What is the role and mechanism of Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans in diagnosing Pyrexia of Unknown Origin (PUO)?

FDG-PET/CT in Pyrexia of Unknown Origin: Mechanism and Role

FDG-PET/CT is highly recommended as a valuable second-line investigation in the diagnostic workup of pyrexia of unknown origin (PUO), with a high diagnostic yield of 56% and sensitivity of 84%. 1

Mechanism of FDG in PET Imaging

FDG (18F-fluorodeoxyglucose) is a glucose analog that accumulates in cells with high metabolic activity through the following mechanism:

• FDG is transported into cells via glucose transporters (primarily GLUT-1 and GLUT-3), which are overexpressed in:

  • Malignant cells
  • Activated inflammatory cells
  • Infectious foci 2

• Once inside the cell, FDG is phosphorylated by hexokinase to FDG-6-phosphate

• Unlike glucose, FDG-6-phosphate cannot proceed further in the glycolytic pathway

• FDG becomes trapped within metabolically active cells, allowing visualization on PET imaging

Diagnostic Performance in PUO

FDG-PET/CT demonstrates excellent diagnostic capabilities in PUO evaluation:

• 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

Clinical Role in PUO Management

When to Use FDG-PET/CT

FDG-PET/CT should be considered in patients with PUO when:

1. Initial standard workup fails to identify the cause
2. Inflammatory markers (ESR/CRP) are elevated 3
3. Conventional imaging is negative or inconclusive 1

Key Benefits

• Guides further investigations and directs biopsy sites when positive
• Leads to treatment modifications in approximately 53% of cases 1
• Provides whole-body assessment in a single examination
• High negative predictive value essentially rules out focal pathology as the cause of fever 4
• More cost-effective when performed early in the diagnostic workup 1

Common Diagnoses Identified by FDG-PET/CT in PUO

1. Infections (43% of cases) 5

   • Focal abdominal, thoracic, or soft-tissue infections
   • Chronic osteomyelitis
   • Orthopedic prosthetic infections

2. Non-infectious inflammatory diseases (16% of cases) 5

   • Large-vessel vasculitis
   • Inflammatory bowel disease
   • Sarcoidosis
   • Systemic juvenile idiopathic arthritis (5%)

3. Malignancies (14% of cases) 5

   • Lymphomas (Hodgkin's and aggressive non-Hodgkin's)
   • Colorectal cancer
   • Sarcomas

4. Other specific diagnoses:

   • Endocarditis (11%) 1
   • Splenic abscesses 1

Practical Considerations

Timing and Preparation

• Perform FDG-PET/CT within 3 days of initiating oral glucocorticoid therapy to avoid false negatives
• Consider myocardial suppression preparation when cardiac etiology is suspected 1
• Prior extended antibiotic therapy may reduce sensitivity 1

Predictors of Positive Results

• Short duration of fever
• Male gender
• Elevated inflammatory markers (ESR/CRP) 5

Limitations and Pitfalls

• False positives can occur due to:

  • Recent surgical procedures
  • Foreign body reactions
  • Physiological uptake in certain organs

• False negatives can occur due to:

  • Prior extended antibiotic therapy
  • Small or mobile lesions
  • Systemic diseases without focal manifestations 1
  • Normal ESR and CRP (FDG-PET/CT is not helpful in these cases) 3

Emerging Technologies

PET/MRI shows potential but currently has insufficient data to support routine use in PUO evaluation 1, 6.

Comparative Advantages

FDG-PET/CT has several advantages over other imaging modalities:

• Diagnoses a wider spectrum of diseases compared to labeled white blood cell scans
• Higher sensitivity compared to gallium-67 citrate scanning 2
• Provides both functional and anatomical information in a single examination

In conclusion, FDG-PET/CT plays a crucial role in the diagnostic algorithm for PUO, particularly when conventional methods fail to identify the cause, and should be considered early in the evaluation of patients with persistent unexplained fever and elevated inflammatory markers.