Helminth therapy (worms) for induction of remission in inflammatory bowel disease

Inflammatory bowel disease (IBD) is comprised of two disorders: ulcerative colitis and Crohn’s disease. These disorders have both distinct and overlapping symptoms, but the underlying cause remains incompletely understood. Standard therapy for IBD includes sulfasalazine, 5-ASA drugs, steroids, immunosuppressives such as azathioprine, 6-mercaptopurine and methotrexate and biological agents such as infliximab. Helminths are worm-like parasites, that inhabit larger organisms. Helminths cause changes in the immune systems of their hosts including an altered immunological response to antigens and this has implications for the treatment of inflammatory bowel disease which is thought to be caused by immune dysregulation.

The purpose of this systematic review was to examine the effectiveness and safety of helminth therapy for inducing remission in people with IBD. This review identified two randomised controlled trials including a total of 90 participants. One study compared twice weekly treatment with helminths (an 0.8 mL solution containing 2500 live eggs of the helminth Trichuris suis) for 12 weeks to a matching placebo (an 0.8 ml identical looking solution with no Trichuris suis eggs) in 54 patients with active ulcerative colitis. Few remissions occurred during the trial and helminth treatment had no detectable effect on these remissions. Ten per cent (3/30) of patients in the helminth group achieved remission compared to four per cent (1/24) of placebo patients. A higher proportion of patients in the helminth group (43% or 13/30) improved clinically compared to the placebo group (17% or 4/24). However, this difference could be a chance effect. We could not determine whether the proportion of patients who had a side effect was higher in either group. No observed side effects were thought to be related to treatment were reported in this study. The other study compared one treatment with various doses of helminths (a solution of 500, 2500 or 7500 Trichuris suis eggs) to a matching placebo in 36 patients with Crohn's disease. This study was designed to assess side effects and did not measure clinical remission or improvement. There amount of information available on side-effects at two weeks was limited and the results were uncertain due to the small number of participants in the study. The only side effect that was judged to be possibly related to the study treatment was dysgeusia (a distortion of the sense of taste). This was reported in one patient in the helminth group and in one patient in the placebo group. Currently, there is insufficient evidence to allow any firm conclusions regarding the effectiveness and safety of helminths used to treat patients with IBD. The only information available relating to clinical improvement in patients with active ulcerative colitis comes from one small study. We do not know how safe helminths are when used in patients with ulcerative colitis and Crohn's disease. Further randomised controlled trials are required to assess the efficacy and safety of helminth therapy in IBD.

Authors' conclusions: 

Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of helminths used to treat patients with IBD. The evidence for our primary efficacy outcomes in this review comes from one small study and is of low quality due to serious imprecision. We do not have enough evidence to determine whether helminths are safe when used in patients with UC and CD. Further RCTs are required to assess the efficacy and safety of helminth therapy in IBD.

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Background: 

Inflammatory bowel disease (IBD) is a chronic, globally-occurring gastrointestinal disorder and a major cause of illness and disability. It is conventionally classified into Crohn’s disease (CD) and ulcerative colitis (UC). Helminths are parasitic worms with complex life cycles involving tissue- or lumen-dwelling stages in their hosts, and causing long-lasting or chronic infections that are frequently asymptomatic. Helminths modulate immune responses of their hosts, and many observational and experimental studies support the hypothesis that helminths suppress immune-mediated chronic inflammation that occurs in asthma, allergy and IBD.

Objectives: 

The objective was to evaluate the efficacy and safety of helminth treatment for induction of remission in IBD.

Search strategy: 

We searched the following databases from inception to 13 July 2013: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register. We also searched four online trials registries, and abstracts from major meetings. There were no language restrictions.

Selection criteria: 

Randomised controlled trials (RCTs) where the intervention was any helminth species or combination of helminth species, administered in any dose and by any route and for any duration of exposure to people with active CD or UC, confirmed through any combination of clinical, endoscopic and histological criteria were eligible for inclusion.

Data collection and analysis: 

Two authors independently extracted data and assessed eligibility using a standardized data collection form. We used the RevMan software for analyses. The primary outcome was induction of remission as defined by the included studies. Secondary outcomes included clinical, histologic, or endoscopic improvement as defined by the authors, endoscopic mucosal healing, change in disease activity index score, change in quality of life score, hospital admissions, requirement for intravenous corticosteroids, surgery, study withdrawal and the incidence of adverse events. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes. We calculated the mean difference (MD) and 95% CI for continuous outcomes. We assessed the methodological quality of included studies using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria.

Main results: 

Two RCTs (90 participants) were included. One trial assessed the efficacy and safety of Trichuris suis (T. suis) ova in patients with UC (n = 54). The other RCT was a phase one that assessed the safety and tolerability of T. suis ova in patients with CD (n = 36). The risk of bias in both studies was judged to be low. In the UC study, during the 12-week study period, participants in the active arm received 2-weekly aliquots of 2500 T. suis eggs, added to 0.8 mL of saline; those in the placebo arm received 0.8 mL saline only. There were sparse data available for the outcomes clinical remission and clinical improvement. Ten per cent (3/30) of patients in the T. suis arm entered remission compared to 4% (1/24) of patients in the placebo arm (RR 2.40, 95% CI 0.27 to 21.63). Forty-three per cent (13/30) of patients in the T. suis group achieved clinical improvement compared to 17% (4/24) of placebo patients (RR 2.60, 95% CI 0.97 to 6.95). The mean ulcerative colitis disease activity index (UCDAI) score was lower in the T. suis group (6.1 +/- 0.61) compared to the placebo group (7.5 +/- 0.66) after 12 weeks of treatment (MD -1.40, 95% CI -1.75 to -1.05). There was only limited evidence relating to the proportion of patients who experienced an adverse event. Three per cent (1/30) of patients in the T. suis group experienced at least one adverse event compared to 12% (3/24) of placebo patients (RR 0.27, 95% CI 0.03 to 2.40). None of the adverse events reported in this study were judged to be related to the study treatment. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission and improvement) as low due to serious imprecision. In the CD study, participants received a single treatment of T. suis ova at a dosage of 500 (n = 9), 2500 (n = 9), or 7500 (n = 9) embryonated eggs or matching placebo (n = 9). The CD study did not assess clinical remission or improvement as outcomes. There were sparse data on adverse events at two weeks. Thirty-seven per cent (10/27) of patients in the T. suis group experienced at least one adverse event compared to 44% (4/9) of placebo patients (RR 0.83, 95% CI 0.35 to 2.01). Only one adverse event (dysgeusia) was judged to be possibly related to treatment in this study. Dysgeusia was reported in one patient in the T. suis group and in one patient in the placebo group.

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