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Cochrane Database of Systematic Reviews Protocol - Intervention

Specific allergen immunotherapy for the treatment of atopic eczema

Authors' declarations of interest

Version published: 06 October 2010 Version history

https://doi.org/10.1002/14651858.CD008774

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view the current version 12 February 2016
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the efficacy and safety of specific allergen immunotherapy, including subcutaneous and sublingual immunotherapy, compared with placebo or standard treatment in people with atopic eczema.

Background

Description of the condition

Atopic eczema (AE) is a chronic inflammation of the skin which affects 15% to 30% of children and 2% to 10% of adults world wide (Odhiambo 2009; Williams 2006). The terms 'atopic eczema' and 'atopic dermatitis' are synonymous. This condition is characterised by severe itching, and patches of dry, inflamed skin in varying locations depending on the age of the person. In infants AE is usually found on the cheeks, forehead, or scalp. In childhood AE usually involves the hands, feet, wrists, ankles, and the creases of the elbows and backs of the knees. In adults AE causes dry, scaly patches and large plaques of thickened (lichenified) skin in the flexural folds, the face and neck, the upper arms and back, and the backs of the hands, feet, fingers and toes (Akdis 2006). Strictly speaking, the term 'atopic eczema' should only refer to individuals who have the physical features of eczema plus evidence of specific immunoglobulin E (IgE) antibodies to common environmental allergens such as house dust mite (Johansson 2004). We have used this strict definition throughout this report unless specified otherwise.

Several observations suggest that allergens may be important causes of atopic eczema. Firstly direct exposure of the skin to environmental allergens, including perennial allergens like house dust mite, and seasonal allergens like pollen, have been shown to increase the severity of atopic eczema (Capristo 2004; Purvis 2005; Schäfer 1999). Secondly other diseases triggered by allergens are common in those with atopic eczema. For example, of those children who develop the condition during the first two years of life, an estimated 50% may develop asthma during subsequent years (Warner 2001). Finally, those with more severe AE have increased risk of asthma and allergic rhinitis (Gustafsson 2000; Illi 2004).

Despite the current available topical treatment with emollients, corticosteroids and calcineurin inhibitors, and other treatments such as antihistamines, people with atopic eczema often cannot keep their condition completely under control. In some cases, the medications used can cause more harm than benefit. Therefore, considering the atopic background of the disease and its possible correlation with allergen‐triggering factors, some other types of treatment have been proposed, which include specific allergen immunotherapy (SIT).

Description of the intervention

Specific allergen immunotherapy is a treatment for allergic disease which involves the administration of an allergen in high doses in order to induce immune tolerance to that allergen and relieve symptoms. For example, in people with hayfever who are allergic to grass pollen SIT may involve treatment with injections, drops, or tablets of grass pollen over a period of months in order to relieve symptoms (Calderon 2007; Wilson 2005). Specific allergen immunotherapy is the only treatment shown to provide longer term benefit in allergic diseases after treatment has stopped (Durham 1999). It has been shown to be an effective treatment for allergic rhinitis and allergic asthma, although the treatment carries a risk of severe allergic reaction (Calderon 2007; CSM report 1986; Wilson 2005).

How the intervention might work

In recent years, several randomised controlled trials evaluating the efficacy of SIT for atopic eczema have demonstrated a significant reduction in skin symptoms, cutaneous rescue medication requirements, and reduction in the severity of the SCORing Atopic Dermatitis index (SCORAD) (Bussmann 2009). Specific allergen immunotherapy works by inducing changes in the immune response to the relevant allergen, so that in diseases caused by an abnormal response to that allergen there may be an improvement in symptoms. The specific immune changes caused by SIT include an increase in activity of suppressive components of the immune system (regulatory T cells), and an increase in antibodies (immunoglobulin G (IgG) antibodies) to the allergen (Allam 2006; Bussmann 2007; Maintz 2007). The presence of allergic sensitisation in those with AE, and the relationship between AE and other allergic diseases suggest that allergic immune responses are an important part of the disease process in AE. It is therefore plausible that SIT might be able to reduce symptoms in people with AE by inhibiting abnormal immune responses to allergens.

Why it is important to do this review

Specific immunotherapy is a disease‐modifying treatment which reduces symptoms in people with allergic rhinitis, allergic conjunctivitis, and asthma (Abramson 2003; Calderon 2007; Dahl 2006; Didier 2007; Penagos 2008). Specific allergen immunotherapy might be potentially effective in reducing atopic eczema (Pajno 2007). An evaluation of its effects on skin manifestations in the context of randomised controlled trials, could provide an alternative treatment for people with atopic eczema.

Objectives

To evaluate the efficacy and safety of specific allergen immunotherapy, including subcutaneous and sublingual immunotherapy, compared with placebo or standard treatment in people with atopic eczema.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

Adults and children with atopic eczema and allergic sensitisation to an inhalant or food allergen. Allergy must be proven using an objective test such as a positive skin prick test or high circulating levels of allergen‐specific IgE antibody detected by a specific blood test for allergy called the radioallergoabsorbent test. Trials dealing with allergic rhinitis and/or asthma without eczema will be excluded. Where trials include participants with and without atopic eczema, the trial will only be included if the results for the participants with atopic eczema are separately reported. Where separate data are not reported for atopic and non‐atopic eczema, we will request original data for a subgroup analysis of participants with atopic eczema from the study authors.

Types of interventions

High dose immunotherapy with standardised single allergen extracts administered either by the sublingual (under the tongue) or subcutaneous (under the skin) route, compared with placebo or standard treatment such as emollients, topical corticosteroids, or topical calcineurin inhibitors. All appropriate allergens will be considered at all doses and all durations of treatment

Types of outcome measures

Primary outcomes

(a) The proportion of participants who show good or excellent improvement in a participant‐ or parent‐reported global assessment of disease severity at the end of treatment, i.e. the proportion with good or excellent improvement at this time as reported in the trials (whether treatment was given for 1, 2, 3 years, or other duration).

(b) Participant‐ or parent‐reported specific symptoms of eczema such as itch.

(c) Adverse events such as acute episodes of asthma or anaphylaxis.

Secondary outcomes

(a) Investigator‐ or physician‐rated global assessment of disease severity at the end of treatment,i.e. the proportion with good or excellent improvement at this time.

(b) Parent‐ or participant‐rated eczema severity assessed using a published scale (e.g. POEM).

(c) Investigator‐rated eczema severity assessed using a published scale (e.g. SCORAD).

(d) Use of other medication for treatment of eczema during the intervention period (e.g. topical/systemic corticosteroids, calcineurin inhibitors, oral antihistamines).

(e) Validated eczema‐related quality of life scores (e.g. Dermatitis Family Impact Questionnaire, Children's Dermatology Life Quality Index) (Lewis‐Jones 1995).

Search methods for identification of studies

Electronic searches

We shall search the following databases for relevant randomised controlled trials:

  • The Cochrane Skin Group Specialised Register;

  • The Cochrane Central Register of Controlled Trials (Clinical Trials) in The Cochrane Library (latest issue);

  • MEDLINE (from 2005 to the present);

  • EMBASE (from 2007 to the present);

  • LILACS (Latin American and Caribbean Health Science Information database, from inception); and

  • ISI Web of Science (from 2005 to the present).

We have devised a draft search strategy for RCTs for MEDLINE (OVID) which is displayed in Appendix 1. This will be modified to include additional search terms where necessary and will be used as the basis for search strategies for the other databases listed.

The UK Cochrane Centre (UKCC) has an ongoing project to systematically search MEDLINE and EMBASE for reports of trials which are then included in the Cochrane Central Register of Controlled Trials. Searching has currently been completed in MEDLINE to 2004 and in EMBASE to 2006. Further searching will be undertaken for this review by the Cochrane Skin Group to cover the years that have not been searched by the UKCC.

Ongoing Trials

We shall search for reports of trials in the following ongoing trials databases using the terms: 'allergen', 'dust mite', 'pollen', 'dander', 'mould', 'immunotherapy', 'desensitisation', 'dermatitis', and 'eczema'.

Searching other resources

We will create a database of first and last authors of potentially eligible studies and search The Science Citation Index Expanded (SCI‐EXPANDED, 1945 to the present) using these names for additional studies.

Reference lists

We will check the bibliography of each included study and of other published reviews for further reports of trials.

Correspondence

We will contact the primary author of each included study to identify additional published and unpublished studies. We will contact allergen immunotherapy product manufacturers to request details of published or unpublished studies of allergen immunotherapy which have included eczema as an outcome measure. We aim to identify other trials through discussion with specialist allergist colleagues and professional acquaintances with an interest in the area to find out if they are aware of any unpublished or ongoing trials meeting the selection criteria.

Conference proceedings

We will search abstracts of relevant conferences for relevant trials including those held by the World Allergy Organisation, European Academy of Allergy and Clinical Immunology, and the American Academy of Allergy, Asthma and Immunology meetings for 2009 to 2010.

Language

We will consider studies published in languages other than English if the translated abstract indicates that the study is a RCT of allergen specific immunotherapy for atopic dermatitis and we will aim to get translations done where necessary.

Data collection and analysis

Selection of studies

Two of us (MC, RB) will independently check titles and abstracts identified from the searches. We will both look at the full text of all studies of possible relevance for assessment. We will also (MC, RB) read all abstracts and decide which trials meet the inclusion criteria. Any disagreement will be resolved by discussion between the authors with recourse to a third author (HN) for arbitration where necessary. Further information will be sought from trial authors when needed.

Data extraction and management

Data will be extracted individually by RB and IGN onto a specially designed data extraction sheet. MC will collect all data to compare results. MC and RB will write to all authors requesting additional information if required.

Assessment of risk of bias in included studies

We will assess and document the risk of bias in included studies by concentrating on using the following six parameters to assess quality: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and early withdrawal from treatment as specified in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

Each domain will be addressed in the 'Risk of bias' table for each study which is part of the 'Characteristics of Included Studies' table.

Two of us (HN and IGN) will independently assess risk of bias: we will not be masked to study details. Our agreement on risk of bias assessment will be assessed and disagreements will be resolved by discussion and, if necessary, with the involvement of a third author (RB or MC).

Measures of treatment effect

For continuous data we will calculate individual and pooled statistics as mean differences (MD) where studies use the same outcome measure, or standardised mean differences where studies use different outcome measures, in either case reported with 95% Confidence Interval (CI). For dichotomous outcomes we will express results as a risk ratio (RR) with 95% CI. The result for dichotomous outcomes will also be expressed as number needed to treat (NNT), where appropriate, with a 95% CI and the baseline risk to which it applies.

Unit of analysis issues

We will analyse cross‐over trials using techniques appropriate for paired designs. We will analyse data from parallel trials and cross‐over trials as separate subgroups, since cross‐over studies may not be appropriate for immunotherapy studies. We will list non‐randomised controlled studies but not discuss them further. Where studies report more than one active intervention, we will combine the two active interventions and analyse them together. Where studies report non‐parametric statistics we will include these in meta‐analyses where possible, following the guidance of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

Dealing with missing data

We will contact authors when details about study design or descriptive statistics for outcomes are not presented in the paper (mean, SD). If the authors do not respond within a reasonable time (six to eight weeks), we will conduct the review based on available information.

Assessment of heterogeneity

We will test for heterogeneity using the I² statistic and substantial statistical heterogeneity will be assumed if I² is > 50% (Higgins 2002). Any statistical or clinical heterogeneity will be explored using sensitivity or subgroup analysis (see below). Quantitative analyses of outcomes will be, wherever possible, on an intention‐to‐treat basis, i.e. participants will be evaluated in the groups to which they were randomised, rather than according to the actual treatment which they received.

We will give consideration to the appropriateness of meta‐analysis in the presence of significant clinical or statistical heterogeneity. We will use a random‐effects model.

Assessment of reporting biases

We will assess publication bias graphically using Funnel plots (where there are sufficient included studies) and statistically using Begg and Egger tests (Begg 1994; Egger 1997).

Data synthesis

We will combine appropriate data from individual studies in a meta‐analysis only if heterogeneity measured by I² is < 75%, using a random‐effects model. Where heterogeneity is observed between individual study results we will not combine studies but a tabulated summary of results will be presented.

Subgroup analysis and investigation of heterogeneity

In the event of uncovering substantial heterogeneity, we will investigate by undertaking subgroup analyses. Our subgroups of interest are:

1. Immunotherapy type: sublingual and subcutaneous.

2. Allergen type: seasonal inhalant, perennial inhalant, food, microbial.

3. Age of participants: up to 4 years, 5 to 11, 12 to 17, and 18 or over.

4. Immunotherapy regimens to be subdivided empirically into low, intermediate, and high dose therapy according to content of major allergen per dose (e.g. Phleum p5 for grass, Bet v1 for Birch pollen, Fel d1 for cat etc):

a) for subcutaneous immunotherapy, content of major allergen 1 to 5 mcg, 6 to 10 mcg, and > 11 mcg per 4 to 6 weekly maintenance injection doses; and

b) for sublingual immunotherapy, content of major allergen 1 to 5 mcg, 6 to 10mcg, and > 11 mcg per daily maintenance sublingual dose (or equivalent if taken less frequently).

5. Severity of AE at randomisation: mild (SCORAD mean objective score 0 to 15), moderate (SCORAD mean objective score 16 to 40), and severe (SCORAD mean objective score > 40).

Sensitivity analysis

We will undertake sensitivity analysis for the allocation of missing data by best and worst case analysis. Where significant heterogeneity is found in meta‐analysis, possible reasons for this will be explored by sensitivity analysis, including risk of bias in included studies.