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Difficulty: MediumImmunologic and Inflammatory Processes

A 28-year-old woman is admitted to the medical ward with a 3-day history of high fever, marked facial swelling, and a widespread skin eruption. She reports that the rash began on her face and upper trunk before spreading to her extremities. Four weeks ago, she was prescribed sulfasalazine for newly diagnosed inflammatory bowel disease. Her temperature is 39.2°C (102.6°F), blood pressure is 110/70 mmHg, and pulse is 112/min. Physical examination reveals prominent periorbital edema, generalized cervical lymphadenopathy, and a diffuse, confluent, erythematous maculopapular rash covering 70% of her body surface area. There is no mucosal ulceration or epidermal detachment. Laboratory studies show:

Leukocyte count: 18,500/mm318,500/\text{mm}^3
Eosinophils: 2,500/mm32,500/\text{mm}^3 (normal: 15–500/mm315–500/\text{mm}^3)
Alanine aminotransferase (ALT): 450 U/L
Aspartate aminotransferase (AST): 410 U/L
Serum creatinine: 1.1 mg/dL

Which of the following best describes the predominant immunopathologic mechanism driving this patient's clinical syndrome?

  1. Oligoclonal expansion of T-lymphocytes with subsequent release of interleukin-5Answer
  2. B
    CD8+ T-lymphocyte mediated widespread keratinocyte apoptosis via perforin and granzyme B
  3. C
    Cross-linking of drug-specific IgE leading to widespread mast cell degranulation
  4. D
    Deposition of circulating immune complexes and subsequent classical complement cascade activation
  5. E
    Drug binding to cellular surfaces triggering IgG-mediated opsonization and phagocytosis

Answer

The correct mechanism is the oligoclonal expansion of T-lymphocytes with subsequent release of interleukin-5, which characterizes DRESS syndrome.
The patient's presentation (a latency period of 4 weeks, prominent facial edema, fever, generalized rash, lymphadenopathy, profound eosinophilia, and hepatic injury) is the classic triad for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Sulfasalazine, alongside anticonvulsants and allopurinol, is a notorious trigger. DRESS is classified as a severe, delayed-type (Type IVb) hypersensitivity reaction. The pathogenesis is driven by the oligoclonal expansion of drug-specific T-lymphocytes (predominantly Th2 cells). These T-cells secrete massive amounts of interleukin-5 (IL-5), a cytokine that specifically stimulates eosinophil production, activation, and subsequent infiltration into tissues such as the liver, skin, and heart, resulting in severe end-organ damage.

Step-by-Step Solution

1
Analyze the timeline and clinical presentation.
The patient developed high fever, facial edema, diffuse rash, and lymphadenopathy exactly 4 weeks after starting sulfasalazine.
This specific 2 to 8-week latency period combined with systemic signs and facial edema strongly suggests a delayed-type drug reaction rather than an acute allergy.
2
Evaluate the laboratory findings in the context of the physical exam.
Labs reveal profound peripheral eosinophilia (2,500/mm32,500/\text{mm}^3) and severe transaminitis (ALT 450 U/L), without mucosal ulceration or skin sloughing.
Visceral organ involvement (most commonly hepatic) combined with significant eosinophilia confirms the diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, differentiating it from Stevens-Johnson syndrome (SJS).
3
Identify the underlying immunopathologic mechanism.
DRESS is a Type IVb hypersensitivity reaction.
It is mediated by drug-specific T-cells (primarily Th2 phenotype) that secrete large amounts of interleukin-5 (IL-5), driving the proliferation, activation, and tissue infiltration of eosinophils that cause end-organ damage.

Key Concept

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe Type IVb hypersensitivity reaction mediated by T-cells that secrete IL-5, leading to eosinophilic tissue infiltration and organ damage.
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Topics

Immunologic and Inflammatory Processes

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