Soluble fms-like tyrosine kinase 1, placental growth factor and procalcitonin as biomarkers of gram-negative sepsis: Analysis through a derivation and a validation cohort

Vasileios Vittoros, Evdoxia Kyriazopoulou, Malvina Lada, Iraklis Tsangaris, Ioannis M Koutelidakis, Evangelos J Giamarellos-Bourboulis, Vasileios Vittoros, Evdoxia Kyriazopoulou, Malvina Lada, Iraklis Tsangaris, Ioannis M Koutelidakis, Evangelos J Giamarellos-Bourboulis

Abstract

Further improvement of the diagnostic and prognostic performance of biomarkers for the critically ill is needed. Procalcitonin (PCT), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 raise interest for sepsis diagnosis and prognosis.Serum samples from 2 cohorts of 172 patients (derivation cohort) and of 164 patients (validation cohort) comprising only patients with microbiologically confirmed gram-negative infections were analyzed. PlGF, s-Flt-1 and procalcitonin (PCT) were measured in serum within 24 hours from sepsis onset and repeated on days 3 and 7.PCT and s-Flt-1 baseline levels were higher in sepsis and septic shock compared to non-sepsis; this was not the case for PlGF. s-Flt-1 at concentrations greater than 60 pg/ml diagnosed sepsis with sensitivity 72.3% and specificity 54.9% whereas at concentrations greater than 70 pg/ml predicted unfavorable outcome with specificity 73.0% and sensitivity 63.7%. At least 80% decrease of PCT and/or PCT less than 0.5 ng/ml on day 7 was protective from sepsis-associated death.Both s-Flt-1 and PCT should be measured in the critically ill since they provide additive information for sepsis diagnosis and prognosis.ClinicalTrials.gov numbers NCT01223690 and NCT00297674.

Conflict of interest statement

E.J. Giamarellos-Bourboulis has received honoraria from Abbott CH, Brahms GmbH, bioMérieux Inc, InflaRx GmbH, MSD Greece, Sobi and XBiotech Inc; independent educational grants from Abbott CH, Astellas Pharma Europe, AxisShield, bioMérieux Inc, InflaRx GmbH, Sobi and XBiotech Inc.; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis). The other authors have no conflicts of interest to disclose.

Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.

Figures

Figure 1
Figure 1
Study flow chart. PCT = procalcitonin, PlGF = placental growth factor, s-Flt-1 = soluble fms-like tyrosine kinase-1, SIRS = systemic inflammatory response syndrome.
Figure 2
Figure 2
Overtime changes of biomarkers in the derivation cohort. Serum concentrations of procalcitonin (PCT) (A) and of soluble fms-like tyrosine kinase-1 (s-Flt-1) (B) on days 1 (baseline), 3, and 7. P values of the indicated comparisons are provided. Comparisons are done by the Wilcoxon rank sum test.
Figure 3
Figure 3
Serum procalcitonin (PCT) as surrogate marker of final outcome. (A) ROC curves of percent change of serum procalcitonin (PCT), of placental growth factor (PlGF) and of soluble fms-like tyrosine kinase-1 (s-Flt-1) between baseline day 1 and 7 for the prognosis of unfavorable outcome; AUC = area under the curve. Kaplan-Meier curves of survival in the derivation (B) and (C) validation cohorts. Yes and No applies to meeting or not meeting the following criteria of kinetic change on day 7: at least 80% decrease of PCT and/or PCTP values of significance are provided.
Figure 4
Figure 4
Biomarkers for the diagnosis of sepsis. Derivation cohort: comparison of serum levels of (A) procalcitonin (PCT); (B) soluble fms-like tyrosine kinase-1 (s-Flt-1); and (C) placental growth factor (PlGF) between patients with infection/SIRS (systemic inflammatory response syndrome) and patients with severe sepsis/septic shock. Validation cohort: comparison of serum levels of s-Flt-1 (D) between patients with infection/SIRS and patients with severe sepsis/septic shock. P values of comparisons are indicated by the arrows.
Figure 5
Figure 5
Diagnostic cut-off of s-Flt-1 in the derivation cohort. (A) ROC curve of procalcitonin (PCT), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (s-Flt-1) for the diagnosis of severe sepsis/septic shock; AUC = area under the curve. (B) Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of serum s-Flt-1 above 64 pg/ml for the diagnosis of severe sepsis/septic shock.
Figure 6
Figure 6
Development of biomarkers for the prognosis of sepsis in the derivation cohort. (A) Comparison of serum levels of soluble fms-like tyrosine kinase-1 (s-Flt-1) between survivors and non-survivors; (B) ROC curve of soluble fms-like tyrosine kinase-1 (s-Flt-1) for the prognosis of unfavorable outcome; AUC = area under the curve; (C) Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of serum s-Flt-1 above 70 pg/ml for the prognosis of unfavorable outcome; P values are provided.
Figure 7
Figure 7
Validation of soluble fms-like tyrosine kinase-1 (s-Flt-1) for outcome prediction. Kaplan-Meier curves of survival in the derivation (A) and validation cohorts (B). Log-rank tests and P values are provided. (C) Multivariable logistic regression analysis of predictors of 28-d outcome. Cut-off values were calculated by the Youden index of the respective ROC curves for prediction of 28-d mortality. P values are provided. APACHE = acute physiology and chronic health evaluation, CCI = Charlson comorbidity index, CI = confidence interval, OR = odds ratio, s-Flt-1 = soluble fms-like tyrosine kinase-1, SOFA = sequential organ failure assessment.
Figure 8
Figure 8
Development of soluble fms-like tyrosine kinase-1/placental growth factor ratio (s-Flt-1/PlGF) for the diagnosis and prognosis of sepsis in the derivation cohort. ROC curve of s-Flt-1/PlGF for (A) the diagnosis and (B) prognosis of severe sepsis/septic shock; AUC = area under the curve. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of s-Flt-1/PlGF above 2.8 for (C) the diagnosis of severe sepsis/septic shock; and (D) the prognosis of final outcome. (E) Validation cohort: comparison of serum levels of s-Flt-1/PlGF between patients with infection/SIRS (systemic inflammatory response syndrome) and patients with severe sepsis/septic shock. (F) Kaplan-Meier curves of survival between patients with s-Flt-1/PlGF ≥2.8 or less than 2.8. The value of the log-rank test and the P value of comparison are provided.

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Source: PubMed

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