence in this area, from more than 50% to < 1%, likely the result of 30 years of PC.⁸ Of note, no STH infections were identified in Ivamirapinta in 2013 during a parasitological survey, which involved 111 inhabitants (median age 30 years, range 1–73).¹⁵ During the same period, a significant decrease in seroprevalence was documented also for S. stercoralis, although no large-scale control measures potentially affecting strongyloidiasis were implemented.⁹ No significant change in intestinal protozoan parasite infections was observed during the same time interval, indicating socioeconomic conditions have not substantially improved during that period. In the two communities surveyed, the seropositivity for S. stercoralis observed in Javillo in 1987 was 12%, and 7% in Ivamirapinta in 2013 (unpublished data). No recent data are available on the prevalence of other helminth infections potentially affecting Th type 2 response, in the Bolivian Chaco. A high rate of Mansonella ozzardi microfilaremia (26%) was found in 1997, whereas in 1999, a 3% point prevalence for anti–Trichinella spiralis antibodies, and a high seroreactivity against Taenia solium and Toxocara canis antigens were detected in the population living in this area.^16,17

Meanwhile, no specific interventions were implemented against these infections.

The capacity of helminth infection to modulate host immune response, and thus their impact on allergic and/or inflammatory diseases, has been a matter of a large volume of research since the 1970s.¹⁸ The “hygiene hypothesis” links the reduction in endemic infections due to housing, sanitation, and health improvements in high-income countries with the concomitant rise in the prevalence of asthma and atopy in childhood.¹⁹ In brief, the removal of the regulatory effect of microorganisms and other parasites, after millennia of coevolution and genetic adaptation with humans and other mammalian, might produce an imbalance in the host pro- and anti-inflammatory immune responses and an excess of immune-mediated diseases. However, little consensus exists among the studies that have explored the interaction between helminth infection and allergic diseases, including meta-analysis and systematic reviews.²⁰ For instance, as for the development of asthma, hookworm infection showed a strong protective role, but T. trichiura, Enterobius vermicularis, and S. stercoralis did not have an impact, whereas A. lumbricoides infection resulted a significant risk factor.²¹ Most of the published studies agree that helminth infection protects against atopic sensitization and allergic skin reactivity, although these infections appear associated with increased allergen-specific IgE.^18,22 In recent years, deliberate infection of patients with worms has been proposed in non-endemic, high-income countries, as a possible treatment for inflammatory diseases, such as allergies, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, and psoriasis, with inconsistent results.²³

This study is not without limitations. One is that the two surveys took place in different communities—however, the Bolivian Chaco is a homogeneous ecological zone, where rural populations share the same hygienic and sanitary conditions, and no substantial differences in infestation rates are expected between two neighboring communities. Another limitation is that no parasitological data are available from Javillo—however, a parasitological survey conducted in 1987 in different rural communities of the Chaco region showed a homogenously high STH prevalence.⁵ A third concern would be that the population of the second survey is older—however, different analyses concur to show the observed changes are age independent. Last and importantly, no information on allergic symptoms experienced by the participants and other epidemiological information on allergy-related clinical syndromes or immune-mediated diseases in the population are available. Further studies are warranted to address the clinical and epidemiological correlation of the serological rearrangements in populations where STH infestation has virtually disappeared. Longitudinal studies carried out in settings where mass deworming programs are ongoing may help elucidate whether the removal of helminth infections would lead to an increased prevalence of allergic and other immune-mediated diseases in the long term.

Supplemental table