What are the markers of sepsis in serum, including C-reactive protein (CRP), procalcitonin (PCT), and cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha)?

Serum Markers of Sepsis

Primary Recommendation

Procalcitonin (PCT) is the single most valuable serum marker for diagnosing sepsis and predicting severity, with levels ≥1.5 ng/mL having 100% sensitivity and 72% specificity for identifying sepsis, and levels >10 ng/mL indicating septic shock. 1, 2

Procalcitonin (PCT): The Superior Marker

PCT outperforms all other inflammatory markers for sepsis diagnosis and prognostication. 3, 4

• PCT rises within 2-3 hours of bacterial exposure, peaks at 6-8 hours, and clears more rapidly than other markers as inflammation resolves 2
• Diagnostic thresholds:
  • <0.5 ng/mL: Sepsis unlikely 2
  • 0.5-2.0 ng/mL: Systemic inflammatory response syndrome 2
  • 2.0-10 ng/mL: Severe sepsis 2

  • 10 ng/mL: Septic shock 2

• PCT levels ≥1.5 ng/mL demonstrate 100% sensitivity and 72% specificity for sepsis in ICU patients 1
• PCT correlates directly with sepsis severity and mortality better than IL-6, TNF-α, or CRP 5
• Serial PCT measurements are more valuable than single measurements—a 50% rise from baseline strongly indicates secondary bacterial infection 2
• Decreasing PCT by >25% indicates treatment response and improved survival 2

Critical PCT Caveats

• Early sampling (<6 hours from symptom onset) may produce false-negative results 2
• Severe viral illnesses (influenza, COVID-19) can falsely elevate PCT despite absence of bacterial co-infection 2
• Renal dysfunction and renal replacement therapy significantly affect PCT levels 2

C-Reactive Protein (CRP): Complementary Marker

CRP is a useful adjunct marker but inferior to PCT for sepsis diagnosis. 1

• CRP ≥50 mg/L has 98.5% sensitivity and 75% specificity for identifying probable or definite sepsis 1
• CRP rises more slowly than PCT and clears more slowly during resolution 1
• Persistent CRP >100 mg/L beyond postoperative day 5 may indicate abscess or septic complications 1
• CRP correlates with degree of inflammatory response and is valuable for monitoring treatment response 1

Interleukin-6 (IL-6): Prognostic Value

IL-6 is significantly correlated with sepsis severity, septic shock development, and mortality, making it superior to other cytokines for prognostic assessment. 6, 7

• IL-6 levels >1000 pg/mL are associated with significantly increased mortality 7
• IL-6 correlates directly with APACHE II scores and temperature 7
• IL-6 remains elevated in non-survivors while decreasing in survivors 7
• Major limitation: Wide range of cut-off values (12-2760 pg/mL) across studies prevents standardized clinical use 1, 6
• IL-6 assays require rapid sample processing and freezing to -70°C, limiting routine clinical utility 1

Tumor Necrosis Factor-Alpha (TNF-α): Limited Clinical Utility

TNF-α has minimal clinical utility as a sepsis marker due to its transient nature and lack of prognostic value. 5, 7

• TNF-α levels are typically <100 pg/mL except during acute septic shock episodes 7
• TNF-α elevations are brief (lasting only hours), making timing of measurement critical 7
• TNF-α shows no significant difference between survivors and non-survivors 5
• Short half-life and analyte instability limit clinical applicability 1

Serum Amyloid A (SAA): Emerging Marker

SAA is an independent predictor of sepsis when combined with PCT and CRP in trauma patients. 8

• A bioscore combining SAA, CRP, and PCT is superior to any single marker for predicting sepsis in severe trauma 8
• SAA remains primarily a research tool with limited standardization 1

Optimal Clinical Algorithm

For suspected sepsis, obtain PCT and CRP immediately upon clinical suspicion (fever, chills, hypothermia, leukocytosis, neutropenia, hemodynamic compromise, or renal failure). 1

1. If PCT ≥1.5 ng/mL or CRP ≥50 mg/L: Sepsis is highly likely—initiate appropriate antimicrobial therapy and obtain blood cultures 1
2. Repeat PCT daily—a 50% increase indicates worsening infection; a >25% decrease indicates treatment response 2
3. If PCT remains <0.5 ng/mL after 6-8 hours: Consider alternative diagnoses 2
4. Blood cultures should be drawn immediately before scheduled antibiotic doses to minimize interference 1

Key Pitfalls to Avoid

• Do not rely on traditional markers (neutrophilia, fever) alone—they lack sufficient specificity in hospitalized patients 1
• Do not draw PCT too early (<6 hours)—wait for adequate time to rise 2
• Do not use IL-6 or TNF-α for routine clinical decision-making—they remain research tools requiring specialized handling 1
• Do not interpret single PCT or CRP values in isolation—serial measurements provide superior diagnostic and prognostic information 1, 2