Tratamiento con helmintos (gusanos) para la rinitis alérgica
Resumen
Antecedentes
La rinitis alérgica es un trastorno de las membranas nasales y los tejidos circundantes, y constituye una causa de enfermedad y discapacidad a nivel mundial. Los helmintos son microorganismos complejos que habitan en los tejidos o en la luz de organismos más grandes y suelen ser asintomáticos. Los helmintos modulan las respuestas inmunitarias naturales de los huéspedes humanos y pueden prevenir o curar las enfermedades inmunológicas o alérgicas (p.ej. la rinitis alérgica) del huésped. Estudios no aleatorizados apoyan esta hipótesis.
Objetivos
Evaluar la seguridad y la efectividad del tratamiento con helmintos en pacientes con rinitis alérgica.
Métodos de búsqueda
Se realizaron búsquedas en el Registro Especializado de Ensayos Controlados del Grupo Cochrane de Enfermedades de Oído, Nariz y Garganta (Cochrane Ear, Nose and Throat Disorders Group); Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP y otras fuentes adicionales de ensayos publicados y no publicados. La fecha de la búsqueda fue el 24 de junio de 2011.
Criterios de selección
Todos los ensayos controlados aleatorizados de intervenciones con helmintos de cualquier especie o una combinación de especies, administrados a pacientes con rinitis alérgica a cualquier dosis, por cualquier vía y con cualquier duración de la exposición. Se aceptaron pacientes con rinitis alérgica intermitente y persistente.
Obtención y análisis de los datos
La extracción de los datos y la evaluación de la elegibilidad y del riesgo de sesgo se realizaron de forma independiente y se utilizó un formulario estandarizado de obtención de datos. Cualquier desacuerdo se resolvió mediante discusión. Los datos dicotómicos se combinaron mediante el cociente de riesgos (CR) y los datos continuos mediante la diferencia de medias (DM), ambos con intervalos de confianza (IC) del 95%.
Resultados principales
Se encontraron cinco informes de dos estudios de centro único, doble ciego y controlados con placebo (130 participantes). Ambos estudios incluyeron una combinación de participantes adultos con rinitis alérgica intermitente o persistente. Ambos estudios tuvieron bajo riesgo de sesgo. Un estudio, con un seguimiento de 12 semanas, utilizó una aplicación percutánea única de diez larvas de Necator americanus (es decir, uncinaria humana). El otro estudio, con un seguimiento de 24 semanas, utilizó una dosis oral de 2500 huevos de Trichuris suis (es decir, tricocéfalo del cerdo) tres veces por semana en forma de suspensión acuosa. De 17 resultados evaluados en esta revisión, ocho fueron positivos (es decir, a favor de los helmintos). Los participantes que recibieron helmintos no presentaron reducciones en los síntomas de rinitis alérgica, en el porcentaje de días sin enfermedad (es decir, días con síntomas mínimos y sin uso de medicación para la rinitis alérgica), en las medidas de la función pulmonar ni las puntuaciones de calidad de vida. No se observaron cambios en el uso total de medicación para la rinitis alérgica (gotas oculares, sprays nasales, comprimidos); sin embargo, en el grupo de helmintos hubo una reducción estadísticamente significativa en el porcentaje de días durante la temporada de polen de gramíneas que los participantes necesitaron tomar comprimidos como medicamento de rescate para sus síntomas de rinitis alérgica (DM ‐14).0%, IC del 95%: ‐26,6 a ‐1,40); en una temporada típica de polen de 60 días, esta reducción del 14% se traduce en 19 días en que se necesitarían comprimidos en el grupo de helmintos frente a 27 días en que se necesitarían comprimidos en el grupo de placebo. Los participantes que recibieron helmintos por vía percutánea (es decir, larvas de uncinaria) presentaron prurito y enrojecimiento cutáneo local en los primeros días posteriores a la administración. Los participantes que ingirieron helmintos tuvieron mayores probabilidades de informar eventos adversos gastrointestinales (CR 1,79; IC del 95%: 1,31 a 2,45), dolor abdominal moderado o intenso (CR 7,67; IC del 95%: 1,87 a 31,57), flatulencias moderadas o graves (CR 2,01; IC del 95%: 1,06 a 3,81) y diarrea moderada o grave (CR 1,99; IC del 95%: 1,18 a 3,37). No hubo diferencias entre los grupos de helmintos y placebo en la incidencia de eventos adversos graves ni en los retiros del estudio.
Conclusiones de los autores
Actualmente no hay evidencia suficiente sobre la eficacia, la tolerabilidad ni los costos probables del tratamiento con helmintos para apoyar su uso como tratamiento habitual de la rinitis alérgica. La administración de helmintos a los seres humanos en dosis medidas cuidadosamente parece ser segura. Se deben realizar más estudios preclínicos antes de realizar ensayos más grandes y de duración prolongada de los helmintos para la rinitis alérgica. Los estudios futuros deben obtener e informar datos comparativos sobre los costos del tratamiento con helmintos versus el tratamiento farmacológico convencional.
PICOs
Resumen en términos sencillos
Tratamiento con helmintos (gusanos) para la rinitis alérgica
La rinitis alérgica es un problema de salud frecuente que afecta a unos 500 millones de personas en todo el mundo; su prevalencia va en aumentando. Los síntomas de la rinitis alérgica incluyen estornudos, picazón, rinorrea y congestión nasal. Para tratar la rinitis alérgica se utilizan varios tipos de fármacos, pero estos fármacos pueden no ser efectivos y algunos tipos de fármacos tienen efectos secundarios después de su uso prolongado. Los fármacos también pueden ser relativamente caros. Los helmintos son microorganismos multicelulares complejos que habitan en organismos más grandes y en los seres humanos suelen ser asintomáticos. Los helmintos modulan (o sea, regulan de forma óptima) los sistemas inmunitarios de los huéspedes y se cree que esta propiedad de los helmintos se podría utilizar terapéuticamente para prevenir o tratar las enfermedades alérgicas, como la rinitis alérgica. Se incluyeron dos estudios bien diseñados con 130 participantes adultos, cada estudio utilizó como intervención una especie diferente de helminto gastrointestinal (uncinaria humana en un estudio y tricocéfalo del cerdo en el otro). Ninguno de los dos estudios encontró una eficacia significativa de los helmintos, aunque una especie de helmintos (Trichuris suis, el tricocéfalo del cerdo) redujo la necesidad de que los participantes de tomar comprimidos como "medicación de rescate" durante la estación del polen de las gramíneas. Los eventos adversos como el dolor abdominal y las flatulencias fueron más frecuentes en el grupo de helmintos, aunque ninguna especie de helmintos estudiada provocó reacciones adversas graves. Actualmente no hay evidencia suficiente a favor del uso de helmintos para la rinitis alérgica en la práctica clínica habitual. Se necesitan más estudios preclínicos antes de realizar ensayos clínicos más grandes y de duración prolongada de los helmintos para la rinitis alérgica.
Authors' conclusions
Summary of findings
| Helminths (worms) for allergic rhinitis | ||||||
| Patient or population: patients with allergic rhinitis1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Helminths (worms) | |||||
| All‐cause study withdrawal | Study population | RR 0.75 | 130 | ⊕⊕⊕⊕ | ||
| 62 per 1000 | 46 per 1000 | |||||
| Moderate | ||||||
| 63 per 1000 | 47 per 1000 | |||||
| Change in allergic rhinitis daily symptom score during the grass pollen season Scale from: 0 to 9 | The mean change in allergic rhinitis daily symptom score during the grass pollen season in the intervention groups was | 100 | ⊕⊕⊕⊝ | |||
| Percentage of well days during the grass pollen season Scale from: 0 to 100 | The mean percentage of well days during the grass pollen season in the intervention groups was | 100 | ⊕⊕⊕⊝ | |||
| Total quality of life score over 12 weeks Scale from: 0 to 168 | The mean total quality of life score over 12 weeks in the intervention groups was | 30 | ⊕⊕⊕⊝ | |||
| Percentage of days requiring rescue medication (i.e. as tablets) during the grass pollen season Scale from: 0 to 100 | The mean percentage of days requiring rescue medication (i.e. as tablets) during the grass pollen season in the intervention groups was | 100 | ⊕⊕⊕⊝ | |||
| Hospitalisation due to any adverse event | Study population | RR 2.88 | 96 | ⊕⊕⊕⊝ | ||
| 21 per 1000 | 61 per 1000 | |||||
| Moderate | ||||||
| 21 per 1000 | 60 per 1000 | |||||
| Any gastrointestinal adverse event | Study population | RR 1.79 | 96 | ⊕⊕⊕⊝ | ||
| 489 per 1000 | 876 per 1000 | |||||
| Moderate | ||||||
| 489 per 1000 | 875 per 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Allergic rhinitis is a disorder of the nasal membranes and surrounding tissues, and a worldwide cause of illness and disability. | ||||||
Background
Description of the condition
Epidemiology
Allergic rhinitis is a global health problem that causes significant illness and disability worldwide. Although there is huge international 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 19th century, at which time it became common in both Europe and North America. The prevalence of allergic rhinitis is increasing in most countries 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 membranes to an allergen (ARIA 2008). The disease has two phases, as follows.
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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).
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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 patient’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.
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Intermittent allergic rhinitis: lasting for less then four days per week or for less than four weeks per year (ARIA 2008).
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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.
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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).
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Skin prick testing. This tests for an IgE‐mediated immediate hypersensitivity reaction, using the suspected allergens or other aeroallergens.
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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 examination. Subsequently:
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four officers (33%) remained free of allergic rhinitis for three years;
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three officers (25%) remained free of allergic rhinitis for two years;
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four officers (33%) remained free of allergic rhinitis for one year; and
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one officer was lost to follow‐up.
In October 1974 a researcher at the Medical Research Council laboratory 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 countries have found that in some poor communities helminth infestation, which is often asymptomatic, is protective against allergic 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 concept has been tested for some common diseases through randomised 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 supported 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 following four groups:
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annelids (segmented worms);
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nematodes (roundworms);
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trematodes (flukes); and
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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:
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oral (the human participant swallows helminth eggs or cysts); or
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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 participants 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 industrialised countries suffers from at least one of the three main allergic diseases: allergic rhinitis, asthma and eczema (ISAAC 1998). Allergy 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 several reasons. Allergen avoidance, the first‐line treatment for allergic rhinitis, is usually impractical (Reid 2010) and furthermore there exists considerable uncertainty around the efficacy and effectiveness 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 hypertension (Austen 2011). Abuse of over‐the‐counter preparations may cause long‐term damage to nasal function (Nasser 2010). Allergen 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.
Objectives
To assess whether helminths are a safe and effective treatment for people with allergic rhinitis.
Methods
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 intermittent allergic rhinitis. This was confirmed by one or more of the following:
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abnormal systemic levels of allergen‐specific IgE;
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positive skin prick test;
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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:
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in any dose;
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by any route (oral, percutaneous, other);
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for any duration of exposure (days, weeks, months); and
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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
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Allergic rhinitis symptoms, self reported (efficacy).
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Well days (i.e. days with no or very mild symptoms, and no use of medication for allergic rhinitis) (efficacy).
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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
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Use of rescue medication (i.e. non‐routine drugs taken to relieve acute exacerbations), reported validly and regardless of how recorded.
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Rhinoconjunctivitis quality of life scores, self reported.
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Serious adverse events (e.g. hospitalisation, death).
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Other adverse events (i.e. any non‐serious systemic or regional or local adverse event).
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Dropouts (i.e. all‐cause study withdrawal) (adherence).
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Costs of therapy.
Search methods for identification of studies
We conducted systematic searches for randomised controlled trials. 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 published, 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 Science; BIOSIS Previews; CNKI; ISRCTN; ClinicalTrials.gov; ICTRP 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 subject strategies with adaptations of the highly sensitive search strategy designed by the Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in theCochrane 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 additional trials and contacted trial authors where necessary. In addition, 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 reference lists for additional trials. We searched for conference abstracts 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 studies 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 particular 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 potentially relevant for further assessment, and for a final decision on inclusion (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.
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Study characteristics (study design, date of study, total study duration, number of study centres and their location, study withdrawals).
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Participants (N, mean age, age range, gender distribution, sociodemographic characteristics, ethnicity, allergic rhinitis presentation, inclusion criteria, exclusion criteria).
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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).
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Controls (for each control: total number in control arm; where control was an active pharmacological intervention: nature, dose, route of administration, cost).
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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 contacted 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.
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Random sequence generation
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Allocation concealment
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Blinding of participants and investigators
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Blinding of outcome assessment
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Incomplete outcome data
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Selective reporting
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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
We performed statistical analysis using RevMan 5. We used a fixed‐effect or random‐effects model, depending on the absence or presence of heterogeneity across the studies.
Dichotomous data
We calculated risk ratios (RRs) with 95% confidence intervals for dichotomous outcomes. Where appropriate, we expressed estimated effects as NNTB (number needed to treat to benefit). The NNTB corresponds mathematically to the inverse of the risk difference, 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
For continuous variables, we calculated a mean difference (MD) or standardised mean difference (SMD), along with 95% confidence intervals, as follows:
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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);
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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 available were summary measures of effect, along with precision estimates, 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’ comparison group was to be divided into the number of treatment groups, and comparisons between each treatment group and the split comparison 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 intracluster 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 information in other sources, where such information existed. This was to constitute the primary analysis. We were to perform a sensitivity 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 standard 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 participants completing the trial. We performed intention‐to‐treat analyses 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 analysis.
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 were to 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 explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect, by using sensitivity analyses.
Assessment of heterogeneity
We assessed heterogeneity between pooled trials using:
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the Chi2 test; in conjunction with
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the I2 statistic, 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 heterogeneity using subgroup analyses. We displayed results graphically 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 I2 value of:
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< 25% to denote low heterogeneity;
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≥ 50% to denote significant heterogeneity; and
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≤ 75% to denote substantial and major heterogeneity.
Assessment of reporting biases
Had been there more than 10 studies, we were to attempt to assess 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 contact 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 design or outcome reporting of industry‐sponsored research that shows that a drug or other therapeutic product to have an apparently favourable outcome (Bekelman 2003). Relationships between industry, scientific investigators and academic institutions are widespread and often result in conflicts of interest.
Data synthesis
We pooled the results of clinically similar studies in meta‐analyses. We used adjusted summary statistics if available; otherwise we were to use unadjusted results. Pooling of data was as follows:
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for dichotomous outcomes we calculated RRs for each study and then pooled these;
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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);
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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.
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The study design
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Risk of bias
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Inconsistency of results
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Indirectness (i.e. non‐generalisability)
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Imprecision (i.e. insufficient data)
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Other factors (e.g. reporting bias)
We reduced the quality of the evidence by one level for each domain where poor quality was encountered. We assessed all plausible 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 population of interest, in 75% of RCTs with low risk of bias. There are sufficient data, with narrow confidence intervals. 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:
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different helminth species or combination of helminth species;
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different developmental stages of the administered helminths;
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different routes of administration of the helminths;
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different exposure intensities; and
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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, including 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:
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trials at high or unclear risk of bias;
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unpublished studies (since these may not have been subjected to the peer review process and may have had intrinsic biases);
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industry‐sponsored studies; and
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trials that had not assessed adherence.
Results
Description of 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.
Fifty‐four adults with current symptoms of allergic rhinitis to any allergen were recruited, and 30 with measurable bronchial reactivity were randomised into two groups. In 15 participants 10 Necator 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) required to reduce FEV1 by 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 rhinoconjunctivitis quality of life score (Juniper RQLQ); and peak expiratory flow rate (PEFR) variability, change in skin wheal diameter in response 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.
One hundred and sixty‐two adults with grass pollen‐induced allergic rhinitis were recruited, and 100 with allergic rhinitis symptoms in the previous two grass pollen seasons or more were randomised into two groups. Before the peak of the grass pollen season, 50 participants received a total of two to five oral doses of embryonated Trichuris suis (i.e. pig whipworm) eggs in an aqueous 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 included 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 excluded 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 details) 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.
Process of screening search results and selecting studies for inclusion
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 explanations 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: eye 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).
Forest plot of comparison: 3 Use of rescue medication, outcome: 3.4 % days requiring rescue medication (tablets) during grass pollen season.
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 hospitalisation 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 itching 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.
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 significant difference between groups for all‐cause study withdrawal (RR 0.75, 95% CI 0.18 to 3.21) (Figure 4).
Forest plot of comparison: 1 Study withdrawal, outcome: 1.1 All‐cause withdrawal
Costs
Neither study reported data on costs (i.e. costs of helminth therapy, costs of pharmacotherapy, clinic visit costs, healthcare worker costs).
Discussion
This is the first ever systematic review of helminths for allergic rhinitis and the first Cochrane review to investigate 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 between 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 participants needed to take tablets as rescue medication (mean difference (MD) –14.0%, 95% confidence interval (CI) –26.6 to –1.40) (Figure 2); 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. This finding may have been an artefact, however, explicable through the helminths having induced a reluctance 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 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) 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 exception 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).
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'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 follows 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.
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 reported 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 findings may be explained by a lack of rigour in the study methodologies, or by biased reporting.
Process of screening search results and selecting studies for inclusion
Forest plot of comparison: 3 Use of rescue medication, outcome: 3.4 % days requiring rescue medication (tablets) during grass pollen season.
Forest plot of comparison: 5 Other adverse events, outcome: 5.2 Any gastrointestinal adverse event.
Forest plot of comparison: 1 Study withdrawal, outcome: 1.1 All‐cause withdrawal
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Allergic rhinitis symptoms, Outcome 1 Mean daily symptom score during grass pollen season.
Comparison 2 Well days, Outcome 1 % of well days during grass pollen season.
Comparison 3 Lung function measures, Outcome 1 Bronchial reactivity change.
Comparison 4 Use of rescue medication, Outcome 1 Mean total daily medication use score during grass pollen season.
Comparison 4 Use of rescue medication, Outcome 2 % days requiring rescue medication (as eye drops) during grass pollen season.
Comparison 4 Use of rescue medication, Outcome 3 % days requiring rescue medication (as nasal sprays) during grass pollen season.
Comparison 4 Use of rescue medication, Outcome 4 % days requiring rescue medication (as tablets) during grass pollen season.
Comparison 5 Rhinoconjunctivitis quality of life score, Outcome 1 Total quality of life score over 12 weeks.
Comparison 6 Serious adverse events, Outcome 1 Hospitalisation due to any adverse event.
Comparison 6 Serious adverse events, Outcome 2 Hospitalisation due to any gastrointestinal adverse event.
Comparison 7 Other adverse events, Outcome 1 Any adverse event.
Comparison 7 Other adverse events, Outcome 2 Any gastrointestinal adverse event.
Comparison 7 Other adverse events, Outcome 3 Moderate or severe abdominal pain.
Comparison 7 Other adverse events, Outcome 4 Moderate or severe diarrhoea.
Comparison 7 Other adverse events, Outcome 5 Moderate or severe flatulence.
Comparison 7 Other adverse events, Outcome 6 Moderate or severe pruritus ani.
Comparison 8 Drop‐outs, Outcome 1 All‐cause study withdrawal.
| Helminths (worms) for allergic rhinitis | ||||||
| Patient or population: patients with allergic rhinitis1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Helminths (worms) | |||||
| All‐cause study withdrawal | Study population | RR 0.75 | 130 | ⊕⊕⊕⊕ | ||
| 62 per 1000 | 46 per 1000 | |||||
| Moderate | ||||||
| 63 per 1000 | 47 per 1000 | |||||
| Change in allergic rhinitis daily symptom score during the grass pollen season Scale from: 0 to 9 | The mean change in allergic rhinitis daily symptom score during the grass pollen season in the intervention groups was | 100 | ⊕⊕⊕⊝ | |||
| Percentage of well days during the grass pollen season Scale from: 0 to 100 | The mean percentage of well days during the grass pollen season in the intervention groups was | 100 | ⊕⊕⊕⊝ | |||
| Total quality of life score over 12 weeks Scale from: 0 to 168 | The mean total quality of life score over 12 weeks in the intervention groups was | 30 | ⊕⊕⊕⊝ | |||
| Percentage of days requiring rescue medication (i.e. as tablets) during the grass pollen season Scale from: 0 to 100 | The mean percentage of days requiring rescue medication (i.e. as tablets) during the grass pollen season in the intervention groups was | 100 | ⊕⊕⊕⊝ | |||
| Hospitalisation due to any adverse event | Study population | RR 2.88 | 96 | ⊕⊕⊕⊝ | ||
| 21 per 1000 | 61 per 1000 | |||||
| Moderate | ||||||
| 21 per 1000 | 60 per 1000 | |||||
| Any gastrointestinal adverse event | Study population | RR 1.79 | 96 | ⊕⊕⊕⊝ | ||
| 489 per 1000 | 876 per 1000 | |||||
| Moderate | ||||||
| 489 per 1000 | 875 per 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Allergic rhinitis is a disorder of the nasal membranes and surrounding tissues, and a worldwide cause of illness and disability. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean daily symptom score during grass pollen season Show forest plot | 1 | 100 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [‐0.45, 0.45] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 % of well days during grass pollen season Show forest plot | 1 | 100 | Mean Difference (IV, Fixed, 95% CI) | 3.0 [‐7.98, 13.98] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Bronchial reactivity change Show forest plot | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.51 [‐0.68, 1.70] |
| 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 Show forest plot | 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 Show forest plot | 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 Show forest plot | 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 Show forest plot | 1 | 100 | Mean Difference (IV, Fixed, 95% CI) | ‐14.0 [‐26.60, ‐1.40] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total quality of life score over 12 weeks Show forest plot | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.33 [‐0.27, 0.93] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Hospitalisation due to any adverse event Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.88 [0.31, 26.69] |
| 2 Hospitalisation due to any gastrointestinal adverse event Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.01, 7.66] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Any adverse event Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.91, 1.23] |
| 2 Any gastrointestinal adverse event Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.79 [1.31, 2.45] |
| 3 Moderate or severe abdominal pain Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.67 [1.87, 31.57] |
| 4 Moderate or severe diarrhoea Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.99 [1.18, 3.37] |
| 5 Moderate or severe flatulence Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.01 [1.06, 3.81] |
| 6 Moderate or severe pruritus ani Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.27, 1.92] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause study withdrawal Show forest plot | 2 | 130 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.18, 3.21] |
