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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.
Drug hypersensitivity differs from toxic and adverse effects that may be expected from the drug and from problems due to drug interactions (see Factors Affecting Response to Drugs: Drug Interactions).
Pathophysiology
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 immunogenic, stimulating antidrug antibody production, T-cell responses against the drug, or both. Haptens may also bind directly to the MHC II molecule, directly activating T cells. 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.
How primary sensitization occurs and how the immune system is initially involved is unclear, but once a drug stimulates an immune response, cross-reactions with other drugs within and between drug classes can occur. For example, penicillin-sensitive patients are highly likely to react to semisynthetic penicillins (eg, amoxicillin, carbenicillin, ticarcillin). In early, poorly designed studies, about 10% of patients who had a vague history of penicillin sensitivity reacted to cephalosporins, which have a similar β-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. Also, not every apparent reaction is allergic; for example, amoxicillin causes a rash that is not immune-mediated and does not preclude future use of the drug.
Symptoms and Signs
Symptoms and signs vary by patient and drug, and a single drug may cause different reactions in different patients. The most serious is anaphylaxis; 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 exist:
Diagnosis
Time of onset, known effects of a drug, and results of a repeat drug challenge can help differentiate drug hypersensitivity from toxic and adverse drug effects and from problems due to drug interactions (see Factors Affecting Response to Drugs: Drug Interactions). 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 immediate-type (IgE-mediated) hypersensitivity help identify reactions to β-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 testing is needed if patients with a history of an immediate hypersensitivity reaction must take a penicillin. BPO-polylysine conjugate and penicillin G are used with histamine and saline as controls. The prick test (see Allergic, Autoimmune, and Other Hypersensitivity Disorders: Specific tests) is used first. If patients have a history of a severe explosive reaction, reagents should be diluted 100-fold for initial testing. If prick tests are negative, intradermal testing may follow. If skin tests are positive, treating patients with penicillin may induce an anaphylactic reaction. If tests are negative, a serious reaction is less likely but not excluded. Although the penicillin skin test has not induced de novo sensitivity in patients, patients should usually be tested only immediately before essential penicillin therapy is begun.
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 min 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 HLA-B haplotypes, genotyping of patients may be able to predict sensitivity.
Tests for hematologic drug reactions include direct and indirect antiglobulin tests (see Anemias Caused by Hemolysis: Diagnosis). Tests for other specific drug hypersensitivity (eg, radioallergosorbent testing [RAST], histamine release, basophil or mast cell degranulation, lymphocyte transformation) are unreliable or experimental.
Prognosis
Hypersensitivity decreases with time. IgE antibodies are present in 90% of patients 1 yr after an allergic reaction but in only about 20 to 30% after 10 yr. 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
Treatment 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, NSAIDs for arthralgias, corticosteroids for severe reactions (eg, exfoliative dermatitis, bronchospasm), and epinephrine for anaphylaxis. Conditions such as drug fever, a nonpruritic rash, or mild organ system reactions require no treatment (for treatment of specific clinical reactions, see elsewhere in The Manual).
Desensitization:
Rapid desensitization may be necessary if sensitivity has been established and if treatment is essential and no alternative exists. Rapid desensitization reduces sensitivity only temporarily. If possible, desensitization should be done in collaboration with an allergist. The procedure should not be attempted in patients who have had Stevens-Johnson syndrome. Whenever desensitization is used, O2, epinephrine, and resuscitation equipment must be available for prompt treatment of anaphylaxis.
Desensitization is based on incremental dosing of the antigen every 30 min, beginning with a minute dose to induce subclinical anaphylaxis before exposure to therapeutic doses. This procedure depends on constant presence of drug in the serum and so must not be interrupted; desensitization is immediately followed by full therapeutic doses. Hypersensitivity typically returns 24 to 48 h after treatment is stopped. Minor reactions (eg, itching, rash) are common during desensitization.
For penicillin, oral or IV regimens can be used; sc or IM regimens are not recommended. If only the intradermal skin test is positive, 100 units (μg)/mL IV in a 50-mL bag (5000 units total) should be given very slowly (eg, < 1 mL/min) at first. If no symptoms appear after 20 to 30 min, flow rate can be increased gradually until the bag is empty. The procedure is then repeated with concentrations of 1,000 units/mL and 10,000 units/mL, followed by the full therapeutic dose. If any allergic symptoms develop, flow rate should be slowed, and patients are given appropriate drug treatment (see above). If the prick test for penicillin was positive or patients have had a severe anaphylactic reaction, the starting dose should be lower.
Oral penicillin desensitization begins with 100 units (μg); doses are doubled every 15 min up to 400,000 units (dose 13). Then, the therapeutic dose of the drug is given parenterally to treat the infection, and if symptoms of drug hypersensitivity occur, appropriate antianaphylactic drugs are used.
For allergies to trimethoprim-sulfamethoxazole and vancomycin, regimens similar to those for penicillin can be used.
If a skin test to xenogeneic serum is positive, risk of anaphylaxis is high. If serum treatment is essential, desensitization must precede it.
Key Points
Last full review/revision July 2012 by Peter J. Delves, PhD
Content last modified November 2012
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