Evaluation of the relation between cardiac biomarkers and thorax computerized tomography findings in COVID-19 patients

Background: Troponin levels may be elevated in COVID-19 infection. The aim of this study was to the explore relation between troponin levels and COVID-19 severity. Materials & methods/Results: One hundred and forty consecutive patients with COVID-19 pneumonia were included. Diagnosis of COVID-19 pneumonia was based on positive chest computed tomography (CT) findings. Quantitative PCR test was performed in all patients. Only 74 patients were quantitative PCR-positive. Twenty four patients had severe CT findings and 27 patients had progressive disease. These patients had significantly lower albumin and higher ferritin, D-dimer, lactate dehydrogenase, C-reactive protein, and high-sensitivity cardiac troponin I (hs-cTnI). Conclusion: COVID-19 patients with severe CT findings and progressive disease had higher hs-cTnI levels suggesting the use of hs-cTnI in risk stratification.


<0.001
Length of hospital stay (days) (range) (IQR) 10 ± 5 † (4-24)  not any significant differences in the frequencies of hypertension, diabetes, coronary artery disease, heart failure and renal failure among patients according to the severity of chest CT findings. Patients with severe CT findings had significantly lower albumin and higher total lung severity scores, ferritin, peak values of D-dimer and basal and peak values of LDH, CRP and hs-cTnI levels.
Disease progression was noted in 27 patients (19.3%) and 14 (10%) patients were taken into the ICU. The general characteristics and laboratory parameters of these patients are listed in Tables 2 & 3, respectively. The patients with progressive disease had significantly higher frequencies of diabetes and PCR positivity, higher total lung severity scores, ferritin, basal and peak values of hs-cTnI, LDH and CRP, peak procalcitonin and D-dimer levels, and lower albumin levels and lymphocyte counts compared with those without disease progression. The patients who needed ICU were elderly and had higher frequencies of diabetes, higher basal and peak values of hs-cTnI, LDH, CRP, procalcitonin and D-dimer levels, and also higher ferritin and lower albumin values.
Two patients (1.4%) died in the ICU. They were both male and had higher basal and peak values of LDH, CRP, procalcitonin and D-dimer levels and also higher ferritin values. Their baseline hs-cTnI values were normal but peak troponin levels were higher. One of them had comorbidities like hypertension, diabetes, coronary artery disease, heart failure and renal failure with negative PCR test and bilateral moderate CT findings while the other patient had severe CT findings and positive PCR test with no comorbidities.
Logistic regression analysis did not reveal troponin levels as an independent predictor for severe CT findings, progressive disease or need for ICU when adjusted by age, sex, CRP, LDH, ferritin and D-dimer.

Discussion
In our study, we found that patients with severe CT findings, disease progression and need for ICU had significantly higher troponin levels although the significance of hs-cTnI was lost when adjusted by age, sex and other inflammatory markers.
Troponin levels have been reported to be elevated in 8-28% of COVID-19 patients suggesting the presence of myocardial injury [20]. The release of modest levels of troponin caused by either viral or immune-mediated cardiac injury at the initial phase of the infection indicates a worse outcome [20]. Guo et al. have reported that myocardial injury characterized by moderate troponin elevation was mostly seen in patients with underlying CVD or other comorbidities and high levels of troponin together with natriuretic peptides on admission or at follow-up conferred up to five-times the risk of arrhythmias, mortality and ventilation need [11].
This situation may be similar to troponin elevation observed in acute respiratory distress syndrome or sepsis. Circulating troponin is detectable in over 90% of patients with acute respiratory distress syndrome and is associated with degree of critical illness [21]. While major signs of infection including tachycardia and fever increase the oxygen demand, hypotension due to cytokine storm or sepsis and pneumonia induced hypoxemia can result in insufficient supply impairing the balance of myocardial oxygen need and supply [22]. This imbalance may lead to ischemic signs and/or symptoms with a typical rise and fall pattern of troponin without classical plaque rupture and   coronary thrombosis and is named as type-II myocardial infarction [23]. Patients with type-II myocardial infarction or injury usually have multiple comorbidities and poor prognosis. One of the most common precipitating factors for type-II myocardial infarction or injury is sepsis, which is originated predominantly from the lower respiratory tract. Anemia, electrolyte imbalance, arrhythmia and hypotension are also among the common factors associated with type-II myocardial infarction or injury [24]. In our study, troponin was elevated in 25 patients. The typical rise and fall pattern of troponin was observed in five patients while most of the patients (18 patients) had steady-state low positive troponin values. Two patients had continuously increasing troponin levels.
Whether the exact mechanism of myocardial injury is due to primary infection or is secondary to respiratory system involvement is still not known. It is also not clear whether it reflects a systemic or local ischemic/inflammatory process [25]. In addition, troponin elevation may result from epicardial coronary artery lesions, myocarditis or pulmonary embolism. However, continuous increase in biomarkers can be a sign of uncontrolled and amplified inflammatory response [20].
According to the data of The Chinese Center for Disease Control and Prevention for COVID-19 in mainland China, the overall case fatality rate was 2.3% (1023 deaths among 44,672 confirmed cases), and the mortality reached 10.5% in patients with an underlying CVD [1]. Mortality rate of our study was 1.4%, which was lower compared with the global data. Higher mortality rates are expected in patients with comorbidities [26]. However, in our study, one of the patients who died had CVD while the other patient had no comorbidity.
Viral load, host immune system, age and comorbidities are the major factors that lead to clinical differences [20]. One of the important results of our study was the higher frequency of diabetes among patients with progressive disease and ICU need. This result was consistent with the previous study of first 138 hospitalized patients in Wuhan [27]. Although this study pointed out cerebrovascular diseases and CVDs, especially hypertension, as important comorbidities in clinical deterioration, we did not confirm this in our study.
The most prominent laboratory changes in our study were elevations in CRP (91%), D-dimer (85%) and LDH levels (99%). According to the data obtained from the first 138 patients at the beginning of the pandemic, the most common biochemical abnormalities were lymphopenia, prolonged prothrombin time and elevated LDH [27]. Zhu et al. has reported biochemical findings of COVID-19 patients as elevated CRP (73.6%), elevated D-dimer levels (37.2%), lymphopenia (56.5%), elevated procalcitonin (17.5%) and leukocytosis (12.6%) [28]. Unlike the previous studies, lymphopenia was a less common finding of our study (26%). While procalcitonin levels are generally normal because of the absence of a bacterial infection, high CRP level is a common finding [28]. Liu et al. reported that CRP levels but not procalcitonin levels had a significant correlation with disease severity [29]. The course of the laboratory parameters during hospitalization is also related with outcome [10]. Lymphopenia is highly prognostic and recovery of lymphocyte count is related with clinical improvement [20]. D-dimer is one of the most common laboratory abnormalities of the disease and increasing levels of D-dimer are related with in-hospital mortality [30]. In our study, patients with disease progression and need of ICU had a continuous increase in hs-cTnI, CRP, procalcitonin and D-dimer levels.

Study limitations
The major limitations of our study were the relatively small sample size and its being a single-center study. A larger cohort study is needed to verify our results. In our study, the diagnosis of COVID-19 was based on chest CT findings. These CT findings are not specific to COVID-19 disease and may be seen in other viral pneumonia cases. Thus there might be the possibility of overdiagnosis of COVID-19 in our cohort. Cardiovascular involvements of patients with elevated troponin levels could not be verified by transthoracic echocardiography or cardiac MRI due to the isolation condition in our hospital. N-terminal pro-brain natriuretic peptide levels of the patients were not assessed in our study.

Conclusion
COVID-19 patients with severe CT manifestations, disease progression and need for ICU have significantly higher troponin levels in addition to elevations in ferritin, D-dimer LDH and CRP suggesting the use of troponin levels in the risk stratification of COVID-19 patients. There is need for further studies with larger sample sizes to understand the associations between high troponin and cardiovascular complications of COVID-19.

Summary points
• Troponin levels may be elevated in patients with COVID-19.
• Patients with severe computed tomography findings had significantly higher troponin levels in addition to higher total lung severity scores, ferritin, D-dimer, lactate dehydrogenase, and C-reactive protein and lower albumin levels. • Patients with disease progression and need for intensive care unit had also significantly higher troponin levels in addition to higher total lung severity scores, ferritin, D-dimer, lactate dehydrogenase, and C-reactive protein and lower albumin levels. • The significance of troponin on predicting disease severity or progression is lost when adjusted by age, sex and other biochemical markers.
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