Molecular Imaging Enhances Diagnosis of Fever of Unknown Origin

Study Identifies New Biomarker and Patient Selection Parameters

Reston, VA (May 26, 2026)—PET/CT can add valuable information to aid the diagnosis of fever of unknown origin (FUO), according to a new multicenter, retrospective study published in the June issue of The Journal of Nuclear Medicine. In a cohort of more than 900 FUO patients, molecular imaging directly influenced the clinical management in nearly 75 percent, contributing to improved patient outcomes, increased patient safety, and reduced healthcare costs.

FUO presents a significant diagnostic challenge because of its wide range of potential causes. Currently, there is no diagnostic gold standard for FUO evaluation, and investigations are typically tailored to each patient’s characteristics and clinical features. The cornerstone of diagnosis is a comprehensive history, physical examination, and first-line testing. Advanced imaging techniques, such as PET/CT, are utilized for second-line testing.

“Although predominantly used in oncology, ¹⁸F-FDG PET/CT has demonstrated significant diagnostic utility in the evaluation of several inflammatory and infectious diseases. Its application in FUO is increasing, although its diagnostic value remains debated,” said Domenico Albano, MD, nuclear medicine physician at the Università degli Studi of Brescia and ASST Spedali Civili di Brescia, Italy. “In this study, we sought to investigate the diagnostic performance and the clinical impact of ¹⁸F-FDG PET/CT on the management of patients with FUO.”

The study included 929 patients from 12 centers who underwent ¹⁸F-FDG PET/CT for FUO. The final diagnosis (infectious disease, noninfectious inflammatory disease, malignancy, or unknown cause) for each patient was established on the basis of laboratory, imaging, histopathologic or pathologic examinations, and at least six months of clinical follow-up data. Researchers then evaluated the role that ¹⁸F-FDG PET/CT played in diagnosis and clinical management, as well as its association with clinical, epidemiologic, and biochemical parameters.

¹⁸F-FDG PET/CT scans had positive results for 549 patients and negative results for the remaining 380 patients. Researchers found that PET/CT directly influenced the clinical management—introduction of new therapies, modulation of previous treatment, or recommendation of specific invasive procedures—in approximately 75 percent of patients. In addition, the study identified several predictive markers for a positive PET/CT scan: high C-reactive protein, high neutrophil-to-lymphocyte ratio, the presence of fever at the time of PET, and short duration of prior antibiotic therapy.

“Based on these findings, ¹⁸F-FDG PET/CT has the potential to be a first-line tool in the work-up of FUO, rather than a second- or third-line test,” said Albano. “In addition, the integration of clinical and biochemical parameters may help improve performance of ¹⁸F-FDG PET/CT, reducing the time to diagnosis and preventing unnecessary treatments and investigations.”

Figure 3: Images from a 59-year-old man admitted to intensive care unit with fever and back pain after prior intestinal surgical procedure. Despite intravenous meropenem, fever persisted. White blood cell and CRP levels were high. (A) Maximum-intensity-projection PET images showed increased uptake in column corresponding to the sixth and seventh thoracic vertebrae. Subsequent sagittal (B), axial (C), and coronal (D) PET/CT images confirmed increased 18F-FDG uptake in intervertebral disk and adjacent vertebrae in which spondylodiskitis was suspected.

The authors of “Diagnostic Yield of [18F]FDG PET/CT in FUO: An Italian Multicenter Study of 929 Patients” include Domenico Albano and Francesco Bertagna, Department of Nuclear Medicine, University of Brescia, Brescia, Italy, and Department of Nuclear Medicine, ASST Spedali Civili di Brescia, Brescia, Italy; Francesco Lanfranchi and Matteo Bauckneht, Department of Health Science, University of Genoa, Genoa, Italy; Michela Massollo and Arnoldo Piccardo, Department of Nuclear Medicine, E.O. Ospedali Galliera, Genoa, Italy; Michele Balma, Simona Peano, and Virginia Liberini, Department of Nuclear Medicine, S. Croce e Carle, Cuneo, Italy; Alessandro Coccarelli and Silvia Morbelli, Department of Nuclear Medicine, Azienda Ospedaliero–Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Riccardo Laudicella and Giulia Giacoppo, Department of Biomedical, Dental Sciences and Morpho-Functional Imaging, Messina University, Messina, Italy; Selene Capitanio and Annalisa Franchini, Department of Nuclear Medicine, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Alfredo Muni, Alberto Miceli, and Roberta Piva, Department of Nuclear Medicine, Azienda Ospedaliera SS, Antonio E Biagio E Cesare Arrigo, Alessandria, Italy; Elisabetta Abenavoli, Department of Nuclear Medicine, Careggi University Hospital, Florence, Italy; Flavia Linguanti, Department of Nuclear Medicine, Ospedale San Donato, Arezzo, Italy; Angelina Filice and Rexhep Durmo, Department of Nuclear Medicine, Azienda Unità Sanitaria Locale–IRCCS di Reggio Emilia, Reggio Emilia, Italy; Cristina Ferrari, Claudia Battisti, and Giuseppe Rubini, Department of Nuclear Medicine, University Aldo Moro, Bari, Italy; Giulia Santo, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy; Elena Busnardo, Department of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy; Arturo Chiti, Department of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy, and Vita-Salute San Raffaele University, Milan, Italy; and Desiree Deandreis, Department of Nuclear Medicine, Gustave Roussy Cancer Campus, Villejuif, France.

Visit the JNM website for the latest research and follow our Twitter and Facebook pages @JournalofNucMed or follow us on LinkedIn.

###

Please visit the SNMMI Media Center for more information about molecular imaging and precision imaging. To schedule an interview with the researchers, please contact Rebecca Maxey at (703) 652-6772 or [email protected].

About JNM and the Society of Nuclear Medicine and Molecular Imaging

The Journal of Nuclear Medicine (JNM) is the world’s leading nuclear medicine, molecular imaging and theranostics journal, accessed 15 million times each year by practitioners around the globe, providing them with the information they need to advance this rapidly expanding field. Current and past issues of The Journal of Nuclear Medicine can be found online at http://jnm.snmjournals.org.

JNM is published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI), an international scientific and medical organization dedicated to advancing nuclear medicine, molecular imaging, and theranostics—precision medicine that allows diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes. For more information, visit www.snmmi.org.