Hypersensitivity to medicines: causes, symptoms, diagnosis, treatment

Hypersensitivity to drugs is an immune-mediated response. Symptoms range from mild to severe and include skin rashes, anaphylaxis, and serum sickness. The diagnosis is made clinically; informative are skin tests. Treatment consists in stopping the medication, prescribing antihistamines (according to indications) and sometimes desensitization.

Drug hypersensitivity must be differentiated from the toxic and side effects that may occur when taking individual medications or a combination thereof.

[1], [2], [3], [4], [5], [6], [7]

Pathogenesis

Some proteins and most polypeptide drugs (such as insulin, therapeutic antibodies) can directly stimulate the production of antibodies. However, most drugs play the role of haptens, which covalently bind to serum or cellular proteins, including proteins that make up the molecules of the main complex of histocompatibility of MHC. Such binding makes these proteins immunogenic by stimulating the production of antibodies against drugs, a T cell response against the drug, or both. Haptens can also bind directly to MHC class II molecules, directly activating T-lymphocytes. Propagens become haptes during the course of metabolic reactions; for example, penicillin itself is not an antigen, but its main degradation product, benzylpenicillic acid, can be combined with tissue proteins to form benzylpenicilloyl (BPO), the main antigenic determinant. Some drugs directly bind to and stimulate T-cell receptor (TCR, TCR-T-cell receptor) receptors; the clinical significance of binding of neaptens to TCR has yet to be established.

It is not clear how the primary sensitization takes place and how the innate immunity forces are initially involved, but if the drug once stimulated an immune response, then there is a cross-reaction to drugs within and between individual drugs of this class. For example, it is very likely that penicillin-sensitized patients will have a reaction to semisynthetic penicillins (eg, amoxicillin, carbenicillin, ticarcillin), and about 10% of these patients will have a reaction to cephalosporins with a similar beta-lactam structure. However, some visible cross-reactivity reactions (for example, between sulfonamide antibiotics and non-antibiotics) are mainly a consequence of predisposition to allergic reactions than a consequence of a specific immune cross-reaction. Thus, not every visible reaction is allergic; for example, amoxicillin is the cause of the rash, but it is not immune mediated and does not prevent the prescription of this drug in the future.

[8], [9], [10], [11], [12], [13], [14], [15]

Symptoms of the hypersensitivity to drugs

Symptoms and signs are very diverse depending on the patient and the medication, and the same medications can cause different reactions in different patients. The most serious manifestation is anaphylaxis; more often there are exanthema, urticaria and fever. Strong reactions to medicines are rare.

There are other distinctive clinical syndromes. Serum sickness usually begins on the 7th-10th day after contact with the drug and is manifested by fever, arthralgia and a rash. The mechanism of development involves the formation of drug-antibody complexes and complement activation. Some patients develop severe arthritis, swelling, or symptoms of the gastrointestinal tract. Symptoms stop on their own, their duration is from 1 to 2 weeks. Beta-lactam antibiotics and sulfonamide preparations, iron dextran and carbamazepine most often cause this condition.

Hemolytic anemia develops when the antibody-drug-erythrocyte complex is formed, or when the drug (eg, methyldopa) changes the erythrocyte membrane, exposing the antigens that induce the production of autoantibodies. Some drugs induce lung damage. Tubulointerstitial nephritis is a common allergic reaction from the kidneys; methicillin, antimicrobials, cimetidine often cause this condition. Hydralazine and procainamide can lead to the development of SLE-like syndrome. This syndrome occurs relatively favorably, sparing the kidneys and the central nervous system; the test for antinuclear antibodies is positive. Penicillamine can cause SLE and other autoimmune diseases (eg, myasthenia gravis).

[16], [17], [18], [19], [20], [21]

Diagnostics of the 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 note a late reaction of an uncertain nature. In some cases, when it is not possible to find an equivalent substitute (for example, penicillin in the treatment of syphilis), skin tests should be performed.

Skin tests. Skin tests for immediate-type hypersensitivity (IgE-mediated) help in the diagnosis of reactions to beta-lactam antibiotics, foreign (xenogeneic) serum, certain vaccines and polypeptide hormones. However, usually only 10-20% of patients who have a reaction to penicillin have positive skin tests. For many drugs (including cephalosporins), samples are unreliable, and since they diagnose only lgE-mediated allergies, they do not predict the development of a crustacean rash, hemolytic anemia, or nephritis.

Penicillin skin tests are necessary for patients with an immediate history of hypersensitivity who need to prescribe penicillin. VPO-polylysine conjugate and penicillin G are used with histamine and saline as a control. First, the technique of pricking (prik-test) is used. If a patient has a history of severe violent reactions, for the primary sample it is necessary to dilute the reagents 100 times. If the result of the prick test is negative, you can conduct intradermal tests. If the result of the skin test is positive, then treatment of the patient with penicillin can cause an anaphylactic reaction. If the results of the tests are negative, a serious reaction is unlikely, but not ruled out. Although penicillin skin tests do not induce de novo hypersensitivity , patients undergo tests immediately before initiation of penicillin therapy.

When carrying out skin tests for xeno-gene serum, patients who did not have a history of atopy and who had not previously received preparations from horse serum were first given a prick by using a dilution of 1:10; if the result of the test is negative, 0.02 ml in a dilution of 1: 1000 is administered intradermally. In sensitive patients, a blister larger than 0.5 cm in diameter forms within 15 minutes. All patients who were able to receive earlier serum preparations - whether they had a reaction or not - and with the alleged allergy in the anamnesis, the first sample was diluted 1: 1000. Negative results rule out the possibility of anaphylaxis, but do not allow predicting the occurrence of serum sickness in the future.

Other tests. For carrying out medicinal provocative samples, drugs that can produce hypersensitivity reactions are used in increasing doses prior to the appearance of the reaction. Such a test appears to be safe and effective if conducted under control. Samples for hematological drugs include direct and indirect antiglobulin assays. Drug samples that cause other types of hypersensitivity (eg, RAST, histamine release, degranulation of mast cells or basophils, transformation of lymphocytes) are unreliable or are at the experimental development stage.

[22], [23], [24], [25], [26]

Differential diagnosis

Drug hypersensitivity must be differentiated from the toxic and side effects that may occur when taking individual medications or a combination thereof.

Treatment of the hypersensitivity to drugs

Treatment consists in refusal from reception of the preparations causing a reaction; Most of the symptoms and complaints become most clear within a few days after the drug is stopped. Supportive therapy for acute reactions consists in the appointment of antihistamines for the relief of pruritus, NSAIDs for arthralgia, glucocorticoids in more severe reactions (exfoliative dermatitis, bronchospasm) and adrenaline for anaphylaxis. Conditions such as drug fever, unhealthy skin rash, mild reactions from other organs and systems, do not require treatment (treatment of specific clinical reactions, see other chapters of this publication).

Desensitization. Rapid desensitization may be necessary in the case of precisely defined sensitivity and, if necessary, treatment with this drug in the absence of alternative options. If possible, desensitization is best done in cooperation with an allergist. The procedure is not performed in patients with Stevens-Johnson syndrome. Before carrying out desensitization, 0 ₂, epinephrine, and other equipment for resuscitation should always be prepared in case of anaphylaxis.

Desensitization is based on a gradual increase in the dose of the allergen administered every 30 minutes, starting with a minimal 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; followed by desensitization followed by a full therapeutic dose. The hypersensitivity reaction is usually observed 24-48 hours after discontinuation of the drug administration. During the course of desensitization, minimal reactions (eg, pruritus, rash) are often observed.

For penicillin, an oral or intravenous route of administration may be used; subcutaneous or intramuscular route of administration is not recommended. With a positive intradermal sample, 100 units (or μg / ml) are injected intravenously in a 50 ml balloon (a total of 5000 units) very slowly. If no symptoms are observed, the rate of administration gradually increases until the balloon is fully emptied within 20-30 minutes. The procedure is then repeated at a concentration of 1000 or 10 000 U / ml, followed by the introduction of a complete therapeutic dose. If any allergic symptoms develop during the procedure, the rate of administration should be reduced and the patient undergoes appropriate drug therapy. If the test result is prickly to penicillin positive or if the patient has had severe allergic reactions, the initial dose should be lower.

When desensitizing per os, the dose begins with 100 units (μg); The dose doubles every 15 minutes to 400,000 units (dose 13). Then the drug is injected parenterally, and if allergic symptoms appear, they are stopped by appropriate anti-anaphylactic drugs.

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

For xenogeneic serum. If the result of a skin test for xenogeneic serum is positive, the risk of anaphylaxis is very high. If treatment with serum is necessary, then it should be preceded by desensitization. To determine the appropriate starting dose for desensitization, skin tests are used and the minimum dose obtained as a result of the dilution series (concentration at which there is no reaction or it is very weak) is chosen. 0.1 ml of this solution is administered subcutaneously or slowly intravenously; The intravenous route of administration, although unconventional, requires medical control until the therapeutic concentration and rate of administration is reached. If no reaction occurred within 15 minutes, the dose doubles 15 minutes before reaching 1 ml of undiluted serum. The administration of this dose is repeated intramuscularly, and if no reaction is observed within the next 15 minutes, a full dose is administered. If the reaction has appeared, then treatment may still be possible; the dose is reduced, antihistamines are prescribed, as in acute urticaria, and then the dose rises very slightly.

Forecast

Over time, hypersensitivity is reduced. IgE is present in 90% of patients within a year after an allergic reaction, and only in 20-30% in 10 years. In patients with anaphylaxis in the history of antibodies to the drug persist longer. Patients with drug allergies should remember the need to avoid taking medications and wear an identification or "anxious" bracelet; on the medical maps should always be marked with appropriate marks.

[27], [28], [29], [30]