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Trichuris suis therapy in Crohn's disease
R W Summers, D E Elliott, J F Urban, Jr, R Thompson and J V Weinstock Updated information and services can be found at: These include: This article cites 16 articles, 7 of which can be accessed free at: 5 online articles that cite this article can be accessed at: You can respond to this article at: Receive free email alerts when new articles cite this article - sign up in the box at the top right corner of the article Articles on similar topics can be found in the following collections To order reprints of this article go to: INFLAMMATORY BOWEL DISEASE Gut 2005;54:87–90. doi: 10.1136/gut.2004.041749 See end of article for authors' affiliations Background: Crohn's disease is common in highly industrialised Western countries where helminths are rare and uncommon in less developed areas of the world where most people carry worms. Helminthsdiminish immune responsiveness in naturally colonised humans and reduce inflammation in experimental Correspondence to: Dr R W Summers, James A colitis. Thus exposure to helminths may help prevent or even ameliorate Crohn's disease.
Clifton Center for Digestive Aims: The aim of the study was to determine the safety and possible efficacy of the intestinal helminth Diseases, Department of Trichuris suis in the treatment of patients with active Crohn's disease.
Internal Medicine, University of Iowa Roy J Patients: Twenty nine patients with active Crohn's disease, defined by a Crohn's disease activity index and Lucille A Carver (CDAI) >220 were enrolled in this open label study.
College of Medicine, 200 Methods: All patients ingested 2500 live T suis ova every three weeks for 24 weeks, and disease activity Hawkins Drive, Iowa City, was monitored by CDAI. Remission was defined as a decrease in CDAI to less than 150 while a response was defined as a decrease in CDAI of greater than 100.
Results: At week 24, 23 patients (79.3%) responded (decrease in CDAI .100 points or CDAI ,150) and21/29 (72.4%) remitted (CDAI ,150). Mean CDAI of responders decreased 177.1 points below Revised version received baseline. Analysis at week 12 yielded similar results. There were no adverse events.
Accepted for publication Conclusions: This new therapy may offer a unique, safe, and efficacious alternative for Crohn's disease management. These findings also support the premise that natural exposure to helminths such as T suis affords protection from immunological diseases like Crohn's disease.
Crohn's disease is a chronic relapsing inflammatory aminotransferase and alanine aminotransferase ,100U/dl, reaction that may affect any part of the gastrointestinal tract. It is common in parts of the world where ,40 mg/dl, serum creatinine ,2.0 mg/dl, and stool exam- helminthic colonisation is rare and uncommon in those ination negative for pathogens or Clostridium difficile toxin.
areas where most people carry worms.1 It appears to result Women had a negative pregnancy test and practised birth from an inappropriate immune response to normal gut flora.
Helminths down-modulate the host immune response to .50 cm, obstructive symptoms, or anticipated need for unrelated antigens,2–4 a property that could be beneficial in surgery were excluded. They were not enrolled if (1) Crohn's disease. Helminths reduce inflammation in experi- treatment in the last 12 weeks included cyclosporine, mental murine colitis.1 5–7 Trichuris suis, the porcine whip- worm, is similar to human whipworm T trichiura. Ingestion of agents, (2) treatment in the last two weeks included T suis ova results in short term self limited colonisation of antibiotics, antifungal, or antiparasitic medications, and (3) humans.8 We therefore conducted a 24 week clinical trial to they had other diseases that could interfere with compli- evaluate the safety and possible efficacy of live T suis therapy ance or interpretation of the results.
in Crohn's disease.
Specific pathogen free pigs were given T suis ova by gastric gavage. After allowing time for worm maturation, adult worms were isolated from the colon and cultured in vitro.
Patients were enrolled in a 24 week open label study after Ova produced in vitro were collected and allowed to giving informed consent. The University of Iowa Institutional embryonate for 5–6 weeks in phosphate buffered saline Review Board approved the protocol. Subjects with Crohn's containing penicillin/streptomycin/amphotericin B at 22˚C.
disease, as defined by standard clinical, radiological, and The embryonated ova were then made bacteria free using histological criteria, were recruited and followed at the 0.2% K2Cr2O7, washed with sterile saline, and stored at 5˚C in University of Iowa and clinical practices in the State of phosphate buffered saline. Standard viral and bacterial Iowa. Patients 18–72 years old were eligible if they had a cultures were performed on aliquots of ova to assure that Crohn's disease activity index (CDAI) between 220 and 450.9 they contained no pathogens. Pigs were inoculated with A small bowel series and colonoscopy were required within stored ova at regular time intervals to assure that the ova the year before enrolment. Patients continued their Crohn's remained infective. This analysis demonstrated that stored disease medications if they met the following enrolment ova retained viability for at least nine months. Eggs were criteria: (1) mesalamine or derivatives if they had been divided into individual aliquots of 2500. This number of ova receiving it for .8 weeks and the same dose for .4 weeks; was the same as that used in our earlier pilot study.10 Subjects (2) oral prednisone up to 25 mg/day if patients had been returned every three weeks to drink the ova suspended in a receiving it for .8 weeks and the same dose for .4 weeks; commercial drink. The study coordinator witnessed that all of and (3) azathioprine or 6-mercaptopurine (6-MP) if patients the subjects consumed the drink.
had been receiving it for .6 months and the same dose for.8 weeks. Before enrolment, patients had to have ahaemoglobin concentration of .10.0 g/dl, white blood count Abbreviations: CDAI, Crohn's disease activity index; 6-MP, 6- of 5000–15 000/mm3, platelet count .150 000/mm3, no iron or mercaptopurine; DNBS, ditrinitrobenzene sulphonic acid; TNBS, vitamin B12 deficiency, total bilirubin ,1.5 mg/dl, aspartate trinitrobenzene sulphonic acid Summers, Elliott, Urban, et al Table 1 Baseline characteristics of the patients* No of patients (n = 29) Smoking status (yes/total) Median duration of disease (y) Small bowel and colon Medications at entry Figure 1 (A) Percentage of patients achieving remission or response at week 12 or 24 after initiating ova therapy. (B) Mean change in Crohn's disease activity index (CDAI, mean (SD)) for respondents to ova therapy.
CDAI ,150 is remission. p,0.0001, week 12 or week 24 compared with baseline (time 0).
CDAI, Crohn's disease activity index; 6-MP, 6-mercaptopurine.
(fig 1A). Mean initial CDAI of responders was 287.1 (47.8). Itdecreased to 92.0 (49.2) at week 12 and 99.9 (35.6) at week Patients kept daily diaries of clinical symptoms. Dosing of 24 (fig 1B). Thus the mean improvement in CDAI for these all other inflammatory bowel disease medications was held patients was 195.1 and 187.2 at weeks 12 and 24, constant. The following were obtained at entry and every six respectively. There were six patients with a baseline CDAI weeks: medical history and physical examination, pregnancy between 250 and the minimum entry criterion of 220. All six test, complete blood count, liver profile, and stool examina- achieved both a response (improvement in CDAI of .100) tion for ova, pathogens, and C difficile toxin. Means (SD) are and remission (CDAI ,150).
given. Medians are presented with interquartile range. The We performed subset analysis of patient characteristics two tailed Fisher's exact test was used to examine patient looking for predictors of outcomes. Sex, patient age, disease characteristics that might predict response or remission.
duration, smoking status, or disease location did notinfluence the frequency of response or remission. There was a trend for patients using immunosuppressive drugs toimprove to a greater degree than those not using these A total of 29 patients were enrolled and their baseline agents (table 2). Also, patients with a prior history of characteristics are shown in table 1. Most patients had terminal ileum resection were less responsive.
longstanding disease (median 3.9 (1.5–6.8) years) and wererefractory to standard inflammatory bowel disease therapybefore enrolment. Fourteen patients were on corticosteroids and/or azathioprine/6-MP. Only 5/29 (17%) were on no Human helminthic parasites were considered as a therapeutic medications; of these, 10 previously had tried corticosteroids option. Many could not be used because there are no and/or other immunosuppressants (azathioprine, 6-MP, available sources other than a human carrier. Eggs from infliximab). Mean CDAI was 294, indicating that patients such a source would risk inadvertent transmission of were moderately ill. The cohort included patients with pathogenic microbial agents. Also, some human helminths anatomical disease distribution similar to that of the have disease potential or raise public health concerns.
Crohn's disease population at large.
Trichuris species are helminths with favourable character- Patients were compliant with the protocol; all patients istics for therapeutic use. Their life cycle minimises the risk of completed their symptom diaries, attended all clinic visits, inadvertent colonisation. Trichuris ova mature in the soil and and received all doses of the ova. None was lost to follow up.
are ingested by the host. Ova hatch in the duodenum, Four withdrew at or before week 12 because of ongoing releasing larvae that ultimately grow in 6–8 weeks into adult disease activity, and one withdrew between weeks 12 and 24 worms. They migrate to the terminal ileum and colon but do because of pregnancy. Ongoing disease activity was defined not invade the host. Worms can remain viable for 1–2 years as failure to respond or achieve remission and these in the natural host. Adult worms release ova that are shed individuals are included in the analysis. There was no into the stool. These ova are immature and are not capable of indication that the ova therapy made any patient more ill, colonising another host until they incubate in the soil for and there were no side effects or complications attributable to several weeks to allow embryonation.
therapy. Patients developed no new symptoms such as We chose T suis as the helminth to colonise subjects in this nausea, vomiting, abdominal pain, or worsening of diar- study. T suis, the porcine whipworm, is genetically related to T rhoea. There was no deterioration in CDAI in the four trichiura, the human whipworm. T suis is not a natural human patients that withdrew before week 12. Analysis of laboratory parasite but it has been shown experimentally to colonise data collected during the study showed no significant humans briefly without causing disease.8 The ova can be changes in complete blood count or differential, blood urea produced using pathogen free pigs, and processed to assure nitrogen or creatinine, or aspartate aminotransferase, alanine absence of biological contaminants.
aminotransferase, or alkaline phosphatase. All stool speci- Treatment with T suis ova for 24 weeks yielded a response mens were negative for ova and parasites.
rate of nearly 80% and a remission rate of nearly 73%, which At week 12, 22 patients (75.9%) responded (decrease in was much greater than the anticipated placebo effect.11–14 This CDAI .100 points or CDAI ,150) and 19/29 (65.5%) were in was particularly notable as many patients had refractory remission (CDAI ,150). At week 24, 23 patients (79.3%) disease. Thus T suis ova therapy may produce substantial and experienced a response and 21/29 (72.4%) were in remission sustained improvement in active Crohn's disease. However, Helminth ova therapy in Crohn's disease Table 2 Subset analysis of patient characteristics for response and remission Current smoking status Small bowel and colon Use of immuosuppressives* *Immunosuppressives = corticosteroids, azathioprine, or 6-mercaptopurine.
the study was open label, and we cannot exclude a high Colonisation with helminths augments several immuno- placebo effect. The treatment caused no side effects or regulatory pathways that limit Th1-type inflammation.
complications even in patients receiving multiple immuno- Helminths induce production of interleukin 4 and interleukin suppressants (for example, corticosteroids and azathioprine/ 13, which are Th2 cytokines. This Th2 response inhibits 6-MP), suggesting a high safety profile.
production of Th1 cytokines thereby reducing colitis severity.6 Subset analysis of the data suggested that patients on Helminths also induce regulatory T cells and immune immunosuppressive therapy faired better, as did patients regulatory substances such as transforming growth factor b, with an intact terminal ileum. We can only speculate on the interleukin 10, and prostaglandin E2 that assist in maintain- reason for these observations. It is possible that immuno- ing host mucosal homeostasis.4 suppressives could have influenced T suis colonisation. Also, In summary, T suis is well tolerated and appears efficacious there could have been a synergistic interaction between for Crohn's disease in this open label trial. Helminths the immunomodulatory effect of the helminths and the probably inhibit intestinal inflammation by mechanisms immunosuppressive effect of the other drugs. Terminal ileal different from current medications. Helminths may offer an resection also could have affected worm colonisation, or easy to administer alternative or supplement to currently perhaps residual symptoms from the surgery confounded available therapeutic agents. These results justify a double CDAI scoring. Both of these observations need confirmation blind controlled clinical trial. Furthermore, these results in a prospective trial to assure that they were not artefacts.
support the hypothesis that helminthic exposure provides There is an immunological basis to expect that exposure to protection against some immune mediated inflammatory helminths such as T suis will prove beneficial in Crohn's disease like Crohn's disease.
disease. Crohn's disease involves over reactive Th1 pathways,and helminths blunt Th1 responses. For example, helminths attenuate intestinal inflammation in animal models of The authors gratefully acknowledge the support of Betty Musgrave, inflammatory bowel disease. Interleukin 10 deficient mice clinical research coordinator. Drs Miriam B Zimmerman and William spontaneously develop a Th1-type colitis characterised by Clarke, Department of Biostatistics provided assistance with studydesign, statistical methods, and data analysis. Additional participat- infiltration of the lamina propria with interferon c producing ing University of Iowa gastroenterologists included Drs Jeffrey Field, CD4+ T cells.15 Colonisation with T muris or Heligmosomides Khurram Qadir, and David Ramkumar. Collaborating gastroenterol- polygyrus retards development of colitis in interleukin 10 ogists from the State of Iowa included: Drs Dean Abramson, Nile deficient mice.1 Mice and rats treated with di- or trinitro- Dusdieker, Joseph Ewing, Jon Gibson, Bernard Leman, Randall benzene sulphonic acid (DNBS, TNBS) develop a Th1 Lengeling, Sudhakar Misra, James Piros, Douglas Purdy, Leon Qiao, cytokine driven colitis that shares features with Crohn's Surish Reddy, Robert Silber, Joseph Truszkowski, and Gary disease.16 Mice and rats exposed to Schistosoma mansoni are resistant to TNBS colitis.6 7 Colonisation of mice with The Crohn's and Colitis Foundation of America provided the primary support for this study. The Broad Medical Research Program Trichinella spiralis diminishes DNBS induced colits.5 This of the Eli and Edythe L Broad Foundation, the Ed and Liliane protection is associated with decreased systemic and colonic Schneider Family Foundation, and the Thomas Irwin Memorial Fund interferon c and interleukin 12 expression, which are also provided partial support. The study sponsors had no involvement critically important Th1 cytokines.
in the study design, collection, analysis, and interpretation of the


Summers, Elliott, Urban, et al data, in the writing of the report; or in the decision to submit the 6 Elliott DE, Li J, Blum A, et al. Exposure to schistosome eggs protects mice from paper for publication.
TNBS colitis. Am J Physiol 2003;284:G385–91.
7 Moreels TG, Nieuwendijk RJ, De Man JG, et al. Concurrent infection with Schistosoma mansoni attenuates inflammation induced changes in colonicmorphology, cytokine levels, and smooth muscle contractility of Authors' affiliations trinitrobenzene sulphonic acid induced colitis in rats. Gut 2004;53:99–107.
R W Summers, D E Elliott, R Thompson, J V Weinstock, James A Clifton 8 Beer RJ. The relationship between Trichuris trichiura (Linnaeus 1758) Center for Digestive Diseases, Department of Internal Medicine, of man and Trichuris suis (Schrank 1788) of the pig. Res Vet Sci University of Iowa Roy J and Lucille Carver College of Medicine, 9 Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease University of Iowa, Iowa City, Iowa, USA activity index. National Coorperative Crohn's Disease Study.
J F UrbanJr, Nutrient Requirements and Functions Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United 10 Summers RW, Elliott DE, Qadir K, et al. Trichuris suis seems to be safe and States Department of Agriculture, Beltsville, Maryland, USA possibly effective in the treatment of inflammatory bowel disease.
Am J Gastroenterol 2003;98:2034–41.
Conflict of interest: None declared.
11 Sands BE, Winston BD, Salzberg B, et al. Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn's disease.
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12 Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human 1 Elliott DE, Urban JF Jr, Argo CK, et al. Does the failure to acquire helminthic antibody to TNF (CDP571) for active Crohn's disease: a randomized double- parasites predispose to Crohn's disease? FASEB J 2000;14:1848–55.
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2 Sabin EA, Araujo MI, Carvalho EM, et al. Impairment of tetanus toxoid- 13 Panaccione R, Canadian Consensus Group on the use of infliximab in Crohn's specific Th1-like immune responses in humans infected with Schistosoma disease. Infliximab for the treatment of Crohn's disease: review and mansoni. J Infect Dis 1996;173:269–72.
indications for clinical use in Canada. Can J Gastroenterol 2001;15:371–5.
3 Borkow G, Leng Q, Weisman Z, et al. Chronic immune activation associated 14 Feagan B. Infliximab in the treatment of Crohn's disease. Can J Gastroenterol with intestinal helminth infections results in impaired signal transduction and anergy. J Clin Invest 2000;106:1053–60.
15 Berg DJ, Davidson N, Kuhn R, et al. Enterocolitis and colon cancer in 4 Weinstock JV, Summers R, Elliott DE. Helminths and harmony. Gut interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest 1996;98:1010–20.
5 Khan WI, Blennerhasset PA, Varghese AK, et al. Intestinal nematode infection 16 Neurath MF, Fuss I, Kelsall BL, et al. Antibodies to interleukin 12 abrogate ameliorates experimental colitis in mice. Infect Immun 2002;70:5931–7.
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EDITOR'S QUIZ: GI SNAPSHOT .
Robin Spiller, Editor Vomiting in the recently anticoagulated patientClinical presentationA 42 year old previously healthy man presented with an eighthour history of retrosternal tightness. While clinical exam-ination was unremarkable, his cardiac enzymes were raisedand his electrocardiogram showed ST segment elevation inleads II, III, and aVf. He was diagnosed with an acute inferiormyocardial infarction and received 1.5 million units ofstreptokinase over the next hour. His pain settled and hewas comfortable overnight.
The following morning he developed epigastric pain and tenderness and vomited twice. His haemoglobin leveldropped to 12 g/dl (15 g/dl on admission). Although overallhe improved over the next 48 hours, he continued to vomiteven though fasting. An upper gastrointestinal endoscopywas preformed and demonstrated the duodenal abnormalityshown in fig 1.
QuestionWhat is the abnormality shown (fig 1) and what is the mostappropriate course of subsequent treatment?See page 102 for answerThis case is submitted by: R A Cahill, S Siddique, J O'Connor Department of General Surgery, Waterford Regional Hospital, Waterford, Figure 1 Upper gastrointestinal endoscopy.
Correspondence to: Mr R Cahill, Department of General Surgery, Waterford Regional Hospital, Waterford, Ireland; rcahill@rcsi.ie

Source: http://lumen.lumc.edu/lumen/MedEd/hostdef/ARTICLES1/worms%20to%20the%20rescue.pdf

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