Q&A: Drug allergy diagnosis project could ‘touch every single specialty’
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Key takeaways:
- Research will explore mechanisms in non-IgE-mediated immediate drug hypersensitivity reactions.
- The goal is a comprehensive methodology for understanding other immediate drug allergy mechanisms.
Drug allergy diagnosis could become more precise, cutting down on mislabeled allergies and needless drug avoidance, as a result of upcoming work comparing different types of drug hypersensitivity reactions.
The project will examine vancomycin — a common antibiotic often mislabeled as an allergen — to explore the differences between two types of immediate hypersensitivity reactions: those so severe they require drug avoidance, and those that might be tempered through slower infusion or other means.
Its findings could be the foundation of a methodology for understanding hypersensitivity reactions across a range of mechanisms, impacting a variety of medical fields, the project’s leader, Santiago Alvarez-Arango, MD, assistant professor of medicine and pharmacology at The Johns Hopkins University School of Medicine, associate director of the Johns Hopkins Drug Development Unit and co-director of The Johns Hopkins Center of Excellence for Anaphylaxis, told Healio.
“You can just name the specialty. Each one of them is going to have a drug that they have been avoiding because people reported being allergic,” he said. “This work can touch every single specialty.”
Alvarez-Arango is conducting the project with funding from the American Academy of Allergy, Asthma & Immunology’s 2023 Foundation Faculty Development Awards. Healio spoke to Alvarez-Arango for more information and context about how this project could advance clinical care.
Healio: What is the goal of this study, and how will it be conducted?
Alvarez-Arango: The study aims to investigate the mechanisms underlying non-IgE-mediated immediate drug hypersensitivity reactions (IDHSRs), specifically focusing on vancomycin as a prototype drug. The overarching hypothesis is that vancomycin IDHSRs are primarily driven by a non-IgE-mediated mechanism characterized by low vancomycin immunogenicity frequency and a reactor phenotype influenced by genetic variation in the Mas-related G protein-coupled receptor X2 (MRGPRX2) gene, and demonstrated by skin hyperreactivity and a functional basophil test.
We will explore three critical questions to improve knowledge and differentiate IgE- and non-IgE-IDHSR:
- comparing vancomycin-specific IgG (sIgG) frequency in vancomycin-IDHSR individuals and vancomycin-tolerant controls using an optimized vancomycin sIgG ELISA assay;
- exploring whether those with vancomycin IDHSR have IDHSRs to other MRGPRX2-ligands, suggesting a phenotype of hyperreactivity possible driven by MRGPRX2 genetic variation, which involves analyzing the association between MRGPRX2-ligands allergy labels as well as performing targeted deep sequencing of the MRGPRX2 gene; and
- investigating skin hyperreactivity to vancomycin and basophil responsiveness to vancomycin, which includes conducting skin testing with vancomycin and performing functional basophil assays to identify diagnostic tools for vancomycin non-IgE-mediated IDHSR.
By addressing these aims simultaneously, the study aims to advance the understanding of non-IgE IDHSR mechanisms, contribute to developing specific diagnostics and enhance clinical care for patients experiencing IDHSRs to vancomycin and potentially other MRGPRX2 ligands.
Healio: What prompted you to investigate this topic?
Alvarez-Arango: The investigation of this topic was prompted by the significant impact of misclassifying IDHSRs, which can result in detrimental consequences such as unnecessary drug avoidance and reliance on less effective and costlier alternatives. The lack of reliable diagnostic tests for distinguishing between IgE-mediated and non-IgE-mediated IDHSRs further contributes to this misclassification. Consequently, there is a pressing need to enhance existing methods to identify risk factors and underlying mechanisms more accurately, thereby preventing misclassification and optimizing clinical care.
Additionally, the recent discovery of MRGPRX2 as one of the mechanisms responsible for non-IgE-mediated mast cell activation in IDHSRs has played a crucial role in prompting the investigation of this topic. Understanding these mechanisms and the ability to differentiate between IgE-mediated and non-IgE-mediated IDHSRs is paramount for improving clinical management and avoiding unnecessary drug avoidance, leading to more effective and efficient patient care.
Healio: Why is vancomycin a good window into differentiating between IgE-mediated and non-IgE-mediated reactions?
Alvarez-Arango: Vancomycin serves as a prototype drug in this proposal because it is a described ligand for MRGPRX2. Most vancomycin-induced IDHSRs appear to occur through a non-IgE-mediated mechanism, but it remains uncertain whether vancomycin elicits a specific antibody response. In contrast to drugs like penicillin, which are known to induce drug-specific IgE production and activate mast cells and basophils upon re-exposure, other IDHSRs often manifest on the first dose via a non-IgE-mediated mechanism, such as the recently identified MRGPRX2. Unfortunately, vancomycin IDHSRs, like those associated with other MRGPRX2 ligands, are frequently misclassified as IgE-mediated, leading to the discontinuation of potential future use. True IgE-mediated IDHSRs to vancomycin are rare, with only seven probable cases reported from 1982 to 2015, and there have been no reports of vancomycin-specific IgE.
By focusing on vancomycin, researchers can delve into its immunogenicity, investigate risk factors for non-IgE-mediated IDHSRs to MRGPRX2 ligands and develop diagnostic tools to identify vancomycin non-IgE IDHSRs accurately. The insights gained from this study can then be extrapolated to differentiate other non-IgE-mediated IDHSRs triggered by similar MRGPRX2 ligands.
Healio: Are there any other drugs in which you would be interested to study non-IgE-mediated reaction mechanisms?
Alvarez-Arango: In addition to vancomycin, other drugs show potential for studying non-IgE-mediated IDHSR mechanisms, particularly those involving MRGPRX2 ligands. For instance, fluoroquinolones and neuromuscular blocker agents have been identified as drugs capable of activating mast cells through MRGPRX2. One intriguing question is whether individuals with a history of a previous reaction to one MRGPRX2 ligand have an increased risk for reacting to another. By investigating non-IgE-mediated IDHSRs associated with these and other MRGPRX2 ligands, we can achieve a more comprehensive understanding of the underlying mechanisms at play.
Moreover, this study will pave the way for developing a comprehensive methodology to investigate other non-IgE-mediated mechanisms, such as those potentially involved in hypersensitivity reactions to biologics and chemotherapy agents. This broader investigation holds great promise in advancing our knowledge and comprehension of immune and nonimmune hypersensitivity reactions, thereby providing valuable insights for developing diagnostic tools and strategies.
Healio: How might this work translate into clinical care?
Alvarez-Arango: IDHSRs are a significant health concern, with approximately 221,600 cases occurring annually in the U.S., of which 6% result in anaphylaxis. IgE-mediated anaphylaxis is the most severe among these reactions and requires complete drug avoidance. However, it is essential to note that most IDHSRs are non-IgE-mediated.
This research holds significant implications for clinical care, particularly in the diagnosis and management of IDHSRs. Misclassifying IDHSRs often leads to unnecessary drug avoidance and reliance on alternative drugs with inferior safety, efficacy and cost profiles. This limits treatment options and increases the risk for drug-related side effects, drives up health care costs and ultimately harms patients.
By accurately distinguishing between IgE-mediated and non-IgE-mediated IDHSRs, health care professionals can implement appropriate modifications to treatment plans, such as adjusting dosages or administration methods, based on the specific nature of the reaction, instead of resorting to complete drug avoidance. This personalized approach can significantly improve patient outcomes and quality of life.
Furthermore, developing specific diagnostic tools, including techniques to define immunogenicity and the utilization of in vivo and in vitro tests would greatly assist in identifying patients with non-IgE-mediated IDHSRs. These tools would provide health care providers valuable information to make informed decisions regarding the safest and most effective course of action for individual patients. This research can optimize clinical care, minimize unnecessary risks and improve patient well-being by reducing reliance on broad drug avoidance and enabling targeted diagnostic approaches.
Healio: Are there any colleagues you would like to recognize for their work on this project?
Alvarez-Arango: I have had the privilege of working closely with my primary mentor and co-mentors, who have been instrumental in equipping me with the necessary skills to execute my proposed research plan and foster my career development toward independence. The invaluable multidisciplinary mentorship I have received serves as the foundation for my career growth, ensuring the successful completion of this research and training plan. In addition, I have established vital collaborations with esteemed experts in drug allergy epidemiology, informatics and genomics at The Johns Hopkins University School of Medicine department of molecular biology and genetics, forming a collaborative group of mentors and collaborators from Johns Hopkins, Mass General Brigham, and Vanderbilt University Medical Center.
I am fortunate to be guided by distinguished individuals in the field whose contributions to this project are highly recognized. N. Franklin Adkinson, MD; Donald MacGlashan, MD, PhD; Corinne Keet, MD, MS; Elizabeth Phillips, MD; Robert Wood, MD; and Kimberly Blumenthal, MD, MSC, are among the mentors whose expertise and guidance are crucial to the successful execution of the research plan and my overall career development.
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For more information:
Santiago Alvarez-Arango, MD, can be reached at salvarez@jhmi.edu.