ANALYSIS

The Debate

Since 2002, when Dr. Maria Yazdanbakhsh et al. published a breakthrough article on the relationship between allergy and parasites, there has been an explosion of research on this topic. While many clinical trials have supported Yazdanbakhsh's claim that intestinal helminth infection is protective against allergy, there have also been trials that have shown that parasite infection may actually induce allergy . Research on this topic is ongoing, and at present there are no definitive answers. We will attempt to give you an overview of the arguments and studies conducted thus far, with a hope of allowing you to see the benefits and drawbacks of parasite infection in regards to allergic response.

Parasites as Protective Against Allergy

Although the Hygiene Hypothesis was a great preliminary step in the search for an explanation of the increase of allergies in developed countries, there was little consistent evidence in clincial trials to support it. Dr. Yazdanbakhsh expanded upon the Hygiene Hypothesis with a focus on the fact that infections at a young age seemed to have a protective effect against allergy in childhood and later life. With a close study on the effect of parasites on the immune system, Dr. Yazdanbakhsh was able to demonstrate that infection with parasites during development allows the body to create regulatory T-helper cells, keeping the immune system in check, and reducing the incidence of allergy and autoimmune disease .

Dr. Rook expanded on this finding, coining the term, "Old Friends Hypothesis" and officially updating and revising the Hygiene Hypothesis. In his original paper in 2003, Dr. Rook identified specific organisms that are needed for protection against allergy and autoimmune disease. Mycobacteria, lactobacilli, intestinal helminths, and viruses were all identified as the "old friends" needed for correct immune function, but it is still unclear in exactly what combination or capacity each of these organisms is needed, and may vary greatly within the individual .

Various clinical trials have been conducted to test this new hypothesis. Results suggest that intestinal parasites may be protective against allergy. Specifically, there has been much research on helminth infection's protective effects against skin sensitization, eczema. In a 2006 Flohr et. al study, a total of 1742 Vietnamese schoolchildren took part in a cross-sectional survey. The schoolchildren were tested for skin allergens using the skin prick test and stool samples were also analyzed to determine geohelminth status in terms of parasite eggs per gram feces. The children were then tested for malaria using a thick blood smear. The results of this cross-sectional study showed that the risk of sensitizaiton was reduced in individuals with higher hookworm and Ascaris infection. There was also a correlation between the intensity of helminth infection and the risk reduction of sensitivity. The highest category (intensity) of hookworm infection showed a 39% risk reduction. Although it could not be analyzed based on intensity of infection because there were too few infections of this type, Asacaris infection showed a 72% risk reduction for skin sensitization to allergens. Various other factors that correlated with lower socioeconomic status were shown to reduce risk of sensitization, which supports the old friends hypothesis .

Additionally, other studies have been conducted on the reduction of allergy due to parasitic infection. Shafer et. al conducted a similar study in East Germany focusing on specific worm infestation's effects on eczema. The study showed a 55% risk reduction of eczema with a prior worm infestation, but could neither deny or accept causal relationship . Each study demonstrates a negative correlation between parasite infection and allergy, but none have been decisive.

Both Rook and Yazdanbakhsh identify parasites as protective against allergy, but the role of parasites as a therapy for people with existing allergic conditions remains unclear. Yet in a recent conversation with Dr. Rook, he suggested that parasites may not only be crucial in the formation of T regulatory cells at a young age, but may also contribute to the effectiveness of T regulatory cells throughout life, thus there is potential to use parasites as therapy for allergy .

In preparation for the use of parasites as therapy, a pilot trial was completed in which adults were artificially infected with Hookworm as therapy for allergies. Different doses of hookworm larvae were given to subjects to find the appropriate dose for therapy, and it was determined that humans could handle 10 larvae . It is important to look at the specific number of parasites and length of infection, as Dr. Keane-Meyers of the NIH suggested, “the longer you are infected and the more worms you have the less likely you are to have allergic disease.

Source: http://courses.bio.psu.edu/fall2005/biol110/tutorials/tutorial39.htm

Parasites Induce Allergy

Although the immunological evidence for parasites as protective mechanisms is sound, several clinical trials have demonstrated that parasites actually induce allergy. A recent trial conducted in Costa Rica demonstrated that children infected with Ascaris lumbricoides were more likely have severe allergic responses. The study was conducted with 439 school-age children throughout Costa Rica. Costa Rica is a nation with relatively low prevalence of ascariasis (2%, vs. 100% in some undeveloped countries), and a high prevalence of allergy. Through questionaires, skin tests, and IgE serum counts, it was determiend that those infected with Ascaris were more likely to be sent to the hospital for asthma in the previous year, and also exhibit higher IgE and eosinophil counts. Similar studies in Brazil, South Africa, and Germany have also come to the conclusion that parasites may induce allergy, but these were small studies with low sample sizes .

Because these clinical trials were conducted in areas with low parasitic prevalence, it may be the case that there were not enough 'Old Friends' present during development to allow for proper production of regulatory T cells. Thus, when children who have not developed T regulatory cells are infected with parasites, their immune system may overcompensate for the infection, with Th2 cells overreacting. An overrepresentation of Th2 cells is also correlated with allergic response, and therefore presence of parasites may be associated with the induction of allergy.

John Fincham of the Medical Research Council in South Africa recently shared his thoughts with us about the relationship between helminths and allergy. Fincham believes that "the theory that the prevalence of allergic conditions, especially those expressing as bronchospasm and hypersensitivity of the upper airways, is generally low in African people who are often infected by helminthic parasites, may be wrong". In regards to the seemingly low prevalence of allergy in developing countries, he said that "people who are desperately poor, like the vast majority in Africa, have to focus on survival. Ailments like allergic bronchospasm may generally be ignored or be relegated to a low priority compared to getting food, water and some form of shelter". Fincham shares the opinion that parasite infection may not be protective against allergy, and is a supporter of further research of the consequences of co-infection parasites and HIV. He thinks that immune responses to helminthic antigens may facilitate HIV infection (and other viruses), and impair vaccine efficacy. If this is the case, it will be "necessary to take vigorous public health measures to minimise the causes of dangerous immunological imbalance."

Further Research

Along with the debate on the interactions between parasitic infection and allergy, research is being conducted on other interesting interactions between intestinal parasites and disease. In a study by Obihara et. al, the authors explore the relationship between Ascaris and allergy in an area where mycobacterium tuberculosis is hyperendemic. The results of the study suggest that Ascaris infection may be a risk factor for allergy and that mycobacterium tuberculosis infection may be protective against this risk, probably by stimulating an anti-inflammatory response . Although these results promote the theory that parasites induce allergy, it is interesting to note that co-infection with another disease, changes the effect of the parasite on allergy. This phenomenon also occurs the Adams et. al study on co-infection of intestinal helminthiasis and HIV. This study shows that there is a discrepancy between the amount of people that were seropositive for Ascariasis and the amount of people who experienced Ascaris eggs in their stool sample. This result suggests that there may be some interaction between HIV and Ascaris (or other helminths), but must be researched in more depth .

Other research that could be done in the future is the possible use of parasite products as a therapy option against allergy. In Flohr et. al, the conclusion of the study introduces the idea that pharmaceutical drugs derived from parasite products may help to alleviate clinical allergic disease. This study also touched upon the affects of co-infection with malaria and helminthiasis. Flohr et. al offer the opinion that further investigation on the relationship between malaria infection and allergic disease should be done in light of the immunomodulatory mechanisms associated with malaria .

In general, this field is relatively new and needs to be explored in much greater depth. Randomized controlled clinical trials that determine a causal relationship between parasite infection and allergy need to be completely. This research offers great potential for future public health initiatives to fight allergy and autoimmune disease.

Yazdanbakhsh, Maria, Peter G. Kremsner, and Ronald Van Ree. "Allergy, Parasites, and the Hygiene Hypothesis." Science. 296 (2002): 490-494.

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Schåfer, T, T Meyer, J Ring, H E. Wichmann, and J Heinrich. "Worm Infestation and the Negative Association with Eczema (Atopic/Nonatopic) and Allergic Sensitization." Allergy. 60 (2005): 1014-1020.

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Fincham, John. “Second reply: Questions Regarding Parasites and Allergy.” E-mail to Erin Kobashigawa and Claire C. Sadler. 17 May 2007

Obihara, C C., N Beyers, R P. Gie, M O. Hoekstra, J E. Fincham, B J. Marais, C J. Lombard, L A. Dini, and J L. Kimpen. "Respiratory Atopic Disease, Ascaris-Immunoglobulin E and Tuberculin Testing in Urban South African Children." Journal of Clinical and Experimental Allergy. 36 (2006): 640-648.

Adams, V J., M B. Markus, Z L. Kwitshana, M A. Dhansay, L Van Der Merwe, G Walzl, and J E. Fincham. "Recall of Intestinal Helminthiasis by HIV-Infected South Africans and Avoidance of Possible Misinterpretation of Egg Excretion in Worm/HIV Co-Infection Analyses." BMC Infectious Diseases 6.88 (2006): 1-8.

Flohr, Carsten, L N. Tuyen, S Lewis, R Quinnell, T T. Minh, H T. Liem, J Campbell, D Pritchard, T T. Hien, J Farrar, and H Williams. "Poor Sanitation and Heminth Infection Protect Against Skin Sensitization in Vietnamese Children: a Cross-Sectional Study." Journal of Allergy and Clinical Immunology 118 (2006): 1305-1311.

 


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