Feary, Johanna Ruth
(2012)
Asthma and allergic disease: their relation with Necator americanus and other helminth infections.
PhD thesis, University of Nottingham.
Abstract
Background
The rate at which the prevalence of allergic disease is increasing in many countries suggests that environmental exposures may be important aetiological factors. Epidemiological evidence indicates that infection with helminth parasites may be one such factor: in particular, in a systematic review and meta-analysis, current hookworm (Necator americanus) infection at an intensity of 50 eggs/g faeces was shown to be associated with a halving of risk of asthma. The relation between parasite infection and atopy has not been subjected to the same rigorous and comprehensive review. Based on the results of the studies in asthma, it is possible that hookworm infection may have potential in the treatment of this disease, but to date, no clinical trials have been carried out to test this hypothesis. For ethical and safety reasons, before embarking on a clinical trial in asthma it is necessary to establish the dose of larvae required to produce at least 50 eggs/g faeces, and to determine whether experimental hookworm infection might exacerbate bronchial hyper-responsiveness during larval lung migration.
Aims and objectives
The first aim of this thesis was to establish whether experimental hookworm infection improves asthma by carrying out a series of three intervention studies. The second aim was to determine the association between intestinal parasite infection and atopy (defined as positive allergen skin sensitisation or the presence of specific IgE) and to establish whether the association was species-specific. This thesis therefore consists of two main components: a series of three clinical trials of experimental hookworm infection; and a systematic review and metaanalysis of the association between intestinal parasite infection and atopy.
Methods and Results
Dose-ranging study of experimental hookworm infection
Aim: To identify the dose of hookworm larvae necessary to achieve 50 eggs/g faeces and to monitor any adverse effects of infection.
Methods: Ten healthy volunteers, without asthma or bronchial responsiveness to inhaled methacholine, received 10, 25, 50, or 100 Necator americanus larvae administered double-blind to an area of skin on the arm and were monitored weekly for 12 weeks.
Results: All doses resulted in the production of at least 50 eggs/g faeces in the eight subjects who completed the study. Skin itching at the entry site and gastrointestinal symptoms were common at higher doses.
Study of experimental hookworm infection in allergic rhinoconjunctivitis
Aim: To determine whether hookworm larval migration through the lungs increases bronchial responsiveness in allergic individuals with measurable bronchial responsiveness but not clinical asthma, and to investigate the general tolerability of infection and its effect on allergic symptoms.
Methods: Thirty individuals with allergic rhinoconjunctivitis and measurable bronchial responsiveness to adenosine monophosphate (AMP) but not clinically diagnosed asthma were randomised, double-blind, to cutaneous administration of either ten Necator americanus larvae or histamine placebo, and followed for 12 weeks. The primary outcome was the maximum fall from baseline in provocative dose of inhaled AMP required to reduce one-second forced expiratory volume by 10% (PD10AMP) measured at any time over the four weeks after active or placebo infection. Secondary outcomes included peak flow variability in the four weeks after infection, adverse effect diary scores and rhinoconjunctivitis symptom severity over the 12-week study period, and change in allergen skin sensitisation between baseline and 12 weeks.
Results: Mean maximum change in PD10AMP from baseline was slightly but not significantly greater in the hookworm than the placebo group (-1.67 and -1.16 doubling doses; mean difference -0.51, 95% confidence interval: -1.80 to 0.78; p=0.42). There were no significant differences in peak flow variability, rhinoconjunctivitis symptoms or allergen skin sensitisation between groups. Symptom scores of potential adverse effects were more commonly reported in the hookworm group, but infection was generally well tolerated.
Study of experimental hookworm infection in asthma
Aim: To determine the effects of experimental hookworm infection on asthma.
Methods: Thirty-two individuals with asthma and measurable bronchial hyperresponsiveness to adenosine monophosphate (AMP) were randomised, doubleblind, to cutaneous administration of either ten Necator americanus larvae or histamine placebo, and followed for 16 weeks. The primary outcome was the change in provocation dose of inhaled AMP required to reduce one-second forced expiratory volume by 20% (PD20AMP) from baseline to week 16. Secondary outcomes included change in several measures of asthma control and allergen skin sensitisation and the occurrence of adverse effects.
Results: Mean PD20AMP improved in both groups, more in the hookworm (1.49 doubling doses (DD)) than the placebo group (0.98 DD), but the difference between groups was not significant (0.51 DD, 95% confidence interval: -1.79 to 2.80; p=0.65). There were no significant differences between the two groups for other measures of asthma control or allergen skin sensitisation. Infection was generally well tolerated.
Systematic review and meta-analysis of the association between intestinal parasite infection and atopy
Aim: To quantify the association between current intestinal parasite infection and the presence of atopy in a systematic review and meta-analysis of epidemiological studies, and to determine whether, as with asthma, this relation is species-specific.
Methods: MEDLINE, EMBASE, LILIACS and CAB Abstracts (to March 2009); reviews; and reference lists from publications were searched. No language restrictions were applied. Studies that measured current parasite infection using direct faecal microscopy and defined atopy as allergen skin sensitisation or presence of specific IgE were included. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) using data extracted from published papers using random effect models were calculated.
Results: 20 studies met the inclusion criteria. Current parasite infection was associated with a reduced risk of allergen skin sensitisation (OR 0.69, 95% CI: 0.60 to 0.79; p<0.01). When analyses were restricted to current geohelminth infection, the size of effect remained similar (OR 0.68, 95% CI: 0.60 to 0.76; p<0.01). In species-specific analysis, a consistent protective effect was found for infection with Ascaris lumbricoides, Trichuris trichiura and hookworm. There were insufficient data to pool results for chistosomiasis or atopy defined by presence of specific IgE.
Conclusions
Experimental infection with ten Necator americanus larvae produces at least 50 eggs/g faeces, the intensity of infection seen to protect against asthma in observational studies. This dose is safe, well tolerated, feasible to use in clinical trials and does not cause clinically significant exacerbation of bronchial responsiveness during larval pulmonary migration. In clinical trials, it did not result in significant improvement in symptoms of allergic rhinoconjunctivitis, or in bronchial hyper-responsiveness or other measures of asthma control. However, a non-significant improvement in bronchial hyper- responsiveness was seen, indicating that further studies incorporating revised dosing regimens that more closely mimic natural infection are feasible, and should be undertaken, with the aim of identifying novel treatments for asthma. As with asthma, there appears to be an inverse association between intestinal parasite infection and atopy. Work should continue to identify the mechanisms of this effect and means of harnessing these to reduce the global burden of allergic disease.
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