Work

Circulating calprotectin and S100A8/A9-related biomarkers for diagnosis and prognostic stratification in adult acute infection and sepsis: a systematic review and meta-analysis

Year: 2026

Type: review

Study designs: Systematic Review, Meta-Analysis

Abstract: Background: Circulating calprotectin is a proposed marker of acute innate immune activation, but reported diagnostic and prognostic performance is inconsistent. We assessed circulating calprotectin and S100A8/A9-related biomarkers for diagnosing acute infection and sepsis and stratifying prognosis in adults. Methods: We searched biomedical databases and trial registries through July 4, 2026, for adult studies of circulating calprotectin/S100A8/A9 in acute infection or sepsis. Random-effects models pooled diagnostic and reported prognostic areas under the receiver operating characteristic curve (AUC). Threshold-based sensitivity and specificity were analyzed separately using bivariate random-effects models. We used the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess diagnostic risk of bias and evidence certainty. Exploratory subgroup, sensitivity, biomarker-comparison, and combined-model analyses were also performed. Results: Twenty-two reports representing 21 independent cohorts were included. The primary diagnostic meta-analysis yielded a pooled AUC of 0.741 (95% confidence interval [CI], 0.657-0.810). The pooled AUC was 0.703 (95% CI, 0.600-0.789) for sepsis and 0.758 (95% CI, 0.636-0.849) for acute infection or infection-source-related outcomes. In separate threshold-based analyses, pooled sensitivity and specificity were 0.70 (95% CI, 0.46-0.86) and 0.57 (95% CI, 0.55-0.59) for sepsis, and 0.46 (95% CI, 0.09-0.88) and 0.86 (95% CI, 0.60-0.96) for acute infection or infection-source-related outcomes, respectively. For mortality/survival outcomes, pooled sensitivity and specificity were 0.72 (95% CI, 0.65-0.77) and 0.66 (95% CI, 0.53-0.77), respectively, while the pooled reported prognostic AUC was 0.737 (95% CI, 0.688-0.786). Exploratory analyses were directionally stable, but paired biomarker comparisons did not provide definitive evidence of superiority. Certainty was very low for all major outcomes. Conclusions: Circulating calprotectin and S100A8/A9-related biomarkers provide moderate, context-dependent information in adult acute infection and sepsis. They may serve as adjunctive host-response markers, particularly for selected infection/source contrasts, but current evidence does not support stand-alone diagnosis, universal thresholds, or replacement of established biomarkers and clinical assessment. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261441569, identifier CRD420261441569.

Source: Frontiers in Cellular and Infection Microbiology

DOI: 10.3389/fcimb.2026.1934020