A Diagnostic Challenge: Disseminated Herpes Simplex Virus Type 2 Infection Presenting in Stages and Mimicking Sepsis and Biliary Disease Across Two Healthcare Systems.

Disseminated herpes simplex virus type 2 (HSV-2) infection in adults is rare but can result in severe complications including hepatitis, encephalitis, and sepsis-like illness. Early symptoms are often nonspecific and may mimic common conditions, leading to delayed diagnosis and treatment. We present the case of a 74-year-old woman with Sjögren's syndrome who initially developed left upper eyelid erythema and swelling, followed by a viral-like prodrome with fever and myalgia, and subsequent urinary symptoms prior to traveling abroad. She was hospitalized in Spain with fever, dysuria, and transaminitis. Abdominal ultrasound demonstrated gallbladder wall thickening and free fluid without biliary obstruction, and she was empirically treated with broad-spectrum antibiotics and corticosteroids for presumed urinary tract infection and biliary disease. A language barrier complicated communication and clinical evaluation. After approximately one week of persistent symptoms, she returned to the United States and was admitted to our institution, where she was found to have culture-negative sepsis, hyponatremia, encephalopathy, anasarca, and persistent transaminitis. Extensive bacterial and fungal infectious workup was negative. HSV-2 polymerase chain reaction (PCR) was positive, confirming disseminated HSV-2 infection. During the latter part of hospitalization, she developed a small cluster of vesicular lesions. The patient improved with intravenous acyclovir followed by oral valacyclovir. Diagnostic complexity was compounded by care across different healthcare systems and a language barrier. This case highlights the staged progression of disseminated HSV-2 infection, from localized mucocutaneous involvement through a systemic viral prodrome to organ-threatening disease, and underscores the importance of considering disseminated HSV-2 in patients presenting with culture-negative sepsis and transaminitis. Early recognition and prompt antiviral therapy are essential to reduce morbidity and mortality.