Diagnostic Approach to Pyrexia of Unknown Origin (PUO)

Definition and Classification

Pyrexia of Unknown Origin (PUO) 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 2

The initial step in evaluating a patient with PUO should be a thorough clinical history and detailed physical examination, followed by basic laboratory testing to guide further diagnostic workup, as recommended by Praxis Medical Insights 1
Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) should be included in the first-line laboratory testing, as suggested by the European Journal of Nuclear Medicine and Molecular Imaging and Praxis Medical Insights 2, 1
Chest radiography should be performed if pulmonary symptoms are present or if there is concern for atypical bacterial infection, tuberculosis, or oncologic processes, according to the Journal of the American College of Radiology 3, 4

If fever persists after initial evaluation (72-96 hours), consider advanced imaging such as thoracic CT scan, as recommended by Annals of Oncology 5
Bronchoalveolar lavage (BAL) should be performed within 24 hours if lung infiltrates are detected on CT scan, and BAL samples should be processed within 4 hours of collection, as suggested by Annals of Oncology 5

FDG-PET/CT is recommended as a valuable second-line imaging modality when initial workup fails to identify the cause, with high sensitivity (84-86%) in identifying the source of fever, according to Praxis Medical Insights and European Journal of Nuclear Medicine and Molecular Imaging 1, 2
The diagnostic yield of FDG-PET/CT is approximately 56% in patients with PUO, and it should ideally be performed within 3 days of initiation of oral glucocorticoid therapy, as recommended by European Journal of Nuclear Medicine and Molecular Imaging and Praxis Medical Insights 2, 1

Neutropenic patients require prompt evaluation and empiric antimicrobial therapy, and consider imaging tests to identify sources of infection, including chest radiography, CT of paranasal sinuses, chest CT, and CT of abdomen and pelvis with IV contrast, according to Annals of Oncology and Journal of the American College of Radiology 6, 5, 4
In children with PUO, imaging tests that may be appropriate include chest radiography, whole body MRI, and FDG-PET/CT, as recommended by Journal of the American College of Radiology 3, 4
For febrile infants and young children without signs of respiratory infection, medical management without imaging is usually appropriate, according to Journal of the American College of Radiology 3, 4

Avoid premature closure on a diagnosis before adequate evaluation, and do not initiate empiric antimicrobial therapy before obtaining appropriate cultures, as this may mask the underlying cause, according to Annals of Oncology 5
Be aware that early use of glucocorticoids may suppress inflammatory activity and lead to false negative results on imaging studies, as recommended by European Journal of Nuclear Medicine and Molecular Imaging and Praxis Medical Insights 2, 1