Multiple factors place an individual at increased risk for developing an ADR including the drug itself. Clinicians should maintain a heightened awareness when their patients are receiving medications that are known to be high risk for ADR. Overall, aminopenicillins, sulfonamides, and nonsteroidal anti-inflammatory drugs (NSAIDs) account for the largest number of drug-related cutaneous eruptions. Other risk factors include the following:

Physical examination findings often mimic other skin disorders and may occur days or even years after beginning drug therapy, making the diagnosis challenging. An important variable that impacts the quality of the physical assessment is a complete body examination. Often, patients perceived their “rash” to be independent of any other symptoms or lesions occurring on other parts of their body (see chapter 1).

A detailed physical examination should be performed carefully, making note of the primary morphology and distribution of the cutaneous symptoms. Close examination of the oral cavity and other mucous membranes is extremely important. Vital signs should be taken to assess for fever, hypotension, tachycardia, and other systemic symptoms signaling a possible life-threatening ADR.

Diagnosis of a cutaneous ADR eruption is based on clinical suspicion, chronology, and probability. Clinicians should always consider drug eruption in the differential diagnosis in patients presenting with pruritic, symmetrical, and generalized skin rashes. There are several valuable resources and online databases available, such as Litt’s Drug Eruption Manual (2009), which can enable clinicians to view specific drug information, reaction, and incidence. It also provides content regarding the most common drug eruptions and patterns that can aid in predicting, diagnosing, and managing the patients with suspected ADRs.

Most ADRs are diagnosed based on history and physical findings and do not require any diagnostics. In severe or persistent cases, further testing may be necessary. Skin biopsy may be indicated to support the clinician’s suspicion and to rule out other disease processes. Histologic findings typically show spongiosis with perivascular infiltrates of lymphocytes and eosinophils, and require clinicopathologic correlation. Patients and clinicians must understand that even if histology supports the diagnosis of an ADR, it cannot identify the offending agent. This is a patient expectation that should be discussed and managed before a biopsy is performed. Immunofluorescence is performed when a connective tissue disease or autoimmune blistering disease is suspected.

Other diagnostics including laboratory studies are indicated in patients with systemic symptoms. In addition to a complete blood count with differential and chemistry panel, antinuclear antibodies (ANA) screening can be helpful. Antihistone antibodies may support a diagnosis of drug-induced lupus. Blood cultures, urinalysis, and stool guaiac will help to rule out infection and vasculitis. Provocation testing is only considered in specific circumstances and is generally performed in carefully controlled settings.

Management of an ADR is relative to the specific drug and reaction type which will be discussed in this chapter. However, the first and universal approach to all ADRs is discontinuation of the offending drug (Box 17-2).

Regardless of the type of drug eruption, any patient diagnosed with an ADR must be educated about lifelong avoidance of the offending drug, medications in the same drug class, or other classes that may have potential cross-reactivity. Good communication between the patient and health care team should ensure that all personal health records and medic-alert identifiers reflect the patient’s history of serious ADRs. Most importantly, patients with an ADR should be instructed to notify their health care provider should the rash recur or worsen, indicating a severe hypersensitivity reaction. Clinicians should be alerted if the patient develops fever, redness that starts to expand over the body, blisters, ulcerations, or sores on any mucous membrane, or the patient experiences a new onset of pain. In the event that the provider is unavailable, the patient should be referred to the emergency department (Box 17-3).

The onset of exanthematous ADRs usually occurs within hours to weeks after initiation of the drug. They generally develop as bright red, pruritic macules and papules that symmetrically appear on the trunk but may coalesce and spread to the extremities (Figure 17-1A). In adults, it usually spares the face, whereas in children, it may be limited to the face and extremities. Confluent lesions may develop bilaterally (Figure 17-1B) and in the intertriginous areas. Palms, soles, and mucous membranes can be involved. The associated pruritus often disturbs sleep. A low-grade fever and/or chills may be present compared to the high-grade fever associated with a hypersensitivity syndrome reaction. The onset of exanthematous eruptions usually occurs within hours to weeks after initiation of the drug.

An exanthematous drug eruption is usually a clinical diagnosis that correlates with a history of drug administration. In most cases, it is not necessary to perform a skin biopsy except when the diagnosis is in question or to rule out other causes. Histopathology typically shows eosinophilia, perivascular lymphocytes, and vacuolar if the patient interface dermatitis. If the patient’s morbilliform rash progresses or if the patient develops fever, chills, lymphadenopathy, or angioedema, additional diagnostics would be indicated for evaluation of systemic involvement.

In addition to discontinuing the suspected drug, symptomatic treatment is all that is needed for a mild or moderate exanthematous drug eruption. Antihistamines, both H₁ and H₂ blockers, may be used to reduce pruritus. Mid-potency topical corticosteroids may be used during the acute phase, if necessary. Since this eruption is often widespread, triamcinolone 0.1% cream or ointment, prescribed in a large quantity (1-lb jar), is usually sufficient but should be avoided on the face, skin folds, and genital areas (see chapter 2). Application of cool compresses, fragrance-free moisturizing creams, and anti-itch lotions can be helpful in controlling discomfort. In a rare instance that the offending drug cannot be discontinued or the patient has a severe eruption, a short course of oral prednisone may be prescribed at a dose of 1.0 to 2.0 mg/kg/day for 7 to 10 days to provide symptomatic relief and induce rapid remission.

An exanthematous drug rash lasts for 1 to 2 weeks and then fades. Resolving lesions have hues of tan and purple, scaling, or desquamation. Clinicians should use great caution when patients with a morbilliform rash progress to develop fever, mucositis, erythroderma, facial edema, or blisters. They should be seen and evaluated immediately.

FDE takes a few days to appear after initiation of the culprit drug. Yet if the patient has been previously sensitized to the drug, lesions could develop within minutes of taking a single dose. A classic feature of FDE is the reappearance of lesions with subsequent exposures to the drug. Lesions usually recur in the same localized areas as the initial eruptions. New lesions can develop in new areas as well. FDE can occur anywhere on the body but favors the dorsal hands, glans penis and groin area, periorbital, perioral, and occasionally the oral mucosa (Figure 17-2A). In males presenting with penile lesions, FDE should always be at the top of the differential diagnosis (Figure 17-2B).

FDE has a distinct appearance as sharply demarcated, round/oval, dusky-red patches or plaques that may be solitary or multiple. Plaques sometimes become edematous and form central vesicle/bulla,
giving it a target-like appearance and then eroding. There may be no other associated symptoms or there may be some mild itching or burning.

FDR is generally a clinical diagnosis. History is the most helpful diagnostic tool as patients often do not correlate the offending medication with the eruption. Sometimes, a biopsy is performed and shows basal cell destruction and pigment incontinence.