Fever of unknown origin in adults: diagnostic spectrum, the contribution of FDG-PET/CT and targeted sequencing, and spontaneous resolution
7 affiliations
- 1Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences
- 2Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences
- 3Nagasaki Medical Education Center (N-MEC), Nagasaki University Hospital
- 4Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Science
- 5Department of Rheumatology, Saiseikai Nagasaki Hospital
- 6Acute and Critical Care Center, Nagasaki University Hospital
- 7Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University
Abstract
The diagnostic paradigm for fever of unknown origin (FUO) has shifted with the advent of functional imaging and genomic technologies. This study evaluated the clinical impact of targeted next-generation sequencing (NGS) and 18-FDG-PET/CT in a single-center FUO cohort, while examining clinical features associated with spontaneous resolution. Among 116 patients analyzed, definitive diagnoses were established in 75.9%. In a selected subgroup with strong clinical suspicion of autoinflammatory disease, targeted NGS identified candidate variants in 88.9%, supporting clinico-genomic diagnostic confirmation in integration with clinical criteria. In a descriptive series of 15 cases evaluated by FDG-PET/CT at attending physicians’ discretion, imaging contributed to direct diagnosis in 33.3%. Notably, 25 of 28 undiagnosed patients experienced spontaneous resolution. Higher hemoglobin, higher albumin, absence of renal dysfunction, and a preserved appetite were identified as exploratory clinical markers associated with spontaneous remission; however, the association for appetite was attenuated in multivariable models adjusted for baseline status. While advanced technologies are valuable diagnostic tools in selected high-pre-test probability settings, a substantial proportion of undiagnosed FUO cases resolve spontaneously. A preserved appetite, alongside systemic baseline stability, may serve as an exploratory clinical surrogate supporting a cautious “watchful waiting” strategy in selected patients.
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BibTeX
@article{umeda2026fever,
title = {{Fever of unknown origin in adults: diagnostic spectrum, the contribution of FDG-PET/CT and targeted sequencing, and spontaneous resolution}},
author = {Masataka Umeda and Lamiaa Mohamed and Kazusato Hara and Mizuna Otsuka and Shota Kurushima and Tomohisa Uchida and Toru Michitsuji and Yoshika Tsuji and Yushiro Endo and Ayuko Takatani and Shoichi Fukui and Remi Sumiyoshi and Tomohiro Koga and Shin-ya Kawashiri and Naoki Iwamoto and Takashi Igawa and Mami Tamai and Tomoki Origuchi and Hiroo Izumino and Takahiro Maeda and Koya Ariyoshi and Atsushi Kawakami},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1899032},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1899032/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Fever of unknown origin in adults: diagnostic spectrum, the contribution of FDG-PET/CT and targeted sequencing, and spontaneous resolution
AU - Masataka Umeda
AU - Lamiaa Mohamed
AU - Kazusato Hara
AU - Mizuna Otsuka
AU - Shota Kurushima
AU - Tomohisa Uchida
AU - Toru Michitsuji
AU - Yoshika Tsuji
AU - Yushiro Endo
AU - Ayuko Takatani
AU - Shoichi Fukui
AU - Remi Sumiyoshi
AU - Tomohiro Koga
AU - Shin-ya Kawashiri
AU - Naoki Iwamoto
AU - Takashi Igawa
AU - Mami Tamai
AU - Tomoki Origuchi
AU - Hiroo Izumino
AU - Takahiro Maeda
AU - Koya Ariyoshi
AU - Atsushi Kawakami
PY - 2026
DA - 2026/10/23
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1899032
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1899032/full
AB - The diagnostic paradigm for fever of unknown origin (FUO) has shifted with the advent of functional imaging and genomic technologies. This study evaluated the clinical impact of targeted next-generation sequencing (NGS) and 18-FDG-PET/CT in a single-center FUO cohort, while examining clinical features associated with spontaneous resolution. Among 116 patients analyzed, definitive diagnoses were established in 75.9%. In a selected subgroup with strong clinical suspicion of autoinflammatory disease, targeted NGS identified candidate variants in 88.9%, supporting clinico-genomic diagnostic confirmation in integration with clinical criteria. In a descriptive series of 15 cases evaluated by FDG-PET/CT at attending physicians’ discretion, imaging contributed to direct diagnosis in 33.3%. Notably, 25 of 28 undiagnosed patients experienced spontaneous resolution. Higher hemoglobin, higher albumin, absence of renal dysfunction, and a preserved appetite were identified as exploratory clinical markers associated with spontaneous remission; however, the association for appetite was attenuated in multivariable models adjusted for baseline status. While advanced technologies are valuable diagnostic tools in selected high-pre-test probability settings, a substantial proportion of undiagnosed FUO cases resolve spontaneously. A preserved appetite, alongside systemic baseline stability, may serve as an exploratory clinical surrogate supporting a cautious “watchful waiting” strategy in selected patients.
SN - 1664-3224
ER -