Anaphylaxis in Clinical Trials of Sublingual Immunotherapy Tablets.

BACKGROUND: There is no consensus method to identify anaphylaxis in sublingual immunotherapy (SLIT) trials. Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (SMQs) are standardized groupings of MedDRA terms used in drug safety monitoring. OBJECTIVE: To develop a method to identify potential anaphylaxis in SLIT-tablet trials using SMQ searches and case definitions of anaphylaxis adopted from the National Institute of Allergy and Infectious Disease. METHODS: The SMQ search tool contained 2 criteria including treatment-emergent adverse events (AEs): (1) narrow MedDRA terms related to anaphylaxis and (2) all AEs with broad MedDRA terms from at least 2 of 3 categories (respiratory/skin/cardiovascular) occurring on the same day. Criteria were applied to a pooled data set of all subjects from 48 timothy grass, ragweed, house dust mite, and tree SLIT-tablet trials (SLIT-tablet, N = 8200; placebo, N = 7033). Additional search strategies were any treatment-emergent AE with MedDRA preferred term "hypersensitivity" and epinephrine administrations. Identified potential cases underwent blinded independent medical expert review. Nonanaphylaxis cases were designated local AEs or mild to moderate systemic reactions. RESULTS: Using the SMQ search tool and after subsequent medical review, 8 anaphylaxis cases were identified; 3 were considered treatment-related, resulting in a proportion of anaphylaxis cases/subject of 0.02% (2 of 8200) with SLIT-tablet and 0.01% (1 of 7033) with placebo. One additional anaphylaxis case related to SLIT-tablet was identified by the preferred term "hypersensitivity." The 3 anaphylaxis cases associated with SLIT-tablet treatment were not life-threatening. The epinephrine administration rate was 17 of 8200 (0.2%) with SLIT-tablet treatment and 2 of 7033 (0.03%) with placebo. CONCLUSIONS: SMQ search criteria for identifying potential anaphylaxis related to SLIT were developed. Anaphylaxis was rare for SLIT-tablets.

CHOICE international survey: Clusters of allergen immunotherapy prescription from French and Spanish cohorts.

Background: There is no description of the drivers of prescription for allergen immunotherapy (AIT) for respiratory allergic diseases. Methods: A prospective, multicentre, observational, non-interventional real-life study was performed in France and Spain for 20 months. Data were gathered using 2 different questionnaires, anonymously collected in an online platform. No names of AIT products were recorded. Multivariate analysis and unsupervised cluster analysis were performed. Results: One hundred and three physicians (50.5% from Spain and 49.5% from France) reported 1735 patients (433 in France and 1302 in Spain), 47.9% males, 64.8% adults with a mean age 26.2 years old. They suffered from allergic rhinitis (99%), allergic conjunctivitis (70.4%), allergic asthma (51.8%), atopic dermatitis (13.9%), and food allergy (9.9%). A clustering analysis based on 13 predefined relevant variables for AIT-prescription identified 5 different clusters, each of them including information regarding doctor's profile and patient demographics, baseline disease characteristics, and main AIT indication: 1) Looking at the future: focusing on asthma prevention (n = 355), 2) Efficacy after discontinuation of AIT (n = 293), 3) Fighting severe allergic disease (n = 322), 4) Looking at the present, facing current symptoms (n = 265) and 5) Doctor's own clinical experience (n = 500). Each one of these clusters have specific patients' and doctors' characteristics, representing distinctive AIT prescription drivers. Conclusion: Using data-driven analysis, we identified for the first time some reasons and patterns of AIT prescriptions in real-life clinical settings. There is no uniform indication for prescribing AIT, which varies amongst patients and doctors with multiple but specific drivers, taking into account several relevant parameters.

Criteria used by health professionals on the selection of allergen immunotherapy in real clinical practice: Methodology.

Background: Allergen immunotherapy (AIT) is today the only etiological therapy for respiratory allergic diseases, including allergic rhinitis, allergic conjunctivitis, and allergic asthma. Even though interest in real-world data has recently increased, publications mainly focus on short-term and long-term efficacy and safety of AIT. Indeed, information is still lacking regarding the "key parameters" or "drivers of prescription" used by doctors to prescribe AIT or by the patients to accept AIT as treatment for their respiratory allergic disease. Examining these factors is therefore the main goal of the CHOICE-Global Survey: "Criteria Used by Health Professionals on the Selection of Allergen Immunotherapy in Real Clinical Practice: An international academic electronic survey". Methods: We present the methodology of the CHOICE-Global Survey, an academic, prospective, multicenter, observational, transversal, web-based e-survey, conducted in real-life clinical settings designed to collect data from 31 countries representing 9 global different socio-economic and demographic regions. In the present document, we describe the survey, how it was conceived and developed, how data are stored and analyzed, and the different steps that will provide this information to the allergy community. Conclusions: The CHOICE-Global Survey will be able to provide, from an academic point of view, information on the drivers of prescription of AIT in real-life practice and improve understanding regarding the key parameters considered by doctors and patients for such therapy.

Extrapolating Evidence-Based Medicine of AIT Into Clinical Practice in the United States.

Allergy/immunology specialists in the United States prescribing allergy immunotherapy (AIT) have placed a heavy value on practical experience and anecdotal evidence rather than research-based evidence. With the extensive research on AIT conducted in the last few decades, the time has come to better implement evidence-based medicine (EBM) for AIT. The goal of this review was to critically assess EBM for debated concepts in US AIT practice for respiratory allergies in the context and quality of today's regulatory standards. Debated topics reviewed were the efficacy and safety of AIT in various subgroups (eg, polyallergic patients, older patients, patients with asthma, and pregnant women), diagnosis topics (eg, skin prick test vs allergen-specific serum IgE, factors affecting skin prick tests, use of nasal or conjunctival allergen challenges, and telemedicine for diagnosis), and dosing topics (eg, optimal dosing for subcutaneous immunotherapy and sublingual immunotherapy tablets, US liquid allergen extract history, duration of treatment, and biomarkers of efficacy). In addition, EBM for patient-centered AIT issues (eg, adherence, use of practice guidelines, and pharmacoeconomics) and the approach to implementation of AIT EBM in future clinical practice were addressed. The EBM for each concept was briefly summarized, and when possible, a practical, concise recommendation was given.

Integrating the evidence in allergen immunotherapy: Why real-world data should be important for the practicing clinician?

Data obtained from controlled clinical trials are the gold standard for evaluation of allergen immunotherapy (AIT) efficacy and safety. Less prone to biases (with a strong internal validity), they allow their use and external validation in the real world. The quantity and diversity of real-world data has increased exponentially, and access to large cohorts and electronic medical records have made this information increasingly accessible and useful for research and regulatory purposes. New retrospective database studies have confirmed the sustained benefits of grass, birch pollen, and house dust mite AIT for both allergic rhinitis and asthma symptom and medication scores, the prevention of asthma (when used in nonasthmatic rhinitics), and the real rate of adverse systemic reactions. They also have addressed clinical practice issues not elsewhere analyzed, including the management of polysensitized patients with respiratory allergies and adherence to AIT. Real-world evidence has its own biases and limits that need to be taken into account. In this article we present a concise summary of the literature about the role of real-world evidence in AIT.

Controversies in Allergy: A Pro/Con Review of Sublingual Allergen Immunotherapy and Allergic Asthma.

Sublingual allergen immunotherapy (SLIT) is a therapeutic intervention used in the treatment of respiratory allergies, including asthma. Multiple randomized, double-blind, placebo controlled clinical trials have evaluated the efficacy and safety of SLIT for asthma. These data provide a good platform to appraise the evidence critically to evaluate the effect of SLIT in the management of asthma for the administration of SLIT by both SLIT drops and SLIT tablets, from a clinical perspective. In this clinical review, presented in a pro and con format, we examined (1) evidence from systematic reviews and meta-analyses; (2) clinical efficacy on asthma symptoms, asthma exacerbations, and quality of life; (3) clinical efficacy on reduction of asthma controller medication; (4) asthma severity; (5) safety profile; (6) long-term effect and prevention; (7) international guidelines, and (8) real-world evidence. Identified inconsistency in the data results from wide variations and differences in outcome measures, specific allergens, delivery approaches, schedules, and age groups. The house dust mite SLIT tablet demonstrated efficacy when it was used in the add-on management of house dust mite-associated allergic asthma in adults. Sublingual allergen immunotherapy for asthma may represent an important advance in incorporating a personalized medicine approach for patients with allergic asthma.

Personalized medicine for allergy treatment: Allergen immunotherapy still a unique and unmatched model.

The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.

Clinical Practice of Allergen Immunotherapy for Allergic Rhinoconjunctivitis and Asthma: An Expert Panel Report.

Allergen immunotherapy (AIT) reduces symptoms and medication use associated with allergic rhinitis with or without conjunctivitis and allergic asthma. Although several AIT guidelines exist, there remain unanswered questions about AIT that are relevant to everyday practice. Our objective was to prepare an evidence-based overview addressing the practical aspects of AIT in clinical practice based on published evidence and the experience of international experts in the field. Topics covered include interpretation and translation of clinical trial data into everyday clinical practice (eg, allergen doses and treatment duration), assessment of risk and treatment of local and systemic allergic reactions, recommendations for improvement of AIT guidelines, and identification of appropriate data for seeking regulatory approval, to name a few. Many informational gaps in AIT practice need further evaluation as products and practices evolve.

Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.

Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence.

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.

2019 ARIA Care pathways for allergen immunotherapy.

Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow-up of patients.

Validation of Patient-Reported Outcomes for Clinical Trials in Allergic Rhinitis: A Systematic Review.

Although regulatory authorities have recently recommended the use of a combined symptom-medication score as a primary efficacy end point, none has been psychometrically validated. Here, we sought to determine to what extent allergic rhinitis (AR)-related patient-reported outcomes (symptom scores, medication scores, disease control scores, and satisfaction or quality-of-life scales) have been assessed for construct, content, and/or criterion validity, reliability, responsiveness, and the minimal clinically important difference. We searched the PubMed database from January 1997 to June 2018 with logical combinations of key words related to validation, AR, and patient-rated outcomes and scales. From a total of 1705 potentially relevant publications, 55 were reviewed. Despite the current emphasis on a combined symptom-medication score for evaluating the efficacy of allergen immunotherapy in AR, symptom scores have not been extensively validated, and we did not find any publications describing the validation of a medication score. Disease control scales (mainly the Rhinitis Control Assessment Test, the Control of Allergic Rhinitis and Asthma Test, and the Allergic Rhinitis Control Test) and health-related quality-of-life scales (mainly the Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ] and the mini-RQLQ) have been extensively validated in AR but have some practical disadvantages as primary efficacy criteria in clinical trials.

Comparison of International Systemic Adverse Reactions Due to Allergen Immunotherapy.

BACKGROUND: Several classifications of systemic adverse reactions (SARs) during allergen immunotherapy have been proposed, but the comparison of their usefulness in daily clinical practice is lacking. OBJECTIVE: The present post hoc analysis was aimed at investigating the practicality of the most relevant international classifications proposed by the European Academy of Allergology and Clinical Immunology (EAACI), the American Academy of Asthma, Allergology and Clinical Immunology/American College of Allergy, Asthma and Immunology (AAAACI/ACAAI), and the World Allergy Organization (WAO) using data provided by the longitudinal European Survey on Adverse Systemic Reactions in Allergen Immunotherapy (EASSI) based on daily clinical practice in 3 countries in Europe. METHODS: One hundred nine SARs over 4363 allergen immunotherapy courses were classified as mild (n = 78 [71.5%]), moderate (n = 27 [24.8%]), and severe (n = 4 [3.7%]) by EASSI-doctors, which served as a criterion standard. Every SAR was further classified according to the following grading systems: EAACI 2006 Grading System (EAACI2006), WAO 2010 Grading System (WAO2010), WAO 2017 Grading System (WAO2017), and AAAAI/ACAAI Grading System. All SAR rankings were also cross-compared among each other (Kendall correlation coefficient Tau-b). In general, a low epinephrine use was identified, severe reactions occurred within 15 minutes, and milder reactions were skin only. RESULTS: The analysis indicated disparities in mild and moderate SARs in the different grading systems. The correlation between EASSI-severity and EAACI2006, WAO2010, WAO2017, and AAAAI/ACAAI Grading System was 0.639, 0.502, 0.315, and 0.663, respectively (P < .001 in all cases). However, correlation of severe reactions was good. The best correlation with the onset of the reaction and the number of System Organ Class involved were detected in WAO grading systems. CONCLUSIONS: Despite having a lower correlation than EAACI and AAAAI/ACAAI, the WAO grading appears to provide a moderate correlation among these classifications. The analysis might help to inform clinicians and investigators on selecting the most appropriate classification.

Critical view of anaphylaxis epidemiology: open questions and new perspectives.

In contrast to the majority of allergic or hypersensitivity conditions, worldwide anaphylaxis epidemiological data remain sparse with low accuracy, which hampers comparable morbidity statistics. Data can differ widely depending on a number of variables. In the current document we reviewed the forms on which anaphylaxis has been defined and classified; and how it can affect epidemiological data. With regards to the methods used to capture morbidity statistics, we observed the impact of the anaphylaxis coding utilizing the World Health Organization's International Classification of Diseases. As an outcome and depending on the anaphylaxis definition, we extracted the cumulative incidence, which may not reflect the real number of new cases. The new ICD-11 anaphylaxis subsection developments and critical view of morbidity statistics data are discussed in order to reach new perspectives on anaphylaxis epidemiology.

Implementation gaps for asthma prevention and control.

Asthma and allergic diseases can start in childhood and persist throughout life, but could also be manifested later, at any time for still misunderstood reasons. They are major chronic multifactorial respiratory diseases, for which prevention, early diagnosis and treatment is recognized as a priority for the Europe's public health policy and the United Nations. Given that allergy triggers (including infections, rapid urbanization leading to loss in biodiversity, pollution and climate changes) are not expected to change in a foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies. Currently there are good treatments for asthma, several risk factors are known (e.g., allergies, rhinitis, tobacco smoke) and tools to control the disease have been developed. However, we are still uncertain how to prevent patients from developing asthma and allergic diseases. In this paper, we list the positive and negative experiences in this field as well as analyze the missing links in the process. This critical analysis will be the basis of setting-up an effective program for prevention and making, a process labeled as "implementation gaps".