• Petar I Trifonov, Vesselin K Koltchakov, Raynichka P Mihaylova-Garnizova, Aleksandar Y Yordanov, Liliya Sokolova, Rosen K Nikolov, and Zahariy A Krastev.
• Clinic of Gastroenterology, UMHAT St. Ivan Rilski, Sofia, Bulgaria.
• Medicine (Baltimore). 2024 Jan 19; 103 (3): e36974e36974.

IntroductionFever of unknown origin (FUO) remains one of the most challenging clinical conditions. It demands an exhaustive diagnostic approach, considering its varied etiologies spanning infectious, autoimmune, inflammatory, and malignant causes.Patient ConcernsThis report shows the journey of diagnosing a 28-year-old male who presented with persistent fever and lower-extremity weakness over 9 months. Despite seeking care at multiple hospitals, a definitive diagnosis remained elusive.DiagnosisThe patient underwent a series of evaluations in various specialties, including gastroenterology, infectious diseases, rheumatology, hematology, and cardiology. Multiple tests and treatments were administered, including antiviral therapy for hepatitis B and antibiotics for suspected infections.InterventionsAfter an initial misdiagnosis and unsuccessful treatments, a positron emission tomography-computed tomography scan and lymph node biopsy ultimately led to the diagnosis of peripheral T-cell lymphoma-T follicular helper type (PTCL-TFH) lymphoma. The patient was referred to the hematology clinic and initiated on CHOEP (cyclophosphamide, vincristine, etoposide, and prednisone) chemotherapy.OutcomesThe patient showed a positive response to CHOEP therapy, as indicated by a posttreatment positron emission tomography-computed tomography scan. He reported a significant improvement in his quality of life. Additional rounds of the same regimen were planned to further manage the lymphoma.ConclusionThis case emphasizes the importance of a comprehensive and persistent diagnostic approach in managing FUO. Initially, the focus on infectious causes led to extensive treatments, but the disease's progression and complications shifted attention to other specialties. The eventual diagnosis of PTCL-TFH lymphoma highlights the significance of advanced imaging techniques and multidisciplinary collaboration in uncovering elusive diagnoses. Thorough surveillance, timely reassessments, and repeated testing can uncover definitive changes critical for diagnosis. PTCL-TFH lymphoma, although rare, should be considered in the differential diagnosis of FUO, especially when initial evaluations are inconclusive.Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.

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