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Drug Hypersensitivity

By Peter J. Delves, PhD, Professor of Immunology, Division of Infection & Immunity, Faculty of Medical Sciences, University College London, London, UK

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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.


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. 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.

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 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. 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.

Pearls & Pitfalls

  • Penicillin allergy does not always rule out use of cephalosporins.

Symptoms and Signs

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; 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:

  • Serum sickness: This reaction typically occurs 7 to 10 days after exposure and causes fever, arthralgias, and rash. Mechanism involves drug-antibody complexes and complement activation. Some patients have frank arthritis, edema, or GI symptoms. Symptoms are self-limited, lasting 1 to 2 wk. Beta-lactam and sulfonamide antibiotics, iron-dextran, and carbamazepine are most commonly implicated.

  • Hemolytic anemia: This disorder may develop when an antibody-drug-RBC interaction occurs or when a drug (eg, methyldopa) alters the RBC membrane, uncovering an antigen that induces autoantibody production.

  • DRESS (drug rash with eosinophilia and systemic symptoms): This reaction, also called drug-induced hypersensitivity syndrome (DHS), can start up to 12 wk after initiation of drug treatment and can occur after a dose increase. Symptoms may persist or recur for several weeks after stopping drug treatment. Patients have prominent eosinophilia and often develop hepatitis, exanthema, facial swelling, generalized edema, and lymphadenopathy. Carbamazepine, phenytoin, allopurinol, and lamotrigine are frequently implicated.

  • Pulmonary effects: Some drugs induce respiratory symptoms (distinct from the wheezing that may occur with type I hypersensitivity), deterioration in pulmonary function, and other pulmonary changes (see Drug-Induced Pulmonary Disease).

  • Renal effects:Tubulointerstitial nephritis is the most common allergic renal reaction; methicillin, antimicrobials, and cimetidine are commonly implicated.

  • Other autoimmune phenomena: Hydralazine, propylthiouracil, and procainamide can cause an SLE-like syndrome. The syndrome may be mild (with arthralgias, fever, and rash) or fairly dramatic (with serositis, high fevers, and malaise), but it tends to spare the kidneys and CNS. The antinuclear antibody test is positive. Penicillamine can cause SLE and other autoimmune disorders (eg, myasthenia gravis). Some drugs can cause perinuclear antineutrophil cytoplasmic autoantibodies (p-ANCA)–associated vasculitis. These autoantibodies are directed against myeloperoxidase (MPO).


  • 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 immediate-type (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 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 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 class I haplotypes, genotyping of patients from particular ethnic groups can identify those at higher risk of hypersensitivity reactions.

Some HLA-Based Risk Factors for Drug Hypersensitivity



HLA Haplotype





Han Chinese, Japanese, Koreans, Thai

Less often, Europeans



Caucasians, Japanese












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.


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.


  • Drug discontinuation

  • Supportive treatment (eg, antihistamines, corticosteroids, epinephrine)

  • 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

  • NSAIDs for arthralgias

  • Corticosteroids for severe reactions (eg, exfoliative dermatitis, bronchospasm)

  • 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).


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, oxygen, epinephrine, and resuscitation equipment must be available for prompt treatment of anaphylaxis.

Desensitization is based on incremental dosing of the antigen every 15 to 20 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 (mcg)/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 (mcg); 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

  • Diagnosis can usually be based on history (mainly the patient's report of a reaction soon after taking 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.

  • A negative skin test result rules out the possibility of anaphylaxis but does not predict incidence of subsequent serum sickness.

  • Hypersensitivity tends to decrease over time.

  • Treat acute reactions supportively with antihistamines for pruritus, NSAIDs for arthralgias, corticosteroids for severe reactions (eg, exfoliative dermatitis, bronchospasm), and epinephrine for anaphylaxis.

  • If the causative drug must be used, try rapid desensitization, in collaboration with an allergist if possible, to temporarily reduce drug sensitivity.

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