Stein et. al. Biotherapy Journal Review Spring 2016

Helminthic Therapy Reviews

Journal Citation

Stein M, Greenberg Z, Boaz M, Handzel ZT, Meshesha MK, and Bentwich Z. The Role of Helminth Infection and Environment in the Development of Allergy: A Prospective Study of Newly-Arrived Ethiopian Immigrants in Israel. PLoS.Negl.Trop.Dis. 2016; 10(1):e0004208

Published Abstract

Helminth infection may be protective against allergy and account for the low prevalence of allergy in developing countries. We studied prospectively the prevalence of allergy in Ethiopian immigrants with heavy helminth infection on arrival in Israel, and again after a year of adjustment to an urban industrialized setting, to explore the roles of helminth infection, changed environment and background immunity on the manifestations of allergy. 126 newly arrived Ethiopian immigrants were studied at baseline and 115 after a year of follow up in Israel. Allergic symptoms, Skin prick tests (SPT), Tuberculin (PPD) skin tests, stool and blood samples were obtained for determining parasites, blood IgE and eosinophil levels, respectively. Anti-helminthic therapy was offered to the entire infected individuals, but only 50/108 (46.3%) took the medication. At baseline, there was a significant negative association between helminth infection and allergy, 4/18 (22.2%) of uninfected participants were allergic compared to 7/108 (6.5%) of helminth-infected participants (p = 0.028), as well as between helminth infection and SPT reactivity, 12/18 (66.6%) of uninfected participants compared to 43/108 (39.8%) of helminth-infected participants (p = 0.033). After one year, a significant general increase in allergy and SPT was observed. While only 11/126 (8.7%) were allergic at baseline, 30/115 (26.1%) became allergic at follow-up (p<0.0001), and while 55/126 (43.7%) were SPT+ at baseline, 79/115 (68.7%) became SPT+ at follow-up (p<0.001). A twofold increase in allergen sensitization was also observed after one year in Israel, particularly for dust mites, grasses and olive tree (p<0.001). These results show that: a) Helminth infection is significantly associated with low allergy and low SPT reactivity; b) One year after immigration to Israel, allergy and SPT reactivity increased significantly in all immigrants; c) Higher increases in positive SPT and allergy were observed after a year in the group that remained infected with helminths, even though they had a lowered helminth load; d) The reasons for the increased allergy one year after immigration needs further investigation but probably reflects the combined influence of the decreased helminth load and novel environmental factors.

Introduction & Background to Study

It is well documented that allergic symptoms are more common in people living in developed countries than in people living in developing countries. Studies have shown an association between allergy, affluence, environment. The often quoted “hygiene hypothesis” suggests that improved sanitary conditions of the developed world – or more specific, fewer parasitic infections – is a major contributing factor behind this discrepancy in the prevalence of allergies. But data to this effect has been conflicting.

Over 60,000 Ethiopian Jews immigrated from Ethiopia to Israel in recent years, primarily in a large airlift in the mid-eighties and again in 1991. These immigrants came mostly from rural areas in Northern Ethiopia, and after arrival in Israel, they underwent medical evaluations and treatment. On arrival of both waves of immigration, they were found to have a very high prevalence of helminth infections with a very low prevalence of allergy, while after a year in Israel, many of them developed allergy. The aim of this study was to investigate the prevalence of allergy in relation to helminth infection and a changing environment in a population of Ethiopian immigrants to Israel.

Materials & Methods

Study Design: Prospective randomized longitudinal epidemiologic study, conducted between 1997–2001.

Study population: Ethiopian immigrants were recruited during their first three months of arrival, in Israel. They were selected randomly from three immigrant absorption centers.

Exclusion Criteria: Subjects found to have tuberculosis, syphilis, or HIV infections were excluded from the study.

Clinical and laboratory testing: The immigrants were interviewed by the physician with the help of an experienced Ethiopian social worker. A questionnaire about respiratory symptoms relating to asthma and allergic rhinitis (based on the International Union Against Tuberculosis and Lung Disease questionnaire and the European Community Respiratory Health Survey) was administered to each subject. Laboratory testing was performed at the time of enrollment and 1 year later. Testing included a skin prick test (SPT) for ten common allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, feather mix, cockroach, cat pelt, dog epithelium, grass pollens mix, weed mix, olive, and cypress trees). Mantoux skin test for delayed type hypersensitivity with intracutaneous injection of tuberculin (PPD) were administered, and induration of 10 mm or more was interpreted as a positive response. Helminth infections were identified by stool studies (quantitative parasite egg counts). Complete blood count, total eosinophil count and total serum IgE levels were also evaluated.

Antihelminthic treatment: Helminth infected subjects were offered appropriate infection-specific treatment. Those who consented to treatment were treated directly by the physician and/or by the health worker.

Definitions: Allergic individuals were defined as those having both, positive SPT and clinical history of asthma and/or allergic rhinitis. Individuals with a negative clinical history of asthma or rhinitis, but with a positive SPT were defined as non-allergic SPT-positives (sensitized asymptomatic atopic individuals). Individuals with a negative clinical history and a negative SPT were defined as non-allergic normal individuals.

Study Results

A total of 126 participants were enrolled in the study (66 male, 60 female, mean age 31.2 ± 14.5). At baseline, helminthic infections were detected in 108 out of 126 (85.7%). Hookworm was the most prevalent species, being found in 79 individuals (73.1%). Schistosoma mansoni was found in 51 (47.2%), Ascaris species in 50 (46.3%), and Trichuris trichiura in 16 subjects (14.8%). Multiple worm infections were found in 70 (64.8%) of the infected subjects.

Eosinophil counts were elevated across the entire cohort, whether or not they were infected with helminths. However, helminth-infected individuals had significantly higher levels of eosinophilia than uninfected individuals (p = 0.01). Similarly, IgE levels were elevated across the entire cohort, but tended to be higher in the helminth-infected group (p = 0.06).

Allergy was present in 11/126 (8.7%) subjects at baseline. There were 3/126 (2.4%) subjects with clinical rhinitis but with negative SPT, who were not categorized as allergic individuals. Allergic individuals were predominantly male (9/11, p = 0.041) and older (mean age 41.2 ± 14.4 versus 29.7 ± 14.1, p = 0.01). There was a significant negative association between helminth infection and allergy. Seven of 108 (6.5%) of helminth infected subjects were allergic, while only 4 of 18 (22.2%) of uninfected subjects were allergic (p = 0.028). Helminth infected subjects were also less likely to have SPT reactivity at baseline (p = 0.033) and less likely to have PPD skin test reactivity at baseline (p = 0.019). Among helminth infected subjects, those with multiple infections and/or high egg burdens were less likely to be allergic.

Out of the 126 original study participants, 115 individuals were available for follow-up testing one year later. The 11 individuals who withdrew from the study were all helminth infected and all non-allergic. Only 50 (46.3%) of the original 108 helminth infected individuals agreed to receive treatment for their helminth infection; 28 (56%) of these achieved successful eradication.

In the group of subjects with helminths whose infections were not successfully eradicated, peripheral blood eosinophilia did not change significantly, and total IgE increased slightly. The mean egg burden in this group decreased from a mean of 1327 to a mean of 699 eggs/cm3 of stool, (p = 0.02).

Allergy increased significantly in the overall cohort from 11/126 (8.7%) allergic individuals at baseline to 30/115 (26.1%) at follow-up (p<0.001). Clinical history of allergy but with negative SPT was found in two individuals with rhinitis that were considered as non-allergic rhinitis patients.

Several new asthma cases arose by the end of the year, but this rise was statistically significant only in the group of subjects who were initially infected with helminths and remained so (p = 0.002). SPT reactivity also increased significantly in the overall cohort, but again that increase was significant only in the groups that was initially infected with helminths and either remained infected or was successfully treated. 

The mean allergen sensitization increased by 2 fold, with an increase in the number of allergens sensitizations per individual after a year in all the groups. Individuals who were infected with helminths, whether or not that infection was cured, showed an increase in the numbers of allergens to which they were sensitive; but those were not infected showed no significant increase.

Author’s Conclusions

“The results of the present study suggest that helminth infection confers protection from allergy but also point to the possible role of the new environment and the change in the helminth load, in increasing allergy . . . . Additional studies . . . would be important in gaining a better understanding of these phenomena and will be of great importance to public health in the coming years.”

Reviewer’s Conclusions

For many years is has been clear that populations infected with helminths had a significantly lower prevalence of allergies (and other diseases). But it has been difficult to demonstrate that it was the helminth infection that was somehow protective. Some researchers suggested that the reason it was difficult to prove this relationship was because it did not exist. In this study we have evidence to indicate a more common alternative explanation: the relationship holds, but it is not the only factor in the relationship. Clearly, environmental factors (and/or behavioral factors triggered by the environment) were at play in this cohort, in which the prevalence of allergies increased whether or not the subjects were infected with helminths. Indeed, for some of the tests, those who were initially infected with helminths and remained infected demonstrated an increase in allergic signs more so than did their uninfected cohorts. This reviewer agrees completely that further study is necessary to understand the factors at play in the development of allergy, as well as the directly and/or indirectly protective roles that helminths appear to play.

The ability to study and compare individuals who both cleared their helminthic infection and those who did not was a particularly strong point in this study. Hopefully future studies will be large enough to look even deeper into these cohorts and separate meaningful differences in behavior (i.e., cultural adaptations), environmental exposures (i.e., changes in diet, animal and material exposures), and even sort out differences between those immigrants to remained infected because their antibiotic treatment failed and those who remained infected because they refused treatment. Refusing treatment on the basis of cultural beliefs may itself correlate with a difference in the level of integration with their new society and environment.