What are the causes of a raised procalcitonin level?

Causes of Raised Procalcitonin

Severe systemic bacterial infections and sepsis are the predominant cause of procalcitonin elevation, with levels rising within 4 hours of bacterial exposure and peaking at 6-8 hours. 1, 2

Primary Infectious Causes

Bacterial Infections

• Severe sepsis and septic shock are the most common causes, with PCT levels reaching 2-10 ng/mL in severe sepsis and exceeding 10 ng/mL in septic shock 1, 3
• Ventilator-associated pneumonia (VAP) in ICU patients causes significant PCT elevation and is the only biomarker that reliably differentiates VAP from non-VAP cases 1
• Nosocomial or secondary bacterial infections in hospitalized patients, particularly in ICU settings, cause serial PCT rises 1
• Local bacterial infections such as pneumonia and pyelonephritis cause moderate PCT elevation 4
• Bacterial meningitis results in marked PCT elevation 4

Parasitic Infections

• Severe falciparum malaria can cause false PCT elevation mimicking bacterial sepsis 1
• Parasitic infections generally trigger PCT production through similar inflammatory pathways as bacterial infections 5

Fungal Infections

• Invasive fungal infections trigger extrathyroidal procalcitonin production through systemic release of proinflammatory cytokines (TNF-α, IL-6, IL-8) 1
• COVID-19-associated pulmonary aspergillosis (CAPA) occurs in 10.2-14.9% of severe COVID-19 patients, though PCT interpretation is confounded by the hyperinflammatory state 6

Non-Infectious Inflammatory Causes

Respiratory Conditions

• Acute respiratory distress syndrome (ARDS) can cause false PCT elevation without bacterial infection 1
• Chemical pneumonitis may falsely elevate PCT levels 1

Viral Infections (Important Caveat)

• Severe COVID-19 can elevate PCT in approximately 21% of cases without bacterial co-infection due to hyperinflammatory state or cytokine storm, though rarely above 10 ng/mL 1, 2
• Severe influenza can elevate PCT despite absence of bacterial co-infection 1
• The hyperinflammatory state in COVID-19 may result in higher PCT production than other viral pneumonias 1, 6

Critical distinction: Viral infections typically do NOT elevate PCT or cause only moderate elevation, making bacterial infection the primary consideration when PCT is significantly raised. 4, 5

Clinical Interpretation by PCT Level

The Society of Critical Care Medicine and American College of Critical Care Medicine provide the following thresholds 1, 2:

• <0.05 ng/mL: Normal range in healthy individuals
• 0.5-2.0 ng/mL: Systemic inflammatory response syndrome (SIRS)
• 2.0-10 ng/mL: Severe sepsis
• >10 ng/mL: Septic shock
• ≥8 ng/mL: Strongly indicates bacterial sepsis (approximately 160 times higher than normal)

Important Clinical Caveats

Timing Considerations

• Early sampling (<6 hours from admission) may produce false-negative results since PCT requires 2-3 hours to rise and 6-8 hours to peak 1, 6
• PCT rises approximately 4 hours after bacterial exposure, significantly faster than CRP (12-24 hours) 2

Patient-Specific Factors

• Renal function markedly influences PCT levels, and different renal replacement therapy techniques affect measurements 1, 2
• Patients with cirrhosis may have elevated PCT both with and without infection, though persistent elevation indicates poor prognosis 1

Serial Measurements

• Serial measurements are more predictive than single point measurements, especially in ICU patients 1, 6
• A 50% rise in PCT from previous value at any time point is significantly associated with secondary bacterial infection 1
• Decreasing PCT by >25% from peak indicates treatment response and improved outcomes 1, 2

Diagnostic Limitations

• PCT has 77-83% specificity for bacterial infections, meaning a 17-23% false positive rate 1
• No single PCT threshold can reliably distinguish viral from bacterial pneumonia, so PCT should never be used in isolation for antibiotic decisions 1
• Chronic inflammatory states do NOT typically elevate PCT, making it specific for acute processes 1, 2