Biomarkers in predictıon of pulmonary thromboembolism in COVID-19 infection?

Authors

Abstract

Aim This study aimed to investigate whether there is a biomarker that can indicate pulmonary thromboembolism (PTE), which plays a major role in the severity and mortality of COVID-19, at the beginning of treatment.
Materials and Methods A total of 160 adult patients who were admitted to the Chest Diseases Clinic between April 2020 and April 2021 were retrospectively included in this study. The patients were divided into three groups: COVID PCR + PTE + (group 1), COVID PCR – PTE + (group 2), and PCR + PTE – (group 3). Demographic data and biomarker levels, including D-dimer, ferritin, fibrinogen, troponin-I, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), were obtained from the hospital’s electronic data system. Statistical analyses were performed using the STATISTICA 13.0 software package.
Results No statistically significant differences were found between the patient groups regarding median age, sex, D-dimer, or troponin-I levels (p > 0.05). Statistically significant differences were observed between some groups in ferritin, fibrinogen, CRP, NLR, and PLR values (p < 0.05).
Discussion In this study evaluating the potential of biomarkers to indicate pulmonary thromboembolism at the time of diagnosis in SARS-CoV-2 patients, the parameters showing statistically significant differences were not considered reliable for early detection of PTE, as they can be affected by multiple factors. Since current data on COVID-19 remains limited, further studies are needed to clarify these findings.

Keywords

Introduction

Coronavirus disease 2019 (COVID-19) is an illness caused by a novel coronavirus that first emerged in Wuhan, China, in December 2019. The main clinical manifestations include fever, dry cough, fatigue, myalgia, and dyspnea. Although COVID-19 infection is predominantly characterized by pulmonary involvement, disease severity may progress to multiple organ failure in some cases [1, 2].
Therefore, several biomarkers have been used to assess the prognosis of COVID-19 infection. Among these are ferritin, D-dimer, fibrinogen, C-reactive protein (CRP), and troponin levels, as well as neutrophil, lymphocyte, and platelet counts. Previous studies have demonstrated that CRP, D-dimer, and ferritin levels increase in COVID-19 patients due to hyperinflammation [3]. Cardiac biomarkers are also widely used in both pulmonary embolism (PE) and COVID-19, and elevated troponin levels have been found to be associated with increased mortality in COVID-19 patients [4]. Fibrinogen, as an acute- phase reactant and a coagulation factor, is also used in the follow-up of COVID-19 patients [5].
Although the associations of platelet, lymphocyte, and neutrophil levels with inflammation are well known, recent studies have shown that the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are also preferred markers in COVID-19 patients for prognostic prediction due to their easy accessibility [6].
COVID-19 has been shown to cause endothelial injury as a result of widespread inflammation and hypoxia. Furthermore, it has been associated with an increased risk of thrombosis through hemostatic changes such as intravascular coagulopathy, pulmonary microthrombi, thrombocytopenia, and stasis related to immobility [7].
Pulmonary embolism (PE) occurs as a result of thrombus fragments detaching from systemic deep veins and obstructing the pulmonary artery and/or its branches. It is associated with high mortality and morbidity, can be recurrent, and may cause diagnostic challenges; however, it is mostly preventable [8]. Since the prognosis of COVID-19 patients with PE is known to be worse, early diagnosis in these patients is of great importance [9].
Performing advanced embolism tests in all COVID-19 patients at the time of diagnosis is not a reasonable approach due to unnecessary exposure to contrast agents and radiation, as well as inefficient use of healthcare resources. To both protect patients and ensure optimal resource utilization, a better approach is to identify high-risk patient groups for PE and perform advanced diagnostic tests only in these patients. Therefore, this study aimed to investigate whether any biomarkers measured at the time of diagnosis and treatment initiation could indicate the presence of PE in COVID-19 patients.

Materials and Methods

Patients who were treated as inpatients in the Chest Diseases Clinic between April 2020 and April 2021 were evaluated retrospectively. A total of 160 patients were included in the study.
Inclusion criteria were as follows: age ≥ 18 years, confirmed COVID-19 PCR positivity, presence or absence of pulmonary embolism (PE) confirmed by chest computed tomography (CT), and availability of sufficient clinical and laboratory data in the hospital’s electronic health record system.
Exclusion criteria were age < 18 years, outpatient follow-up, and hospitalization in clinics other than the Pulmonology Clinic. Patients with a positive COVID-19 PCR test were divided into two groups according to the presence of PE: group 1 (COVID-19 PCR +, PE +, n = 36) and group 3 (COVID-19 PCR +, PE −, n = 50). The control group (group 2) consisted of 74 patients with COVID PCR − and PE +.
Demographic characteristics, comorbidities, and biomarkers (D-dimer, ferritin, fibrinogen, troponin-I, and C-reactive protein [CRP] levels), as well as platelet, lymphocyte, and neutrophil counts and neutrophil-to-lymphocyte (NLR) and platelet-to- lymphocyte (PLR) ratios, were obtained and compared among the three groups.
Statistical Evaluation
The normality of data distribution (D-dimer, ferritin, and other quantitative parameters) was tested using the Shapiro– Wilk test. Since the data were not normally distributed, the Kruskal–Wallis test followed by post hoc pairwise comparisons was applied to determine intergroup differences. Differences between sexes were analyzed using the Mann–Whitney U test. Categorical variables, such as sex distribution among groups, were evaluated using the chi-square test. All analyses were performed using STATISTICA 13.0 (StatSoft Inc., USA). A p-value < 0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Clinical Research Ethics Committee of Mersin University Faculty of Medicine (Date: 2021-06-09, No: 420) and by the COVID-19 Scientific Research Evaluation Board of the Turkish Ministry of Health, General Directorate of Health Services.

Results

A total of 160 patients were included in the study: 93 (58.1%) were female and 67 (41.9%) were male. In group 1, 18 (50%) patients were female and 18 (50%) male; in group 2, 50 (67.6%) were female and 24 (32.4%) male; and in group 3, 25 (50%) were female and 25 (50%) male. No significant sex differences were found among patients with COVID-19; however, patients with PE were predominantly female. The difference among groups was not statistically significant (p > 0.05).
The median age of all patients was 72 years (range: 24–97 years). The median age was 74 years (32–91) in group 1, 70 years (24–92) in group 2, and 74.5 years (33–97) in group 3. No statistically significant difference in median age was observed among the groups (p > 0.05). The median age was 74 years for females (24–92) and 69 years for males (36–97). Demographic characteristics of the patients are summarized in Tables 1 and 2.
D-dimer and troponin-I levels did not differ significantly among the three groups (p > 0.05 for both parameters).
Ferritin levels were higher in group 1 than in group 2 (p = 0.008), and significantly higher in group 3 than in group 2 (p < 0.0001). There was no significant difference between groups 1 and 3 (p = 0.145). In summary, ferritin levels were higher in patients with COVID-19 (groups 1 and 3) than in those without (group 2), regardless of PE status.
Fibrinogen levels were significantly lower in group 2 than in group 3 (p = 0.011). No significant differences were found between groups 1 and 3 (p = 0.067) or between groups 1 and 2 (p = 1.00).
CRP levels were significantly higher in group 3 than in both group 2 (p < 0.0001) and group 1 (p = 0.01), with no difference between groups 1 and 2 (p = 1.00).
The NLR was significantly lower in group 2 than in group 3 (p < 0.0001), with no significant differences between groups 1 and 2 (p = 0.084) or groups 1 and 3 (p = 0.086).
The PLR was significantly higher in group 3 than in group 2 (p = 0.039), with no significant differences between groups 1 and 2 (p = 0.10) or groups 1 and 3 (p = 0.176) (Table 3).

Discussion

Previous studies have demonstrated an increased incidence of pulmonary embolism (PE) in COVID-19 infection as a consequence of inflammation, immobility, hypoxia, and disseminated intravascular coagulopathy [7]. Therefore, in this study, the patient groups were compared in terms of age, sex, D-dimer, ferritin, fibrinogen, troponin, and CRP levels, as well as neutrophil/lymphocyte and lymphocyte/platelet ratios, to evaluate the usefulness of these parameters in detecting PE among patients infected with COVID-19. The results of this study revealed that none of the examined biomarkers could be used to detect pulmonary embolism in COVID-19 infection at an early stage.
Except for certain risk factors, PE does not show a significant difference between men and women [9]. In a study by Sharif et al., including 1,075 PE patients, 69.6% were women [10]. This finding is consistent with our results, in which the proportion of female patients in the PE group was higher. Another study investigating PE incidence in COVID-19 patients reported a homogeneous sex distribution with no statistically significant difference, consistent with our findings [11].
In a retrospective study by Silverstein et al., including 2,218 patients, the mean age was 61.7 ± 20.4 years [12]. Similarly, a study investigating PE incidence in COVID-19 patients found that the mean age in the PE-positive COVID-19 group was significantly higher [11]. In our study, the median age was 72 years, with no statistically significant difference between the groups (p > 0.05).
According to the 2019 guidelines of the European Society of Cardiology and the European Respiratory Society, a negative D-dimer test may be used to exclude PE in patients with low clinical probability [13]. This approach prevents unnecessary exposure to radiation and contrast agents and promotes more efficient use of healthcare resources. In addition to its role in the diagnosis and follow-up of PE, D-dimer measurement has been shown to have potential value in predicting prognosis and mortality in COVID-19 [14]. In our study, D-dimer levels were elevated in COVID-19 patients; however, the presence of PE did not cause a statistically significant difference. Likewise, comparison of the three groups revealed no significant difference in D-dimer levels. These results suggest that D-dimer may be used to predict prognosis in COVID-19 rather than to confirm PE. Consistent with previous studies, high D-dimer levels should be used to predict mortality, clinical prognosis, and to identify patients who may benefit from embolism prophylaxis. Furthermore, low D-dimer levels in COVID-19 patients with low clinical probability of PE may provide additional accuracy in ruling out PE.
Cardiac biomarkers are commonly used in both PE and COVID-19. A meta-analysis of 13 studies including 2,389 patients found that elevated troponin levels, as an indicator of cardiac injury, were associated with disease severity, intensive care requirement, and mortality [15]. In our study, elevated troponin levels were detected in all three groups, with no statistically significant difference. This supports the notion that troponin cannot be used as a biomarker for detecting PE in COVID-19 patients. Both COVID-19 infection and PE, which are associated with inflammation, are accompanied by alterations in ferritin metabolism. According to the clinical classification developed by Siddiqi et al., ferritin levels increase in stage III (the hyperinflammation phase) of COVID-19 [16]. In our study, ferritin levels were elevated in all groups but were lower in patients with PE alone compared with the other two groups; the coexistence of COVID-19 and PE did not cause any additional change in ferritin levels. The higher ferritin levels observed in COVID-19 patients may be attributed to its role as an acute- phase reactant and its association with complications such as PE, disease severity, and mortality.
Fibrinogen is known to decrease as a result of consumption during activation of the coagulation cascade in PE [17]. Conversely, significantly higher fibrinogen levels have been reported in COVID-19 infection [18]. Our findings are consistent with the literature, showing higher fibrinogen levels in COVID-19 patients than in the other two groups. The elevated levels may reflect its role as an acute-phase reactant, whereas the lower levels in PE patients may be due to consumption in the coagulation cascade. Therefore, normal or decreased fibrinogen levels in COVID-19 patients may indicate the presence of concomitant PE. Although elevated CRP levels are common in DVT and PE, primarily due to endothelial injury mechanisms, Abul et al. reported that CRP levels in PE patients were closely associated with right ventricular dysfunction and right-sided survival [19]. Elevated CRP levels in COVID-19 have also been shown to be associated with mortality and clinical prognosis [20]. In our study, CRP levels in COVID-19 patients were significantly higher than in the other two groups. When the other two groups were compared, CRP levels were lower in the PE-only group. Considering the presence of infection, this is not unexpected, but it supports reports suggesting that CRP measurement can be used for predicting prognosis in COVID-19 during clinical follow-up, although it does not provide guidance for concomitant PE.
Neutrophil/lymphocyte and platelet/lymphocyte ratios are easily obtainable from routine laboratory tests. Ateş et al. reported that these ratios could be used to determine clinical severity in PE patients [21]. Similarly, the neutrophil/lymphocyte ratio was found to be elevated in COVID-19 patients and was associated with higher mortality [22]. Several studies have supported the notion that lymphopenia is a marker of poor prognosis in COVID-19. For example, Huang et al. identified 1,100 / μL as a threshold value and reported that levels below this were associated with severe disease [23]. A meta-analysis including 3,508 patients found that an elevated platelet/lymphocyte ratio was a prognostic factor for disease severity in COVID-19 [22]. In our study, the neutrophil/lymphocyte and platelet/lymphocyte ratios were significantly higher in the COVID-19 group than in the other two groups. However, the expected difference was not observed in the group with both COVID-19 and PE. Elevated ratios in COVID-19 patients may therefore be more useful for predicting disease severity and the need for intensive care or mechanical ventilation rather than for diagnosing pulmonary embolism.

Limitations

This study has some limitations. It is a retrospective, single- center study.

Conclusion

Our study aims to identify parameters that can be easily used in clinical practice to predict the relationship between COVID-19 and PE. This protects patients from unnecessary tests, excessive radiation, and contrast medium exposure, and encourages the efficient use of healthcare resources. Furthermore, considering the literature, embolism prophylaxis should be initiated in all hospitalized and at-risk patients.

References

1. Riou J, Althaus CL. Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020. Euro Surveill. 2020;25(4):2000058. doi:10.2807/1560-7917.ES.2020.25.4.2000058.
   Article PubMed Google Scholar
2. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-42. doi:10.1001/jama.2020.2648.
   Article PubMed Google Scholar
3. Huang I, Pranata R, Lim MA, Oehadian A, Alisjahbana B. C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease 2019: A meta-analysis. Ther Adv Respir Dis. 2020;14:1753466620937175. doi:10.1177/1753466620937175.
   Article PubMed Google Scholar
4. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802-10. doi:10.1001/jamacardio.2020.0950.
   Article PubMed Google Scholar
5. Hayıroğlu MI, Çınar T, Tekkeşin AI. Fibrinogen and D-dimer variances and anticoagulation recommendations in COVID-19: Current literature review. Rev Assoc Med Bras (1992). 2020;66(6):842-8. doi:10.1590/1806-9282.66.6.842.
   Article PubMed Google Scholar
6. Colaneri M, Genovese C, Fassio F, et al. Prognostic significance of NLR and PLR in COVID-19: A multi-cohort validation study. Infect Dis Ther. 2024;13(5):1147-57. doi:10.1007/s40121-024-00967-6.
   Article PubMed Google Scholar
7. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-73. doi:10.1016/j.jacc.2020.04.031.
   Article PubMed Google Scholar
8. Arseven O, Kurt E, Itil O, editors. Temel akciğer sağlığı ve hastalıkları (Basic lung health and diseases). İstanbul: Toraks Kitapları; 2020.p.269-305.
   PubMed Google Scholar
9. Arseven O, Bingöl Z, Çöplü L, et al. Pulmoner tromboembolizm tanı ve tedavi uzlaşı raporu [Consensus report on diagnosis and treatment of pulmonary embolism]. Ankara: Türk Toraks Derneği; 2021. ISBN: 978-625-409-811-6.
   PubMed Google Scholar
10. Sharif S, Eventov M, Kearon C, et al. Comparison of the age-adjusted and clinical probability-adjusted D-dimer to exclude pulmonary embolism in the ED. Am J Emerg Med. 2019;37(5):845-50. doi:10.1016/j.ajem.2018.07.053.
    Article PubMed Google Scholar
11. Güllü Arslan N. COVID-19 enfeksiyonu ile birliktelik gösteren pulmoner tromboemboli olgularının değerlendirmesi [Evaluation of pulmonary thromboembolism cases associated with COVID-19 infection]. İKÇÜSBFD. 2023;8(1):15-8.
    PubMed Google Scholar
12. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: A 25- year population-based study. Arch Intern Med. 1998;158(6):585-93. doi:10.1001/archinte.158.6.585.
    Article PubMed Google Scholar
13. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603. doi:10.1093/eurheartj/ehz405.
    Article PubMed Google Scholar
14. Lippi G, Favaloro EJ. D-dimer is associated with severity of coronavirus disease 2019: A pooled analysis. Thromb Haemost. 2020;120(5):876-8. doi:10.1055/s-0040-1709650.
    Article PubMed Google Scholar
15. Santoso A, Pranata R, Wibowo A, Al-Farabi MJ, Huang I, Antariksa B. Cardiac injury is associated with mortality and critically ill pneumonia in COVID-19: A meta-analysis. Am J Emerg Med. 2021;44:352-7. doi:10.1016/j.ajem.2020.04.052.
    Article PubMed Google Scholar
16. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405-7. doi:10.1016/j.healun.2020.03.012.
    Article PubMed Google Scholar
17. Kucher N, Kohler HP, Dornhöfer T, Wallmann D, Lämmle B. Accuracy of D-dimer/ fibrinogen ratio to predict pulmonary embolism: A prospective diagnostic study. J Thromb Haemost. 2003;1(4):708-13. doi:10.1046/j.1538-7836.2003.00145.x.
    Article PubMed Google Scholar
18. Bi X, Su Z, Yan H, et al. Prediction of severe illness due to COVID-19 based on an analysis of initial fibrinogen to albumin ratio and platelet count. Platelets. 2020;31(5):674-9. doi:10.1080/09537104.2020.1760230.
    Article PubMed Google Scholar
19. Abul Y, Karakurt S, Ozben B, Toprak A, Celikel T. C-reactive protein in acute pulmonary embolism. J Investig Med. 2011;59(1):8-14. doi:10.2310/ jim.0b013e31820017f2.
    Article PubMed Google Scholar
20. Xu J-B, Xu C, Zhang R-B, et al. Associations of procalcitonin, C-reactive protein and neutrophil-to-lymphocyte ratio with mortality in hospitalized COVID-19 patients in China. Sci Rep. 2020;10(1):15058. doi:10.1038/s41598-020-72164-7.
    Article PubMed Google Scholar
21. Ates H, Ates I, Kundi H, Yilmaz FM. Diagnostic validity of hematologic parameters in evaluation of massive pulmonary embolism. J Clin Lab Anal. 2017;31(5):e22072. doi:10.1002/jcla.22072.
    Article PubMed Google Scholar
22. Chan AS, Rout A. Use of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in COVID-19. J Clin Med Res. 2020;12(7):448-53. doi:10.14740/jocmr4240.
    Article PubMed Google Scholar
23. Huang I, Pranata R. Lymphopenia in severe coronavirus disease 2019 (COVID-19): Systematic review and meta-analysis. J Intensive Care. 2020;8:36. doi:10.1186/s40560-020-00453-4.
    Article PubMed Google Scholar

Declarations

Additional Information

Publisher’s Note
Bayrakol MP remains neutral with regard to jurisdictional and institutional claims.

Rights and Permissions

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). To view a copy of the license, visit https://creativecommons.org/licenses/by-nc/4.0/

View full license details →

About This Article