Diagnostic Approach to Fever Without Localizing Signs or Symptoms
Begin with chest radiography and at least two sets of blood cultures (ideally 60 mL total) drawn simultaneously from different anatomical sites before initiating any antibiotics, as these are the cornerstone initial investigations for fever of unknown origin. 1, 2
Initial Mandatory Workup
The following tests should be obtained in all patients presenting with isolated fever:
- Chest radiograph is recommended as the only first-line imaging study, given that pneumonia is the most common infection in febrile patients and may present without respiratory symptoms 1, 3
- Blood cultures: Collect at least two sets from different anatomical sites without interval between them, totaling at least 60 mL of blood 1, 2
- Complete blood count with differential to assess for leukocytosis, neutropenia, or other hematologic abnormalities 2, 3
- Inflammatory markers: C-reactive protein and erythrocyte sedimentation rate help risk-stratify patients and guide further testing 2, 3
- Comprehensive metabolic panel to identify hepatobiliary sources and assess organ function 2, 3
Critical Pitfall to Avoid
Never administer antibiotics before obtaining blood cultures, as this will obscure the diagnosis and reduce culture yield 2, 3, 4. The only exceptions are neutropenic patients or those who are critically ill and hemodynamically unstable 2, 4.
When Initial Workup is Unrevealing
If the above evaluation does not identify a source after 3 weeks of fever >38.3°C:
Advanced Imaging
- 18F-FDG PET/CT is the highest-yield advanced imaging modality, with diagnostic yield of 56% and sensitivity of 84-86% 2, 3
- PET/CT should ideally be performed within 3 days of starting oral glucocorticoid therapy if steroids are necessary 2, 3
- A negative PET/CT predicts favorable prognosis through spontaneous remission and may allow watchful waiting 2
Selective Imaging Based on Clinical Context
Do not routinely perform abdominal ultrasound or point-of-care ultrasound in patients without abdominal signs, symptoms, or liver function abnormalities 1
However, perform formal diagnostic abdominal ultrasound if any of the following are present 1:
- Recent abdominal, thoracic, or pelvic surgery
- Abdominal symptoms or abnormal physical examination
- Elevated transaminases, alkaline phosphatase, or bilirubin
For post-surgical patients (thoracic, abdominal, or pelvic surgery), perform CT imaging of the operative area if fever occurs several days postoperatively and no alternative cause is identified 1, 2
Special Populations
Patients with Central Venous Catheters
- Obtain simultaneous central and peripheral blood cultures to calculate differential time to positivity 1, 2
- Sample at least two lumens of the central catheter 1
- Do not systematically remove catheters in clinically stable patients unless there is microbiological evidence of catheter-related infection 2
Neutropenic Patients
- Initiate broad-spectrum antibiotics with antipseudomonal activity immediately before completing full workup 2, 3
- High-risk patients (neutrophils <100 cells/mm³ expected >7 days) should receive monotherapy with piperacillin-tazobactam as first-line treatment 2
Invasive Diagnostic Procedures
If noninvasive testing remains unrevealing, tissue biopsy has the highest diagnostic yield among invasive procedures 4. Consider the following based on clinical suspicion:
- Liver biopsy
- Lymph node biopsy
- Temporal artery biopsy (if giant cell arteritis suspected)
- Bone marrow biopsy
- Skin or skin-muscle biopsy
Management Principles
What NOT to Do
Avoid empiric antibiotics in non-neutropenic patients unless critically ill, as up to 75% of fever of unknown origin cases resolve spontaneously without definitive diagnosis 2, 3, 4
Do not use high-dose steroids without specific indication, as they increase risk of hospital-acquired infection, hyperglycemia, gastrointestinal bleeding, and delirium 2, 3
Avoid NSAIDs as they impair renal and coagulation function and increase stress ulcer risk 2, 3
Do not perform non-directed antibiotic changes or switch from one empirical regimen to another without clinical or microbiological justification 2
Rapid Molecular Testing
If rapid molecular tests on blood are performed, they must be used in conjunction with conventional blood cultures, never as replacement 1, 2
Temperature Monitoring
Central temperature monitoring methods are preferred when accurate measurements are critical, including thermistors for pulmonary artery catheters, bladder catheters, or esophageal balloon thermistors 1. For patients without these devices, use oral or rectal temperatures over less reliable methods such as axillary, tympanic, temporal artery, or chemical dot thermometers 1.
Key Clinical Principle
Most fever of unknown origin cases result from uncommon presentations of common diseases, not rare diseases 3, 4. The diagnostic approach should be clue-directed based on subtle findings in history, physical examination, and initial laboratory abnormalities rather than ordering extensive non-targeted testing early in the workup 5, 6.