What are the biomarkers for sepsis?

Biomarkers for Sepsis

The most clinically useful biomarkers for sepsis are procalcitonin (PCT) and C-reactive protein (CRP), with PCT demonstrating superior diagnostic accuracy and faster kinetics for bacterial infections. 1

Primary Biomarkers

Procalcitonin (PCT)

• PCT rises within 4 hours of bacterial exposure and reaches maximum levels after 6-8 hours, making it the fastest-responding biomarker for sepsis 2, 1
• PCT levels ≥1.5 ng/mL demonstrate 100% sensitivity and 72% specificity for identifying sepsis in ICU populations 1
• PCT has superior diagnostic accuracy compared to CRP, with an area under the ROC curve of 0.85 versus 0.73 for CRP 1
• PCT levels correlate with sepsis severity and decrease rapidly after appropriate antibiotic treatment 2, 3
• The Surviving Sepsis Campaign recommends using low PCT levels to assist in discontinuing empiric antibiotics in patients who initially appeared septic but have no subsequent evidence of infection (Grade 2C) 2

C-Reactive Protein (CRP)

• CRP rises 12-24 hours after inflammatory or infectious insult, reaching maximum values after 48 hours 2, 1
• CRP levels ≥50 mg/L demonstrate 98.5% sensitivity and 75% specificity for identifying probable or definite sepsis 1
• CRP is less specific than PCT for bacterial infections but remains widely available and cost-effective 2

Clinical Application Guidelines

When to Use Biomarkers

• For low-to-intermediate probability of bacterial infection with new fever and no clear focus: measure either PCT or CRP in addition to bedside clinical evaluation 2
• For high probability of bacterial infection: do not rely on PCT or CRP to rule out infection; proceed with empiric antimicrobial therapy 2
• Biomarker kinetics (serial measurements) are more useful than single values for diagnosis and assessing treatment response 3

Limitations and Caveats

• No single biomarker can accurately differentiate sepsis from other causes of systemic inflammatory response syndrome (SIRS) 1, 3
• Biomarkers must be integrated with clinical examination and directed diagnostic techniques, not used in isolation 1
• PCT may be elevated in severe viral illnesses including influenza and COVID-19, reducing its discriminatory power 2
• In cirrhotic patients, lactate clearance is impaired and inflammatory markers are often elevated even without infection, though persistent elevation indicates poor prognosis 2
• Traditional markers like white blood cell count lack sufficient sensitivity to distinguish sepsis in hospitalized patients 1

Additional Biomarkers

Lactate

• Lactate >4 mmol/L defines sepsis-induced tissue hypoperfusion and triggers resuscitation protocols 2
• Normalizing lactate rapidly is a resuscitation target in patients with elevated levels (Grade 2C) 2
• Lactate interpretation is complicated in liver dysfunction where clearance is impaired 2

Composite Biomarker Panels

• Combinations of PCT, neutrophil-lymphocyte count ratio (NLCR), CRP, and lactate improve diagnostic accuracy for severe bacterial sepsis or septic shock (AUC 0.85-0.86) compared to single biomarkers 4
• For less severe septic conditions, either NLCR or PCT alone exhibit equivalent performance to composite panels 4

Emerging Biomarkers

• 1,3-β-D-glucan assay (Grade 2B) and mannan/anti-mannan antibody assays (Grade 2C) should be used when invasive candidiasis is in the differential diagnosis 2
• Interleukin-6 (IL-6) has been studied but lacks consistent cut-off values and clinical utility remains uncertain 2
• Endogenous damage-associated molecular patterns (DAMPs) including mitochondrial DNA and HMGB1 show promise but require further validation 2

Practical Algorithm for Biomarker Use

1. Obtain blood cultures before antimicrobials if no delay >45 minutes 2
2. Measure lactate immediately in all suspected sepsis cases 2
3. For unclear infection probability: obtain baseline PCT or CRP 2
4. Initiate antimicrobials within 1 hour regardless of biomarker results if clinical suspicion is high 2
5. Repeat PCT/CRP at 24-48 hours to assess treatment response and guide antibiotic discontinuation 2, 3
6. Consider fungal biomarkers (1,3-β-D-glucan) if not responding to antibiotics 2