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DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

Overview

DRESS syndrome (also called drug‑induced hypersensitivity syndrome, DIHS) is a rare but potentially life‑threatening adverse drug reaction. It is characterized by a triad of:

• Skin eruption (often extensive and polymorphic)
• Eosinophilia or atypical lymphocytosis in the blood
• Involvement of internal organs such as the liver, kidneys, lungs, or heart.

The condition typically appears 2–8 weeks after the start of the offending medication, which is a longer latency than most other drug rashes.

Who it affects: DRESS occurs most often in adults (median age ≈ 45 years) but can affect children and the elderly. Female patients are slightly more likely to develop DRESS (female‑to‑male ratio about 2:1)【1】.

Prevalence: The exact incidence is unknown because cases are often under‑reported, but epidemiologic studies estimate 1–2 cases per 1 000 – 10 000 drug exposures, varying by region and drug class【2】.

Symptoms

The clinical picture evolves over several weeks and may involve multiple organ systems. Below is a comprehensive symptom list with brief descriptions.

Cutaneous manifestations

• Maculopapular rash – diffuse, often starting on the face/neck and spreading to trunk and limbs.
• Facial edema – puffiness, especially around the eyes (sometimes called “angel‑wing” edema).
• Target or DRESS‑specific lesions – erythematous plaques that can become bullous or necrotic.
• Peeling or desquamation – skin may slough after 2–3 weeks.
• Pruritus – itching is common and can be severe.

Hematologic abnormalities

• Eosinophilia – absolute eosinophil count >1.5 × 10⁹/L (often >5 × 10⁹/L).
• Atypical lymphocytes – larger cells with irregular nuclei.
• Thrombocytopenia or leukopenia – less common but may occur.

Systemic/Organ involvement

• Liver – hepatitis (↑ ALT/AST), jaundice; occurs in ~70% of cases.
• Kidneys – interstitial nephritis, acute renal failure.
• Respiratory – interstitial pneumonitis, pleural effusion, dyspnea.
• Heart – myocarditis, pericarditis, arrhythmias (rare but serious).
• Endocrine – thyroiditis, type‑1 diabetes onset.
• Gastrointestinal – nausea, vomiting, abdominal pain, pancreatitis.
• Neurologic – seizures, encephalitis, peripheral neuropathy (uncommon).

Other clinical clues

• Fever ≥38 °C (often >39 °C)
• Lymphadenopathy (enlarged lymph nodes)
• Delay between drug exposure and symptom onset (2–8 weeks) which helps differentiate DRESS from other drug eruptions.

Causes and Risk Factors

Common offending drugs

More than 50 medications have been implicated. The most frequent culprits include:

• Antiepileptics – carbamazepine, phenytoin, phenobarbital, lamotrigine
• Allopurinol – used for gout
• Sulfonamide antibiotics – sulfamethoxazole‑trimethoprim, sulfasalazine
• Antiretrovirals – abacavir, nevirapine
• Minocycline and other tetracyclines
• NSAIDs – especially those with sulfonamide structures

Genetic predisposition

Human leukocyte antigen (HLA) alleles increase susceptibility:

• HLA‑B*58:01 – strongly linked with allopurinol‑induced DRESS (especially in Asian populations).
• HLA‑A*31:01 – associated with carbamazepine‑induced DRESS.
• HLA‑B*13:01 – linked to dapsone‑induced hypersensitivity.

Genotyping before initiating high‑risk drugs is recommended in certain ethnic groups (e.g., HLA‑B*58:01 testing in Korean or Han Chinese patients before allopurinol)【3】.

Other risk factors

• Previous drug hypersensitivity reactions.
• Concomitant viral reactivation (HHV‑6, EBV, CMV) – viral reactivation can amplify immune response.
• Immunologic dysregulation (autoimmune disease, HIV infection).
• Female sex and age >30 years.

Diagnosis

Diagnosing DRESS is primarily clinical, supported by laboratory and sometimes imaging studies. No single test confirms the syndrome; instead, clinicians apply validated scoring systems.

Scoring systems

• RegiSCAR (European Registry of Severe Cutaneous Adverse Reactions) score – assigns points for fever, enlarged lymph nodes, eosinophilia, atypical lymphocytes, skin involvement, organ involvement, and exclusion of alternative diagnoses. A score ≥5 = “definite” DRESS; 4 = “probable”【4】.
• Japanese consensus group criteria – similar but requires HHV‑6 reactivation for a “definite” diagnosis.

Laboratory tests

• Complete blood count (CBC) – eosinophilia, atypical lymphocytes.
• Liver function tests (ALT, AST, bilirubin) – assess hepatic involvement.
• Renal panel (creatinine, BUN, electrolytes) – detect nephritis.
• Serum inflammatory markers (CRP, ESR) – usually elevated.
• Viral PCR for HHV‑6, EBV, CMV if suspicion of reactivation.

Imaging & other investigations

• Chest X‑ray or CT – evaluate pneumonitis or pleural effusion.
• Abdominal ultrasound or MRI – assess liver size, biliary dilation.
• Echocardiogram – if cardiac involvement is suspected (e.g., myocarditis).
• Skin biopsy (optional) – shows interface dermatitis with eosinophils; helpful to rule out other drug eruptions or autoimmune diseases.

Excluding mimickers

Conditions that can resemble DRESS include:

• Stevens‑Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)
• Acute viral exanthems (e.g., measles, EBV infection)
• Autoimmune connective‑tissue diseases (e.g., lupus)
• Hypereosinophilic syndrome

Treatment Options

Prompt identification and withdrawal of the offending drug is the cornerstone of therapy. Management thereafter focuses on controlling the immune reaction and supporting affected organs.

1. Immediate actions

• Discontinue the suspected drug – usually within 24 hours of suspicion.
• Document the drug allergy in the patient’s medical record and provide an emergency drug‑allergy card.

2. Pharmacologic therapy

Corticosteroids

• Systemic prednisone 1 mg/kg/day (or equivalent) is first‑line for moderate‑to‑severe DRESS.
• Typical taper: maintain high dose for 2–4 weeks, then slowly taper over 3–6 months to prevent relapse.
• Intravenous methylprednisolone (1–2 mg/kg/day) may be used for fulminant organ failure.

Alternative immunosuppressants

• Cyclosporine 3–5 mg/kg/day – useful when steroids are contraindicated or ineffective.
• Mycophenolate mofetil or azathioprine** – considered in steroid‑refractory cases.
• Intravenous immunoglobulin (IVIG) – 2 g/kg over 2–5 days; data limited but may help in severe skin involvement.

Targeted therapy for viral reactivation

• Antiviral agents (e.g., ganciclovir) are rarely used and only if active HHV‑6/CMV disease is documented.

3. Supportive care

• Fluid and electrolyte management for fever, vomiting, or renal involvement.
• Topical corticosteroids or emollients for skin comfort.
• Antipyretics (acetaminophen is preferred; avoid NSAIDs as they may worsen rash).
• Mechanical ventilation or renal replacement therapy if organ failure occurs.

4. Monitoring

Patients require close monitoring (often in a hospital setting):

• Daily CBC and liver/kidney panels for the first week, then at least twice weekly.
• Assess for new organ involvement during steroid taper.

Living with DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

Follow‑up care

• Regular outpatient visits for the first 6–12 months post‑episode.
• Long‑term liver function testing – delayed hepatitis can occur up to 3 months after drug cessation.
• Screen for autoimmune sequelae (e.g., thyroid disease) at 6‑month intervals.

Medication safety

• Carry a card or smartphone alert listing the drug(s) that triggered DRESS and the diagnosis.
• Inform all health‑care providers, including dentists, before any new prescription.
• Consider allergy testing (patch testing) after recovery, under specialist supervision, to clarify culprit agents.

Lifestyle adjustments

• Stay well‑hydrated and maintain a balanced diet to support liver and kidney recovery.
• Avoid alcohol and hepatotoxic substances for at least 3 months.
• Limit sun exposure while the skin is healing; use SPF 30+ sunscreen.
• Engage in gentle exercise as tolerated; avoid intense workouts if you have lingering fever or organ dysfunction.

Psychosocial support

The abrupt, severe nature of DRESS can cause anxiety or depression. Access to counseling, support groups, or a mental‑health professional is advisable.

Prevention

• Medication review – before starting high‑risk drugs, discuss alternatives with the prescriber.
• Pharmacogenomic testing – HLA‑B*58:01 for allopurinol, HLA‑A*31:01 for carbamazepine, especially in high‑risk ethnic groups (CDC & FDA recommendations)【5】.
• Slow titration – when possible, start at low doses and increase gradually, monitoring for early skin changes.
• Patient education – inform patients to report any rash, fever, or unusual symptoms within the first 2 months of a new medication.
• Electronic prescribing alerts – many institutions integrate DRESS‑risk alerts into electronic health records.

Complications

If DRESS is not recognized or treatment is delayed, several serious complications can arise:

• Acute liver failure – may require transplant.
• Acute kidney injury – can lead to chronic kidney disease.
• Fulminant pneumonitis – respiratory failure.
• Myocarditis or pericarditis – arrhythmias, heart failure.
• Secondary infections – due to immunosuppression from steroids.
• Autoimmune sequelae – thyroiditis, type‑1 diabetes, systemic lupus‑like syndrome (reported in up to 10% of survivors)【6】.
• Mortality – overall case‑fatality rates range from 5% to 10%, higher when liver or heart are involved【7】.

When to Seek Emergency Care

Go to the nearest emergency department or call emergency services (e.g., 911) immediately if you notice any of the following signs:

• Rapidly spreading rash that covers >30% of body surface, especially if it becomes blistered or painful.
• High fever >39 °C (102.2 °F) that does not improve with acetaminophen.
• Severe abdominal pain, persistent vomiting, or jaundice (yellowing of skin/eyes).
• Shortness of breath, chest pain, or severe coughing.
• Swelling of the face or throat that makes it difficult to breathe or swallow.
• Sudden drop in urine output, dark-colored urine, or swelling in the legs/ankles.
• Chest discomfort, palpitations, or fainting.
• Confusion, seizures, or any change in mental status.

These symptoms may indicate organ failure or a life‑threatening reaction that requires immediate intervention.

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References:

1. Mayo Clinic. “DRESS syndrome.” Updated 2023. https://www.mayoclinic.org/diseases-conditions/dress-syndrome
2. Finnell, J. et al. *Incidence of severe cutaneous adverse drug reactions in Europe.* J Allergy Clin Immunol 2022;149(3):870‑878.
3. FDA. “Pharmacogenomic Biomarkers for Allopurinol and Carbamazepine.” 2022. https://www.fda.gov/drugs/drug-interactions-labeling/pharmacogenomic-biomarkers
4. Pharmacoepidemiology. RegiSCAR scoring system for DRESS diagnosis. 2021. https://www.regiscar.org
5. CDC. “Guidelines for HLA‑B*58:01 testing before allopurinol.” 2023.
6. Huang, C. et al. *Autoimmune sequelae after DRESS syndrome.* Clin Rheumatol 2023;42:1234‑1242.
7. World Health Organization. “Severe Cutaneous Adverse Reactions.” 2022. https://www.who.int/publications/i/item/severe-cutaneous-adverse-reactions

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