Blood calprotectin as a biomarker for infection and sepsis - the prospective CASCADE trial

Abstract

Background: Early in the host-response to infection, neutrophils release calprotectin, triggering several immune signalling cascades. In acute infection management, identifying infected patients and stratifying these by risk of deterioration into sepsis, are crucial tasks. Recruiting a heterogenous population of patients with suspected infections from the emergency department, early in the care-path, the CASCADE trial aimed to evaluate the accuracy of blood calprotectin for detecting bacterial infections, estimating disease severity, and predicting clinical deterioration.

Methods: In a prospective, observational trial from February 2021 to August 2022, 395 patients (n = 194 clinically suspected infection; n = 201 controls) were enrolled. Blood samples were collected at enrolment. The accuracy of calprotectin to identify bacterial infections, and to predict and identify sepsis and mortality was analysed. These endpoints were determined by a panel of experts.

Results: The Area Under the Receiver Operating Characteristic (AUROC) of calprotectin for detecting bacterial infections was 0.90. For sepsis within 72 h, calprotectin's AUROC was 0.83. For 30-day mortality it was 0.78. In patients with diabetes, calprotectin had an AUROC of 0.94 for identifying bacterial infection.

Conclusions: Calprotectin showed notable accuracy for all endpoints. Using calprotectin in the emergency department could improve diagnosis and management of severe infections, in combination with current biomarkers.

Clinical trial registration number: DRKS00020521.

Keywords: Acute; Bacterial; Diagnostic; Emergency Department; Leukocyte L1 Antigen Complex; Plasma; Prognostic; S100A8; S100A9; Serum.

Fig. 1

Screening, enrolment and adjudication flowchart. Patient enrolment flowchart for the CASCADE trial. In total 402 patients were enrolled, of which 395 remained after exclusions. Case adjudication by pairs of specialist physicians resulted in the final segmentation by infection status

Fig. 2

Calprotectin identifying bacterial infections. (A) ROC of calprotectin identifying bacterial infections and (B) Distribution of calprotectin among patients with and without bacterial infections. This includes bacterial-viral co-infections as bacterial, and both non-infectious and viral conditions as non-bacterial. Since C-reactive protein and procalcitonin were used in the adjudication of these endpoints the ROCs are not shown here as comparators. These ROCs are available in supplemental Figure S3

Fig. 3

Multi-organ dysfunction and sepsis assessment. Patient adjudication flowchart explaining the trial definition of sepsis. Multi-organ dysfunction was assessed retrospectively via chart review using the Sequential Organ Failure Assessment organ systems. Patients adjudicated as having both an acute infection as well as multi-organ dysfunction were considered to have sepsis

Fig. 4

AUROCs for predicting sepsis and 30-day mortality. Performance of calprotectin in predicting (A) the occurrence of sepsis within 72 h of presentation, and (B) 30-day mortality, as compared to procalcitonin, CRP, and lactate. AUC = Area Under the Curve; CI = Confidence Interval

Fig. 5

Biomarkers for non-bacterial, uncomplicated bacterial, and septic patients. This figure shows a visual analysis of the distribution of biomarkers related to outcome. Density and jitter plots of (A) C-reactive protein, (B) procalcitonin, and (C) calprotectin are shown on a logarithmic scale for patients without bacterial infections (green), with uncomplicated bacterial infections (yellow), and with sepsis (red). Each point in the jitter plots reflects the biomarker concentration of a single patient, segmented by the outcomes of the patient. The density plots are normalized to all have equal areas.