Role of PET/CT in Workup for Pyrexia of Unknown Origin (PUO)
[18F]FDG PET/CT should be considered a valuable second-line investigation in the diagnostic workup of PUO after standard initial evaluations have failed to identify the cause, with a high diagnostic yield of 56% and sensitivity of 84%. 1, 2
Diagnostic Performance of PET/CT in PUO
- Sensitivity: 84% (79-89%)
- Specificity: 62% (49-75%)
- Diagnostic yield: 56% (50-61%)
- Diagnostic accuracy: 76%
- Positive predictive value: 67-84.1%
- Negative predictive value: 80.9-100% 1, 2
The high negative predictive value is particularly valuable as it essentially rules out focal pathology as the cause of fever when negative.
Indications for PET/CT in PUO
Strongly Recommended:
- PUO without a diagnosis despite standard workup 1
- Cases where conventional imaging is negative or inconclusive 2
- Patients with elevated inflammatory markers (CRP, ESR) 1
Insufficient Evidence:
- Evaluation of patients with PUO and normal inflammatory markers 1
Optimal Timing and Protocol
- PET/CT should ideally be performed within 3 days of initiation of oral glucocorticoid therapy to avoid false negatives 1
- Consider myocardial suppression preparation when cardiac etiology is suspected 1
- Early implementation in the diagnostic workup may improve outcomes by allowing timelier diagnosis 2
Clinical Impact
PET/CT has demonstrated significant clinical impact in PUO management:
- Guides further investigations and biopsy when positive 1
- Directs specific treatment when the cause is established 1
- Predicts favorable prognosis through spontaneous remission when negative 1
- Leads to treatment modifications in approximately 53% of cases 2
- Cost-effective, particularly when performed early in the diagnostic workup 1
Common Diagnoses Identified by PET/CT in PUO
- Infectious causes (including pneumonia, abscesses)
- Malignancies (particularly lymphomas)
- Non-infectious inflammatory diseases (vasculitis, particularly aortoarteritis) 3
- Endocarditis (11%)
- Systemic juvenile idiopathic arthritis (5%)
- Inflammatory bowel disease (5%) 2
Advantages Over Other Imaging Modalities
- Wider diagnostic spectrum compared to labeled white blood cell scans 4
- Higher sensitivity compared to gallium-67 citrate scanning 4
- PET/CT technology improves specificity over PET alone 4
Potential Pitfalls and Limitations
False Positives:
- Recent surgical procedures
- Foreign body reactions
- Inadequate suppression of myocardial FDG uptake
- Physiological uptake in certain organs 2
False Negatives:
- Prior extended antibiotic therapy
- Small or mobile lesions
- Systemic diseases without focal manifestations 2
- Physiologic excretion of FDG in the urinary tract may interfere with detection of renal infections 5
Practical Recommendations
- Use PET/CT as a second-line investigation after initial standard workup fails to identify the cause of PUO 1, 3
- Particularly consider PET/CT in suspected non-infectious inflammatory disorders 3
- A negative PET/CT scan has excellent negative predictive value and can help rule out focal pathology 6
- For suspected renal infections, use diuretics and delayed imaging to improve detection 5
- PET/CT is especially valuable in evaluating patients with suspected focal infection or inflammation with a positive predictive value of 95% 7
The latest evidence from the 2025 EANM/SNMMI guideline strongly supports the use of [18F]FDG PET/CT in the diagnostic workup of PUO, particularly after standard initial evaluations have failed to identify the cause 1.