Drug Reaction with Eosinophilia and Systemic Symptoms

Aka: Drug Reaction with Eosinophilia and Systemic Symptoms, DRESS Syndrome, Dilantin Hypersensitivity Syndrome, Anti-Convulsant Hypersensitivity Syndrome, Drug Induced Hypersensitivity Syndrome

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II. Epidemiology

  1. U.S. Incidence: 2 per 100,000 per year
    1. Occurs in 1 in 1000 to 1 in 10,000 drug exposures

III. Causes: Medications

  1. Causative drug is identified in 80% of cases (and suspected drug identified in most of the remainder)
    1. No causative agent is found in a small fraction of cases (2%)
  2. Anticonvulsants (most common, causes 50% of cases in children)
    1. Lamotrigine
    2. Phenobarbital
    3. Phenytoin
    4. Carbamazepine
    5. Levetiracetam
    6. Clobazam
  3. Antimicrobials
    1. SulfonamideAntibiotics (TMP-SMZ, Dapsone)
    2. Minocycline
    3. Vancomycin
    4. HIV Medications
  4. Other Causes
    1. Allopurinol
      1. Dose dependent reaction (esp. in renal Impairment)
    2. Dapsone
    3. NSAIDs
    4. Aspirin
    5. Proton Pump Inhibitors

IV. Findings

  1. Onset 15-40 days (2-6 weeks, up to 8 weeks) after offending medication exposure (long latency)
  2. Pruritic rash (99% of cases)
    1. Similar initial Morbilliform rash as with Fixed Drug Eruption
    2. Symmetric distribution on the trunk
    3. Initial Characteristics
      1. Rash may be erythematous, Macular or papular (Urticarial in some cases)
      2. Follicular prominence
    4. Later
      1. Coalescing erythematous rash may involve 50% of body surface area
      2. Rash desquamates after 2 weeks (after up to 90 days in some prolonged cases)
        1. Differentiate from the more severe skin sloughing and Blistering in Toxic Epidermal Necrolysis
  3. Systemic findings
    1. Fever (>72% of cases)
    2. Lymphadenopathy (>55% of cases)
    3. Periorbital edema or Facial Edema (>50% of cases, esp. more severe cases)
    4. Mild mucosal involvement may be present
      1. Differentiate from the more severe mucosal involvement in Stevens-Johnson Syndrome
  4. Associated organ involvement (1 organ in 90%, 2 organs in 35%, 3+ organs in 20% of cases)
    1. Hepatic Involvement (>50% of cases)
      1. Cholestasis (37%)
      2. Hepatocellular (19%)
      3. MIxed (27%)
    2. Renal Involvement (>11% of cases)
    3. Pulmonary Involvement (30% of cases)
      1. Pneumonitis
      2. Pleural Effusions
      3. Pneumonia
      4. Acute Respiratory Distress Syndrome (ARDS)
    4. Cardiac Involvement (>2% of cases)
      1. Typically mycocarditis (and associated with higher mortality)
    5. Neurologic Involvement (>2%)
      1. Bell Palsy
      2. Peripheral Neuropathy
      3. Aseptic Meningitis
      4. Cerebral Vasculitis
      5. Limbic Encephalitis

V. Labs

  1. Complete Blood Count
    1. Leukocytosis (>52%)
    2. Eosinophilia
      1. Eosinophils > 700 to 1500/mm3 in >30% of patients
    3. Other findings
      1. Monocytosis (69%)
      2. Atypical lymphocytes (>35%)
      3. Thrombocytosis (25%)
  2. Comprehensive metabolic panel
    1. Renal Insufficiency
    2. Transaminitis
      1. Increased AST and ALT in >50% of patients
  3. Urinalysis
    1. Proteinuria if renal involvement

VI. Imaging

  1. Chest XRay
    1. Abnormal in 50% of patients (see pulmonary findings as above)

VII. Diagnosis

  1. Bocquet DRESS Criteria
    1. Cutaneous Drug Eruption AND
    2. Eosinophil Count >1500/mm3 or Atypical lymphocytes AND
    3. At least 1 of the following findings consistent with organ involvement
      1. Lymphadenopathy >2 cm diameter
      2. Liver Enzymes more than twice the upper limit of normal
      3. Interstitial Nephritis
      4. Interstitial pneumonitis
      5. Carditis
    4. References
      1. Bocquet (1996) Semin Cutan Med Surg 15(4):250-7 +PMID: 9069593 [PubMed]
  2. Shiohara DRESS/DIHS Criteria (atypical DIHS if 5 of 7 positive, typical DIHS if 7 of 7 positive)
    1. Maculopapular rash >3 weeks after starting a limited number of medications AND
    2. Prolonged clinical symptoms 2 weeks after stopping a causative medication AND
    3. Fever >38 C AND
    4. Renal or liver abnormalities AND
    5. Lymphadenopathy AND
    6. Human Herpes Veris 6 Reactivation AND
    7. Eosinophil Count >1500/mm3, atypical Lymphocytosis >5% OR Leukocytosis >11/mm3
    8. References
      1. Shiohara (2019) Allergol Int 68(3):301-8 +PMID: 31000444 [PubMed]
  3. RegiSCAR DRESS Criteria
    1. https://www.mdcalc.com/calc/10084/regiscar-score-drug-reaction-eosinophilia-systemic-symptoms-dress
    2. Interpretation
      1. Score <2: Not consistent with DRESS
      2. Score 2-3: Possible DRESS
      3. Score 4-5: Probable DRESS
      4. Score >5: Definite DRESS
    3. References
      1. Kardaun (2013) Br J Dermatol 169(5):1071-80 +PMID: 23855313 [PubMed]

VIII. Differential Diagnosis

  1. Fixed Drug Eruption
    1. Onset is earlier than DRESS Syndrome, typically <2 weeks after exposure
  2. Stevens-Johnson Syndrome
    1. Associated with greater mucous membrane involvement and less Facial Edema than DRESS Syndrome

IX. Management

  1. Stop the offending medication
  2. Antipyretics
  3. Avoid empiric Antibiotics (may worsen status)
  4. Mild cases (non-toxic, LFTs <3x normal, no renal or lung involvement)
    1. Topical Corticosteroids
  5. Moderate to severe cases (systemic involvement)
    1. Admit to monitored setting
    2. Intravenous Fluids
      1. Similar hydration levels to Burn Injury (Parkland Formula for Fluid Resuscitation in Burn Injury)
    3. High-dose Corticosteroids tapered over months
      1. Start Prednisone 1 mg/kg/day and taper over 2 months (up to 3 to 6 months)
      2. In refractory cases, 3 days of very high dose Methylprednisolone (30 mg/kg/day) may be used
    4. Other management
      1. IV Immunoglobulin
      2. Immunosuppressants
      3. Plasmapheresis

X. Complications

  1. Nephritis
  2. Arthritis
  3. Myositis
  4. Encephalitis
  5. Liver failure
  6. Reactivation of herpes family viruses (e.g. HSV, VZV, EBV)

XI. Prognosis

  1. Mortality approaches 10% (due to fulminant hepatic failure)

XII. References

  1. (2024) Presc Lett 31(7): 37-8
  2. Behar and Claudius in Herbert (2020) EM:Rap 20(7): 8-9
  3. Jhun and DeClerck in Herbert (2015) EM:Rap 15(2): 9-11
  4. Long and Werber in Swadron (2023) EM:Rap 23(5): 3-7
  5. Choudhary (2013) J Clin Aesthet Dermatol 6(6):31-7 +PMID: 23882307 [PubMed]
  6. De (2018) Indian J Dermatol 63(1):30-40 +PMID: 29527023 [PubMed]

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