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

In addition to the treatment of autoimmune disorders the anti inflammatory effects of helminth infection are creating interest and research into diseases that involve inflammation but that are not currently considered to include autoimmunity as a component. Heart disease and arteriosclerosis both have similar epidemiological profiles as autoimmune diseases and both involve inflammation. Nor can their increase be solely attributed to environmental factors. Recent research has focused on the eradication of helminths to explain this discrepancy. [10]

The therapy involves inoculation of the patient with specific parasitic intestinal nematodes (helminths). There are currently two closely related treatments available, either inoculation with Necator americanus, commonly known as hookworms, or Trichuris Suis Ova, commonly known as Pig Whipworm Eggs.

Helminthic therapy has emerged from the extensive research into why the incidence of autoimmune diseases and allergies is relatively low in less developed countries, while there has been a significant and sustained increase in autoimmune diseases in the industrialized countries[7][11][12][13]. 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.


Incidence of autoimmune diseases and parasitic infestation

The incidence of a disease in a population is the number of new occurrences of a disease in a population over time. The study of the factors involved in why the incidence of a disease changes forms part of the scientific discipline called Epidemiology. 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[14][15].

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[16][7], 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.


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.[17] The Old Friends Hypothesis refines the Hygiene Hypothesis by proposing 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. It is thought that appropriate immune response is in part learned by exposure to these microorganisms and parasites. 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 man. 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[18]. 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.

Depending on the particular autoimmune disease in question, infection with helminths results in remission of symptoms in approximately 70% of patients[3]. While this is not conclusive proof that these two hypotheses are correct, it is strong evidence that our own immune response, and particularly the dysfunction of regulatory inflammatory response, may be a key factor in the development of autoimmune diseases, and the parasitic behaviour of a helminth infection can bring this response into balance.


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 patients 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: each Hookworm takes from 0.03 to 0.1 ml of blood per day from the host[19], 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[20] 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[21]: 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, with Ovamed offering repeated therapeutic doses on a 1-3 week basis, while Autoimmune Therapies suggest one dose every five years. 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 a single 400 mg dose of albendazole.


Description and efficacy of therapy

Ovamed is the first and only company to offer TSO for the treatment of Crohn’s disease and Ulcerative colitis. TSO 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[3]. No side effects were reported in either study.

Autoimmune Therapies is the first company to offer Hookworm for the treatment of allergies, asthma, Crohn's disease, eczema, inflammatory bowel disease, multiple sclerosis and ulcerative colitis. The therapy is contra-indicated in people with anemia, stenosis of the intestine and during pregnancy.

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 dependant, 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.


Relative efficacy and side effects of helminthic therapy

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[8], 72% for Crohn's using TSO[3], and 100% for Crohn's disease using hookworm. citation needed. 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[22]. 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.


Comparison to existing therapies

With all the autoimmune diseases discussed so far, one of the common factors is the dysregulation of the body’s inflammatory response. Front line treatment for inflammation in autoimmune disease has relied on synthetic glucocorticoids (steroids) such as prednisone, dexamethasone and hydrocortisone. These are derivatives of the natural occurring glucocorticoid cortisol. Treatment is generally highly effective for acute inflammation, but the doses required are very high when compared to natural cortisol production. Prolonged used of these steroids in supra-physiological doses, results in exactly the same side effects seen in patients with an overactive adrenal gland, often referred to as Cushing's disease or syndrome. These side effects include immunosuppression, thinning of the bones, truncal obesity, moon face, glucose intolerance and many other side effects.

Second line, or maintenance therapy, in many diseases is immunosuppressive such as azathioprine or the closely related metabolite 6-mercaptopurine (6-MP), cyclosporine. While highly effective in many patients, these more targeted class of drugs are generally very expensive, do not work in many patients and carry the risk of complete immunosuppression[23].

Several new medical therapies have recently become available or are undergoing clinical trials. This new class of drugs is based on antibody targeting of specific factors involved in the immune response. Specifically the monoclonal antibodies, which target specific inflammatory provoking cytokines. Drug such as Infliximab (Remicade), which is a chimeric IgG monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor, and Adalimumab (Humira), which is a human IgG monoclonal antibody specific for human tumor necrosis factor (TNF). The use of these new monoclonal therapies can give highly effective result in patients who have become refractory (resistant) to first line therapies. However, there is risk of significant side effects. Immune response modulation by these drugs is reported to have resulted in patients being susceptible to tuberculosis (including re-emergence) and sepsis. Other side effects, such as the development of demyelinating disorders (similar to multiple sclerosis), hypersensitivity reactions, pancytopenia (a decrease in all types of blood cells), congestive heart failure, Lupus-like syndrome and an increased incidence of lymphatic cancer (lymphoma) in treated populations have all been reported[24][25].

Recent studies by the Mayo Clinic suggests that patients may not only be at an increased risk of lymphoma may be at increased risk of skin, gastrointestinal system, breast and lung cancer. While this may sound rather alarmist we must point out that patients treated with these drugs are only at an increased risk of developing these types of cancer, when compared to the general population. The overall risk of development of lymphoma or other cancers as a result of treatment with Remicade or Humira still remains low.

Other therapies such as anti-inflammatory cytokines: Interleukin 10 (IL-10) and interleukin 11 (IL-11) have been found by some researchers to elicit a moderate response in Crohn's disease; however, more trials are needed.


Research

Helminthic therapy with both hookworm and TSO has been investigated in research published by the University of Nottingham[26] and University of Iowa.[27] 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.

Hookworm 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 expectancy of necator americanus is 3-10 years.[28]



References

1. ^ Hunter MM, McKay DM (2004). "Review article: helminths as therapeutic agents for inflammatory bowel disease". Aliment. Pharmacol. Ther. 19 (2): 167–77. PMID 14723608. 
2. ^ 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. 
3. ^ a b c d 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. 
4. ^ Summers RW, Elliott DE, Qadir K, Urban JF, Thompson R, Weinstock JV (2003). "Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease". Am. J. Gastroenterol. 98 (9): 2034–41. PMID 14499784. 
5. ^ Correale J, Farez M. (2007). "Association between parasite infection and immune responses in multiple sclerosis.". Annals of Neurology 61 (2): 97-108. PMID 17230481. 
6. ^ Falcone FH, Pritchard DI (2005). "Parasite role reversal: worms on trial". Trends Parasitol. 21 (4): 157–60. doi:10.1016/j.pt.2005.02.002. PMID 15780835. 
7. ^ a b c Leonardi-Bee J, Pritchard D, Britton J (2006). "Asthma and current intestinal parasite infection: systematic review and meta-analysis.". American Journal of Respiratory and Critical Care Medicine 174: 512-523. doi:10.1164/rccm.200603-331OC. PMID 16778161. 
8. ^ a b Summers RW, Elliott DE, Urban JF, Thompson RA, Weinstock JV (2005). "Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial". Gastroenterology 128 (4): 825–32. PMID 15825065. 
9. ^ 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. 
10. ^ Magen E, Borkow G, Bentwich Z, Mishal J, Scharf S (2005). "Can worms defend our hearts? Chronic helminthic infections may attenuate the development of cardiovascular diseases". Med. Hypotheses 64 (5): 904–9. doi:10.1016/j.mehy.2004.09.028. PMID 15780483. 
11. ^ P ZACCONE,* Z FEHERVARI,* J M PHILLIPS, D W DUNNE, and A COOKE (2006). "Parasitic worms and inflammatory diseases.". Parasite Immunol 28 (10): 515-523. doi:10.1111/j.1365-3024.2006.00879.x.. 
12. ^ Pugliatti M, Sotgiu S and Rosati G. (2002). "The worldwide prevalence of multiple sclerosis.". Clin Neurol Neurosurg July (104): 182-191. PMID 14684567. 
13. ^ Weinstock JV, Summers R, Elliott DE. (2004). "Helminths and harmony". Gut 53: 7-9. PMID 14684567. 
14. ^ David E. Elliott; Robert W. Summers; Joel V. Weinstock. (2005). "Helminths and the Modulation of Mucosal Inflammation.". Current Opinion in Gastroenterology 21 (2): 51-58. PMID 15687885. 
15. ^ Mohan C. (2006). "Environment versus genetics in autoimmunity: a geneticist's perspective.". Lupus. 15 (11): 791-793. PMID 17153852. 
16. ^ Strachan D P. (2006). "Hay fever, hygiene, and household size.". BMJ. 18 (299): 1259-1260. PMID 2513902. 
17. ^ Hadley C (2004). "Should auld acquaintance be forgot..". EMBO Rep. 5 (12): 1122–4. doi:10.1038/sj.embor.7400308. PMID 15577925. 
18. ^ Weinstock J V, Summers R and Elliott D E. (2004). "Helminths and harmony.". Gut. 53 (1): 7-9. PMID 14684567. 
19. ^ Hookworm Information page National Institute of Health
20. ^ Hookworm Information page National Institute of Health
21. ^ Foundations of Parasitology, Schmidt & Roberts, ISBN: 0-07-234898-4
22. ^ 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)
23. ^ Perri D, Cole DE, Friedman O, Piliotis E, Mintz S and Adhikari NK. (2007). "Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase.". Eur. Respir. J. 30 (5): 1014-1017. PMID 17978158. 
24. ^ Kuijken I and Bouwes Bavinck J N. (2000). "Skin cancer risk associated with immunosuppressive therapy in organ transplant recipients: epidemiology and proposed mechanisms.". BioDrugs. 14 (5): 319-329. PMID 18034576. 
25. ^ Leone G, Pagano L, Ben-Yehuda D and Voso M T. (2007). "Therapy-related leukemia and myelodysplasia: susceptibility and incidence.". Haematologica. 92 (10): 1389-1398. PMID 17768113. 
26. ^ Mortimer K, Brown A, Feary J, et al (2006). "Dose-ranging study for trials of therapeutic infection with Necator americanus in humans". Am. J. Trop. Med. Hyg. 75 (5): 914–20. PMID 17123987. 
27. ^ UI Study Finds Worm Eggs Help Patients With Severe Bowel Disorders - University News Service - The University of Iowa. Retrieved on 2007-10-01.
28. ^ eMedicine - Hookworm Infection : Article by Christopher M Watson, MD. Retrieved on 2007-10-01.







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