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A proof of concept study establishing Necator americanus in Crohn's
patients and reservoir donors

J Croese1, J O'Neil2, J Masson3, S Cooke3, W Melrose4, D Pritchard5
and R Speare6
1 Department of Gastroenterology, Townsville Hosptial, Townsville,
Australia
2 Department of Gastroenterology, Royal Brisbane Hospital, Brisbane,
Australia
3 Department of Gastroenterology, Townsville Hosptial, Townsville,
Australia
4 School of Public Health, Tropical Medicine and Rehabilitation
Sciences, James Cook University, Townsville, Australia
5 Boots Science Building, School of Pharmacy, University of
Nottingham, Nottingham, UK
6 School of Public Health, Tropical Medicine and Rehabilitation
Sciences, James Cook University, Townsville, Australia

Correspondence to:
Dr J Croese
Department of Gastroenterology, Townsville Hosptial, Townsville, Q
4814, Australia; jcro...@bigpond.com

Keywords: Necator americanus; hookworms; Crohn's disease;
autoimmunity.

The emergence of autoimmunity, including Crohn's disease (CD) where
the immune relationship with commensal bacteria is corrupted, has been
linked to hygiene.1,2 A gradual decline in endoparasites is but one
argument that might explain this phenomenon.3 Weinstock and colleagues
have successfully tested the pig whipworm, Trichuris suis, in patients
with inflammatory bowel disease (IBD).4,5 However, repeated
inoculation was required and concern has been raised that aberrant
migration could occur.6 The haematophagous hookworm, Necator
americanus (NA), is proposed as an alternative. We have tested if CD
patients tolerate hookworm infection, and the practical issues
associated with establishing reservoir donors (RDs).

Over 700 million people remain infected with hookworms. Infective
larvae (L3i) are acquired through skin contact with contaminated soil.
7 Auto-reinfection, direct person to person infection, aberrant
migration, and hypobiosis do not occur. Adult worms live in the host
small intestine for an average of five years. Infection can be easily
terminated with an anthelminthic. Anaemia is the only disease of
consequence but is an unusual outcome in properly nourished
individuals. Using L3i originally obtained from Madang, Papua New
Guinea, but maintained in a healthy researcher in the UK, five CD
subjects with longstanding but mostly inactive disease and three RDs
each received a carefully measured inoculum (table 1). Subsequently,
four additional CD subjects with chronic and mostly active disease
were inoculated with L3i cultured from faeces provided by an RD, and
the original CD cohort were reinoculated from week 27 to week 30.
Ethics approval was granted by the Townsville Health Service District
Institutional Ethics Committee. Haematological and clinical
measurements are expressed as mean (95% confidence interval).

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        Table 1  Crohn's disease activity index (CDAI) in CD subjects
inoculated with infective larvae (L3i). Subsequently, the five CD
subjects first inoculated were reinoculated from week 27 to week 30
and four CD subjects with chronic and mostly active disease were
inoculated with larvae sourced from one of the authors

The inoculation caused a mild itch within five minutes that
disappeared after a few days in eight CD subjects and a pruritic rash
that lasted two weeks in the RDs, who also developed a painful
transient enteropathy. Neither respiratory symptoms nor detectable
aberrant migration occurred. In the CD cohort, blood eosinophilia
developed from week 5 (mean 2.60x109/l (1.89) v week 1 0.18x109/l
(0.10) v week 20 0.59 (0.20)). Patent infection had established by
week 20 in all cases. CD activity index (CDAI) remained unchanged
until week 17, possibly in part due to a hookworm related enteropathy
recognisable because of blood eosinophilia and faecal Charcot-Leydon
crystals.8 After 20 weeks, the IBD questionnaire was improved (mean
151 (14) v 179 (20)) and the four week cumulated CDAI scores was
decreased (mean 141 (31) v 87 (15)).9 Haemoglobin fell marginally
(week 1 mean 135.6 (7.8) g/l v week 20 129.3 (4.1) g/l). Reinoculation
of the five CD subjects first exposed caused no apparent adverse
effect. Disease reactivation, as defined by a CDAI >150, occurred in
two (CD4, CD5; table 1) after the doses of long term immune
suppressive drugs had been reduced. The subject (CD3-7) driven trend
was to reduce immune suppression as health improved, a strategy often
associated with worsening of symptoms. The five CD subjects first
inoculated were in remission at week 45 (fig 1).

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        Figure 1  Initial Crohn's disease activity index (CDAI) score for
each CD patient versus score at week 20 and at week 45 for the first
five inoculated cases (mean 165 (95% confidence interval 145) v 64
(25), p = 0.132; mean 165 v 75 (29), p = 0.246).

Our pilot study has established a potential for NA, already a fact of
life for many millions, as a candidate parasite to inoculate those
with autoimmune disease. The natural advantages are lifecycle and
migration predictability, ability to control the size of and eliminate
a colony, and the parasite's longevity. Inoculation proved safe, even
in immune suppressed patients. Our hope that NA would suppress
autoreactivity sufficiently to allow immune suppressive therapy to be
stopped was unrealistic. Recent and compelling evidence has shown that
IBD is self sustaining.10 It may be that after remission is achieved,
endoparasites will offer an alternative or adjunct to immune
suppressive therapy, a priority for some people with CD.

FOOTNOTES
Conflict of interest: None declared.

References

Bach JF. The effect of infections on susceptibility to autoimmune and
allergic diseases. N Engl J Med 2002;347:911-20.[Free Full Text]
Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417-29.
[Free Full Text]
Weinstock JV, Summers RW, Elliott DE, et al. The possible link between
de-worming and the emergence of immunological disease. J Lab Clin Med
2002;139:334-8.[Medline]
Summers RW, Elliott DE, Urban JF, et al. Trichuris therapy for active
ulcerative colitis: a randomised trial. Gastroenterology 2005;128:825-
32.[CrossRef][Medline]
Summers RW, Elliott DE, Urban JF Jr, et al. Trichuris suis therapy in
Crohn's disease. Gut 2005;54:87-90.[Abstract/Free Full Text]
Van Kruiningen HJ, West AB. Potential danger in the medical use of
Trichuris suis for the treatment of inflammatory disease. Inflamm
Bowel Dis 2005;11:515.[CrossRef][Medline]
Hotez PJ, Brooker S, Bethony JM, et al. Hookworm infection. N Engl J
Med 2004;351:799-807.[Free Full Text]
Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's
disease activity index. National Cooperative Crohn's Disease Study.
Gastroenteroogy 1976;70:439-44.
Guyatt G, Mitchell A, Irvine EJ, et al. A new measure of health status
for clinical trials in inflammatory bowel disease. Gastroenterology
1989;96:804-10.[Medline]
Faubion WA, de Jong YP, Molina AA, et al. Colitis is associated with
thymic destruction attenuating CD4+25+ regulatory T cells in the
periphery. Gastroenterology 2004;126:1759-71.[CrossRef][Medline]