Management of Fever of Unknown Origin

Definition and Classification

Fever of unknown origin (FUO) is defined as fever higher than 38.3°C (100.9°F) persisting for at least 3 weeks, with no diagnosis despite 3 outpatient visits or in-patient days, according to the European Journal of Nuclear Medicine and Molecular Imaging 1
FUO is divided into four subcategories: classical, nosocomial, neutropenic, and HIV-related, with etiology varying according to subcategory and geographical location, as stated by the European Journal of Nuclear Medicine and Molecular Imaging 1
Inflammation of unknown origin (IUO), defined as unexplained and prolonged elevation of inflammatory markers without fever, shares similar etiologies, as reported by the European Journal of Nuclear Medicine and Molecular Imaging 1

First-line laboratory testing should include complete blood count with differential, as recommended by MMWR Recommendations and Reports 3
Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) should be included in the initial diagnostic approach, according to the European Journal of Nuclear Medicine and Molecular Imaging 1
Chest radiography is recommended as part of the initial diagnostic approach, as stated by the Journal of the American College of Radiology 5

[18F]FDG PET/CT is highly recommended when initial workup is non-diagnostic, with high sensitivity (84-86%) and diagnostic yield of approximately 56%, as reported by the European Journal of Nuclear Medicine and Molecular Imaging 1
[18F]FDG PET/CT should ideally be performed within 3 days of initiation of oral glucocorticoid therapy, as recommended by the European Journal of Nuclear Medicine and Molecular Imaging 1
Consider myocardial suppression preparation when there is potential cardiac etiology, as stated by the European Journal of Nuclear Medicine and Molecular Imaging 1

Empiric therapy may be necessary in critically ill patients while awaiting diagnostic results, as recommended by MMWR Recommendations and Reports 3
For suspected bacterial infections without identified source, broad-spectrum antibiotics may be initiated, as stated by MMWR Recommendations and Reports 3
In cases of suspected tickborne rickettsial diseases, doxycycline should be considered, as recommended by MMWR Recommendations and Reports 6
For suspected autoimmune conditions like Adult-onset Still's disease, NSAIDs, corticosteroids, or immunosuppressive drugs may be indicated, as reported by Annals of the Rheumatic Diseases 7

Neutropenic patients require prompt evaluation and empiric antimicrobial therapy, as stated by Praxis Medical Insights: Practical Summaries of Clinical Guidelines, but a more reliable source is needed, however, the American College of Radiology recommends appropriate imaging tests for children with FUO, including chest radiography, whole body MRI, and FDG-PET/CT 8
In children with FUO, appropriate imaging tests include chest radiography, whole body MRI, and FDG-PET/CT, as recommended by the Journal of the American College of Radiology 8
For febrile infants and young children without signs of respiratory infection, medical management without imaging is usually appropriate, as stated by the Journal of the American College of Radiology 8
Early use of glucocorticoids may suppress inflammatory activity and lead to false negative results on imaging studies, as reported by the European Journal of Nuclear Medicine and Molecular Imaging 1