Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, also referred to as Drug-Induced Hypersensitivity Syndrome (DiHS), is a severe, T-cell–mediated drug hypersensitivity reaction characterized by an extensive cutaneous eruption, fever, lymphadenopathy, hematologic abnormalities, and multi-organ involvement [1–3]. Disease-modifying antirheumatic drugs (DMARDs) and immunosuppressants, including sulfasalazine and hydroxychloroquine, are essential agents widely utilized in the long-term management of autoimmune conditions such as rheumatoid arthritis and Sjögren’s syndrome [1-3]. Although these therapies are generally well-tolerated, hypersensitivity reactions related to DMARDs represent a significant clinical concern due to their potential to trigger life-threatening adverse cutaneous reactions, accounting for substantial mortality among hospitalized patients [3,4].

Multi-organ involvement significantly elevates the complexity and mortality of severe DRESS syndrome [4, 5]. In the setting of early pregnancy, treatment becomes a delicate clinical balance between aggressive maternal resuscitation and fetal preservation [1–4]. While prompt withdrawal of the offending drug and systemic corticosteroid initiation remain the mainstays of therapy, the development of severe ARDS and secondary ventilator-associated pneumonia requires a coordinated critical care approach involving dermatology, rheumatology, critical care, and obstetrics [5–7].

Despite increasing recognition of DRESS syndrome worldwide, documented cases of severe DRESS complicated by ARDS and septic shock during the first trimester of pregnancy remain extremely rare.

Case Presentation

A 28-year-old pregnant woman presented with a 1-week history of persistent dry cough, high-grade fever (38.8°C), oppressive chest pain, and left upper extremity paresthesias. Her medical history was significant for rheumatoid arthritis and Sjögren’s syndrome both diagnosed 8 months prior,  and maintained on prednisone, hydroxychloroquine, and sulfasalazine. She received outpatient symptomatic treatment without clinical improvement, subsequently developing disseminated erythematous rash, progressive pruritus, and facial edema. 

Upon evaluation by dermatology the patient exhibited a maculopapular rash involving the face, trunk, and extremities, affecting approximately 64% of total body surface area, with negative Nikolsky sign (Figure 1). Initial laboratory work showed severe leukocytosis (20.8 x 10^3/μL) with progressive eosinophilia (3.56 x 10^3/μL, 17.1%), transaminitis (AST 164 U/L), and acute kidney injury (creatinine 1.2 mg/dl). Given the suspicion of DRESS, rheumatology was consulted. Discontinuation of sulfasalazine was recommended, and immunosuppression with methylprednisolone 80 mg/day was initiated.  Skin biopsy confirmed a reactional dermatitis with endothelial damage, erythrocyte extravasation, apoptotic bodies, and epidermal hypoxia. During hospitalization the patient experienced rapid respiratory and hemodynamic collapse, requiring emergency intubation and ICU transfer. Ultrasonography revealed a single fetus with normal heart rate (128 BPM) and fetometry corresponding to 16.1 weeks. Respiratory virus PCR panel, measles PCR, and serologies for HIV, HBV, HCV, and Dengue were negative.

During her ICU stay, the patient developed ventilator-associated pneumonia (VAP) and secondary septic shock. Blood cultures drawn on day 3 yielded methicillin-resistant Staphylococcus aureus (MRSA). Bronchoalveolar lavage (BAL) fluid cultures obtained on day 4 confirmed MRSA (50,000 CFU/mL) and Klebsiella aerogenes (50,000 CFU/mL). Antimicrobial therapy consisting of  vancomycin, ertapenem, alongside topical mupirocin was initiated. Concurrently, she developed ARDS (Figure 3) with an initial PaO2/FiO2 of 91 mmHg, which improved substantially to 217 PaO2/FiO2 of mmHg following a 16-hour prone positioning session.

During her ICU stay, the patient achieved progressive clinical improvement with gradual resolution of organ dysfunction, by day 8 her absolute eosinophil count had diminished to 0.395 x 10^3/μL. The patient transitioned into a high-output polyuric phase of acute tubular necrosis, leading to complete renal recovery. Following extubation on day 9, she maintained adequate oxygenation on low-flow nasal cannula, demonstrating continuous clinical recovery without recurrent respiratory failure, allowing for her ICU discharge on day 10 at 17.4 weeks of gestation, with documented fetal stability and continued viability throughout her critical illness.

Discussion

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome represents a rare and rapidly progressive severe cutaneous adverse reaction  characterized by an extensive morbilliform eruption, facial edema, fever, lymphadenopathy, severe hematologic derangements, and multi-organ involvement [2–5]. Data from epidemiological registries indicate that DRESS carries a high mortality rate 10–20%, primarily driven by hepatic necrosis, acute respiratory failure, or secondary septic shock [1–5, 7].

The establishment of large international registries, such as the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR), has provided crucial insights into the demographics, precipitating drugs, and clinical patterns of DRESS [1-4, 6]. According to RegiSCAR data, solid-organ involvement affects up to 90% of confirmed cases, with the hepatic system being the most frequently involved (60–80%), followed by renal (10–30%), pulmonary (25–32%), and cardiac (5–10%)  manifestations [1–5, 7]. Hematologic derangements are a hallmark of the syndrome, with peripheral hypereosinophilia (>1.5 × 10³/μL) occurring in up to 70% of patients alongside atypical lymphocytosis and leukocytosis [1]. While our patient presented with classic features including extensive cutaneous involvement (64% TBSA), facial edema, severe hypereosinophilia (3.56 × 10³/μL), transaminitis, and acute kidney injury, her clinical course rapidly escalated to include severe ARDS and secondary MRSA septic shock, highlighting the wide variability and potentially catastrophic trajectory of DRESS presentations [1–5, 7].

The diagnostic criteria (Table 1) proposed by the RegiSCAR uses a combination of clinical, histological, and laboratory criteria to categorize cases as negative (<2), possible (2–3), probable (4–5), or definitive (>5). With a score exceeding 5, our patient fulfilled the requirements for a definitive diagnosis of DRESS [1,2]. Over 40 medications are linked to DRESS syndrome, in which a drug trigger is established in roughly 80% of cases. Primary offending agents include aromatic anticonvulsants, sulfonamides, dapsone, NSAIDs, vancomycin, allopurinol, and beta-lactam antibiotics. Notably, secondary agents such as amoxicillin often function as aggravating co-factors rather than primary drivers [1].

Table 1. RegiSCAR criteria used in DRESS syndrome

* Heart, liver, kidney, muscle, pancreas or others; **: ANA, ANCA, HIV serologies; Evaluation: Score 1–3: possible; 4–5: probable; 6 or higher: definite.

Table 2. Drugs most commonly associated with DRESS

NSAID: Nonsteroidal Anti-Inflammatory Drug