Lars Jacobsen

A controlled dose-response study of immunotherapy with standardized, partially purified extract of house dust mite: Clinical efficacy and side effects

BACKGROUND Seventy-four asthmatic patients allergic to house dust mite were included in a double-blind, controlled study to establish the optimal maintenance dose of a standardized extract of Dermatophagoides pteronyssinus (Der p I) during 24 months of immunotherapy (IT). METHODS The patients were given the following maintenance doses: 19 patients 10,000 standardized quality units (SQ-U) (group 10, 0.7 microgram Der p I), 20 patients 100,000 SQ-U (group 100, 7 micrograms Der p I), 16 patients 300,000 SQ-U (group 300, 21 micrograms Der p I), and 19 control patients (group 0) had no injections. After 24 months bronchial challenge demonstrated a dose-related increased tolerance to Der p I, group 10 (p = 0.003), group 100 (p = 0.0005), group 300 (p = 0.0007), with no change in group 0 (p = 0.6). Patients given IT had a decrease in medication and peak expiratory flow score. In total, 2104 injections were given, and 3.5% were followed by a systemic reaction, defined as a fall 15% or greater in forced expiratory volume in 1 second within 30 minutes. A dose-response relation was demonstrated, with rates of systemic reactions in percent of injections; group 10, 0.56%; group 100, 3.30%; and group 300, 7.10% (p < 0.0001). No anaphylactic reactions occurred, and no late systemic reactions were observed. This study demonstrated a dose dependence of efficacy and side effects of IT in asthmatic patients. We suggest a maintenance dose of 100,000 SQ-U (7 micrograms Der p I) as an appropriate guideline for IT with house dust mite extract.

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.

EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy

Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe’s policy-makers to coordinate actions and improve individual and public health in allergy by: Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.

Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy

Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases.

EAACI Guidelines on Allergen Immunotherapy: Allergic Rhinoconjunctivitis.

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side‐effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease‐modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunologys (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project “EAACI Guidelines on Allergen Immunotherapy.” It aims to provide evidence‐based clinical recommendations and has been informed by a formal systematic review and meta‐analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product‐specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short‐term benefit. The strongest evidence for long‐term benefit is documented for grass AIT (especially for the grass tablets) where long‐term benefit is seen. To achieve long‐term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long‐term benefit and use in children.

Allergen immunotherapy for allergic rhinoconjunctivitis: A systematic review and meta‐analysis

The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost‐effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis.

Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper

Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers.

How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma

Purpose of reviewThe purpose of this review is to describe the scientific evidence that specific immunotherapy can prevent the development of asthma in patients suffering from rhinoconjunctivitis as well as reduce the number of new allergies developing. Recent findingsProposed strategies for the prevention of the development of allergic rhinoconjunctivitis and asthma include allergen avoidance, pharmacological treatment (antihistamines and steroids) and specific immunotherapy. Long-term follow-up on immunotherapy studies demonstrates that specific immunotherapy for 3 years shows persistent long-term effects on clinical symptoms after termination of treatment and long-term, preventive effects on later development of asthma in children with seasonal rhinoconjunctivitis. It is so far the only treatment for allergic diseases that has been shown to be able to prevent worsening of disease and development of asthma. Also, specific immunotherapy seems to reduce the development of new allergic sensitivities as measured by the skin prick test as well as specific IgE measurements. SummarySpecific immunotherapy is the only treatment that interferes with the basic pathophysiological mechanisms of the allergic disease and thereby carries the potential for changes in the long-term prognosis of respiratory allergy. Specific immunotherapy should be recognized not only as first-line therapeutic treatment for allergic rhinoconjunctivitis, but also as secondary preventive treatment for respiratory allergic diseases.

Defining pollen exposure times for clinical trials of allergen immunotherapy for pollen‐induced rhinoconjunctivitis – an EAACI Position Paper

Clinical efficacy of pollen allergen immunotherapy (AIT) has been broadly documented in randomized controlled trials. The underlying clinical endpoints are analysed in seasonal time periods predefined based on the background pollen concentration. However, any validated or generally accepted definition from academia or regulatory authorities for this relevant pollen exposure intensity or period of time (season) is currently not available. Therefore, this Task Force initiative of the European Academy of Allergy and Clinical Immunology (EAACI) aimed to propose definitions based on expert consensus.

100 Years of Immunotherapy: The Monaco Charter

Aims of the Monaco Charter: (1) to present the current evidence on the efficacy and safety of allergen-specific immunotherapy (SIT) and to address the reasons for its underuse in clinical practice; (2) to develop strategies to increase the awareness about the benefits and the hazards of SIT in allergic patients, lay public and healthcare professionals not trained in allergy, and (3) to make SIT accessible and affordable to eligible patients.