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A larva under a microscope resembling a worm with one end across the other
Infectious Necator Americanus L3 Larva.
Invisible to the naked eye, from 10 to 35 are applied to the skin in therapy, either in a single dose or in multiple smaller doses over the course of two or three months.

Helminthic therapy, a type of Immunotherapy, is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth or with the ova of a helminth. Helminths are parasitic worms such as hookworms. Helminthic therapy is currently being studied as a treatment for several (non-viral) auto-immune diseases including Celiac disease, [1] Crohn's disease,[2][3][4][5] multiple sclerosis,[6] asthma,[7][8] and ulcerative colitis.[9] Autoimmune liver disease has also been demonstrated to be modulated by active helminth infections.[10]

In addition to these autoimmune disorders, interest is increasing regarding diseases that involve inflammation but that are not currently considered to include autoimmunity as a component. For example, heart disease and arteriosclerosis both have similar epidemiological profiles as autoimmune diseases and both involve inflammation, and their recent increase in incidence cannot be solely attributed to environmental factors according to a recent paper proposing the eradication of helminths as an explanation of this discrepancy.[11]

Helminthic therapy consists of the inoculation of the patient with specific parasitic intestinal nematodes (helminths). There are currently three closely related treatments available. Inoculation with Necator americanus [12]', commonly known as hookworms, or Trichuris suis Ova[13], commonly known as Pig Whipworm Eggs, or inoculation with Trichuris trichiura Ova [12] commonly referred to as human whipworm eggs.

Helminthic therapy has emerged as one possible explanation for the low incidence of autoimmune diseases and allergies in less developed countries, together with the significant and sustained increase in autoimmune diseases in industrialized countries.[8][14][15][16] Current research and available therapy is targeted at, or available for, the treatment of Crohn’s disease, ulcerative colitis, inflammatory bowel disease (IBD), multiple sclerosis, asthma, eczema, dermatitis, hay fever and food allergies.

Contents

Incidence of autoimmune diseases and parasitic infestation

While it is recognized that there is probably a genetic disposition in certain individuals for the development of autoimmune diseases, the rate of increase in incidence of autoimmune diseases cannot be explained by genetics alone. There is a significant amount of evidence that one of the primary reasons for the increase in autoimmune diseases in the industrialized nations is the significant change in environmental factors over the last century. Environmental factors include exposure to certain artificial chemicals from industrial processes, medicines, farming and food preparation. It is now also becoming clear that the absence of exposure to certain parasites, bacteria and viruses is playing a significant role in the development of autoimmune diseases in the more sanitized Western industrialized nations.[17][18]

Why lack of exposure to naturally occurring pathogens and parasites results in an increased incidence of autoimmune diseases forms the core of the hygiene hypothesis[8][19], which partially explains these observations. A complete explanation of how environmental factors play a role in autoimmune diseases has still not been proposed. However epidemiological studies, such as the meta analysis by Leonardi-Bee et al., have helped to established the link between parasitic infestation and its protective role in autoimmune disease development.

Recent research demonstrating that the central tenet of the Hygiene Hypothesis is true, that parasites, and in particular helminths, have shaped the evolution of at least parts of the human immune system, and even the genes responsible for Crohn's Disease, Ulcerative Colitis and Celiac Disease, provides further evidence that it is the absence of parasites, and in particular helminths, that has caused a substantial portion of the increase in incidence of diseases of immune dysregulation and inflammation in industrialized countries in the last century[20].

Theoretical explanation of helminthic therapy

Although the mechanism of autoimmune disease development is not fully defined, there is broad agreement that the majority of autoimmune diseases are caused by inappropriate immunological responses to innocuous antigens, driven by a branch of the immune system known as the TH1 type immune response. Extra-cellular antigens primarily trigger the TH2 response, as observed with allergies, while intracellular antigens trigger a TH1 response. The relationship between these two types of immune response is a central theme of the Hygiene hypothesis, which suggests that there is a regulatory action between the two types of response. However, the observation that allergies and autoimmune response are increasing at a similar rate in the industrialized nations, appears to undermine the Hygiene Hypothesis.

A refinement of the Hygiene Hypothesis, which overcomes this apparent contradiction, is the Old Friends Hypothesis.[21] The Old Friends Hypothesis modifies the Hygiene Hypothesis by proposing that T regulator cells can only become fully effective if they are stimulated by exposure to microorganisms and parasites that have low levels of pathogenicity, and which have coexisted universally with human beings throughout our evolutionary history. This theory has recently been given more credibility by a study demonstrating the impact of infectious organisms, and helminths in particular, upon genes responsible for production of various cytokines, some involved in the regulation of inflammation, in particular those associated with the development of Crohn's Disease, Ulcerative Colitis, and Celiac Disease[20].

The Hygiene Hypothesis proposes that appropriate immune response is in part learned by exposure to these microorganisms and parasites, and in part regulated by their presence. In the industrialised nations, we live in a relatively sterile environment. The development of vaccines, hygienic practices and effective medical care have diminished or eliminated the prevalence and impact of many parasitic organisms, as well as bacterial and viral infections. This has been of obvious benefit with the effective eradication of many diseases that have plagued human beings. However, while many severe diseases have been eradicated, our exposure to benign and apparently beneficial parasites has also been reduced commensurately. The central thrust of the theory is, therefore, that correct development of T regulator cells in individuals may depend on exposure to organisms such as lactobacilli, various mycobacterium and helminths.[22] Lack of exposure to sufficient benign antigens, particularly during childhood, is now widely accepted in the scientific community as the cause for the increase in autoimmune diseases and diseases for which chronic inflammation is a major component in the industrialized world.

Helminth characteristics required for use in therapy

For use as a therapeutic agent, the specific helminth should meet all the following minimum requirements:

  • should not have the potential to cause disease in man at therapeutic doses
  • should not be able to reproduce in a host, thus allowing control of dose
  • should not be a potential vector for other parasites, viruses, or bacteria
  • should not be easily transmissible from the host to other people
  • should be compatible with a patient's existing medication
  • should have a significant period of residence in the host
  • must be easily eradicated from the host, if required

Both Necator americanus and Trichuris suis ova meet these requirements. Neither is known to cause any specific disease in man, although allergic reactions have been reported with T. suis, and anemia has been reported in individuals hosting very large numbers of N. americanus: N. americanus, the species of hookworm used therapeutically, takes on average 0.03ml of blood per day from the host[23], so anemia is only observed in malnourished individuals with very large numbers of hookworms; this scenario has traditionally been a problem with children in developing countries. Neither helminth is known to be a vector for the infection of the host with other parasites, viruses or bacterium.

In addition, neither helminth[24] reproduces in the host; in both cases, the reproductive cycle requires a period outside the host, with both worms requiring several weeks' incubation in moist soil. As a result, the therapeutic dose can be tightly controlled. The complexity of both helminths' life cycles also means that cross-infestation, even with people living in very close proximity to the host, is highly improbable. The main difference between N. americanus and T. suis is residency time[25]: T. suis has a lifespan of only 2–3 weeks in humans, while N. americanus has an average life span of 5 years. Frequency of dose corresponds directly to lifespan. Both helminths have been demonstrated to have beneficial effects when used in conjunction with existing (conventional) therapies. If eradication of helminths from the host is required at any point, both respond to either albendazole or mebendazole.

Description and efficacy of therapy

TSO (Trichuris Suis Ova - pig whipworm eggs) is contra-indicted in patients known to be hypersensitive to Trichuris or compounds made from Trichuris and patients experiencing acute symptoms associated with their respective autoimmune disease. Inoculation with TSO is achieved by multiple oral doses. Patients are normally started with four separate doses taken every one to three weeks. Starting dose is normally 500 ova/dose, for the first 4 doses. Failure to respond after the first four doses will result in an increase in dose to 1000 ova/dose, up to a maximum of 2500 ova/dose every two weeks. A clinical trial(summers) on patients with ulcerative colitis, indicated that 13 of 30 patients (43%), given 2500 ova/dose bi-weekly for a twelve week period, showed improvement in their disease index activity. Better results were obtained in Crohn’s patients, with a 72% remission rate following eight doses of 2500 ova over a 24 week period[4]. No side effects were reported in either study.

Inoculation with Hookworm is achieved by a single application of the infectious L3 larvae to the skin; dose is set at 50 larvae for all conditions because this gives the best balance between the chance of achieving remission and the occurrence of the transient side effects associated with inoculation. Immediate side effects of inoculation include a rash at the inoculation site, followed by gastrointestinal symptoms in some individuals over the following 1–4 weeks. It is unclear if side effects are dose dependent, they vary by individual, but it is clear from the studies cited above that a therapeutic effect occurs at much lower doses of worms in comparison to TSO.

Comparison of helminthic therapy to orthodox medicines and therapies

The potential benefits of Helminthic Therapy are even more startling when taken in the context of the success rates and side-effects experienced by people on currently accepted medications that are immune-modulating and or anti-inflammatory. Success rates for helminthic therapy, as measured by the number of people achieving remission range from 56% for Ulcerative Colitis using TSO as the helminth,[9] 72% for Crohn's using TSO,[4] and 100% for Crohn's disease using hookworm. However, although the hookworm paper is encouraging, the study was only intended to prove safety and is a not an appropriate paper to project efficacy from.[3] Contrast that with the remission rates for the new biologicals as described below, in one study sponsored by the drug maker, Humira achieved only a 52% remission rate in Crohn's patients.[26] As well, side effects of helminthic therapies are not universal and are temporary, usually lasting only two to four weeks. They consist of abdominal pain, cramping, gas, diarrhea and fatigue. The side effects of conventional immune-modulating drugs, such as Beta-interferon and Remicade, or of anti-inflammatories such prednisone, are much more severe and potentially harmful. As with any immunosuppressive therapies patients using helminthic therapy are likely to be more susceptible to certain infectious diseases.

Side Effects

Few side effects of treatment with TSO have been reported, although adult Trichuris Suis have been found in more than one subject, something which originally was not expected to happen and the reason for the banning order by US Customs preventing the importation into the USA for personal use of TSO.

Hookworm cause more side effects. One of the remarkable aspects of helminthic therapy with hookworm is the enormous range of reactions in patients to therapy. Side effects are transient, generally occurring episodically for days or weeks at a time starting day four after inoculation and ending around week 10. Side effects can include a rash at the inoculation site, nausea, diarrhea, gas, bloating, cramping, epigastric pain and episodes of fatigue. In extreme cases the diarrhea can be debilitating and the epigastric pain intense, causing termination of therapy.

The incidence of side effects for most subjects is dose dependent, but for a minority (less than 5%) side effects are severe regardless of dose. This appears to occur more commonly in women than men.

Research

Helminthic therapy with both hookworm and TSO has been investigated in research published by the University of Nottingham[27] and University of Iowa.[28] Both TSO and Hookworm are well tolerated, and safe at therapeutic doses. Neither organism is by any standard definition infectious in the industrialized world. That is, it neither presents an infection risk to others from a treated individual, nor does either organism proliferate within the host once established.

Hookworms depend upon a period of eight to ten days outside the host within narrow environmental parameters to become infectious after being passed in stool. Trichuris suis is similar to the human whipworm Trichuris trichiura, but its normal host is pigs. T. suis can colonize people but only for a short term and the worms cannot replicate in people.

For this reason treatment with TSO requires regular doses, at intervals of two weeks. Treatment with hookworm requires inoculation at intervals of approximately five years. This is because the average life of life expectancy of necator americanus is 3–10 years.[29]

Clinical trials of the therapy were approved by ethics committee of the National Health Service and the success of early trials is leading to more trials on a larger scale.[30]

See also

References

  1. ^ "Inoculating Celiac Disease Patients With the Human Hookworm Necator Americanus: Evaluating Immunity and Gluten-Sensitivity - Full Text View - ClinicalTrials.gov". http://clinicaltrials.gov/ct2/show/NCT00671138. Retrieved 2009-05-22.  
  2. ^ Hunter MM, McKay DM (2004). "Review article: helminths as therapeutic agents for inflammatory bowel disease". Aliment. Pharmacol. Ther. 19 (2): 167–77. doi:10.1111/j.0269-2813.2004.01803.x. PMID 14723608.  
  3. ^ a b Croese J, O'neil J, Masson J, Cooke S, Melrose W, Pritchard D, Speare R. (2006). "A proof of concept study establishing Necator americanus in Crohn’s patients and reservoir donors". Gut 55: 136–137. doi:10.1136/gut.2005.079129. PMID 16344586.  
  4. ^ a b c Summers RW, Elliott DE, Urban JF, Thompson R, Weinstock JV (2005). "Trichuris suis therapy in Crohn's disease". Gut 54 (1): 87–90. doi:10.1136/gut.2004.041749. PMID 15591509.  
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  10. ^ Aoyama H, Hirata T, Sakugawa H, et al. (2007). "An inverse relationship between autoimmune liver diseases and Strongyloides stercoralis infection". Am. J. Trop. Med. Hyg. 76 (5): 972–6. PMID 17488925.  
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  13. ^ "Ovamed". http://ovamed.org/english/home/home.html. Retrieved 2009-05-22.  
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  15. ^ Pugliatti M, Sotgiu S and Rosati G. (2002). "The worldwide prevalence of multiple sclerosis". Clin Neurol Neurosurg July (104): 182–191. doi:10.1016/S0303-8467(02)00036-7. PMID 14684567.  
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  23. ^ Hookworm Information page National Institute of Health
  24. ^ Hookworm Information page National Institute of Health
  25. ^ Foundations of Parasitology, Schmidt & Roberts, ISBN 0-07-234898-4
  26. ^ October 23, 2006 - New Phase III Data Shows Abbott's HUMIRA (adalimumab) Induced Clinical Remissions in Patients with Crohn's Disease Who Lost Response To, or Were Intolerant To, Remicade (infliximab)
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