Drug Reactions

DRESS

Background/Overview 

• Recent review articles incorporated here include:

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Part I. Epidemiology, pathogenesis, clinicopathological features, and prognosis. J Am Acad Dermatol. 2024. PMID: 37516359.​

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Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Part II diagnosis and management. J Am Acad Dermatol. 2024. PMID: 37516356.​

Pathophysiology

Viral Reactivation

• In some patients with DRESS, expansion of T-regs induces immunosuppression and hypogammaglobulinemia leading to viral reactivation. This can lead to a prolonged course, severe organ involvement, and autoimmune sequelae. 

HLA Associations

Allopurinol

• HLA: HLA-B*58:01

• Populations studied: African American, European, Han Chinese, Korean, Malay, Portuguese, Japanese, Thai

• Association with SJS/TEN: Yes

• Clinical use: ACR recommends testing prior to initiation for individuals belonging to high-risk populations. It is contraindicated per CPIC recommendations. 

Aromatic anticonvulsants

• HLA: HLA-B*13:01; HLA-B*51:01

• Populations studied: Japanese, Taiwanese, Han Chinese, Thai (HLA-B*13:01); Han Chinese, South Indian Tamil, Thai children (HLA-B*51:01)

• Association with SJS/TEN: Yes

Carbamazepine

• HLA: HLA-A*31:01

• Populations studied: European-descent, Canadian children, Han Chinese, Japanese

• Association with SJS/TEN: Yes

• Clinical use: CPIC recommends alternative agents in carbamazepine-naïve patients if available. The FDA notes the potential impact on safety, but genotyping is not a substitute for clinical vigilance.

Dapsone

• HLA: HLA-B*13:01

• Populations studied: Han Chinese, Thai

• Association with SJS/TEN: Yes

• Clinical use: Screening programs are implemented in China and Southeast Asia where leprosy is prevalent.

Vancomycin

• HLA: HLA-A*32:01

• Populations studied: European-descent, US Americans

• Association with SJS/TEN: No

• Clinical use: Not specified.

Clinical Presentation

Epidemiology

• Median (IQR) age at diagnosis: 50yo (31-64)​

Timing​

• ​Onset typically 2-6 weeks after drug exposure.  Median duration (IQR) 52 (32-89) days. 

• Systemic manifestations present early, ie hepatic involvement ~7.5 days after rash.  

Cutaneous Manifestations

• Morbilliform eruption (rash starting from the upper trunk and extremities).  May be polymorphic and exfoliative.  Erythrodermic, eczematous, dyshidrosiform, vesiculobullous, pustular, lichen-planus like, EM like, urticarial, purpuric, photodistributed. 

• May include facial edema and erythema, exfoliation, purpura, and vesiculobullous lesions.

• Mild mucositis (primarily oral), but severe mucositis is rare.

Systemic Manifestations​

Hematologic (100%)

• Fever, lymphadenopathy, leukocytosis (neutrophilia, eosinophilia), atypical lymphocytosis, abnormal erythrocyte morphology, thrombocytosis, thrombocytopenia, deep vein thrombosis (DVT), hemophagocytic lymphohistiocytosis (HLH).

Hepatic (75%)

• Hepatosplenomegaly, hepatitis, hepatic necrosis, end-stage: hepatic failure.

Renal (37%)

• Acute interstitial nephritis (AIN), acute kidney injury (AKI), chronic kidney disease (CKD) exacerbation, proteinuria, hematuria, vasculitis, end-stage: renal failure.

Pulmonary (32%)

• Interstitial pneumonitis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), pneumonia, pulmonary nodules, pleural effusion, end-stage: acute respiratory distress syndrome (ARDS), respiratory failure.

Cardiac (13%)

• Pericarditis, myocarditis, atrioventricular (AV) block, acute necrotizing eosinophilic myocarditis, end-stage: heart failure.

Rare

• Endocrine: euthyroid sick syndrome, thyroiditis, pancreatitis.

• Gastrointestinal: esophagitis, gastroenteritis, colitis, gastrointestinal ulcers/bleeding, bowel perforation.

• Neurologic: meningitis, encephalitis, SIADH

• Ocular: bilateral marginal corneal infiltrates, acute anterior uveitis.

• Rheumatologic: myositis

Special Populations

• Immunocompromised and ICI-exposed patients may show atypical presentations with diagnostic challenges.

Variation with causative drug​

• The clinical presentation (timing, pattern of systemic involvement, etc) is something many have looked at to try and correlate with the causative drug.  This table and chart is informative along those lines.​

Sequelae​

• Relapses during taper of systemic steroids is common.

• The rate of long-term sequelae of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) is reported to range from 5.9% to 16%. These sequelae include organ dysfunction and autoimmune diseases, which may develop even years after the acute reaction. Common autoimmune sequelae include:

  • Cutaneous: Alopecia areata, bullous pemphigoid, chronic autoimmune urticaria, sclerodermoid skin lesions, and vitiligo.

  • Hematologic: Aplastic anemia and autoimmune hemolytic anemia (AIHA)/Evans’ syndrome.

  • Hepatic: Autoimmune hepatitis.

  • Endocrine: Autoimmune thyroiditis (Graves’ disease or Hashimoto’s thyroiditis), type 1 diabetes mellitus (T1DM), and type III autoimmune polyglandular syndrome (T3APS).

  • Gastrointestinal: Autoimmune enteropathy.

  • Rheumatologic: Lupus erythematosus (LE), rheumatoid arthritis (RA), and sialadenitis/complete sicca syndrome

Culprit Drugs

• From PMID 39002560:

High Risk

Allopurinol, Carbamazepine, Phenytoin, Vancomycin, Sulfasalazine, Amoxicillin, Dapsone, Lamotrigine, Trimethoprim-sulfamethoxazole, Phenobarbital, Clozapine, Piperacillin-tazobactam, Minocycline, Strontium ranelate.

Intermediate Risk

Cefotaxime, Valproic acid, Ceftriaxone, Isoniazid, Amoxicillin-clavulanic acid, Nevirapine, Telaprevir, Rifampin, Ethambutol, Meropenem, Mexiletine, Raltegravir, Iodinated contrast media, Ibuprofen, Vemurafenib, Captopril, Hydroxychloroquine, Imatinib, Oxcarbazepine, Azithromycin, Imipenem, Olanzapine, Trimethoprim, Zonisamide, Atovaquone, Cefepime, Celecoxib, Enoxaparin, Furosemide, Amlodipine.

Low Risk

Abacavir, Acetazolamide, Acyclovir, Alectinib, Alpelisib, Alverine citrate, Amikacin, Amiodarone, Amphotericin, Ampicillin, Apremilast, Apalutamide, Apixaban, Aripiprazole, Aspirin, Azathioprine, Benznidazole, Benzylpenicillin, Bortezomib, Canakinumab, Carvedilol, Cefdinir, Cefixime, Cefotetan, Ceftazidime, Certolizumab, Chloral hydrate, Cisplatin, Citalopram, Clarithromycin, Clotiapine, Cocaine, Codeine phosphate, Dasatinib, Denosumab, Desloratadine, Dicloxacillin, Dinndolylmethane, Dolutegravir, Efavirenz, Epoetin alfa, Erlotinib, Ethosuximide, Etodolac, Etoricoxib, Everolimus, Fenofibrate, Flavoxate, Flucloxacillin, Gabapentin, Glimepiride, Griseofulvin, Hydantoin, Icotinib.

• From PMID 37516359:

Anticonvulsants (37.3%)

Aromatic anticonvulsants 

• Carbamazepine, Lamotrigine, Phenobarbital, Phenytoin, Cenobamate, Felbamate, Oxcarbazepine, Primidone, Zonisamide

Nonaromatic anticonvulsants

• Valproic acid, Ethosuximide, Gabapentin, Levetiracetam, Perampanel

Antibiotics (24.8%)

Aminoglycosides

• Amikacin, Streptomycin

Antitubercular antibiotics

• Dapsone, Aminosalicylate Sodium, Cycloserine, Ethambutol, Isoniazid, Pyrazinamide, Rifampin

Beta-lactams

• Amoxicillin, Ampicillin, Penicillin V, Piperacillin, Piperacillin/Tazobactam

Cephalosporins

• Cefadroxil, Cefixime, Cefotaxime, Ceftriaxone

Fluoroquinolones

• Ciprofloxacin, Moxifloxacin

Glycopeptides

• Vancomycin, Teicoplanin

Lincomycin antibiotics

• Clindamycin

Macrolides

• Azithromycin

Nitrofuran antibiotics

• Nitrofurantoin

Oxazolidinones

• Linezolid

Sulfonamides

• Trimethoprim/Sulfamethoxazole, Sulfadiazine

Tetracyclines

• Minocycline, Doxycycline

Xanthine Oxidase Inhibitors (8.2%)

• Allopurinol, Febuxostat

Antivirals (5.6%)

Integrase inhibitors

• Raltegravir

NNRTIs

• Nevirapine, Efavirenz

NS3/4A and NS5A inhibitors

• Daclatasvir, Telaprevir

Nucleoside/nucleotide analog

• Cidofovir, Ribavirin

NRTIs

• Emtricitabine, Tenofovir Disoproxil

Protease inhibitors

• Boceprevir, Darunavir, Nelfinavir, Ritonavir

Antineoplastics (4.1%)

Cytotoxic drugs

• Chlorambucil, Leflunomide, Mitoxantrone, Temozolomide

ICIs

• Ipilimumab, Nivolumab

TKIs

• Afatinib, Binimetinib, Encorafenib, Erlotinib, Imatinib, Sorafenib, Vemurafenib

  • 62% of BRAFi related DRESS was prior to ICI exposure (ref 29)​

Analgesics (2.5%)

• Acetaminophen

Miscellaneous (17.5%)

• Acenocoumarol, Amitriptyline, Amlodipine, Anakinra, Atenolol, Atorvastatin, Benznidazole, Bosentan, Bupropion, Caffeine, Canakinumab, Captopril, Cilostazol, Clomipramine, Clopidogrel, Clozapine, Codeine, Cyclobenzaprine, Dextromethorphan, Efalizumab, Esomeprazole, Fenofibrate, Fluoxetine, Ginseng, Hydroxychloroquine, Lenalidomide, Leucovorin, Lithium, Mesalamine, Metamizole, Metformin, Methimazole, Olanzapine, Pandemic Influenza Vaccine (H1N1), PEG-Interferon, Perindopril, Promethazine, Propylthiouracil, Pyrimethamine, Quetiapine, Quinine, Ramipril, Rivaroxaban, Sildenafil, Spironolactone, Strontium ranelate, Sulfasalazine, Terbinafine, Teriflunomide, Thiamine, Tocilizumab, Torsemide, Warfarin, Ziprasidone​

Histopathology

Skin Features

• Nonspecific findings with a combination of epidermal and dermal changes.

• Key features: Perivascular lymphocytic infiltration (97%), epidermal spongiosis (78%), dyskeratosis (97%), and interface vacuolization (91%), eosinophilic infiltration (72%), dermal edema, red blood cell extravasation.

• Severe cases may show atypical lymphocytes, granulysin expression, and deep dermal involvement.

Lymph Node Features

• Four histopathologic patterns:

  • Reactive lymphoid hyperplasia.

  • Necrotizing lymphadenitis.

  • Hodgkin lymphoma-like.

  • Angioimmunoblastic T-cell lymphoma-like.

Visceral Organs

• Eosinophilic infiltration with or without necrosis.

• Hepatic injury: Cholestatic, hepatocellular, or mixed patterns.

Diagnosis/Workup 

JAAD CME (May 2024)

Diagnosis

• Consider diagnostic criteria: Bocquet criteria, J-SCAR criteria, RegiSCAR criteria/scoring system

• Skin biopsy: Included in RegiSCAR scoring system, may be helpful but not required for diagnosis

Identification of Suspected Drug Culprit(s)

• Develop a comprehensive drug chart: Assess exposure to prescription drugs, over-the-counter drugs, supplements, recreational drugs, toxins, contrast media, and vaccines.  Consider exposures extending at least 6 weeks prior to disease onset

Initial Evaluation

• Hematologic: CBC with differential, peripheral smear for atypical lymphocytes

  • consider CRP, HLH screen in appropriate circumstance

• Hepatic: LFTs

• Renal: BUN, creatinine, urinalysis; spot urine for protein:creatinine ratio

  • consider wright stain of urine for eosinophilia in appropriate circumstance

• Additional testing to consider:​

  • Cardiac: ECG, troponin T, echocardiogram

  • Endocrine: TSH, free T4, fasting glucose, lipase

  • Rheumatologic: CK

  • Viral: quantitative PCR for HHV6, HHV7, EBV, and CMV​​

Ongoing Evaluation

• In the appropriate clinical context, consider:

  • Repeat CBC with differential, LFTs, BUN, creatinine, urinalysis, CK at least twice weekly

  • Quantitative PCR for HHV6, HHV7, EBV, and CMV in severe or refractory cases​​

Longitudinal Evaluation for Sequelae

• Organ Dysfunction: in the appropriate clinical context, consider CBC with differential, LFTs, BUN, creatinine, urinalysis, CK for at least 1 year

• Autoimmune Diseases: monitor TSH and free T4 at 3 months, 1 year, and 2 years

• Psychiatric Symptoms: monitor for symptoms consistent with PTSD, depression, and anxiety for at least 1 year

Adjunctive Tests for Risk Stratification and Drug Culprit Identification

• Many of these may not be readily or clinically available: HLA genotyping, CYP genotyping, patch testing (PT), delayed intradermal testing (diDT), lymphocyte transformation test (LTT), ELISpot assay, gene expression profiling

Delphi Consensus

• Although recommendations very widely, Delphi consensus published in JAMA Derm suggested the following (Figure):​

Organ Workup​

• CBC with diff (including platelets)

• Kidney function tests: BUN, creatinine, eGFR, urine sediment

• Liver function tests

• Electrocardiogram

• For patients with specific organ specific disease, or severe disease, consider the following driven by specialist of respective discipline:

  • coagulation tests (PT, Factor V, etc)​

  • skin biopsy

  • for severe liver involvement, liver biopsy, evidence of hemophagocytosis

  • ProBNP/BNP, troponin T, transthoracic echo

  • pancreatic enzymes

  • Chest CT or Xray; in selected cases, PFTs, bronchoscopy

  • CT/MRI brain, lumbar puncture​

Viral workup

• Serum PCR for HHV6, EBV, CMV.  If positive, can consider HHV7.  

• If planning systemic therapy, consider hep B and C screening

Treatment

JAAD CME (May 2024)

Initial Treatment

• Discontinue suspected drug culprit(s) and all non-essential medications

• Document suspected drug culprit(s) in medical records

• Provide supportive care

• Consider:

  • Topical corticosteroids for symptomatic relief

  • Systemic corticosteroids (e.g., 1-2 mg/kg/day prednisone or equivalent)

  • Steroid-sparing therapies: azathioprine, cyclophosphamide, cyclosporine, infliximab, IVIG, mepolizumab, methotrexate, mycophenolate, N-acetylcysteine, plasma exchange, plasmapheresis, rituximab, tocilizumab, tofacitinib.

Ongoing Treatment

• When cutaneous and systemic involvement improve:

  • Initiate gradual taper of systemic corticosteroids and/or steroid-sparing therapy

  • Monitor, prevent, and manage iatrogenic adverse events

Delphi-based international consensus recommendations 37966824​

Treatment

• Base treatment on disease severity.  

• Corticosteroids should be given to all patients with confirmed DRESS

  • Mild DRESS: very high potency topical steroids tapering 6wks - 3mo​

  • Moderate DRESS: very high potency topical steroids or systemic steroids tapered over 6wks - 3mo

  • Severe DRESS: systemic steroids tapered over 6wks - 3mo

• For steroid-refractory DRESS: cyclosporine, IL-5 or IL-5r inhibitors, or IVIG​

• For DRESS with high CMV viral loads, consider addition of ganciclovir or valganciclovir

Follow-up

• Monthly follow up for 6 months to assess:

  • bloodwork determined by organ involvement at diagnosis​

  • autoantibody screening

  • thyroid dysfunction screening

  • side-effect of prolonged steroid screening and management​

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