Task force report: Future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions

doi:10.1067/mai.2002.122214

Journal of Allergy and Clinical Immunology

Volume 109, Issue 3, March 2002, Pages S461-S478

https://doi.org/10.1067/mai.2002.122214 Get rights and content

Abstract

Immune-mediated drug hypersensitivity reactions (IDHR) have a significant impact on clinical practice, drug development, and public health. However, research to understand IDHR mechanisms and to develop diagnostic and predictive tests has been limited. To stimulate more research, a task force with representatives from the key stakeholders (research clinicians, regulatory scientists, and immunotoxicologists from the pharmaceutical industry) was assembled to identify critical data gaps and opportunities and to make recommendations on how to overcome some of the barriers to IDHR research and address research needs. It is hoped that this report will act as a springboard for future discussions and progress toward increased funding and development of organizational structures for IDHR research. (J Allergy Clin Immunol 2002;109:S461-78.)

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)

K Sarlo et al.
A tier approach for evaluating the respiratory allergenicity of low molecular weight chemicals
Fundam Appl Toxicol
(1992)
RD. DeSwarte
Drug allergy: problems and strategies
J Allergy Clin Immunol
(1984)
H Olson et al.
Concordance of the toxicity of pharmaceuticals in humans and in animals
Regul Toxicol Pharmacol
(2000)
HU Weltzien et al.
T cell immune responses to haptens: structural models for allergic and autoimmune reactions
Toxicology
(1996)
PE. Bigazzi
Autoimmunity caused by xenobiotics
Toxicology
(1997)
P Griem et al.
Allergic and autoimmune reactions to xenobiotics: how do they arise?
Immunol Today
(1998)
BC. Gilliland
Drug-induced autoimmune and hematologic disorders
Immunol Allergy Clin North Am
(1991)
D Larrey et al.
Genetic predisposition to drug-induced hepatotoxicity
Hepatology
(1997)
JR Batchelor et al.
Hydralazine-induced systemic lupus erythematosis: influence of HLA-DR and sex on susceptibility
Lancet
(1980)
NF Adkinson
Risk factors for drug allergy
J Allergy Clin Immunol
(1984)

EK Moseley et al.

Allergic reactions to antimicrobial drugs in patients with a history of prior drug allergy

J. Allergy Clin Immunol

(1991)

KM Kurtz et al.

Evidence for familial aggregation of immunologic drug reactions

J Allergy Clin Immunol

(2000)

A Romano et al.

A diagnostic protocol for evaluating nonimmediate reactions to aminopenicillins

J Allergy Clin Immunol

(1999)

KE Barke et al.

Opiates, mast cells and histamine release

Life Sci

(1993)

G Choquet-Kastylevsky et al.

Value of animal models for predicting hypersensitivity reactions to medicinal products

Toxicology

(1998)

B Magnusson et al.

The identification of contact allergen by animal assay: the guinea pig maximization test

J Invest Dermatol

(1969)

MK Robinson et al.

A review of the Buehler guinea pig skin sensitization test and its use in a risk assessment process for human skin sensitization

Toxicology

(1990)

H. Gleichmann

Studies on the mechanism of drug sensitization: T-cell dependent popliteal lymph node reaction to diphenylhydantoin

Clin Immunol Immunopathol

(1981)

R Albers et al.

The use of reporter antigens in the popliteal lymph node assay to assess immunomodulation by chemicals

Toxicol Appl Pharmacol

(1997)

N Katsutani et al.

Popliteal lymph node enlargement induced by procainamide

Int J Immunopharmacol

(1992)

H. Kiefer

The chemical modification of proteins, haptens, and solid supports

DA Basketter et al.

An alternative strategy to the use of guinea pigs for the identification of skin sensitization hazard

Food Chem Toxicol

(1995)

I Kimber et al.

Contact sensitization: a new approach to risk assessment

Human and Ecological Risk Assessment

(1997)

MH. Karol

Animal models of occupational asthma

Eur Respir J

(1994)

GF Gerberick et al.

An approach to allergic contact sensitization risk assessment of new chemicals and product ingredients

Am J Contact Dermat

(1993)

J Lazarou et al.

Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies

JAMA

(1998)

DC Classen et al.

Adverse drug events in hospitalized patients

JAMA

(1997)

DW Bates et al.

The costs of adverse drug events in hospitalized patients

JAMA

(1997)

Lehman Brothers

P Griem et al.

T cell crossreactivity to heavy metals: identical cryptic peptides may be presented from protein exposed to different metals

Eur J Immunol

(1998)

BK Park et al.

Role of drug hypersensitivity: a chemical, molecular, and clinical perspective

Chem Res Toxicol

(1998)

B Schnyder et al.

Recognition of sulfmethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals

J Immunol

(2000)

MP Zanni et al.

Characterization of lidocain-specific T cells

J Immunol

(1997)

E Padovan et al.

Penicilloyl peptides are recognized as T cell antigenic determinants in penicillin allergy

Eur J Immunol

(1997)

D Mauri-Hellweg et al.

Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine

J Immunol

(1995)

H Tsutsui et al.

Drug-specific T cells derived from patients with drug-induced allergic hepatitis

J Immunol

(1992)

LL Kosuda et al.

Chemical-induced autoimmunity

N Ahmad et al.

Cytochrome P-450 and drug development for skin diseases

Skin Pharmacol

(1996)

JL Raucy et al.

Drug metabolizing enzymes in lymphocytes

J Biochem Mol Toxicol

(1999)

M Kubicka-Muranyi et al.

Mercuric chloride alters nuclear self antigen, upregulates its presentation, and activates specific T helper cells for auto-antibody formation

Immunobiology

(1994)

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Citation 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 article is one of a series of international consensus documents developed from the International Drug Allergy Symposium held at the Joint Congress of the American Academy of Allergy, Asthma & Immunology/World Allergy Organization on March 1, 2018, in Orlando, Florida, USA. The symposium was sponsored by The Journal of Allergy and Clinical Immunology, The Journal of Allergy and Clinical Immunology: In Practice, and The World Allergy Organization Journal and chaired by Mariana Castells, MD, PhD, and Pascal Demoly, MD, PhD.

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^☆: 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]

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SupplementTask force report: Future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions☆,☆☆,★,★★

Abstract

Section snippets

Background

Background: Mechanisms of IDHR

Preventing and managing IDHR

Future research funding, training, and organizational needs

Priorities and conclusions

Acknowledgements

Fundam Appl Toxicol

J Allergy Clin Immunol

Regul Toxicol Pharmacol

Toxicology

Toxicology

Immunol Today

Immunol Allergy Clin North Am

Hepatology

Lancet

J Allergy Clin Immunol

J. Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Life Sci

Toxicology

J Invest Dermatol

Toxicology

Clin Immunol Immunopathol

Toxicol Appl Pharmacol

Int J Immunopharmacol

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

Supplement
Task force report: Future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions☆,☆☆,★,★★