Workup for Procalcitonin Negative Fever
A comprehensive workup for a patient with procalcitonin (PCT) negative fever should focus on both infectious and non-infectious causes, as a negative PCT has high negative predictive value for bacterial infections but does not rule out all causes of fever. 1
Understanding PCT Negative Fever
- PCT levels typically rise within 2-3 hours of bacterial infection onset, with higher levels correlating with infection severity (0.6-2.0 ng/mL for SIRS, 2-10 ng/mL for severe sepsis, >10 ng/mL for septic shock) 1, 2
- PCT levels <0.5 ng/mL have a high negative predictive value (96-98.6%) for bacterial infections, particularly for gram-negative infections 1, 3
- Important limitations: PCT may not elevate with certain pathogens, including gram-positive bacteria, and some viral infections can cause PCT elevation 4, 2
Initial Diagnostic Approach
- Obtain detailed history focusing on recent surgeries, immunocompromised status, drug exposures, and travel history 1
- Perform thorough physical examination to identify potential sources of infection not detected by PCT 1
- Order basic laboratory tests:
Imaging Studies
- Chest radiography should be performed to evaluate for pneumonia, though bedside chest X-rays have low positive predictive value in critically ill patients 1
- For patients with recent thoracic, abdominal, or pelvic surgery, CT imaging should be considered if an etiology is not readily identified by initial workup 1
- Abdominal ultrasound is recommended for patients with:
- Recent abdominal surgery
- Abdominal symptoms or abnormal physical examination
- Elevated liver enzymes or bilirubin 1
- For patients with persistent fever of unknown origin after initial workup, consider 18F-FDG PET/CT if transport risk is acceptable 1
Non-Infectious Causes to Consider
- Drug-induced fever (may take up to 21 days after administration to develop and 1-7 days to resolve after discontinuation) 1
- Malignant hyperthermia and neuroleptic malignant syndrome (rare but important considerations with high fever) 1, 2
- Serotonin syndrome (may be confused with neuroleptic malignant syndrome) 1
- Shock states including cardiogenic and hemorrhagic shock can elevate temperature independent of infection 2
Special Considerations
- PCT ratio (day 1 to day 2) following surgical procedures can help indicate successful surgical intervention, with a ratio >1.14 suggesting successful source control 1
- For patients with suspected skin and soft tissue infections, even with negative PCT, aggressive broad-spectrum empiric antimicrobial therapy should be considered until culture results are available 1
- In patients with neutropenia, PCT has poor sensitivity for infection, particularly with gram-positive organisms, so additional workup is essential despite negative PCT 4
Follow-up Testing
- Serial PCT measurements may be more valuable than a single reading, particularly in post-surgical patients 1
- Consider C-reactive protein (CRP) as a complementary marker, as combining PCT, CRP, and WBC count improves diagnostic accuracy for bacterial infections 6, 5
- If fever persists without clear etiology after initial workup, consider specialized testing based on clinical suspicion (e.g., endocarditis workup, bone marrow evaluation) 1
Pitfalls to Avoid
- Do not rely solely on PCT to rule out infection, as sensitivity varies by pathogen type 4
- Avoid assuming all PCT-negative fevers are non-infectious, as gram-positive infections may not elevate PCT 4
- Remember that PCT can be elevated in non-infectious conditions including shock states and drug reactions 2
- Do not delay empiric antibiotic therapy in critically ill patients while awaiting PCT results if bacterial infection is clinically suspected 1