Placental growth factor level in plasma predicts COVID-19 severity and in-hospital mortality

Abstract

Background: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with vascular inflammation and endothelial injury.

Objectives: To correlate circulating angiogenic markers vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), and fibroblast growth factor 2 (FGF-2) to in-hospital mortality in COVID-19 adult patients.

Methods: Consecutive ambulatory and hospitalized patients with COVID-19 infection were enrolled. VEGF-A, PlGF, and FGF-2 were measured in each patient ≤48 h following admission.

Results: The study enrolled 237 patients with suspected COVID-19: 208 patients had a positive diagnostic for COVID-19, of whom 23 were mild outpatients and 185 patients hospitalized after admission. Levels of VEGF-A, PlGF, and FGF-2 significantly increase with the severity of the disease (P < .001). Using a logistic regression model, we found a significant association between the increase of FGF-2 or PlGF and mortality (odds ratio [OR] 1.11, 95% confidence interval [CI; 1.07-1.16], P < .001 for FGF-2 and OR 1.07 95% CI [1.04-1.10], P < .001 for PlGF) while no association were found for VEGF-A levels. Receiver operating characteristic curve analysis was performed and we identified PlGF above 30 pg/ml as the best predictor of in-hospital mortality in COVID-19 patients. Survival analysis for PlGF confirmed its interest for in-hospital mortality prediction, by using a Kaplan-Meier survival curve (P = .001) and a Cox proportional hazard model adjusted to age, body mass index, D-dimer, and C-reactive protein (3.23 95% CI [1.29-8.11], P = .001).

Conclusion: Angiogenic factor PlGF is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that PlGF blocking strategies could be a new interesting therapeutic approach in COVID-19.

Keywords: COVID-19; FGF-2; PlGF; angiogenesis; mortality; placental growth factor.

FIGURE 1

Involvement of angiogenic biomarker plasma levels in COVID‐19 severity. A–B–C, Boxplot of plasma level (pg/ml) of each circulating angiogenic biomarkers (fibroblast growth factor 2 [FGF‐2], placental growth factor [PlGF], and vascular endothelial growth factor A [VEGF‐A]) according to COVID‐19 severity (control, outpatients, non‐critical, and critical). Data points represent individual measurements, whereas horizontal bars represent the means with standard deviations. We compared the level of angiogenic biomarkers among the four groups (control, outpatients, non‐critical, and critical) using the Kruskal‐Wallis test. D–O, Scatter plots showing the correlations between VEGF‐A, FGF‐2, and PlGF and biomarkers of multiorgan failure (C‐reactive protein [CRP], D‐dimer, creatinine, and high‐sensitivity cardiac Troponin I [Hs‐TnI]). Data points represent individual measurements. The black bold line indicates line of best fit and the lightly colored area 95% confidence interval. r for Kendall rank correlation coefficient

FIGURE 2

Involvement of placental growth factor (PlGF) in COVID‐19 mortality. (A) Receiving operating curve (ROC) for PlGF involvement in in‐hospital mortality. AUC, Area under the curve; PPV, positive predictive value; NPV, negative predictive value; CI, confidence interval. (B) Kaplan–Meier survival curves illustrating prognostic impact of PlGF levels (≤ or >30 pg/ml) regarding in‐hospital mortality. P‐value refers to the log rank test used to compare survival curves according to PlGF levels (≤ or >30 pg/ml). (C) Forest plot of Cox proportional hazard model. The model was adjusted on age (≤ or > 59 years old), body mass index (BMI) (≤ or > 25), D‐dimer (≤ or >1377 ng/ml), and on C‐reactive protein (CRP; ≤ or > 110 mg/L)