Drug-induced dermatitis

Introduction to drug dermatitis Dermatitis medicinal dermatitis (dermatitis medicinosa) refers to the various inflammatory reactions of the skin and mucous membrane caused by the injection of drugs into the human body through injection, inhalation, etc., and is the most common reaction in drug reactions. Also known as drug rash (drugeruption), Chinese medicine said the disease is drug poison. basic knowledge The proportion of illness: 0.13% Susceptible people: no special people Mode of infection: non-infectious Complications: jaundice sepsis bronchopneumonia

Cause of drug-induced dermatitis

Drug entry into the body (20%):

Drugs enter the human body including oral, injection, perfusion, eye drops, nose drops, mouthwash, containment, spray, inhalation, topical, drug smoke, vaginal and bladder irrigation. Incorrect choice of route may cause drug dermatitis.

Arsenic (10%):

After several injections of arsenic, it can occur. Due to the acute poisoning symptoms of allergies, some skin rashes appear after long-term application. The skin lesions are often extensive bullae, papules, pustules, and can cause exfoliative dermatitis in severe cases. People can cause damage such as parapsoriasis, lichen planus, pityriasis rosea or spotted spots.

Steroid corticosteroids (15%):

Steroid corticosteroids, scarlet fever or measles-like erythema, lupus-like rash, fixed erythema, severe exfoliative dermatitis, malignant bullous erythema or toxic epidermal lysis, some neutropenia or inherent Death due to anemia.

1. Antipyretic and analgesic drugs often cause scarlet fever or measles-like erythema, fixed erythema, exfoliative dermatitis and other damage.

2. Sleeping sedatives are measles-like erythema, angioedema, polymorphous erythema, lichen planus dermatitis, fixed drug eruption and exfoliative dermatitis.

3. The injection of antibiotics, especially penicillin, can cause an allergic shock reaction, which is characterized by pruritus, measles-like erythema, urticaria and angioedema, and even exfoliative dermatitis.

4. Immunosuppressants and anti-tumor preparations often cause hair loss, exfoliative dermatitis, jaundice and neutropenia or granulocyte reduction.

5. Traditional Chinese medicine causes an allergic reaction, which is the most common, urticaria, measles-like erythema, fixed drug eruption and oral mucosal erosion.

Pathogenesis

The pathogenesis of drug-induced dermatitis is complex and can occur through immune or non-immune mechanisms.

1. The pathological mechanism of immune drug reaction is allergic reaction. Most drug eruptions are caused by allergic reaction mechanism. Some drugs that cause immune drug reactions are macromolecular substances, which are whole antigens, such as serum, vaccines, biological organs and protein products. Most drugs are low molecular weight compounds, which are haptens or incomplete antigens. They are not antigenic in nature and must be covalently bound to carrier proteins or tissue proteins in the body to become whole antigens, which are antigenic and cause drug allergies. The drug itself can be combined with a protein carrier to form a whole antigen, and some drugs are combined with a protein carrier to form a whole antigen by a degradation product thereof or a metabolite thereof in the body, and the drug has different metabolites in the body due to different chemical structures. It also contains various impurity components, which can also cause allergic reactions (such as insulin and ACTH, etc.), so the pathogenesis and symptoms of drug eruption are more complicated, often a drug can cause different rashes and symptoms, and the same kind of rash and symptoms It can also be caused by different drugs. The mechanism of general allergic drug eruption is as follows: :

(1) Type I allergy: IgE-mediated drug response, immediate response can occur within a few minutes after the application of the drug, the incidence of penicillin is high, clinical skin, digestive tract, respiratory tract, cardiovascular can be affected, Generally, there are varying degrees of itching, urticaria, bronchospasm and laryngeal edema, which can cause anaphylactic shock or death in severe cases, mainly due to the release of various chemical mediators from mast cells and basophils. These mediators include histamine. , adenosine, lipids such as lymphokines, prostaglandins, platelet activating factors and various enzymes.

(2) Type II allergy: drug-induced cytotoxicity, which can affect various organs including kidney, heart, lung, liver, muscle, peripheral nerve, hematopoietic system, etc. There are three possible mechanisms:

1 The drug reacts directly with the tissue to form a hapten cluster on the cell surface, which increases the susceptibility of the cell to antibody and suffers from antibody or lymphocyte-mediated toxicity.

2 The drug antibody complex binds to the cell surface and damages the cell.

3 drugs can induce immune response against tissue-specific antigens, such as patients taking alpha methyldopa can form antibodies against red blood cell antigen, cytotoxic reactions often involve hematopoietic systems such as platelets, red blood cells.

(3) Type III allergy: immune complex-mediated drug response, which is characterized by fever, arthritis, nephritis, neuritis, edema, urticaria and macules. The above reaction must be the long-term circulation of the antigen. Preservation, formation of antigen-antibody complexes, serum disease is caused by this mechanism, serum disease occurs when the drug enters for 6 days or longer, and the incubation period is the time required for antibody synthesis. The antibody that produces the immune complex type reaction is mainly IgG. , IgM, drugs that produce a similar serum-like reaction include penicillin, sulfonamide, thiouracil, gallbladder contrast agent, dye, diphenylacetamide, p-aminosalicylic acid, streptomycin, and the like.

(4) Type IV allergic reaction: cell-mediated delayed type reaction, which has been confirmed in skin contact allergic reactions in local exposure to drugs, measles-like drug eruption, eczema-type drug eruption, contact dermatitis and pulmonary allergic pleurisy Cell-mediated delayed allergic response mechanisms play an important role.

In recent years, there has been continuous progress in the pathogenesis of rash-type drug eruptions. At present, the sensitized lymphocytes, specific antibodies and their relationship with Langerhans cells and some inflammatory factors have been compared. Deep research.

2. Factors affecting drug allergy Drugs cause allergic reactions, only a few people will occur, such as penicillin antibody in most patients who have used penicillin, and not all drug reactions occur when penicillin is used again, resulting in allergic drug eruption, during which Many factors influence.

(1) Relationship with viral infection: Viral infection increased the incidence of drug eruption, especially eruptive drug eruption. It was observed that in patients with acute Epstein Barr virus (EBV) infection, ampicillin (ampicillin) was used to treat the incidence of drug eruption. It can be as high as 80% to 100%. Later, the incidence of cytomegalovirus (CMV) infection is also increased, which may be related to two factors. First, viral infection can be obtained by injuring the activity of cell-metabolizing enzymes. Abnormal drug metabolism, and second, due to viral infection increased non-specific cytotoxicity.

(2) Characteristics of drugs: increased molecular weight and structural complexity, and increased antigenicity. These are macromolecular drugs, such as proteins and peptide hormones. Most drugs are small molecules with a molecular weight of less than 1000Dal, which can only be used as a hapten. In vivo tissue macromolecules bind to form a complete antigen to cause an allergic reaction, and small molecule drugs alone cannot induce an allergic reaction.

(3) Medication methods and individual differences: the drug route affects the nature of the immune response, the skin external drug generally develops delayed allergic reaction, while the oral and nasal drugs secrete IgG, IgA, few IgM, some antigens (such as poison ivy) It is sensitive to skin sensitization, but it is not sensitized to oral or mucosal surface. Intravenous administration is a common route of clinical allergic reaction. Compared with gastrointestinal administration, oral -lactam antibiotics are more common. Less causes the reaction, in addition, there is variation in the metabolism of the individual, and the degree of absorption and metabolism can change the immune response. For example, in patients with slower acetylation of indextrin, the drug can cause lupus-like syndrome associated with ANA formation. However, the above symptoms are not common in patients with normal metabolism of other drugs.

(4) Genetic factors: drugs can be metabolized by oxidation, reduction, hydrolysis and binding in the body, and various enzymes related to metabolism change on the basis of genetics, such as certain drug metabolizing enzymes such as acetylase in the body, gluten Defects such as sucrose S transferase and epoxide hydrolase may cause imbalance between the production of this substance and the metabolism of cells, and thus cause the body to react. In addition, these intermediate products may also coexist with macromolecular proteins in the cells. The combination of valence causes allergic reactions. Some studies have found that the occurrence of drug eruption is related to the type of human leukocyte antigen (HLA). For example, the occurrence of steroid rash is closely related to HLA. It is also believed that some people have a genetic deficiency in the gastrointestinal tract, which is susceptible to Bacterial invasion and destruction, protein substances into the body are prone to allergic reactions, these genetic factors are also called idiosyncratic.

3. Light-sensing effect Some drugs have photosensitivity, and react only when exposed to ultraviolet light. There are two kinds of light-sensing effects, namely, photoallergic reaction and phototoxic reaction. Light allergic reaction is that light changes the drug hapten itself or changes the antigen. The protein carrier forms a complete photoantigen and produces an allergic reaction. The drug itself is harmless and generally has nothing to do with the dose. This reaction can last for a long time. After stopping the drug, the patient often maintains an allergic state even if there is no sunlight. The reaction often manifests as aggravated sunburn, which occurs when the drug is first applied. The incidence and severity are dose-dependent and related to the amount of illumination. Three pharmacological mechanisms have been demonstrated in vitro:

(1) Excitatory state phototoxic molecules form a covalent compound with a biological target to directly act on the target tissue;

(2) Phototoxic molecules absorb protons to form stable photoproducts that are toxic to biological substrates;

(3) Phototoxic molecules transfer energy to oxygen molecules under light stimulation to form toxic activated oxygen such as monooxygen, superoxide and hydrogenated oxygen. Studies have suggested that circulating effector cells and serum protein-dependent systems play a key role. There are more than 50 kinds of drugs causing photosensitivity, including 5 sulfonamides and their derivatives, phenothiazines, tetracyclines, psoralen, others such as griseofulvin, antihistamines, etc. It is reported that nalidixic acid, oral contraceptives, etc. can also be caused.

4. Drug cross-allergy and multi-allergy cross-allergy is a chemically similar or contains the same basic structure of the drug, can cause allergic reactions, such as sulfonamides have "aniline" core, allergic to sulfonamides, may also For other drugs containing "aniline" core, such as procaine, allergic to salicylic acid, then the disease can occur within 24 hours after the first dose, no need to go through the incubation period of 4 to 5 days, more Allergies refer to patients with some drug eruptions. When the drug eruption reaches its peak, it is also allergic to other drugs. The chemical structure of these drugs has no similarities.

5. Pathological mechanism of non-immune drug response

(1) Non-immune activation of the immune effect pathway: The drug directly stimulates the clinically similar allergic reaction, but does not rely on immune mediation. The following three mechanisms of action are common:

1 The drug can directly act on the release medium of mast cells and eosinophils, clinically manifested as allergic urticaria, angioedema, common drugs are opium, polymyxin B, tetracycline D, radioactive medium, levulin glycoside;

2 directly activate complement, such as urticaria caused by radio contrast agents;

3 arachidonic acid metabolism abnormalities, such as aspirin and other non-hormonal anti-inflammatory drugs allergic reaction, the mechanism is to inhibit cyclooxygenase and interfere with prostaglandin synthesis, so that arachidonic acid prostaglandin decreased.

(2) Overdose: The performance of drug overdose is mostly consistent and predictable. It is often aggravated by the pharmacological effects of the drug, but there are differences in the rate of drug absorption, metabolism or excretion, so it can also occur in conventional doses. More common in the elderly and liver, kidney dysfunction.

(3) Cumulative toxicity: common drugs or metabolites accumulate in the skin and have a colored distribution. For example, long-term use of silver, gold, mercury, etc., these drugs can be precipitated in phagocytic cells in the skin or mucous membranes, and some patients take large doses. After chlorpromazine, the drug or its metabolites bind to pigments in the skin.

(4) side effects of drugs: Some drugs have some side effects at the same time as the normal therapeutic effect, such as the use of cytotoxic drugs during chemotherapy to cause hair loss, gastrointestinal diseases, bleeding and coagulation disorders.

(5) Ecological imbalance: As the drug changes the skin mucosa, the normal flora of the viscera distributes and inhibits the growth of certain microorganisms, while other microorganisms overgrow, such as the oral cavity, external genital tract, and visceral candidiasis caused by the application of broad-spectrum antibiotics.

(6) Drug interactions: There are three mechanisms that interact to cause adverse reactions:

1 competing for the same protein binding site, such as aspirin or phenylbutazone can replace coumarin, leading to hemorrhagic reaction;

2 a metabolic enzyme required for a drug to stimulate or inhibit degradation of another drug;

3 One drug interferes with the excretion of another drug, such as probenecid can reduce the excretion of penicillin by the kidney.

(7) Metabolic changes: drugs can change the body's metabolic status to induce skin reactions. For example, phenytoin (Dalendin) interferes with folic acid absorption and metabolism, increasing the risk of arfluostalization. Cis-retinoic acid can alter lipid metabolism and improve Low density lipoprotein levels cause xanthomatosis.

(8) aggravation of the original skin disease: many drugs can aggravate existing skin diseases, such as lithium can aggravate acne and psoriasis, and there is a dose-dependent effect, receptor antagonist can induce psoriasis-like Dermatitis; corticosteroids are exacerbated after psoriasis and allergic dermatitis; a variety of drugs can induce or aggravate lupus erythematosus without skin manifestations, while cimetidine (cimetidine) can aggravate skin lupus erythematosus; Retinoic acid can increase the slag and so on.

(9) Hereditary enzyme or protein deficiency: Hereditary enzyme deficiency can cause drug reactions. Two mechanisms are known:

1 Enzyme deficiency that eliminates the metabolism of drug toxic products, such as phenytoin (Dalendin) allergic syndrome, which is necessary for the metabolism of phenytoin toxic products due to the lack of cyclooxygenase in patients.

2 The enzymes necessary for normal biochemical metabolism are insufficient, and the drug can further reduce it. For example, in heterozygous patients with hemolytic thromboplastin C deficiency, coumarin causes skin necrosis.

Chinese medicine believes that endowment is intolerant, ingestion is contraindicated, heat poisoning, or because the spleen is not transported, the heat is toxic, the damp heat poison is on the skin and causes disease. In severe cases, the poison is hot and can cause qi and blood. Two.

Drug dermatitis prevention

1. Before using the medicine, you must inquire about the patient's history of drug allergy. If you have had drug allergy before, you should avoid using drugs with known allergies or similar structures.

2. During the course of medication, for any rash that is unclear, it is necessary to be highly alert to whether it is allergic to the drug, to suspend suspicious drugs in time and to make a clear diagnosis.

3. Mark allergy medications in a prominent position in the medical record, and let the patient know that he is allergic to a certain drug to avoid recurrence of the drug rash.

4. For allergic drugs such as penicillin, serum products, procaine, etc., allergy tests should be performed first.

Attachment: The following drugs are sensitive to light and can cause light-sensitive rash: sulfonamides, chlorpromazine, promethazine (phenazone), tetracycline, griseofulvin, safflower, hydrochlorothiazide, anti- Histamine drugs, oral contraceptives, chlordiazepoxide (limonine), vincristine, white sputum method.

Drug dermatitis complications Complications jaundice sepsis bronchopneumonia

Liver damage complicated by drug eruption is often diagnosed as liver complications of measles and infectious mononucleosis. Kidney damage of drug eruption can also be mistaken for proteinuria caused by scarlet fever. Drug eruption is often symmetrical. Itching, skin lesions are often seen in the appearance of oozing or angioedema, target changes, etc. For patients with drug eruption should check blood routine, eosinophil count, liver function, to determine whether there is bone marrow suppression, liver function damage and other drugs Adverse reactions.

Exfoliative dermatitis is easy to secondary to hemorrhoids, bronchial pneumonia, and even sepsis and heart failure, resulting in life-threatening, easy to cause systemic nutritional disorders, and can be complicated by jaundice hepatitis, proteinuria and so on.

Symptoms of drug-induced dermatitis Common symptoms Superficial lymphadenopathy Diffuse redness of the skin Back acne exfoliative dermatitis Low heat dyspnea scarring Circulatory failure Proteinuria

Examination of drug dermatitis

1. Blood routine examination of eosinophils often increases, white blood cells can be increased, and sometimes white blood cells, red blood cells, thrombocytopenia.

2. If there is a visceral reaction, the relevant related tests, such as liver and kidney function tests, should be performed.

3. Drug allergy test

(1) In vivo test:

1 patch test (patch test): the positive rate in drug eruption is low, has reported a positive rate of 31.5%, the positive rate of phenobarbital, phenytoin, carbamazepine is higher, patch test is safer, simple If there is a positive, there is no need to do the intradermal test and the challenge test. The concentration of penicillin and cephalosporin can be 10% to 20%, the positive rate of Vaseline or 70% alcohol is higher, and the concentration of carbamazepine should be higher. It is 3% to 10%.

2 intradermal test: mainly used to detect type I allergic reaction, the positive rate can reach 89.7%, the positive rate of penicillin, cephalosporin and gold salt preparation is higher, should start from low concentration, and then gradually increase the concentration when the result is negative. This will be safer.

3 stimulating test: a certain period of time after drug dermatitis subsided (1 to 2 months), using sensitizing drugs to follow the original route of administration, re-administering to observe the reaction to judge, the method is reliable, but very dangerous, Severe drug rash can not be applied, in the case of rash type drug eruption, severe excitatory test can develop into exfoliative dermatitis, this method can be used for fixed erythema and non-latent risk erythema type, the dosage varies from person to person, in the heavier The dosage should be small, and the light dose can be large. Generally, the initial dose is 1/10 constant or less. If there is no reaction, the dose is increased again to 1/10 to 1/4, and then 1/2. Until the full amount, each excitation should be observed for 6 to 24 hours. If there is no reaction, then another excitation should be observed.

(2) In vitro test:

1 Detection of specific antibodies in serum: Antibodies in serum include IgG, IgM, IgA and IgE. The detection methods include radioallergo-sorbent assay (RAST), hemagglutination assay and enzyme-linked immunosorbent assay ( Enzyrme-linked immunosobent assay (ELISA), RAST is a method for detecting type I allergic drug eruption IgE. Some scholars have proved that sensitive hemagglutination can detect a small amount of penicillin IgG and IgM antibodies, and then found 1/ 4 patients with penicillin rash type drug eruption have high titer IgM hemagglutination antibody, and the positive rate of penicillin antibody (IgG and IgM) is improved by modified ELISA, but some patients with non-drug rash treated by penicillin are also found in vivo. There are penicillin-specific IgM antibodies present, so this assay is limited in diagnostic applications.

2 basophil degranulation: using patient basophils and sensitizing drugs (direct method) or rabbit basophils and patient serum plus sensitizing drugs (indirect method), degranulation to check drug allergy Originally, it is only used for type I allergies.

3 lymphocyte transformation test (SLTT): a small lymphocyte sensitized in peripheral blood, stimulated by a drug (specific antigen), cultured in vitro for 2 to 3 days, can be transformed into lymphoblasts and undergoes proliferation and division. Methods, found that 60% of patients with allergy to allergy are positive for SLTT, domestic studies have shown that the positive rate is 53.7%, although the sensitivity of SLTT is low, but its specificity is high, so far no false positive report, so it is a drug rash An experimental diagnostic method.

4 Macrophage migration inhibition test (MIF test): The patient lymphocytes + guinea pig macrophages + test drugs were observed after 24 hours of incubation, and the positive rate was found to be 53% to 70%.

5 lymphocyte toxicity test: eczema drug eruption caused by antiepileptic drugs (such as phenobarbital, phenytoin, carbamazepine) and sulfa drugs, due to consideration of certain enzyme defects in the detoxification process of drug metabolites The toxicity is related, so this test can be used to culture the in vitro cells with suspicious drugs and patient lymphocytes, and the number of lymphocyte deaths can be observed to detect the drug toxicity. As a result, 7 cases of sulfa drug eruption are positive, and 50 cases of 50 anti-epileptic drug eruptions are positive. This trial is still in the research stage.

The above-mentioned in vitro test has limited application range, reproducibility and stability are still insufficient, and the operation is complicated, and it is difficult to be widely applied in clinical practice.

Diagnosis and differentiation of drug dermatitis

diagnosis

Detailed medical history, familiar with various types of drug eruptions, observation of clinical manifestations and development process, comprehensive analysis, before the diagnosis of drug eruption, but still can not be diagnosed, because until today, there is still no reliable experimental diagnosis of drug eruption, skin test positive People do not have a drug rash after taking the drug, while a negative person may have a drug rash. Moreover, the intradermal test can cause severe drug rash or other drug reactions in people with high sensitivity, and even death caused by allergic shock, and then take the drug. The test is not safe and reliable. It can only be used with caution in patients with fixed drug eruptions or patients who do not have serious reactions. The drug rash occurs after clinical use, and the history of drug disappearance after relapse and relapse is very diagnostic.

Modern immunoassays such as lymphocyte transformation test, radioallergen adsorption test (RAST), basophil degranulation test, macrophage migration inhibition test, leukocyte histamine test, etc., can help us understand drugs and organisms. There is no practical diagnostic value between the immune relationship. In short, the drug rash is a common disease. When diagnosing a drug rash, it should be objectively analyzed to rule out the possibility of disease.

Drug-induced urticaria, polymorphous erythema, nodular erythema, eczema, erythroderma, folliculitis, vasculitis are the same as other idiopathic diseases, and will not be explained here. Describe the characteristic drug rash.

1. The fixed type of drug eruption shows most necrotic keratinocytes in the epidermis. The acanthosis cells are degenerated and can develop into epidermal vesicles. Because the membrane of the ruptured cells remains in the blister, the vesicles are honeycomb-shaped, and the dermal papilla height Edema, epidermis blister can appear, a large number of phagocytes can be seen in the upper part of the dermis, the dermis is shallow, deep lymphatic infiltration and a little acidophilic neutrophils can be seen, and tissue cells and mast cells can also be seen.

2. Drug-induced bullous epidermolysis epithelial keratinocytes large-scale fusion necrosis, cell structure disappeared, visible nuclear dissolution, nuclear shrinkage and nuclear fragmentation, the stratum corneum still has a basket-like shape, interface vacuoles change, epidermis blister Shallow edema of the dermis, infiltrating cells are mainly lymphocytes, and a few tissue cells and eosinophils infiltrate.

3. The lichenin-like drug rash has focal keratosis in the stratum corneum, the granule layer is thin or disappeared, the interface vacuolar degeneration, and the papillary dermis is densely infiltrated by the band, mainly lymphocytes, tissue cells, and sometimes plasma cells. Eosinophils, inflammatory infiltration not only in the shallow layer, but also deep.

Differential diagnosis

Mainly to exclude internal medicine, dermatology related diseases, such as scarlet fever measles-like drug eruption should be differentiated from scarlet fever, measles, bullous epidermal necrolysis drug eruption should be differentiated from toxic epidermal necrolysis (Lyell's disease), purpura Type drug eruption should be differentiated from related diseases such as allergic purpura. The clinical manifestations of drug-induced dermatitis are complex and can mimic the rash of many diseases. Therefore, drug eruption must be differentiated from related rash disease.

First, infectious diseases (measles, scarlet fever): no history of medication, systemic poisoning symptoms are more obvious, rash color is not as bright as drug rash, consciously itchy or itchy, infectious diseases have their own inherent signs, such as scarlet fever, bayberry tongue and pale around the mouth Circle, skin whitening test positive, can be found in the buccal mucosa.

Second, non-drug-sensitized urticaria, polymorphous erythema, etc.; no history of medication, the condition is milder, the rash color is less vivid, the skin lesions are widely distributed, and the subjective itch is lighter.

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