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Background: Allergic rhinitis is a disorder of the nasal membranes and surrounding tissues, and a worldwide cause of illness and disability. Helminths are complex tissue-dwelling or lumen-dwelling organisms that inhabit larger organisms and are frequently asymptomatic. Helminths modulate the natural immune responses of their human hosts, and may prevent or cure immune-mediated or allergic diseases (e.g. allergic rhinitis) in the host. Non-randomised studies support this hypothesis. Objectives: To assess the safety and effectiveness of helminth therapy in people with allergic rhinitis. Search methods: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 24 June 2011. Selection criteria: All randomised controlled trials where the intervention was any helminth species or combination of helminth species, administered to people with allergic rhinitis in any dose, by any route and for any duration of exposure. We accepted both intermittent and persistent allergic rhinitis patients. Data collection and analysis: We independently extracted data and assessed eligibility and risk of bias using a standardised data collection form. We resolved any disagreement through discussion. We combined dichotomous data using risk ratio (RR) and continuous data using mean difference (MD), presenting both with 95% confidence intervals (CI). Main results: We found five reports of two single-centre, placebo-controlled, double-blinded studies (130 participants). Participants in both studies were a mix of adults with either intermittent or persistent allergic rhinitis. Both studies had a low risk of bias. One study, with 12 weeks' follow-up, used a single percutaneous application of 10 Necator americanus (i.e. human hookworm) larvae. The other study, with 24 weeks' follow-up, used three-weekly oral dosing with 2500 Trichuris suis (i.e. pig whipworm) eggs in aqueous suspension. Of 17 outcomes evaluated in this review, eight were positive (i.e. favoured helminths). Participants taking helminths had no reduction in allergic rhinitis symptoms, percentage of well days (i.e. days with minimal symptoms and no use of medication for allergic rhinitis), lung function measures and quality of life scores. Total use of medication for allergic rhinitis (eye drops, nasal sprays, tablets) did not change; however, in the helminth group there was a statistically significant reduction in the percentage of days during the grass pollen season when participants needed to take tablets as rescue medication for their allergic rhinitis symptoms (MD -14.0%, 95% CI -26.6 to -1.40); in a typical 60-day pollen season this 14% reduction translates into 19 days when tablets would be needed in the helminth group versus 27 days when tablets would be needed in the placebo group. Participants taking helminths percutaneously (i.e. as hookworm larvae) had local skin itching and redness in the first few days after administration. Participants taking helminths were more likely to report any gastrointestinal adverse event (RR 1.79, 95% CI 1.31 to 2.45), moderate or severe abdominal pain (RR 7.67, 95% CI 1.87 to 31.57), moderate or severe flatulence (RR 2.01, 95% CI 1.06 to 3.81) and moderate or severe diarrhoea (RR 1.99, 95% CI 1.18 to 3.37). There was no difference between the helminth and placebo groups in the incidence of serious adverse events, and in study withdrawals. Authors' conclusions: There is currently insufficient evidence on the efficacy, tolerability and likely costs of helminth therapy to support its use in the routine management of allergic rhinitis. Administered to humans in carefully measured doses, helminths appear to be safe. More preclinical studies should be performed, before larger and extended duration trials of helminths for allergic rhinitis are carried out. Future studies should collect and report comparative data on the costs of helminth therapy versus conventional pharmacotherapy.
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Helminth therapy (worms) for allergic rhinitis (Review)
Croft AM, Bager P, Kumar S
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 4
http://www.thecochranelibrary.com
Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
7BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
17DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
19AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Allergic rhinitis symptoms, Outcome 1 Mean daily symptom score during grass pollen
season. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Analysis 2.1. Comparison 2 Well days, Outcome 1 % of well days during grass pollen season. . . . . . . . . 31
Analysis 3.1. Comparison 3 Lung function measures, Outcome 1 Bronchial reactivity change. . . . . . . . . 32
Analysis 4.1. Comparison 4 Use of rescue medication, Outcome 1 Mean total daily medication use score during grass
pollen season. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Analysis 4.2. Comparison 4 Use of rescue medication, Outcome 2 % days requiring rescue medication (as eye drops) during
grass pollen season. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Analysis 4.3. Comparison 4 Use of rescue medication, Outcome 3 % days requiring rescue medication (as nasal sprays)
during grass pollen season. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Analysis 4.4. Comparison 4 Use of rescue medication, Outcome 4 % days requiring rescue medication (as tablets) during
grass pollen season. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Analysis 5.1. Comparison 5 Rhinoconjunctivitis quality of life score, Outcome 1 Total quality of life score over 12 weeks. 34
Analysis 6.1. Comparison 6 Serious adverse events, Outcome 1 Hospitalisation due to any adverse event. . . . . 35
Analysis 6.2. Comparison 6 Serious adverse events, Outcome 2 Hospitalisation due to any gastrointestinal adverse event. 35
Analysis 7.1. Comparison 7 Other adverse events, Outcome 1 Any adverse event. . . . . . . . . . . . . . 36
Analysis 7.2. Comparison 7 Other adverse events, Outcome 2 Any gastrointestinal adverse event. . . . . . . . 36
Analysis 7.3. Comparison 7 Other adverse events, Outcome 3 Moderate or severe abdominal pain. . . . . . . . 37
Analysis 7.4. Comparison 7 Other adverse events, Outcome 4 Moderate or severe diarrhoea. . . . . . . . . . 37
Analysis 7.5. Comparison 7 Other adverse events, Outcome 5 Moderate or severe flatulence. . . . . . . . . . 38
Analysis 7.6. Comparison 7 Other adverse events, Outcome 6 Moderate or severe pruritus ani. . . . . . . . . 38
Analysis 8.1. Comparison 8 Drop-outs, Outcome 1 All-cause study withdrawal. . . . . . . . . . . . . . 39
39APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
45INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iHelminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Helminth therapy (worms) for allergic rhinitis
Ashley M Croft1, Peter Bager2, Sushil Kumar3
1Headquarters Surgeon General, Whittington Barracks, Lichfield, UK. 2Department of Epidemiology Research, Statens Serum Institut,
Copenhagen, Denmark. 3Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis,
MN, USA
Contact address: Ashley M Croft, Headquarters Surgeon General, Whittington Barracks, Lichfield, Staffordshire, WS14 9PY, UK.
Ashley.Croft810@mod.uk.AshleyCroft@doctors.org.uk.
Editorial group: Cochrane Ear, Nose and Throat Disorders Group.
Publication status and date: New, published in Issue 4, 2012.
Review content assessed as up-to-date: 24 June 2011.
Citation: Croft AM, Bager P, Kumar S. Helminth therapy (worms) for allergic rhinitis. Cochrane Database of Systematic Reviews 2012,
Issue 4. Art. No.: CD009238. DOI: 10.1002/14651858.CD009238.pub2.
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Allergic rhinitis is a disorder of thenasal membranes and surrounding tissues, and a worldwide cause of illness and disability. Helminths
are complex tissue-dwelling or lumen-dwelling organisms that inhabit larger organisms and are frequently asymptomatic. Helminths
modulate the natural immune responses of their human hosts, and may prevent or cure immune-mediated or allergic diseases (e.g.
allergic rhinitis) in the host. Non-randomised studies support this hypothesis.
Objectives
To assess the safety and effectiveness of helminth therapy in people with allergic rhinitis.
Search methods
We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled
Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and
additional sources for published and unpublished trials. The date of the search was 24 June 2011.
Selection criteria
All randomised controlled trials where the intervention was any helminth species or combination of helminth species, administered to
people with allergic rhinitis in any dose, by any route and for any duration of exposure. We accepted both intermittent and persistent
allergic rhinitis patients.
Data collection and analysis
We independently extracted data and assessed eligibility and risk of bias using a standardised data collection form. We resolved any
disagreement through discussion. We combined dichotomous data using risk ratio (RR) and continuous data using mean difference
(MD), presenting both with 95% confidence intervals (CI).
1Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
We found five reports of two single-centre, placebo-controlled, double-blinded studies (130 participants). Participants in both studies
were a mix of adults with either intermittent or persistent allergic rhinitis. Both studies had a low risk of bias. One study, with 12
weeks’ follow-up, used a single percutaneous application of 10 Necator americanus (i.e. human hookworm) larvae. The other study,
with 24 weeks’ follow-up, used three-weekly oral dosing with 2500 Trichuris suis (i.e. pig whipworm) eggs in aqueous suspension. Of
17 outcomes evaluated in this review, eight were positive (i.e. favoured helminths). Participants taking helminths had no reduction in
allergic rhinitis symptoms, percentage of well days (i.e. days with minimal symptoms and no use of medication for allergic rhinitis),
lung function measures and quality of life scores. Total use of medication for allergic rhinitis (eye drops, nasal sprays, tablets) did
not change; however, in the helminth group there was a statistically significant reduction in the percentage of days during the grass
pollen season when participants needed to take tablets as rescue medication for their allergic rhinitis symptoms (MD -14.0%, 95%
CI -26.6 to -1.40); in a typical 60-day pollen season this 14% reduction translates into 19 days when tablets would be needed in the
helminth group versus 27 days when tablets would be needed in the placebo group. Participants taking helminths percutaneously (i.e.
as hookworm larvae) had local skin itching and redness in the first few days after administration. Participants taking helminths were
more likely to report any gastrointestinal adverse event (RR 1.79, 95% CI 1.31 to 2.45), moderate or severe abdominal pain (RR 7.67,
95% CI 1.87 to 31.57), moderate or severe flatulence (RR 2.01, 95% CI 1.06 to 3.81) and moderate or severe diarrhoea (RR 1.99,
95% CI 1.18 to 3.37). There was no difference between the helminth and placebo groups in the incidence of serious adverse events,
and in study withdrawals.
Authors’ conclusions
There is currently insufficient evidence on the efficacy, tolerability and likely costs of helminth therapy to support its use in the routine
management of allergic rhinitis. Administered to humans in carefully measured doses, helminths appear to be safe. More preclinical
studies should be performed, before larger and extended duration trials of helminths for allergic rhinitis are carried out. Future studies
should collect and report comparative data on the costs of helminth therapy versus conventional pharmacotherapy.
P L A I N L A N G U A G E S U M M A R Y
Helminth therapy (worms) for allergic rhinitis
Allergic rhinitis is a common health problem affecting about 500 million people worldwide; its prevalence is increasing. The symptoms
of allergic rhinitis include sneezing, and an itchy, runny and blocked nose. Several classes of drugs are used to treat allergic rhinitis,
but these drugs may be ineffective, and some drug classes have side effects after long-term use. Drugs may also be relatively expensive.
Helminths are complex multicellular organisms that inhabit larger organisms, and in humans are often symptomless. Helminths
modulate (that is, optimally adjust) the immune systems of their hosts and it is thought that this property of helminths could be used
therapeutically, to prevent or treat allergic diseases, such as allergic rhinitis. We included two well-designed studies with a total of 130
adult participants, each study using a different species of gastrointestinal helminth (human hookworm in one study and pig whipworm
in the other) as the intervention. Both studies found no significant efficacy from helminths, although one helminth species (Trichuris
suis, the pig whipworm) reduced the need for participants to take tablets as ‘rescue medication’ during the grass pollen season. Adverse
events such as abdominal pain and flatulence were commoner in the helminth group, but the two helminths species studied did not
cause serious adverse reactions. Currently there is insufficient evidence to support the use of helminths for allergic rhinitis in routine
clinical practice. More preclinical studies are needed, before larger and extended duration clinical trials of helminths for allergic rhinitis
are performed.
2Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Helminths (worms) for allergic rhinitis
Patient or population: patients with allergic rhinitis1
Settings: primary care, community, outpatient
Intervention: helminths (worms)2
Outcomes Illustrative comparative risks* (95% CI) Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed risk Corresponding risk
Control Helminths (worms)
All-cause study with-
drawal
Investigator-recorded
Follow-up: 12 to 24
weeks
Study population RR 0.75
(0.18 to 3.21)
130
(2 studies)
⊕⊕⊕⊕
high
62 per 1000 46 per 1000
(11 to 198)
Moderate
63 per 1000 47 per 1000
(11 to 202)
Change in allergic rhini-
tis daily symptom score
during the grass pollen
season
Each daily symptom
score was the summa-
tion of (i) runny nose
score, (ii) itchy nose
score and (iii) sneez-
ing score (each of these
scores self recorded on
a severity scale of 0 =
best to 3 = worst, giving
The mean change in aller-
gic rhinitis daily symptom
score during the grass
pollen season in the inter-
vention groups was
0 higher
(0.45 lower to 0.45
higher)
100
(1 study)
⊕⊕⊕
moderate3
3Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
a maximum daily score of
9)
Scale from: 0 to 9
Follow-up: 61 days
Percentage of well days
during the grass pollen
season
Well days were those
days with a symptom
score of less than or equal
to 2, and no use of rescue
medication
Scale from: 0 to 100
Follow-up: 61 days
The mean percentage of
well days during the grass
pollen season in the inter-
vention groups was
3 higher
(7.98 lower to 13.98
higher)
100
(1 study)
⊕⊕⊕
moderate3
Total quality of life score
over 12 weeks
Assessed as the total
score over the entire 12-
week study period in the
Juniper RQLQ, i.e. a pa-
tient-specific test instru-
ment derived from 28
questions drawn from 7
dimensions (sleep, non-
hay fever symptoms,
practical problems, nose
symptoms, eye symp-
toms, activities, emo-
tions), with a maximum
daily score of 168 denot-
ing extremely poor quality
of life, self reported daily
and calculated at the end
of the study as the log of
the area under the curve
Scale from: 0 to 168
The mean total quality of
life score over 12 weeks
in the intervention groups
was
0.33 higher
(0.27 lower to 0.93
higher)
30
(1 study)
⊕⊕⊕
moderate3
4Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Follow-up: 12 weeks
Percentage of days re-
quiring rescue medica-
tion (i.e. as tablets) dur-
ing the grass pollen sea-
son
Self recorded each day4
Scale from: 0 to 100
Follow-up: 61 days
The mean percentage
of days requiring res-
cue medication (i.e. as
tablets) during the grass
pollen season in the inter-
vention groups was
14 lower
(26.6 to 1.4 lower)
100
(1 study)
⊕⊕⊕
moderate3
Hospitalisation due to
any adverse event
Investigator-assessed
Follow-up: 24 weeks
Study population RR 2.88
(0.31 to 26.69)
96
(1 study)
⊕⊕⊕
moderate3
21 per 1000 61 per 1000
(7 to 568)
Moderate
21 per 1000 60 per 1000
(7 to 560)
Any gastrointestinal ad-
verse event
Self recorded
Follow-up: 24 weeks
Study population RR 1.79
(1.31 to 2.45)
96
(1 study)
⊕⊕⊕
moderate3
489 per 1000 876 per 1000
(641 to 1000)
Moderate
489 per 1000 875 per 1000
(641 to 1000)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire; RR: Risk ratio
5Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1Allergic rhinitis is a disorder of the nasal membranes and surrounding tissues, and a worldwide cause of illness and disability.
2Helminths are ubiquitous symbionts of humans and are usually asymptomatic; they modulate the natural immune responses of their
human hosts.
3Sparse data.
4Other self recorded classes of rescue medication were: eye drops, nasal sprays.
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6Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
B A C K G R O U N D
Description of the condition
Epidemiology
Allergic rhinitis is a global health problem that causes significant
illness and disability worldwide. Although there is huge interna-
tional variation in the incidence of allergic rhinitis, people from
all countries, all ethnic groups, all socioeconomic conditions and
of all ages suffer from the condition (ARIA 2008).
Allergic rhinitis was a rare condition until the 19t h century, at
which time it became common in both Europe and North Amer-
ica. The prevalence of allergic rhinitis is increasing in most coun-
tries and, at a conservative estimate, the condition afflicts over 500
million people worldwide (ARIA 2008). In North America the
overall prevalence is nearly 20%, with a peak prevalence of nearly
40% occurring in childhood and adolescence (Austen 2011). In
Europe around 1 in 10 adults has chronic rhinosinusitis, although
there is marked regional variation in the burden of disease (Hastan
2011).
Clinical symptoms
Allergic rhinitis is defined clinically as a symptomatic disorder of
the nasal membranes and surrounding tissues, induced by an IgE-
mediated inflammation and following exposure of the nasal mem-
branes to an allergen (ARIA 2008). The disease has two phases, as
follows.
1. An early-phase response (also known as a type 1 or
immediate hypersensitivity reaction). In this phase, histamine
and other inflammatory mediators are released into the nasal
mucosa by mast cells which were previously sensitised by an
antigen. This causes the characteristic nasal symptoms of
sneezing, pruritus (itching), rhinorrhoea (runny nose) and nasal
congestion (Nasser 2010).
2. A late-phase response. This phase occurs approximately
four to 12 hours after antigen exposure and nasal congestion is
the predominant symptom (Nasser 2010).
Classification
Historically, allergic rhinitis was classified as either seasonal (‘hay
fever’) or perennial, based on any observed seasonality in the pa-
tient’s symptoms. A more modern classification, endorsed by the
World Health Organization, is based on the duration of symptoms
and recognises two forms of the disease, as follows.
1. Intermittent allergic rhinitis: lasting for less then four days
per week or for less than four weeks per year (ARIA 2008).
2. Persistent allergic rhinitis: lasting for more than four days
per week or for more than four weeks per year (ARIA 2008).
The classification is further divided, depending on the degree of
disease severity and its impact on the patient’s quality of life, into
mild disease, and moderate to severe disease (ARIA 2008).
Diagnosis
A diagnosis of allergic rhinitis is based on a typical history of
allergic symptoms. However, as some of these symptoms may not
necessarily be of allergic origin, the diagnosis may additionally be
confirmed through a combination of in vitro and in vivo diagnostic
tests (Al Sayyad 2007). These additional tests may include the
following.
1. Serological testing for circulating allergen-specific IgE. This
aims to detect free or cell-bound IgE, using enzyme
allergosorbent tests (EAST) or a radioallergosorbent test (RAST).
2. Skin prick testing. This tests for an IgE-mediated
immediate hypersensitivity reaction, using the suspected
allergens or other aeroallergens.
3. Nasal provocation testing (rhinomanometry). This is
principally a research tool but may in time become a routine
diagnostic test.
Common treatments
Current treatment approaches to allergic rhinitis include allergen
avoidance (Sheikh 2010), pharmacotherapy and immunotherapy.
Commonly used drug treatments include antihistamines (Nasser
2010), topical nasal steroids (Al Sayyad 2007), anti-leukotriene
receptor antagonists, mast cell stabilisers and, in some cases, a short
course of systemic steroids, or of nasal decongestants (Sur 2010).
For patients whose symptoms remain uncontrolled despite these
drug treatments, allergen immunotherapy is advised (Calderon
2007;Radulovic 2010).
Description of the intervention
In March 1970 Preston reported a remarkable case series of 12
naval officers who were serving in London, in government offices
adjacent to a park (Preston 1970). All had suffered from allergic
rhinitis (‘hay fever’) for some years, had positive skin prick tests
to lime and plane tree pollen, and were afflicted with the disorder
while at work in London, when the trees in the park came into
pollen. The 12 patients all developed ascariasis during holidays or
duty visits abroad, and the diagnosis was made by demonstrating
the eggs of Ascaris lumbricoides in stools obtained at rectal exami-
nation. Subsequently:
four officers (33%) remained free of allergic rhinitis for
three years;
7Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
three officers (25%) remained free of allergic rhinitis for
two years;
four officers (33%) remained free of allergic rhinitis for one
year; and
one officer was lost to follow-up.
In October 1974 a researcher at the Medical Research Council lab-
oratory at Carshalton, England, infested himself with 250 larvae
of the nematode helminth Necator americanus. He had suffered
for 25 years from allergic rhinitis (‘hay fever’) and had needed to
take antihistamine drug treatment each summer. In September
1976 he reported: “The most pertinent finding in the context of the
discussion on IgE, parasites, and allergy was that during the summers
of 1975 and 1976 I remained completely free from all symptoms of
hay fever” (Turton 1976).
Subsequent observational studies carried out in developing coun-
tries have found that in some poor communities helminth infes-
tation, which is often asymptomatic, is protective against aller-
gic rhinitis, asthma and eczema (Scrivener 2001;Huang 2002;
Medeiros 2003;Haileamlak 2005). It has also been postulated
that helminth infestation may protect against immune-mediated
diseases, such as inflammatory bowel disease and multiple sclerosis
(Erb 2009).
The implication for clinical practice of this knowledge is that
deliberately exposing patients with allergic or immune-mediated
diseases to controlled exposures of some helminth species may
be a safe and effective treatment for the diseases. This con-
cept has been tested for some common diseases through ran-
domised controlled trials (RCTs) involving different helminth
species (Summers 2005a;Blount 2009;Feary 2009b;Bager 2010;
Daveson 2011). Some of these trials, though not all, have sup-
ported the concept of using helminths to treat allergic or immune-
mediated diseases.
Helminths
’Helminth’ is derived from the Greek word helmins, meaning
worm. The helminths of humans include species from the follow-
ing four groups:
annelids (segmented worms);
nematodes (roundworms);
trematodes (flukes); and
cestodes (tapeworms).
The commonly encountered human helminths are listed in
Appendix 1. The important biological characteristics of helminths
are listed in Appendix 2.
The intervention to be assessed in this review is the deliberate
exposure of a person with confirmed allergic rhinitis to one or
more helminth species. The routes of deliberate exposure are likely
to be:
oral (the human participant swallows helminth eggs or
cysts); or
percutaneous (helminth larvae or cercariae are applied to
the skin of the human participant, and penetrate the epidermis
to reach their preferred end-stage body structures).
The intervention may or may not be terminated through partici-
pants in the active arm taking an appropriate anthelmintic drug;
we will analyse the data from studies regardless of whether or not
the intervention is terminated in this way.
How the intervention might work
Helminths modulate the natural immune responses of their animal
hosts, and in this way evade immune surveillance and immune
challenge. An indirect effect of this immune modulation may be
the remission or cure of pre-existing allergic or immune-mediated
diseases in the host (Flohr 2008).
Why it is important to do this review
Allergic diseases were once rare but are now epidemic in affluent
countries (Austen 2011). About one in five children in industri-
alised countries suffers from at least one of the three main allergic
diseases: allergic rhinitis, asthma and eczema (ISAAC 1998). Al-
lergy accounts for up to one-third of school absences because of
chronic illness; it is likely to be a significant, though lesser, cause
of work absence also (Peakman 2009).
Current treatments for allergic rhinitis are sub-optimal for sev-
eral reasons. Allergen avoidance, the first-line treatment for aller-
gic rhinitis, is usually impractical (Reid 2010) and furthermore
there exists considerable uncertainty around the efficacy and effec-
tiveness of allergen avoidance in treating allergic rhinitis (Sheikh
2010). Drug treatments for allergic rhinitis may be expensive, or
be ineffective, or both. The adverse effects of systemic drugs limit
their usefulness (Reid 2010). Topical decongestants are associated
with rebound rhinitis and with systemic responses such as hyper-
tension (Austen 2011). Abuse of over-the-counter preparations
may cause long-term damage to nasal function (Nasser 2010). Al-
lergen injection immunotherapy is resource-intensive because it
needs to be performed in the immediate presence of a physician,
and administered by fully trained personnel who are experienced
in the early recognition and prompt treatment of adverse reactions
to the therapy (Calderon 2007).
A Cochrane review to assess the effectiveness and safety of helminth
treatment for allergic rhinitis is warranted.
O B J E C T I V E S
To assess whether helminths are a safe and effective treatment for
people with allergic rhinitis.
8Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs) using adequate
or quasi methods of randomisation. Single-blind, double-blind,
triple-blind or unblinded (i.e. ‘open label’) studies were all eligible
for inclusion.
Types of participants
Participants were persons of any age with persistent or intermit-
tent allergic rhinitis. This was confirmed by one or more of the
following:
abnormal systemic levels of allergen-specific IgE;
positive skin prick test;
positive nasal provocation test (rhinomanometry).
Where the older terminology was used we assumed ‘seasonal’ to
be equivalent to ‘intermittent’ and ‘perennial’ to be equivalent to
‘persistent’.
Types of interventions
Intervention
We considered studies for inclusion where any helminth species or
combination of helminth species (either tissue-dwelling helminths
or lumen-dwelling gastrointestinal helminths) was administered
to a human host:
in any dose;
by any route (oral, percutaneous, other);
for any duration of exposure (days, weeks, months); and
at any developmental stage of the organism (eggs, cercariae,
larvae, adult worms).
Helminth-derived molecular products were outside the scope of
this review and were not included.
Control
The control group received placebo (i.e. sham helminth exposure),
no treatment or any other active intervention.
Types of outcome measures
Primary outcomes
1. Allergic rhinitis symptoms, self reported (efficacy).
2. Well days (i.e. days with no or very mild symptoms, and no
use of medication for allergic rhinitis) (efficacy).
3. Lung function measures (e.g. change in bronchial reactivity,
forced expiratory volume in one second (FEV1), NO, acute
asthma symptoms, asthma medication use) (safety).
Secondary outcomes
1. Use of rescue medication (i.e. non-routine drugs taken to
relieve acute exacerbations), reported validly and regardless of
how recorded.
2. Rhinoconjunctivitis quality of life scores, self reported.
3. Serious adverse events (e.g. hospitalisation, death).
4. Other adverse events (i.e. any non-serious systemic or
regional or local adverse event).
5. Dropouts (i.e. all-cause study withdrawal) (adherence).
6. Costs of therapy.
Search methods for identification of studies
We conducted systematic searches for randomised controlled tri-
als. There were no language, publication year or publication status
restrictions. The date of the search was 24 June 2011.
Electronic searches
We searched the following databases from their inception for pub-
lished, unpublished and ongoing trials: the Cochrane Ear, Nose
and Throat Disorders Group Trials Register; the Cochrane Central
Register of Controlled Trials (CENTRAL, The Cochrane Library
2011, Issue 2); PubMed; EMBASE; CINAHL; AMED; LILACS;
KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Sci-
ence; BIOSIS Previews; CNKI; ISRCTN; ClinicalTrials.gov; IC-
TRP and Google. We also searched the Networked Digital Library
of Theses and Dissertations (NDLTD).
We modelled subject strategies for databases on the search strategy
designed for CENTRAL. Where appropriate, we combined sub-
ject strategies with adaptations of the highly sensitive search strat-
egy designed by the Cochrane Collaboration for identifying ran-
domised controlled trials and controlled clinical trials (as described
in the Cochrane Handbook for Systematic Reviews of Interventions
Version 5.1.0, Box 6.4.b. (Handbook 2011). Search strategies for
major databases including CENTRAL are provided in Appendix
3.
Searching other resources
We scanned the reference lists of identified publications for addi-
tional trials and contacted trial authors where necessary. In addi-
tion, we searched PubMed, TRIPdatabase, NHS Evidence - ENT
& Audiology and Google to retrieve existing systematic reviews
relevant to this systematic review, so that we could scan their refer-
ence lists for additional trials. We searched for conference abstracts
9Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
using the Cochrane Ear, Nose and Throat Disorders Group Trials
Register.
Data collection and analysis
Selection of studies
Phase one
The principal review author (AC) inspected all abstracts of stud-
ies identified as above, to determine potentially relevant reports.
In addition, and to ensure reliability, PB inspected 100% all the
identified abstracts.
Where disagreement existed as to the potential relevance of a par-
ticular report, we were to resolve this through discussion. Where
doubt persisted, we were to retrieve the full text of the report for
inspection.
Phase two
We retrieved the full text of all those reports judged to be poten-
tially relevant for further assessment, and for a final decision on in-
clusion (see Criteria for considering studies for this review). Once
the full texts were obtained, AC and PB in turn inspected the full
reports and independently decided whether or not they met the
inclusion criteria. AC and PB were not be blinded to the names
of the authors, source institutions or journal of publication.
Where difficulties or disputes on study eligibility arose, we asked
SK for help; if agreement was still not reached, we were to add
these disputed studies to those awaiting assessment and contact
the authors of the original reports for clarification.
PRISMA flow diagram
We included a PRISMA flow diagram to illustrate the results of
our various searches and the process of screening and selecting
studies for inclusion in the review (Moher 2009).
Data extraction and management
We designed and used a structured data collection form to record
data from five key domains of each included study, as follows.
1. Study characteristics (study design, date of study, total
study duration, number of study centres and their location,
study withdrawals).
2. Participants (N, mean age, age range, gender distribution,
sociodemographic characteristics, ethnicity, allergic rhinitis
presentation, inclusion criteria, exclusion criteria).
3. Interventions (for each intervention: total number in
intervention arm, helminth species used, developmental stage of
the organism, dose of exposure, route of exposure, duration of
exposure, cost).
4. Controls (for each control: total number in control arm;
where control was an active pharmacological intervention:
nature, dose, route of administration, cost).
5. Outcomes (outcomes specified and collected, time points
reported).
For eligible studies, AC and PB extracted the data using the agreed
form. AC and PB resolved discrepancies through discussion;failing
resolution, we were to consult SK.
We entered the data into Review Manager (RevMan) software
version 5.1 (RevMan 2011) and checked data for accuracy.
When information regarding any data item was unclear, we con-
tacted the authors of the original reports to provide further details.
Assessment of risk of bias in included studies
AC and PB independently assessed the methodological quality of
each included study using The Cochrane Collaboration’s ‘Risk of
bias’ tool (Handbook 2011).
The study features we assessed were the following.
1. Random sequence generation
2. Allocation concealment
3. Blinding of participants and investigators
4. Blinding of outcome assessment
5. Incomplete outcome data
6. Selective reporting
7. Other bias
We recorded each of these factors as ‘low risk’, ‘high risk’ or ‘unclear
risk’, with a brief overview provided in table format. If ‘unclear’,
we attempted to seek clarification from the trial authors. After this
process, we gave each paper an overall quality assessment grade of
low, high or unclear risk of bias.
Appendix 4 gives more information about the assessment scheme
that we used.
Measures of treatment effect
Weper formed statistical analysis using RevMan 5. We used a fixed-
effect or random-effects model, depending on the absence or pres-
ence of heterogeneity across the studies.
Dichotomous data
We calculated risk ratios (RRs) with 95% confidence intervals
for dichotomous outcomes. Where appropriate, we expressed esti-
mated effects as NNTB (number needed to treat to benefit). The
NNTB corresponds mathematically to the inverse of the risk dif-
ference, and clinically to the number of patients to be treated to
achieve one desirable event. It was calculated using the pooled risk
ratio.
Continuous data
10Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
For continuousvariables, we calculated a mean diff erence (MD) or
standardised mean difference (SMD), along with 95% confidence
intervals, as follows:
when two or more studies presented their data as derived
from the same instrument of evaluation, and with the same units
of measurement, we pooled data as a mean difference (MD);
conversely, when primary studies expressed the same
variables through different instruments, and with different units
of measurement, we were to use the standardised mean difference
(SMD).
Summary data
For those RCTs (e.g. cross-over studies) where the only data avail-
able were summary measures of effect, along with precision es-
timates, we were to use the generic inverse variance method to
analyse the data.
Unit of analysis issues
If any trials had multiple treatment groups, the ‘shared’ compari-
son group was to be divided into the number of treatment groups,
and comparisons between each treatment group and the split com-
parison group were to be treated as independent comparisons.
Dealing with missing data
Where data were missing, we contacted trial authors directly to
obtain this missing information.
For cluster-RCTs, we were to contact study authors for an intra-
cluster correlation coefficient (ICC) where data were not adjusted
and could not be identified from the trial report. Where ICCs
were neither available from trial reports nor available from trialists
directly, we were to derive an average ICC based on existing infor-
mation in other sources, where such information existed. This was
to constitute the primary analysis. We were to perform a sensitiv-
ity analysis without the studies, and derive alternative estimates of
the ICC.
For all outcomes, in all studies, we carried out analyses, as far
as possible, on an intention-to-treat basis, i.e. we attempted to
include all participants randomised to each group in the analyses,
and we analysed all participants in the group to which they were
allocated, regardless of whether or not they received the allocated
intervention.
For continuous data that were missing, we were to estimate stan-
dard deviations from other available data such as standard errors,
or else we were to impute them using the methods suggested in the
Handbook 2011. We made no assumptions about loss to follow-
up for continuous data, and we based analyses on those partici-
pants completing the trial. We performed intention-to-treat anal-
yses where appropriate. We were to perform a sensitivity analysis
by calculating the treatment effect including and excluding the
imputed data, to see whether this altered the outcome of the anal-
ysis.
We were to investigate the effect of drop-outs and exclusions by
conducting worst versus best-case scenario analyses.
If there was discrepancy between the number randomised and the
number analysed in each treatment group, we were to calculate
and report the percentage lost to follow-up in each group.
If drop-outs exceeded 10% for any trial, we were to assign the worst
outcome to those lost to follow-up for dichotomous outcomes,
and assess the impact of this sensitivity analysis against the results
for those completing the study.
Where it was not possible to obtain missing data, we wereto record
this in the data collection form and report it in the ‘Risk of bias’
table.
For included studies, we noted levels of attrition. We were to ex-
plore the impact of including studies with high levels of missing
data in the overall assessment of treatment effect, by using sensi-
tivity analyses.
Assessment of heterogeneity
We assessed heterogeneity between pooled trials using:
the Chi2test; in conjunction with
the I2statistic, which describes the percentage of the
variability in effect estimates that is due to heterogeneity rather
than sampling error, or chance (Handbook 2011).
We considered a P value of < 0.10 as statistically significant.
If enough trials were identified, we were to explore sources of het-
erogeneity using subgroup analyses. We displayed results graphi-
cally using forest plots, with a summary statistic presented if there
was no major statistical heterogeneity (i.e. no overlap of confidence
intervals in the forest plots). We used a I2value of:
< 25% to denote low heterogeneity;
50% to denote significant heterogeneity; and
75% to denote substantial and major heterogeneity.
Assessment of reporting biases
Had been there more than 10 studies, we were to attempt to as-
sess publication bias by preparing a funnel plot. We were to then
perform a visual assessment of funnel plot asymmetry. We were
to carry out exploratory analyses to investigate any suggestion of
visual asymmetry in the funnel plots. We considered that our
searches for trial protocols and completed trials listed in clinical
trial registers would help to avoid publication bias, and assist in
assessing outcome selection bias. Where necessary, we were to con-
tact study authors in an attempt to either establish a full dataset
or else obtain reasons for the non-reporting of certain outcomes.
We were to conduct a sensitivity analysis to investigate the role
of funding bias. Funding bias is defined as any bias in the de-
sign or outcome reporting of industry-sponsored research that
shows that a drug or other therapeutic product to have an ap-
parently favourable outcome (Bekelman 2003). Relationships be-
tween industry, scientific investigators and academic institutions
are widespread and often result in conflicts of interest.
11Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data synthesis
We pooled the results of clinically similar studies in meta-analyses.
Weused adjusted summary statistics if available; otherwise we were
to use unadjusted results. Pooling of data was as follows:
for dichotomous outcomes we calculated RRs for each
study and then pooled these;
for continuous outcomes, we pooled the mean differences
between the treatment arms at the end of follow-up if all trials
measured the outcome on the same scale (if not, then we pooled
standardised mean differences);
for time-to-event data, we were to pool hazard ratios (HRs)
using the generic inverse variance facility of RevMan 5
(Handbook 2011).
If any trials had multiple treatment groups, we were to divide the
‘shared’ comparison group into the number of treatment groups
and treat comparisons between each treatment group and the split
comparison group as independent comparisons.
We were to use random-effects models with inverse variance
weighting for all meta-analyses (DerSimonian 1986). If possible,
we were to synthesise studies making different comparisons using
the methods of Bucher 1997.
We assessed the quality of the body of the evidence using the
approach adopted by the Grades of Recommendation,Assessment,
Development and Evaluation (GRADE) Working Group (Furlan
2009;Handbook 2011). We considered the following to represent
those domains that might decrease the quality of the evidence.
1. The study design
2. Risk of bias
3. Inconsistency of results
4. Indirectness (i.e. non-generalisability)
5. Imprecision (i.e. insufficient data)
6. Other factors (e.g. reporting bias)
We reduced the quality of the evidence by one level for each do-
main where poor quality was encountered. We assessed all plau-
sible confounding factors and consider their effects as a reason to
reduce any claimed effect and dose response gradient.
We defined levels of evidence as below.
High-quality evidence
The following statement applies to all of the domains: ’Further
research is very unlikely to change our confidence in the estimate of
effect. There are consistent findings, that are generalisable to the pop-
ulation of interest, in 75% of RCTs with low risk of bias. There are
sufficient data, with narrow confidence inter vals. There are no known
or suspected reporting biases’.
Moderate-quality evidence
The following statement applies to one of the domains: ’Further
research is likely to have an important impact on our confidence in
the estimate of effect, and may change the estimate’.
Low-quality evidence
The following statement applies to two of the domains: ’Further
research is very likely to have an important impact on our confidence
in the estimate of effect, and is likely to change the estimate’.
Very low-quality evidence
The following statement applies to three of the domains: We are
very uncertain about the estimate’.
No evidence
The following statement applies: ’No RCTs were identified that
measured the outcome of interest’.
We also considered a number of other factors to place the results
into a wider clinical context: temporality, plausibility, strength of
association, adverse events and costs.
Subgroup analysis and investigation of heterogeneity
If sufficient data were available, we were to perform subgroup
analyses to explore the effects of:
different helminth species or combination of helminth
species;
different developmental stages of the administered
helminths;
different routes of administration of the helminths;
different exposure intensities; and
different durations of exposure to the helminths.
Sensitivity analysis
Where possible, we were to perform sensitivity analyses to explore
the effects of various aspects of trial and review methodology, in-
cluding the effects of missing data and of whether or not allocation
was concealed.
If sufficient data were available, we were to perform sensitivity
analyses to determine the impact of excluding those studies with
lower methodological quality, for example:
trials at high or unclear risk of bias;
unpublished studies (since these may not have been
subjected to the peer review process and may have had intrinsic
biases);
industry-sponsored studies; and
trials that had not assessed adherence.
R E S U L T S
Description of studies
12Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
See: Characteristics of included studies;Characteristics of excluded
studies.
We found five published reports, describing two studies.
Included studies
We included two studies in the review (see Characteristics of
included studies for full study details). Ethics review and approval
and patient consent were noted in both studies.
Feary 2009a
Fifty-four adults with current symptoms of allergic rhinitis to any
allergen were recruited, and 30 with measurable bronchial reactiv-
ity were randomised into two groups. In 15 participants 10 Neca-
tor americanus (L3) larvae in 200 µL of water were applied to an
area of forearm skin and then covered for 24 hours with gauze and
a waterproof adhesive dressing. The other group had 200 µL of
histamine dihydrochloride solution (1.7 mg/mL) applied in the
same way. The primary outcomes were the change in bronchial
reactivity, calculated as the maximum fall from baseline in the
provocative dose of inhaled adenosine monophosphate (AMP) re-
quired to reduce FEV1by 10%, measured at any time over the
four weeks after active or placebo infection. Secondary outcomes
included the change over 12 weeks in a validated rhinoconjunc-
tivitis quality of life score (Juniper RQLQ); and peak expiratory
flow rate (PEFR) variability, change in skin wheal diameter in re-
sponse to skin prick testing with various allergens, adverse event
diary scores and study withdrawals.
This study was also reported in Blount 2009 and Falcone
2009.
Bager 2010
One hundred and sixty-two adults with grass pollen-induced al-
lergic rhinitis were recruited, and 100 with allergic rhinitis symp-
toms in the previous two grass pollen seasons or more were ran-
domised into two groups. Before the peak of the grass pollen sea-
son, 50 participants received a total of two to five oral doses of
embryonated Trichuris suis (i.e. pig whipworm) eggs in an aque-
ous suspension of 2500 eggs per dose, and with a 21-day interval
between doses; participants ingested eight helminth doses in total
and were followed up for 24 weeks. The other group ingested a
placebo solution which was similar in taste and smell . The primary
outcomes were the change in mean daily total symptom score for
runny, itchy or sneezing nose; and the change in the percentage of
well days during the grass pollen season. Secondary outcomes in-
cluded medication use, change in skin wheal diameter in response
to skin prick testing with grass pollen and nine other allergens,
titres of grass pollen-specific IgE, adverse event frequencies and
study withdrawals.
This study was also reported in Bager 2011.
Excluded studies
Of the 103 papers taken forward for first-level screening, we ex-
cluded 77 on the basis of their abstracts because they were not
clinical trials. We retrieved the full text of 26 papers, and excluded
a further 21 papers (see Characteristics of excluded studies for de-
tails) due to inappropriateness of study setting (two papers) or of
study design (19 papers). This left five papers, reporting on two
studies, as described above.
The PRISMA flow diagram (Moher 2009) of the full screening
process is in Figure 1.
13Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 1. Process of screening search results and selecting studies for inclusion
14Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Risk of bias in included studies
Allocation
Both studies described an adequate process for random sequence
generation (see Characteristics of included studies). Allocation
concealment was also satisfactory and was described clearly in both
study reports.
Blinding
In one study (Bager 2010) both participants and investigators were
blinded and there was consequently a low risk of bias; blinding of
participants was unclear in the other study (Feary 2009a).
Incomplete outcome data
All outcome data were reported adequately in both studies. Both
studies reported the study drop-outs and recorded clear explana-
tions for the withdrawals.
Selective reporting
There was no evidence of selective outcome reporting in either
study. Both studies reported additional outcomes, not central to
the primary objective of the study, through multiple reports.
Other potential sources of bias
Both of the included studies were carried out at a single centre. In
Bager 2010 only 5% of the participants were female.
Both studies assumed that participants were not harbouring any
helminths at the time of enrolment. This assumption, if incorrect,
may have introduced bias.
Imprecision may also derive from the fact that participants in both
studies were a mix of adults with either intermittent allergic rhinitis
or persistent allergic rhinitis.
Effects of interventions
See: Summary of findings for the main comparison Helminths
(worms) for allergic rhinitis
Of 17 outcomes evaluated in this review, eight were positive (i.e.
favoured helminths).
Allergic rhinitis symptoms
Bager 2010 reported the change in the mean daily symptom score
during the grass pollen season; there was no difference between
groups (mean difference (MD) 0.0, 95% confidence interval (CI)
-0.45 to 0.45).
Well days
Bager 2010 reported the percentage of well days during the grass
pollen season; there was no difference between groups (MD 3.0,
95% CI -7.98 to 13.98).
Lung function measures
Feary 2009a reported the bronchial reactivity change over 12
weeks; there was no difference between groups (MD 0.51, 95%
CI -0.68 to 1.70).
Use of rescue medication
Bager 2010 reported the mean total daily medication use score
during the grass pollen season; there was no difference between
groups (MD -1.10, 95% CI -2.41 to 0.21). The investigators also
reported the percentage of days during the grass pollen season
when participants had to take rescue medication in various forms:
as eye drops, nasal sprays and as tablets. There was a difference
between groups only in the case of tablets: e ye drops (MD -2.00%,
95% CI -12.40 to 8.40), nasal sprays (MD -3.00%, 95% CI -
14.19 to 8.19) and tablets (MD -14.00%, 95% CI -26.60 to -
1.40) (Figure 2).
Figure 2. Forest plot of comparison: 3 Use of rescue medication, outcome: 3.4 % days requiring rescue
medication (tablets) during grass pollen season.
15Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Rhinoconjunctivitis quality of life score
Feary 2009a reported the total quality of life score over 12 weeks;
there was no difference between groups (MD 0.33, 95% CI -0.27
to 0.93).
Serious adverse events
There were no serious adverse events in Feary 2009a.Bager 2010
reported hospitalisation due to any adverse event and hospitalisa-
tion due to any gastrointestinal adverse event, and there was no
difference between groups in either category (hospitalisation due
to any adverse event risk ratio (RR) 2.88, 95% CI 0.31 to 26.69;
due to any gastrointestinal adverse event RR 0.32, 95% CI 0.01
to 7.66).
Other adverse events
In Feary 2009a adverse events were self reported on a 10-point
scale, instead of being dichotomised; the investigators found that
the data were not distributed normally and hence were only able
to report the median scores under various symptom categories.
Median scores were higher for indigestion, and localised skin it-
ching and redness - the latter two symptoms peaked on day two
at the site of hookworm administration.
Bager 2010 reported any adverse event (RR 1.06, 95% CI 0.91 to
1.23), any gastrointestinal adverse event (RR 1.79, 95% CI 1.31
to 2.45) (Figure 3), moderate or severe abdominal pain (RR 7.67,
95% CI 1.87 to 31.57), moderate or severe diarrhoea (RR 1.99,
95% CI 1.18 to 3.37), moderate or severe flatulence (RR 2.01,
95% CI 1.06 to 3.81) and moderate or severe pruritus ani (RR
0.72, 95% CI 0.27 to 1.92). All categories of adverse event were
more likely to be reported by participants taking helminths.
Figure 3. Forest plot of comparison: 5 Other adverse events, outcome: 5.2 Any gastrointestinal adverse
event.
Drop-outs
Drop-outs were reported in both studies. There was no signifi-
cant difference between groups for all-cause study withdrawal (RR
0.75, 95% CI 0.18 to 3.21) (Figure 4).
Figure 4. Forest plot of comparison: 1 Study withdrawal, outcome: 1.1 All-cause withdrawal
16Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Costs
Neither study reported data on costs (i.e. costs of helminth ther-
apy, costs of pharmacotherapy, clinic visit costs, healthcare worker
costs).
D I S C U S S I O N
This is the first ever systematic review of helminths for allergic
rhinitis and the first Cochrane review toinve stigate the therapeutic
use of helminths.
Summary of main results
We found five published reports, describing two studies (130 adult
participants). One safety study, with 12 weeks’ follow-up, used
a single percutaneous application of 10 Necator americanus (i.e.
human hookworm) larvae. One efficacy and safety study, with
24 weeks’ follow-up, used three-weekly oral dosing with 2500
Trichuris suis (i.e. pig whipworm) eggs in aqueous suspension.
The primary outcomes of allergic rhinitis symptoms, well days
and lung function measures were not significantly different be-
tween treatment groups, nor were quality of life scores. In the
helminth group there was a statistically significant reduction in
the percentage of days during the grass pollen season when par-
ticipants needed to take tablets as rescue medication (mean dif-
ference (MD) -14.0%, 95% confidence interval (CI) -26.6 to -
1.40) (Figure 2); in a typical 60-day pollen season this 14% re-
duction translates into 19 days when tablets would be needed in
the helminth group versus 27 days when tablets would be needed
in the placebo group. This finding may have been an artefact,
however, explicable through the helminths having induced a re-
luctance in their human hosts to take oral medication, secondary
to the transient adverse gastrointestinal effects (abdominal pain,
diarrhoea, flatulence) of the helminths themselves.
Participants taking helminths were more likely to report any gas-
trointestinal adverse event (RR 1.79, 95% CI 1.31 to 2.45) (Figure
3), moderate or severe abdominal pain (RR 7.67, 95% CI 1.87
to 31.57), moderate or severe diarrhoea (RR 1.99, 95% CI 1.18
to 3.37) and moderate or severe flatulence (RR 2.01, 95% CI
1.06 to 3.81). Participants taking helminths percutaneously (i.e.
as hookworm larvae) had local skin itching and redness in the first
few days after administration. There was no difference between
the helminth and the placebo groups in the incidence of serious
adverse events, and of all-cause study withdrawals (Figure 4).
Overall completeness and applicability of
evidence
Outcomes in both studies were reported completely, with the ex-
ception of costs data, which were not reported in either study.
Outcomes were relevant to the anticipated target groups for the
intervention (Figure 5;Figure 6).
Figure 5. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
17Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 6. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.
Quality of the evidence
The two included studies were small and single-centre and had
limited follow-up. All of these study characteristics could have
introduced imprecision into the estimates of effect (Handbook
2011). Imprecision may also derive from the fact that in Feary
2009a some of the participants began their exposure to helminths
some weeks after the onset of the ambient allergy season, instead
of before it; there is some evidence that if helminths exposure fol-
lows rather than precedes allergen exposure a potentiated allergic
response may result, with a worsening of symptoms (Turner 1979;
Pritchard 1992).
With the exception of study drop-outs, different outcomes were
reported by the studies. We were therefore not able to pool data
in a manner that contributed greatly to what is already known on
this topic.
Potential biases in the review process
PB was lead investigator of one of the studies included in this
review. We know of no other potential sources of bias. On account
of the comprehensive nature of our search strategy, we believe that
we did not miss any studies.
18Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Agreements and disagreements with other
studies or reviews
The results of this systematic review suggest no clinical effect from
helminth therapy in adults with allergic rhinitis, and do not bear
out the dramatic improvement in allergic rhinitis symptoms re-
ported in two early non-randomised studies (Preston 1970;Turton
1976). The findings in those two non-randomised studies, both of
them highly favourable towards the therapeutic use of helminths
for allergic rhinitis, may be valid findings. Alternatively, the find-
ings may be explained by a lack of rigour in the study methodolo-
gies, or by biased reporting.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
There is currently insufficient evidence regarding the efficacy, tol-
erability and likely costs of helminth therapy to support its use
in the routine management of allergic rhinitis. Administered to
humans in carefully measured doses, helminths appear to be safe.
Implications for research
For each currently available specific helminth therapy, more ex-
perimental studies should be undertaken, in various models of al-
lergy, of dose range, duration of action and mode of action, be-
fore further clinical studies are ethically justified. If the results of
these further preclinical studies are positive, then large, multi-cen-
tre randomised clinical trials are warranted.
These larger clinical trials should explore the effects of different
doses of helminths, and possibly of helminth combinations, in
people with allergic rhinitis. Standardised instruments should be
used to assess change in allergic rhinitis symptoms and medication
use, and in quality of life.
Adverse events should be measured and reported as dichotomous,
not as continuous variables. Cost data for the therapies tested
should be collected and included in study reports, along with costs
of conventional pharmacotherapy, and clinic visit and associated
healthcare staff costs. The studies should be designed with ex-
tended periods of follow-up (up to one year), if there is experi-
mental evidence to support this.
In future studies of helminth therapy for allergic rhinitis, partici-
pants should be categorised at the time of enrolment as suffering
either from intermittent allergic rhinitis or from persistent allergic
rhinitis. In seasonal allergic rhinitis trials, the onset of the inter-
vention (i.e. exposure of the participants to helminths) should pre-
cede the usual date of onset of the pollen season in that location,
by at least several months.
If helminth therapy is shown in the future to be of benefit in al-
lergic rhinitis, and in other allergic or immune-mediated diseases,
qualitative research may be needed to identify the psychological
barriers that might inhibit patients from adopting this novel mode
of treatment.
A C K N O W L E D G E M E N T S
We thank Gemma Sandberg from the Cochrane Ear, Nose and
Throat Disorders Group for her help in designing the CENTRAL
search strategy; and Jenny Bellorini for her outstanding editorial
assistance.
We also thank Dr Andrew Herxheimer, of the Cochrane Adverse
Effects Methods Group, for his helpful advice on assessing adverse
events.
R E F E R E N C E S
References to studies included in this review
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measurable airway responsiveness: a randomized placebo-
controlled feasibility study. Clinical and Experimental
Allergy 2009;39(7):1060–8.
19Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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22Helminth therapy (worms) for allergic rhinitis (Review)
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C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Bager 2010
Methods RCT (setting: single centre; country: Denmark; length of follow-up: 24 weeks)
Ethical approval: Danish Ethics Committee
Participants Number randomised: 100 (helminths = 50, placebo = 50)
Mean age: 35 years (helminths), 39 years (placebo)
Gender (M/F): 48/2 (helminths), 47/3 (placebo)
Interventions 8 successive oral doses of Trichuris suis (i.e. pig whipworm) with a 21-day interval between
doses; each dose comprising a 15 mL pH-neutral aqueous suspension containing 2500
embryonated T. suis eggs
Outcomes Mean daily symptom score during the 61-day grass pollen season, each daily symptom
score being the summation of (i) runny nose score, (ii) itchy nose score and (iii) sneezing
score (each of these scores recorded on a severity scale of 0 = best to 3 = worst, giving a
total maximum daily score of 9)
Percentage of well days during the 61-day grass pollen season (well days = days with
symptom score of <
= 2, and no use of rescue medication)
Mean daily score for medication use during the 61-day grass pollen season, with a
maximum daily score of 32
Percentage of days during the 61-day grass pollen season when rescue medication for
allergic rhinitis was required, recorded by medication class (i.e. eye drops, nasal sprays,
tablets)
Measurable change (mm) in diameter of skin wheal, between prick testing with grass
pollen allergen at enrolment, and repeat testing after final treatment
Adverse events (self recorded and categorised in intensity as 0 = none, 1 = mild, 2 =
moderate, 3 = severe)
Participants hospitalised due to adverse events
Drop-outs (i.e. all-cause study withdrawal)
Notes The pollen season was defined as starting after 3 consecutive days with a pollen count
of >
= 10 pollen grains/m3, and lasted 61 days (i.e. from 28 May 2008 to 27 July 2008,
with the peak day on 9 June 2008); all dosing took place between March and October,
starting 4 to 13 weeks before the peak day
Participants were men (or women not of childbearing potential) aged 18 to 65 years with
(i) symptoms of grass pollen-induced allergic rhinitis in the previous 2 pollen seasons,
(ii) a wheal diameter of >
= 3 mm on skin prick testing with grass pollen allergen, (iii) a
specific IgE level against grass pollen allergen of >
= 0.7 kilo units antigen per litre (kUA/
L), (iv) a spirometric FEV1of >
= 70% of predicted, and (v) no significant asthma
Participants were supplied with standardised classes and quantities of rescue medication
at the start of the trial, and this rescue medication was replenished every 3 weeks
Placebo was 15 mL of a pH-neutral oral solution similar in taste and smell to the
intervention solution, administered at 21-day intervals
Risk of bias
23Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bager 2010 (Continued)
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “The sponsor electronically ran-
domized subjects 1 to 1 in blocks of 10
to receive 8 treatments of placebo or TSO
with an interval of 21 days”
Allocation concealment (selection bias) Low risk Quote: “The taste, smell and appearance of
TSO and placebo were similar”
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “Treatment assignment was
blinded to all personnel at the trial clinic
[and to] subjects... for the duration of the
trial”
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “Treatment assignment was
blinded to... data management personnel
for the duration of the trial”
Incomplete outcome data (attrition bias)
All outcomes
Low risk Quote: “98% of treatments and 100% of
sampling visits were performed as sched-
uled”
Withdrawals were few and were described
and reported adequately
Selective reporting (reporting bias) Low risk No evidence of selective outcome reporting
Adverse events were reported in a publica-
tion (Bager 2011) separate to the main re-
port (Bager 2010)
Other bias Unclear risk Very low numbers of female participants
100% of participants were Caucasian
The study assumed that participants were
not harbouring any helminths at the time
of enrolment
Participants in both studies were a mix
of adults with either intermittent allergic
rhinitis or persistent allergic rhinitis
The study was carried out at a single centre
Statens Serum Institute, Copenhagen acted
as the (non-commercial) sponsor
24Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Feary 2009a
Methods RCT (setting: single centre; country: UK; length of follow-up: 12 weeks)
Ethical approval: Nottingham Research Ethics Committee
Participants Number randomised: 30
Mean age: 30 years (helminths), 33 years (placebo)
Gender (M/F): 9/15 (helminths), 9/15 (placebo)
Interventions 10 Necator americanus (L3) larvae in 200 µL of distilled water, applied to an area of
forearm skin and then covered for 24 hours with gauze and a waterproof adhesive dressing
Outcomes Change in bronchial reactivity, expressed as the change between Week 0 and Week 4 in
the in the number of provocation doubling doses of inhaled adenosine monophosphate
required to reduce FEV1by 10% (and where a fall in the number of doubling doses = a
better clinical outcome)
PEFR self recorded each morning and evening as the best of 3 attempts; PEF variability
then calculated for the 4 weeks of the intervention and expressed as the mean of the 2
lowest PEFR values during the entire 4-week period, as a percentage of the 4-week PEFR
period mean (and with a value of 100 indicating no variability, i.e. perfect control)
Measurable change (mm) in diameter of skin wheal, between prick testing at enrolment
with various allergens (cat fur, Dermatophagoides pteronyssinus, grass pollen) and repeat
testing after final treatment
Total score over the entire 12-week study period in Juniper Rhinoconjunctivitis Quality
of Life Questionnaire (RQLQ), with the score calculated at the end of the study by the
investigators, as the log of the area under the curve
Self recorded daily symptom scores, each score based on a visual analogue scale of 0 =
none to 10 = maximal, for a range of 12 pre-specified likely adverse effects of helminths
(i.e. localised skin itching/redness, wheeze, cough, breathlessness, nausea, diarrhoea,
abdominal pain, flatulence, indigestion, loss of appetite, tiredness), investigator-assessed
during the predicted period of high risk for helminth adverse effects
Drop-outs (i.e. all-cause study withdrawal)
Notes Recruitment and enrolment took place between February to August 2006
Participants were men and non-pregnant women aged >
= 18 years, with current symptoms
of allergic rhinoconjunctivitis and with subclinical asthma (i.e. with measurable airway
responsiveness to inhaled adenosine monophosphate, but no clinical diagnosis of asthma)
Juniper RQLQ (Juniper 1991) was interviewer-administered at baseline, then again at
2-weekly clinic visits; this is a patient-specific test instrument derived from 28 questions
drawn from 7 dimensions (sleep, non-hay fever symptoms, practical problems, nose
symptoms, eye symptoms, activities, emotions) and with a maximum score of 168,
denoting extremely poor quality of life
Placebo was 200 µL of histamine dihydrochloride solution (at a strength of 1.7 mg/
mL) applied to an area of forearm skin and then covered for 24 hours with gauze and a
waterproof adhesive dressing
Risk of bias
Bias Authors’ judgement Support for judgement
25Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Feary 2009a (Continued)
Random sequence generation (selection
bias)
Low risk Quote: “Subjects [were randomised to] ac-
tive or placebo infection, allocated in blocks
of four according to a computer generated
random code”
Allocation concealment (selection bias) Low risk Quote: “the solutions were administered
by an independent member of the research
team who was not involved in any of the
study measurements, to ensure that the
clinical researcher carrying out the proto-
col measures remained blind to treatment
allocation”
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Quote: “of the 14 individuals in the placebo
group who completed the study, three cor-
rectly thought they had received placebo.
.. Of the 13 with hookworm infection
who completed the study, eight correctly
thought they had received hookworm”
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “To maintain blinding of the clini-
cal researcher, subjects were asked to cover
their arm at the site of the dressing appli-
cation during [assessment] visits in case of
local skin redness and to discuss any queries
relating to the study with a different mem-
ber of the research team”
Incomplete outcome data (attrition bias)
All outcomes
Low risk > 95% of assessments were carried out at
the appropriate time
Withdrawals were few and were described
and reported adequately
Selective reporting (reporting bias) Low risk No evidence of selective outcome reporting
Additional outcomes were reported in two
publications (Blount 2009;Falcone 2009)
separate to the main report (Feary 2009a)
Other bias Low risk Some participants used antihistamine (lo-
ratadine 10 mg tablets) daily or as rescue
medication; one took a daily steroid nasal
spray throughout the study
The study assumed that participants were
not harbouring any helminths at the time
of enrolment
Participants in both studies were a mix
of adults with either intermittent allergic
rhinitis or persistent allergic rhinitis
The study was carried out at a single centre
26Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Feary 2009a (Continued)
Two of the investigators declared a conflict
of interest as being “inventors of patents
supporting the use of molecules derived
from helminths as immune modulatory
agents”
F: female
FEV1: forced expiratory volume in one second
IgE: class E circulating immunoglobulin
Juniper RQLQ: Juniper Rhinoconjunctivitis Quality of Life Questionnaire (Juniper 1991), a patient-specific test instrument derived
from 28 questions drawn from 7 dimensions (sleep, non-hay fever symptoms, practical problems, nose symptoms, eye symptoms,
activities, emotions), with a maximum score of 168 denoting extremely poor quality of life
L3: third stage larval moult
M: male
PEFR: peak expiratory flow rate
RCT: randomised controlled trial
RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire
TSO: Trichuris suis ova
UK: United Kingdom
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Abreu 2008 Not RCT
Baqueiro 2007 Not RCT
Bousquet 2003 Not a helminth intervention
Corne 1997 Not a helminth intervention
Daniluk 2008 Not RCT
Diesel 2011 Study not conducted in humans
Fernandes 2010 Not RCT
Gaspar-Sobrinho 2010 Not RCT
Guerrier 1991 Not RCT
Hamid 2011 Wrong study outcome
Hepworth 2010 Not RCT
27Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Herrera 1992 Not RCT
Horak 2009 Not a helminth intervention
Hrdlickova 2009 Not RCT
Mortemousque 2004 Not a helminth intervention
Nagata 1995 Not RCT
Ollerstam 2002 Study not conducted in humans
Snyman 1998 Not a helminth intervention
Souza 1985 Not a helminth intervention
van Bever 1992 Not a helminth intervention
Yuasa 1981 Not RCT
RCT: randomised controlled trial
28Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Allergic rhinitis symptoms
Outcome or subgroup title No. of
studies
No. of
participants Statistical method Effect size
1 Mean daily symptom score
during grass pollen season
1 100 Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.45, 0.45]
Comparison 2. Well days
Outcome or subgroup title No. of
studies
No. of
participants Statistical method Effect size
1 % of well days during grass
pollen season
1 100 Mean Difference (IV, Fixed, 95% CI) 3.0 [-7.98, 13.98]
Comparison 3. Lung function measures
Outcome or subgroup title No. of
studies
No. of
participants Statistical method Effect size
1 Bronchial reactivity change 1 30 Mean Difference (IV, Fixed, 95% CI) 0.51 [-0.68, 1.70]
Comparison 4. Use of rescue medication
Outcome or subgroup title No. of
studies
No. of
participants Statistical method Effect size
1 Mean total daily medication use
score during grass pollen season
1 100 Mean Difference (IV, Fixed, 95% CI) -1.10 [-2.41, 0.21]
2 % days requiring rescue
medication (as eye drops)
during grass pollen season
1 100 Mean Difference (IV, Fixed, 95% CI) -2.0 [-12.40, 8.40]
3 % days requiring rescue
medication (as nasal sprays)
during grass pollen season
1 100 Mean Difference (IV, Fixed, 95% CI) -3.0 [-14.19, 8.19]
4 % days requiring rescue
medication (as tablets) during
grass pollen season
1 100 Mean Difference (IV, Fixed, 95% CI) -14.0 [-26.60, -1.40]
29Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 5. Rhinoconjunctivitis quality of life score
Outcome or subgroup title No. of
studies
No. of
participants Statistical method Effect size
1 Total quality of life score over 12
weeks
1 30 Mean Difference (IV, Fixed, 95% CI) 0.33 [-0.27, 0.93]
Comparison 6. Serious adverse events
Outcome or subgroup title No. of
studies
No. of
participants Statistical method Effect size
1 Hospitalisation due to any
adverse event
1 96 Risk Ratio (M-H, Fixed, 95% CI) 2.88 [0.31, 26.69]
2 Hospitalisation due to any
gastrointestinal adverse event
1 96 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.66]
Comparison 7. Other adverse events
Outcome or subgroup title No. of
studies
No. of
participants Statistical method Effect size
1 Any adverse event 1 96 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.91, 1.23]
2 Any gastrointestinal adverse
event
1 96 Risk Ratio (M-H, Fixed, 95% CI) 1.79 [1.31, 2.45]
3 Moderate or severe abdominal
pain
1 96 Risk Ratio (M-H, Fixed, 95% CI) 7.67 [1.87, 31.57]
4 Moderate or severe diarrhoea 1 96 Risk Ratio (M-H, Fixed, 95% CI) 1.99 [1.18, 3.37]
5 Moderate or severe flatulence 1 96 Risk Ratio (M-H, Fixed, 95% CI) 2.01 [1.06, 3.81]
6 Moderate or severe pruritus ani 1 96 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.27, 1.92]
Comparison 8. Drop-outs
Outcome or subgroup title No. of
studies
No. of
participants Statistical method Effect size
1 All-cause study withdrawal 2 130 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.18, 3.21]
30Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.1. Comparison 1 Allergic rhinitis symptoms, Outcome 1 Mean daily symptom score during grass
pollen season.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 1 Allergic rhinitis symptoms
Outcome: 1 Mean daily symptom score during grass pollen season
Study or subgroup Helminths Placebo
Mean
Difference Weight
Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Bager 2010 50 1.4 (1.2) 50 1.4 (1.1) 100.0 % 0.0 [ -0.45, 0.45 ]
Total (95% CI) 50 50 100.0 % 0.0 [ -0.45, 0.45 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
Test for subgroup differences: Not applicable
-1 -0.5 0 0.5 1
Favours helminths Favours placebo
Analysis 2.1. Comparison 2 Well days, Outcome 1 % of well days during grass pollen season.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 2 Well days
Outcome: 1 % of well days during grass pollen season
Study or subgroup Experimental Control
Mean
Difference Weight
Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Bager 2010 50 36 (29) 50 33 (27) 100.0 % 3.00 [ -7.98, 13.98 ]
Total (95% CI) 50 50 100.0 % 3.00 [ -7.98, 13.98 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.54 (P = 0.59)
Test for subgroup differences: Not applicable
-20 -10 0 10 20
Favours placebo Favours helminths
31Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.1. Comparison 3 Lung function measures, Outcome 1 Bronchial reactivity change.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 3 Lung function measures
Outcome: 1 Bronchial reactivity change
Study or subgroup Experimental Control
Mean
Difference Weight
Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Feary 2009a 15 1.67 (1.72) 15 1.16 (1.6) 100.0 % 0.51 [ -0.68, 1.70 ]
Total (95% CI) 15 15 100.0 % 0.51 [ -0.68, 1.70 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.84 (P = 0.40)
Test for subgroup differences: Not applicable
-4 - 2 0 2 4
Favours helminths Favours placebo
Analysis 4.1. Comparison 4 Use of rescue medication, Outcome 1 Mean total daily medication use score
during grass pollen season.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 4 Use of rescue medication
Outcome: 1 Mean total daily medication use score during grass pollen season
Study or subgroup Helminths Placebo
Mean
Difference Weight
Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Bager 2010 50 4 (2.8) 50 5.1 (3.8) 100.0 % -1.10 [ -2.41, 0.21 ]
Total (95% CI) 50 50 100.0 % -1.10 [ -2.41, 0.21 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.65 (P = 0.099)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours helminths Favours placebo
32Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.2. Comparison 4 Use of rescue medication, Outcome 2 % days requiring rescue medication (as
eye drops) during grass pollen season.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 4 Use of rescue medication
Outcome: 2 % days requiring rescue medication (as eye drops) during grass pollen season
Study or subgroup Helminths Placebo
Mean
Difference Weight
Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Bager 2010 50 23 (25) 50 25 (28) 100.0 % -2.00 [ -12.40, 8.40 ]
Total (95% CI) 50 50 100.0 % -2.00 [ -12.40, 8.40 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.38 (P = 0.71)
Test for subgroup differences: Not applicable
-50 -25 0 25 50
Favours helminths Favours placebo
Analysis 4.3. Comparison 4 Use of rescue medication, Outcome 3 % days requiring rescue medication (as
nasal sprays) during grass pollen season.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 4 Use of rescue medication
Outcome: 3 % days requiring rescue medication (as nasal sprays) during grass pollen season
Study or subgroup Helminths Placebo
Mean
Difference Weight
Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Bager 2010 50 22 (27) 50 25 (30) 100.0 % -3.00 [ -14.19, 8.19 ]
Total (95% CI) 50 50 100.0 % -3.00 [ -14.19, 8.19 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.53 (P = 0.60)
Test for subgroup differences: Not applicable
-50 -25 0 25 50
Favours helminths Favours placebo
33Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.4. Comparison 4 Use of rescue medication, Outcome 4 % days requiring rescue medication (as
tablets) during grass pollen season.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 4 Use of rescue medication
Outcome: 4 % days requiring rescue medication (as tablets) during grass pollen season
Study or subgroup Helminths Placebo
Mean
Difference Weight
Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Bager 2010 50 31 (29) 50 45 (35) 100.0 % -14.00 [ -26.60, -1.40 ]
Total (95% CI) 50 50 100.0 % -14.00 [ -26.60, -1.40 ]
Heterogeneity: not applicable
Test for overall effect: Z = 2.18 (P = 0.029)
Test for subgroup differences: Not applicable
-50 -25 0 25 50
Favours helminths Favours placebo
Analysis 5.1. Comparison 5 Rhinoconjunctivitis quality of life score, Outcome 1 Total quality of life score
over 12 weeks.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 5 Rhinoconjunctivitis quality of life score
Outcome: 1 Total quality of life score over 12 weeks
Study or subgroup Helminths Placebo
Mean
Difference Weight
Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Feary 2009a 15 6.01 (0.82) 15 5.68 (0.85) 100.0 % 0.33 [ -0.27, 0.93 ]
Total (95% CI) 15 15 100.0 % 0.33 [ -0.27, 0.93 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.08 (P = 0.28)
Test for subgroup differences: Not applicable
-2 - 1 0 1 2
Favours helminths Favours placebo
34Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 6.1. Comparison 6 Serious adverse events, Outcome 1 Hospitalisation due to any adverse event.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 6 Serious adverse events
Outcome: 1 Hospitalisation due to any adverse event
Study or subgroup Helminths Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 3/49 1/47 100.0 % 2.88 [ 0.31, 26.69 ]
Total (95% CI) 49 47 100.0 % 2.88 [ 0.31, 26.69 ]
Total events: 3 (Helminths), 1 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.93 (P = 0.35)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100
Favours helminths Favours placebo
Analysis 6.2. Comparison 6 Serious adverse events, Outcome 2 Hospitalisation due to any gastrointestinal
adverse event.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 6 Serious adverse events
Outcome: 2 Hospitalisation due to any gastrointestinal adverse event
Study or subgroup Helminths Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 0/49 1/47 100.0 % 0.32 [ 0.01, 7.66 ]
Total (95% CI) 49 47 100.0 % 0.32 [ 0.01, 7.66 ]
Total events: 0 (Helminths), 1 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.70 (P = 0.48)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100
Favours helminths Favours placebo
35Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 7.1. Comparison 7 Other adverse events, Outcome 1 Any adverse event.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 7 Other adverse events
Outcome: 1 Any adverse event
Study or subgroup Helminths Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 44/49 40/47 100.0 % 1.06 [ 0.91, 1.23 ]
Total (95% CI) 49 47 100.0 % 1.06 [ 0.91, 1.23 ]
Total events: 44 (Helminths), 40 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.69 (P = 0.49)
Test for subgroup differences: Not applicable
0.5 0.7 1 1.5 2
Favours helminths Favours placebo
Analysis 7.2. Comparison 7 Other adverse events, Outcome 2 Any gastrointestinal adverse event.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 7 Other adverse events
Outcome: 2 Any gastrointestinal adverse event
Study or subgroup Helminths Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 43/49 23/47 100.0 % 1.79 [ 1.31, 2.45 ]
Total (95% CI) 49 47 100.0 % 1.79 [ 1.31, 2.45 ]
Total events: 43 (Helminths), 23 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 3.69 (P = 0.00022)
Test for subgroup differences: Not applicable
0.2 0.5 1 2 5
Favours helminths Favours placebo
36Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 7.3. Comparison 7 Other adverse events, Outcome 3 Moderate or severe abdominal pain.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 7 Other adverse events
Outcome: 3 Moderate or severe abdominal pain
Study or subgroup Helminths Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 16/49 2/47 100.0 % 7.67 [ 1.87, 31.57 ]
Total (95% CI) 49 47 100.0 % 7.67 [ 1.87, 31.57 ]
Total events: 16 (Helminths), 2 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 2.82 (P = 0.0047)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100
Favours helminths Favours placebo
Analysis 7.4. Comparison 7 Other adverse events, Outcome 4 Moderate or severe diarrhoea.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 7 Other adverse events
Outcome: 4 Moderate or severe diarrhoea
Study or subgroup Helminths Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 27/49 13/47 100.0 % 1.99 [ 1.18, 3.37 ]
Total (95% CI) 49 47 100.0 % 1.99 [ 1.18, 3.37 ]
Total events: 27 (Helminths), 13 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 2.56 (P = 0.010)
Test for subgroup differences: Not applicable
0.05 0.2 1 5 20
Favours helminths Favours placebo
37Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 7.5. Comparison 7 Other adverse events, Outcome 5 Moderate or severe flatulence.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 7 Other adverse events
Outcome: 5 Moderate or severe flatulence
Study or subgroup Helminths Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 21/49 10/47 100.0 % 2.01 [ 1.06, 3.81 ]
Total (95% CI) 49 47 100.0 % 2.01 [ 1.06, 3.81 ]
Total events: 21 (Helminths), 10 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 2.15 (P = 0.031)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100
Favours helminths Favours placebo
Analysis 7.6. Comparison 7 Other adverse events, Outcome 6 Moderate or severe pruritus ani.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 7 Other adverse events
Outcome: 6 Moderate or severe pruritus ani
Study or subgroup Helminths Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 6/49 8/47 100.0 % 0.72 [ 0.27, 1.92 ]
Total (95% CI) 49 47 100.0 % 0.72 [ 0.27, 1.92 ]
Total events: 6 (Helminths), 8 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.66 (P = 0.51)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100
Favours helminths Favours placebo
38Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 8.1. Comparison 8 Drop-outs, Outcome 1 All-cause study withdrawal.
Review: Helminth therapy (worms) for allergic rhinitis
Comparison: 8 Drop-outs
Outcome: 1 All-cause study withdrawal
Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bager 2010 1/50 3/50 75.0 % 0.33 [ 0.04, 3.10 ]
Feary 2009a 2/15 1/15 25.0 % 2.00 [ 0.20, 19.78 ]
Total (95% CI) 65 65 100.0 % 0.75 [ 0.18, 3.21 ]
Total events: 3 (Experimental), 4 (Control)
Heterogeneity: Chi?? = 1.21, df = 1 (P = 0.27); I?? =18%
Test for overall effect: Z = 0.39 (P = 0.70)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100
Favours helminths Favours placebo
A P P E N D I C E S
Appendix 1. Commonly encountered helminths of humans
Phylum Common species/definitive anatomical sites as adult worms
Annelids (segmented worms) Class: Hirudinea (leeches) - ectoparasites only
Nematodes (roundworms) Class: Nematoda (roundworms)
The dermis:
Mansonella streptocercac
The gut - small intestine:
Ancylostoma duodenale (hookworm)a,Ascaris lumbricoides (roundworm)a,Capillaria philippinensisd,
Necator americanus (hookworm)a,Strongyloides stercoralis (threadworm)a,Trichostrongylus orientalis
d
The gut - large intestine:
Trichuris trichiura (whipworm)d
The gut - caecum:
Enterobius vermicularis (pinworm)d
The lymphatic system:
Brugia malayia,Brugia timoria,Wuchereria bancroftia
The pericardial, peritoneal and pleural cavities:
Dracunculus medinensis (Guinea worm)b,Mansonella perstansa
39Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
The subcutaneous tissues:
Loa loac,Mansonella ozzardic,Onchocerca volvulusc
Platyhelminths (flatworms) Class: Trematoda (flukes)
The bronchi:
Paragonimus sppa
The gut - small intestine:
Echinostoma sppd,Fasciolopsis sppd,Gastrodiscoides sppd,Heterophyes sppd,Metagonimus sppd
The hepatobiliary system:
Clonorchis sinensisd,Fasciola giganticaa,Fasciola hepaticaa,Opisthorchis felineusd,Opisthorchis viverrini
d
The venous system - mesenteric veins:
Schistosoma intercalatuma,Schistosoma japonicuma,Schistosoma mansonia,Schistosoma mekongia
The venous system - vesical plexus:
Schistosoma haematobiuma
Class: Cestoda (tapeworms)
The gut - small intestine:
Diphyllobothrium latum (fish tapeworm)d,Diphyllobothrium pacificumd,Dipylidium caninumd,Hy-
menolepsis diminuta (rat tapeworm)d,Hymenolepsis nana (dwarf tapeworm)d,Taenia saginata (beef
tapeworm)d,Taenia solium (pork tapeworm)d
aMigrates through host tissues, in larval forms.
bMigrates through host tissues, as adult worm.
cMigrates through host tissues in both larval forms and as adult worm.
dNo significant tissue migration through host tissues.
Appendix 2. Biological characteristics of helminths
Helminths have the following important biological characteristics:
1. Helminths are complex multicellular organisms. When mature, they range in length from 2 mm (Strongyloides stercoralis adults)
to 8 m (Taenia saginata adults) (Weller 2008).
2. Most helminth species are free-living and inhabit either bodies of fresh water, or else warm, moist soil. The latter group of
helminths are known collectively as soil-transmitted helminths (or ‘geohelminths’).
3. Helminths have highly developed internal structures, including alimentary and reproductive tracts.
4. Helminths have complex and highly varied life cycles, with multiple developmental stages. Some developmental stages may take
place in an intermediate host. Some helminth species require two distinct, successive intermediate hosts.
5. Helminths are highly species-specific, in most cases with a biological dependence on a single definitive host; where they have one
or more intermediate hosts, they are highly species-specific for these also (Strickland 2000).
6. A very few helminth species (e.g. Enterobius vermicularis and Strongyloides stercoralis) can be transmitted directly from person to
person. Generally, however, person-to-person transmission is not possible (and hence helminths meet minimum safety criteria as
therapeutic interventions).
7. With the exception of leeches, which are solely ectoparasites, helminths enter their definitive, human hosts either orally (as eggs
or cysts) or percutaneously (as larvae or cercariae). A specific arthropod vector such as a specific mosquito species (in lymphatic
filariasis) or a specific species of biting fly or midge (in loiasis, onchocerciasis and mansonellosis) may be necessary for the helminth to
achieve successful percutaneous penetration of the host.
8. Multiple infections with different helminth species are common in endemic areas (Finch 2009).
9. The larval and adult forms of helminths are always motile. Many helminths species have a larval migratory phase in their human
hosts, before taking up residence as adult worms in their definitive anatomical site (see Appendix 1). Some adult helminths species
migrate also. Eosinophilia and elevated serum IgE levels are features of many helminth infestations (Weller 2008).
40Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
10. Once established in their definitive anatomical site, adult helminths may be very long-lived (up to 30 years in the case of the
schistosomes) (Finch 2009). However, because most helminth parasites do not self replicate, the acquisition of a heavy burden of
adult worms requires repeated exposure to the parasite in its infectious stage, whether egg or larva. Hence clinical disease, as opposed
to asymptomatic infection, generally develops only with prolonged residence in an endemic area (Weller 2008).
11. On account of their large size, helminths are solely extracellular; hence they are sometimes referred to as ‘macroparasites’ (Olano
2006).
12. Because of their size, and their prolonged life cycles and generation times, helminths have limited capacity for genetic alteration,
compared to smaller, simpler microbes or ‘microparasites’ (Olano 2006).
Appendix 3. Search strategies
CENTRAL PubMed EMBASE (Ovid) CINAHL (EBSCO)
#1 MeSH descriptor Rhinitis
explode all trees with qualifier:
PS
#2 MeSH descriptor Rhinitis
explode all trees
#3 (rhiniti* OR rhinopath* OR
rhinosinusit* OR rhinocon-
junctivitis OR ozena* OR
hayfever OR hay NEXT fever
OR pollinosis OR pollenosis
OR pollonosis)
#4 (allerg* :ti OR hypersensi-
tiv*:ti)
#5 (nose:ti OR nasal*:ti OR
cat*:ti OR dander:ti OR mite*:
ti OR dust*:ti OR dog*:ti OR
ragweed:ti OR pollen:ti OR
grass*:ti OR cedar:ti OR alder:
ti OR willow:ti OR birch:ti
OR mugwort:ti OR tree*:ti OR
weed*:ti OR rapeseed*:ti OR
perennial*:ti OR season*:ti OR
spring:ti OR summer:ti OR res-
piratory:ti OR SAR:ti OR PAR:
ti))
#6 #4 AND #5
#7 #2 OR #3 OR #6
#8 MeSH descriptor
Helminths explode all trees
#9 MeSH descriptor Antigens,
Helminth explode all trees
#10 MeSH descriptor Antibod-
ies, Helminth explode all trees
#11 MeSH descriptor Parasitol-
ogy explode all trees
#12 (helminth*
#1 “Rhinitis/
parasitology”[Mesh]
#2 “Rhinitis”
[Mesh] OR rhiniti* [tiab] OR
rhinopath* [tiab] OR rhinosi-
nusit* [tiab] OR rhinoconjunc-
tivitis [tiab] OR ozena* [tiab]
OR hayfever [tiab] OR (hay
[tiab] AND fever [tiab] ) OR
pollinosis [tiab] OR pollenosis
[tiab] OR pollonosis [tiab]
#3 ((allerg* [ti] OR hyper-
sensitiv*[ti]) AND (nose[ti]
OR nasal*[ti] OR cat*[ti] OR
dander[ti] OR mite*[ti] OR
dust*[ti] OR dog*[ti] OR rag-
weed[ti] OR pollen[ti] OR
grass*[ti] OR cedar[ti] OR
alder[ti] OR willow[ti] OR
birch[ti] OR mugwort[ti] OR
tree*[ti] OR weed*[ti] OR rape-
seed*[ti] OR perennial*[ti] OR
season*[ti] OR spring[ti] OR
summer[ti] OR respiratory[ti]
OR SAR[ti] OR PAR[ti]))
#4 #2 OR #3
#5
“Helminths” [Mesh] OR “Anti-
gens, Helminth” [Mesh] OR
Antibodies, Helminth” [Mesh]
OR “Parasitology” [Mesh]
#6
(helminth* OR anti-helminth*
OR antihelminth* OR an-
thelmint* OR aschelminth*
1 exp rhinitis/
2 (rhiniti* or rhinopath* or rhi-
nosinusit* or rhinoconjunctivi-
tis or ozena* or hayfever or (hay
and fever) or pollinosis or pol-
lenosis or pollonosis).tw.
3 ((allerg* or hypersensitiv*)
and (nose or nasal* or cat* or
dander or mite* or dust* or dog*
or ragweed or pollen or grass* or
cedar or alder or willow or birch
or mugwort or tree* or weed* or
rapeseed* or perennial* or sea-
son* or spring or summer or res-
piratory or SAR or PAR)).ti.
4 1 or 2 or 3
5 exp helminth/
6 exp parasite antigen/
7 exp parasite antibody/
8 (helminth* or anti-helminth*
or an-
tihelminth* or anthelmint* or
aschelminth* or geohelminth*
or parasit* or annelid* or hiru-
dine* or leech* or nematod* or
roundworm* or hookworm* or
pinworm* or threadworm* or
whipworm* or ancylostom* or
ascari* or brugia or enterobi* or
loa or mansonell* or onchocerc*
or necator or strongyl* or tox-
ocar* or trichin* or trichur*
or wuchereria or worm* or fi-
lariasis or onchocerca or on-
chocerciasis or loa-loa or loia-
S1 (MH “Rhinitis+”)
S2 TX (rhiniti* or rhinopath*
or rhinosinusit* or rhinocon-
junctivitis or ozena* or hayfever
or (hay and fever) or pollinosis
or pollenosis or pollonosis)
S3 TI ((allerg* or hypersensi-
tiv*) and (nose or nasal* or cat*
or dander or mite* or dust* or
dog* or ragweed or pollen or
grass* or cedar or alder or willow
or birch or mugwort or tree*
or weed* or rapeseed* or peren-
nial* or season* or spring or
summer or respiratory or SAR
or PAR))
S4 S1 or S2 or S3
S5 (MH “Helminths”)
S6 TX (helminth* or anti-
helminth* or antihelminth* or
anthelmint* or aschelminth* or
geohelminth* or parasit* or an-
nelid* or hirudine* or leech*
or nematod* or roundworm*
or hookworm* or pinworm*
or threadworm* or whipworm*
or ancylostom* or ascari* or
brugia or enterobi* or loa or
mansonell* or onchocerc* or
necator or strongyl* or tox-
ocar* or trichin* or trichur*
or wuchereria or worm* or fi-
lariasis or onchocerca or on-
chocerciasis or loa-loa or loia-
41Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
OR anti-helminth* OR an-
tihelminth* OR anthelmint*
OR aschelminth* OR soil-
transmitted helminth* OR geo-
helminth* OR parasit*)
#13 (annelid* OR hirudine*
OR leech*)
#14 (nematod* OR round-
worm* OR hookworm* OR
pinworm* OR threadworm*
OR whipworm* OR ancy-
lostom* OR ascari* OR brugia
OR enterobi* OR loa OR man-
sonell* OR onchocerc* neca-
tor OR strongyl* OR toxocar*
OR trichin* OR trichur* OR
wuchereria)
#15 ((filarial AND worm*) OR
filariasis OR onchocerca OR
onchocerciasis OR loa-loa OR
loiasis OR wuchereria OR bru-
gia OR mansonella OR man-
sonellosis )
#16 (dracuncul* OR (guinea
AND worm*))
#17 (platyhelminth* OR flat-
worm* OR trematod* OR
fluke* OR clonorchis OR echi-
nostom* fasciol* OR gastrodis-
coid* OR heterophy* OR
metagonim* OR opisthorch*
OR paragonim* OR schisto-
som*)
#18 (cestod* OR tapeworm*
OR diphyllobothrium OR hy-
menolepis OR taenia* OR
tenia* OR cysticerc*)
#19 #8 OR #9 OR #10 OR #
11 OR #12 OR #13 OR #14
OR #15 OR #16 OR #17 OR
#18
#20 #7 AND #19
#21 #1 OR #20
OR soil-transmitted helminth*
OR geohelminth* OR para-
sit* OR annelid* OR hiru-
dine* OR leech* OR nema-
tod* OR roundworm* OR
hookworm* OR pinworm* OR
threadworm* OR whipworm*
OR ancylostom* OR ascari*
OR brugia OR enterobi* OR
loa OR mansonell* OR on-
chocerc* necator OR strongyl*
OR toxocar* OR trichin* OR
trichur* OR wuchereria OR (fi-
larial AND worm*) OR filar-
iasis OR onchocerca OR on-
chocerciasis OR loa-loa OR
loiasis OR wuchereria OR bru-
gia OR mansonella OR man-
sonellosis OR dracuncul* OR
(guinea AND worm*)
#7 (platyhelminth* OR flat-
worm* OR trematod* OR
fluke* OR clonorchis OR echi-
nostom* fasciol* OR gastrodis-
coid* OR heterophy* OR
metagonim* OR opisthorch*
OR paragonim* OR schisto-
som* OR cestod* OR tape-
worm* OR diphyllobothrium
OR hymenolepis OR taenia*
OR tenia* OR cysticerc*)
#8 #5 OR #6 OR #7
#9 #4 AND #8
#10 #1 OR #9
sis or wuchereria or brugia or
mansonella or mansonellosis or
dracuncul* or platyhelminth*
or flatworm* or trematod* or
fluke* or clonorchis or echinos-
tom* or fasciol* or gastrodis-
coid* or heterophy* or metago-
nim* or opisthorch* or parago-
nim* or schistosom* or cestod*
or tapeworm* or diphylloboth-
rium or hymenolepis or taenia*
or tenia* or cysticerc*).tw.
9 5 or 6 or 7 or 8
10 4 and 9
sis or wuchereria or brugia or
mansonella or mansonellosis or
dracuncul* or platyhelminth*
or flatworm* or trematod* or
fluke* or clonorchis or echinos-
tom* or fasciol* or gastrodis-
coid* or heterophy* or metago-
nim* or opisthorch* or parago-
nim* or schistosom* or cestod*
or tapeworm* or diphylloboth-
rium or hymenolepis or taenia*
or tenia* or cysticerc*)
S7 S5 or S6
S8 S4 and S7
Cochrane
ENT Disorders Group Trials
Register (ProCite database)
Web of Science/BIOSIS Pre-
views (Web of Knowledge)
CAB Abstracts ICTRP
42Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
(helminth* OR anti-helminth*
OR antihelminth* OR an-
thelmint* OR aschelminth*
OR geohelminth* OR para-
sit* OR annelid* OR hirudine*
OR leech* OR nematod* OR
roundworm* OR hookworm*
OR pinworm* OR thread-
worm* OR whipworm* OR an-
cylostom* OR ascari* OR bru-
gia OR enterobi* OR loa OR
mansonell* OR onchocerc* OR
necator OR strongyl* OR tox-
ocar* OR trichin* OR trichur*
OR wuchereria OR worm*
OR filariasis OR onchocerca
OR onchocerciasis OR loa-
loa OR loiasis OR wuchere-
ria OR brugia OR mansonella
OR mansonellosis OR dracun-
cul* OR platyhelminth* OR
flatworm* OR trematod* OR
fluke* OR clonorchis OR echi-
nostom* OR fasciol* OR gas-
trodiscoid* OR heterophy* OR
metagonim* OR opisthorch*
OR paragonim* OR schisto-
som* OR cestod* OR tape-
worm* OR diphyllobothrium
OR hymenolepis OR taenia*
OR tenia* OR cysticerc*)
#1 TS=(rhiniti* or rhinopath*
or rhinosinusit* or rhinocon-
junctivitis or ozena* or hayfever
or (hay and fever) or pollinosis
or pollenosis or pollonosis)
#2 TI=((allerg* or hypersensi-
tiv*) and (nose or nasal* or cat*
or dander or mite* or dust* or
dog* or ragweed or pollen or
grass* or cedar or alder or willow
or birch or mugwort or tree*
or weed* or rapeseed* or peren-
nial* or season* or spring or
summer or respiratory or SAR
or PAR))
#3 #2 OR #1
#4 TS=(helminth* or anti-
helminth* or antihelminth* or
anthelmint* or aschelminth* or
geohelminth* or parasit* or an-
nelid* or hirudine* or leech*
or nematod* or roundworm*
or hookworm* or pinworm* or
threadworm* or whipworm* or
ancylostom* or ascari* or bru-
gia or enterobi* or loa or man-
sonell* or onchocerc* or neca-
tor or strongyl* or toxocar* or
trichin* or trichur*)
#5 TS=(wuchereria or worm*
or filariasis or onchocerca or on-
chocerciasis or loa-loa or loia-
sis or wuchereria or brugia or
mansonella or mansonellosis or
dracuncul* or platyhelminth*
or flatworm* or trematod* or
fluke* or clonorchis or echinos-
tom* or fasciol* or gastrodis-
coid*)
#6 TS=(heterophy* or metago-
nim* or opisthorch* or parago-
nim* or schistosom* or cestod*
or tapeworm* or diphylloboth-
rium or hymenolepis or taenia*
or tenia* or cysticerc*)
#7 #6 OR #5 OR #4
#8 #7 AND #3
1 (rhiniti* or rhinopath* or rhi-
nosinusit* or rhinoconjunctivi-
tis or ozena* or hayfever or (hay
and fever) or pollinosis or pol-
lenosis or pollonosis).tw.
2 ((allerg* or hypersensitiv*)
and (nose or nasal* or cat* or
dander or mite* or dust* or dog*
or ragweed or pollen or grass* or
cedar or alder or willow or birch
or mugwort or tree* or weed* or
rapeseed* or perennial* or sea-
son* or spring or summer or res-
piratory or SAR or PAR)).ti.
3 1 or 2
4 (helminth* or anti-helminth*
or an-
tihelminth* or anthelmint* or
aschelminth* or geohelminth*
or parasit* or annelid* or hiru-
dine* or leech* or nematod* or
roundworm* or hookworm* or
pinworm* or threadworm* or
whipworm* or ancylostom* or
ascari* or brugia or enterobi* or
loa or mansonell* or onchocerc*
or necator or strongyl* or tox-
ocar* or trichin* or trichur*
or wuchereria or worm* or fi-
lariasis or onchocerca or on-
chocerciasis or loa-loa or loia-
sis or wuchereria or brugia or
mansonella or mansonellosis or
dracuncul* or platyhelminth*
or flatworm* or trematod* or
fluke* or clonorchis or echinos-
tom* or fasciol* or gastrodis-
coid* or heterophy* or metago-
nim* or opisthorch* or parago-
nim* or schistosom* or cestod*
or tapeworm* or diphylloboth-
rium or hymenolepis or taenia*
or tenia* or cysticerc*).tw.
5 3 and 4
rhinti* AND helminth* OR
rhiniti* AND worm*
OR rhiniti* AND parasit* OR
hayfever AND helminth* OR
hayfever AND worm* OR
hayfever AND parasit* OR pol-
lenosis AND helminth* OR
pollenosis AND worm* OR
pollenosis AND parasit*
43Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 4. ’Risk of bias’ assessment
Strategy to assess risk of bias
We will assess each of the following study features and record them as ’Yes’, ’No’ or ’Unclear’.
1. Sequence generation for randomisation
Was the allocation sequence adequately generated, e.g. coin toss, random number tables, computer-generated, other?
2. Allocation concealment
Was allocation adequately concealed in a way that would not allow both the investigators and the participants to know or
influence the intervention group before an eligible participant is entered into the study, e.g. central randomisation or sequentially
numbered, opaque, sealed envelopes?
3. Blinding
Were investigators blinded to the helminth interventions they were administering?
Were participants blinded to the helminth interventions they were receiving?
Were assessors blinded to the effects they were assessing?
For each of the three groups, we will record blinding as: ’Yes’, ’No’, ’Not possible’ or ’Unclear’. We will record the study as double-
blind if both the investigators and participants were blinded, and as triple-blind if all three groups were blinded.
4. Incomplete outcome data
Were incomplete outcome data adequately addressed?
If any withdrawals occurred, were these withdrawals described and reported by treatment group?
Were clear explanations recorded for withdrawals and drop-outs in treatment groups?
Incomplete outcome data essentially include attrition, exclusions and missing data. An example of an adequate method to address
incomplete outcome data is the use of intention-to-treat analysis (ITT).
5. Selective reporting of outcomes
Are reports of the study free from any suggestion of selective outcome reporting?
If ’Yes’, this will be interpreted as no evidence that statistically non-significant results might have been selectively withheld from
publication (e.g. through selective under-reporting of data, or through selective reporting of a subset of the data).
6. Other potential sources of bias
Was the study apparently free of other defects that could put it at a high risk of bias (e.g. baseline imbalance, or the use of an
insensitive instrument to measure outcomes)?
44Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
H I S T O R Y
Protocol first published: Issue 7, 2011
Review first published: Issue 4, 2012
C O N T R I B U T I O N S O F A U T H O R S
AC conceived and co-ordinated the review, registered the title, wrote the protocol, helped design the CENTRAL search strategy,
searched for studies, carried out initial screening and quality assessment, wrote to authors, performed data extraction and data
analysis, and wrote the review text.
PB helped develop the protocol, carried out initial screening and quality assessment, and helped write the review text.
SK helped develop the protocol, helped with data analysis and helped write the review text.
D E C L A R A T I O N S O F I N T E R E S T
PB was lead investigator in one of the studies included in this review. He has signed a consultancy contract with Colorado Biosciences
Inc, who hold the license for Trichuris suis ova in the USA.
There are no other financial conflicts of interest and the review authors declare that they have no other association with any manufacturer
or promoter of pharmaceutical or helminth products, and no association with any parties who may have vested interests in the results
of this review.
S O U R C E S O F S U P P O R T
Internal sources
Commander Regional Forces, UK.
External sources
None, Not specified.
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
Between drafting the protocol and writing the review we added some outcomes, and renamed or reordered others. This is unusual in a
Cochrane review but we felt it to be necessary as this was the first review of its kind in this field and a logical structure for the important
outcomes associated with helminth therapy only emerged after some considerable reflection and discussion between the authors. Our
intention was not to manipulate the results in any particular direction.
We extracted the data for but did not systematically analyse a number of physiological measurements (change in diameter of skin wheal
on skin prick testing, assessment of basophil activation) and laboratory values (serum antibodies, serum haemoglobin, total histamine).
These data were of interest to the investigators but not important to patients, and hence were not central to this review.
PB inspected 100% all the identified abstracts, instead of a 10% sample as proposed in the protocol.
45Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Ancylostomatoidea [immunology]; Helminths [immunology]; Immunotherapy [methods]; Randomized Controlled Trials as Topic;
Rhinitis, Allergic, Perennial [immunology; therapy]; Rhinitis, Allergic, Seasonal [immunology; therapy]; Trichuris [immunology]
MeSH check words
Adult; Animals; Humans
46Helminth therapy (worms) for allergic rhinitis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
... In animal models of arthritis and allergic asthma, immunomodulatory effects were shown (Song et al. 2011;Pitrez et al. 2015). Furthermore, the therapeutic efficacy has been observed in clinical trials of inflammatory diseases including rhinitis and multiple sclerosis (Croft et al. 2012;Correale and Farez 2007). Helminths have molecules that have potential therapeutic action against inflammatory diseases. ...
... Parasitic infections appear to inhibit allergic and inflammatory immune responses (Maizels et al. 2004;Fallon and Mangan 2007). Helminths produce immunomodulatory molecules to suppress immune responses at various levels, from innate immunity to end-effector mechanisms in adaptive responses, offering potential opportunities to treat a range of human diseases (Daniłowicz-Luebert et al. 2011;Song et al. 2011;Pitrez et al. 2015;Croft et al. 2012;Correale and Farez 2007). Our study revealed that early immunisation with the TE and specific systems (AcD, AcR, and AcC) of A. cantonensis adult worms protects against an inflammatory response in an allergic asthma model. ...
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