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.

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.

• 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.

• 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).

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.