Hypersensitivity reactions to biologicals: An EAACI position paper.

Biologicals are crucial targeted therapeutic agents in oncological, immunological, and inflammatory diseases, and their use in clinical practice is broadening. In recent years, the spread of Personalized Precision Medicine has facilitated a proliferation of new treatment options, especially biologicals. Consequently, biologicals are now among the drugs that most frequently cause hypersensitivity reactions (HSRs). Patients can develop HSRs to these agents during the first-lifetime exposure or after repeated exposure, and these HSRs can be potentially life-threatening or limit therapeutic options. Despite the relatively high prevalence, the underlying mechanisms of these HSRs remain obscure, and the optimal management pathways are still a matter of discussion. In this Position Paper, the authors will provide evidence-based recommendations for diagnosing and managing HSRs to biologicals. Additionally, the document defines unmet needs as an opportunity to shape future research.

Hypersensitivity reactions to chemotherapy: an EAACI Position Paper.

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug-induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work-up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section.

[Successful oral desensitization to levothyroxine. Report of one case]. / Desensibilización a levotiroxina. Caso clínico.

We report a 39-year-old female who underwent a total thyroidectomy as treatment for a thyroid papillary cancer. She suffered several episodes of mild angioedema in lips and tongue, after using different commercial Levothyroxine formulations, with and without excipients. Given the need to use this drug, the patient was admitted in our hospital and we proceeded to desensitize her with oral Levothyroxine. The patient fasted throughout the whole procedure, was properly monitored and had an adequate peripheral venous access. On the first day of the procedure, a 15-step protocol was performed, first administering placebo and then, compounded formulations of Levothyroxine starting from 0.01 ug, followed by doubling doses every 15 minutes until the cumulative dose of 111.95 ug was completed, corresponding to the daily dose of Levothyroxine her endocrinologist prescribed (112 ug). The patient was monitored at baseline, between each dose and up to 3 hours after the procedure was completed. There were no incidents such as urticaria, angioedema, or others. On the second day, the patient received a single-full dose of 112 ug on an empty stomach. The medication was successfully tolerated and she was discharged. Thereafter, she tolerates daily Levothyroxine.

Drug allergy desensitization is not a unique recipe.

PURPOSE OF REVIEW: Drug desensitization is the only therapeutic option for patients with drug allergies who need to receive the drugs they are allergic to, and it is especially critical in patients with an urgent need for chemotherapy, biologics, or antibiotics, where equally effective alternatives might not be available. However, drug desensitization is not a cookbook where anyone with no experience or specific training can find a general recipe. This review article will approach the singularities that make personalized and highly specialized care essential in this field. RECENT FINDINGS: Drug desensitization needs to be personalized for each individual patient bearing in mind countless factors. Recent articles have tried to define the optimal resources and the most important factors to account for in personalization. However, drug desensitization is only a tool within the wider management pathway, and we will discuss recent findings in allergy delabelling in chemotherapy, biologics, and antibiotics. SUMMARY: Risk-assessment, delabelling, and desensitization protocols, as a part of wider management pathways, can be adapted locally along with comprehensive and multifactorial risk-management strategies. These high-complexity and high-risk procedures, such as drug desensitization, need to be managed by expert allergists who can provide personalization, innovation, continuous improvement, research, and teaching in expert centres.

Standards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement.

Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).

A Large Single-Hospital Experience Using Drug Provocation Testing and Rapid Drug Desensitization in Hypersensitivity to Antineoplastic and Biological Agents.

BACKGROUND: Large-scale studies of drug provocation testing (DPT) or rapid drug desensitization (RDD) for hypersensitivity to antineoplastics and biologicals are scarce and limited to a few institutions. OBJECTIVE: Our aim was to review our experience with DPT and RDD in a large number of patients with a history of hypersensitivity to antineoplastics and biologicals and summarize the practical implications of that experience. METHODS: This was a 7-year prospective, observational, longitudinal study with reactive patients referred to the Desensitization Program at Ramon y Cajal University Hospital (RCUH). Patients were selected after following our systematic and validated diagnostic approach (clinical history, skin test, risk assessment, specific IgE, DPT) before RDD. Candidate patients underwent RDD using the RCUH protocol. Cetuximab reactors underwent 1-bag RDDs. RESULTS: A total of 1027 intravenous RDDs were performed using the RCUH protocol (399 platins, 395 taxanes, 178 biologicals, 55 other drugs), and 1026 were successfully accomplished in the 186 patients (of 515 referred patients) who met inclusion criteria for RDD. No breakthrough reactions occurred in 88% of RDDs. Most breakthrough reactions were mild. A total of 341 DPTs were performed, and 229 results were negative (67%). DPTs helped exclude hypersensitivity in 44% (229 of 515) of referred patients. In addition, 77 one-bag RDDs were performed in 6 cetuximab-reactive patients. CONCLUSIONS: This experience allows us to describe general management plans, as well as specific patient phenotypic patterns, predictors for reactions, and risk considerations that need a tailored approach (taking into account the 3 prominent drug categories: platins, taxanes, and biologicals).

Assessment of Antihistamines and Corticosteroids as Premedication in Rapid Drug Desensitization to Paclitaxel: Outcomes in 155 Procedures.

BACKGROUND: In early clinical trials, infusion reactions during the administration of taxanes were managed using systematic premedication with antihistamines and corticosteroids before standard infusions. Consequently, these premedications are also administered before rapid drug desensitization (RDD) with taxanes. However, their role in RDD has not been studied. OBJECTIVE: To assess the need for premedication with antihistamines and corticosteroids to prevent hypersensitivity reactions in RDD to paclitaxel. METHODS: Over a 4-year period, we selected patients with confirmed hypersensitivity to paclitaxel (positive skin testing and/or drug provocation testing results) who had received paclitaxel through RDD. These patients were assigned to 2 prospective noninception cohorts: one cohort premedicated with antihistamine and corticosteroids and another cohort that was not. RESULTS: We assessed 66 paclitaxel-reactive patients, of whom 22 met the inclusion criteria. A total of 155 RDDs to paclitaxel were performed. There were no significant differences in tolerance to RDD between the cohorts. CONCLUSIONS: Administering systematic premedication with corticosteroids and antihistamines had no significant effect on the effectiveness or safety of RDD in patients with confirmed hypersensitivity to paclitaxel in the study population. Moreover, these premedications can mask early signs of hypersensitivity and delay treatment. We believe that systematic premedication with these drugs for patients undergoing RDD should be carefully and individually assessed if their only purpose is to prevent breakthrough reactions during RDD.

A Phase I clinical trial with subcutaneous immunotherapy vaccine of Timothy grass pollen extract according to EMA guidelines.

AIM: A double-blind placebo-controlled study was conducted according to EMA guidelines, to evaluate safety, tolerability and short-term treatment effects of three up-dosing regimens of Phleum pratense subcutaneous immunotherapy. MATERIALS & METHODS: Forty-two patients were randomized to groups: A (6 weekly doses), B (8 weekly doses) or C (eight doses, two clustered increasing doses over 3 weeks). RESULTS: The most frequent adverse events were local reactions. No serious adverse events were found. Higher number and more severe systemic reactions were reported in group C. A decrease in cutaneous responses and an increase of specific antibodies was shown in all active groups even at very short-term. CONCLUSION: Phleum pratense subcutaneous immunotherapy in depot presentation exhibited good safety and tolerability. Group A seemed to show the best profile.

Desensibilización a levotiroxina: caso clínico / Successful oral desensitization to levothyroxine: report of one case

We report a 39-year-old female who underwent a total thyroidectomy as treatment for a thyroid papillary cancer. She suffered several episodes of mild angioedema in lips and tongue, after using different commercial Levothyroxine formulations, with and without excipients. Given the need to use this drug, the patient was admitted in our hospital and we proceeded to desensitize her with oral Levothyroxine. The patient fasted throughout the whole procedure, was properly monitored and had an adequate peripheral venous access. On the first day of the procedure, a 15-step protocol was performed, first administering placebo and then, compounded formulations of Levothyroxine starting from 0.01 ug, followed by doubling doses every 15 minutes until the cumulative dose of 111.95 ug was completed, corresponding to the daily dose of Levothyroxine her endocrinologist prescribed (112 ug). The patient was monitored at baseline, between each dose and up to 3 hours after the procedure was completed. There were no incidents such as urticaria, angioedema, or others. On the second day, the patient received a single-full dose of 112 ug on an empty stomach. The medication was successfully tolerated and she was discharged. Thereafter, she tolerates daily Levothyroxine.

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.