Case Presentation: A 66-year-old male with no significant medical history initially presented with fever, night sweats, cough, dyspnea, and fatigue and was diagnosed with community-acquired pneumonia (CAP). CT chest revealed a 2.2 cm right lung nodule. He was treated with azithromycin, amoxicillin-clavulanate, and prednisone. Ten days later, he was re-admitted with persistent symptoms and progressive respiratory discomfort. Repeat CT demonstrated rapid enlargement of the pulmonary nodule to 6.6 cm with mediastinal and left hilar adenopathy, raising concern for an evolving infectious or inflammatory process. He was started on piperacillin-tazobactam and azithromycin.Within 48 hours, he developed a pruritic maculopapular rash involving the interdigital spaces, chest, and upper back without mucosal lesions or desquamation. Concurrent eosinophilia and acute liver injury led to a presumptive diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) attributed to penicillin-class antibiotics. Piperacillin-tazobactam was discontinued and high-dose corticosteroids were initiated, resulting in near-immediate improvement in rash, pruritus, and systemic symptoms. He was discharged on cefdinir and a steroid taper with plans for lung biopsy to evaluate the rapidly enlarging nodule.After discharge, Coccidioides IgM and IgG returned positive. Infectious disease initiated fluconazole for acute pulmonary coccidioidomycosis. Given the atypical clinical course and dramatic steroid response, allergy/immunology performed further evaluation. Testing demonstrated normal total IgE, negative environmental and food allergen panels, and undetectable specific IgE to penicillin G and V. This ruled out drug hypersensitivity and supported an exaggerated immune response secondary to acute coccidioidomycosis as the cause of this patient’s DRESS-like presentation.
Discussion: This case illustrates that acute coccidioidomycosis can closely mimic DRESS, including rash, eosinophilia, hepatic involvement, and improvement with corticosteroids. Although beta-lactams were implicated initially, comprehensive allergy testing and the clinical timeline indicated that systemic inflammation from Coccidioides infection, not medication exposure, drove the clinical presentation. To our knowledge, this phenomenon has not been previously described and expands the differential considerations for DRESS-like syndromes in endemic areas.
Conclusions: Clinicians should maintain a high index of suspicion for coccidioidomycosis when DRESS-like features arise in patients with pulmonary findings in endemic regions. Early fungal serology can help distinguish infection-driven immune activation from true drug hypersensitivity. Mislabeling patients with antibiotic allergy may unnecessarily restrict future treatment options. Allergy/immunology evaluation is essential for confirming drug safety and preventing long-term avoidance. Finally, rapid steroid responsiveness should not exclude infectious etiologies, as coccidioidomycosis can transiently improve with immunosuppression.