Drug Hypersensitivity

ByJames Fernandez, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University
Reviewed/Revised Aug 2024
View Patient Education

Drug hypersensitivity is an immune-mediated reaction to a medication. Symptoms range from mild to severe and include rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing is occasionally useful. Treatment is medication 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 medication and from problems due to drug interactions.

Pathophysiology of Drug Hypersensitivity

Some protein and large polypeptide medications (eg, insulin, therapeutic antibodies) can directly stimulate antibody production. However, most medications 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-medication complex immunogenic, stimulating anti-medication antibody production, T-cell responses against the medication, or both. Haptens may also bind directly to class II MHC molecules, directly activating T cells. Some medications 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 medications bind and stimulate T-cell receptors (TCR) directly; the clinical significance of nonhapten TCR binding is being determined (1).

How primary sensitization occurs and how the immune system is initially involved is unclear, but once a medication stimulates an immune response, cross-reactions with other medications within and between medication classes can occur. For example, patients who are penicillinpenicillin sensitivity reacted to cephalosporins, which have a similar beta-lactam structure; this finding has been cited as evidence of cross-reactivity between these medication classes. However, in better-designed studies (2), 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 medications). 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

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

Pathophysiology references

  1. 1. Pichler WJ, Watkins S, Yerly D. Risk Assessment in Drug Hypersensitivity: Detecting Small Molecules Which Outsmart the Immune System. Front Allergy 3:827893, 2022. doi:10.3389/falgy.2022.827893

  2. 2. Caruso C, Valluzzi RL, Colantuono S, Gaeta F, Romano A. β-Lactam Allergy and Cross-Reactivity: A Clinician's Guide to Selecting an Alternative Antibiotic. J Asthma Allergy 14:31-46, 2021. doi:10.2147/JAA.S242061

Symptoms and Signs of Drug Hypersensitivity

Symptoms and signs of medication allergies vary by patient and medication, and a single medication 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 medication reactions—reactions that recur at the same body site each time a patient is exposed to the same medication—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 type II hypersensitivity reactions.

DRESS (drug rash with eosinophilia and systemic symptoms), also called drug-induced hypersensitivity syndrome (DHS), is a type IV hypersensitivity reaction that can start up to 12 weeks after initiation of medication treatment and can occur after a dose increase. Symptoms may persist or recur for several weeks after stopping medication treatment. Patients have prominent eosinophilia

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 erythematosusmyasthenia gravisvasculitis. The p-ANCA autoantibodies are directed against myeloperoxidase (MPO), causing type II hypersensitivity reactions. Immune checkpoint inhibitors, a commonly used class of cancer immunotherapy, can have immune-related adverse effects. These effects result from nonspecific immune activation and can affect almost any organ system; however, they most commonly affect the skin, liver, gastrointestinal tract, heart, and endocrine system.

Diagnosis of Drug Hypersensitivity

  • Patient’s report of a reaction after taking a medication

  • Skin testing

  • Sometimes medication provocation testing

  • Sometimes direct and indirect antiglobulin assays

The following can help differentiate drug hypersensitivity from toxic and adverse medication effects and from problems due to drug interactions.

  • Time of onset

  • Known effects of a medication

  • Results of a repeat medication challenge

For example, a dose-related reaction is often medication toxicity, not drug hypersensitivity.

Drug hypersensitivity is suggested when a reaction occurs within minutes to hours after medication 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 a minority of patients who report a penicillin allergy have a positive reaction on skin tests (1). Also, for most medications (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 medication provocation testing, a medication 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 (2).

Table
Table

Tests for hematologic medication 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.

Diagnosis references

  1. 1. Providencia R, Aali G, Zhu F, et al. Penicillin Allergy Testing and Delabeling for Patients Who Are Prescribed Penicillin: A Systematic Review for a World Health Organization Guideline. Clin Rev Allergy Immunol 66(2):223-240, 2024. doi:10.1007/s12016-024-08988-2

  2. 2. Deshpande P, Hertzman RJ, Palubinsky AM, et al. Immunopharmacogenomics: Mechanisms of HLA-Associated Drug Reactions. Clin Pharmacol Ther 110(3):607-615, 2021. doi:10.1002/cpt.2343

Treatment of Drug Hypersensitivity

  • Medication discontinuation

  • Sometimes desensitization

Treatment of medication allergies is stopping the implicated medication; most symptoms and signs clear within a few days after the medication 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)

Conditions such as medication fever, a nonpruritic rash, or mild organ system reactions require no treatment other than discontinuation of the medication (for treatment of specific clinical reactions, see elsewhere in THE MANUAL).

Desensitization

Rapid desensitization may be necessary if IgE-mediated hypersensitivity has been established and if treatment is essential and no alternative exists. Rapid desensitization creates a temporary tolerance—ie, for the time during which the patient is exposed to the antigen (medication). If the patient goes 24 to 48 hours without exposure, sensitization will occur, and the patient is once again vulnerable if exposed. 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

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 medication 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 medication reaction and are effective for medications thought to be responsible for these reactions (1, 2). 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 medication 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. 1. Castells M: Desensitization for drug allergy. Curr Opin Allergy Clin Immunol 6 (6):476–481, 2006.

  2. 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

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 (1). Patients who have anaphylactic reactions are more likely to retain antibodies to the causative medication longer.

People with medication allergies should be taught about avoiding the medication and should carry identification or an alert bracelet. Charts should always be appropriately marked.

Prognosis reference

  1. 1. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA 321(2):188-199, 2019. doi:10.1001/jama.2018.19283

Key Points

  • Hypersensitivity reactions to medications 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 medication), but known adverse and toxic effects of the medication and -medication interactions must be excluded.

  • If the diagnosis is unclear, usually skin tests but occasionally medication provocation testing or other specific tests can identify some medications 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.

  • If the causative medication 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 medication.

  • Hypersensitivity tends to decrease over time.

Drugs Mentioned In This Article
quizzes_lightbulb_red
Test your KnowledgeTake a Quiz!
Download the free Merck Manual App iOS ANDROID
Download the free Merck Manual App iOS ANDROID
Download the free Merck Manual App iOS ANDROID