H.-J. Malling

Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce

Specific Immunotherapy for respiratory allergy is used since about one century and there is now solid documentation of its efficacy. Nevertheless, the methods and experimental designs used in clinical trials are quite heterogeneous and there is no unanimously accepted methodological standard. Many studies are planned with study designs that may not confirm the clinical value of SIT as an effective treatment to reduce disease severity. To ensure that patients are treated based on sound scientific evidence and to minimize the risk of misusing limited financial resources for scientific studies, the World Allergy Organization (WAO) convened a group of experts to provide guidelines for the methodology of future immunotherapy studies.

Standards for practical allergen‐specific immunotherapy

Foreword The paper was drafted by Emilio Alvarez-Cuesta (chairman), Spain, Jean Bousquet, France, G Walter Canonica, Italy, Stephen Durham, England, Hans-Jorgen Mailing, Denmark and Erkka Valovirta, Finland. The paper was revised and input added by a European Reference Group, endorsed by National Societies associated EAACI and approved by the Executive Committee of EAACI. Reference group: U Muller, G Passalacqua, M Jutel, B Niggemann, T Frew, M. Franchi, R Pinto, D Price, K Nekam, P Eigenmann, L Delgado. F Bonifaci and H Mosbeck supervised the venom section.

Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position Paper.

BACKGROUND Allergen immunotherapy (AIT) has been thoroughly documented in randomized controlled trials (RCTs). It is the only immune-modifying and causal treatment available for patients suffering from IgE-mediated diseases such as allergic rhinoconjunctivitis, allergic asthma and insect sting allergy. However, there is a high degree of clinical and methodological heterogeneity among the endpoints in clinical studies on AIT, for both subcutaneous and sublingual immunotherapy (SCIT and SLIT). At present, there are no commonly accepted standards for defining the optimal outcome parameters to be used for both primary and secondary endpoints. METHODS As elaborated by a Task Force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) Immunotherapy Interest Group, this Position Paper evaluates the currently used outcome parameters in different RCTs and also aims to provide recommendations for the optimal endpoints in future AIT trials for allergic rhinoconjunctivitis. RESULTS Based on a thorough literature review, the TF members have outlined recommendations for nine domains of clinical outcome measures. As the primary outcome, the TF recommends a homogeneous combined symptom and medication score (CSMS) as a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner. All outcomes, grouped into nine domains, are reviewed. CONCLUSION A standardized and globally harmonized method for analysing the clinical efficacy of AIT products in RCTs is required. The EAACI TF highlights the CSMS as the primary endpoint for future RCTs in AIT for allergic rhinoconjunctivitis.

The safety and efficacy of subcutaneous birch pollen immunotherapy - a one-year, randomised, double-blind, placebo-controlled study

Background: There is only very limited documentation of the efficacy and safety of high‐dose subcutaneous birch pollen immunotherapy (IT) in double‐blind, placebo‐controlled (DBPC) studies. Birch pollen is a major cause of allergic morbidity in northern Europe and in eastern parts of North America.

European Academy of Allergy and Clinical Immunology task force report on ‘dose–response relationship in allergen‐specific immunotherapy’

To cite this article: Calderón MA, Larenas D, Kleine‐Tebbe J, Jacobsen L, Passalacqua G, Eng PA, Varga EM, Valovirta E, Moreno C, Malling HJ, Alvarez‐Cuesta E, Durham S, Demoly P. European Academy of Allergy and Clinical Immunology task force report on ‘dose–response relationship in allergen‐specific immunotherapy’. Allergy 2011; 66: 1345–1359.

Skin Prick Testing and the Use of Histamine References

The skin prick test is a fundamental test in biological allergen standardization and in evaluation of changes in skin sensitivity due to treatment. The allergen concentration eliciting a wheal equal to that produced by histamine 1 mg/ml is generally accepted as the skin sensitivity. Using a standardized quantitative skin prick test, 25 mould allergic patients were tested with quadruplicate determinations of five 10‐fold allergen concentrations of highly purified and standardized extracts. Histamine 1 and 10 mg/ml were used as positive references. The 10‐fold increase of histamine resulted in a doubling of the histamine reaction and increased the mean wheal diameter from 4 to 7 mm. The correlation between skin sensitivity estimated by histamine 1 and 10 mg/ml is significant, but with a dissociation between the two ways of estimating the sensitivity of 0.25 log step in the low sensitivity range and 1.8 log step in the high sensitivity range (the difference at median sensitivity is 1 log step). No correlation was found between histamine‐ and allergen‐induced wheal area increase, and the discrepancy might be caused by a difference in the endogenous histamine release and/or difference in the number of histamine receptors at different degrees of sensitivity. With the use of median values it is possible to perform biological standardization with histamine 10 mg/ml and interpolate to histamine 1 mg/ml. However, the response in individual patients varies, and because of the small wheal area and the low reproducibility with histamine 1 mg/ml we recommend the exchange of histamine 1 mg/ml to histamine 10 mg/ml as an international positive reference.

How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA(2) LEN statement

To cite this article: Bousquet J, Schünemann HJ, Bousquet PJ, Bachert C, Canonica GW, Casale TB, Demoly P, Durham S, Carlsen K‐H, Malling H‐J, Passalacqua G, Simons FER, Anto J, Baena‐Cagnani CE, Bergmann K‐C, Bieber T, Briggs AH, Brozek J, Calderon MA, Dahl R, Devillier P, Gerth van Wijk R, Howarth P, Larenas D, Papadopoulos NG, Schmid‐Grendelmeier P, Zuberbier T. How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA‐GA2LEN statement. Allergy 2011; 66: 765–774.

Reproducibility of Histamine Skin Prick Test

The reproducibility of skin prick test using histamine dihydrochloride 1, 5, and 10 mg/ml was tested by three nurses in five non‐atopics in a double‐blind trial. The variations day‐to‐day, within‐day, between and for the same tester were calculated. Seventy‐five percent of wheal reactions obtained by histamine 1 mg/ml were < 15 mm2. With histamine 5 mg/ml there were only a few wheals < 15 mm2 and none at all with bistamine 10 mg/ml. The mean coefficient of variation of wheals > 15 mm2 was between 20–30%, in contrast to figures between 30‐60% with wheals < 15 mm2. No significant day‐to‐day or within‐day variation was shown concerning histamine wheal areas. It is suggested that histamine dihydrochloride 10 mg/ml should replace histamine dihydrochloride 1 mg/ml as the positive reference in routine skin prick tests and biological standardization.

The CONSORT statement checklist in allergen-specific immunotherapy: a GA2LEN paper

The methodology of randomized clinical trials is essential for the critical assessment and registration of therapeutic interventions. The CONSORT (Consolidated Standards of Reporting Trials) statement was developed to alleviate the problems arising from the inadequate reporting of randomized controlled trials. The present article reflects on the items that we believe should be included in the CONSORT checklist in the context of conducting and reporting trials in allergen‐specific immunotherapy. Only randomized, blinded (in particular blinding of patients, health care providers, and outcome assessors), placebo‐controlled Phase III studies in this article. Our analysis focuses on the definition of patients’ inclusion and exclusion criteria, allergen standardization, primary, secondary and exploratory outcomes, reporting of adverse events and analysis.

Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients.

To cite this article: Howarth P, Malling H‐J, Molimard M, Devillier P. Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients. Allergy 2012; 67: 321–327.