To investigate the magnitude of efficacy and side-effects of immunotherapy in the treatment of allergic diseases.

MEDLINE was searched from 1980 onwards (presumably until 1997). The review included only peer-reviewed full papers published in English after 1980, because this corresponded to the period when adequately standardised extracts became widely used.

Study designs of evaluations included in the review

The included studies were double-blind placebo-controlled. In most studies, the duration of treatment was quite short, i.e. a few months. The treatment was rarely continued for more than a year. The duration of treatment ranged from 5 weeks to 3 years for rhinitis studies, and from 1.5 months to 2 years for asthma studies.

Specific interventions included in the review

Allergen extracts from various sources including animals, grass, ragweed, mountain cedar and mould. Varying formulations of allergen extracts were used. Most studies used native aqueous or slow-release extracts, but some studies used chemically- or physically-modified allergoids. The types of extract used for rhinitis immunotherapy studies were: aqueous, glutaraldehyde, alum, polymerised, allergoid, tyrosine, polyethylene glycol, alginate, peptide, and an aluminium-antigen complex. The types of extract used for asthma immunotherapy studies were: aqueous, tyrosine, aluminium, GOID, HMW-GOID and antigen-antibody complexes.

Participants included in the review

No details of the inclusion criteria for the participants were presented. However, the author stated that only 8 of the 43 rhinitis studies, and 'several' of the 25 asthma studies, involved children.

Outcomes assessed in the review

Clinical efficacy and side-effects were assessed. Clinical efficacy was measured by the mean symptom or medication scores, or by measuring the area under the curve of the symptom as medication scores, as compared with time for the active group and the placebo group, respectively. The magnitude of improvement induced by the active treatment was calculated as the percentage reduction of disease severity, compared with placebo.

How were decisions on the relevance of primary studies made?

The author does not state how the papers were selected for the review, or how many of the reviewers performed the selection.

The author does not state that they assessed validity.

The author does not state how the data were extracted for the review, or how many of the reviewers performed the data extraction. The efficacy of the individual studies was graded on a scale of 1 to 4.

1. No efficacy: the symptom or medication scores were improved by less than 30%.

2. Low efficacy: an improvement of 30 to 44% was achieved.

3. Moderate efficacy: an improvement of 45 to 59% was achieved.

4. High efficacy: an improvement of at least 60% was achieved.

How were the studies combined?

The studies were combined narratively in terms of the number of studies which demonstrated clinically relevant efficacy (i.e. symptom or medication scores diminished by at least 30% in the actively-treated group).

Trials were divided into studies investigating the clinical efficacy of immunotherapy in arthritis and asthma. These were then discussed in terms of the efficacy compared with drugs, and the side-effects.

How were differences between studies investigated?

The author does not state how differences between the primary studies were investigated.

Forty-three rhinitis studies (2,001 participants) and 25 asthma studies (726 participants, of which 16 provided symptom or medication scores) were included in the review.

Immunotherapy in rhinitis: most of the immunotherapy studies investigated the efficacy of pollen allergies. Nine of the 13 studies investigating the efficacy of ragweed allergy showed relevant clinical efficacy, i.e. symptom or medication scores diminished by at least 30% in the actively-treated group. Fourteen of the 15 studies investigating the efficacy of immunotherapy in grass-pollen allergy proved efficacy. Nine studies investigated other pollen allergies: mountain cedar (n=3), Parietaria (n=3), Cupressus (n=1), Cocus (n=1) and mixtures (n=1). Six of these demonstrated efficacy. Three of the 5studies investigating house-dust mite immunotherapy showed efficacy. In mould allergies, efficacy was documented in one study investigating Alternaria.

In the 43 rhinitis studies, there was no efficacy documented in 10 studies, low efficacy in 13 studies, moderate efficacy in 14 studies, and high efficacy in 6 studies. The mean clinical improvement was a 45% reduction in the symptom or medication scores, compared with placebo. The best results were obtained in grass-pollen immunotherapy. The magnitude of efficacy of immunotherapy in ragweed allergy was modest. The clinical efficacy of immunotherapy with other pollens, house-dust mite, animal dander and moulds was insufficiently documented.

Immunotherapy in asthma: 5 of the 6 studies demonstrated that grass-pollen immunotherapy was effective, and 2 of the 4 studies found that mite immunotherapy was effective. Among animal danders, 2 cat allergen studies showed efficacy whilst one dog study did not. With respect to moulds, one of the 2 Cladosporium studies documented efficacy. In asthma studies assessing the efficacy on bronchial challenge (bronchial provocation test, BPT) or exposure tests, one grass-pollen study noted a reduction in BPT sensitivity, as did one of the 3 mite studies. Three of the 5 studies which investigated the efficacy of cat and/or dog immunotherapy documented a reduction in challenge test or improvement in exposure tests.

Of the 16 studies providing symptom or medication scores, 5 showed no efficacy, 3 showed low efficacy, 4 showed moderate efficacy, and 4 showed high efficacy. There was a mean reduction of 40% in disease severity of active treatment compared with placebo. The results indicated that immunotherapy was effective in grass-pollen-induced asthma and in asthma caused by cats. Several studies performed in children indicated that immunotherapy may be of value in this age group.

Efficacy compared with drugs: no studies using an appropriate allergen extract have investigated efficacy in comparison with topical steroids.

The efficacy of immunotherapy in many studies was higher than that for antihistamines (one study) and was equivalent to the reduction in clinical symptoms obtained with standard doses of intranasal or inhaled corticosteroids (7 studies).

Side-effects: of the 68 papers included in the review, 15% failed to supply any information on side-effects. Fifteen papers (26%) reported that no systemic side-effects were elicited by injection of allergens. Systemic side-effects of varying degree of severity were observed in 24% (mean value) of the patients. Most of the reactions were mild, requiring either no treatment or only minor treatment. However, a few reactions were rather severe, including anaphylaxis necessitating the administration of epinephrine. The frequency of side-effects was unrelated to allergen species, types of extracts or dosage regimens.

Based on both the number of double-blind placebo-controlled studies and the number of patients included in these studies, the clinical efficacy of immunotherapy in rhinitis and asthma was well documented. Although some studies demonstrated no, or a low degree of clinical efficacy, most demonstrated efficacy equivalent to that obtained with pharmacological treatment. Immunotherapy has the potential to reduce symptoms and the need for drugs significantly, and could possibly prevent progression into more severe disease.

Systemic side-effects induced by immunotherapy represent the primary argument against this type of specific treatment of allergic diseases. Although severe anaphylactic reactions may be induced, the risk of life-threatening diseases is low. Most systemic reactions are rather mild, requiring no or minor treatment.

The review focused on a well-defined question. The studies were summarised appropriately.

The literature review could have been extended to include other databases, such as EMBASE, and an attempt could have been made to identify unpublished literature. The search was limited to English language publications, and relevant articles may therefore have been missed, potentially leading to a publication bias. No search terms were given and consequently the validity of the search cannot be commented upon. Some details of the individual studies were presented, but it would have been useful to include more of the patients' characteristics, such as age and gender. The inclusion and exclusion criteria were not reported, and validity was not assessed. The primary studies involved a wide variety of extracts and some of the sample sizes were quite small, thus making it difficult to summarise the data and draw clear conclusions about the effectiveness of any one specific regimen.

The author's conclusions follow from the results, but should be interpreted with caution considering the limitations of the primary studies in terms of size and heterogeneity.

Only eight studies investigating the clinical efficacy of immunotherapy in rhinitis have involved children. More studies on children are required.

The most important aspect in successful immunotherapy is to select those patients most likely to respond adequately. This means identifying symptoms primarily induced by allergens, patients with sensitivity to a single allergen or a few allergens, and young patients without chronic irreversible changes in the airways. To meet these requirements, the indication for immunotherapy should be made by an allergist.

To minimise the risk of side-effects, the patient should be assessed carefully, and the appropriate dose decided before the injection is given.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.