In a patient with Pyrexia of Unknown Origin where initial investigations are negative, should a whole body PET scan or whole body MRI be preferred as the initial imaging modality?

Imaging Sequence in Pyrexia of Unknown Origin: PET vs MRI

When initial investigations in PUO are negative, FDG-PET/CT should be preferred over whole body MRI as the next imaging modality. 1

Evidence Supporting FDG-PET/CT as First-Line Advanced Imaging

Diagnostic Performance

The American College of Radiology (2025) demonstrates that FDG-PET/CT has superior diagnostic yield with sensitivity of 80-100% and specificity of 66.7-79.2% in identifying the source of fever in PUO patients. 1 In the largest pediatric study of 110 patients, FDG-PET/CT identified the fever source in 48% of cases and led to treatment modifications in 53% of patients. 1

The most commonly detected causes include:

• Endocarditis (11% of cases) 1
• Systemic juvenile idiopathic arthritis (5%) 1
• Inflammatory bowel disease (5%) 1
• Occult abscesses and deep-seated infections 2

Clinical Impact

FDG-PET/CT demonstrates high clinical impact in 79% of cases, prompting specialist referrals or changes to antimicrobial/antifungal therapy. 1, 2 In immunosuppressed patients specifically, the accuracy reaches 88% in identifying the fever source. 2

Limited Evidence for Whole Body MRI

Insufficient Data

The American College of Radiology explicitly states there is no relevant literature to support the use of whole body MRI (with or without contrast) in the initial evaluation of PUO. 1 The few existing studies are limited:

• One small retrospective study of 24 adults showed 71% detection rate for inflammatory foci, with 50% having management changes 1
• A pediatric study of only 3 patients with FUO showed limited utility—identifying septic arthritis in one case and pneumonia in another 1
• Another pediatric review of 61 patients described whole body MRI as "useful to rule out oncologic disease and occult abscesses" but provided no specific diagnostic performance metrics 1

Guideline Recommendations

The ACR Appropriateness Criteria (2025) classify both FDG-PET/CT and whole body MRI as "may be appropriate" for PUO, but the evidence base strongly favors PET/CT. 1 FDG-PET/MRI is mentioned as having "potential usefulness" but insufficient data to support routine use. 1

Optimal Timing and Patient Selection

When to Perform FDG-PET/CT

• Perform within 3 days of initiating oral glucocorticoid therapy if steroids are necessary, as they suppress inflammatory activity and reduce diagnostic yield 2, 3
• Higher diagnostic yield occurs in patients with elevated inflammatory markers (CRP, ESR) 2, 3
• Extended antibiotic therapy prior to PET/CT may reduce inflammatory activity and cause false negatives 2

Patient Preparation

• Fast for 4-6 hours before FDG injection to minimize physiologic glucose uptake 2
• Maintain adequate hydration before and after FDG injection 2
• Check blood glucose levels before FDG administration (optimal <150-180 mg/dL) 2
• Consider myocardial suppression preparation (high-fat, low-carbohydrate diet for 24 hours) when cardiac etiology is suspected 2

Critical Caveats

False Positives

FDG-PET/CT can produce false positives due to:

• Recent valve implantation 2
• Inadequate suppression of myocardial FDG uptake 2
• Prior use of certain surgical adhesives 2

False Negatives

• Small or mobile vegetations in endocarditis may be missed 2
• Prior antibiotic use can mask inflammatory activity 2

Interpretation Challenges

Physiologic FDG uptake in brain, heart, urinary tract, and bowel must be distinguished from pathologic uptake. 2 This requires experienced nuclear medicine interpretation.

Practical Algorithm

1. Complete mandatory initial workup first: blood cultures (before antibiotics), CBC with differential, inflammatory markers (CRP, ESR), chest radiography if pulmonary symptoms present 3, 4

2. If initial workup negative and fever persists: Proceed directly to FDG-PET/CT whole body 1, 2

3. Reserve whole body MRI for specific scenarios where PET/CT is contraindicated or when ruling out specific anatomic abnormalities after PET/CT findings 1

4. Avoid empiric antibiotics in non-neutropenic patients unless critically ill, as they reduce diagnostic yield and up to 75% of cases resolve spontaneously 4

The evidence overwhelmingly supports FDG-PET/CT over whole body MRI as the preferred advanced imaging modality when initial PUO investigations are negative, based on superior diagnostic performance, extensive validation studies, and demonstrated clinical impact on management decisions.