BASICS
DESCRIPTION
- An adverse cutaneous reaction in response to administration of a drug. Rashes are the most common adverse drug reactions.
- Severity can range from mild eruptions that resolve within 48 hours after the removal of the inciting agent to severe skin damage with multiorgan involvement.
- Morbilliform/simple exanthem (75-95%) and urticarial (5-6%) eruptions are most common, but multiple morphologic types may occur.
- System(s) affected: skin/mucosa/exocrine, hematologic/lymphatic/immunologic
EPIDEMIOLOGY
- All ages affected
- Predominant sex: female > male
- No correlation between development of adverse reaction and patient's age, diagnosis, or survival.
- Special consideration in the geriatric population who are on multiple medications: increased likelihood of severe cutaneous and systemic reactions; also consider in the pediatric group: difficult to distinguish from viral exanthems
Incidence
In the United States, prevalence of 2-3% in hospitalized patients; estimated 1/1,000 hospitalized patients has had a severe cutaneous reaction.
ETIOLOGY AND PATHOPHYSIOLOGY
- Predictable adverse reactions are due to overdose, side effect, or drug interaction.
- Unpredictable reactions include intolerance, drug idiosyncrasy secondary to abnormality in metabolism, or immune reaction. >700 drugs are known to cause a dermatologic reaction:
- Immunologically mediated reaction: immunoglobulin (Ig) E-mediated reaction (type I hypersensitivity), cytotoxic/IgG/IgM induced (type II), immune complex reactions (type III), and delayed-type hypersensitivity (type IV) with T cells, eosinophils, neutrophils, and monocytes
- Acneiform: OCPs, corticosteroids, iodinated compounds, hydantoins, lithium
- Erythema multiforme/Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): >100 drugs reported. Most common include sulfonamides, cephalosporins NSAIDs, barbiturates, hydantoins, anticonvulsants tetracycline, terbinafine.
- Fixed drug eruptions: NSAIDS, sulfonamides, tetracycline, barbiturates, salicylates, OCPs
- Lichenoid: thiazides, NSAIDs, gold, ACE inhibitors, proton pump inhibitors, antimalarials, sildenafil
- Photosensitivity: doxycycline, thiazides, sulfonylureas, quinolones, sulfonamides, NSAIDs
- Hypersensitivity vasculitis: hydralazine, penicillins, cephalosporins, thiazides, gold, sulfonamides, NSAIDs, propylthiouracil
- Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome: anticonvulsants, sulfonamides, dapsone, minocycline, allopurinol
- Acute generalized exanthematous pustulosis (AGEP): penicillins, cephalosporins, macrolides, calcium channel blockers, antimalarials, carbamazepine, acetaminophen, terbinafine, nystatin, vancomycin
- Sweet syndrome (acute febrile neutrophilic dermatosis): sulfa drugs, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), diazepam, minocycline, nitrofurantoin, captopril, penicillamine
- Serum sickness-like reaction: cephalosporins, penicillins, TMP-SMX, propranolol, bupropion, minocycline
- Morbilliform/urticarial/exfoliative erythroderma: numerous medications, including penicillins, cephalosporins, sulfonamides, tetracyclines, ibuprofen, naproxen, allopurinol, acetylsalicylic acid, radiocontrast media (1)[A]
Genetics
Genetics may play a role, as certain HLA antigens have been associated with increased predisposition to specific drug eruptions:
- HLA-B*5801, HLA-B*5701, and HLA-B*1502 have been linked to allopurinol-induced and carbamazepine-induced SJS/TEN, respectively.
- HLA class I antigens, such as HLA-A2, HLA-B12, and HLA-B22, have been linked to TEN and fixed drug eruptions, respectively.
RISK FACTORS
Previous drug reaction, multiple medications, concurrent infections, immunocompromised, disorders of metabolism, and certain genetic HLA haplotypes
GENERAL PREVENTION
Always ask patients about prior adverse drug events. Be aware of medications with higher incidence of reactions as well as drug cross-reactions.
DIAGNOSIS
HISTORY
- New medications within the preceding 6 weeks, most commonly within preceding 2 weeks: all oral, parenteral, and topical agents, including over the counter drugs, vitamins, and herbal remedies
- Consider other etiologies: bacterial infections, viral exanthems, or underlying skin disease including cutaneous lymphoma
PHYSICAL EXAM
May present as a number of different eruption types, including, but not limited to the following:
- Morbilliform eruptions (exanthems)
- Most frequent cutaneous reaction (75-95%); difficult to distinguish from viral exanthem; often secondary to antibiotic
- Starts on trunk as pruritic red macules and papules and extends to extremities in confluent fashion, sparing face, palms, soles, and mucous membranes
- Onset 7 to 21 days after drug initiation (2)[C].
- Urticaria
- Pruritic erythematous wheals distributed anywhere on the body, including mucous membranes; may progress to angioedema, appears as nonpitting edema without erythema or margins
- Individual lesions fade within 24 hours, but new lesions may develop (2).
- Acneiform eruptions
- Folliculocentric, monomorphous pustules typically involving the face, chest, and back distinguished from acne vulgaris by absence of gross and/or microscopic comedones
- Often may become secondarily infected (2)[C]
- Fixed drug eruptions
- Single/multiple, round, sharply demarcated, violaceous plaques with gray center that may leave postinflammatory hyperpigmentation; occur on skin or mucous membrane
- Appear shortly after drug exposure and recur in identical location after reexposure; some patients have a refractory period during which the drug fails to activate lesions.
- Onset usually is 48 hours after ingestion of drug (2).
- AGEP
- Multiple nonfollicular sterile pustules on erythematous background with desquamation after 7 to 10 days
- Involves intertriginous areas but can be generalized and involve the face
- Appears similar to pustular psoriasis, but AGEP has fever and marked leukocytosis with neutrophilia and/or eosinophilia (2)[C]
- DRESS syndrome
- Classic triad of fever, exanthem, and internal organ involvement with possible pharyngitis and lymphadenopathy
- Can lead to exfoliative dermatitis, often accompanied by facial edema
- Internal organ involvement: 80% hepatic, 40% renal, 33% pulmonary, and cardiac lab tests show elevated liver transaminases and eosinophilia.
- Onset 2 to 8 weeks after drug exposure; may develop 3 months or later into therapy (3)[B]
- Erythema multiforme
- Relatively common, acute, often recurrent
- Most commonly associated with herpes simplex virus and other viral/bacterial etiologies (i.e., mycoplasma); less likely secondary to drug exposure. 50% with unknown etiology
- Three-zone target lesions and raised atypical two-zone targets with localized erythema
- Lesions predominant on distal extremities including on acral surface with limited mucosal involvement; <10% epidermal detachment (4)[B]
- SJS/TEN
- Classification and distinction between SJS and TEN determined by affected body surface area (BSA)
- SJS: <10% BSA; SJS-TEN overlap: 10-30% BSA; TEN: >30% BSA
- Unlike erythema multiforme, strong association with preceding drug exposure as opposed to infection except in children where infection is more common (e.g., mycoplasma)
- Onset is 1 to 3 weeks after starting offending agent: Flat atypical two-zone target lesions and erythematous macules that are truncal and generalized with mucosal involvement
- May develop confluent areas of bullae, erosions, and necrosis; significant risk for infection and sepsis
- SJS: 5-15% mortality; TEN: 30% mortality (5)[C],(6)[A]
- Lichenoid eruptions
- Flat-topped, violaceous, pruritic papules on extensor surfaces and involving oral mucosa
- Reticular pattern: Lesions heal with hyperpigmentation.
- Chronic lesions persist for weeks/months after the drug discontinued (2)
- Photosensitivity reaction
- Phototoxic reactions: occur within 24 hours of light exposure with exaggerated sunburn reaction; confined to sun-exposed areas
- Photoallergic reactions: caused by UVA exposure; more pruritic than painful; can involve non-sun-exposed areas
- Hypersensitivity vasculitis
- Petechiae/palpable purpura and/or maculopapular rash concentrated on lower extremities and dependent areas
- Biopsy shows neutrophils around an arteriole or venule.
- Possible renal, joint, and CNS involvement with fever, myalgias, arthritis, and abdominal pain (2)
- Sweet syndrome
- Fever, neutrophilia, tender edematous violaceous papules, plaques, or nodules, with or without pustules/vesicles that spontaneously resolve
- May have oral ulcers or ocular manifestations, such as conjunctivitis
- Classically seen in young women after a mild respiratory illness or GI infection, but 7-56% associated with malignancy and pregnancy
- Serum sickness-like reaction
- Fever, nonspecific cutaneous eruption with possible bullous lesions, arthralgias
- Onset 7 to 14 days
- Exfoliative dermatitis/erythroderma
- Generalized erythema with exfoliation and/or fine desquamation over 90% of body surface
- Difficult to distinguish between drug, primary cutaneous lymphoma, or inflammatory etiology
- Lymphadenopathy, hepatosplenomegaly, leukocytosis, eosinophilia, or anemia may be present.
- Increased risk of secondary infection and insensible fluid and temperature loss with hemodynamic instability
DIFFERENTIAL DIAGNOSIS
- Viral exanthem: Presence of fever, lymphocytosis, and other systemic findings may help in narrowing differential.
- Primary dermatosis: Correlation of drug withdrawal to rash resolution may clarify diagnosis; skin biopsy is helpful.
- Bacterial infection: Cultures of pustules may distinguish primary infection from AGEP and acneiform eruptions.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
A minimum number of tests are useful in evaluating for internal organ involvement. CBC with differential; significant eosinophilia may be seen in DRESS and other drug-induced allergic reactions. LFT, urinalysis, and serum creatinine; chest x-ray if suspected vasculitis
Diagnostic Procedures/Other
- Special tests depend on suspected mechanism:
- Type I: skin/intradermal testing, radioallergosorbent (RAST)
- Type II: direct/indirect Coombs test
- Type III: ESR, C-reactive protein, ANA, antihistone antibody, tissue biopsy for immunofluorescence studies
- Type IV: patch testing, lymphocyte proliferation assay (investigational)
- Anaphylaxis/nonimmunologic mast and basophil cell reaction: serum tryptase levels
- Cultures useful in excluding infectious etiology; skin biopsy is nonspecific but useful in characterizing an eruption and excluding primary skin pathologies.
- Develop a timeline documenting the onset and duration of all drugs, dosages, and onset of cutaneous eruption. (1)[A]
Test Interpretation
- Nonspecific histologic findings are superficial epidermal and dermal infiltrates composed variably of lymphocytes, neutrophils, and eosinophils.
- SJS/TEN: partial or full-thickness necrosis of the epidermis necrotic keratinocytes, vacuolization leading to subepidermal blister at basal membrane zone
TREATMENT
GENERAL MEASURES
- Monitor for signs of impending cardiovascular collapse: Anaphylactic reactions, DRESS, SJS/TEN, extensive bullous reactions, and generalized erythroderma may require inpatient treatment.
- Do not rechallenge with drugs causing urticaria, bullae, angioedema, DRESS, anaphylaxis, or erythema multiforme.
MEDICATION
- Withdrawal of offending drug. Depending on the type of eruption, symptomatic treatment may be useful, but most require no additional therapy except cessation of offending agent.
- Anaphylaxis or widespread urticaria: epinephrine 0.1 to 0.5 mg (1:1,000 [1 mg/mL] solution) SC every 5 to 15 min; prednisone may be given to prevent recurrence.
- Acute urticaria (<6 weeks) and chronic urticaria (>6 weeks): 2nd-generation antihistamines (preferred, less sedating): cetirizine 10 to 20 mg daily, loratadine 10 to 20 mg daily, fexofenadine 180 mg daily, levocetirizine 5 to 10 mg daily. 1st-generation antihistamines: diphenhydramine 10 to 25 mg QHS, hydroxyzine 10 to 25 mg TID, doxepin 10 to 50 mg QHS H2 antagonists: cimetidine 400 mg BID, ranitidine 150 mg BID
- Anaphylaxis, severe urticaria: prednisone PO 1 mg/kg in tapering doses
- Erythema multiforme
- Treatment is generally supportive with management of suspected underlying infection.
- Herpes simplex virus (HSV)-associated: prophylaxis with acyclovir 400 mg BID, valacyclovir 500 to 1,000 mg/day, or famciclovir 250 mg BID
- "Magic mouthwash" BID or TID is helpful for mucosal erosions. Consider ophthalmology consult for severe ocular involvement. (4)[B]
- SJS/TEN: Treatment is supportive. Consult with a dermatologist and ophthalmologist. Systemic corticosteroid use remains controversial. Consider IVIG 2 to 3 g/kg for severe disease. In pediatric TEN patients, low-dose IVIG (0.05 to 0.1 g/kg/day) was effective. Varied success rates reported with use of anti-tumor necrosis factor-α agents, cyclosporine, cyclophosphamide, and plasmapheresis. (5)[C],(6)[A]
- DRESS: prompt removal of offending drug and supportive measures; high-potency topical steroids for rash; systemic steroids with severe organ involvement; prednisone 0.5 to 2 mg/kg/day with prolonged taper 8 to 12 weeks. (3)[B]
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- For urticarial, bullous, DRESS, or erythema multiforme spectrum lesions, close follow-up is needed.
- Patients with anaphylaxis/angioedema should be given EpiPen for secondary prevention and a Med-Alert bracelet; label the patient's medical record with the agent and reaction.
- If the patient needs to take the inciting drug (e.g., antibiotic) in the future, induction of drug tolerance or graded challenge procedures may be necessary.
PROGNOSIS
- Eruptions generally begin fading within days after removing offending agent. With morbilliform eruptions, eruption may spread distally even when agent is removed, resolving over time.
- Anaphylaxis, angioedema, DRESS, SJS/TEN, and bullous reactions are potentially fatal.
COMPLICATIONS
Anaphylaxis, bone marrow suppression, hepatitis (dapsone, hydantoin), renal failure, and pulmonary and thyroid toxicity
REFERENCES
11 Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, et al. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273.22 Ahmed AM, Pritchard S, Reichenberg J. A review of cutaneous drug eruptions. Clin Geriatr Med. 2013;29(2):527-545.33 Chen YC, Chiu HC, Chu CY. Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases. Arch Dermatol. 2010;146(12):1373-1379.44 Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45-53.55 Mockenhaupt M. Stevens-Johnson syndrome and toxic epidermal necrolysis: clinical patterns, diagnostic considerations, etiology, and therapeutic management. Semin Cutan Med Surg. 2014;33(1):10-16.66 Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR study. J Am Acad Dermatol. 2008;58(1):33-40.
CODES
ICD10
- L27.1 Loc skin eruption due to drugs and meds taken internally
- L50.0 Allergic urticaria
- R21 Rash and other nonspecific skin eruption
- L27.0 Gen skin eruption due to drugs and meds taken internally
- L30.8 Other specified dermatitis
ICD9
- 693.0 Dermatitis due to drugs and medicines taken internally
- 708.0 Allergic urticaria
- 782.1 Rash and other nonspecific skin eruption
- 709.8 Other specified disorders of skin
- 692.89 Contact dermatitis and other eczema due to other specified agents
SNOMED
- 200892002 Generalized skin eruption due to drugs and medicaments
- 40178009 Allergic urticaria (disorder)
- 247470007 Morbilliform eruption (disorder)
- 62014003 Adverse reaction to drug (disorder)
- 271807003 eruption of skin (disorder)
CLINICAL PEARLS
- Virtually, any drug can cause a rash; antibiotics are the most common culprits that cause cutaneous drug reactions.
- Focus on drug history with new suspicious skin eruptions.
- Usually self-limited after withdrawal of offending agent
- Symptoms such as tongue swelling/angioedema, skin necrosis, blisters, high fever, dyspnea, and mucous membrane erosions signify more severe drug reactions.
- Useful resources: Drug Eruption Reference Manual by Jerome Litt; www.drugeruptiondata.com; www.druginteractions.com