Keywords

Overview

  • Drug rash with eosinophilia and systemic symptoms (DRESS) is a systemic drug hypersensitivity reaction ranging in clinical presentation from more mild (rash, transient eosinophilia, lymphadenopathy) to severe (multi-organ dysfunction)

    • Encompassing term including: Anti-convulsant hypersensitivity syndrome, drug-induced hypersensitivity syndrome, drug-induced delayed multiorgan hypersensitivity syndrome

  • Mortality rate is 10%, with most patients dying from fulminant liver failure or cardiac complications

  • Most common offending agents: Antiepileptic drugs (carbamazepine, phenytoin, lamotrigine), Sulfa-based antimicrobials (trimethoprim/sulfamethoxazole, sulfasalazine), NSAIDs, minocycline, allopurinol, abacavir, and nevirapine

  • Latency period: 2–6 weeks from drug exposure to disease onset

  • Symptoms may persist for weeks following discontinuation of the inciting medication

  • The exact mechanism of pathogenesis is unknown but leading theories include:

    • Drug-induced transient host lymphocyte suppression, allowing latent virus reactivation

    • EBV, CMV, HHV7, and particularly HHV6 reactivation can be seen in as many as 75% of cases

    • Another possible contributor to disease is a deficiency in detoxifying enzymes (such as epoxide hydrolase) which prevents proper clearing of drug metabolites with their accumulation resulting in an immunologic response

Fig. 6.1
figure 1

Drug reaction with eosinophilia and systemic symptoms (DRESS): (a) A full-body morbilliform eruption, often deeply erythematous, is typical of DRESS syndrome. (b, c) Erythema and swelling of the face are typical findings in DRESS but may be subtle in those with darker skin (c). (d) Patients may develop impetigo-like crusting, as is seen here on the chin of a patient with DRESS syndrome. (e) This patient with DRESS from phenytoin exhibits extensive impetigo-like crusting of the chin. (f) Erythematous macules and papules coalescing into larger patches and plaques can occur in DRESS.

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Fig. 6.2
figure 2

Drug reaction with eosinophilia and systemic symptoms (DRESS) (20×, 40×; H&E): (a) The histologic presentation of DRESS is variable. Features can include epidermal spongiosis, interface dermatitis with vacuolar change, perivascular lymphocytic infiltration, and eosinophils. (b) The perivascular lymphocytes may appear large and atypical.

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Clinical Presentation

  • Extensive deep red-erythematous morbilliform eruption involving the face with facial and sometimes acral swelling (Fig. 6.1)

    • The facial edema is a prominent and an essential diagnostic feature as most morbilliform drug eruptions spare the face

    • There is typically periorbital sparing (relative pallor), and occasionally impetigo-like crusting around the chin

  • Rarely there is isolated mucous membrane inflammation, and vesicles/bullae, pustules, target lesions, and purpura have been reported

  • There are no validated, internationally agreed upon diagnostic criteria, but suggested criteria include:

    • Drug rash

    • Fever >38 °C

    • Lymphadenopathy

    • Peripheral eosinophilia (>1000–1500 absolute eosinophilia), or atypical lymphocytosis

    • Internal organ involvement (liver, kidneys, lungs, heart)

    • HHV6 PCR may be elevated but testing is not widely available

  • Despite its name, eosinophilia is not always present and is not a requirement for diagnosis

    • 90% of DRESS cases will have associated eosinophilia

    • Atypical lymphocytosis may be seen as in a viral syndrome

Histopathology

  • Histology for DRESS is nonspecific and can include the following (Fig. 6.2):

    • Lymphocytic infiltrate of the papillary dermis may be band-like or perivesicular and may contain eosinophils

    • Dyskeratotic keratinocytes, vacuolar change in basilar keratinocytes, “activated” lymphocytes, and eosinophils may be seen at the dermal/epidermal junction and around follicles

    • May see papillary dermal edema and epidermal spongiosis with subcorneal pustules

    • Variable parakeratosis

Differential Diagnosis

  • Morbilliform drug eruption : spares the face, less deep-red, no systemic inflammation

  • Viral exanthem : varied depending on the virus, but facial involvement is less common

  • Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN): DRESS-SJS overlap can occur; in SJS, mucositis is prominent, and cutaneous lesions have dusky targetoid macules

  • Acute generalized exanthematous pustulosis (AGEP) : DRESS-AGEP overlap can occur; in AGEP, fine pustules are present

  • Staphylococcal scalded skin syndrome : diffuse and flexural superficial desquamation

  • Kawasaki disease : red tongue, acral and intertriginous peeling, conjunctivitis

  • Graft-versus-host disease : bilirubinemia and diarrhea can help distinguish; cutaneous GVHD often displays a fine scale and may be folliculocentric, often involves the ears

Work-Up

  • Complete blood cell count with differential, liver function tests, serum creatinine level, urinalysis to evaluate for extracutaneous involvement

  • Organ specific indications depending on symptomatology and presentation:

    • Low threshold to consider cardiac evaluation (EKG, echocardiogram) and pulmonary imaging

    • Small case series suggest specific drugs may be more likely to lead to specific organ dysfunction (allopurinol-renal, minocycline-pulmonary, etc.)

  • Patients are at risk for delayed autoimmunity, including thyroid disease and diabetes, and should have thyroid function and glucose testing regularly for 3–6 months post-DRESS onset

Management

  • Removal of offending agent and labeling patients allergic; re-exposure may be fatal

    • DRESS may have a genetic component, and ideally patients’ first degree relatives will avoid similar agents

    • Avoid cross-reacting drugs, which is a particular issue with anti-epileptic agents

  • Systemic corticosteroids at moderately high to high doses (e.g. prednisone 1-2mg/kg per day)

    • Median duration of systemic corticosteroids is 50 days

    • Patients often require close follow-up for delayed autoimmunity, flares of DRESS with steroid taper, and steroid-related adverse effects

  • Supportive care