Drug-associated rashes are very common in hospitalized patients, and uncommonly can be associated with conditions that prompt admission. In large prospective studies and systematic reviews, 2.9% to 4% of pediatric hospital admissions were related to adverse drug reactions.^1,2 The Boston Drug Surveillance Project estimated that approximately 30% of hospitalized patients experience adverse drug events,³ and in 1991 the Harvard Medical Practice Study II published data showing that drug events were the most common type of adverse event in the hospital.⁴ Pediatric adverse drug reaction rates were estimated in a large systematic review at 0.6% to 16.8% of all children exposed to drugs during a hospital stay.² A study in the 1980s in New York state estimated that as many as 20% of serious drug reactions involve the skin. Certain categories of common pediatric medications, including antibiotics and anticonvulsants, are associated with rates of drug eruption ranging from as high as 1% to 5%.⁵ Many unique cutaneous reaction patterns have been described, and the same medication may cause different reaction patterns in different patients, thus making accurate diagnosis challenging. A subset of drug eruptions are serious and may even be life threatening and require rapid diagnosis and intervention. Therefore it is important in the inpatient setting to be able to recognize the common patterns of cutaneous drug reaction, identify the probable causative agent, and institute appropriate therapy when indicated.

PATHOPHYSIOLOGY

Drug reactions result from both immunologic and nonimmunologic mechanisms. Nonimmunologic adverse reactions account for the majority of drug reactions and include those related to factors such as overdose, cumulative toxicity, metabolic alterations, drug–drug interactions, and idiosyncrasy. Alternatively, many drug eruptions are mediated by immunologic mechanisms. Generally, these eruptions are hypersensitivity reactions and are classified by the Gell and Coombs classification of hypersensitivity: types I to IV. For example, although the classic Gell-Coombs type IV category is a contact dermatitis, where sensitization is entirely limited to the skin, it appears that type IV reactions may also be responsible for some delayed cutaneous eruptions, including antibiotic-induced mobilliform exanthems and acute generalized exanthematous pustulosis.⁶ These Gell and Coombs reactions are described further in Chapter 48.

The diagnosis of a drug-induced eruption begins with a careful history and physical examination. The clinician should evaluate the timeline of initiation of the medication as it relates to development of the rash. Frequently, chronology is the most helpful factor in correctly diagnosing a drug reaction. Most reactions occur within 1 to 3 weeks of starting a new medication and resolve when the medication is fully excreted or metabolized. However, reactions may occur earlier if the patient is being re-exposed to the drug. An accurate description of the eruption is extremely important, including the morphology and distribution of the rash. Additionally, the patient’s current and recent medication list, including over-the-counter drugs, should be carefully reviewed for possible offending agents. In general, diagnostic tests are of limited value in the evaluation of drug eruptions, though should be considered to assess concurrent systemic reactions or dysfunction associated with the immunologic processes. For instance, the determination of drug hypersensitivity syndrome may require screening of organ systems by blood tests, radiographic imaging, or other physiologic testing. Skin biopsy may be helpful in categorization of drug-associated rashes, and can assist with the diagnosis of urticaria, exanthema, erythema multiforme, toxic epidermal necrolysis, and other entities in the differential diagnosis, such as graft vs. host disease. Radioallergosorbent testing (RAST), skin testing, and patch testing may be helpful in selected cases. Additionally, for a subset of patients with non-serious reactions, rechallenge with the medication may be appropriate.^6,7

EXANTHEMATOUS DRUG ERUPTIONS

An exanthem is the most common type of cutaneous drug eruption. The terms maculopapular and morbilliform (“measles-like”) are also often used to describe this class of drug rash. The eruption is characterized by pruritic, red- to salmon-colored macules or papules that at times coalesce into plaques (Figure 63-1). The lesions tend to be bilateral and symmetrical; they generally appear on the trunk initially and then spread peripherally to the extremities. They may spare the face, palms, and soles, but this is inconsistent. A long list of drugs may cause exanthematous eruptions (Table 63-1), but penicillin antibiotics are among the most frequently implicated agents. The eruption classically appears 7 to 14 days after the start of a new medication, although it may appear sooner or later. The presence of a viral infection is thought to increase the likelihood of an exanthematous drug eruption. The most well-recognized example occurs in patients with mononucleosis who experience a morbilliform eruption when exposed to aminopenicillin agents (e.g. amoxicillin).

The most common differential diagnosis of an exanthematous drug eruption is primary viral exanthems, although other conditions to be considered include eczematous dermatitis and graft-versus-host disease, among others. Viruses often cause rashes identical to those of drug eruptions. If histopathology is available, the presence of an eosinophilic infiltrate supports a drug etiology, but the findings are generally nonspecific. Drug hypersensitivity syndrome (see discussion later in this chapter) can also initially present with an exanthematous rash, although these patients typically have high fever, characteristic facial edema, eosinophilia, and other evidence of organ system involvement.

The mechanism behind the development of exanthematous drug eruptions is unclear, even though a T-cell–mediated process seems likely based on the time delay between exposure and the development of symptoms. It appears, however, that this may not be a classic Gell and Coombs type IV reaction because it does not consistently occur on rechallenge.

Exanthematous eruptions typically last days to weeks but almost universally resolve after removal of the offending agent. Time to resolution is dependent on a variety of factors, including the half-life of the involved drug. Specific therapeutic interventions are not required, but topical corticosteroids may be useful in providing symptomatic relief, and antihistamines may be helpful for relief of itching. An exanthematous reaction is not necessarily an absolute contraindication to future use of the drug, although many patients will experience recurrence of the rash with rechallenge. Therefore, in the majority of cases, the patient should be considered “allergic” to the medication. However, one study shows that such drug “allergies” may be overdiagnosed. In a prospective study of children presenting with maculopapular or delayed-onset urticarial rashes thought to be due to β-lactam antibiotics, oral challenge test (OCT) only reproduced a skin rash in 6.8% of patients.⁸ Blood and patch testing provided no additional useful information in that study.⁸ The authors concluded that β-lactam allergy is overdiagnosed and OCTs may be useful in determining if a true allergy exists.⁸

FIXED DRUG ERUPTION

A fixed drug eruption presents as a distinct lesion or lesions after systemic drug exposure. It is often underdiagnosed, which leads to recurrences when and if the drug is readministered. This eruption generally appears as sharply circumscribed, round to oval patches or plaques that may be single or multiple (Figure 63-2). The lesions are usually asymptomatic or only mildly pruritic. The eruption typically develops within 1 to 2 weeks of starting a new medication. The lesions may be red, gray, violaceous, or brown, and a central vesicle or bullae may be present. They tend to progress from erythematous to hyperpigmented. The rash may occur anywhere on the body, but the most common locations are the face, lips, hands, feet, and genitalia. A classic characteristic of a fixed drug eruption is that when patients are rechallenged with the offending medication, the lesion reappears in the same anatomic location and tends to appear much more rapidly, even within hours of taking the medication.⁹ The most common agents implicated in fixed drug eruptions include sulfonamides, tetracyclines, nonsteroidal anti-inflammatory drugs (NSAIDs), laxatives containing phenolphthalein, barbiturates, and carbamazepine, although a large number of other medications have been reported (Table 63-2).^10-13 Cross-reactivity may occur within a class of similar drugs. Biopsy of an early lesion of a fixed drug eruption reveals a lichenoid infiltrate, hydropic degeneration of the basal cell layer, and dyskeratotic keratinocytes. A later-stage biopsy will reveal large amount of melanin within macrophages in the upper dermis.¹⁴

The differential diagnosis includes an insect bite when the lesion is solitary and urticaria and erythema multiforme when multiple lesions are present. Diagnosis may be aided by biopsy. If the diagnosis is unclear, the physician may choose to rechallenge the patient with the medication.

Treatment involves removal of the offending agent. The eruption generally resolves after discontinuation of the medication, but hyperpigmentation in the area may persist for months to years. The cause of the disorder is unknown, although familial cases have been described, as well as an association with HLA-B22.¹⁵

PHOTOSENSITIVITY REACTIONS

Photosensitivity reactions, including both phototoxic and photoallergic reactions, comprise up to 8% of cutaneous drug reactions.¹³ Phototoxic reactions are dose dependent and non-immunologic.¹³ Prior sensitization is not required. Commonly implicated drugs include tetracyclines (most significantly doxycycline), psoralens, NSAIDs, griseofulvin, amiodarone, fluoroquinolones, antipsychotic agents, and voriconazole.^13,16 Clinically, this typically presents as an exaggerated sunburn in sun-exposed areas within hours to 1 day of sunlight exposure.¹³ Additionally, phototoxic reactions secondary to tetracyclines have been associated with onycholysis.¹³

In contrast, photoallergic reactions require sensitization and present as eczematous, pruritic eruptions, with or without papulovesicles, in sun-exposed areas 1 to 14 days after sunlight exposure.¹³ Commonly implicated medicines include thiazide diuretics (may appear lichenoid clinically), griseofulvin, sulfonamides, sulfonureas, quinidine, and pyridoxine.¹³ NSAIDs, particularly naproxen, have also been implicated in pseudoporphyria, a specific type of photosensitivity.¹³ In addition to discontinuing the offending agent in severe cases, treatment typically consists of symptomatic management and sun protection/sun avoidance.¹³

URTICARIAL DRUG ERUPTIONS

Urticaria is among the most frequent of the drug eruptions. It may be IgE-induced, such as with antibiotics, or non–IgE-induced, such as a pseudoallergic reaction seen with NSAIDs or opiates. Intensely pruritic erythematous, edematous papules, and plaques characterize an urticarial rash (Figure 63-3). Lesions occur anywhere on the body, including the palms and soles, and occasionally have a “dusky” appearance or central pallor. The rash may appear within minutes of exposure to the offending agent or as long as several days later. Each individual hive usually persists for a period of hours but less than 24 hours. If lesions remain fixed for longer than 24 hours, other diagnoses should be entertained, such as urticarial vasculitis, erythema multiforme, or acute hemorrhagic edema of infancy. Additional differentials include serum sickness-like reaction and acute annular urticaria. Annular urticaria, also known as urticaria multiforme, is a common variant hypersensitivity reaction in children presenting with arcuate, polycyclic annular lesions, often with acral edema.¹⁷ Lesions may have a dusky appearance, often causing concerns of a diagnosis of erythema multiforme, though the absence of target lesions and central blisters or necrosis will differentiate these conditions.

A number of inflammatory mediators are thought to be involved in the pathogenesis of urticaria. Release of histamine from mast cells plays an important role. Additional mediators that may be involved include prostaglandins, leukotrienes, neutrophil and eosinophil chemotactic factors, platelet-activating factor, interleukin-1, and kinins. Urticarial lesions occur when these inflammatory mediators cause a local increase in the permeability of capillaries in the skin with subsequent dermal edema.

Urticaria may be acute or chronic and is classified as the latter when persistent beyond 6 weeks. Many drugs can induce acute urticaria. Antibiotics are commonly implicated, with penicillin being the most frequent. Other important agents include cephalosporins, sulfonamides, and tetracyclines. The urticaria caused by factors other than drug exposure is morphologically identical. Such factors include infection, autoimmune disease, temperature changes, pressure, sunlight, and exercise, among others.¹⁸

The first line of therapy is removal of the offending agent. Oral antihistamines are the recommended therapy for uncomplicated acute urticaria and are generally sufficient to control symptoms. Depending on the individual situation, both sedating and nonsedating H₁ blockers may be appropriate. There is also evidence to support adjunctive use of H₂ blockers. Patients with very severe acute urticaria may occasionally require systemic corticosteroids, although the vast majority can be managed with antihistamines alone. Allergy to the medication should be documented in the medical record.¹⁹