Evaluation Algorithm for Pyrexia of Unknown Origin

Definition and Classification

The American College of Physicians defines pyrexia of unknown origin (PUO) 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, with a classification into four subcategories: classical, nosocomial, neutropenic, and HIV-related 1, 2
Inflammation of unknown origin (IUO) shares similar etiologies with PUO, defined as unexplained and prolonged elevation of inflammatory markers without fever 1, 2

First-line laboratory testing should include complete blood count with differential, inflammatory markers, blood cultures, urinalysis, urine culture, liver function tests, and basic imaging such as chest radiography, according to the European Society of Clinical Microbiology and Infectious Diseases 1, 3
The Infectious Diseases Society of America recommends that blood cultures should be taken at least 3 sets, before antibiotics 3

The European Journal of Nuclear Medicine and Molecular Imaging recommends FDG-PET/CT as the most valuable second-line imaging modality when initial workup fails to identify the cause, with high sensitivity (84-86%) and diagnostic yield of approximately 56% 1, 2
The American College of Radiology suggests that CT of abdomen and pelvis with IV contrast should be considered as a second-line investigation 4, 5
The Journal of the American College of Radiology recommends whole body MRI as a potential third-line investigation, especially in pediatric patients 4, 6

The American College of Physicians recommends prompt evaluation and empiric antimicrobial therapy for neutropenic patients, with consideration of imaging tests to identify sources of infection 1, 4
The Journal of the American College of Radiology suggests that appropriate imaging tests for pediatric patients include chest radiography, whole body MRI, and FDG-PET/CT 4, 6
The Journal of Travel Medicine recommends that all patients with relevant travel history should have an assessment for viral hemorrhagic fever risk, with up to three daily blood films to exclude malaria 7, 8

The European Society of Clinical Microbiology and Infectious Diseases recommends an initial evaluation (0-72 hours) including thorough history and physical examination, first-line laboratory tests, and chest radiography 1, 4
The American College of Radiology suggests a secondary evaluation (72-96 hours if fever persists) including targeted CT imaging based on clinical findings, specialized blood tests based on exposure and risk factors, and consideration of infectious disease consultation 4, 5
The Journal of Nuclear Medicine recommends a tertiary evaluation (>96 hours if diagnosis remains elusive) including FDG-PET/CT as the preferred advanced imaging modality, tissue biopsy of suspicious lesions, and consideration of multidisciplinary discussion for complex cases 4, 6

The American College of Radiology defines prolonged fever in children as a temperature persisting more than 3 weeks without an identifiable cause after the initial work‑up, and in adults as fever > 38.3 °C for at least 3 weeks despite three outpatient evaluations or days of hospitalization. 9, 10
“Fever without source” (FWS) is an acute febrile episode in which no origin is apparent after a thorough history, physical examination, and initial laboratory testing. 9, 10
Pediatric fever of unknown origin (FUO) is defined as fever lasting > 3 weeks without an identifiable infectious source. 9, 10

In infants ≤ 90 days with prolonged fever, the prevalence of invasive bacterial infection is 1–2 %; therefore, clinicians should maintain a low threshold for further evaluation. 9, 10
In neonates < 28 days, the risk of serious bacterial infection is even higher, warranting a more aggressive diagnostic approach. 9, 10
Kawasaki disease must be considered in any child with unexplained fever lasting ≥ 5 days, especially in those < 1 year where incomplete presentations are common and the risk of coronary artery aneurysms is increased. 11

For patients with neutropenia, fever is deemed prolonged when it persists > 4–7 days despite appropriate antimicrobial therapy, raising suspicion for abscess formation, resistant organisms, or the need for surgical intervention. 12
High‑risk neutropenic patients are those expected to have profound neutropenia for > 7 days (absolute neutrophil count < 100 cells/µL). 12

After > 3 weeks of fever without a diagnosis, the classic definition of FUO is fulfilled. 9, 10