key: cord-0785779-78hbvvk9
authors: Li, Chenze; Jiang, Jiangang; Wang, Feng; Zhou, Ning; Veronese, Giacomo; Moslehi, Javid J.; Ammirati, Enrico; Wang, Dao Wen
title: Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients
date: 2020-08-20
journal: J Mol Cell Cardiol
DOI: 10.1016/j.yjmcc.2020.08.008
sha: 72ce4a69f79d20c4621739e9073e96aa32587213
doc_id: 785779
cord_uid: 78hbvvk9

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.

patients had radiological findings of pneumonia. Elevation of biomarkers per se were not used as a factor in deciding on admission. We excluded patients younger than 18 years of age and those with recent history of acute myocardial infarction (< 1 month before admission), or patients without cardiac troponin tested on admission. Clinical characteristics of patients without cardiac troponin vs. patients with cardiac troponin that were included in this study are presented as Supplementary Table 1 . Based on the Guidelines on the Diagnosis and Treatment of COVID-19 [24] , patients were further categorized into two groups: non-critically ill (moderate and/or severe) and critically ill patients during the course of hospitalization. Among the critically ill patients, 294 out of 476 (61.8%) were critically ill on admission, whereas 182 out of 476 (38.2%) became critically ill during hospitalization. The median time from admission to become critically ill patients was 0 (interquartile range [Q1-Q3]: 0-2) day in those patients that on admission were not critically ill. All patients who died were critically ill at a certain point during hospitalization.

Thus, critically ill patients were further differentiated in survivors vs. non-survivors (death or survival at last follow up; April 1 th , 2020).

All biomarkers were measured using standard hospital assays. We also explored other myocardial biomarkers of cardiac injury such as creatine kinase-myocardial band (CK-MB, URL 7.2 ng/mL), myoglobin (Mb, URL 154.9 pg/mL) and N-terminal pro-brain natriuretic peptide (NT-proBNP, URL 62.9 pg/mL) as marker of cardiac dysfunction or fluid overload. IL-6 (URL 7 pg/mL), IL-8 (URL 62 pg/mL), IL-10 (URL 9.1 pg/mL), IL-2 receptor (IL-2R, URL 710 U/mL), and tumor necrosis factor-α (TNF-α, URL 8.1 pg/mL), C-reactive protein (CRP, URL 35.4mg/L) were used as markers of inflammation. At least one of the abovementioned markers of inflammation was available at admission in 97. 1% markers of coagulation we reported d-dimer levels (URL 0.5 ug/mL and an upper limit of 21 ug/ml of the kit), fibrinogen level (URL 4.0 g/L) and international normalized ratio (INR; normal range 0.8-1.2). A sensitivity subanalysis has been performed in 234 patients with available data J o u r n a l P r e -p r o o f Journal Pre-proof on both hs-cTnI and IL-6 on admission, day 4-7, and day 8-14. Similarly, analyses were performed on 407 patients with available data on hs-cTnI and CRP, and 396 patients with available data on hs-cTnI and d-dimer at the same timepoints.

Continuous values were shown as medians and Q1-Q3 and categorical variables as counts and percentages. Wilcoxon or Kruskal-Wallis rank-sum tests were used to evaluate the differences in non-normal distributed continuous values, and Pearson's X 2 test was used to evaluate the differences in categorical variables. These tests were used appropriately to compare baseline characteristics between non-critically ill and critically ill patients, as well as survivors and non-survivors among critically ill patients. Furthermore, they were used appropriately across the same groups to test differences in median values of markers of myocardial injury, inflammation and coagulation at different time points during the hospitalization. Additionally, Spearman correlation analyses were used to assess the association the association of inflammatory and coagulative markers with myocardial injury biomarkers. We further quantified the independent association between hs-cTnI, IL-6 and d-dimer levels with mortality among critically ill patients by computing odds ratios (OR) and their 95% confidence intervals (CI), testing different time points. For regression analyses, variables were all log-transformed before modelling to reduce skewness observed in this population. To address the impact of potential confounders, we incorporated several variables into multivariable regression models: age, sex, history of arterial hypertension, diabetes mellitus, coronary heart disease, heart failure, arrhythmia, chronic obstructive pulmonary disease (COPD), cancer, stroke and renal disease. All statistical analyses were performed using R packages (version 3.1.4, Vienna, Austria). 9 1). In total, 2068 patients were included in the analysis. Study population median age was 63 (Q1-Q3: 51-70) years, 51.4% of whom were women. On admission, cardiac injury was observed in 8.8% of admitted patients. Furthermore, CK-MB was increased in 2.6%, Mb in 11.2% and NT-proBNP in 64.3%. Among markers of inflammation recorded on admission, IL-6 was increased in 43.8%, IL-8 in 6.0%, IL-10 in 13.9%, IL-2R in 29.4%, TNF-α in 49.7% and CRP in 51.2%. Markers of coagulation were also increased in a large subset, d-dimer in 58.6%, fibrinogen in 58.0% and INR in 10.9% of cases. Overall mortality occurred in 183 patients (8.8%) ( Table 1) .

When compared to non-critically ill (N=1592, 77.0%) patients, 476 critically ill COVID-19 patients (23.0%) were more likely to be older, male, with a higher prevalence of arterial hypertension, diabetes mellitus, history of coronary heart disease, heart failure, arrhythmia, cancer, stroke, COPD, renal disease, and a higher titer of SARS-CoV-2 IgG and IgM (IgG data available in 381 patients and IgM in 382 patients on admission) ( Table 1) . On admission, critically ill COVID-19 patients had a higher proportion of elevated levels of markers of cardiac injury, as defined by increased hs-cTnI, inflammation and coagulation compared with non-critically ill cases. Additionally, absolute values for each marker of cardiac injury, inflammation and coagulation were significantly increased in critically ill patients compared with non-critically ill patients; hs-cTnI was 15.9 (6.3-52.9) vs. 3.0 (1.9-7.0) pg/mL, IL-6 was 40.1 (18.2-85.9) vs. 3.1 (1.5-9.9) pg/mL, CRP was 72.7 (37.1-125.5) vs. 5.2 (1.2-31.0) mg/L, and d-dimer was 2.4 (1.2-8.1) vs. 0.5 (0.2-1.1) ug/mL, respectively (p<0.001 for all) ( Table 1) . Finally, critically ill versus non-critically ill patients had a higher rate of fatalities (38.4% vs. 0%, p<0.001).

Among, critically ill patients, non-survivors were older, and more frequently men, with 45.4% having cardiac injury compared to 20.8% in survivors (p<0.001). On admission, the proportion of patients with markers Mb, CK-MB and NT-proBNP beyond the URL was significantly higher in non-survivors compared with survivors, as well as the following inflammatory markers: IL-6, IL8, IL-10 and CRP (Table 1) . Among coagulation markers, d-dimer was above the URL in >90% of critically ill patients but the proportion of cases with increased d-dimer was not different in non-survivors vs. survivor, whereas INR was increased in a larger proportion of non-survivors (Table 1) . Finally, absolute values at J o u r n a l P r e -p r o o f Journal Pre-proof admission of each marker of cardiac injury, inflammation and coagulation were significantly increased in critically ill non-survivors vs.

survivors with the exception of TNF-α and fibrinogen ( 

Hs-cTnI levels as well as other markers of cardiac injury (Mb, CK-MB and NT-proBNP) were higher at any time point (admission, day 1-3, day 4-7, day 8-14 and >14) in critically ill compared to non-critically ill patients. Among non-critically ill patients, hs-cTnI, Mb, CK-MB, and NT-proBNP remained significantly lower compared with critically ill patients, and most of values were within URL throughout hospitalization.

Higher levels of markers of cardiac injury were also confirmed at any time point in non-survivors compared with survivors ( Table 2 ). In critically ill non-survivors, almost all markers of inflammation and coagulation increased throughout the entire course of hospitalization. Of note, d-dimer levels peaked at day 1-3 and subsequently decreased both in survivors and non-survivors, although median values were persistently and significantly higher at any time point in non-survivors compared to survivors. Finally, when we assessed the levels of biomarkers on admission comparing non-survivors that died within 7 days (N=69) vs. non-survivors that died beyond 7 days (N=114) after admission, we observed that hs-cTnI, NT-proBNP, IL-6, INR were significantly increased in non-survivors that died within 7 days after hospitalization compared to those that died later (Supplementary Table 2 ).

To further assess the correlation between myocardial and inflammation biomarkers, as well as myocardial and coagulation biomarkers, we analyzed these makers among patients for whom one-to-one data were available at individual time points during hospitalization (Figure 2) .

Scatter plots demonstrated a moderate magnitude and statistically significant correlation of hs-cTnI with IL-6 levels (ranging between r=0.59 to 0.66, all p<0.001), hs-cTnI with CRP levels (ranging between r=0.54 to 0.62, all p<0.001), as well as with d-dimer levels (ranging between r=0.54 to 0.65, all p<0.001) on admission, middle (day 4-7), and beyond the first week of hospitalization (day 8-14; Figure 2 ). We also observed significant correlations between the levels of hs-cTnI and other markers of cardiac injury with other inflammatory and coagulation markers across different time points ( Table 2) . Correlations at further time points reported consistent results (day 1-3 and day >14; Supplementary Table 3 ). To reduce the risk of inconsistencies in number of samples at each time point, we performed a sensitivity subanalysis in patients with complete data on admission, day 4-7 and day 8-14 for the correlations between hs-cTnI with IL-6 levels (N=234, ranging between r=0.52 to 0.66, all p<0.001), hs-cTnI with CRP levels (N=407, ranging between r=0.54 to 0.62, all p<0.001) and hs-cTnI with d-dimer (N=396, ranging between r=0.55 to 0.65, all p<0.001) confirmed the results obtained with the larger sample size (Supplementary Figure 2) .

We further assessed whether hs-cTnI elevation on admission correlated with cardiovascular events in critically ill patients during hospitalization.

Critically ill patients with hs-cTnI elevation had significant higher rate of serious cardiovascular events compared with critically ill patients without hs-cTnI elevation: including higher risk for cardiac arrest (25.7% vs. 12.0% p<0.001), cardiac rhythm disturbances (42.4% vs. 23.2%, p<0.001), and myocardial infarction (2.1% vs 0%, p=0.027), and mortality (57.6% vs. 30.1%, p<0.001) ( Table 4 ). These differences still held if the criteria were changed to hs-cTnI elevation on admission and during hospitalization ( Table 4 ). To better characterize the cardiovascular manifestations in 267 patients with hs-cTnI elevation on admission or during hospitalization, including non-critically ill patients, we identified 118 patients who had J o u r n a l P r e -p r o o f electrocardiogram (ECG) and 49 patients who had echocardiographic data. Abnormal ECG was defined as presence of T wave depression/inversion, ST segment depression/elevation and new onset of pathogenic Q waves. Overall, 51 (43.2%) patients had ECG abnormalities, including 28 (54.9%) patients with T wave depression/inversion, 37 (72.5%) patients with ST segment depression/elevation, and 6 (11.8%) patients with pathogenic Q waves. On the other hand, of those patients who had an echocardiogram, median left ventricular ejection fraction (LVEF) was 58% with only 5 (10.2%) patients having at least moderate left ventricular dysfunction (LVEF ≤40%). Interestingly pericardial effusion was observed in 12 (24.5%) echocardiograms examined.

We next explored the prognostic value of hs-cTnI elevation in relation to, and independent of inflammatory and coagulation markers. As shown in Supplementary Table 4 , we confirmed a significant independent association of elevated levels of hs-cTnI with the mortality among critically ill patients. In the demographically adjusted model (Model 1), 1 per standard deviation increase in hs-cTnI indicated a 1.29-fold higher risk of death among critically ill patients on admission. The associations remained significant after adjustment for traditional cardiovascular risk factors (Model 2) and IL-6 and d-dimer levels (Model 3). Similarly, hs-cTnI was independently associated with death among critically ill patients throughout hospitalization, both on day 4-7 and day >14. Furthermore, the associations of IL-6 and d-dimer levels at different time points with the occurrence of death were also evaluated and displayed in Supplementary Table 4 . Both IL-6 and d-dimer had an independent association with mortality after adjustment for the previous models.

In this large population-based study, 8.8% of COVID-19 patients have elevation in hs-cTnI on admission, increasing to 30.3% among critically ill patients, the latter associated with an in-hospital mortality rate of 38.4%. Longitudinal follow-up of hs-cTnI suggests significant divergence between critically ill survivors compared with critically ill patients who died. Importantly, our data suggest that hs-cTnI is an independent J o u r n a l P r e -p r o o f 13 prognostic marker of mortality at baseline and at later timepoints independently of several variables including inflammatory and coagulative markers, supporting the value to monitor hs-cTnI in critically ill COVID-19 patients. Cardiac injury on admission was associated with increased serious cardiac events including cardiac arrest, arrhythmias and acute myocardial infarction among critically ill patients. In addition to hs-cTnI, median levels of inflammatory markers, in particular IL-6 and CRP, peak at day 3 and gradually decreased between day 4 and 7 of hospitalization in critically ill survivors while they continuous increased among non-survivors. Similarly, d-dimer, as a marker of coagulation, remained significantly increased in non-survivors compared with survivors at all timepoints.

We observed consistent positive correlation between levels of hs-cTnI and inflammation markers, including CRP, IL-6, IL-8, IL-10, TNF-α and IL-2R at each explored timepoint. The strongest correlations (r ranging from 0.54 to 0.66) were observed on admission, day 4-7 and day 8-14 among hs-cTnI, IL-6 and CRP levels. This association further holds when considering other marker of cardiac injury such as Mb, CK-MB or NT-proBNP. The overall interplay between inflammatory cytokines and cardiac injury in this study suggests the possibility that cardiac damage occurs as a result of hyperinflammatory disorder triggered by the SARS-CoV-2 and resembling cytokine release syndrome observed after treatment with cancer immunotherapies, such as chimeric antigen receptor T cells [25] . Our comprehensive biomarker phenotyping presented in this large COVID-19 population at several timepoints during hospitalization can provide a framework for future interventional studies aimed to attenuate the inflammatory response that is associated with cardiac injury. Finally, observational studies that report a potential therapeutic effect of corticosteroids and low molecular weight heparin in specific settings of severe COVID-19 patients [8, 21] , support the idea that markers of inflammation and activation of coagulation can guide intervention trials in high risk patients.

In the present study, cardiac injury was based on elevated hs-cTnI. We show that serious cardiac events were more common in critically ill patients with cardiac injury compared to those without cardiac injury. These data suggest that hs-cTnI elevation does have cardiovascular disease manifestations and consequences. To further assess the nature of cardiac disease, we assessed ECG and echocardiograms when available. ECG J o u r n a l P r e -p r o o f abnormalities were present in 43.2% of cases. On the other hand, echocardiogram showed at lease moderate LVEF impairment in only 10.2% of patients. On the other hand, 25.8% of cases had pericardial effusion. While merely hypothesis-generating, the presence of ECG abnormalities, pericardial effusion, and reduced LVEF are potentially compatible with an inflammatory cardiac injury [26] , at least in a proportion of COVID-19 patients with elevated hs-cTnI. In addition, these data suggest that the nature of cardiac manifestations in critically ill COVID-19 patients is more arrhythmogenic than classic cardiomyopathy and acute pump failure, in agreement with previous observations [11, 13] .

Previous studies that assessed the prognostic value of cardiac injury in COVID-19 patients reported ECG abnormalities in 14 out of 22 (63.6%) patients with available ECG [10] , or did not report ECG data [11] . These limitations reflect the real clinical practice that healthcare personnel have to face during COVID-19 outbreak. In fact, physicians' choices are mainly guided by laboratory tests, vital signs and basic radiological assessment, limiting the use of more sophisticated diagnostic tools with the aim to reduce the personnel exposure to potentially contagious patients. In this view, prognostic information derived by biomarkers is of paramount importance.

Our data suggest potential insights into the mechanisms of cardiac injury in COVID-19 patients. There have been a number of proposed explanations for cardiac injury in COVID-19 patients including the potential for SARS-CoV-2 to infect cardiomyocytes, pericytes and fibroblasts via the angiotensin converting enzyme (ACE)-2 pathway leading to direct myocardial injury [27] . Alternatively, myocardial injury may be due to cytokine excess and/or antibody mediated mechanisms. Currently, limited data exist from endomyocardial biopsy or autopsies [17, 18, 20] , or cardiac imaging in COVID-19 patients. Although acute myocarditis associated with COVID-19 has been described in isolated cases [15, 16, 28] , a much larger body of literature suggests little resemblance to classic viral myocarditis with inflammatory cellular infiltration [17, 18] . Our data show a consistent correlation between markers of inflammatory response, as well as coagulative activation and cardiac injury suggesting that myocardial injury could be mediated by the cytokine release syndrome. Other studies support our data for unlikelihood of a direct virus-mediated myocardial infection in most of cases of COVID-19. For example, among COVID-19 patients, SARS-CoV-2 was detected J o u r n a l P r e -p r o o f 15 in blood in less than 1% of blood specimens [29] . Other studies have shown no evidence of SARS-CoV-2 in the cardiomyocytes with suspected myocarditis [17, 18] . Another possibility is that critically ill COVID-19 patients present with more severe lung injury and hypoxia, leading to myocardial ischemia.

There are a number of limitations in our study. Data were not collected prospectively. Additionally, long-term clinical outcomes of survivors

are not yet available. We did not have results of all biomarkers at any time point. Furthermore, the type and degree of anti-cardiac immune-mediated injury, including levels of antibody response to anti-cardiac epitopes, were not available, which would provide a proper insight into the pathophysiological stage of the cardiac injury from viral infection to the immune mediated autoreactivity. Finally, the impact of therapies, for instance initiation of corticosteroids or the effect of angiotensin II receptor blocker were not reported. Therapies could affect the clinical course (e.g. viral entry) and cytokine levels, but in a retrospective trial these variables cannot be completely controlled. For instance, in this series, drugs such as corticosteroids or anticoagulant drugs have been frequently initiated late in the course of hospitalization and in patients that developed clinical complications as observed also in other reports of critically ill patients [9, 12] . Nevertheless, our study is the largest to date to longitudinally follow cardiac, inflammatory and coagulation biomarkers and correlate these with outcomes during hospitalization. Our data also provide hypotheses regarding mechanism of cardiac injury. Future prospective studies should aim to define if the early use of immunomodulating drugs such as corticosteroids or IL-6 receptor and IL-1 inhibitors may have an impact on prognosis by hampering the cytokine storm, reducing cardiac injury, thus improving the disease outcomes.

In conclusion we analyzed the dynamic changes in biomarkers of cardiac injury, inflammation and coagulation in hospitalized COVID-19 patients and correlated these to patient outcome. Myocardial injury not only occurs in the late stages of the disease, but a subclinical elevation of hs-cTnI already starts at the initial stages of infection. We found that changes in the biomarkers of myocardial injury in the first week largely 

The data and code that supporting the findings of the present study are available via the corresponding author under reasonable request.

JM has served on advisory boards for Pfizer, Novartis, Bristol Myers Squibb, Takeda, GSK and AstraZeneca and is supported by the National Table 1 for details). Anticoagulant drugs include dabigatran, heparin, warfarin, rivaroxaban, and sulodexide. Antiplatelet drugs include aspirin, clopidogrel, ticagrelor, and dipyridamole; Anti-viral drugs include oseltamivir, lopianvir, ribavirin, ganciclovir, and peramivir; immue modulators include tocilizumab and pirfenidone. † Of these, 3 out of 9 were VA-ECMO. ‡ Each cardiac event was counted independently. Cardiac rhythm disturbances include ventricular tachycardia, supraventricular tachycardia, atrial fibrillation, atrial flutter, second-degree (type 2) or third-degree atrioventricular block, and sick sinus syndrome. Myocardial infarction was confirmed by coronary angiography. Abbreviations: hs-cTnI, High-sensitivity cardiac troponin I; NT-proBNP, N-terminal pro-brain natriuretic peptide; Mb, myoglobin; CK-MB, Creatine Kinase-MB; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; IL-2R, interleukin-2 receptor; TNF-α, Tumor necrosis factor-α; INR, international normalized ratio.

Spearmen correlation was used. 

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Abbreviations: hs-cTnI, High-sensitivity cardiac troponin I; NT-proBNP, N-terminal pro-brain natriuretic peptide; Mb, myoglobin; CK-MB, Creatine Kinase-MB; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; IL-2R, interleukin-2 receptor; TNFα, Tumor necrosis factor-α; INR, international normalized ratio.