Drug hypersensitivity is an immune-mediated reaction to a drug. Symptoms range from mild to severe and include rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing is occasionally useful. Treatment is drug discontinuation, supportive treatment (eg, with antihistamines), and sometimes desensitization.
(See also Overview of Allergic and Atopic Disorders.)
Drug hypersensitivity differs from toxic and adverse effects that may result from the drug and from problems due to drug interactions.
Pathophysiology of Drug Hypersensitivity
Some protein and large polypeptide drugs (eg, insulin, therapeutic antibodies) can directly stimulate antibody production. However, most drugs act as haptens, binding covalently to serum or cell-bound proteins, including peptides embedded in major histocompatibility complex (MHC) molecules. The binding makes the protein-drug complex immunogenic, stimulating antidrug antibody production, T-cell responses against the drug, or both. Haptens may also bind directly to class II MHC molecules, directly activating T cells. Some drugs act as prohaptens. When metabolized, prohaptens become haptens; eg, penicillin itself is not antigenic, but its main degradation product, benzylpenicilloic acid, can combine with tissue proteins to form benzylpenicilloyl (BPO), a major antigenic determinant. Some drugs bind and stimulate T-cell receptors (TCR) directly; the clinical significance of nonhapten TCR binding is being determined.
penicillin sensitivity reacted to cephalosporins, which have a similar beta-lactam structure; this finding has been cited as evidence of cross-reactivity between these drug classes. However, in recent, better-designed studies, only about 2% of patients with a penicillin allergy detected during skin testing react to cephalosporins; about the same percentage of patients react to structurally unrelated antibiotics (eg, sulfa drugs). Sometimes this and other apparent cross-reactions (eg, between sulfonamide antibiotics and nonantibiotics) are due to a predisposition to allergic reactions rather than to specific immune cross-reactivity.
Pearls & Pitfalls
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Symptoms and Signs of Drug Hypersensitivity
Symptoms and signs of drug allergies vary by patient and drug, and a single drug may cause different reactions in different patients. The most serious is anaphylaxis (type I hypersensitivity reaction); exanthema (eg, morbilliform eruption), urticaria, and fever are common. Fixed drug reactions—reactions that recur at the same body site each time a patient is exposed to the same drug—are uncommon.
Some distinct clinical syndromes can involve other types of hypersensitivity reactions:
Serum sickness
Drug-induced immune hemolytic anemia
DRESS (drug rash with eosinophilia and systemic symptoms)
Pulmonary effects
Renal effects
Other autoimmune phenomena
Serum sickness typically occurs 7 to 10 days after exposure and causes fever, arthralgias, and rash. Mechanism is a type III hypersensitivity reaction
Drug-induced immune hemolytic anemia
DRESS (drug rash with eosinophilia and systemic symptoms), also called drug-induced hypersensitivity syndrome (DHS), is a type IV hypersensitivity reaction
Pulmonary effectsdrug-induced pulmonary disease, most commonly interstitial lung disease). These effects are thought to be primarily type III and type IV hypersensitivity reactions.
The most common allergic renal effect is tubulointerstitial nephritis
Other autoimmune phenomenasystemic lupus erythematosusSLE and other autoimmune disorders (eg, myasthenia gravis, which is a type II hypersensitivity reaction). Some drugs can cause perinuclear antineutrophil cytoplasmic autoantibodies (p-ANCA)–associated vasculitis
Diagnosis of Drug Hypersensitivity
Patient’s report of a reaction soon after taking a drug
Skin testing
Sometimes drug provocation testing
Sometimes direct and indirect antiglobulin assays
The following can help differentiate drug hypersensitivity from toxic and adverse drug effects and from problems due to drug interactions.
Time of onset
Known effects of a drug
Results of a repeat drug challenge
For example, a dose-related reaction is often drug toxicity, not drug hypersensitivity.
Drug hypersensitivity is suggested when a reaction occurs within minutes to hours after drug administration. However, many patients report a past reaction of uncertain nature. In such cases, if there is no equivalent substitute (eg, when penicillin is needed to treat syphilis), testing should be considered.
Skin testing
Tests for type I (IgE-mediated) hypersensitivity help identify reactions to beta-lactam antibiotics, foreign (xenogeneic) serum, and some vaccines and polypeptide hormones. However, typically, only 10 to 20% of patients who report a penicillin allergy have a positive reaction on skin tests. Also, for most drugs (including cephalosporins), skin tests are unreliable and, because they detect only IgE-mediated reactions, do not predict the occurrence of morbilliform eruptions, hemolytic anemia, or nephritis.
Penicillin skin testingprick test is used first. If patients have a history of a severe anaphylactic reaction, reagents should be diluted 100-fold for initial testing. If prick tests are negative, intradermal testing may follow. If skin tests are positive, patients should be given penicillin
For xenogeneic serum skin testing, patients who are not atopic and who have not previously received xenogeneic (eg, horse) serum should first be given a prick test with a 1:10 dilution; if this test is negative, 0.02 mL of a 1:1000 dilution is injected intradermally. A wheal > 0.5 cm in diameter develops within 15 minutes in sensitive patients. Initially, for all patients who may have previously received serum—whether or not they reacted—and for those with a suspected allergic history, a prick test should be done using a 1:1000 dilution; if results are negative, 1:100 is used, and if results are again negative, 1:10 is used as above. A negative result rules out the possibility of anaphylaxis but does not predict incidence of subsequent serum sickness.
Other testing
For drug provocation testing, a drug suspected of causing a hypersensitivity reaction is given in escalating doses to precipitate the reaction. This test is usually safe and effective if done in a controlled setting.
Because drug hypersensitivity is associated with certain human leukocyte antigen (HLA) class I haplotypes, genotyping of patients from particular ethnic groups can identify those at higher risk of hypersensitivity reactions.
Tests for hematologic drug reactions include direct and indirect antiglobulin tests. Tests for other specific drug hypersensitivity (eg, allergen-specific serum IgE testing, histamine release, basophil or mast cell degranulation, lymphocyte transformation) are unreliable or experimental.
Prognosis for Drug Hypersensitivity
Hypersensitivity decreases with time. IgE antibodies are present in 90% of patients 1 year after a type I allergic reaction but in only about 20 to 30% of patients after 10 years. Patients who have anaphylactic reactions are more likely to retain antibodies to the causative drug longer.
People with drug allergies should be taught about avoiding the drug and should carry identification or an alert bracelet. Charts should always be appropriately marked.
Treatment of Drug Hypersensitivity
Drug discontinuation
Sometimes desensitization
Treatment of drug allergies is stopping the implicated drug; most symptoms and signs clear within a few days after the drug is stopped.
Symptomatic and supportive treatment for acute reactions may include
Antihistamines for pruritus
Nonsteroidal anti-inflammatory drugs (NSAIDs) for arthralgias
Corticosteroids for severe reactions (eg, exfoliative dermatitis, bronchospasm)
Conditions such as drug fever, a nonpruritic rash, or mild organ system reactions require no treatment other than discontinuation of the drug (for treatment of specific clinical reactions, see elsewhere in THE MANUAL).
Desensitization
Desensitization is based on incremental dosing of the antigen every 15 to 20 minutes, beginning with a minute dose to induce subclinical anaphylaxis before exposure to therapeutic doses. This procedure depends on the constant presence of the drug in the serum and so must not be interrupted; desensitization is immediately followed by full therapeutic doses. Hypersensitivity typically returns 24 to 48 hours after treatment is stopped. Minor reactions (eg, itching, rash) are common during desensitization.
Desensitization protocols can be designed for an IgE-mediated drug reaction and are effective for drugs thought to be responsible these reactions (1X, Y2). Typical protocols are oral or IV and are typically an 8- to 16-step protocol with increasing doses at each step until the target dose is reached. The target dose is continued for the standard duration; a pause in drug administration allows sensitization to return. When an IV route is used, multiple solutions at increased concentrations are prepared, and infusions rates are adjusted to increase the dose with each step.
If a skin test to xenogeneic serum is positive, risk of anaphylaxis is high. If serum treatment is essential, desensitization must precede it.
Treatment references
1. Castells M: Desensitization for drug allergy. Curr Opin Allergy Clin Immunol 6 (6):476–481, 2006.
2. Chastain DB, Hutzley VJ, Parekh J, et al: Antimicrobial desensitization: A review of published protocols. Pharmacy (Basel) 7 (3):112, 2019. doi: 10.3390/pharmacy7030112
Key Points
Hypersensitivity reactions to drugs are often type I (immediate, IgE-mediated), but they can be type II, III, or IV.
Drug hypersensitivity can often be diagnosed based on history (mainly the patient's report of a reaction after starting to take the drug), but known adverse and toxic effects of the drug and drug-drug interactions must be excluded.
If the diagnosis is unclear, usually skin tests but occasionally drug provocation testing or other specific tests can identify some drugs as the cause, particularly if type I hypersensitivity reactions are primarily involved.
A negative skin test result rules out the possibility of anaphylaxis but does not predict incidence of subsequent serum sickness or other non-IgE–mediated reactions.
Hypersensitivity tends to decrease over time.
If the causative drug must be used, try rapid desensitization, in collaboration with an allergist if possible, to temporarily reduce the risk of type I hypersensitivity reactions to the drug.
