Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19

Abstract

Background: Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic value of GDF-15 in coronavirus disease 2019 (COVID-19) is unknown.

Methods: Consecutive, hospitalized patients with laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptoms of COVID-19 were enrolled in the prospective, observational COVID Mechanisms Study. Biobank samples were collected at baseline, day 3 and day 9. The primary end point was admission to the intensive care unit or death during hospitalization, and the prognostic performance of baseline and serial GDF-15 concentrations were compared with that of established infectious disease and cardiovascular biomarkers.

Results: Of the 123 patients enrolled, 35 (28%) reached the primary end point; these patients were older, more often had diabetes, and had lower oxygen saturations and higher National Early Warning Scores on baseline. Baseline GDF-15 concentrations were elevated (>95th percentile in age-stratified healthy individuals) in 97 (79%), and higher concentrations were associated with detectable SARS-CoV-2 viremia and hypoxemia (both P<0.001). Patients reaching the primary end point had higher concentrations of GDF-15 (median, 4225 [IQR, 3197-5972] pg/mL versus median, 2187 [IQR, 1344-3620] pg/mL, P<0.001). The area under the receiver operating curve was 0.78 (95% CI, 0.70-0.86). The association between GDF-15 and the primary end point persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate, previous myocardial infarction, heart failure, and atrial fibrillation (P<0.001) and was superior and incremental to interleukin-6, C-reactive protein, procalcitonin, ferritin, D-dimer, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide. Increase in GDF-15 from baseline to day 3 was also greater in patients reaching the primary end point (median, 1208 [IQR, 0-4305] pg/mL versus median, -86 [IQR, -322 to 491] pg/mL, P<0.001).

Conclusions: GDF-15 is elevated in the majority of patients hospitalized with COVID-19, and higher concentrations are associated with SARS-CoV-2 viremia, hypoxemia, and worse outcome. The prognostic value of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04314232.

Keywords: biomarkers; cardiovascular disease; coronavirus; growth differentiation factor 15; risk.

Figure 1.

GDF-15 concentrations, ICU admission or death, and SARS-CoV-2 viremia. Proportion of patients hospitalized for COVID-19 with SARS-CoV-2 viremia at baseline and proportion of patients reaching the primary end point by quartiles of GDF-15 concentrations. P values are for trend in viremia across quartiles of GDF-15. *Adjusted for age, sex, race, body mass index, cardiovascular disease, and eGFR. COVID-19 indicates coronavirus disease 2019; eGFR, estimated glomerular filtration rate; GDF-15, growth differentiation factor 15; ICU, intensive care unit; and SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Changes in cardiovascular and inflammatory biomarkers during hospitalization for COVID-19. Changes in IL-6, PCT, CRP, ferritin, D-dimer, cTnT, NT-proBNP, and GDF-15 concentrations among patients hospitalized for COVID-19. Data shown are for 49 patients with samples available at baseline, day 3, and day 9 (ie, those hospitalized for ≥9 day). Values are median concentrations; groups are stratified by the composite primary end point: ICU admission or death. COVID-19 indicates coronavirus disease 2019; CRP, C-reactive protein; cTnT, cardiac troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide; GDF-15, growth differentiaion factor 15; ICU, intensive care unit; IL-6, interleukin-6; and PCT, procalcitonin.