Sepsis presents a diagnostic challenge because bacterial sepsis and sterile inflammation from trauma, surgery, or ischemia activate overlapping immune pathways. Distinguishing them is critical: accurate identification of bacterial infection guides prompt antibiotic therapy, while false-positive diagnoses drive unnecessary antibiotics, fueling antimicrobial resistance and harming patients.
Common plasma biomarkers
Procalcitonin is the most widely studied single biomarker for bacterial infection. Philipp Schuetz University Hospital Basel has led randomized trials and meta-analyses showing that PCT-guided algorithms can safely reduce antibiotic exposure in respiratory and critically ill patients. C-reactive protein is a sensitive marker of acute-phase inflammation but is less specific for bacterial infection because viral infections, autoimmune flares, and tissue injury also raise CRP. Cytokines such as interleukin-6 and acute neutrophil activation markers rise early in both infectious and noninfectious inflammation, which limits their standalone diagnostic value. Timing matters: early sampling, the kinetics of marker rise and fall, and prior interventions such as antibiotics strongly influence interpretation.
Host gene-expression signatures
Advances in transcriptomics have produced host-response classifiers that better discriminate bacterial infection from sterile inflammation. Purvesh Khatri Stanford University and Timothy Sweeney Icahn School of Medicine at Mount Sinai have published meta-analyses and multicohort studies identifying small panels of host mRNAs whose expression patterns differ between bacterial and nonbacterial inflammatory states. These gene-expression signatures reflect coordinated innate immune and interferon responses that differ by pathogen class and by noninfectious triggers. Such molecular tests can outperform single proteins in heterogeneous clinical cohorts, but they require standardized sampling and validated algorithms before routine bedside use.
Causes and consequences of diagnostic uncertainty extend beyond individual care. Misclassification can prolong hospital stays, increase adverse drug effects, and accelerate community-level antimicrobial resistance, with environmental and territorial implications in regions where broad-spectrum antibiotics are readily available. Cultural and resource factors shape which biomarkers are feasible: low-resource settings often rely on clinical assessment and basic tests such as CRP, while tertiary centers may access advanced molecular assays.
Clinical best practice integrates biomarker data with bedside assessment, imaging, and microbiology. Continued multicenter validation led by recognized researchers and institutions is needed to translate promising host-response tools into equitable, actionable diagnostics. No single biomarker is definitive; a combined, context-aware approach achieves the best balance between timely treatment and stewardship.