Drug Eruptions Clinical Presentation

The first step is to review the patient's complete medication list, including over-the-counter supplements. Document any history of previous adverse reactions to drugs or foods. Consider alternative etiologies, especially viral exanthems and bacterial infections. Exanthematous eruptions in children are more likely to be due to a viral infection than another infection; however, most such reactions in adults are due to medications.

Note any concurrent infections, metabolic disorders, or immunocompromise (eg, due to HIV infection, cancer, chemotherapy) because these increase the risk of drug eruptions. Immunocompromised persons have a 10-fold higher risk of developing a drug eruption than the general population. Although HIV infection causes profound anergy to other immune stimuli, the frequency of drug hypersensitivity reactions, including severe reactions (eg, TEN), is markedly increased in HIV-positive individuals. Patients with advanced HIV infection (CD4 count < 200 cells/µL) have a 10- to 50-fold increased risk of developing an exanthematous eruption to sulfamethoxazole.

Note and detail the following:

• All prescription and over-the-counter drugs, including topical agents, vitamins, and herbal and homeopathic remedies

• The interval between the introduction of a drug and onset of the eruption

• Route, dose, duration, and frequency of drug administration

• Use of parenterally administered drugs, which are more likely than oral agents to cause anaphylaxis

• Use of topically applied drugs, which are more likely than other drugs to induce delayed-type hypersensitivity reactions

• Use of multiple courses of therapy and prolonged administration of a drug, which can cause allergic sensitization

• Any improvement after drug withdrawal and any reaction with readministration

Although most drug eruptions are exanthematous, different types of drug eruptions are described.

With every drug eruption, it is important to evaluate for certain clinical features that may indicate a severe, potentially life-threatening drug reaction, such as TEN or hypersensitivity syndrome. Such features include the following:

• Mucous membrane erosions

• Blisters (Blisters herald a severe drug eruption.)

• Nikolsky sign (epidermis sloughs with lateral pressure; indicates serious eruption that may constitute a medical emergency)

• Confluent erythema

• Angioedema and tongue swelling

• Palpable purpura

• Skin necrosis (see the image below)

  Warfarin (Coumadin) necrosis involving the leg.

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• Lymphadenopathy

• High fever, dyspnea, or hypotension

Appreciating the morphology and features of drug eruptions is important. This can help the clinician determine the causative medication and the most appropriate treatment.

Acneiform

This is characterized by inflammatory papules or pustules that have a follicular pattern. They are localized primarily on the upper body. In contrast to acne vulgaris, comedones are absent in acneiform eruptions.

Acral erythema (erythrodysesthesia)

This is a relatively common reaction to chemotherapy and is characterized by symmetric tenderness, edema, and erythema of the palms and soles. It is thought to be a direct toxic effect on the skin. Acral erythema often resolves 2-4 weeks after chemotherapy is discontinued.

Acute generalized exanthematous pustulosis (AGEP)

Acute-onset fever and generalized scarlatiniform erythema occur with many small, sterile, nonfollicular pustules. The clinical presentation is similar to pustular psoriasis, but AGEP has more marked hyperleukocytosis with neutrophilia and eosinophilia. Most cases are caused by drugs (primarily antibiotics) often in the first few days of administration. A few cases are caused by viral infections, mercury exposure, or UV radiation. AGEP resolves spontaneously and rapidly, with fever and pustules lasting 7-10 days then desquamation over a few days.

Dermatomyositis like

Cutaneous findings include dermatomyositis (eg, Gottron papules), but patients tend to lack muscle involvement, associated malignancy, and antinuclear antibodies. Improvement is usually noted after the drug is withdrawn.

DRESS (ie, drug reaction with eosinophilia and systemic symptoms) syndrome or DIHS drug-induced hypersensitivity syndrome

These are characterized by the triad of fever, skin eruption, and internal organ involvement, and they usually are associated with intake of anticonvulsant drugs.

Erythema multiforme

This includes a spectrum of diseases (eg, EM minor, EM major), as described below; however, many authorities categorize SJS and TEN as EM major and differentiate them by body surface involvement

• EM minor - Overall, this is a mild disease; patients are healthy. It is characterized by target lesions distributed predominantly on the extremities (see the images below). Mucous membrane involvement may occur but is not severe. Patients with EM minor recover fully, but relapses are common. Most cases are due to infection with herpes simplex virus, and treatment and prophylaxis with acyclovir is helpful.

  Erythema multiforme.

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  Target lesions of erythema multiforme.

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• SJS: This is characterized by widespread skin involvement, large and atypical targetoid lesions, significant mucous membrane involvement, constitutional symptoms, and sloughing of 10% of the skin. SJS can be caused by drugs and infections (especially those due to Mycoplasma pneumoniae).

• SJS/TEN overlap: Epidermal detachment involves 10-30% of body surface area.

• TEN: This is a severe skin reaction that involves a prodrome of painful skin (not unlike sunburn) quickly followed by rapid, widespread, full-thickness skin sloughing. It typically affects 30% or more the total body surface area (see the images below). Secondary infection and sepsis are major concerns, and pneumonia may develop from aspiration of sloughed mucosa. Most cases are due to drugs. The risk of TEN in HIV-positive patients is 1000-fold higher than in the general population.

  Toxic epidermal necrolysis.

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  Stevens-Johnson syndrome.

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Erythema nodosum

This is characterized by tender, red, subcutaneous nodules that typically appear on the anterior aspect of the legs. Lesions do not suppurate or become ulcerated (see the image below). It is a reactive process often secondary to infection, but it may be due to medications, especially oral contraceptives and sulfonamides.

Erythroderma

This is widespread inflammation of the skin (see the image below), and it may result from an underlying skin condition, drug eruption, internal malignancy, or immunodeficiency syndrome. Lymphadenopathy is often noted, and hepatosplenomegaly, leukocytosis, eosinophilia, and anemia may be present.

Fixed drug eruptions

Lesions recur in the same area when the offending drug is given (see the image below). Circular, violaceous, edematous plaques that resolve with macular hyperpigmentation is characteristic. Lesions occur 30 minutes to 8 hours after drug administration. Perioral and periorbital lesions may occur, but the hands, feet, and genitalia are the most common locations.

Hypersensitivity syndrome

This is a potentially life-threatening complex of symptoms often caused by anticonvulsants. Patients have fever, sore throat, rash, lymphadenopathy, hepatitis, nephritis, and leukocytosis with eosinophilia. It usually begins within 1-3 weeks after a new drug is started, but it may develop 3 months or later into therapy. Aromatic anticonvulsant drugs cross-react (ie, phenytoin, phenobarbital, carbamazepine); valproic acid is a safe alternative.

Leukocytoclastic vasculitis

This is the most common severe drug eruption seen in clinical practice (see the image below). It is characterized by blanching erythematous macules quickly followed by palpable purpura. Fever, myalgias, arthritis, and abdominal pain may be present. It typically appears 7-21 days after the onset of drug therapy, and a laboratory evaluation to exclude internal involvement is mandatory.

Lichenoid

This reaction appears similar to lichen planus and may be severely pruritic (see the image below). The eruption may include eczematous or psoriasiform papules.

Lupus

Drug-induced systemic lupus erythematosus (SLE) produces symptoms identical to those of SLE, but skin findings are uncommon. Lesions are also identical to drug-induced subacute cutaneous lupus erythematosus (SCLE), which is characterized by annular, psoriasiform, nonscarring lesions in a photodistributed pattern.

Morbilliform or exanthematous

This is the most common pattern of drug eruptions; it is the quintessential drug rash. Exanthem is typically symmetric, with confluent erythematous macules and papules that spare the palms and soles. It typically develops within 2 weeks after the onset of therapy.

Pseudoporphyria  ^[7]

While largely a drug-induced condition, it can also occur with use of tanning beds and hemodialysis. Patients have blistering and skin fragility that is clinically and pathologically (see the image below) identical to that of porphyria cutanea tarda, but hypertrichosis and sclerodermoid changes are absent and urine and serum porphyrin levels are normal. Treatment is sun protection and withdrawal of the medication.

Serum sickness and serum sickness–like

These are type III hypersensitivity reactions mediated by the deposition of immune complexes in small vessels, activation of complement, and recruitment of granulocytes. Cutaneous signs typically begin with erythema on the sides of the fingers, hands, and toes and progress to a widespread eruption (most often morbilliform or urticarial). Viscera may be involved, and fever, arthralgia, and arthritis are common. Serum sickness–like reactions have a clinical presentation similar to that of serum sickness reactions, without the immune complex deposition. Renal involvement is rare. Serum sickness–like reactions usually occur with antibiotic therapy, especially with cefaclor.

Sweet syndrome (acute febrile neutrophilic dermatosis)

Tender erythematous papules and plaques occur most often on the face, neck, upper trunk, and extremities. The surface of the lesions may become vesicular or pustular. Systemic findings are common and include fever (most often), arthritis, arthralgias, conjunctivitis, episcleritis, and oral ulcers. Laboratory evaluation usually reveals an elevated sedimentation rate, neutrophilia, and leukocytosis. Sweet syndrome often occurs in association with cancers, inflammatory disorders, pregnancy, and medication use.

Urticaria

This usually occurs as small wheals that may coalesce or may have cyclical or gyrate forms. Lesions usually appear shortly after the start of drug therapy and resolve rapidly when the drug is withdrawn (see the image below). Giant urticaria is easily mistaken for EM.

Vesiculobullous

These reactions can resemble pemphigus, bullous pemphigoid, linear immunoglobulin A (IgA) dermatosis, dermatitis herpetiformis, herpes gestationis, or cicatricial pemphigoid. Most causative drugs have a thiol group, disulfide bonds, or sulfur-containing rings that are metabolized to thiol forms. Thiol-induced pemphigus tends to resemble pemphigus foliaceus or pemphigus erythematosus; nonthiol eruptions may resemble pemphigus vulgaris or pemphigus vegetans. Mucosal findings may be most common with nonthiol drugs. Results from direct and indirect immunofluorescence may be positive in persons with drug-induced pemphigus and bullous pemphigoid. Eruptions usually resolve after the inducing drug is discontinued, but D-penicillamine–induced pemphigus may take months to resolve and corticosteroids are often needed.

(Also see the Pill Identifier tool.)

The diagnosis and management of adverse reactions attributable to cancer therapies is a rapidly growing and evolving area. The side effects of conventional cytotoxic chemotherapies are extensive and include mucositis, alopecia, pigmentary changes and changes attributable to cytopenias.

Diffuse hyperpigmentation can be seen in busulfan therapy.  Flagellate serpentine pigmentation can be seen with ifosfamide, docetaxel, and other agents in addition to bleomycin.  Taxanes are strongly associated with onycholysis and paronychia.   

Targeted therapies such as epidermal growth factor inhibitors (EGFR inihibitors) often trigger papulopustular reactions.   KIT and BCR-ABL inhibitors are associated with exanthems, hypopigmentation, and hand-foot reactions.  mTOR inhibitors (everolimus,rapamycin, sirolimus) are associated with stomatitis. 

Some adverse effects may be helpful in predicting a beneficial clinical effect and good prognosis.  Accurately documenting adverse reactions in a uniform manner is therefore of great importance. 

The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) is used to document and grade toxic effects of oncologic treatments. More information can be found here.