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Drug Eruptions

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Drug Eruptions
Author: Jonathan E Blume, MD; Chief Editor: Dirk M Elston, MD more... Updated: Apr 8, 2013

Practice Essentials
Drug eruptions can mimic a wide range of dermatoses. The morphologies are myriad and include morbilliform, urticarial, papulosquamous, pustular, and bullous. Medications can also cause pruritus and dysesthesia without an obvious eruption. A drug-induced reaction should be considered in any patient who is taking medications and who suddenly develops a symmetric cutaneous eruption.

Essential update: Drug patch tests can identify agents responsible for severe cutaneous adverse reactions
In a study of 134 patients with severe cutaneous adverse drug reactions, Barbaud et al found that drug patch tests could be safely used to identify the responsible drug. Of the 134 patients, 45 had acute generalized exanthematous pustulosis (AGEP), 72 had drug reaction with eosinophilia and systemic symptoms (DRESS), and 17 had Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Positive drug patch test results were obtained for 64% of the patients in the DRESS group, 58% of those in the AGEP group, and 24% of those in the SJS/TEN group; 1 AGEP patient experienced relapse.[1]

Signs and symptoms

The first steps in the history are as follows: Review the patients complete medication list, including prescription and over-the-counter drugs Document any history of previous adverse reactions to drugs or foods Consider alternative etiologies (eg, viral exanthems and bacterial infections) Note any concurrent infections, metabolic disorders, or immunocompromise In addition, the following should be noted and detailed: Interval between introduction of a drug and onset of the eruption Route, dose, duration, and frequency of drug administration Use of parenterally administered drugs (more likely to cause anaphylaxis) Use of topically applied drugs (more likely to induce delayed-type hypersensitivity) Use of multiple courses of therapy and prolonged administration (risk of allergic sensitization) Any improvement after drug withdrawal and any reaction with readministration Physical examination should address clinical features that may indicate a severe, potentially life-threatening drug reaction, including the following: Mucous membrane erosions Blisters
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Nikolsky sign Confluent erythema Angioedema and tongue swelling Palpable purpura Skin necrosis Lymphadenopathy High fever, dyspnea, or hypotension It is important to appreciate the morphology and physical features of drug eruptions, as follows: Acneiform Acral erythema (erythrodysesthesia) AGEP Dermatomyositislike DRESS Erythema multiforme (EM), including EM minor, SJS, TEN, and SJS/TEN overlap Erythema nodosum Erythroderma Fixed drug eruptions Hypersensitivity syndrome Leukocytoclastic vasculitis Lichenoid Lupus Morbilliform or exanthematous Pseudoporphyria[2] Serum sickness and serum sicknesslike Sweet syndrome (acute febrile neutrophilic dermatosis) Urticaria Vesiculobullous See Clinical Presentation for more detail.

Diagnosis
With mild asymptomatic eruptions, the history and physical examination are often sufficient for diagnosis; with severe or persistent eruptions, further diagnostic testing may be required, as follows: Biopsy Complete blood count (CBC) with differential Serum chemistry studies (especially for electrolyte balance and indices of renal or hepatic function in patients with severe reactions) Antibody or immunoserology tests Direct cultures to investigate a primary infectious etiology or secondary infection Urinalysis, stool guaiac tests, and chest radiography for vasculitis Skin prick or patch testing to confirm the causative agent See Workup for more detail.

Management
Principles of medical care are as follows: The ultimate goal is to identify and discontinue the offending medication if possible Patients can sometimes continue to be treated through morbilliform eruptions; nevertheless, all patients with severe morbilliform eruptions should be monitored for mucous membrane lesions, blistering, and skin sloughing Treatment of a drug eruption depends on the specific type of reaction Therapy for exanthematous drug eruptions is supportive, involving the administration of oral antihistamines,
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topical steroids, and moisturizing lotions Severe reactions (eg, SJS, TEN, and hypersensitivity reactions) warrant hospital admission TEN is best managed in a burn unit, and intravenous immunoglobulin (IVIG) may improve outcomes [3, 4, 5] Hypersensitivity syndrome, may have to be treated with liver transplantation if the offending drug is not stopped in time; treatment with systemic corticosteroids has been advocated For most drug eruptions, full recovery without any complications is expected; however, the following should be noted: Patients with exanthematous eruptions should expect mild desquamation as the rash resolves Patients with hypersensitivity syndrome are at risk of becoming hypothyroid, usually within the first 4-12 weeks after the reaction The prognosis for patients with TEN is guarded; scarring, blindness, and death are possible See Treatment and Medication for more detail.

Image library

Stevens-Johnson syndrome.

Background
Drug eruptions can mimic a wide range of dermatoses. The morphologies are myriad and include morbilliform (most common, see image below), urticarial, papulosquamous, pustular, and bullous. Medications can also cause pruritus and dysesthesia without an obvious eruption.

Morbilliform drug eruption.

A drug-induced reaction should be considered in any patient who is taking medications and who suddenly develops a symmetric cutaneous eruption. Medications that are known for causing cutaneous reactions include antimicrobial agents,[6] nonsteroidal anti-inflammatory drugs (NSAIDs), cytokines, chemotherapeutic agents, anticonvulsants, and psychotropic agents. Prompt identification and withdrawal of the offending agent may help limit the toxic effects associated with the drug. The decision to discontinue a potentially vital drug often presents a dilemma.

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Pathophysiology
Drug eruptions may be divided into immunologically and nonimmunologically mediated reactions.

Immunologically mediated reactions

Coombs and Gell proposed 4 types of immunologically mediated reactions, as follows: Type I is immunoglobulin E (IgE)dependent reactions, which result in urticaria, angioedema, and anaphylaxis (see the image below).

Urticaria.

Type II is cytotoxic reactions, which result in hemolysis and purpura (see the image below).

Oral ulcerations in a patient receiving cytotoxic therapy.

Type III is immune complex reactions, which result in vasculitis, serum sickness, and urticaria. Type IV is delayed-type reactions with cell-mediated hypersensitivity, which result in contact dermatitis, exanthematous reactions, and photoallergic reactions. Insulin and other proteins are associated with type I reactions. Penicillin, cephalosporins, sulfonamides, and rifampin are known to cause type II reactions. Quinine, salicylates, chlorpromazine, and sulfonamides can cause type III reactions. Type IV reactions, the most common mechanism of drug eruptions, are often encountered in cases of contact hypersensitivity to topical medications, such as neomycin. Sulfonamides are most frequently associated with toxic epidermal necrolysis (TEN). Although most drug eruptions are type IV hypersensitivity reactions, only a minority are IgE-dependent. That is, antibodies can be demonstrated in less than 5% of cutaneous drug reactions. Type IV cell-mediated reactions are not dose dependent, they usually begin 7-20 days after the medication is started, they may involve blood or tissue eosinophilia, and they may recur if drugs chemically related to the causative agent are administered.

Nonimmunologically mediated reactions

Nonimmunologically mediated reactions may be classified according to the following features: accumulation, adverse effects, direct release of mast cell mediators, idiosyncratic reactions, intolerance, Jarisch-Herxheimer phenomenon, overdosage, or phototoxic dermatitis. (Symptoms of Jarisch-Herxheimer reactions disappear with continued therapy. Drug therapy should be continued until the infection is fully eradicated.) An example of accumulation is argyria (blue-gray discoloration of skin and nails) observed with use of silver nitrate nasal sprays. Adverse effects are normal but unwanted effects of a drug. For example, antimetabolite chemotherapeutic agents, such as cyclophosphamide, are associated with hair loss.
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The direct release of mast cell mediators is a dose-dependent phenomenon that does not involve antibodies. For example, aspirin and other NSAIDs cause a shift in leukotriene production, which triggers the release of histamine and other mast-cell mediators. Radiographic contrast material, alcohol, cytokines, opiates, cimetidine, quinine, hydralazine, atropine, vancomycin, and tubocurarine also may cause release of mast-cell mediators. Idiosyncratic reactions are unpredictable and not explained by the pharmacologic properties of the drug. An example is the individual with infectious mononucleosis who develops a rash when given ampicillin. Imbalance of endogenous flora may occur when antimicrobial agents preferentially suppress the growth of one species of microbe, allowing other species to grow vigorously. For example, candidiasis frequently occurs with antibiotic therapy. Intolerance may occur in patients with altered metabolism. For example, individuals who are slow acetylators of the enzyme N -acetyltransferase are more likely than others to develop drug-induced lupus in response to procainamide. Jarisch-Herxheimer phenomenon is a reaction due to bacterial endotoxins and microbial antigens that are liberated by the destruction of microorganisms. The reaction is characterized by fever, tender lymphadenopathy, arthralgias, transient macular or urticarial eruptions, and exacerbation of preexisting cutaneous lesions. The reaction is not an indication to stop treatment because symptoms resolve with continued therapy. This reaction can be seen with penicillin therapy for syphilis, griseofulvin or ketoconazole therapy for dermatophyte infections, and diethylcarbamazine therapy for oncocerciasis. Overdosage is an exaggerated response to an increased amount of a medication. For example, increased doses of anticoagulants may result in purpura. Phototoxic dermatitis is an exaggerated sunburn response caused by the formation of toxic photoproducts, such as free radicals or reactive oxygen species (see the image below).

Phototoxic reaction after use of a tanning booth. Note sharp cutoff w here clothing blocked exposure.

Frequency
United States
Drug eruptions occur in approximately 2-5% of inpatients and in greater than 1% of outpatients.

International
Drug eruptions occur in approximately 2-3% of inpatients.

Mortality/Morbidity
Most drug eruptions are mild, self-limited, and usually resolve after the offending agent has been discontinued. Severe and potentially life-threatening eruptions occur in approximately 1 in 1000 hospital patients. Mortality rates for erythema multiforme (EM) major are significantly higher. Stevens-Johnson syndrome (SJS) has a mortality rate of less than 5%, whereas the rate for TEN approaches 20-30%; most patients die from sepsis.

Sex
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Adverse cutaneous reactions to drugs are more prevalent in women than in men.

Age
Elderly patients have an increased prevalence of adverse drug reactions.

Contributor Information and Disclosures

Author Jonathan E Blume, MD Instructor in Clinical Dermatology, Columbia University College of Physicians and Surgeons; Dermatologist, Westwood Dermatology and Dermatologic Surgery Group PA Jonathan E Blume, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, and International Society of Dermatology Disclosure: Nothing to disclose. Coauthor(s) Liaqat Ali, MD Assistant Professor, Department of Dermatology, Wayne State University School of Medicine; Dermatopathologist, Pinkus Dermatopathology Laboratory, Monroe, MI Liaqat Ali, MD is a member of the following medical societies: American Society for Clinical Pathology, American Society of Dermatopathology, College of American Pathologists, and United States and Canadian Academy of Pathology Disclosure: Nothing to disclose. Michelle Ehrlich, MD Director of Cosmetic Dermatology and Surgery Residency Program, Harbor-UCLA Medical Center; Clinical Instructor, Department of Dermatology, University of California, Los Angeles, David Geffen School of Medicine Michelle Ehrlich, MD is a member of the following medical societies: American Academy of Cosmetic Surgery and American Academy of Dermatology Disclosure: Nothing to disclose. Charles Camisa, MD Head of Clinical Dermatology, Vice-Chair, Department of Dermatology, Cleveland Clinic Foundation Charles Camisa, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology Disclosure: Nothing to disclose. Thomas N Helm, MD Clinical Professor of Dermatology and Pathology, University of Buffalo, State University of New York School of Medicine and Biomedical Sciences; Director, Buffalo Medical Group Dermatopathology Laboratory Thomas N Helm, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for Dermatologic Surgery, and American Society of Dermatopathology Disclosure: Nothing to disclose. Specialty Editor Board Neil Shear, MD Professor and Chief of Dermatology, Professor of Medicine, Pediatrics and Pharmacology, University of Toronto Faculty of Medicine; Head of Dermatology, Sunnybrook Women's College Health Sciences Center and Women's College Hospital, Canada
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Neil Shear, MD is a member of the following medical societies: American Academy of Dermatology, American Society for Clinical Pharmacology and Therapeutics, Canadian Dermatology Association, Canadian Medical Association, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada Disclosure: Nothing to disclose. Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association Disclosure: Nothing to disclose. Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology Disclosure: Amgen Honoraria Consulting; Celgene Honoraria Safety Monitoring Committee Catherine M Quirk, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology Disclosure: Nothing to disclose. Chief Editor Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology Disclosure: Nothing to disclose.

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