Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients

Abstract

Background: Cardiac injury, as measured by troponin elevation, has been reported among hospitalized coronavirus disease 2019 (COVID-19) patients and portends a poor prognosis. However, how the dynamics of troponin elevation interplay with inflammation and coagulation biomarkers over time is unknown. We assessed longitudinal follow-up of cardiac injury, inflammation and coagulation markers in relation to disease severity and outcome.

Methods: We retrospectively assessed 2068 patients with laboratory-confirmed COVID-19 between January 29 and April 1, 2020 at Tongji Hospital in Wuhan, China. We defined cardiac injury as an increase in high sensitivity cardiac troponin-I (hs-cTnI) above the 99th of the upper reference limit. We explored the dynamics of elevation in hs-cTnI and the relationship with inflammation (interleukin [IL]-6, IL-8, IL-10, IL-2 receptor, tumor necrosis factor-α, C-reactive protein) and coagulation (d-dimer, fibrinogen, international normalized ratio) markers in non-critically ill versus critically ill patients longitudinally and further correlated these markers to survivors and non-survivors.

Results: Median age was 63 years (first to third quartile 51-70 years), 51.4% of whom were women. When compared to non-critically ill patients (N = 1592, 77.0%), critically ill (defined as requiring mechanical ventilation, in shock or multiorgan failure) patients (N = 476, 23.0%), had more frequent cardiac injury on admission (30.3% vs. 2.3%, p < 0.001), with increased mortality during hospitalization (38.4% vs. 0%, p < 0.001). Among critically ill patients, non-survivors (N = 183) had a continuous increase in hs-cTnI levels during hospitalization, while survivors (N = 293) showed a decrease in hs-cTnI level between day 4 and 7 after admission. Specifically, cardiac injury is an independent marker of mortality among critically ill patients at admission, day 4-7 and 8-14. Consistent positive correlations between hs-cTnI and interleukin (IL)-6 on admission (r = 0.59), day 4-7 (r = 0.66) and day 8-14 (r = 0.61; all p < 0.001) and d-dimer (at the same timepoints r = 0.54; 0.65; 0.61, all p < 0.001) were observed. A similar behavior was observed between hs-cTnI and most of other biomarkers of inflammation and coagulation.

Conclusions: Cardiac injury commonly occurs in critically ill COVID-19 patients, with increased levels of hs-cTnI beyond day 3 since admission portending a poor prognosis. A consistent positive correlation of hs-cTnI with IL-6 and d-dimer at several timepoints along hospitalization could suggest nonspecific cytokine-mediated cardiotoxicity.

Keywords: COVID-19; Cardiac injury; Coagulation; Critically ill patients; Cytokine response syndrome; Inflammation.

Graphical abstract

Fig. 1

Proportions of patients with elevated biomarkers and the absolute levels of biomarkers during hospitalization. A) Proportion of patients with elevated high sensitivity cardiac troponin I (hs-cTnI). B) Hs-cTnI absolute level. C) Proportion of patients with elevated interleukin (IL)-6. D) IL-6 absolute level. E) Proportion of patients with elevated d-dimer. F) d-dimer absolute level. Asterix indicates at least p < 0.05 (see Table 1 for details).

Fig. 2

Spearman correlations of high sensitivity cardiac troponin I (hs-cTnI) with interleukin (IL)-6, C-reactive protein (CRP), and d-dimer on admission, in the time interval between day 4–7 and in the time interval between day 8–14. A) hs-cTnI and IL-6 on admission. B) Hs-cTnI and IL-6 values in the time interval between day 4 and 7. C) Hs-cTnI and IL-6 values in the time interval between day 8 and 14. D) Hs-cTnI and CRP on admission. E) Hs-cTnI and CRP values in the time interval between day 4 and 7. F) Hs-cTnI and CRP values in the time interval between day 8 and 14. G) Hs-cTnI and d-dimer on admission. H) Hs-cTnI and d-dimer values in the time interval between day 4 and 7. I) Hs-cTnI and d-dimer values in the time interval between day 8 and 14.