| disease | Drug-induced Dermatitis |
| alias | Dermatitis Medicamentosa |
Drug-induced dermatitis, also known as drug rash, refers to various inflammatory reactions of the skin and mucous membranes caused by different drugs entering the body through various routes.
bubble_chart Etiology
(1) Routes of drug entry into the body include oral administration, injection, infusion, eye drops, nasal drops, gargling, mouth-melt, spray, inhalation, topical application, fumigation, vagina and bladder irrigation, etc.
(2) Common drugs that cause drug rash
1. Arsenic agents: May appear after several injections. Due to allergic acute poisoning symptoms, some may develop rashes only after long-term use. Skin lesions often manifest as extensive bullae, papules, and pustules. In severe cases, it can lead to exfoliative dermatitis, and a few may develop parapsoriasis, lichen planus, pityriasis rosea, or spotted pigmentation.
2. Antipyretic and analgesic drugs: Often cause scarlet fever-like or measles-like erythema, fixed erythema, exfoliative dermatitis, and other lesions.
3. Hypnotic and sedative drugs: Measles-like erythema, angioedema, multiform erythema, lichen planus-like dermatitis, fixed drug rash, and exfoliative dermatitis.
4. Antibiotics: Especially penicillin injections can cause anaphylactic shock reactions. Delayed reactions may manifest as cutaneous pruritus, measles-like erythema, urticaria, and angioedema, or even exfoliative dermatitis.
5. Steroid corticosteroids: Scarlet fever-like or measles-like erythema, drug-induced lupus-like rash, fixed erythema. Severe cases may present as exfoliative dermatitis, malignant bullous erythema, or toxic epidermal necrolysis. Some may develop granulocytopenia or aplastic anemia, leading to death.
6. Immunosuppressants and antineoplastic agents: Often cause alopecia areata, exfoliative dermatitis, jaundice, and neutropenia or granulocytopenia.7. Chinese medicinals: Allergic reactions caused by Chinese medicinals are gradually increasing. The most common manifestations include urticaria, measles-like erythema, fixed drug rash, and oral mucosal erosion.
The mechanism of disease is highly complex and can be either immunological or non-immunological. However, most drug rashes are allergic reactions. Since allergic drug rashes occur only in a small number of individuals taking medication, and many people take various drugs, the occurrence of drug rashes is ultimately rare. Moreover, because allergic drug rashes are not related to pharmacological effects or toxic reactions, they are independent of the dose of the drug. Even trace amounts of a drug can cause severe drug rashes in highly sensitive individuals.
There are four types of allergic reactions: 1. Drugs such as serums and vaccines are complete antigens composed of proteins, while certain non-protein chemical drugs act as haptens that bind to the body's tissue proteins to form complete antigens. 2. After exposure to an antigen, following a certain latent period, immune cells become sensitized or produce sufficient antibodies. Upon re-exposure to the antigenic drug, various allergic reactions occur. - Type I reactions include urticaria, angioedema, certain eczematous rashes, and anaphylactic shock. - Type II reactions include conditions like thrombocytopenic purpura. - Type III reactions encompass vasculitis, serum sickness, and serum sickness-like reactions. - Type IV reactions may manifest as erythema, eczematous rashes, exfoliative dermatitis, fixed drug eruptions, erythema nodosum, or lupus-like syndromes.
A minority of drug rashes are unrelated to allergic reactions. Rashes caused by phototoxic effects are also non-allergic but depend on drug concentration, specific wavelengths, and exposure levels. Some individuals have congenital deficiencies in glucose-6-phosphate dehydrogenase activity due to recessive inheritance. Taking drugs like hydralazine, sulfones, or sulfonamides can induce hemolytic anemia in such cases. Certain drugs may directly act on mast cells to release mediators, resulting in urticaria or angioedema. Others alter the metabolic pathway of arachidonic acid by inhibiting cyclooxygenase, reducing prostaglandin production. For example, non-steroidal anti-inflammatory drugs can cause drug rashes. In summary, the mechanism of disease for drug rashes is extremely complex. Many theories remain insufficiently proven and require further in-depth research.
bubble_chart Pathological Changes
Drug-induced urticaria, erythema multiforme, erythema nodosum, eczema, erythroderma, folliculitis, vasculitis, and other idiopathic diseases have similar histological features, which will not be elaborated here. Below, we will describe some characteristic drug rashes.
1. Fixed drug rash: Numerous necrotic keratinocytes are observed within the epidermis, with ballooning degeneration of spinous layer cells, which may progress to intraepidermal blisters. Due to the remnants of ruptured cell membranes remaining in the blisters, the blisters appear honeycombed. The dermal papillae show marked edema, and subepidermal blisters may form. The upper dermis contains abundant pigment-laden macrophages. Lymphocytic infiltrates, along with a few eosinophils and neutrophils, can be seen in the superficial and deep dermis, as well as histiocytes and mast cells.
3. Lichenoid drug rash: Focal parakeratosis is present in the stratum corneum, with thinning or absence of the granular layer and vacuolar changes at the dermoepidermal junction. A band-like dense inflammatory infiltrate is seen in the papillary dermis, mainly composed of lymphocytes and histiocytes, occasionally with plasma cells and eosinophils. The inflammatory infiltrate is not limited to the superficial dermis but may extend to the deep dermis.
bubble_chart Clinical Manifestations
The clinical manifestations of drug rash are diverse. The same drug can cause different types of clinical manifestations in different individuals, while the same clinical manifestation can be caused by completely different drugs. Common drugs are summarized as follows:
1. **Exanthematous drug rash**: The clinical manifestations include measles-like or scarlatiniform erythema, with sudden onset, often accompanied by fear of cold, high fever (39–40°C±), headache, and general malaise. The rash starts on the face and trunk before spreading all over the body, accompanied by cutaneous pruritus of varying severity. Mild cases may present with only scattered erythema and grade I cutaneous pruritus, resolving spontaneously after discontinuation of the drug. Severe cases may involve dense rashes all over the body, often accompanied by generalized superficial lymphadenopathy, and close attention should be paid to the possible progression to exfoliative dermatitis, as the latter has a poor prognosis.
2. **Dermatitis-like drug rash**: This type of drug rash primarily presents clinically as erythema, papules, small blisters, exudation, erosion, and crusted rashes. It can be divided into localized and generalized forms. The localized type is mostly caused by photosensitive drug-induced rashes, primarily occurring in sun-exposed areas, leading to lichenified rashes. The generalized type may present with low-grade fever and cutaneous pruritus, and in severe cases, pustular rashes the size of foxtail millet to rice grains may be interspersed. After resolution, a layer of bran-like scales often peels off.
3. **Fixed drug eruption**: This is mostly caused by sulfonamides, barbiturates, and antipyretic analgesics. However, about one-third of patients have no history of medication, making the allergen difficult to identify. The characteristic rash is a localized round or oval erythema, bright red or purplish-red with pseudo-edema and well-defined borders, leaving pigmented spots after healing. Each time the sensitizing drug is used, the rash recurs in the same location, and new lesions may also appear. The number of rashes can range from a single lesion to multiple lesions, or even generalized distribution. The size of the rash generally varies from 0.2 cm to several centimeters. The rash can occur anywhere on the body, especially at the mucocutaneous junctions such as the lips, perioral area, glans penis, anus, interdigital skin, dorsum of the hands, and dorsum of the feet. About 80% occur at mucocutaneous junctions, and oral mucosa may also be involved. The resolution time for fixed drug rash is generally 1–10 days, but cases with mucosal erosion or ulcers often have a prolonged course, lasting several weeks before healing. When occurring on the foreskin or glans penis, blisters may rupture or become infected, forming ulcers and causing significant distress to the patient. Improper treatment may prolong recovery for weeks to months.
4. **Urticaria-like drug rash**: This is one of the common drug rashes, especially with the widespread use of furazolidone in recent years. Other drugs such as penicillin, streptomycin, sulfonamides, and serum proteins are also major causes of this type of drug rash. When caused by heterologous serum proteins, it is called "serum sickness." The rash is characterized by wheals of varying sizes, which are more erythematous and longer-lasting than typical urticaria, accompanied by cutaneous pruritus, stabbing pain, and tenderness. Urticaria may appear as the sole symptom or be accompanied by other symptoms such as fever and hypotension. Generally, sensitized patients develop wheals and cutaneous pruritus several hours after drug administration. However, a few patients may experience dizziness, restlessness, generalized large red wheals, cutaneous pruritus, and hypotension within minutes after injection of penicillin or serum proteins. Drug rash caused by furazolidone may occur up to a week after discontinuation, often presenting with severe wheals and large erythematous rashes, making treatment more challenging. Serum sickness occurs 1–2 weeks after serum protein injection, with fever (38–39°C), generalized wheals, cutaneous pruritus, abdominal pain, nausea, superficial lymphadenopathy, and arthralgia, resolving spontaneously within 10–14 days.
5. Erythema Multiforme Erythema multiforme induced by drugs is characterized by round or oval edematous erythema or papules, ranging in size from pea to broad bean, often with central blisters and purplish edges. It occurs symmetrically on the limbs and is frequently accompanied by fever, arthralgia, abdominal pain, and other symptoms. In severe cases, it can lead to erosions and pain from mucous membrane blisters. Erythema multiforme caused by other factors presents similar symptoms, often recurs in spring and autumn, and typically lasts 2–4 weeks.
6. Malignant bullous erythema multiforme, also known as Stevens-Johnson syndrome. It is a severe drug rash, with widespread bullous erythema, erosions of the mucous membranes in the mouth, eyes, and throat, and ulceration with crusting at the vermilion border of the lips. Patients often present with systemic symptoms such as high fever, headache, and arthralgia, resembling seasonal disease. The course lasts about 4 weeks, and before the use of hormones, the mortality rate was as high as 30%. Although it manifests as skin lesions in drug rashes, many cases have no history of medication, indicating that only a portion of this type is related to drug reactions. Some patients may also develop the condition due to "sepsis," which warrants attention.
7. Drug-induced bullous epidermal necrolysis is the most severe type of drug rash. Its characteristic feature is a rapid rise in body temperature shortly after medication, which can exceed 39–40°C. The skin initially develops erythema, which rapidly spreads and increases in number, turning from red to brownish-red. Within one or two days, flaccid bullae appear on the widespread erythema. The bullae are irregular, and the bullous membrane is easily rubbed or torn off, exposing large, painful erosive areas resembling burns. Mucous membranes also show extensive erosions and peeling. Patients exhibit severe systemic toxic symptoms, accompanied by high fever and signs of visceral damage. Complications may include jaundice, hematuria, renal failure, pneumonia, unconsciousness, spasms, and even death. Otherwise, after 10–14 days, the condition rapidly improves, with a swift drop in temperature, drying and shedding of the rash, leading to spontaneous recovery.
8. Exfoliative dermatitis can arise from various causes, with drugs being one of the major factors. Often, it results from failing to promptly discontinue sensitizing drugs or provide appropriate treatment for general drug rash patients, leading to disease progression and the merging of rashes into exfoliative dermatitis. Alternatively, the condition may begin abruptly with a high fever of 40–41°C that persists, pruritic measles-like erythema merging into large patches or diffuse redness, significant swelling, generalized superficial lymphadenopathy, hepatomegaly with tenderness, and even jaundice. The spleen may also enlarge, and damage to the brain or kidneys can lead to delirium, unconsciousness, proteinuria, or even death. It should be differentiated from erythroderma caused by psoriasis, dermatitis-like diseases, pityriasis rubra pilaris, Hebra's pityriasis rubra, or mycosis fungoides.
9. Lupus-like syndrome can be induced by drugs, with clinical manifestations and histological changes identical to true systemic lupus erythematosus. Patients exhibit symptoms such as fever, rash, arthralgia, pleuritis, pericarditis, granulocytopenia, and positive lupus erythematosus cells. Therefore, systemic lupus erythematosus syndrome is considered drug-induced systemic lupus erythematosus. Mild cases recover within months after discontinuing the drug, while progressive cases may die from lupus nephritis or other lupus-related damage. The course resolves spontaneously within 2–3 weeks to 3 months. Drugs such as hydralazine and griseofulvin are prone to induce this syndrome.
10. Proliferative drug rash occurs 2 weeks to several months after medication. Patients develop fever, malaise, joint pain, generalized superficial lymphadenopathy, hepatosplenomegaly, and a rash characterized by diffuse erythema, edematous, bullous, or mycosis fungoides-like lesions. The lesions are firm to the touch, mainly distributed sparsely on the trunk, irregular in shape, with well-defined edges and diameters of about 3–4 cm. Symptoms gradually disappear with treatment, and the entire course lasts about 3 weeks.
11. Other drug rashes: Certain drugs or heterologous proteins like serum can cause hypersensitivity vasculitis drug rash. Long-term low-dose arsenic intake may lead to punctate palmoplantar keratosis or follicular keratosis. Mercury poisoning can cause acral erythromelalgia, rash, stomatitis, etc. Prolonged use of iodine or corticosteroids may induce acne-like rashes. Antimalarial drugs can produce lichen planus-like rashes. Some drugs may also cause purpura or eczema-like rashes.
bubble_chart Auxiliary Examination
It can be differentiated from measles, scarlet fever, rubella, epidemic mononucleosis, Kawasaki disease, lichen planus, solar dermatitis, urticaria, and toxic epidermal necrolysis.
A detailed inquiry into the medical history, familiarity with various types of drug rash, observation of clinical manifestations and progression, and comprehensive analysis are necessary to make a diagnosis of drug rash, but a definitive diagnosis still cannot be made. This is because, to this day, there is still a lack of reliable laboratory diagnostic methods for drug rash. Individuals with positive skin tests may not develop drug rash after medication, while those with negative tests may experience it. Moreover, intradermal tests can trigger severe drug rash or other adverse drug reactions in highly sensitive individuals, even leading to anaphylactic shock and death. Additionally, drug challenge tests are neither safe nor reliable and should only be cautiously used in patients with fixed drug rash or those unlikely to develop severe reactions. Clinically, a history of drug rash occurring after medication, disappearing upon discontinuation, and recurring upon re-administration is highly diagnostic.
Modern immunological tests, such as lymphocyte transformation tests, radioallergosorbent tests (RAST), basophil degranulation tests, macrophage migration inhibition tests, and leukocyte histamine release tests, can help us understand the immunological relationship between drugs and the body but have no practical diagnostic value. In summary, drug rash is a common condition, and its diagnosis requires objective analysis and the exclusion of other possible diseases.
bubble_chart Treatment Measures
1. Prevention
(1) When treating diseases, first inquire about the history of drug allergies, or avoid the abuse of drugs that are prone to cause drug rash.
(2) Clearly document the drugs that cause allergies in the medical records to alert attending physicians. Advise patients to avoid the drug or any proprietary medicines containing it, as well as chemically related drugs that may cause cross-reactions.
(3) Before administering penicillin, tetanus antitoxin, or procaine, skin tests must be performed, and all necessary emergency medications and measures should be prepared.
2. Treatment Principles
(1) Discontinue all suspected allergenic drugs and structurally similar drugs.
(2) Promote the excretion of drugs from the body.
(3) Use anti-allergy or toxin-removing drugs.
(4) Prevent and control secondary infections.
(5) Provide supportive therapy, etc.
3. Principles of Anti-Allergy or Toxin-Removing Drug Application
(1) Antihistamines: Histamine is an important chemical mediator in allergic reactions, exerting effects by activating H1, H2, and H3 receptors. H1 receptors cause bronchial and gastrointestinal smooth muscle contraction, vascular smooth muscle relaxation, increased atrial muscle contraction, slowed atrioventricular conduction, and increased gastric acid secretion by parietal cells. H2 receptors increase gastric acid secretion by parietal cells, contract vascular smooth muscle, enhance ventricular contraction, and accelerate sinus rhythm. Antihistamines competitively antagonize histamine at receptor sites. It should be noted that mast cells primarily release histamine (primary mediator) but also synthesize and release secondary mediators during the process. Therefore, stabilizing mast cells is also a crucial part of anti-allergy therapy. Common drugs: cinnarizine, cyproheptadine, doxepin, astemizole, terfenadine.
(2) Mediator Blockers: Drugs that stabilize mast cell membranes, such as piperazine derivatives and diethylcarbamazine, can block the release of SPS but not histamine (used in combination with other drugs).
Sodium cromoglicate inhibits histamine release but has no effect on SPS release, while ketotifen stabilizes mast cell membranes.
(3) Calcium Preparations: Increase capillary density, reduce permeability, and decrease exudation.
1) Block neutrophil adhesion to vessel walls, stabilize lysosomal membranes, and prevent lysosomal enzyme release.
2) Inhibit monocyte bactericidal activity, reduce monocyte response to T-cell-released MIF, decrease mediator (lymphokine) release, and reduce cell migration to inflammation sites.
3) Redistribute circulating T cells to reduce their numbers.
4) Stabilize neutrophils and mast cells.
Drug selection should be based on disease conditions. For severe drug rash, corticosteroids should be administered promptly in appropriate doses until body temperature normalizes and rash blisters and erosions begin to dry, after which the dosage can be gradually reduced. During emergency treatment, monitor water and electrolyte imbalances, control infections, assess heart, liver, kidney, and hematopoietic system functions, monitor blood sugar, and prevent cerebral hemorrhage. Address any abnormal reactions immediately.
For milder drug rash, administer sufficient doses of antihistamines, corticosteroids, vitamin C, and calcium preparations to prevent secondary mediator release, especially for patients treated in outpatient observation rooms. Ensure the condition is fully stable before allowing the patient to return home.
4. Enhanced Care
Actively protect mucous membranes, especially the conjunctiva, to prevent corneal opacity and adhesions. For children, pay attention to glans and foreskin erosions to avoid foreskin stenosis. Clean daily with 3% boric acid solution or apply corticosteroid eye drops. Maintain oral hygiene with frequent rinsing, using a 2% sodium bicarbonate solution.
5. Local Treatment
For mild drug rash, local antipruritic treatment, adsorption of erosive surfaces, keeping clean, and rapid healing are sufficient. For severe drug rash, it is best to adopt dry exposure therapy (under an infrared lamp), local Rivanol wet compress, or topical PC cream application, along with air disinfection and the use of sterile sheets and bedding.
6. Chinese medicinals treat
general rash types such as drug rash, urticaria, multiform erythema, and exfoliative dermatitis. Using cooling blood Xiaofeng Decoction, blazing of both qi and blood formula, and Plague-Clear Toxin-Vanquishing Decoction, among others, effectively clears cooling blood to remove toxin and eliminates spots.
