Drug reaction with eosinophilia and systemic symptoms

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Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, potentially life-threatening adverse drug reaction caused by delayed hypersensitivity to medication (most commonly anticonvulsants or antimicrobials). Risk factors include immunosuppression, human herpesvirus-6 (HHV-6) infection, and pharmacogenetic susceptibility. DRESS is characterized by delayed onset (2–8 weeks after drug exposure), waxing and waning symptoms, and a prolonged course. Symptoms typically include fever, diffuse rash, facial edema, lymphadenopathy, and internal organ involvement. Peripheral blood eosinophilia is common but not universally observed. Diagnosis is based on medication history, physical exam, blood tests, and skin biopsy. Management typically involves prompt withdrawal of all possible triggering agents, supportive care, and guidance from specialists for any affected organ. Patients should be carefully monitored for internal organ involvement and complications. The liver is the most commonly affected organ, usually with asymptomatic hepatic inflammation; necrosis and liver failure are also possible and the leading cause of death from DRESS.

• Drug reaction with eosinophilia and systemic symptoms (DRESS): a rare, potentially fatal immune-mediated adverse drug reaction characterized by cutaneous manifestations and internal organ involvement ^[2][3]

• Common triggers ^[2][4]
  • Antiepileptics: lamotrigine, phenytoin, carbamazepine, levetiracetam, phenobarbital
  • Antimicrobials: dapsone, sulfamethoxazole/trimethoprim; , piperacillin/tazobactam, vancomycin, minocycline; , abacavir , nevirapine, sulfonamides
  • Other: allopurinol, rifampicin, sulfasalazine
• Risk factors ^[2]
  • Immunosuppression
  • Pharmacogenetic susceptibility ^[5]

The pathogenesis of DRESS is not completely understood. Potential mechanisms include: ^[2]

• Delayed hypersensitivity reaction (type IV HSR) to drug metabolites
• Primary infection with or reactivation of HHV-6 ^[6]

Clinical manifestations in DRESS have a delayed onset (typically 2–8 weeks) after exposure to the offending agent. In rare cases in which a patient who has recovered from DRESS is reexposed to the triggering agent, the symptom onset is much faster (hours or days). ^[4]

• Systemic symptoms ^[4][6]
  • Fever, typically high (> 38.5°C/101.3°F) and spiking
  • Lymph node enlargement
  • Dysphagia
• Diffuse rash
  • Typical manifestation: generalized morbilliform pruritic rash with cephalocaudal progression
  • Alternative manifestations: infiltrative papules and plaques with changes that are purpuric, urticarial, lichenoid, pustular, bullous, target-like, or eczematous ^[7]
• Facial edema ^[6]
• Signs of internal organ involvement
  • Liver (most common): can be asymptomatic or manifest as hepatomegaly or alterations in liver chemistries
  • Renal: decreased GFR, proteinuria, acute interstitial nephritis
  • Pulmonary: pneumonitis
  • Cardiac and muscle: myocarditis, muscle pain, and/or weakness
  • Pancreas: can be asymptomatic elevation in amylase and/or lipase, or pancreatitis
  • Multiorgan failure in severe cases

The key features of DRESS are fever, diffuse skin lesions, and symptoms of internal organ involvement. ^[2][4][6]

Symptoms in DRESS usually manifest 2–8 weeks after drug exposure and often have a protracted clinical course with waxing and waning of symptoms even after the triggering agent is withdrawn. ^[2][4][6]

Approach ^[4][7]

• Consider DRESS in patients with suggestive clinical features (e.g., fever, diffuse rash).
• Obtain a detailed history, with emphasis on the following:
  • Medications and supplements started within the last 2–8 weeks
  • Family history of drug-induced severe cutaneous adverse reactions
• Obtain laboratory studies and a skin biopsy.
• Assess for internal organ involvement.
• Confirm diagnosis using a validated score (e.g., RegiSCAR).

Early diagnosis is critical to reducing morbidity and mortality, although death can occur even with proper management. ^[4]

Laboratory studies ^[4]

• Routine laboratory studies
  • CBC: eosinophilia, thrombocytopenia, atypical lymphocytes often present
  • BMP, liver chemistries, amylase, lipase
  • Troponin T, CPK
  • Urinalysis
• Exclude alternative diagnoses
  • Serology: viral hepatitis panel, parvovirus B19, HSV–1, HSV–2, chlamydia, mycoplasma
  • Blood culture
  • Antinuclear antibodies
• Screen for viral reactivation: baseline serology and PCR for HHV–6, HHV–7, CMV, EBV ^[4]

Skin biopsy ^[4][8]

Biopsy findings in DRESS are typically nonspecific and therefore not required for diagnosis.

• Consider in all patients with suspected DRESS ^[4][8]
• Findings can include:
  • Lymphocytic infiltration
  • Eosinophils
  • Dermal edema

Biopsy is not required for diagnosis; findings in DRESS are typically nonspecific, so the procedure is most helpful for ruling out other etiologies of rash.

Evaluation for internal organ involvement ^[3]

The majority of patients (∼ 90%) have involvement of at least one organ/system, most commonly hepatic inflammation. Evaluate all patients for liver and kidney injury and consider other tests depending on the presence of clinical or laboratory features suggestive of involvement of other organs.

• Liver injury ^[4]
  • ALT or conjugated bilirubin ≥ 2 × ULN
  • OR AST, total bilirubin, AND alkaline phosphatase all ≥ 2 × ULN
• Acute kidney injury (AKI)
  • Creatinine ≥ 1.5 × the base value for the patient
  • OR any of the following: ↓ GFR, hematuria, significant proteinuria
• Others
  • Myocarditis: Suspect in patients with hypotension, tachycardia, chest pain, dyspnea, or palpitations.
    • Laboratory studies: ↑ CPK and/or ↑ CPK–MB, ↑ troponin
    • Other tests: ECG changes , abnormal cardiac imaging (e.g., cMRI), possibly endomyocardial biopsy
  • Lung injury: Suspect in patients with cough and/or dyspnea.
    • Consider arterial blood gas, bronchoalveolar lavage, or biopsy.
    • Imaging may show interstitial involvement.
  • Skeletal muscle injury: Suspect in patients with pain or weakness.
    • Laboratory studies: ↑ CPK and/or ↑ CPK–MB
  • Involvement of the GI tract, pancreas, spleen, CNS, and thyroid gland is also possible.

Diagnostic criteria ^[3][4]

Approach ^[4]

• Stop all suspected offending agents immediately (i.e., drug withdrawal).
• Determine severity based on internal organ involvement ^[4][9]
  • Nonserious DRESS: No organ involvement, OR AKI stage 1, OR mild liver injury
  • Serious DRESS: AKI stage 2 and above, OR moderate to severe liver injury , OR involvement of other organs
• Start corticosteroids (topical or systemic based on severity).
• Provide supportive care as needed.
• Post-acute recovery: Consider referral to an allergist and monitoring for autoimmune sequelae. ^[4][7]

Withdrawal of all suspected triggering medications is the cornerstone of management for patients with suspected DRESS. Delays in medication withdrawal are associated with a prolonged course and worse prognosis. ^[4]

Avoid empiric NSAIDS and empiric antibiotics (especially amoxicillin) during the acute period as they may prolong or worsen the course. ^[4]

Nonserious DRESS ^[4]

• Admit all patients with nonserious DRESS to acute care. ^[4]
• Start therapy with topical corticosteroids (high or very high potency, e.g., clobetasol ). ^[4]
• Monitor for progression to serious DRESS and escalate therapy if needed.
  • Evaluate for clinical signs and symptoms of organ involvement daily.
  • Trend baseline laboratory parameters at least every 72 hours.
    • For mild liver injury, reevaluate liver chemistries every 48–72 hours.
    • For stage 1 kidney injury, reevaluate kidney function every 48–72 hours.

Serious DRESS ^[4]

• Admit all patients with serious DRESS.
  • Severe organ involvement: Consider ICU admission.
  • Severe cutaneous involvement : Consider admission to a burn unit.
• Requires multidisciplinary management; consult specialists for affected organs.
• Perform clinical and laboratory monitoring for new or worsening organ involvement at least every 24 hours.
• Start pharmacological treatment in consultation with a specialist.
  • First line: systemic corticosteroids (e.g., prednisone ) with a prolonged taper ^[4]
  • Refractory cases or contraindications to corticosteroids: Consider cyclosporine, cyclophosphamide, plasmapheresis, or IVIG. ^[6]
  • In the case of severe complications of viral reactivation (e.g., HSV encephalitis, CMV colitis): Consider ganciclovir or valganciclovir.

Liver failure secondary to hepatic necrosis is the leading cause of death from DRESS. For patients with severe liver injury, consult hepatology early to evaluate for liver transplant candidacy. ^[4]

Supportive care

• Start IV fluids and replace electrolytes.
• Consider specialized nutrition support depending on disease severity.
• Consider DVT prophylaxis and gastrointestinal prophylaxis.
• Optimize pain management and use antipyretics as needed.
• Provide skin care and topical treatments.

• DRESS is fatal in ∼10% of cases. ^[4]