key: cord-0920964-4olvg44c authors: Dökümcü, Esra title: The Role of Carbohydrate Antigen 125 in COVID-19 date: 2021-03-29 journal: Med Hypotheses DOI: 10.1016/j.mehy.2021.110590 sha: c33c28a840838de313eebe4fae5a0d1b40eba91c doc_id: 920964 cord_uid: 4olvg44c Coronavirus disease 2019 (COVID-19) is an inflammatory process with complex pathophysiology and by affecting the cardiovascular system directly or indirectly that causes life threatening cardiac injuries. Therefore, clarifying the effects of this infection on the cardiovascular system is of importance in terms of the clinical course of the disease. The increases in cardiac and inflammatory biomarkers in COVID-19 have been associated with poor prognosis and mortality. However, there are no specific laboratory markers yet to assess the severity of the disease. In this context, the combination of available biomarkers is needed to better define the clinical course of this disease. Carbohydrate antigen 125 (CA-125) has become a remarkable marker in recent years as a result of the correlation of increasing levels in cardiovascular diseases with clinical, hemodynamic, echocardiographic parameters and its relation with mortality or re-hospitalization due to heart failure. These findings suggest that CA-125 might be useful biomarker to identify the damage mechanisms of COVID-19, monitoring the prognosis of the disease and the course of the treatment. Since one year, Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a significant number of morbidity and mortality worldwide. Uncertainties still continue regarding the pathophysiological mechanism, prognosis and treatment of this infectious disease causing the pandemic [1] . However, clinical studies provide a consensus that increasing age and the presence of comorbidities are associated with severe form of the disease and poor outcome [2] . In particular, individuals with cardiovascular risk factors or cardiovascular disease have a higher risk of developing severe disease and death [3, 4] . COVID-19 may affect the cardiovascular system directly or indirectly that causing complications. Although the pathophysiology underlying cardiac injury caused by this inflammatory disease is unknown exactly, the putative mechanisms are [5, 6] : (i) SARS-CoV-2 binds to Angiotensin converting enzyme 2 (ACE2) receptor which is also found in lung alveoli cells as well as myocardial and vascular endothelial cells and may cause a direct cytotoxic effect in these cells [4, [7] [8] [9] ; (ii) Severe systemic inflammation and cytokine storm [4, 5, [8] [9] [10] [11] [12] ; (iii) Caused by hypoxemia due to respiratory dysfunction myocardial and microvascular injuries [8] ; (iv) İschemia and exacerbation of pre-existing heart disease [11, 12] . Except for causing myocardial damage, all these effects may also lead to myocardial infarction (MI), myocarditis, heart failure, acute coronary syndrome, venous thromboembolism (VTE) and arrhythmia [4, 13] . Laboratory findings play an essential role in assessing illness severity, determining prognosis and guiding treatment in COVID-19 [14] . Evaluation of data on electrocardiographic, echocardiographic, and cardiac specific laboratory parameters are milestones to define cardiac injury during COVID-19 [6] . However, additional data with proven clinical benefit are required to better evaluate the predicted potentials of these markers. Therefore, the use of CA-125 data may have various benefits. Carbohydrate antigen 125 (CA-125) is a high molecular weight glycoprotein that is a member of the mucin family and is synthesized by serous epithelial cells. Its half-life is approximately 7 days. As the physiological role of CA-125 is considered to protect the epithelial lumen surfaces from physical stress through the process of hydration or lubrication [15] [16] [17] . Pathophysiological mechanisms that cause serum levels to increase are expressed as activation of mesothelial cells in response to stimuli such as oxidative stress, mechanical stress 4 (fluid overload and tissue stretching) and systematic inflammatory process (cytokine activation) [15, 16, [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] . There are many publications from the past to present suggesting that CA-125 may be a potential biomarker for heart diseases, especially heart failure. Elevated serum CA-125 levels together cardiac biomarkers have been reported to have prognostic effects in patients with heart failure and correlate well with clinical, hemodynamic, and echocardiographic measurements indicating the severity of the disease [18, 19, 22, 24, 26, [29] [30] [31] . In line with this evidence, adding CA-125 to the COVID-19 test panel may provide prognostic data that can help identify patients at higher risk of adverse outcomes in a timely manner and monitor treatment follow-up. Moreover, it may also contribute to a better understanding of the pathophysiology of the process. In this hypothesis, it is evaluated what the increased CA-125 levels might mean in patients with severe COVID-19. The severe disease state associated with COVID-19 is a complex process in which various systems play a role. Hence, a collaborative biomarker based approach might help to manage the cardiac effects of this disease better. Studies examining the interaction between COVID-19 infection and the cardiovascular system have shown that severe patients may develop cardiac injury and this too provides important information on complications and mortality associated with COVID-19. Patients with cardiac injury have higher levels of Troponin ( cTnI, hs-cTnI), Creatine Kinase-MB (CK-MB), C-reactive protein (CRP or hs-CRP), natriuretic peptide (BNP or NT-proBNP) and abnormal echocardiographic or electrocardiogram (ECG) findings have been reported [4] . It has also been indicated that serum cytokine levels such as interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-α (TNFα) increase significantly in relation to disease severity [1, 5, 7, 10, [32] [33] [34] [35] [36] . In many previous studies have reported that increased CA-125 levels along with cardiac and inflammatory biomarkers are positively correlates with the degree of cardiac dysfunction and the severity of the clinical picture in patients with heart failure [18, 19, 21, [24] [25] [26] [27] . Heart failure condition is closely related to systemic inflammatory activity and congestion (hydrostatic pressure and serosal effusions). Congestion is a hemodynamic parameter and causes the disease to progress by integrating into the circle of inflammatory process defined in 5 heart failure. The most important determinants of the expression of CA-125 in heart failure are factors such as serosal fluid overload, congestion and also positive correlations with various inflammatory cytokines have been detected [15, 19-23, 26, 28, 29, 37] . Considering that CA-125 is a surrogate marker for both congestion and systemic inflammation that can be considered that in COVID-19 patients may have high serum levels by a multifactorial mechanism in the complications that occur. It was reported that patients with increased CA-125 levels have a higher risk of developing atrial fibrillation [15, 17, 18, 27] ; (V) Elevated CA-125 levels were also observed in other cardiac pathologies such as tricuspid stenosis, mitral stenosis, mitral valve endocarditis, atrial septal defect, pulmonary hypertension, aortic stenosis, and acute coronary syndromes [25, 27, 37] ; (VI) There is evidence that changes in serum CA-125 levels as a result of the therapy protocol used heal the clinical course [37] . Clinical studies of COVID-19 indicate that there is cycle between this infection and cardiac dysfunction or heart failure [5, 35, 36, 40] . There are many mechanisms that can cause cardiac hemodynamic disorders in COVID-19, and different types of cardiovascular involvement have been reported in the literatüre [4-8, 10, 35, 41, 42] . Therefore, early diagnosis and timely intervention of critical cases is very important. Up to date, studies suggest that many laboratory biomarkers are deranged in COVID-19 infection, and some are considered predictors of poor prognosis and mortality [14, 43] . Increased levels of procalcitonin, CRP, D-dimer, troponin, natriuretic peptide (NT-pro BNP, BNP) and cytokine (IL-6, IL-10, TNF-α) are associated with risk of cardiovascular 6 complications and death. It has been indicated that all these biomarkers increase each other's prognostic values and have significant positive linear correlations [5, 8, 32, 34, 40, 44] . Studies on combining risk stratification and predictive values of different biomarkers that reflecting different pathophysiological pathways and having prognostic value alone are among the current research topics [19] . CA-125 is one of the remarkable biomarkers in this context because of correlation with many parameters. Although CA-125 and natriuretic peptides have different pathophysiological mechanisms and half-lives (BNP ~ 20-30 minutes), significant correlations have been identified between them in the presence of heart failure. Moreover, strong associations of CA-125 with inflammatory stimuli, echocardiographic and hemodynamic parameters, mortality or re-hospitalization risk of patients during follow-up have been reported [15-23, 25-28, 29, 31, 37, 39, 45] . An improvement in LVEF with a marked decrease in CA 125 levels after treatment in heart failure patients, the observation of reductions in pericardial effusion, and also the ability to monitor treatments that affect cytokine levels through CA-125 levels make it a valuable marker [4, 10, 17, 19, 21, 25, 26, 37] . CA-125 has also other strategic advantages that deserve to be highlighted: (a) the wide availability; (b) in contrast to the disadvantages of cytokines such as high temporal variability, non-standardized measurement techniques and short half-life, there is an easy, standardized and highly reproducible measurement method in a short time; (c) unlike natriuretic peptides (much lower in obese people than normal weight individuals), serum values that are not affected by factors such as kidney function, body weight and age; (d) relatively low cost [17, 19-22, 28, 29, 45] . In line with all these evidences, CA-125 has the potential to be a useful marker in COVID-19 as well. Wei et al., have been reported positive correlations between inflammatory markers and a range of cancer biomarkers, including CA-125, in COVID-19 patients. As a result of this relation, they have suggested that acute lung injury caused by SARS CoV-2 may lead to an increase in some cancer biomarkers as an indicator of widespread and acute pathophysiological injuries [46] . However, there is no mechanism or data yet associated with increased CA-125 levels as a result of cardiac effects in COVID-19. Therefore, these theoretical possibilities will be better evaluated when clinically validated data are available. On the other hand, there are also some uncertainties regarding the CA-125 that should be expressed. It should not be ignored that CA-125 may have increased serum levels not related to heart failure and in different types of both malignant and non-malignant diseases [28, 37] . Hence, the clinical interpretation of elevated CA-125 levels should be done with caution. Such 7 an approach would contribute to the identification of the CA-125's major production sites and stimuli [6, 15] . Accordingly, it may provide evidences as to whether the pathophysiological link between COVID-19 and CA-125 is affected by overlapping intense inflammatory stimuli that may result from underlying stimuli, stimulating environments, effusions, or associated cytokines. In conclusion, COVID-19 is a newly emerged inflammatory process and various complications can occur even after the disease has healed. Because of the strong correlation of CA-125 with many parameters, its combination with key prognostic biomarkers in COVID-19 might make significant contributions to the management process of this disease. Furthermore, both the problems in the supply of many laboratory biomarkers as a result of intensive health services all over the world and the inability to test some biomarkers easily in all laboratories should also encourage its use in this period. There is no conflict of interest. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19 Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and metaanalysis Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis Systematic review of COVID-19 related myocarditis: Insights on management and outcome Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19) Impaired cardiac function is associated with mortality in patients with acute COVID-19 infection Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China COVID-19 and the cardiovascular system Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19) COVID-19 and the heart At the heart of COVID-19 Prognostic Impact of Prior Heart Failure in Patients Hospitalized With COVID-19 Laboratory abnormalities in patients with COVID-2019 infection Beyond malignancy: the role of carbohydrate antigen 125 in heart failure Carbohydrate antigen 125 predicts pulmonary congestion in patients with ST-segment elevation myocardial infarction CA 125 and immunoin-flammatory activity in acute heart failure Carbohydrate antigen 125 in heart failure. New era in the monitoring and control of treatment Prognostic value of carbohydrate antigen 125 combined with N-terminal pro B-type natriuretic peptide in patients with acute heart failure Factors associated with plasma antigen carbohydrate 125 and amino-terminal pro-B-type natriuretic peptide concentrations in acute heart failure The emerging role of carbohydrate antigen 125 in heart failure Acute-Decompensated Heart Failure. Preliminary Study Elevated CA-125 as Humoral Biomarker of Congestive Heart Failure: Illustrative Cases and a Short Review of Literature. Hindawi, Case Reports in Cardiology Clinical and prognostic value of elevated CA125 levels in patients with coronary heart disease Tumour biomarkers in heart failure: is there a role for CA-125? Serum levels of carbohydrate antigen 125 in combination with N-terminal pro-brain natriuretic peptide in patients with acute decompensated heart failure Higher cancer antigen 125 level is associated with the presence of permanent atrial fibrillation in systolic heart failure patients Clinical utility of antigen carbohydrate 125 in heart failure Carbohydrate antigen 125 for mortality risk prediction following acute myocardial infarction Carbohydrate antigen-125 and N-terminal probrain natriuretic peptide levels: compared in heart-failure prognostication The value of cancer antigen 125 (Ca 125) and copeptin as markers in patients with advanced heart failure Cardiac biomarker-based risk stratification algorithm in patients with severe COVID-19 Special Article-The impact of 2019 novel coronavirus on heart injury: A Systematic review and Meta-analysis Meta-analysis of Cardiovascular Events and Related Biomarkers Comparing Survivors Versus Nonsurvivors in Patients With COVID-19 Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Insights into the clinical implications of carbohydrate antigen 125 as a biomarker of heart failure: a meta-analysis and systematic review of published studies Prognostic value of increased carbohydrate antigen in patients with heart failure Relationship between cytokines and tumour markers in patients with chronic heart failure Single-cell Transcriptome Analysis Indicates New Potential Regulation Mechanism of ACE2 and NPs signaling among heart failure patients infected with SARS-CoV-2 Potential Effects of Coronaviruses on the Cardiovascular System: A Review Clinical Characteristics of Coronavirus Disease 2019 in China Unexpected Features of Cardiac Pathology in COVID-19 Infection Prognostic Value of Troponin-T and B-Type Natriuretic Peptide in Patients Hospitalized for COVID-19 Carbohydrate antigen 125 in heart failure. A New era in the monitoring and control of treatment Elevations of serum cancer biomarkers correlate with severity of COVID-19