Prognostic properties of biomarkers in COVID19 infection and concomitant chronic coronary syndromes

. Background. The novel coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an unprecedented challenge for the health care system and has taken a leading position among infectious diseases due to the rapid spread and development of complications from various body systems. The problem of cardiac comorbidity in COVID-19 has several aspects: the impact of concomitant cardiovascular diseases on the incidence of a new viral infection, its severity and risk of mortality, as well as possible side effects of a number of drugs traditionally used to treat certain types of cardiovascular diseases. SARS-CoV-2 is not only a pneumonia pathogen, but also causes serious systemic consequences. Patients with cardiovascular diseases and risk factors for cardiovascular complications, such as hypertension and coronary heart disease, are more exposed to fatal consequences of COVID-19. In addition, a significant proportion of patients develop COVID-associated myocardial injury, which significantly increases the risk of in-hospital mortality. The purpose of the study was to investigate the prognostic role of individual biomarkers in patients with COVID-19-associated pneumonia on the background of chronic coronary syndromes. Materials and methods. This study was defined as an open-label, non-randomized, controlled, comparative one in parallel groups. 124 patients with COVID-19-associated pneumonia were selected upon admission, including 92 participants with a history of chronic coronary syndromes. Results. The study showed that elevated levels of biomarkers such as proinflammatory cytokine interleukin-6, iron-storage protein ferritin, serum angiotensin-converting enzyme-2, ketone body beta-hydroxybutyric acid, and fibrin breakdown product D-dimer may be associated with a more severe course of pneumonia caused by COVID-19 infection. Thus, these biomarkers had good prognostic value in predicting severe disease and death in patients with chronic coronary syndromes during hospitalization. Conclusions. The study confirms that an increase in the level of proinflammatory biomarkers is a predictor for the development of a severe coronavirus infection


Introduction
The novel coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2, has become an unprecedented challenge for the health care system and has taken a leading position among infectious diseases due to its rapid spread and development of complications from various body systems.It began with the identification of a group of patients with unknown pneumonia in Wuhan, China, in December 2019 [1].In March 2020, COVID-19 was recognized as a pandemic by the World Health Organization [2].
As of December 31, 2023, 773 million cases and more than 7 million deaths due to COVID-19 complications have been reported worldwide [3].
Among high-risk patients, a large cohort consists of those with a history of chronic coronary syndromes (CCS).CCS, which are a manifestation of coronary heart disease, include various conditions such as stable angina, asymptomatic myocardial ischemia, etc.It is known that the severe course of COVID-19 is not limited to the respiratory system but is a multisystem disease with the development of various cardio-Оригінальні дослідження / Original Researches vascular manifestations with myocardial damage, arrhythmia, acute coronary syndrome, and venous thromboembolism.These manifestations are closely related to the severity of the disease and progression to death [4].
The purpose of the study was to investigate the prognostic role of individual biomarkers in patients with COVID-19-associated pneumonia in the setting of chronic coronary syndromes.

Materials and methods
Patients with COVID-19 were enrolled upon admission to the cardiology department of the Central City Clinical Hospital in Ivano-Frankivsk, the therapeutic department of the Kolomyia Central District Hospital and the therapeutic department of the Verkhovyna Hospital.One hundred and twenty-four participants with COVID-19-associated pneumonia were selected: 92 with a history of CCS (acute myocardial infarction, symptomatic stable angina pectoris), and 32 patients without it.
The data were collected from primary medical records, which included demographic information, anthropometric data, clinical examination results, and laboratory test data.
All patients signed an informed consent in accordance with the Declaration of Helsinki.
The body mass index (BMI) was calculated based on body weight and height data using the formula: BMI = body weight / (height) 2 .
Pneumonia was verified by chest X-ray and computed tomography of the chest.
The presence of chronic coronary syndromes was detected according to the European Society of Cardiology guidelines for the management and treatment of chronic coronary syndromes [16].
All patients underwent a clinical blood test using Medonic M-series analyzer (Boule, Sweden).
Biochemical blood tests were performed using an automatic biochemical analyzer ACCENT MC240 (CORMAY, Poland).
The level of troponin I, procalcitonin and D-dimer was assessed using Getein 1100 immunofluorescence quantitative analyzer (Getein Biotech, Inc., China).
The Shapiro-Wilk test was used to test the hypothesis of normal distribution.In case of normal distribution, the arithmetic mean (M) and standard error of the arithmetic mean (m) were determined.In case of a distribution other than normal, the median and its 25-75 interquartile range (Me [LQ; UQ]) were calculated.
The Student's t-test was used to compare parametric data of dependent or independent variables.To compare non-parametric data, the Mann-Whitney U test was used for independent variables.Wilcoxon's T-test was used to analyze dependent variables.Frequency (n) and percentage (%) were calculated for qualitative data.Comparative analysis was performed using the χ 2 test.
Logistic regression analysis was performed to identify relationships and assess the degree of influence of individual indicators.
The prognostic significance of the indicators for the occurrence of adverse cardiovascular events (endpoints) was assessed by relative risk and odds ratio (OR) with a confidence interval (CI) of 95 %.
To determine the sensitivity and specificity of the tests, the area under the curve (AUC), the Youden index (J), and ROC curves were calculated.
The difference was considered significant at p < 0.05.

Results
The mean age of the examined patients was 66.2 ± 7.8 years in the CCS group, 59.9 ± 8.9 years in the non-CCS group and was relatively higher in the CCS group (p = 0.0002).In the CCS group, there were 59 (64.1 %) male and 33 (35.9 %) female patients.In the group without CCS, there were 12 (37.5 %) male and 20 (62.5 %) female patients, the gender composition in the CCS group was dominated by men (χ 2 = 6.88, p = 0.008).The average duration of CCS was 10 [5; 13.5] years.
Among the patients with severe course, there were 36 participants (39.1 %) in the CCS group and 10 (31.2 %) in the non-CCS group.In the CCS group, 4 patients (4.3 %) died, and in the non-CCS group, 2 people (6.2 %).The cause of death in all cases was acute respiratory failure.The mean number of days from the onset of symptoms to hospitalization in the CCS and non-CCS group was 7 [5; 7] (p = 0.64).The average length of hospital stay did not differ statistically significant in the CCS (13 [10; 18] days) and non-CCS group (12.5 [11; 17] days) (p = 0.78).
During inpatient treatment, 4 patients with concomitant CCS (4.3 %) were diagnosed with acute ST-segment elevation myocardial infarction (STEMI) for which they underwent percutaneous coronary intervention with stent placement to the infarct-dependent coronary artery.Nineteen patients with concomitant CCS (20.6 %) had more frequent attacks of angina pectoris than before hospitalization, occurring at rest, which required sublingual nitrates.During inpatient treatment, 2 (2.1 %) patients were diagnosed with pulmonary embolism complicated by infarction pneumonia.Among 18 (19.5 %) patients in the CCS group with a history Emergency Medicine (Ukraine), ISSN 2224-0586 (print), ISSN 2307-1230 (online) Оригінальні дослідження / Original Researches of atrial fibrillation, 5 (5.4 %) had its paroxysmal form.In 4 of them, paroxysms of atrial fibrillation were recorded, which required antiarrhythmic drugs.In 1 patient, atrial fibrillation was recorded for the first time.
The general characteristics of the study groups are presented in Table 1.
The present study examined the levels of myocardial injury markers troponin I, the inflammatory cytokine IL-6, ferritin, D-dimer in the dynamics, soluble ACE-2 and one of the ketone bodies, β-HOB, as a marker of the severity of COVID-19-associated pneumonia and procalcitonin.
Table 2 shows the levels of the above markers in the groups at hospitalization.In particular, the level of so-luble ACE-2 was significantly higher in the group with concomitant cardiovascular disease (CVD), 1.853 [1.485; 2.433] versus 1.641 ± 0.440 in the group without CVD (p = 0.01).
No relationship was found between biomarker levels and the risk of arrhythmias.An increased level of D-dimer was associated with a high risk of thromboembolic complications (OR = 1.007; 95% CI 1.002-1.011,p = 0.002).

Discussion
The results of the study showed that patients with severe pneumonia associated with COVID-19 and concomitant CVD have higher levels of IL-6, ferritin, soluble ACE-2, and  In a meta-analysis conducted by Ulhaq Z.S., Soraya G.V., it was found that IL-6 levels were significantly elevated in patients with severe COVID-19 compared to those with non-severe disease (OR = 0.71, 95% CI 0.31-1.12,p = 0.0005) [6].

Figure 1. Predictive value of selected biomarkers for the severity of COVID-19-associated pneumonia in patients with CCS Table 4. Results of ROC analysis of selected biomarkers for predicting the severity of COVID-19-associated pneumonia in patients with CCS
A study published in BMC Infectious Diseases examined the relationship between IL-6 levels and the severity of COVID-19.It showed that patients with increased IL-6 levels stayed in the hospital longer and had a higher risk of intensive care unit admission and death compared to patients with lower IL-6 levels.Researchers have suggested that elevated IL-6 levels are associated with worse outcomes in patients with COVID-19, consistent with its role as a potent proinflammatory cytokine and trigger of the cytokine storm in COVID-19 [7].
Changes in IL-6 levels can serve as a prognostic indicator in patients with COVID-19.The study found significant differences in various health parameters and treatment outcomes between patients with normal and increased IL-6 levels (mortality 0.16 vs. 5 % (HR 10.39; 95% CI 1.09-99.23;p = 0.042)).Patients with elevated IL-6 levels were more likely to have severe symptoms and complications and required more intensive treatment (HR 3.56; 95% CI 2.06-6.19;p < 0.001) [8].
Another study published by Huang L., Zhao X. et al. discusses an increase in IL-6 observed in critical cases of COVID-19 and draws parallels with sepsis: plasma IL-6 levels of more than 453.85 pg/mL (p = 0.001) may pose a risk of death.This study emphasized the importance of IL-6 in the pathogenesis of severe COVID-19 highlighting its role in the hyperinflammatory response [9].
The study by Carubbi F., Salvati L., Alunno A. et al. examined the relationship between serum ferritin levels and lung damage in patients with COVID-19.They found that higher ferritin levels were associated with more severe lung damage (OR = 14.5, 95% CI 2.3-90.9,p = 0.004).However, these elevated ferritin levels were not directly associated with a worse prognosis for patients [10].
The study by Karagiannis F., Peukert K., Surace L. et al. addressed the impact of COVID-19 on ketogenesis, in particular on the level of β-hydroxybutyrate.It showed that while patients with influenza had an increase in β-hydroxybutyrate levels, indicating infection-induced ketogenesis, this response was impaired in those with moderate to severe COVID-19, as well as in participants with bacterial pneumonia.This suggests that the typical ketogenesis response to infection may be impaired in COVID-19, which may be related to metabolic disorders that are risk factors for the severity of COVID-19 [11].
Houston S. links impaired ketogenesis to T-cell dysfunction in COVID-19.The study provided insight into how metabolic changes, in particular in the production of ketone bodies, may be associated with immune dysregulation in severe cases of COVID-19 [12].
According to a study by Poudel A., Poudel Y. et al., the level of D-dimer at hospitalization is an accurate biomarker for predicting mortality in patients with COVID-19.1.5 μg/ml is the optimal value of D-dimer at hospitalization to predict mortality in patients with COVID-19.ROC analysis for D-dimer and mortality was 0.807 (95% CI 0.728-0.886,p < 0.001) [14].
High levels of D-dimer independently correlated with the need for invasive mechanical ventilation.Low levels of this marker can apparently predict survival after mechanical ventilation in patients with COVID-19 who are on mechanical ventilation.Thus, measuring D-dimer levels during routine follow-up of these patients would be useful for predicting treatment outcomes.Levels above 1415 μg/L showed sensitivity and specificity of about 92 and 76 %, respectively.In addition, D-dimer level was very effective in predicting survival after STEMI (AUC = 0.86, p = 0.02) [15].

Conclusions
Elevated levels of IL-6, ferritin, soluble ACE-2, and β-HOB are associated with severe pneumonia caused by COVID-19 in the setting of concomitant chronic coronary syndromes, whereas high levels of IL-6, ferritin, D-dimer, soluble ACE-2, and β-HOB are associated with a higher probability of death.