Hypersensitivity to medicines: causes, symptoms, diagnosis, treatment

Hypersensitivity to drugs is an immune-mediated reaction. Symptoms range from mild to severe and include skin rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing is informative. Treatment involves discontinuing the drug, administering antihistamines (if indicated), and sometimes desensitization.

Drug hypersensitivity must be differentiated from toxic and side effects that may occur when taking individual drugs or their combination.

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Pathogenesis

Some proteins and most polypeptide drugs (eg, insulin, therapeutic antibodies) can directly stimulate antibody production. However, most drugs act as haptens, which bind covalently to serum or cellular proteins, including those that comprise the major histocompatibility complex (MHC) molecules. This binding renders these proteins immunogenic, stimulating the production of antidrug antibodies, a T-cell response against the drug, or both. Haptens can also bind directly to MHC class II molecules, directly activating T cells. Prohaptens become haptens through metabolic reactions; for example, penicillin itself is not an antigen, but its major degradation product, benzylpenicilloic acid, can combine with tissue proteins to form benzylpenicilloyl (BPO), a major antigenic determinant. Some drugs bind directly to and stimulate T-cell receptors (TCRs); the clinical significance of nonhapten binding to TCRs remains to be established.

It is not clear how primary sensitization occurs and how innate immune mechanisms are initially involved, but once a drug has stimulated the immune response, cross-reactivity to drugs within and between drugs of the class is seen. For example, patients sensitized to penicillin are very likely to react to the semisynthetic penicillins (eg, amoxicillin, carbenicillin, ticarcillin), and about 10% of such patients will react to the cephalosporins, which have a similar beta-lactam structure. However, some apparent cross-reactivity (eg, between sulfonamide antibiotics and nonantibiotics) is more likely to be due to a predisposition to allergic reactions than to specific immune cross-reactivity. Thus, not every apparent reaction is allergic; for example, amoxicillin causes a rash, but the rash is not immune-mediated and does not preclude future use of the drug.

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Symptoms hypersensitivity to drugs

Symptoms and signs vary widely depending on the patient and the drug, and the same drugs may cause different reactions in different patients. The most serious manifestation is anaphylaxis; exanthema, urticaria, and fever are more common. Persistent drug reactions are rare.

There are other distinctive clinical syndromes. Serum sickness usually begins 7 to 10 days after exposure to the drug and is characterized by fever, arthralgia, and rash. The mechanism of development involves the formation of drug-antibody complexes and complement activation. Some patients develop severe arthritis, edema, or gastrointestinal symptoms. Symptoms are self-limited and last from 1 to 2 weeks. Beta-lactam antibiotics and sulfonamides, iron dextran, and carbamazepine are the most common causative agents.

Hemolytic anemia occurs when an antibody-drug-erythrocyte complex forms or when a drug (eg, methyldopa) alters the red cell membrane, exposing antigens that induce autoantibody production. Some drugs induce pulmonary damage. Tubulointerstitial nephritis is a common renal allergic reaction; methicillin, antimicrobials, and cimetidine are common causes. Hydralazine and procainamide may cause an SLE-like syndrome. This syndrome is relatively benign, sparing the kidneys and central nervous system; the antinuclear antibody test is positive. Penicillamine may cause SLE and other autoimmune diseases (eg, myasthenia gravis).

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Diagnostics hypersensitivity to drugs

The diagnosis is made when the reaction to the drug develops within a short time: from a few minutes to hours after taking the drug. However, many patients report a late reaction of uncertain origin. In some cases, when it is not possible to find an equivalent replacement (for example, penicillin in the treatment of syphilis), it is necessary to conduct skin tests.

Skin testing. Skin testing in cases of immediate-type (IgE-mediated) hypersensitivity helps in diagnosing reactions to beta-lactam antibiotics, foreign (xenogeneic) serum, some vaccines, and polypeptide hormones. However, only 10-20% of patients who react to penicillin usually have positive skin tests. For many drugs (including cephalosporins), tests are unreliable and, because they diagnose only IgE-mediated allergy, they do not predict the development of morbilliform rash, hemolytic anemia, or nephritis.

Penicillin skin testing is necessary in patients with a history of immediate hypersensitivity who are to be treated with penicillin. BPO-polylysine conjugate and penicillin G are used with histamine and saline as controls. A prick test is used first. If the patient has a history of severe violent reactions, the reagents should be diluted 100-fold for the initial test. If the prick test is negative, intradermal testing can be done. If the skin test is positive, treatment of the patient with penicillin may cause an anaphylactic reaction. If the test is negative, a serious reaction is unlikely but not excluded. Although penicillin skin testing does not induce de novo hypersensitivity, patients are tested immediately before starting penicillin therapy.

In skin testing for xenogenic serum, patients without a history of atopy and who have not previously received horse serum preparations are first tested by prick test using a 1:10 dilution; if the test result is negative, 0.02 ml of a 1:1000 dilution is injected intradermally. In sensitive patients, a wheal greater than 0.5 cm in diameter will form within 15 minutes. All patients who may have previously received serum preparations, whether they have reacted or not, and with a suspected history of allergy are first tested using a 1:1000 dilution. Negative results exclude the possibility of anaphylaxis but do not predict future occurrence of serum sickness.

Other tests. Drug provocation tests use drugs that can cause hypersensitivity reactions in increasing doses until a reaction occurs. This test appears to be safe and effective when performed under supervision. Tests for hematologic drugs include direct and indirect antiglobulin tests. Tests for drugs that cause other types of hypersensitivity (e.g., RAST, histamine release, mast cell or basophil degranulation, lymphocyte transformation) are unreliable or experimental.

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Differential diagnosis

Drug hypersensitivity must be differentiated from toxic and side effects that may occur when taking individual drugs or their combination.

Treatment hypersensitivity to drugs

Treatment consists of stopping the drug causing the reaction; most symptoms and complaints become clearer within a few days after stopping the drug. Supportive therapy for acute reactions consists of antihistamines for itching, NSAIDs for arthralgia, glucocorticoids for more severe reactions (e.g., exfoliative dermatitis, bronchospasm), and adrenaline for anaphylaxis. Conditions such as drug fever, nonpruritic skin rashes, and mild reactions from other organ systems do not require treatment (for treatment of specific clinical reactions, see other chapters in this publication).

Desensitization. Rapid desensitization may be necessary in cases of precisely established sensitivity and when treatment with this drug is necessary in the absence of alternatives. If possible, desensitization is best performed in cooperation with an allergist. The procedure is not performed in patients with Stevens-Johnson syndrome. Before desensitization, 0 ₂, adrenaline, and other equipment for resuscitation in case of anaphylaxis should always be available.

Desensitization is based on a gradual increase in the dose of allergen administered every 30 minutes, starting with the minimum dose inducing subclinical anaphylaxis, bringing the exposure to a therapeutic dose. The effect of this procedure is based on the constant presence of the drug in the blood serum and its administration should not be interrupted; desensitization is followed by a full therapeutic dose. The hypersensitivity reaction is usually observed 24-48 hours after the cessation of drug administration. Minimal reactions (e.g., itching, rash) are often observed during desensitization.

For penicillin, the oral or intravenous route may be used; subcutaneous or intramuscular administration is not recommended. If the intradermal test is positive, 100 units (or mcg)/ml are injected intravenously in a 50 ml balloon (total 5000 units) very slowly for the first time. If no symptoms occur, the rate of administration is gradually increased until the balloon is completely empty within 20 to 30 minutes. The procedure is then repeated with a concentration of 1000 or 10,000 units/ml, followed by the full therapeutic dose. If any allergic symptoms develop during the procedure, the rate of administration should be reduced and the patient given appropriate drug therapy. If the prick test for penicillin is positive or if the patient has had severe allergic reactions, the initial dose should be lower.

For desensitization per os, the dose starts with 100 units (mcg); the dose is doubled every 15 minutes up to 400,000 units (dose 13). The drug is then administered parenterally, and if allergic symptoms appear, they are treated with appropriate antianaphylactic drugs.

For trimethoprim-sulfamethoxazole and vancomycin, the same technique is used as for penicillin.

For xenogeneic serum. If the skin test to xenogeneic serum is positive, the risk of anaphylaxis is very high. If treatment with serum is necessary, it must be preceded by desensitization. Skin tests are used to determine the appropriate starting dose for desensitization, and the lowest dose obtained from a dilution series (the concentration at which there is no or very little reaction) is selected. 0.1 ml of this solution is injected subcutaneously or slowly intravenously; the intravenous route, although unconventional, requires medical supervision until the therapeutic concentration and rate of administration are achieved. If no reaction occurs within 15 minutes, the dose is doubled after 15 minutes to reach 1 ml of undiluted serum. This dose is repeated intramuscularly, and if no reaction occurs within a further 15 minutes, the full dose is given. If a reaction occurs, treatment may still be possible; the dose is reduced, antihistamines are prescribed, as for acute urticaria, and then the dose is increased very slightly.

Forecast

Over time, hypersensitivity decreases. IgE is present in 90% of patients within a year of an allergic reaction, and only in 20-30% after 10 years. In patients with a history of anaphylaxis, antibodies to the drug persist longer. Patients with drug allergies should be reminded to avoid taking the drug and wear an identification or “alert” bracelet; medical records should always be marked accordingly.

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