SupplementTask force report: Future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions☆,☆☆,★,★★
Section snippets
Background
Immune-mediated drug hypersensitivity reactions (IDHR) are uncommon adverse events in clinical medicine that are restricted to a subset of vulnerable patients and pharmaceutical products. Nevertheless, such reactions, and the fear of them as serious and potentially life-threatening consequences of therapy, have a huge impact on clinical practice, drug development, and the public health. IDHRs accounted for 137,000 to 230,000 hospital admissions in the United States in 1998, with estimated
Background: Mechanisms of IDHR
The mechanisms of immune-medicated hypersensitivity reactions to low molecular weight drugs generally fit one of two classifications: (1) reactions that occur when a drug or metabolite acts as a hapten and the immune response is directed against the hapten or hapten-peptide conjugate, or (2) autoimmune reactions in which drug administration results in an immune response to self-antigens. After a brief review of these two mechanisms, the section Determining Risk Factors will describe critical
Preventing and managing IDHR
Data gaps, research needs, and recommendations for better prevention and management of IDHRs are described in this section, which is divided into three subsections: Determining Risk Factors, Clinical Issues, and Preclinical Issues.
Future research funding, training, and organizational needs
The long list of data gaps and issues in the clinical and preclinical areas suggests that a significant amount of research is needed before progress can be made in the prevention and management of IDHRs. To move forward, increased funding for basic and applied research is needed along with increased training and the development of novel cooperative efforts between government, academia, and industry.
Priorities and conclusions
Although there are multiple barriers that must be overcome to advance understanding of IDHR, the public health benefits of understanding this work and successful strategies for prevention and management of IDHR are clear. The following general points summarize the top priorities.
Priorities for research Identify key host risk factors (metabolism, infection, genetic background) and drug characteristics (metabolites, reactive groups) in hypersensitivity reactions. Emphasize research efforts to better understand the
Acknowledgements
The members of the task force gratefully acknowledge the time and expertise generously provided by Dr Kenneth Hastings from the US Food and Drug Administration's Center for Drug Evaluation and Research, Dr John Langone of the Food and Drug Administration's Center for Devices and Radiological Health, and Dr Gregory Downing from the Office of Science Policy at the National Institutes of Health.
The task force would also like to acknowledge Dr Lanny J. Rosenwasser from the National Jewish Medical
References (83)
- et al.
A tier approach for evaluating the respiratory allergenicity of low molecular weight chemicals
Fundam Appl Toxicol
(1992) Drug allergy: problems and strategies
J Allergy Clin Immunol
(1984)- et al.
Concordance of the toxicity of pharmaceuticals in humans and in animals
Regul Toxicol Pharmacol
(2000) - et al.
T cell immune responses to haptens: structural models for allergic and autoimmune reactions
Toxicology
(1996) Autoimmunity caused by xenobiotics
Toxicology
(1997)- et al.
Allergic and autoimmune reactions to xenobiotics: how do they arise?
Immunol Today
(1998) Drug-induced autoimmune and hematologic disorders
Immunol Allergy Clin North Am
(1991)- et al.
Genetic predisposition to drug-induced hepatotoxicity
Hepatology
(1997) - et al.
Hydralazine-induced systemic lupus erythematosis: influence of HLA-DR and sex on susceptibility
Lancet
(1980) Risk factors for drug allergy
J Allergy Clin Immunol
(1984)
Allergic reactions to antimicrobial drugs in patients with a history of prior drug allergy
J. Allergy Clin Immunol
Evidence for familial aggregation of immunologic drug reactions
J Allergy Clin Immunol
A diagnostic protocol for evaluating nonimmediate reactions to aminopenicillins
J Allergy Clin Immunol
Opiates, mast cells and histamine release
Life Sci
Value of animal models for predicting hypersensitivity reactions to medicinal products
Toxicology
The identification of contact allergen by animal assay: the guinea pig maximization test
J Invest Dermatol
A review of the Buehler guinea pig skin sensitization test and its use in a risk assessment process for human skin sensitization
Toxicology
Studies on the mechanism of drug sensitization: T-cell dependent popliteal lymph node reaction to diphenylhydantoin
Clin Immunol Immunopathol
The use of reporter antigens in the popliteal lymph node assay to assess immunomodulation by chemicals
Toxicol Appl Pharmacol
Popliteal lymph node enlargement induced by procainamide
Int J Immunopharmacol
The chemical modification of proteins, haptens, and solid supports
An alternative strategy to the use of guinea pigs for the identification of skin sensitization hazard
Food Chem Toxicol
Contact sensitization: a new approach to risk assessment
Human and Ecological Risk Assessment
Animal models of occupational asthma
Eur Respir J
An approach to allergic contact sensitization risk assessment of new chemicals and product ingredients
Am J Contact Dermat
Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies
JAMA
Adverse drug events in hospitalized patients
JAMA
The costs of adverse drug events in hospitalized patients
JAMA
T cell crossreactivity to heavy metals: identical cryptic peptides may be presented from protein exposed to different metals
Eur J Immunol
Role of drug hypersensitivity: a chemical, molecular, and clinical perspective
Chem Res Toxicol
Recognition of sulfmethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals
J Immunol
Characterization of lidocain-specific T cells
J Immunol
Penicilloyl peptides are recognized as T cell antigenic determinants in penicillin allergy
Eur J Immunol
Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine
J Immunol
Drug-specific T cells derived from patients with drug-induced allergic hepatitis
J Immunol
Chemical-induced autoimmunity
Cytochrome P-450 and drug development for skin diseases
Skin Pharmacol
Drug metabolizing enzymes in lymphocytes
J Biochem Mol Toxicol
Mercuric chloride alters nuclear self antigen, upregulates its presentation, and activates specific T helper cells for auto-antibody formation
Immunobiology
Cited by (82)
Drug-induced hypersensitivity reactions in a Lebanese outpatient population: A decade-long retrospective analysis (2012-2021)
2024, Journal of Allergy and Clinical Immunology: GlobalNon–IgE-Mediated Immediate Drug-Induced Hypersensitivity Reactions
2024, Journal of Allergy and Clinical Immunology: In PracticeAn in silico workflow for assessing the sensitisation potential of extractables and leachables
2023, Computational ToxicologyComplement-mediated hypersensitivity reactions to an amphotericin B-containing lipid complex (Abelcet) in pediatric patients and anesthetized rats: Benefits of slow infusion
2021, Nanomedicine: Nanotechnology, Biology, and MedicineDescriptive analysis of a simplified approach to low-risk drug hypersensitivity reactions
2021, Annals of Allergy, Asthma and ImmunologyImportant questions in drug allergy and hypersensitivity: Consensus papers from the 2018 AAAAI/WAO international drug allergy symposium
2018, World Allergy Organization JournalCitation Excerpt :Although tremendous progress has been made over the past two decades in the understanding of the mechanisms of drug allergy and hypersensitivity and their management, several unmet needs remain. Several task forces with representatives from the key stakeholders (research clinicians, regulatory scientists and immuno-toxicologists) have identified the critical data gaps and opportunities and made recommendations on how to overcome some of the barriers to DHRs research and address research needs [4, 6, 7]. What are the key questions and what has been done since the latest task force?
- ☆
This report is supported by the ILSI Health and Environmental Sciences Institute's Immunotoxicology Technical Committee.
- ☆☆
Dr Haggerty, Dr Kawabata, J. David Sandler, Dr Updyke, and Dr Wierda are members of the Immunotoxicology Technical Committee of the ILSI Health and Environmental Sciences Institute. Dr Kawabata is Task Force Chairman.
- ★
Dr Gruchalla is a member of the speakers bureau for Merck and GlaxoSmithKline, and receives grants or research support from the National Institutes of Health. Dr Kawabata is an employee of Pfizer, Inc. Dr Shear is a consultant for Bristol-Myers Squibb, Sanwa, Pfizer, GlaxoSmithKline, and Novartis. Dr Updyke is an employee of Pfizer, Inc, and has financial interests in Pfizer, Inc, and American Home Products, Inc. Dr Wierda is employed by Eli Lilly and Company. All of the authors have prepared this report to present factual, unbiased information and attest that no commercial association has influenced this report, nor does this publication constitute a commercial or personal conflict of interest.
- ★★
Reprint requests: J. David Sandler, ILSI Health and Environmental Sciences Institute, 1126 16th St NW, Washington, DC 20036-4810. E-mail: [email protected]