Le Infezioni in Medicina, n. 2, 231-241, 2022

doi: 10.53854/liim-3002-8

ORIGINAL ARTICLE

Development of a nomogram to assess the impact of the myocardial injury on the prognosis of COVID-19 patients

Mengdi Jin1, Zhijun Li1, Xinwei Li1, Mengtong Xie1, Weizhen Li1, Lizhe Ai1, Yaoyao Sun1, Xiaodan Cheng2, Yan Sheng2, Jinnan Zhang3, Nan Jiang4, Qiong Yu1

1Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China;

2Department of Critical Care Unit, China-Japan Union Hospital of Jilin University, Changchun, China;

3Department of Neurosurgery, China-Japan union hospital of Jilin University, Changchun, China;

4Department of Emergency, China-Japan Union Hospital of Jilin University, Changchun, China

Article received 31 March 2022, accepted 10 May 2022

Corresponding author

Qiong Yu

E-mail: yuqiong@jlu.edu.cn

Nan Jiang

E-mail: jiangn@jlu.edu.cn

SummaRY

Coronavirus disease 2019 (COVID-19) has been spreading worldwide. Many COVID-19 patients were accompanied by myocardial injury during the course of the disease. To evaluate the association of cardiac injury with clinical outcomes in COVID-19 patients, we recruited 261 COVID-19 cases admitted to Tongji Hospital of Huazhong University of Science and Technology in this study. Compared with patients without myocardial injury, those with myocardial injury were older, with shorter hospital stays and lower survival rates. They also had higher levels of inflammatory biomarkers (Interleukin-6,8,10 and C-reactive protein), coagulation biomarkers, liver and kidney function markers. Kaplan-Meier analysis demonstrated that patients with myocardial injury had a higher mortality rate. The multivariate Cox regression model and the nomogram revealed that myocardial injury, co-morbidity, and abnormal procalcitonin (PCT) levels were independent risk factors of the mortality of COVID-19 patients. The linear correlation analysis and the ROC curve suggested a predictive value of the neutrophil-lymphocyte ratio (NLR) in cardiac injury. Summarily, myocardial injury in COVID-19 patients is associated with a higher mortality risk. Attention should be paid to monitoring myocardial injury in patients with significantly elevated myocardial markers and NLR at admission.

Keywords: COVID-19, myocardial injury, nomogram, prediction, survival.

INTRODUCTION

The coronavirus disease 2019 (COVID-19) is a disease caused of the new coronavirus SARS-CoV-2. It has been spreading across China and worldwide, with high infectious and mortality rate [1]. The clinical manifestations of COVID-19 patients are mainly fever, fatigue, and respiratory symptoms [2, 3]. Acute respiratory failure and multiple organ dysfunction syndromes (MODS) are the leading causes of death. With the increase in the number of cases and related research, it was found that COVID-19 patients were also accompanied by different degrees of myocardial injury during the disease, and the evidence implicating the SARS-CoV-2 as a cause of myocardial injury appears to be more concrete. A study published in JAMA containing 416 confirmed COVID-19 patients concluded that cardiac injury is a common condition among hospitalized patients with COVID-19, and it is one independent risk factor for in-hospital mortality [4]. A study of 41 COVID-19 patients published in the Lancet reported a 12% incidence of acute cardiac injury and 33% of elevated creatine kinase levels [5]. A retrospective case-control study on 70 people showed elevated cardiac biomarkers associated with increased mortality in COVID-19 patients [6]. Wang et al. found that cardiac injury was observed in 23% of 52 severe adult patients [7]. Data from these studies illustrate that different degrees of acute cardiac injury related to SARS-CoV-2 cannot be ignored [8, 9]. This study retrospectively analyzed the clinical characteristics of 261 patients with COVID-19 and evaluated myocardial injury prognostic value in patients with COVID-19.

MATERIALS AND METHODS

Patients

A retrospective single-centre analysis was conducted in 261 continuously admitted patients with positive COVID-19 nucleic acid tests admitted to Tongji Hospital of Huazhong, University of Science and Technology from February 2 to March 2, 2020. Diagnostic criteria refer to the diagnosis and treatment plan of coronavirus disease 2019 by the World Health Organization. All patients in the study were confirmed to be free of HBV, HCV, and HIV [10-13]. The written consent was obtained from patients or their legal guardians. This study has been approved by the Ethics Committee of Tongji Hospital of Huazhong University of Science and Technology (No.TJ-IRB20200364) and the China-Japan union hospital of Jilin University (No.2020032607). The procedures followed the Helsinki Declaration of the World Medical Association.

Data collection and study design

All cases were laboratory-confirmed on admission by nucleic acid and antibody tests. Two researchers collected the following information from electronic medical records: demographic information (age, gender), co-morbidities (hypertension, diabetes, coronary heart disease), laboratory test (myocardial markers: high-sensitivity cardiac troponin I, myoglobin, creatine kinase-MB; blood routine: white blood cell count, red blood cell count, neutrophil, lymphocyte, neutrophil-lymphocyte ratio, monocyte, hemoglobin, hematocrit, platelet count, erythrocyte sedimentation rate, blood glucose; voagulation: D-dimer, prothrombin time, international normalized ratio, fibrinogen, activated partial thromboplastin time; inflammatory biomarkers: Interleukin-2 receptor, IL-6, 8, 10, tumor necrosis factor-α, procalcitonin (PCT), C-reactive protein; liver function: total protein, albumin, globulin, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, γ-glutamyl transpeptidase, total cholesterol, lactate dehydrogenase; kidney function: urea, creatinine, uric acid, bicarbonate; electrolyte levels: potassium, sodium, chlorine, calcium; urine routine: proteinuria, ketone, urobilinogen, specific gravity, PH). Two professional cardiologists divided patients into a myocardial injury group (n=71) and no myocardial injury group (n=190). The cardiac injury was defined as blood levels of cardiac biomarker: hs-cTnI>34.2ng/L in males, 15.6ng/L in females. The levels of the hs-cTnI were obtained on the ARCHITECT i2000SR system. The neutrophil lymphocyte ratio (NLR) was defined as the absolute neutrophil count divided by the absolute lymphocyte count [14]. Clinical observation endpoints include death, cure and discharge, and continued treatment. The survival group consisted of patients who were cured and still in the hospital.

Statistical analysis

Continuous data were presented as median (interquartile range, IQR), and categorical data were presented as frequencies (percentages, %). The Mann-Whitney U test was used to compare continuous variables between groups, and the Chi-square test was used to compare categorical variables, as appropriate. The overall cumulative probability of survival was calculated by the Kaplan-Meier method, and the difference was assessed by the log-rank test by R version 3.6.3. Multivariate Cox regression analysis evaluated the prognostic parameters of overall survival, and visualized by nomogram. The correlation scatters between NLR and myocardial injury were plotted by GraphPad prism 8.0. The ROC curve was plotted to verify the accuracy of NLR for myocardial injury prediction. SPSS 24.0 (IBM) version was used to analyze the data unless otherwise specified. All tests were 2-sided, and P<0.05 was considered statistically significant.

RESULTS

Patient characteristics grouped by myocardial states

A total of 261 patients with COVID-19 were included. The demographics, clinical characteristics, and laboratory tests according to the presence of myocardial injury were shown in Table 1. The median age of the patients was 68.0 (59.0, 73.0), including 133 males (51.0%) and 128 females (49.0%). Myocardial injury was diagnosed in 71 patients (27.2%). Compared with patients without cardiac injury, patients with cardiac injury have significantly higher levels of other myocardial biomarkers like myoglobin (Myo) and creatine kinase-MB (CK-MB), and also have higher levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP). Patients with myocardial injury have significantly higher white blood cell counts (WBC) and neutrophil counts, and lower lymphocyte counts and platelet counts. The prothrombin time of patients with myocardial injury was significantly prolonged, and the international normalized ratio and D-dimer level were significantly increased. As for the inflammation biomarkers, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-2 receptor (IL-2R), interleukin 6, 8, 10 (IL-6.8.10), and TNF-α were higher in patients with myocardial injury (P<0.001). Patients with and without myocardial injury have differences in functional indicators, including liver (e.g. aspartate, aminotransferase, total bilirubin, direct bilirubin, Alkaline phosphatase) and kidney (e.g. urea, creatinine, uric acid, bicarbonate). In addition, patients with myocardial injury have higher blood glucose levels, electrolytes and calcium levels were significantly increased, and there were significantly more cases of proteinuria and urinary ketone bodies than those without myocardial injury. We also found that co-morbidities, including hypertension (24 [33.8%] vs 19 [10.0%]), diabetes (11 [15.5%] vs 10 [5.3%]) and coronary heart disease (7 [9.9%] vs 5 [2.6%]) were more common in patients with myocardial injury (all P<0.001).

Figure 1 - Distribution of hs-cTnI in patients with vs. without myocardial injury. hs-cTnI, high-sensitivity cardiac troponin I.

Myocardial injury and clinical prognosis of COVID-19 patients.

The median survival time of patients with myocardial injury was 21 days (95%CI = 4.40, 37.60). The survival rates of myocardial injured patients on the 5th and 15th days of hospitalization were (68.3±5.6)% and (53.8±6.0)%, patients without myocardial injury were (98.4±0.9)% and (92.1±0.2)%, respectively. Overall, patients with myocardial injury had a higher mortality rate than patients without myocardial injury (40 [56.3%] vs 18 [9.5%]; P<0.001), but their hospital stay was significantly shorter (P=0.008), suggesting that COVID-19 patients with cardiac injury progressed very rapidly. The Log-rank test showed statistically significant differences (χ2=67.486, P<0.001), as shown in Figure 2.

After adjusting for age, gender, NT-proBNP, creatinine, and lactate dehydrogenase (LDH), the multivariate-adjusted Cox proportional hazards regression model showed that the death risk in patients with myocardial injury was significantly higher than that of patients without myocardial injury (HR=2.194, 95% CI=1.083-4.446, P=0.029). Under this hazard regression model, having co-morbidity and abnormal PCT levels (>0.05ng/L) were also independent risk factors for COVID-19 mortality. The death risk for COVID-19 patients with co-morbidities was higher than those who didn’t (HR=2.843, 95% CI=1.634-4.947, P<0.001). Furthermore, patients with abnormal procalcitonin levels were at a higher risk of death than those who didn’t (HR=10.374, 95% CI=2.390-45.0.35, P=0.002).

Figure 2 - (A) Kaplan-Meier curves for all-cause mortality in patients with versus without myocardial injury. Patients with myocardial injury had significantly lower overall survival rates compared to patients without myocardial injury (30.7% versus 87.9%, p<0.001). (B) COVID-19 patients with myocardial injury had higher mortality and shorter hospital stay.

Nomogram construction

We then combined the three independent prognostic factors (myocardial injury, co-morbidity, and procalcitonin) with age and gender to build a model to predict the risk of death in patients with COVID-19. The model was visualized in Figure 3 with a nomogram. Here we use a virtual 75-year-old male patient to explain the usage of this nomogram. Assuming this patient has myocardial injury and hypertension, the procalcitonin is 2.84 ng/mL upon admission. According to the nomogram, points for age, male, comorbidity, myocardial injury, and procalcitonin are 78, 6, 19, 25, and 18, respectively. The total score is 146, which indicates that the patient’s risk of death is 0.68 (Figure 3).

Figure 3 - Nomogram in patients with COVID-19. The usage of the nomogram is illustrated in an assumptive male 75-year-old patient with myocardial injury and hypertension, and procalcitonin of 2.84 ng/mL upon admission (vertical red lines). According to the nomogram, points for age, male, comorbidity, myocardial injury, and procalcitonin were 78, 6, 19, 25, and 18, respectively. The total score is 146, which indicates that the patient’s risk of death is 0.68.

Correlation between NLR and myocardial injury

The correlation analysis revealed a moderate correlation between NLR and hs-cTnI (r=0.632, P<0.001). As shown in the ROC curve in Figure 4, NLR had a great performance in predicting myocardial injury, the AUC=0.837 (95%CI 0.784-0.890, P<0.001).

Figure 4 - (A) Correlation between the NLR and hs-cTnI (r=0.632, p<0.001). (B) The predictive value of NLR on myocardial injury, AUC=0.837 (95%CI 0.784-0.890, p<0.001). NLR, neutrophil lymphocyte ratio, hs-cTnI, high-sensitivity research cardiac troponin I.

DISCUSSION

High-sensitivity cardiac troponin (hs-cTnI) has the characteristics of high sensitivity, strong specificity, and long duration after onset. The present study used the hs-cTnI level as the diagnostic criterion for myocardial injury. Myocardial injury was diagnosed in 71 (27.2%) of 261 patients with 2019-nCoV infection. Compared with patients without cardiac injury, patients with cardiac injury had a more severe acute state, manifested by increased C-reactive protein, NT-proBNP, and creatinine levels, more obvious inflammation, poor blood coagulation and liver function. These all indicated that myocardial damage is related to the severity of the disease in patients with COVID-19.

The main finding of this study was the statistically significant association between cardiac injury and mortality. According to our data, more than half of the cardiac injury patients (56.3%) died in the hospital. The multivariate-adjusted Cox proportional hazard regression model showed that myocardial injury was a powerful predictor of the prognosis of COVID-19. Furthermore, the median hospital stay of myocardial injury patients was 18 days, which was significantly shorter than the 21.5 days of patients without cardiac injury. Indicating that the cardiac injury is associated with the clinical outcomes of COVID-19 patients, and the clinical progress of patients with myocardial injury is more rapid and critical. Although the exact pathological mechanism of myocardial injury caused by COVID-19 is still unclear, the phenomenon of myocardial injury has been confirmed. The autopsy revealed that myocardial cells in COVID-19 patients have degenerated and necrotic, part of the vascular endothelium fell off, and intimal inflammation and thrombosis [15, 16]. It is currently believed that the main mechanisms of COVID-19 patients with myocardial injury are:

1) Immune impairment caused by systemic inflammation state [17]. Immune dysregulation is recognized as one of the most critical factors in the pathogenesis of vascular disease. Severe infections bring out excessive activation of the immune system and release large amounts of cytokines, which may also adversely affect the response to 2019-nCoV infection [18, 19]. An observational study found that plasma levels of IL-6 and IL-10 in patients with severe COVID-19 were significantly increased, accompanied by a decrease in CD4+ and CD8+ T lymphocytes [19]. The significant increase of inflammatory factors can directly lead to the damage of cardiomyocytes [20]. In this study, the CRP level of patients with myocardial injury was significantly higher, suggesting the existence of severe inflammation.

2) ACE2 functions as a receptor for 2019-nCoV entry into the cell [21]. ACE2 is a type 1 membrane protein with a catalytic domain on the outer surface of cells. Early studies have shown that SARS-CoV can invade cells through ACE2 [22]. ACE2 receptors are also widely expressed in the cardiovascular system, which provides the necessary receptors for viruses to invade the heart [23, 24].

3) Hypoxia. Diffuse pulmonary interstitial fibrosis hinders blood gas exchange in critical COVID-19 patients, coupled with decreased systemic oxygenation during pneumonia, leading to severe hypoxemia [15, 25]. Continuous hypoxia leads to the accumulation of acidic metabolites in cardiomyocytes, causing myocardial injury. Therefore, treating patients with myocardial injury should correct hypoxemia as much as possible and improve the supplement of myocardial oxygen.

In the statistics of co-morbidities in patients with myocardial injury, we found that COVID-19 patients with the preexisting cardiovascular disease might be more prone to myocardial injury. Several studies have reported this phenomenon, and these patients are at greater risk of developing cardiac insufficiency and heart failure [7, 26]. Furthermore, the systemic infection could also lead to impaired cardiac auto rhythm, affecting the prognosis. Multiple studies have shown that patients with myocardial injury require more mechanical ventilation and glucocorticoid therapy in COVID-19. Complications such as acute respiratory distress syndrome, acute kidney injury, and coagulation disorders are more common in patients with myocardial injury [4, 27]. Therefore, more attention should be paid to laboratory indicators such as hs-cTnI, Myo, and CK-MB in patients with COVID-19, especially those with underlying cardiovascular diseases.

It should be noted that elevated hs-cTnI levels not only predict myocardial injury, but are also associated with systemic disease and poorer prognosis, which precisely illustrates the importance of hs-cTnI in the management of COVID-19 patients [28]. Clinically, the elevation of hs-cTnI on the one hand reminds us to be alert to the direct infection of cardiomyocytes by SARS-CoV-2, which may lead to myocardial injury, pericardial effusion and heart failure [29]. On the other hand, it suggests the possibility of a “cytokine storm” caused by immune dysregulation [30]. And elevated troponin may be exacerbated by concomitant renal failure [31]. Clinically, the hs-cTnI level of patients with COVID-19 should be closely monitored to predict the severity of the disease and adjust the treatment plan in time.

Under the Cox regression model that we constructed, co-morbidities and abnormal levels of procalcitonin are also independent risk factors for mortality in COVID-19 patients. Studies have found that patients with underlying cardiovascular diseases are more likely to suffer myocardial damage and a higher risk of death after being infected with COVID-19. Our data showed that 62 (23.8%) patients had co-morbidities, of which 69.4% had hypertension, and 19.3% had coronary heart disease. In a report of 138 patients with COVID-19, 64 patients (46.4%) had comorbidities, of which 31.2% were patients with hypertension and 14.5% were patients with cardiovascular disease [7]. Previous studies have demonstrated multiple mechanisms by which viral diseases damage cardiomyocytes, including direct viral injury, systemic inflammation, coronary plaque instability, increased hypoxia, etc. [32, 33]. Procalcitonin, the propeptide of calcitonin, is present in insufficient concentrations in the blood of healthy people individuals. It is often used to indicate bacterial, sepsis, and multiple organ failure [34-36]. Several studies have shown that the serum level of PCT in COVID-19 patients increases significantly as the disease worsens [37, 38]. Consistently, our data also confirmed that could be used to predict the prognosis of COVID-19 patients.

As a potential biomarker reflecting immune balance dysregulation and systemic inflammatory response in vivo, the predictive value of NLR in disease severity in COVID-19 patients has also been extensively explored. The study by Ma et al. suggested that NLR may be a valuable biomarker for identifying severe COVID-19 patients with moderate-to-severe ARDS [39]. However, the study by Kalabin et al. pointed out that it cannot be used as an independent predictor of poor outcomes of SARS-Cov-2 infection [40]. Another study found that NLR has a diagnostic role in the presence of bacterial infections in COVID-19 patients [41]. It is worth mentioning that this study found a correlation between NLR and hs-cTnI. The ROC curve showed that the NLR has a specific predictive value for myocardial injury, which pointed towards inflammation as a potential mechanism for myocardial injury. Several studies have suggested that NLR is a novel, simple, and inexpensive cardiovascular risk marker that can estimate the development of myocardial injury. Weedle et al. pointed out in a study of 906 people that higher NLR before cardiac surgery is associated with postoperative atrial fibrillation [42]. A retrospective analysis of 214 patients revealed that increased NLR on admission has a specific predictive value for myocardial injury induced by acute carbon monoxide poisoning [43]. NLR also correlates with the coronary collateral circulation in patients with chronic total occlusion [44, 45]. Therefore, in the early routine blood test, the significantly increased ratio of neutrophils to lymphocytes can also sound an alarm for myocardial injury, suggesting that changes in myocardial necrosis markers should be dynamically monitored.

This study is aimed at the early stage of global new coronary pneumonia. Since the end of data collection, multiple variants of interest (VOCs) of SARS-CoV-2 have emerged. South Africa reported a novel SARS-CoV-2 variant B.1.1.529 (Omicron) on November 24, 2021, resulting in a rapid increase in COVID-19 cases. An echocardiographic study of Omicron-infected patients published in April 2022 showed ventricular dysfunction in 33 of 61 patients (54.10%). Fifteen patients (25%) had the myocardial injury, a similar proportion of injury to our study (27.2%) [46]. In addition to the similar characteristics of myocardial injury, a comparative study of Omicron and non-Omicron-infected COVID-19 patients found that Omicron patients had a fever and upper respiratory symptoms as the primary clinical manifestations, and lung imaging manifestations were less. However, the hospital stay is extended, which means a long time for virus removal. In terms of laboratory indicators, the neutrophil count, white blood cell count, and hypersensitive CRP in the Omicron group were significantly lower than those in the non-Omicron group; the lymphocyte count, IL-6, IL-8, alpha-interferon, and gamma interferon were significantly higher in the non-Omicron group [47].

Limitations of our study include that it was a single-centre, retrospective study with short follow-up, and hypothesis can be extrapolated, but causal inferences between COVID-19 and myocardial injury have not been established. Additionally, the information contained in this study is primarily based on limited early experience with COVID-19. The continued emergence of new SARS-CoV-2 variants further complicates the control of the COVID-19 pandemic, so generalizations and interpretations of our data conclusions should also be made with great caution.

At present, the task of treating existing patients is still arduous. While performing antiviral therapy, it is necessary to monitor the function of vital organs to prevent myocardial damage and ensure the quality of life of patients after recovery. Fortunately, we have accumulated experience in preventing the spread and clinical response of viral variants. Through global cooperation and rapid data sharing, we will win this battle.

In conclusion, the concern of myocardial injury, the monitoring of procalcitonin levels, and the collection of the history of underlying diseases can help predict the prognosis of COVID-19 patients. It is reasonable to classify COVID-19 patients based on the presence of myocardial damage to implement active strategies. Attention should be paid to monitoring myocardial injury in patients with significantly elevated myocardial markers and NLR at admission.

Acknowledgements

We appreciate all patients and medical staff who contributed to this study.

Conflict of interest

None

Funding

None

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