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Drug Hypersensitivity

By

James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Last review/revision Oct 2022
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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.

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.

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.

Pearls & Pitfalls

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

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 Anaphylaxis Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more (type I hypersensitivity reaction); exanthema (eg, morbilliform eruption), urticaria Urticaria Urticaria consists of migratory, well-circumscribed, erythematous, pruritic plaques on the skin. Urticaria also may be accompanied by angioedema, which results from mast cell and basophil activation... read more 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 typically occurs 7 to 10 days after exposure and causes fever, arthralgias, and rash. Mechanism is a type III hypersensitivity reaction Type III Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more due to drug-antibody complexes and complement activation. Some patients have frank arthritis, edema, or gastrointestinal symptoms. Symptoms are self-limited, lasting 1 to 2 weeks. Beta-lactam and sulfonamide antibiotics, iron-dextran, and carbamazepine are most commonly implicated.

Drug-induced immune hemolytic anemia may develop when an antibody-drug-red blood cell (RBC) interaction occurs (eg, with cephalosporins and with cefotetan) or when a drug (eg, fludarabine, methyldopa) alters the RBC membrane in a way that induces autoantibody production. These reactions are 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 Type IV Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more that can start up to 12 weeks 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 may be caused by some drugs (eg, bleomycin, amiodarone, nitrofurantoin, amphotericin B, sulphonamides, sulfasalazine). These drugs can induce respiratory symptoms (distinct from the wheezing that may occur with type I hypersensitivity), deterioration in pulmonary function, and other pulmonary changes (called drug-induced pulmonary disease, most commonly interstitial lung disease Overview of Interstitial Lung Disease Interstitial lung diseases are a heterogeneous group of disorders characterized by alveolar septal thickening, fibroblast proliferation, collagen deposition, and, if the process remains unchecked... read more ). These effects are thought to be primarily type III and type IV hypersensitivity reactions.

The most common allergic renal effect is tubulointerstitial nephritis Tubulointerstitial Nephritis Tubulointerstitial nephritis is primary injury to renal tubules and interstitium resulting in decreased renal function. The acute form is most often due to allergic drug reactions or to infections... read more Tubulointerstitial Nephritis ; NSAIDs (including COX-2 inhibitors), methicillin, antimicrobials, and cimetidine are commonly implicated. Types I, III, and/or IV hypersensitivity reactions can be involved.

Other autoimmune phenomena may occur. Hydralazine, propylthiouracil, and procainamide can cause a systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more Systemic Lupus Erythematosus (SLE) (SLE)-like syndrome, which is a type III hypersensitivity reaction. 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 central nervous system. The antinuclear antibody test is positive. Penicillamine can cause SLE Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more Systemic Lupus Erythematosus (SLE) and other autoimmune disorders (eg, myasthenia gravis Myasthenia Gravis Myasthenia gravis is characterized by episodic muscle weakness and easy fatigability caused by autoantibody- and cell-mediated destruction of acetylcholine receptors. It is more common among... read more , which is a type II hypersensitivity reaction). Some drugs can cause perinuclear antineutrophil cytoplasmic autoantibodies (p-ANCA)–associated vasculitis Diagnosis Diagnosis . Common drugs associated with drug-induced perinuclear antineutrophil cytoplasmic autoantibodies (p-ANCA)–associated vasculitis include antithyroid drugs, antituberculosis drugs, certain antibiotics, allopurinol, hydralazine, and atorvastatin. These 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, and endocrine system.

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

  • 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 Type I Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more 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 can be done 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 Specific tests Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more 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 only as part of a drug desensitization protocol. If tests are negative, a serious reaction is extremely unlikely but not excluded. Therefore, an oral challenge with amoxicillin is often done after a negative skin test result to completely eliminate the possibility of an IgE-mediated allergy.

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.

Table

Tests for hematologic drug reactions include direct and indirect antiglobulin tests Diagnosis Diagnosis . 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

  • 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

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

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 (drug). 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, serum sickness, DRESS, or other severe delayed or cutaneous hypersensitivity reactions. Desensitization is usually not effective for T-cell–mediated reactions and should not be done in such cases. Whenever desensitization is done, 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 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 (1 Treatment references 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... read more X, Y 2 Treatment references 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... read more ). 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.

Rapid drug desensitization has been successful for many antibiotics, biologics, diabetes drugs, aspirin, and other drugs.

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.

  • Treat acute type I hypersensitivity 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 the risk of type I hypersensitivity reactions to the drug.

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