Helminthic therapy

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A Necator americanus larva Necator Americanus L3 x1000 12-2007.jpg
A Necator americanus larva

Helminthic therapy, an experimental type of immunotherapy, is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth or with the eggs of a helminth. [1] Helminths are parasitic worms such as hookworms, whipworms, and threadworms that have evolved to live within a host organism on which they rely for nutrients. [2] The theory behind helminth therapy is that these worms reduce negative immune responses due to their TH2 immune response that downregulates the abnormal T-cell responses recently associated with autoimmune disorders. [3] This therapy ties to the Hygiene hypothesis in that the lack of exposure to bacteria and parasites such as helminths can cause a weaker immune system leading to being more susceptible to autoimmune disease. [4] [5]

Contents

Helminth worms are members of two phyla: nematodes, which are primarily used in human helminthic therapy, and flat worms (trematodes). [2] Helminthic therapy consists primarily of the inoculation of the patient with specific parasitic intestinal nematodes (or other helminths). A number of such organisms are currently being investigated for their use as treatment, including: Trichuris suis ova, [6] [7] commonly known as pig whipworm eggs; Necator americanus , [8] commonly known as hookworms; Trichuris trichiura ova, [9] commonly referred to as human whipworm eggs; and Hymenolepis diminuta , commonly known as rat tapeworm.

While the latter four species may be considered to be mutualists – providing benefit to their host without causing long term harm – there are other helminth species that have demonstrated therapeutic uses, but these have a potential to cause harmful side effects, and therefore do not share the ideal characteristics for a therapeutic helminth. [10] These include Ascaris lumbricoides , [11] [12] commonly known as human giant roundworm; Strongyloides stercoralis , [11] [12] commonly known as human roundworm; Enterobius vermicularis , [11] [12] commonly known as pinworm or threadworm; and Hymenolepis nana , [11] [12] also known as dwarf tapeworm.

Current research targets Crohn's disease, ulcerative colitis, inflammatory bowel disease, coeliac disease, multiple sclerosis and asthma.

Helminth infection has emerged as one possible explanation for the low incidence of autoimmune diseases and allergies in less developed countries, while reduced infection rates have been linked with the significant and sustained increase in autoimmune diseases seen in industrialized countries. [13] [14] [5] [15]

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 is not a result of genetic changes in humans; the increased rate of autoimmune-related diseases in the industrialized world is occurring in too short a time to be explained in this way. There is evidence that one of the primary reasons for the increase in autoimmune diseases in industrialized nations is the significant change in environmental factors over the last century. [16] It is posited 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 and industrialized Western nations. [17] [4]

Lack of exposure to naturally occurring pathogens and parasites may result in an increased incidence of autoimmune diseases. Correlational data has shown the prevalence of helminthic infections to be greatest south of the equator where the rates of autoimmune diseases such as multiple sclerosis are low. [18] [19] This is consistent with the hygiene hypothesis which suggests that helminthic infections protect individuals from developing auto-immune diseases rather than being an agent responsible for inducing them. [13] [20] [21] A complete explanation of how environmental factors play a role in autoimmune diseases has still not been proposed. Epidemiological studies such as the meta-analysis by Leonardi-Bee et al., [13] however, have helped to establish the link between parasitic infestation and their protective role in autoimmune disease development.

Hypotheses

Although the mechanism(s) of autoimmune disease development is(are) not fully understood, there is broad agreement that the majority of autoimmune diseases are caused by inappropriate immunological responses to innocuous antigens; these are generally called the hygiene hypothesis, but exist in several variants.

One version proposes that the dysfunction is driven by a branch of the immune system known as the T helper cells (Th or TH). Two other refinements to the hygiene hypothesis exist: The "old friends" hypothesis, [22] and the "microbiome depletion" hypothesis. [23]

TH1 vs. TH2 response regulation

Extra-cellular antigens primarily trigger the TH2 response, as observed with allergies, while intracellular antigens trigger a TH1 response. Th cells can be divided into subtypes based on the characteristic cytokines they secrete. [24] TH2 immune responses result in the release of cytokines associated with inflammation reduction such as interleukin 4, interleukin 5, and interleukin 10.

These cytokines are thought to reduce the symptoms of many autoimmune disorders. [24] Conversely, TH1 immune responses are characterized by the cytokines interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα), both of which are thought to increase inflammation and worsen the progression of autoimmune diseases and their symptoms. [24] The antagonism between these two types of immune response is a central theme of one proposal for the biological basis of the hygiene hypothesis, which suggests that there is a regulatory action between the two types of response.

The observation that allergies and autoimmune response are increasing at a similar rate in industrialized nations appears to undermine this explanation of hygiene hypothesis. [25]

Learned appropriate response

The hygiene hypothesis proposes that appropriate immune response is in part learned by exposure to micro-organisms and parasites, and in part regulated by their presence. In industrialized nations, humans are exposed to somewhat lower levels of these organisms, potentially resulting in unbalanced immune systems.

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, humans' exposure to benign and apparently beneficial parasites has also been reduced commensurately. [26]

The central thrust of the hypothesis is, therefore, that correct development of regulatory T cells in individuals may depend on exposure to organisms such as lactobacilli, various mycobacteria, and helminths. [15] Lack of exposure to sufficient benign antigens, particularly during childhood, is sometimes suggested as a cause of the increase in autoimmune diseases and diseases for which chronic inflammation is a major component in the industrialized world.

Old friends' hypothesis

The old friend's hypothesis modifies the hygiene hypothesis by proposing that regulatory T cells can only become fully effective if they are stimulated by exposure to microorganisms and parasites that have low levels of pathogenicity and that have coexisted universally with human beings throughout our evolutionary history. [22] This hypothesis has recently been given more credibility by a study demonstrating the impact of infectious organisms, and helminths in particular, upon genes responsible for the 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. [27]

Microbiome depletion hypothesis

The microbiome depletion hypothesis posits that the absence of an entire class of organisms from the human inner ecology is a profound evolutionary mismatch that destabilizes the immune system, resulting in disease: The microbiome is "depleted". [23] The way to correct the dysregulation is to "reconstitute", or replenish, keystone species in healthy individuals prior to the development of human diseases of modern living.

As keystone organisms, helminths are central to correcting immune dysregulation, and their replenishment may prevent disease. [28] The biome depletion hypothesis departs from a drug model approach, which remains the current focus of helminthic therapy as evidenced by numerous clinical trials now underway for existing disease states.

Proposed mechanism of action

Experimental data support the hypothesis that clinically induced helminthic infections have the ability to alleviate or mitigate immune responses. [7] [11] [12] [21] [10] Most autoimmune disorders are believed to involve hyperactive TH1 or TH17 immune responses that are down-regulated by the promotion of a TH2 response by helminths. [3] Helminths secrete immunoregulatory molecules that promote the induction of regulatory T cells while inhibiting the function of antigen presenting cells and other T cells. [2] As such, helminthic therapy attempts to restore homeostasis by shifting a hyperactive TH1 pro-inflammatory response to a TH2 response with reduced inflammation. [24]

Human and animal studies have provided evidence of decreased TH1 and TH17 immune responses with a shift to TH2 cytokine production resulting in significantly decreased levels of interleukin 12 and IFNy with simultaneous increases in the regulatory T cells, interleukin 4, interleukin 5 and interleukin 10 of test subjects. [7] [11] [12] [21] These observations indicate that helminth therapy can provide protection against autoimmune disease not only through prevention, since helminths can be present before autoimmune disease develops, but also after autoimmune responses are initiated. [12] Furthermore, responses of type-2 T helper cells rarely kill the parasitic worms. [2] Rather, the TH2 response limits the infection by reducing the viability and reproductive capacity of the parasite. [2]

Given the down regulation of TH1 and TH17 immune responses with helminthic therapy, immune responses to other pathogens and allergens may be suppressed. [2] Consequently, unmonitored and uncontrolled helminthic infections may be associated with suppressed immunity to the viruses and bacteria that normally trigger TH1 and TH17 immune responses required for protection against them, leading to illness or disease. [2]

Research

Evidence in support of the idea that helminthic infections reduce the severity of autoimmune diseases is primarily derived from animal models. [21] Studies conducted on mice and rat models of colitis, multiple sclerosis, type 1 diabetes, and asthma have shown helminth-infected subjects to display protection from the disease. [2] The first clinical studies of helminthic therapy on humans started in 2003 with the use of Trichirus suis. [29] While helminths are often considered a homogenous group, considerable differences exist between species and the species used in clinical research varies between human and animal trials. As such, caution must be exercised when interpreting the results from animal models. [21]

Helminthic therapy is currently being studied as a treatment for several (non-viral) autoimmune diseases in humans including celiac disease, [30] [31] Crohn's disease, [32] [33] [34] [35] multiple sclerosis, [11] [36] ulcerative colitis, [37] and atherosclerosis. [38] It is currently unknown which clinical dose or species of helminth is the most effective method of treatment. Hookworms have been linked to reduced risk of developing asthma, while Ascaris lumbricoides (roundworm infection) was associated with an increased risk of asthma. [13] Similarly, Hymenolepis nana, Trichuris trichiura, Ascaris lumbricoides, Strongyloides stercoralis, Enterobius vermicularis, and Trichuris suis ova have all been found to lower the number of symptom exacerbations, reduce the number of symptom relapses, and decrease the number of new or enlarging brain lesions in patients with multiple sclerosis at doses ranging from 1,180 to 9,340  eggs per gram. [7] [11] [12] However, Ascaris lumbricoides , Strongyloides stercoralis and Enterobius vermicularis are not considered suitable for therapeutic use in humans because they do not meet the criteria for a therapeutic helminth. [10]

Trichuris suis ova has been used in most cases to treat autoimmune disorders because it is thought to be non-pathogenic in humans and therefore has been presumed safe. [10] [39] The use of Trichuris suis ova has been granted by the USA Food and Drug Administration as an investigational medicinal product (IMP). [40] A patient will ingest the eggs so the worms can colonize the caecum and colon of the human gut for a short period of time and provide treatment. The beneficial effect is temporary because the worms only live for a few weeks. Because of this short life span, treatments need to be repeated at intervals. Trichirus suis removes any wider public health issues due to species-specificity and lack of chronic infection. [29]

The hookworm Necator americanus has been granted an IMP license by the Medicines and Healthcare Regulatory Authority in the U.K. [41] Necator americanus larvae are administered percutaneously and migrate through the vasculature and lungs to the small intestine. They feed on the blood from the mucosa. [29] This hookworm is likely to be relatively safe, [42] although it can cause temporary gastrointestinal side effects, especially following the initial inoculation, or with increased doses. [10] High doses can also cause anemia. [29]

The general ideal characteristics for a therapeutic helminth are as follows: [10]

While the research is still rudimentary and the treatment is still being studied, helminthic therapy is a viable option as of current due to its lowered cost and seemingly high effectiveness in comparison to other treatments. [43]

Potential side effects

Helminths are extremely successful parasites capable of establishing long-lasting infections within a host. [2] During this time, helminths compete with the host organism's cells for nutrient resources and thus possess the potential to cause harm. [2] However, the number of organisms hosted by individuals undergoing helminthic therapy is very small and any side effects are typically only encountered in the first three months of infection. In the long term, the vast majority of clinically infected individuals are asymptomatic, with no significant nutrient loss. In fact, nutrient uptake can be enhanced in some subjects who are hosting a small number of helminths. [44] If the side effects from helminthic therapy were to become unmanageable, they can be alleviated by the use of anti-helminthic medications. [2] [11] [12] The most common clinical symptoms which may be encountered while undergoing helminthic therapy can include:

Outside of these initial symptoms that can arise, there are other worries attached to using live helminth parasites as treatment including:

Self-Administration

Social media has brought helminth therapy to the forefront of treatment discussion with many false claims and misinformation. Due to this increased online discussion on Helminth therapy, many people struggling with autoimmune diseases have turned to self-administering parasites to treat themselves. Patients have begun to travel or look in the black market to purchase helminths, as the treatment is still in testing stages and generally discouraged by most medical professionals. [45] [46]

See also

Related Research Articles

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

<i>Trichuris trichiura</i> Parasitic roundworm that causes intestinal infection

Trichuris trichiura, Trichocephalus trichiuris or whipworm, is a parasitic roundworm that causes trichuriasis when it infects a human large intestine. It is commonly known as the whipworm which refers to the shape of the worm; it looks like a whip with wider "handles" at the posterior end. The helminth is also known to cause rectal prolapse.

<span class="mw-page-title-main">Trichuriasis</span> Infection by Trichuris trichiura (whipworm)

Trichuriasis, also known as whipworm infection, is an infection by the parasitic worm Trichuris trichiura (whipworm). If infection is only with a few worms, there are often no symptoms. In those who are infected with many worms, there may be abdominal pain, fatigue and diarrhea. The diarrhea sometimes contains blood. Infections in children may cause poor intellectual and physical development. Low red blood cell levels may occur due to loss of blood.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

In medicine, the hygiene hypothesis states that early childhood exposure to particular microorganisms protects against allergies by properly tuning the immune system. In particular, a lack of such exposure is thought to lead to poor immune tolerance. The time period for exposure begins before birth and ends at school age.

<span class="mw-page-title-main">Helminthiasis</span> Any macroparasitic disease caused by helminths

Helminthiasis, also known as worm infection, is any macroparasitic disease of humans and other animals in which a part of the body is infected with parasitic worms, known as helminths. There are numerous species of these parasites, which are broadly classified into tapeworms, flukes, and roundworms. They often live in the gastrointestinal tract of their hosts, but they may also burrow into other organs, where they induce physiological damage.

<span class="mw-page-title-main">Colitis</span> Inflammation of the colon (large intestine)

Colitis is swelling or inflammation of the large intestine (colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.

<span class="mw-page-title-main">Hookworm infection</span> Disease caused by intestinal parasites

Hookworm infection is an infection by a type of intestinal parasite known as a hookworm. Initially, itching and a rash may occur at the site of infection. Those only affected by a few worms may show no symptoms. Those infected by many worms may experience abdominal pain, diarrhea, weight loss, and tiredness. The mental and physical development of children may be affected. Anemia may result.

<i>Necator americanus</i> Species of hookworm

Necator americanus is a species of hookworm commonly known as the New World hookworm. Like other hookworms, it is a member of the phylum Nematoda. It is an obligatory parasitic nematode that lives in the small intestine of human hosts. Necatoriasis—a type of helminthiasis—is the term for the condition of being host to an infestation of a species of Necator. Since N. americanus and Ancylostoma duodenale are the two species of hookworms that most commonly infest humans, they are usually dealt with under the collective heading of "hookworm infection". They differ most obviously in geographical distribution, structure of mouthparts, and relative size.

<span class="mw-page-title-main">Parasitic worm</span> Large type of parasitic organism

Parasitic worms, also known as helminths, are large macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms that are soil-transmitted and infect the gastrointestinal tract. Other parasitic worms such as schistosomes reside in blood vessels.

<i>Heligmosomoides polygyrus</i> Species of roundworm

Heligmosomoides polygyrus, previously named Nematospiroides dubius, is a naturally occurring intestinal roundworm of rodents. It belongs to the family Trychostrongylidae, and male and female worms are morphologically distinguishable. The parasite has a direct lifecycle, with its larval form being the infective stage. H. polygyrus has the ability to establish chronic infections in rodents and alter host immune responses. This nematode is widely used as a gastrointestinal parasitic model in immunological, pharmacological, and toxicological studies.

Immune dysregulation is any proposed or confirmed breakdown or maladaptive change in molecular control of immune system processes. For example, dysregulation is a component in the pathogenesis of autoimmune diseases and some cancers. Immune system dysfunction, as seen in IPEX syndrome leads to immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX typically presents during the first few months of life with diabetes mellitus, intractable diarrhea, failure to thrive, eczema, and hemolytic anemia. unrestrained or unregulated immune response.

<span class="mw-page-title-main">Ancylostomiasis</span> Medical condition

Ancylostomiasis is a hookworm disease caused by infection with Ancylostoma hookworms. The name is derived from Greek ancylos αγκύλος "crooked, bent" and stoma στόμα "mouth".

<span class="mw-page-title-main">Necatoriasis</span> Medical condition

Necatoriasis is the condition of infection by Necator hookworms, such as Necator americanus. This hookworm infection is a type of helminthiasis (infection) which is a type of neglected tropical disease.

<i>Trichuris suis</i> Species of roundworm

Trichuris suis is a whipworm; the variations in thickness of the anterior and posterior segments give the parasite the characteristic "whip-like" appearance. Adult females measure 6 to 8 cm and adult males 3 to 4 cm. T. suis eggs are oval and yellow-brown with bipolar plugs. T. suis is also used in helminthic therapy studies.

<span class="mw-page-title-main">TBX21</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX21, also called T-bet, is a protein that in humans is encoded by the TBX21 gene. Though being for long thought of only as a master regulator of type 1 immune response, T-bet has recently been shown to be implicated in development of various immune cell subsets and maintenance of mucosal homeostasis.

<span class="mw-page-title-main">Hookworm vaccine</span>

Hookworm vaccine is a vaccine against hookworm. No effective vaccine for the disease in humans has yet been developed. Hookworms, parasitic nematodes transmitted in soil, infect approximately 700 million humans, particularly in tropical regions of the world where endemic hookworms include Ancylostoma duodenale and Necator americanus. Hookworms feed on blood and those infected with hookworms may develop chronic anaemia and malnutrition. Helminth infection can be effectively treated with benzimidazole drugs, and efforts led by the World Health Organization have focused on one to three yearly de-worming doses in schools because hookworm infections with the heaviest intensities are most common in school-age children. However, these drugs only eliminate existing adult parasites and re-infection can occur soon after treatment. School-based de-worming efforts do not treat adults or pre-school children and concerns exist about drug resistance developing in hookworms against the commonly used treatments, thus a vaccine against hookworm disease is sought to provide more permanent resistance to infection.

The effects of parasitic worms, or helminths, on the immune system is a recently emerging topic of study among immunologists and other biologists. Experiments have involved a wide range of parasites, diseases, and hosts. The effects on humans have been of special interest. The tendency of many parasitic worms to pacify the host's immune response allows them to mollify some diseases, while worsening others.

<span class="mw-page-title-main">Soil-transmitted helminthiasis</span> Roundworm infection contracted from contaminated soil

Soil-transmitted helminthiasis is a type of worm infection (helminthiasis) caused by different species of roundworms. It is caused specifically by those worms which are transmitted through soil contaminated with faecal matter and are therefore called soil-transmitted helminths. Three types of soil-transmitted helminthiasis can be distinguished: ascariasis, hookworm infection and whipworm infection. These three types of infection are therefore caused by the large roundworm A. lumbricoides, the hookworms Necator americanus or Ancylostoma duodenale and by the whipworm Trichuris trichiura.

References

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  31. ↑ Clinical trial number NCT00671138 for "Inoculating celiac disease patients with the human hookworm Necator Americanus: Evaluating immunity and gluten-sensitivity" at ClinicalTrials.gov
  32. ↑ 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. S2CID   73016367.
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  34. ↑ 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. PMC   1774382 . PMID   15591509.
  35. ↑ 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. CiteSeerX   10.1.1.457.8633 . doi:10.1111/j.1572-0241.2003.07660.x. PMID   14499784. S2CID   2605979.
  36. ↑ Tanasescu, Radu; Tench, Christopher; Constantinescu, Cris; Telford, Gary; Singh, Sonika; Frakich, Nanci; et al. (2020). "Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease". Journal of Allergy and Clinical Immunology. 77 (9): 1089–1098. doi: 10.1016/j.jaci.2014.07.022 . PMID   25248819.
  37. ↑ 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. doi: 10.1053/j.gastro.2005.01.005 . PMID   15825065.
  38. ↑ Magen, Eli; Bychkov, Vitaly; Ginovker, Alexander; Kashuba, Eduard (2013). "Chronic Opisthorchis felineus infection attenuates atherosclerosis – an autopsy study". International Journal for Parasitology. 43 (10): 819–24. doi:10.1016/j.ijpara.2013.04.008. PMID   23792298.
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  40. ↑ Elliott, David; Weinstock, Joel V. (2009). "Helminthic Therapy: Using Worms to Treat Immune-Mediated Disease". Pathogen-Derived Immunomodulatory Molecules. Advances in Experimental Medicine and Biology. Vol. 666. pp. 157–66. doi:10.1007/978-1-4419-1601-3_12. ISBN   978-1-4419-1600-6. PMID   20054982.{{cite book}}: |journal= ignored (help)
  41. ↑ Pritchard, D.I. (2011). "Worm therapy: For or against?". Journal of Helminthology. 85 (3): 225–227. doi:10.1017/S0022149X11000204. PMID   21729383. S2CID   31886317.
  42. ↑ "The safety of Necator americanus" . Retrieved 27 March 2017.[ unreliable medical source? ]
  43. 1 2 3 4 5 6 Maruszewska-Cheruiyot, M.; Donskow-Łysoniewska, K.; Doligalska, M. (2018-01-27). "Helminth Therapy: Advances in the use of Parasitic Worms Against Inflammatory Bowel Diseases and its Challenges". Helminthologia. 55 (1): 1–11. doi:10.1515/helm-2017-0048. ISSN   0440-6605. PMC   6799527 . PMID   31662622.
  44. ↑ "Helminthic therapy and nutritional deficiencies" . Retrieved 2017-03-27.[ unreliable medical source? ]
  45. ↑ Donkers, Sarah; Kirkland, Megan; Charabati, Marc; Osborne, Lisa (2024). "Perspectives of People with Multiple Sclerosis About Helminth Immunotherapy". International Journal of MS Care. 26 (Q4): 43–51. doi:10.7224/1537-2073.2019-044. PMC   7041615 . PMID   32123528.
  46. ↑ Liu, J.; Morey, R. A.; Wilson, J. K.; Parker, W. (May 2017). "Practices and outcomes of self-treatment with helminths based on physicians' observations". Journal of Helminthology. 91 (3): 267–277. doi:10.1017/S0022149X16000316. ISSN   1475-2697. PMID   27240605.

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