Page 676 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Drug Hypersensitivity

Mariana Castells, Rafael Bonamichi-Santos

Reactions to drugs are an important source of morbidity and KEY CONCEPT
mortality and constitute a major hazard in the practice of
medicine. We have an incomplete understanding of the mecha- Main Presentations of Drug Hypersensitivity
nisms of the reactions, few tools for their diagnosis and/or 1. Type I reactions with the involvement of mast cells and basophil
1,2
prevention, and limited treatment options. With the introduc- triggering by IgE and/or non-IgE mechanisms and ranging from urticaria
tion of new and better medications to treat cancer, chronic to anaphylaxis
inflammatory diseases, and infections, there has been a parallel 2. Type IV delayed hypersensitivity reaction presenting as delayed rash;
increase in instances of drug allergy and hypersensitivity. Although drug-specific T cell–specific clones may be identifiable
these new, targeted therapies offer increased survival and quality 3. Severe cutaneous reactions, including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN), drug-induced reactions with
of life, repeated exposures to small molecules and monoclonal eosinophilia and systemic symptoms (DRESS), and acute generalized
antibodies (mAbs) with immunogenic and allergenic capacity exanthematous pustulosis (AGEP), in which HLA genotypes and viral
have increased the rate of sensitizations and reactions. Drug infections play major roles
hypersensitivity prevents patients from receiving first-line therapy,
and doctors have few guidelines on how to diagnose and address
these potentially life-threatening reactions. 3,4
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Identifying drug-hypersensitive patients protects them from antiepileptics are among the most frequent causes. The risk
reexposure to culprit medications and permits access to desen- of sensitization and of a reaction depends on the drug chemistry
sitization procedures when needed and indicated. Identifying and structure, the host immune system, the dose, the route,
patients who are not in fact hypersensitive means they can avoid the duration of treatment, the patient’s gender and specific
receiving second-line therapies with their associated increased HLA alleles. In a study from Brazil, >50% of the anaphylactic
5
costs and resource requirements. The vast majority of patients reactions treated in the emergency department were induced
with a history of penicillin allergy have negative results on skin by nonsteroidal anti-inflammatory drugs (NSAIDs), the most
12
testing and do not react during a challenge or during further frequently implicated medications. A recent US study of drug-
6
courses of penicillin, but there is a lack of standardized reagents induced anaphylaxis found that most patients were female, few
approved by the US Food and Drug Administration (FDA) for received appropriate treatment with epinephrine, and 29% had
the diagnosis of allergy to the majority of antibiotics and other concomitant asthma and allergic rhinitis. A high proportion
drugs. Central to the evaluation of patients with drug hyper- of these patients were receiving antidepressants, angiotensin-
sensitivity is an understanding of the pathophysiology of the converting enzyme (ACE) inhibitors and/or angiotensin II
reactions. Genotype studies of patients with severe hypersensitivity blockers, confirming the association of these medications with
reactions, including drug-induced reactions with eosinophilia severe reactions. 13
and systemic symptoms (DRESS), Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN), have uncovered predis- IMMUNE DRUG RECOGNITION AND GENETIC
posing specific HLA alleles permitting identification of targeted BASIS OF DRUG HYPERSENSITIVITY
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populations and protection against these reactions. Systematic
utilization of available markers of immune cell activation, such Drugs are recognized by the immune system and initiate immune
as tryptase (the major mast cell protease release during anaphy- responses, depending on their structure, size, and multimeric/
lactic IgE- and non-IgE–mediated reactions) can provide useful multivalent presentation. Most drugs are small molecules, which
diagnostic information and help guide the treatment and require haptenization, or binding to carrier proteins, to interact
management of drug reactions. 8 with antigen-presenting cells (APCs), including B cells. Once B
cells are activated, epitope-specific antibodies are made, including
14
EPIDEMIOLOGY OF DRUG HYPERSENSITIVITY IgE if interleukin-4 (IL-4) is present. Beta-lactam antibiotics,
such as penicillin and cephalosporins, are haptens with unstable
Drug hypersensitivity has a spectrum of presentations and beta-lactam rings that acylate lysine residues in proteins, forming
9
can be fatal : the most common presentation is skin rashes, covalent bonds and leading to the major penicilloyl epitope
observed in about 2–3% of hospitalized patients. 10,11 Any drug responsible for urticarial reactions. Carboxyl and thiol groups
can elicit hypersensitivity reactions: antibiotics, chemotherapy in beta-lactams can also haptenate. These hapten–carrier
drugs, mAbs, antihypertensives, radio contrast media, and complexes are called minor allergens because they are found

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