key: cord-0851599-8al36wzg
authors: He, Yiyu; Zheng, Xiaoxin; Li, Xiaoyan; Jiang, Xuejun
title: Key factors leading to fatal outcomes in COVID-19 patients with cardiac injury
date: 2021-02-18
journal: Sci Rep
DOI: 10.1038/s41598-021-82396-w
sha: cc5381cee0cf59b7e2019e3c7ece5e8767488193
doc_id: 851599
cord_uid: 8al36wzg

Cardiac injury among patients with COVID-19 has been reported and is associated with a high risk of mortality, but cardiac injury may not be the leading factor related to death. The factors related to poor prognosis among COVID-19 patients with myocardial injury are still unclear. This study aimed to explore the potential key factors leading to in-hospital death among COVID-19 patients with cardiac injury. This retrospective single-center study was conducted at Renmin Hospital of Wuhan University, from January 20, 2020 to April 10, 2020, in Wuhan, China. All inpatients with confirmed COVID-19 (≥ 18 years old) and cardiac injury who had died or were discharged by April 10, 2020 were included. Demographic data and clinical and laboratory findings were collected and compared between survivors and nonsurvivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with mortality in COVID-19 patients with cardiac injury. A total of 173 COVID-19 patients with cardiac injury were included in this study, 86 were discharged and 87 died in the hospital. Multivariable regression showed increased odds of in-hospital death were associated with advanced age (odds ratio 1.12, 95% CI 1.05–1.18, per year increase; p < 0.001), coagulopathy (2.54, 1.26–5.12; p = 0·009), acute respiratory distress syndrome (16.56, 6.66–41.2; p < 0.001), and elevated hypersensitive troponin I (4.54, 1.79–11.48; p = 0.001). A high risk of in-hospital death was observed among COVID-19 patients with cardiac injury in this study. The factors related to death include advanced age, coagulopathy, acute respiratory distress syndrome and elevated levels of hypersensitive troponin I.

To confirm COVID-19, the Viral Nucleic Acid Kit (Health) was used to extract nucleic acids from clinical samples according to the kit instructions. Throat swab samples were obtained for SARS-CoV-2 Polymerase Chain Reaction (PCR) examination. A SARS-CoV-2 detection kit (Bioperfectus) was used to detect two target genes, including open reading frame 1ab (ORF1ab) and nucleocapsid protein (N), using real-time reverse transcriptase-polymerase chain reaction. An infection was considered laboratory-confirmed if the ORF1ab and N tests both showed positive results 5 .

Routine blood examinations included complete blood count, coagulation profile, serum biochemical tests (including renal and liver function, creatine kinase, lactate dehydrogenase, albumin, total bilirubin, hypersensitive troponin I, N-terminal pro-brain natriuretic peptide, C-reactive protein, procalcitonin, CD4 count, CD8 count, interleukin-6 (IL-6), and tumor necrosis factor α). Chest radiographs or CT scans were also acquired for all inpatients. The criteria for discharge were a temperature that had returned to normal for at least 3 days, substantial improvement in both lungs in chest CT, disappearance of clinical symptoms and two negative SARS-CoV-2 RNA tests over an interval of at least 24 h 6 .

Definitions. Acute kidney injury was identified according to the Kidney Disease: Improving Global Outcomes definition 7 . Acute cardiac injury was diagnosed if serum levels of cardiac biomarkers (e.g., high-sensitivity cardiac troponin I) were above the 99th percentile of the upper reference limit 8 . Acute respiratory distress syndrome (ARDS) was diagnosed according to the Berlin definition 9 . Acute liver injury, defined as either an alanine aminotransferase or aspartate aminotransferase level greater than three times the upper limit of normal 10 . Coagulopathy was defined as a 3-s extension of prothrombin time or a 5-s extension of activated partial thromboplastin time 6 . Statistical analysis. Frequency rates and percentages are used to describe categorical variables, and median and interquartile range (IQR) values are used to describe continuous variables. Continuous variables were compared using the t test and categorical variables were compared using the χ 2 test. Univariable and multivariable logistic regression models were used to explore the risk factors for death during hospitalization. Data were analyzed using SPSS (Statistical Package for the Social Sciences) version 13.0 software (SPSS Inc). For all the statistical analyses, p < 0.05 was considered statistically significant.

Patient characteristics. A total of 187 adult patients confirmed with COVID-19 and cardiac injury were hospitalized in Renmin Hospital of Wuhan University between January 20, 2020 and April 10,2020, After excluding 14 patients who were still hospitalised or did not have available key information in their medical records, we included 173 inpatients in the final analysis. Eighty-seven patients died during hospitalization, and 86 were discharged. The median age of the 173 patients was 73.0 years (IQR 64.0-80.5), ranging from 28 to 97 years, and 111 (64.2%) were male ( Laboratory findings. There were numerous differences in laboratory findings between survivors and nonsurvivors. Compared with the survivors, the nonsurvivors showed higher leukocyte, neutrophil, lactate dehydrogenase, total bilirubin, blood urea nitrogen, hypersensitive troponin I, C-reactive protein, procalcitonin, and IL-6 levels, as well as higher levels of D-dimer and lower lymphocyte, platelet count, CD8 count and CD4 counts (all p < 0.05; Table 2 ). The prothrombin time and activated partial thrombin time were longer in nonsurvivors than in survivors, with significant differences for both (all p < 0.05; Table 2 ). [19. 8%]) was more common in nonsurvivors than in survivors (all p < 0.05; Table 3 ).

In the univariable analysis, the odds of in-hospital death were higher in patients with acute liver injury, acute kidney injury, ARDS, or coagulopathy. Lymphopenia, elevated leucocytes, elevated neutrophil count, elevated hypersensitive troponin I, elevated procalcitonin and a prolonged prothrombin time were also associated with death. We included 173 patients with complete data for all variables (87 nonsurvivors and 86 survivors) in the multivariable logistic regression model, and we found that advanced age, ARDS, coagulopathy, and elevated level of hypersensitive troponin I were associated with increased odds of death (Table 4) . Age was associated with a 1.12-fold higher risk of death (OR: 1.12; 95% CI: 1.05-1.18), ARDS was associated with a 16.56-fold higher risk of death (OR: 16.56; 95% CI: 6.66-41.2), coagulopathy was associated with a 2.54fold higher risk of death (OR: 2.54; 95% CI: 1.26-5.12), and hypersensitive troponin I was associated with a 4.54-fold higher risk of death (OR: 4.54; 95% CI: 1.79-11.48). (Table 4 ).

In this study, we included 173 COVID-19 patients with cardiac injury and 87 of whom died. Notably, COVID-19-induced cardiac injury was associated with a high risk of death. By analyzing the risk factors for death, we found that older age, coagulopathy, ARDS and higher hypersensitive troponin I levels were associated with higher odds of in-hospital death.

According to recent studies in China, myocardial injury is independently associated with an increased risk of mortality among COVID-19 patients 1,2 . However, the reasons for the high mortality associated with cardiac injury are not well described. Advanced age has been reported as an important independent predictor of mortality in patients with COVID-19 6 . Our study confirmed that advanced age was associated with death in COVID-19 patients with cardiac injury. However, there was no difference in comorbidities between survivors www.nature.com/scientificreports/ and nonsurvivors. These data differ from a recent report that showed that comorbidities may be a risk factor for poor outcome 11 . Symptoms including fatigue, myalgia and chest pain were more common in patients who died. Nonsurvivors required more noninvasive ventilation or high-flow nasal cannula therapy. Major complications including ARDS, coagulopathy, acute liver injury, and acute kidney injury, occurred more often in nonsurvivors. Additionally, lymphopenia, elevated leukocyte count, elevated neutrophil count, and elevated hypersensitive troponin I were also associated with death. In our study, nonsurvivors had higher levels of D-dimer, and a longer prothrombin time and activated partial thrombin time, but lower platelet counts than survivors. Coagulation disorders are relatively frequently encountered among COVID-19 patients, especially among those with adverse outcomes. The pathogenetic mechanisms may include endothelial dysfunction, increased consumption of platelets and the decreased production of platelets, von Willebrand factor elevation, Toll-like receptor activation, and tissue-factor pathway activation 12 . COVID-19 patients with coagulation disorders are at risk of developing disseminated intravascular coagulation (DIC), deep vein thrombosis and pulmonary embolism, and multiorgan infarcts, which increase the risk of death 13 . These observations were also reported in a previous autopsy study on SARS-CoV-1-infected patients 14 . Coagulation activation could be related to a sustained systemic pro-inflammatory cytokine release elicited by viral infections. Inflammation not only leads to the activation of coagulation, but coagulation also affects inflammatory activity, suggesting the extensive cross-talk between these two systems 15 . In a coagulation cascade, IL-6 not only increases the production of fibrinogen in the liver, but also activates the coagulation system, and infusion of a monoclonal anti-IL-6 antibody resulted in the complete abrogation of coagulation activation 16 . In our study, the level of IL-6 was much higher in nonsurvivors than in survivors, and IL-6 level appears to be a prognostic indicator of outcome. We also found that markers of inflammatory response, such as leukocytes, neutrophil, C-reactive protein and procalcitonin were significantly increased among nonsurvivors. These abnormalities suggest that the severe inflammatory response may be associated with death among COVID-19 patients with cardiac injury. Previous studies showed that the levels of serum pro-inflammatory cytokines (IL-6 and IFNα) and chemokines (IL-8, CXCL-10, and CCL5) were much higher in patients with severe MERS than in patients Table 2 . Laboratory findings of COVID-19 patients with cardiac injury. SI conversion factors: to convert alanine aminotransferase or aspartate aminotransferase to μkat/L, multiply by 0.0167. IQR, interquartile range; IL-6, interleukin-6.

Blood routine 17, 18 . Increased levels of proinflammatory cytokines (IFN-γ, IL-1, IL-6, IL-12, and TGFβ) and chemokines (CCL2, CXCL10, CXCL9, and IL-8) were observed in severe SARS patients compared to mild individuals 19, 20 . Inflammatory cytokines can be released into the circulation and induce lung epithelial and endothelial cell apoptosis, which results in vascular leakage, alveolar edema, epithelial cell proliferation and 21 . Inflammatory cytokines can also induce hypotension, tissue hypoxia, myocardial dysfunction, and eventually lead to multiple organ dysfunction and DIC 22 . We also observed that the CD4 T cell and CD8 T cell counts decreased more in nonsurvivors than in survivors. These abnormalities suggest that mortality may be associated with cellular immune deficiency. Both CD4 and CD8 T cells play a critical role in clearing viruses by eliminating virus-infected cells. Reduction in CD4 and CD8 T cells were associated with severe pneumonia. A previous study showed that a dramatic loss of CD4 T cells and CD8 T cells strongly correlated with the severity of the acute phase of SARS disease in humans 23, 24 . A recent pathological study also found that the peripheral CD4 and CD8 T cell counts were substantially reduced in COVID-19 patients, while their status was overactivated, which accounts for the severe immune injury, in nonsurvivors 25 . In SARS-CoV-infected mouse models, the depletion of CD4 T and CD8 T cells reduced neutralizing antibody titers in the lungs, delayed virus clearance and further enhanced immune-mediated interstitial pneumonitis 26 .

Patients with coagulation activation, cellular immune deficiency and high levels of inflammatory cytokines are more likely to experience organ injury and a higher risk of death after COVID-19 infection. In this study, the level of hypersensitive troponin I, and incidence of ARDS, acute liver injury and acute kidney injury were much higher in nonsurvivors. Further multivariable logistic regression analysis showed that advanced age, elevated hypersensitive troponin I, coagulopathy and ARDS were independently associated with an increased risk of death in COVID-19 patients with cardiac injury. These observations suggest that the causes of death among COVID-19 patients with cardiac injury may involve multiorgan dysfunction and coagulation disorders, and myocardial injury may only partly explain the cause of death. Cytokine storms and a series of immune responses, or coagulation disorders may be the pathophysiological mechanism underlying organ injury caused by COVID-19. The respiratory system is the most commonly involved system in COVID-19, and some patients can rapidly develop ARDS. Previous reports showed that the incidence of ARDS was 15.6-31%, higher than that of other organ injuries 3, 27 . The main cause of ARDS may be the injury to the alveolar epithelial cells. A recent pathological study showed evident that ARDS in the lungs was caused by SARS-CoV-2 infection. A few interstitial mononuclear inflammatory infiltrates were found in heart tissue, but no other substantial myocardial damage was observed in a patient with COVID-19, indicating that there were no obvious histological changes seen in heart tissue 25 . ARDS may be the main cause of death among COVID-19 patients, which is consistent with our research on COVID-19 patients with cardiac injury. The data in this study suggested that coagulopathy and ARDS are valuable warning models for predicting mortality in COVID-19 patients with cardiac injury.

This study provides novel and valuable warning information for physicians to predict the severity of the COVID19 patients with cardiac injury, and makes it possible to identify patients with a high risk of death earlier and provide timely and active management, leading to better clinical outcomes.

A high risk of in-hospital death was shown among COVID-19 patients with cardiac injury in this study. The factors related to death include advanced age, coagulopathy, acute respiratory distress syndrome and elevated levels of hypersensitive troponin I.

The datasets generated during or analyzed during the current study are available from the corresponding author on reasonable request.

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Association of cardiac injury with mortality in hospitalized patients With COVID-19 in Wuhan

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance

Clinical diagnosis of 8274 samples with 2019-novel coronavirus in Wuhan

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study

KDIGO clinical practice guidelines for acute kidney injury

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Acute respiratory distress syndrome: The Berlin Definition

Clinical characteristics and mechanism of liver injury in patients with severe acute respiratory syndrome. Chin

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A singlecentered, retrospective, observational study

Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Severe acute respiratory syndrome and venous thromboembolism in multiple organs

Coagulation in patients with severe sepsis

Immunotherapeutic implications of IL-6 blockade for cytokine storm

Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection

Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity

Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19

Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome

Rapid loss of both CD4? and CD8? T lymphocyte subsets during the acute phase of severe acute respiratory syndrome

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Cell-mediated immune response to respiratory coronaviruses

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study

Y.H. and X.Z. conceived and designed the study, analyzed the data and wrote the manuscript. X.L. revised the manuscript. X.J. provided study oversight and participated in manuscript revision. All authors had access to the study data and approved the decision to submit the manuscript. 

The authors declare no competing interests.

Correspondence and requests for materials should be addressed to X.J.Reprints and permissions information is available at www.nature.com/reprints.Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.