Can fungal infections cause elevated Procalcitonin (PCT) levels?

Can Fungal Infections Cause Elevated Procalcitonin (PCT) Levels?

Fungal infections typically do NOT cause significant PCT elevation; PCT remains low or normal in most fungal infections, making low PCT levels (<0.5 ng/mL) a useful discriminator between bacterial and fungal infections. 1, 2

Understanding PCT Response in Fungal vs. Bacterial Infections

PCT is an inflammatory biomarker that shows marked elevation during bacterial infections but remains at low levels during viral and fungal infections. 1 This fundamental difference makes PCT valuable in distinguishing infection types:

• In bacterial infections: PCT typically rises to 0.5-2.0 ng/mL in systemic inflammatory response syndrome (SIRS), 2-10 ng/mL in severe sepsis, and >10 ng/mL in septic shock 1
• In fungal infections: PCT levels generally remain <0.5 ng/mL despite active systemic infection 1, 2

Clinical Evidence for PCT in Fungal Infections

Low Sensitivity of PCT for Fungal Detection

The evidence consistently demonstrates poor sensitivity of PCT for invasive fungal infections:

• In invasive aspergillosis: PCT was elevated in only 5.3% of patients in the early phase of infection 3
• In invasive candidiasis: PCT was elevated in fewer than half of episodes during the early phase 3
• Overall diagnostic value: Due to low sensitivity and specificity, PCT adds little to the diagnosis of invasive fungal infections 3

Diagnostic Pattern: High CRP with Low PCT

A characteristic pattern emerges in fungal infections: substantially elevated CRP (100-300 mg/L) combined with low PCT (<0.5 μg/L). 2 This combination offers:

• Specificity: 81% 2
• Sensitivity: 85% 2
• Positive predictive value: 73% 2
• Negative predictive value: 89% 2

Clinical Application in Specific Scenarios

COVID-19-Associated Fungal Infections

In patients with suspected COVID-19-associated pulmonary aspergillosis (CAPA), normal or low PCT levels despite clinical deterioration should raise suspicion for fungal rather than bacterial infection. 1

• Elevated PCT in COVID-19 patients indicates bacterial co-infection, not fungal superinfection 1, 4
• PCT <0.25 ng/mL has high negative predictive value for ruling out bacterial co-infections 1, 4

Immunocompromised Patients

In hematologic patients undergoing chemotherapy or stem cell transplantation:

• CRP elevations occur in all patients with infections (bacterial or fungal), with a tendency toward higher levels in bacterial infections 2
• PCT levels are significantly elevated in bacterial infections (especially gram-negative) but show minimal or no elevation in fungal infections 2

Important Caveats and Exceptions

Moderate PCT Elevation in Severe Fungal Disease

While most fungal infections keep PCT low, severe fungal infections with unfavorable outcomes may show moderate PCT elevation (0.5-1.0 ng/mL on day 3, ≥1.11 ng/mL by day 10). 5 This suggests:

• PCT levels may correlate with severity and outcome of systemic fungal infection 5
• Higher PCT in fungal infection may indicate worse prognosis rather than bacterial co-infection 5

Non-Infectious PCT Elevation

PCT can be elevated in non-infectious conditions including shock states and certain drug reactions, requiring clinical correlation. 1 This is particularly relevant in critically ill patients where multiple confounders exist.

Practical Clinical Algorithm

When evaluating a febrile patient with suspected infection:

1. Measure both PCT and CRP simultaneously 2
2. If PCT >0.5 ng/mL: Strongly consider bacterial infection; initiate or continue antibacterial therapy 1, 2
3. If PCT <0.5 ng/mL with CRP 100-300 mg/L: Suspect fungal infection; pursue fungal diagnostics (galactomannan, beta-D-glucan, imaging) 2
4. If PCT <0.25 ng/mL: High negative predictive value for bacterial infection; consider de-escalating antibiotics 4
5. Serial measurements are more valuable than single readings, particularly in ICU patients 4, 1

Diagnostic Limitations

The diagnostic value of PCT should not be considered in isolation but as part of a comprehensive diagnostic approach including clinical assessment, microbiological cultures, and other biomarkers. 1 The existing literature shows good diagnostic accuracy for PCT in discriminating between invasive fungal infections and bacterial infections, with pooled positive likelihood ratios of 4.65 (95% CI, 2.46-8.79) and negative likelihood ratios of 0.15 (95% CI, 0.05-0.41) 6. However, high heterogeneity in studies means medical decisions must integrate PCT results with clinical findings 6.