Episode 230: Drug Reaction with Eosinoph...

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DRESS vs SJS/TEN vs Anaphylaxis at a Glance

Background

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): drug exposure → rash + systemic involvement (liver, kidneys, lungs, heart, pancreas)
• Systemic dz is what makes pts critically ill → think ICU. Mortality up to ~10% in retrospective series; 1.7% in a prospective multinational registry (SEAIC 2020)
• Eosinophilia not universal → also called drug-induced hypersensitivity syndrome (DIHS)
• Rare, but can’t-miss

Pathophysiology

• Type IV, T-cell–mediated delayed hypersensitivity; Th2 cytokines (IL-5) recruit eosinophils (SEAIC 2020)
• Not IgE-mediated → don’t expect an anaphylaxis-style response to epi
• Exact cause unclear. Two leading contributors:
  • Genetics: HLA polymorphisms, e.g., HLA-A*31:01 w/ carbamazepine DRESS (CPIC 2018)
  • Herpesvirus reactivation (HHV-6, HHV-7, EBV, CMV) in up to ~75%; cause vs consequence still unsettled

The Culprit Drugs

• 200+ drugs implicated; a short list does most of the damage:
  • Allopurinol, vancomycin, TMP-SMX & other sulfas
  • Aromatic antiepileptic drugs (AEDs): phenytoin, phenobarbital, carbamazepine, lamotrigine
  • Less common: NSAIDs, antiretrovirals, ACEi, CCBs, atypical antipsychotics
• Latency: classically 2–8 wks after starting the drug; re-exposure → hrs to days (SEAIC 2020)
• Med rec has to look back: SEAIC treats any drug started <6 mo & stopped <14 d before onset as a compatible suspect

Clinical Presentation

• Rash: itchy morbilliform eruption → diffuse, confluent, infiltrated erythema, often >50% BSA; can be tender. Blisters & sloughing rare
• Facial edema: classic
• Lymphadenopathy (LAD), fever
• Mucosa: mild, ~half of pts, usually 1 site (mouth/pharynx)
• Organs: liver most common (~75%) & the leading cause of death; kidney (esp. allopurinol), lungs, heart (myocarditis), pancreas (SEAIC 2020)
• Sick end of the spectrum: shock, hypoxemia, AMS, multi-organ failure

Diagnosis

Clinical Dx

• Built on hx (new drug, wks back) + exam. Labs & biopsy support it; neither should hold up tx

Sorting the Dangerous Rashes

• Anaphylaxis: min–hrs after exposure; urticaria, angioedema. No response to epi → reconsider
• Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): blisters, sloughing, severe hemorrhagic mucosal dz, Nikolsky pos
• Pemphigus vulgaris: flaccid bullae; Nikolsky & Asboe-Hansen pos
• Necrotizing soft tissue infection: pain out of proportion, crepitus
• Nikolsky: pressure on skin → epidermis shears/sloughs
• Asboe-Hansen: pressure on a bulla → fluid spreads laterally past its border
• Points to DRESS: delayed onset after a new drug, facial edema, LAD, no blistering/sloughing, mild mucosal dz

Labs

• Gauge severity/end-organ damage, not the dx. Can be normal early → don’t use to exclude
• SEAIC admission panel: CBC w/ diff (eos, atypical lymphs), LFTs/INR, Cr + UA, lipase, CK, troponin (SEAIC 2020)
• Delphi: ECG for all; troponin/BNP only if cardiac involvement suspected (Delphi consensus 2024). Crashing pt → send the full panel up front
• Delphi grades severity on liver, kidney & blood derangement; any other organ involved = severe (Delphi consensus 2024)

RegiSCAR Score

• Quantifies suspicion (MDCalc): <2 excluded, 2–3 possible, 4–5 probable, >5 definite (SEAIC 2020)
• Early on, eos may not have appeared & a course ≥15 d can’t be confirmed (scores −1) → a low ED score doesn’t exclude

Management

Stop the Drug, Hold New Ones

• Stop every possible culprit
• Careful adding drugs to a sick pt; SEAIC specifically avoids empiric abx (esp. amoxicillin) & NSAIDs acutely (SEAIC 2020)
• Aromatic AED cross-reactivity 40–80% → avoid phenytoin, phenobarbital, lamotrigine, oxcarbazepine; benzos considered safe

Resuscitate

• ABCs first, like any crashing pt
• Epi for any concern of anaphylaxis: unlikely to hurt, may help
• IVF titrated to dynamic measures & UOP; pressors for refractory shock
• Large BSA → burn-like insensible losses; extensive erythroderma/exfoliation may need a burn center (SEAIC 2020)
• Anticipate RRT, intubation, central & arterial lines

Steroids

• Prednisone equivalent 0.5–1 mg/kg/day; start early
• Prolonged taper (wks–mos) to prevent relapse (~10–15%); Delphi: 6 wk–3 mo for mild/moderate, 3–6 mo for severe (Delphi consensus 2024)
• Delphi: steroids for all confirmed DRESS; very high-potency topicals for mild, topicals or systemic for moderate, systemic for severe
• Don’t wait for consultants or biopsy if suspicion is high & pt unstable

Refractory Disease

• Usually ICU-initiated: cyclosporine, anti–IL-5 antibodies, IVIG, JAK inhibitors; antivirals w/ viral reactivation
• Delphi backs cyclosporine, anti–IL-5/IL-5R & IVIG for steroid-refractory dz; ganciclovir/valganciclovir for high CMV load (Delphi consensus 2024)

Disposition

• ICU; burn center if extensive skin involvement
• All hands early: derm, nephro, ID (viral reactivation), ophtho (ocular involvement), critical care

The Case

• 61M w/ hx of seizures, started carbamazepine 6 wks ago
• Itchy rash on arms ~2 wks ago → trunk, face, oral mucosa; worsening. Family calls 911 for AMS
• EMS: hypotensive, diffuse red rash → EpiPen, no improvement
• ED: hypotensive, tachycardic, tachypneic, hypoxemic on RA. Diffuse tender, blanching erythema; no blisters, sloughing, vesicles, bullae, or petechiae; Nikolsky & Asboe-Hansen neg; facial edema; cervical LAD
• Why DRESS: aromatic AED, ~4-wk latency, facial edema, LAD, no epidermal detachment, no response to epi

Pitfalls

• Anchoring on anaphylaxis when epi isn’t working
• Missing the culprit because it started wks before the rash
• Using normal early labs to exclude DRESS
• Holding steroids for consultants or biopsy in an unstable pt
• Reflexive new drugs: empiric abx, NSAIDs, another aromatic AED
• Calling consultants late

Take-Home Points

1. DRESS is systemic. Diffuse rash + hypotension + liver or kidney injury → keep DRESS high on the ddx.
2. Look back weeks to months. Allopurinol, sulfa drugs & anticonvulsants are the classic offenders.
3. Let the exam sort the rash. Sloughing skin and severe hemorrhagic mucosal dz point to SJS/TEN.
4. Steroids early. High suspicion + unstable pt → start them; don’t wait on consultants or a biopsy.
5. Trust your resuscitation skills. Supportive EM/ICU care carries these pts.

Links & References

DRESS Guidelines & Consensus

• Brüggen MC, et al. Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus. JAMA Dermatol. 2024;160(1):37–44. (54-expert international panel: severity grading, steroid taper, refractory tx) — doi.org/10.1001/jamadermatol.2023.4450
• Cabañas R, et al. Spanish Guidelines for Diagnosis, Management, Treatment, and Prevention of DRESS Syndrome. J Investig Allergol Clin Immunol. 2020;30(4):229–253. (SEAIC: organ-specific steroid dosing, AED cross-reactivity, RegiSCAR) — doi.org/10.18176/jiaci.0480
• Mizukawa Y, et al. Guidelines for the management of drug-induced hypersensitivity syndrome 2023. J Dermatol. 2025;52(3):e189–e209. (Japanese MHLW study group; DIHS & HHV-6) — doi.org/10.1111/1346-8138.17609
• Ingen-Housz-Oro S, et al. French national protocol for diagnosis and management of drug reaction with eosinophilia and systemic symptoms (DRESS) in adults and children. Ann Dermatol Venereol. 2025;152(3):103381. — doi.org/10.1016/j.annder.2025.103381

Related Society Guidelines

• Creamer D, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. 2016;174(6):1194–1227. (British Association of Dermatologists) — doi.org/10.1111/bjd.14530
• Golden DBK, et al. Anaphylaxis: A 2023 practice parameter update. Ann Allergy Asthma Immunol. 2024;132(2):124–176. (AAAAI/ACAAI Joint Task Force) — doi.org/10.1016/j.anai.2023.09.015
• Khan DA, et al. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. 2022;150(6):1333–1393. (AAAAI/ACAAI Joint Task Force) — doi.org/10.1016/j.jaci.2022.08.028
• Phillips EJ, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther. 2018;103(4):574–581. (CPIC) — doi.org/10.1002/cpt.1004

Calculator

• RegiSCAR Score for DRESS — MDCalc