A 38-year-old woman develops fever, rash, hepatitis, and eosinophilia 3 weeks after starting an antituberculous regimen. Which drug in the regimen is the most likely culprit for this drug reaction pattern (DRESS syndrome)?

Explanation

## DRESS Syndrome — Drug Reaction with Eosinophilia and Systemic Symptoms ### Clinical Presentation **Key Point:** DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe, delayed-type hypersensitivity reaction characterized by: - Fever and rash (typically maculopapular, often with facial edema) - Lymphadenopathy - Hepatitis (elevated transaminases, sometimes hepatic failure) - Eosinophilia (≥1,500/μL) and/or atypical lymphocytes - Onset: 2–8 weeks after drug initiation ### Drugs Most Commonly Associated with DRESS | Drug | Incidence | Notes | | --- | --- | --- | | **Aromatic antiepileptics** | Very high | Phenytoin, carbamazepine, phenobarbital | | **Isoniazid** | High | Leading cause among antituberculous drugs | | Allopurinol | High | Especially in HLA-B*5801 carriers | | Sulfonamides | Moderate | TMP-SMX | | Minocycline | Moderate | Delayed hypersensitivity | | NSAIDs | Low | Rare | **High-Yield:** Among antituberculous drugs, **isoniazid** is the most common culprit for DRESS syndrome. Rifampicin and pyrazinamide rarely cause DRESS; ethambutol is associated with optic neuritis, not DRESS. ### Pathophysiology 1. **Metabolic activation:** Isoniazid is acetylated to reactive intermediates (slow acetylators at higher risk) 2. **Hapten formation:** Reactive metabolites bind to proteins 3. **T-cell activation:** Delayed-type hypersensitivity (Type IV) response 4. **Viral reactivation:** HHV-6 and EBV reactivation may amplify immune response **Clinical Pearl:** Slow acetylators of isoniazid (genetic polymorphism in NAT2) have higher risk of DRESS and other hypersensitivity reactions. This is why isoniazid-induced hepatitis and DRESS are more common in certain populations. ### RegiSCAR Scoring System **Mnemonic:** **RegiSCAR** criteria for DRESS diagnosis: - **R**ash (typical or atypical) - **e**osinophilia (≥1,500/μL) - **g**eneral features (fever, lymphadenopathy) - **i**nvolvement of internal organs (hepatitis, nephritis, pneumonitis) - **S**everity (mild, moderate, severe) - **C**ourse (self-limited vs. prolonged) - **A**typical lymphocytes - **R**eactivation of HHV-6/EBV **Warning:** Do not confuse DRESS with: - **Drug-induced lupus** (isoniazid can cause this too, but lupus lacks eosinophilia and hepatitis is less prominent) - **Acute drug fever** (occurs within days, not weeks; no rash or eosinophilia) - **Serum sickness-like reaction** (immune complex-mediated, occurs 7–21 days, resolves faster) ### Management 1. **Immediate:** Discontinue the offending drug (isoniazid) 2. **Systemic corticosteroids:** Prednisolone 0.5–1 mg/kg/day, tapered over 6–12 weeks 3. **Supportive care:** Monitor liver function, manage fever 4. **Restart TB therapy:** Use alternative regimen (e.g., rifampicin, pyrazinamide, ethambutol + fluoroquinolone or linezolid) [cite:KD Tripathi 8e Ch 10; Harrison 21e Ch 375]