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 importance of GDF-15 in 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 MECH study. Biobank samples were collected at baseline, day 3 and day 9. The primary endpoint 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 endpoint; these patients were older, more often had diabetes mellitus, had lower oxygen saturations and higher National Early Warning Score 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 endpoint had higher concentrations of GDF-15 (median 4225 [IQR 3197-5972] pg/mL vs 2187 [1344-3620] pg/mL, p<0.001). The C-statistic value was 0.78 (95% confidence interval 0.70-0.86). The association between GDF-15 and outcome persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate and previous myocardial infarction, heart failure or 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 endpoint (median 1208 [IQR 0-4305] pg/mL versus -86 [IQR -322-491] 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 importance of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers.

Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study

“… 42 43 44 Increases in a variety of inflammatory pathways, including bradykinin, interleukin 6, C reactive protein, and growth differentiation factor 15, have been described in covid-19. 10 11 45 46 47 48 49 50 51 52 53 54 Further, heparin has been shown to block the SARS-CoV-2 viral spike protein from binding in experimental studies. 55 56 57 We postulate that the combination of the known antithrombotic and potential anti-inflammatory effects of heparin, 8 9 in addition to attenuation of viral infectivity might, at least in part, explain the observed benefit associated with prophylactic anticoagulation.…”

“…The cause of elevated thrombosis risk remains unclear, although proposed mechanisms have included systemic inflammation, endothelialitis, and activation of the complement system 424344. Increases in a variety of inflammatory pathways, including bradykinin, interleukin 6, C reactive protein, and growth differentiation factor 15, have been described in covid-19 101145464748495051525354. Further, heparin has been shown to block the SARS-CoV-2 viral spike protein from binding in experimental studies 555657.…”

Cardiovascular biomarkers in patients with COVID-19

“…Among 123 patients hospitalized with COVID-19 in Norway, GDF-15 concentrations showed a C-statistic value of 0.78 for the prediction of ICU admission or in-hospital death. 54 …”

I-FABP is decreased in COVID-19 patients, independently of the prognosis

“…I-FABP should also be measured in stool samples, although there is no current assay appropriate for such measurement. Finally, correlations between I-FABP with other biomarkers of COVID-19 prognosis should be informative, for instance, with Growth differentiation factor 15 (GDF-15) is associated with severe COVID-19, hypoxemia, and SarsCov2 viremia [ 19 ]. Whereas intestinal mucosal injury has been evidenced in COVID-19 [ 20 ], our first study failed to evidence I-FABP as a prognosis marker or a marker associated with gastrointestinal signs in COVID-19.…”