Predictors of Impaired Treatment Outcome in COVID-19 Patients with Acute Pulmonary Embolism - Single Center Observational Study From Serbia

Predictors of Impaired Treatment Outcome in COVID-19 Patients with Acute Pulmonary Embolism - Single Center Observational Study From Serbia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predictors of Impaired Treatment Outcome in COVID-19 Patients with Acute Pulmonary Embolism - Single Center Observational Study From Serbia Tatjana Adzic-Vukicevic, Milan Racic, Nikolina Tovarisic-Racic, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5767328/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: COVID-19 disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is characterized by hypercoagulable state that results in an increased risk for embolic and thrombotic vascular complications. Incidence of pulmonary embolism (PE) in COVID-19 varies between 20-30%. Purpose: To determine predictors for treatment outcome in patients with COVID-19 and its associations with clinical and laboratory parameters. Materials and methods: A retrospective observational single-center study was conducted between 1 st of September 2021 and 24 th of December 2021 involving 2111 patients admitted to the COVID Hospital "Batajnica", University Clinical Center of Serbia, Belgrade. Among them, 100 patients (4.74%) got diagnosis of pulmonary embolism by computed tomography pulmonary angiography (CTPA). Patients were divided in two groups. Study group (100 patients) with COVID-19 and PE and control group (100 patients) with COVID-19 but without PE. Results: According to multivariate regression analysis, predictors of impaired outcome in COVID-19 patients are age (p<0.001, OR 1.134, 95% HR 1.062-1.211), C reactive protein level (CRP) (p=0.043, OR 1.006, 95% 1.000-1.013), invasive mechanical ventilation (p<0.001, OR 58.72, 95%HR 13.784-254.189), pulmonary embolism (p=0.025, OR 3.718, 95% HR 1.183-11.681), and hospitalization in intensive care unit (p=0.012, OR 9.673, 95% 1.660-56.363). Conclusion: We report increased mortality and mechanical ventilation rates in COVID-19 patients with acute PE. Older age, elevated level of CRP, hospitalization in ICU, and PE present independent predictors for impaired outcome in COVID-19 patients. Introduction The past COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was frequently associated with numerous micro and macro-vascular thrombotic events and severe disease outcomes [ 1 , 2 ]. SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE 2) receptors on endothelial cells, especially lungs, kidneys, heart and liver, leading to endothelial cell damage and hypercoagulable state [ 3 , 4 ]. COVID-19 implications for coagulation cascade include overexpression of fibrinogen, thrombin, factor V, VIII, cytokine, fibrinogen and D-dimer. Thrombotic events may occur in both venous and arterial circulation because of extensive inflammation, endothelial dysfunction, platelet activation and stasis. Influence of SARS-CoV-2 on cardiovascular system includes pulmonary embolism (PE), myocarditis, acute myocardial infarction, heart failure and arrhythmias [ 5 ]. Pulmonary embolism as most often found thrombotic vascular complication was presented with a high incidence: in about 20–30% of hospitalized patients with COVID-19 [ 6 ]. Besides clinical presentation of COVID-19 pneumonia, usual symptoms of COVID-19 PE include tachycardia, dyspnea and hypoxia [ 7 , 8 ]. Previously published paper highlights the important role of D-dimer in the assessment of COVID-19 patients with PE. D-dimer is a factor of fibrin degradation process, which could be released during the breakdown process of a blood clot, as was seen in pulmonary embolism [ 9 ]. Materials and Methods A retrospective observational single-center study was conducted between 1st of September 2021 and 24th of December 2021, involving 2111 patients admitted to the COVID Hospital "Batajnica", University Clinical Center of Serbia, Belgrade. One hundred patients (4.74%) had computed tomography pulmonary angiography (CTPA) diagnosed with pulmonary embolism. Patients were divided in two groups. Study group with COVID-19 and PE and control COVID-19 patients group without PE. The inclusion criteria were as follows: (1) patients presenting a positive result in the reverse transcription-polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 in respiratory specimens (nasopharyngeal swab, tracheal aspirate, bronchial aspirate or bronchoalveolar lavage fluid) and (2) pulmonary embolism diagnosis made by radiologists on CTPA. Data extraction Besides positive RT-PCR, data included age, sex, D-dimer, fibrinogen, C reactive protein, interleukin-6, systolic and diastolic blood pressure, supplemental oxygen administration (nasal catheter, high flow oxygenation, non-invasive oxygenation or mechanical ventilation), history of chronic lung disease, cardiovascular disease, diabetes mellitus or malignancy. We also extracted data about place of hospitalization, and stay in semi-intensive or intensive care unit (ICU). Chest CT reports were reviewed in order to determine chest severity score, based on the percentage of area involved in each of the 5 lobes. It can range from 0 (no involvement) to 25 (maximum involvement). Imaging protocol CT pulmonary angiography was performed in all 200 patients (9.47%) on 64-section scan (Somatom go Al, Siemens Healthineers) during breath holding, with injection of 70–100 mL non-ionic contrast (Omnipaque 300) with 100ml saline chaster at 4.5/5ml/s. A small quantity of contrast was injected and sequential axial slices at a set region of interest ( pulmonary trunk) were acquired to calculate the time of peak contrast enhancement and determine an optimal scan delay. Images were reconstructed in the axial, coronal, and sagittal plane with 1.25-section thicknesses. Examination findings were reported primarily by chest radiologists. The radilogical reports were stored in RIS platform ( Radilogy Information System). Statistical analysis The results of the study are presented as numbers (%), means ± standard deviation, or median (25th − 75th percentile), depending on the data type and distribution. The groups were compared using parametric ( t -test) and non-parametric (chi-squared, Fisherʼs exact test, and Mann-Whitney U -test) tests. All values of p under 0.05 were considered significant. The data were analyzed using SPSS 20.0 (IBM Corp.Released 2011, IBM SPSS Statistics for Windows, Version 20.0, Armonk, NY) and R 3.4.2 software [R Core Team (2017).R:A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria]. Results From September 1 st 2021 to December 24 th 2021, 6335 patients were admitted to the COVID Hospital "Batajnica", University Clinical Center of Serbia, Belgrade. Out of them, 100 (1.58%) patients had CTPA diagnosed pulmonary embolism. Baseline characteristics of patients are presented in Table 1. There were equivalent numbers of patients of both sexes according to presence of PE or age. Average age of patients was 70.58±11.23 years. Patients with acute PE had lower prevalence of comorbidities including arterial hypertension (p=0.019) and chronic respiratory disorders including chronic obstructive pulmonary disease and asthma (p=0.024). Oxygen therapy was much more used in COVID-19 patients with PE (p=0.013). COVID-19 patients with PE were significantly more hospitalized in ICU than patients without PE (p<0.001). Lethal outcome was significantly more common in patients with PE (p<0.001). According to laboratory data, D-dimer level was significantly higher in PE patients (p<0.001), as well as CRP (p=0.030) and BNP level (p=0.016), as presented in Table 2. Based on univariate regression analysis, predictors of impaired outcome in COVID-19 patients are age (p=0.004, OR:1.045, 95% HR: 1.014-1.077), diastolic pressure (p=0.027, OR:0.973, 95% HR:0.950-0.997), CRP (p<0.001, OR: 1.008, 95%HR 1.004-1.012), IL-6 (p=0.002, OR:1.003, 95%HR 1.001-1.005), D-dimer level at CTPA (p=0.018, OR:1.020, 95%CI 1.003-1.0037), BNP level (p=0.001, OR:1.003, 95% HR 1.001-1.005), CT severity score (p 1.124, 95% HR 1.057-1.195), invasive mechanical ventilation (p< 0.001, OR: 26/143, 95% HR 11.851-57.672), pulmonary embolism (p<0.001, OR: 3.881, 95% HR 2.038-7.390), and hospitalization in intensive care unit (p<0.001, OR: 52.111, 95% HR 11.851-229.146), as shown in Table 3. According to multivariate regression analysis, predictors of impaired outcome in COVID-19 patients are age (p<0.001, OR 1.134, 95% HR 1.062-1.211), CRP (p=0.043, OR 1.006, 95% 1.000-1.013), invasive mechanical ventilation (p<0.001, OR 58.72, 95%HR 13.784-254.189), pulmonary embolism (p=0.025, OR 3.718, 95% HR 1.183-11.681), and hospitalization in intensive care unit (p=0.012, OR 9.673, 95% 1.660-56.363), as presented in Table 4. Specific characteristics of patients with COVID-19 and PE are presented in Table 5. Discussion Our investigation found worse mortality and morbidity outcomes associated with diagnosis of acute PE in hospitalized COVID-19 patients. We found that male sex was significantly associated with PE. Recent meta-analysis including more than three million COVID-19 patients found that men were almost three times more likely to require admission to intensive care unit and had 40% higher risk of death than women [10]. Besides sex differences in the immune system, male disadvantage in COVID-19 could be explained by androgen influence on endothelial function making male sex more prone for PE [11]. Multivariable analysis found that age is one of the most important predictors for treatment outcome [12]. Patients with lethal outcome were significantly older than cured patients. Possible explanation might be that patients with acute PE have higher prevalence of comorbidities [13]. Contrary to previous studies, our results conclude that comorbidities do not present predictors for acute PE in COVID-19. Possible explanation might be in careful preventive treatment for PE in our patients, as well as treatment of each comorbidity disease. Median levels of arterial pressure in our patients were not pathological, except for low diastolic levels. It was already known that hemodynamic instability in COVID-19 is due to dehydration, sepsis and PE influence of lower left ventricular charge and consecutive cardiac shock reflected in low diastolic pressure [4, 13]. When it comes to laboratory/monitoring parameters, we have noticed higher values of CRP and IL-6. After inflammatory stimulation, vascular endothelial cells, as well as smooth muscles cells, produce large amounts of IL-6. IL-6 intensifies fibrinogen and CRP liver synthesis [14]. Therefore, in cytokine storm with increased levels of IL-6 and CRP due to endothelial dysfunction and hypercoagulability, higher protrombotic activity and lower fibrinolytic activity were noticed. Median CRP levels were higher in COVID-19 patients with PE than those without PA (135.5 vs 95.7 mg/L). Previous findings showed that CRP levels above 108 mg/L were strongly associated with thrombosis (8.3% vs 3.4%), disease severity (47.6% vs 9%) and hospital mortality (32.2% vs 17.8%) [15]. CRP and IL-6 levels seem to be important predictors for treatment outcome in our patients. In patients with clinical deterioration with progressive hypoxemia in cytokine storm, treatment with anti-IL6 agent Tocilizumab proved to be very useful in eight out of 11 our patients with PE. Contrary to levels of CRP and IL-6, fibrinogen level does not differ between groups. Possible explanation might be that rather equivalent fibrinogen levels in groups with and without PE result from higher fibrinogen consumption in pulmonary embolism [16]. The D-dimer level was higher in patients with COVID-19 and PE than in those without PE. D-dimer measures fibrin degradation products and can be used as predictor of treatment outcome in COVID-19 patients [17]. Continued monitoring of D-dimer levels should be especially recommended in the second week of hospitalization. Sudden increase of D-dimer level means that COVID-19 patients should undergo CTPA. Univariate analysis of our results showed significantly higher D-dimer levels in the second week of hospitalization of patients with PE. However, cut off D-dimer values for PE in COVID-19 do not exist. Several previous studies suggested different values between 1.0 and 4.8 mg/L with sensitivity and specificity between 63-100% and 23-84%. Cut off values were at least two times higher in comparison to conventional D-dimer value of 0.5 mg/L usually used in screening for PE in non-COVID-19 conditions [18]. Our results found similar increase of D-dimer values in both groups before hospitalization, between 1.53 and 2.13 mg/L. Repeated D-dimer values in the second week of hospitalization showed two times higher levels among patients with lethal outcome. It was shown that increase of D-dimer level by 2.87 two weeks after beginning of symptoms should be used as predictive marker for PE with sensitivity and specificity of 86% and 80% [18, 19]. Brain natriuretic protein (BNP) presents an important marker of heart failure. In cases of PE, elevated right ventricular pressure can lead to increased myocardial extension and BNP release. BNP is widely used as an important indicator of 30-days mortality in patients with PE [20]. Our results showed that BNP level was four times higher comparing to referent ranges, and almost five times higher in patients with lethal outcome, suggesting that BNP level could be used as prognostic and predictive biomarker in COVID-19 patients with PE. CT severity score, previously reported as percentage of involved pulmonary lobes, was significantly higher in patients who died, but multivariate analysis did not found its importance as predictor of lethal outcome in COVID-19 patients with PE. Previous studies have mentioned increased rate of mechanical ventilation which is consistent with the results of our study [21, 22]. Almost all of our patients (96.5%) needed some kind of oxygen therapy during hospitalization, while one third of them were ventilated with invasive and non-invasive ventilation. We have reported a clear association between mortality in PE COVID-19 patients and mechanical ventilation. Pulmonary embolism was usually diagnosed at the time of clinical deterioration in peri-intubation period. We concluded that mechanical ventilation and hospitalization in ICU were very important predictors of increased mortality in COVID-19 patients with PE. According to CTPA findings, most of our patients (68%) had segmental or sub-segmental PE. Our results were consistent with Kwee RM et al. meta-analysis, suggesting that in cases of sub-massive PE, peripherally located thrombus could play important role in PE, instead of deep venous thrombosis mostly seen in non-COVID-19 patients [19]. Pulmonary thrombosis in situ is a pathological condition not related with deep venous thrombosis of lower extremities. The prothrombotic state in COVID-19 patients results from the immunothrombotic process characterized by the production of microthrombi in pulmonary capillaries and larger primary thrombi in arterioles. Autopsy of lung samples found pathological evidence for immunothrombosis that was not found in other organs such as heart, kidneys and brain[23]. Our investigation found that hospitalization in ICU was five times more common in COVID-19 patients with acute PE. Treatment in ICU presents very important and independent predictor of lethal outcome, as was shown before. Acute pulmonary embolism also presents an independent predictor of lethal outcome in hospitalized COVID-19 patients. We have concluded that risk of lethal outcome was 2.55 times higher in COVID-19 patients with PE than those without PE. Our paper highlights the importance of optimal thromboprophylactic treatment, need for CTPA in COVID-19 patients, and D-dimer monitoring, as was mentioned before [24, 25]. In conclusion, we report increased mortality and mechanical ventilation rates in COVID-19 patients with acute PE. Older age, elevated CRP level, as well as hospitalization in ICU present independent predictors for lethal outcome in COVID-19 patients with PE. Declarations Institutional Review Board Statement The stady was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board, namely the Ethics Committee of the University Clinical Center of Serbia, Belgrade, Serbia (in progress). Informed consent Statement : Informed consent obtain from all subjects all subjects involved in the study. Concflicts of Interest The author declare no conflict of interest. Funding: This research received no external funding. Author Contribution T.A.V and M.L.L wrote the main manuscript textT.A.V and M.L.L wrote original draft preparation;M.R and N.T.R preperd all figures, wrote review and editing;J.R wrote imaginig protocol; data curation.All authors have read and agreed to the published version of the manuscript. Data Availability Statement: Anonymizde study data are available from the coreresponding author upon reasonable request. References Gong X, Yuan B, Yuan Y. Incidence and prognostic value of pulmonary embolism in COVID-19: a systematic review and meta-analysis. PloS One. 2022;17(3):e0263580. Cui LY, Cheng WW, Mou ZW et al. Risk factors for pulmonary embolism in patients with COVID-19: a systematic review and meta-analysis. Int J Infect Dis. 2021;111:154-63 Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19(3):141-54 Gul M, Htun Z, Perez V.Predictors and outcome of acute pulmonary embolism in COVID-19; insights from US National Covid cohort collaborative. Respiratory research 2023;24:59 doi.org/10.1186/s12931-023-02369-7. Chilamakuri R, Agarwal S. COVID-19: characteristics and therapeutics. Cells. 2021;10(2):206. Behzad S, Aghaghazvini L, Radmard AR, Gholamrezanezhad A. Extrapulmonary manifestations of COVID-19: radiologic and clinical overview. Clin Imaging. 2020;66:35-41. Wang YH, Wu CC, Bai CH et al. Evaluation of the diagnostic accuracy of COVID-19 antigen tests: a systematic review and meta-analysis. Journal of the Chinese med assoc. 2021;84(11):1028-37. Alsharif W, Qurashi A. Effectiveness of COVID-19 diagnosis and management tools: a review. Radiography (Lond). 2021;27(2):682-7. Gavriatopoulou M, Ntasasis-Stathopoulos I, Koromoki E, Fotiou D, Migkou M, Tzanninis IG i sur. Emerging treatment strategies for COVID-19 infection. Clinical and experimental medicine. 2020;21(2):167-79. Riyahi S, Dev H, Behzadi A.Pulmonary embolism in hospitalized patients with COVID-19: a multicenter study. Radiology 2021;301:E426-E433. doi.org /10.1148/ radiol.2021210777. Konstantnidis SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for diagnosis and management of acute pulmonary embolism developed in colloration with the European Respiratory Society (ERS): The Task Force for the diagnosis and managment of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J.2019:54:1901647. ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). European Heart Journal (2019)00,161 McFadyen JD, Stevens H, Peter K. The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications. Circulation Research. 2020 Jul 31;127(4):571–87. Smilowitz NR, Kunichoff D, Garshick M, Shah B, Pillinger M, Hochman JS, Berger JS. C-reactive protein and clinical outcomes in patients with COVID-19. Eur Heart J. 2021 Jun 14;42(23):2270-2279. doi: 10.1093/eurheartj/ehaa1103. PMID: 33448289; PMCID: PMC7928982. Di Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies. Semin Thromb Hemost. 2020 ;46(7):763-771. doi: 10.1055/s-0040-1715456. Miro O, Jimenez S, Mebazaa A et al. Pulmonary embolism in patients with COVID-19: incidence, risk factors, clinical characteristics and outcome, Eur Heart J 2021;42:3127-3142. doi 10.1093/eurheartj/ehab314 Zhang L., Feng X., Zhang D et al. Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome. Circulation. 2020 Jul 14;142(2):114-110. Cerdà P, Ribas J, Iriarte A, et al. Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis. PLoS One. 2020 Dec 28;15(12):e0243533. doi: 10.1371/journal.pone.0243533. Kwee RM, Adams HJA, Kwee TC. Pulmonary embolism in patients with COVID-19 and value of D-dimer assessment: a meta-analysis. Eur Radiol. 2021;31(11):8168-8186. doi: 10.1007/s00330-021-08003-8. Mahmoud AA, Abd El-Hafeez HA, Ali AO et al. Plasma brain natriuretic peptide, D-Dimer, and serum troponin-I as predictors for in-hospital death in patients with COVID-19. Egypt J Immunol. 2023;30(3):32-43 Van den Boom W, Hoy M, Sankaran J et al. The search for optimal oxygen saturation targets in critically ill patients: observational data from large ICU databases. Chest. 2020;157:566–573. Siemieniuk RAC, Chu DK, Kim LH et al. Oxygen therapy for acutely ill medical patients: a clinical practice guideline. BMJ. 2018;363:k4169. Niculae C, Hristea A, Mororti R. Mechanisms of COVID-19 associated pulmonary thrombosis: narrative review. Biomedicines 2023;11:99 doi.org /10.3390/ biomedicines 11030929 Zuin M, Rigatelli G, Bilato C et al. COVID-19 patients with acute pulmonary embolism have a higher mortality risk: systematic review and meta-analysis based on Italian cohorts. J Cardiovasc Med (Hagerstown). 2022;23(12):773-778. doi: 10.2459/JCM.0000000000001354. Roncon L, Zuin M, Barco S et al. Incidence of acute pulmonary embolism in COVID-19 patients: Systematic review and meta-analysis. Eur J Intern Med. 2020;82:29-37. doi: 10.1016/j.ejim.2020.09.006. Tables Tables 1 to 5 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5767328","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":406905583,"identity":"be984c37-17f6-4a73-8140-305db9ea3a22","order_by":0,"name":"Tatjana Adzic-Vukicevic","email":"","orcid":"","institution":"University Clinical Centre of Serbia","correspondingAuthor":false,"prefix":"","firstName":"Tatjana","middleName":"","lastName":"Adzic-Vukicevic","suffix":""},{"id":406905584,"identity":"74fb9235-87a1-4509-a020-f080e475e287","order_by":1,"name":"Milan Racic","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Milan","middleName":"","lastName":"Racic","suffix":""},{"id":406905585,"identity":"87f183e5-dc05-4c01-b1b6-8a2c5464bb6b","order_by":2,"name":"Nikolina Tovarisic-Racic","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Nikolina","middleName":"","lastName":"Tovarisic-Racic","suffix":""},{"id":406905586,"identity":"b8ef2b29-282a-48f8-beeb-c69e332d4591","order_by":3,"name":"Marija Laban-Lazovic","email":"","orcid":"","institution":"University Clinical Centre of Serbia","correspondingAuthor":false,"prefix":"","firstName":"Marija","middleName":"","lastName":"Laban-Lazovic","suffix":""},{"id":406905587,"identity":"3526c7b2-242a-4f29-92a7-1ce368f10e14","order_by":4,"name":"Jovana Radmilovic","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYDCCA2xgihnCqwAxmRsIaWFsQGg5A2IyEqcFAhjbwCR+LXzH29IffNzDwM4vkfzswc95tdH87UAtPyq24dQieebYwcYZzxiYJWekmRv2bjueO+MwYwNjz5nbOLUY3EhvbOY5wMBscOaAmQTvtmO5DUAtzIxtRGk5/k3y75xjufMJa0k7CNFyvMdMmrehJncDIS1AvyTOnHFAglmyvadMWubYgdyNQC0H8fkFGGIGHz4csEnmZ2bfJvmmpi533vnDBx/8qMCtBQokkqGMw2DyACH1IGAHpeuIUTwKRsEoGAUjDAAATn1d1v2YKsAAAAAASUVORK5CYII=","orcid":"","institution":"University Clinical Centre of Serbia","correspondingAuthor":true,"prefix":"","firstName":"Jovana","middleName":"","lastName":"Radmilovic","suffix":""}],"badges":[],"createdAt":"2025-01-05 10:38:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5767328/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5767328/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77667990,"identity":"edf5a3a5-284d-494e-b97f-b0846f57ccdb","added_by":"auto","created_at":"2025-03-04 06:24:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":389485,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5767328/v1/bd45be91-bcd8-41f9-ab12-a225e0c68565.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predictors of Impaired Treatment Outcome in COVID-19 Patients with Acute Pulmonary Embolism - Single Center Observational Study From Serbia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe past COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was frequently associated with numerous micro and macro-vascular thrombotic events and severe disease outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE 2) receptors on endothelial cells, especially lungs, kidneys, heart and liver, leading to endothelial cell damage and hypercoagulable state [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. COVID-19 implications for coagulation cascade include overexpression of fibrinogen, thrombin, factor V, VIII, cytokine, fibrinogen and D-dimer. Thrombotic events may occur in both venous and arterial circulation because of extensive inflammation, endothelial dysfunction, platelet activation and stasis. Influence of SARS-CoV-2 on cardiovascular system includes pulmonary embolism (PE), myocarditis, acute myocardial infarction, heart failure and arrhythmias [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Pulmonary embolism as most often found thrombotic vascular complication was presented with a high incidence: in about 20\u0026ndash;30% of hospitalized patients with COVID-19 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Besides clinical presentation of COVID-19 pneumonia, usual symptoms of COVID-19 PE include tachycardia, dyspnea and hypoxia [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Previously published paper highlights the important role of D-dimer in the assessment of COVID-19 patients with PE. D-dimer is a factor of fibrin degradation process, which could be released during the breakdown process of a blood clot, as was seen in pulmonary embolism [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eA retrospective observational single-center study was conducted between 1st of September 2021 and 24th of December 2021, involving 2111 patients admitted to the COVID Hospital \"Batajnica\", University Clinical Center of Serbia, Belgrade. One hundred patients (4.74%) had computed tomography pulmonary angiography (CTPA) diagnosed with pulmonary embolism. Patients were divided in two groups. Study group with COVID-19 and PE and control COVID-19 patients group without PE. The inclusion criteria were as follows: (1) patients presenting a positive result in the reverse transcription-polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 in respiratory specimens (nasopharyngeal swab, tracheal aspirate, bronchial aspirate or bronchoalveolar lavage fluid) and (2) pulmonary embolism diagnosis made by radiologists on CTPA.\u003c/p\u003e \u003cp\u003eData extraction\u003c/p\u003e \u003cp\u003eBesides positive RT-PCR, data included age, sex, D-dimer, fibrinogen, C reactive protein, interleukin-6, systolic and diastolic blood pressure, supplemental oxygen administration (nasal catheter, high flow oxygenation, non-invasive oxygenation or mechanical ventilation), history of chronic lung disease, cardiovascular disease, diabetes mellitus or malignancy. We also extracted data about place of hospitalization, and stay in semi-intensive or intensive care unit (ICU). Chest CT reports were reviewed in order to determine chest severity score, based on the percentage of area involved in each of the 5 lobes. It can range from 0 (no involvement) to 25 (maximum involvement).\u003c/p\u003e \u003cp\u003eImaging protocol\u003c/p\u003e \u003cp\u003eCT pulmonary angiography was performed in all 200 patients (9.47%) on 64-section scan (Somatom go Al, Siemens Healthineers) during breath holding, with injection of 70\u0026ndash;100 mL non-ionic contrast (Omnipaque 300) with 100ml saline chaster at 4.5/5ml/s. A small quantity of contrast was injected and sequential axial slices at a set region of interest ( pulmonary trunk) were acquired to calculate the time of peak contrast enhancement and determine an optimal scan delay. Images were reconstructed in the axial, coronal, and sagittal plane with 1.25-section thicknesses. Examination findings were reported primarily by chest radiologists. The radilogical reports were stored in RIS platform ( Radilogy Information System).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe results of the study are presented as numbers (%), means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, or median (25th \u0026minus;\u0026thinsp;75th percentile), depending on the data type and distribution. The groups were compared using parametric (\u003cem\u003et\u003c/em\u003e-test) and non-parametric (chi-squared, Fisherʼs exact test, and Mann-Whitney \u003cem\u003eU\u003c/em\u003e-test) tests. All values of p under 0.05 were considered significant. The data were analyzed using SPSS 20.0 (IBM Corp.Released 2011, IBM SPSS Statistics for Windows, Version 20.0, Armonk, NY) and R 3.4.2 software [R Core Team (2017).R:A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFrom September 1\u003csup\u003est\u003c/sup\u003e 2021 to December 24\u003csup\u003eth\u003c/sup\u003e 2021, 6335 patients were admitted to the COVID Hospital \"Batajnica\", University Clinical Center of Serbia, Belgrade. Out of them, 100 (1.58%) patients had CTPA diagnosed pulmonary embolism. Baseline characteristics of patients are presented in Table 1. There were equivalent numbers of patients of both sexes according to presence of PE or age. Average age of patients was 70.58±11.23 years. \u0026nbsp;Patients with acute PE had lower prevalence of comorbidities including arterial hypertension (p=0.019) and chronic respiratory disorders including chronic obstructive pulmonary disease and asthma (p=0.024). Oxygen therapy was much more used in COVID-19 patients with PE (p=0.013). COVID-19 patients with PE were significantly more hospitalized in ICU than patients without PE (p\u0026lt;0.001). Lethal outcome was significantly more common in patients with PE (p\u0026lt;0.001). According to laboratory data, D-dimer level was significantly higher in PE patients (p\u0026lt;0.001), as well as CRP (p=0.030) and BNP level (p=0.016), as presented in Table 2. Based on univariate regression analysis, predictors of impaired outcome in COVID-19 patients are age (p=0.004, OR:1.045, 95% HR: 1.014-1.077), diastolic pressure (p=0.027, OR:0.973, 95% HR:0.950-0.997), CRP (p\u0026lt;0.001, OR: 1.008, 95%HR 1.004-1.012), IL-6 (p=0.002, OR:1.003, 95%HR 1.001-1.005), D-dimer level at CTPA (p=0.018, OR:1.020, 95%CI 1.003-1.0037), BNP level (p=0.001, OR:1.003, 95% HR 1.001-1.005), CT severity score (p\u0026lt;0.001. OR\u0026gt; 1.124, 95% HR 1.057-1.195), invasive mechanical ventilation (p\u0026lt; 0.001, OR: 26/143, 95% HR 11.851-57.672), pulmonary embolism (p\u0026lt;0.001, OR: 3.881, 95% HR 2.038-7.390), and hospitalization in intensive care unit (p\u0026lt;0.001, OR: 52.111, 95% HR 11.851-229.146), as shown in Table 3.\u003c/p\u003e\n\u003cp\u003eAccording to multivariate regression analysis, predictors of impaired outcome in COVID-19 patients \u0026nbsp;are age (p\u0026lt;0.001, OR 1.134, 95% HR 1.062-1.211), CRP (p=0.043, OR 1.006, 95% 1.000-1.013), invasive mechanical ventilation (p\u0026lt;0.001, OR 58.72, 95%HR 13.784-254.189), pulmonary embolism (p=0.025, OR 3.718, 95% HR 1.183-11.681), and hospitalization in intensive care unit (p=0.012, OR 9.673, 95% 1.660-56.363), as presented in Table 4. Specific characteristics of patients with COVID-19 and PE are presented in Table 5.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur investigation found worse mortality and morbidity outcomes associated with diagnosis of acute PE in hospitalized COVID-19 patients. We found that male sex was significantly associated with PE. Recent meta-analysis including more than three million COVID-19 patients found that men were almost three times more likely to require admission to intensive care unit and had 40% higher risk of death than women [10]. Besides sex differences in the immune system, male disadvantage in COVID-19 could be explained by androgen influence on endothelial function making male sex more prone for PE [11]. Multivariable analysis found that age is one of the most important predictors for treatment outcome [12]. Patients with lethal outcome were significantly older than cured patients. Possible explanation might be that patients with acute PE have higher prevalence of comorbidities [13]. Contrary to previous studies, our results conclude that comorbidities do not present predictors for acute PE in COVID-19. Possible explanation might be in careful preventive treatment for PE in our patients, as well as treatment of each comorbidity disease. Median levels of arterial pressure in our patients were not pathological, except for low diastolic levels. It was already known that hemodynamic instability in COVID-19 is due to dehydration, sepsis and PE influence of lower left ventricular charge and consecutive cardiac shock reflected in low diastolic pressure [4, 13]. When it comes to laboratory/monitoring parameters, we have noticed higher values of CRP and IL-6. After inflammatory stimulation, vascular endothelial cells, as well as smooth muscles cells, produce large amounts of IL-6. IL-6 intensifies fibrinogen and CRP liver synthesis [14]. Therefore, in cytokine storm with increased levels of IL-6 and CRP due to endothelial dysfunction and hypercoagulability, higher protrombotic activity and lower fibrinolytic activity were noticed. Median CRP levels were higher in COVID-19 patients with PE than those without PA (135.5 vs 95.7 mg/L). Previous findings showed that CRP levels above 108 mg/L were strongly associated with thrombosis (8.3% vs 3.4%), disease severity (47.6% vs 9%) and hospital mortality (32.2% vs 17.8%) [15]. CRP and IL-6 levels seem to be important predictors for treatment outcome in our patients. In patients with clinical deterioration with progressive hypoxemia in cytokine storm, treatment with anti-IL6 agent Tocilizumab proved to be very useful in eight out of 11 our patients with PE. Contrary to levels of CRP and IL-6, fibrinogen level does not differ between groups. Possible explanation might be that rather equivalent fibrinogen levels in groups with and without PE result from higher fibrinogen consumption in pulmonary embolism [16]. The D-dimer level was higher in patients with COVID-19 and PE than in those without PE. D-dimer measures fibrin degradation products and can be used as predictor of treatment outcome in COVID-19 patients [17]. Continued monitoring of D-dimer levels should be especially recommended in the second week of hospitalization. Sudden increase of D-dimer level means that COVID-19 patients should undergo CTPA. Univariate analysis of our results showed significantly higher D-dimer levels in the second week of hospitalization of patients with PE. However, cut off D-dimer values for PE in COVID-19 do not exist. Several previous studies suggested different values between 1.0 and 4.8 mg/L with sensitivity and specificity between 63-100% and 23-84%. Cut off values were at least two times higher in comparison to conventional D-dimer value of 0.5 mg/L usually used in screening for PE in non-COVID-19 conditions [18]. Our results found similar increase of D-dimer values in both groups before hospitalization, between 1.53 and 2.13 mg/L. Repeated D-dimer values in the second week of hospitalization \u0026nbsp; showed two times higher levels among patients with lethal outcome. It was shown that increase of \u0026nbsp;D-dimer level by 2.87 two weeks after beginning of symptoms should be used as predictive marker for PE with sensitivity and specificity of 86% and 80% [18, 19]. Brain natriuretic protein (BNP) presents an important marker of heart failure. In cases of PE, elevated right ventricular pressure can lead to increased myocardial extension and BNP release. BNP is widely used as an important indicator of 30-days mortality in patients with PE [20]. Our results showed that BNP level was four times higher comparing to referent ranges, and almost five times higher in patients with lethal outcome, suggesting that BNP level could be used as prognostic and predictive biomarker in COVID-19 patients with PE. CT severity score, previously reported as percentage of involved pulmonary lobes, was significantly higher in patients who died, but multivariate analysis did not found its importance as predictor of lethal outcome in COVID-19 patients with PE. Previous studies have mentioned increased rate of mechanical ventilation which is consistent with the results of our study [21, 22]. Almost all of our patients (96.5%) needed some kind of oxygen therapy during hospitalization, while one third of them were ventilated with invasive and non-invasive ventilation. We have reported a clear association between mortality in PE COVID-19 patients and mechanical ventilation. Pulmonary embolism was usually diagnosed at the time of clinical deterioration in peri-intubation period. We concluded that mechanical ventilation and hospitalization in ICU were very important predictors of increased mortality in COVID-19 patients with PE. According to CTPA findings, most of our patients (68%) had segmental or sub-segmental PE. Our results were consistent with Kwee RM et al. meta-analysis, suggesting that in cases of sub-massive PE, peripherally located thrombus could play important role in PE, instead of deep venous thrombosis mostly seen in non-COVID-19 patients [19]. Pulmonary thrombosis in situ is a pathological condition not related with deep venous thrombosis of lower extremities. The prothrombotic state in COVID-19 patients results from the immunothrombotic process characterized by the production of microthrombi in pulmonary capillaries and larger primary thrombi in arterioles. Autopsy of lung samples found pathological evidence for immunothrombosis that was not found in other organs such as heart, kidneys and brain[23]. Our investigation found that hospitalization in ICU was five times more common in COVID-19 patients with acute PE. Treatment in ICU presents very important and independent predictor of lethal outcome, as was shown before. Acute pulmonary embolism also presents an independent predictor of lethal outcome in hospitalized COVID-19 patients. We have concluded that risk of lethal outcome was 2.55 times higher in COVID-19 patients with PE than those without PE.\u003c/p\u003e\n\u003cp\u003eOur paper highlights the importance of optimal thromboprophylactic treatment, need for CTPA in COVID-19 patients, and D-dimer monitoring, as was mentioned before [24, 25].\u003c/p\u003e\n\u003cp\u003eIn conclusion, we report increased mortality and mechanical ventilation rates in COVID-19 patients with acute PE. Older age, elevated CRP level, as well as hospitalization in ICU present independent predictors for lethal outcome in COVID-19 patients with PE.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe stady was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board, namely the Ethics Committee of the University Clinical Center of Serbia, Belgrade, Serbia (in progress).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eStatement\u003c/strong\u003e: Informed consent obtain from all subjects all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eT.A.V and M.L.L wrote the main manuscript textT.A.V and M.L.L wrote original draft preparation;M.R and N.T.R preperd all figures, wrote review and editing;J.R wrote imaginig protocol; data curation.All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnonymizde study data are available from the coreresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGong X, Yuan B, Yuan Y. Incidence and prognostic value of pulmonary embolism in COVID-19: a systematic review and meta-analysis. PloS One. 2022;17(3):e0263580.\u003c/li\u003e\n\u003cli\u003eCui LY, Cheng WW, Mou ZW et al. Risk factors for pulmonary embolism in patients with COVID-19: a systematic review and meta-analysis. Int J Infect Dis. 2021;111:154-63\u003c/li\u003e\n\u003cli\u003eHu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19(3):141-54\u003c/li\u003e\n\u003cli\u003eGul M, Htun Z, Perez V.Predictors and outcome of acute pulmonary embolism in COVID-19; insights from US National Covid cohort collaborative. Respiratory research 2023;24:59 doi.org/10.1186/s12931-023-02369-7.\u003c/li\u003e\n\u003cli\u003eChilamakuri R, Agarwal S. COVID-19: characteristics and therapeutics. Cells. 2021;10(2):206.\u003c/li\u003e\n\u003cli\u003eBehzad S, Aghaghazvini L, Radmard AR, Gholamrezanezhad A. Extrapulmonary manifestations of COVID-19: radiologic and clinical overview. Clin Imaging. 2020;66:35-41.\u003c/li\u003e\n\u003cli\u003eWang YH, Wu CC, Bai CH et al. Evaluation of the diagnostic accuracy of COVID-19 antigen tests: a systematic review and meta-analysis. Journal of the Chinese med assoc. 2021;84(11):1028-37.\u003c/li\u003e\n\u003cli\u003eAlsharif W, Qurashi A. Effectiveness of COVID-19 diagnosis and management tools: a review. Radiography (Lond). 2021;27(2):682-7.\u003c/li\u003e\n\u003cli\u003eGavriatopoulou M, Ntasasis-Stathopoulos I, Koromoki E, Fotiou D, Migkou M, Tzanninis IG i sur. Emerging treatment strategies for COVID-19 infection. Clinical and experimental medicine. 2020;21(2):167-79.\u003c/li\u003e\n\u003cli\u003eRiyahi S, Dev H, Behzadi A.Pulmonary embolism in hospitalized patients with COVID-19: a multicenter study. Radiology 2021;301:E426-E433. doi.org /10.1148/ radiol.2021210777.\u003c/li\u003e\n\u003cli\u003eKonstantnidis SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for diagnosis and management of acute pulmonary embolism developed in colloration with the European Respiratory Society (ERS): The Task Force for the diagnosis and managment of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J.2019:54:1901647.\u003c/li\u003e\n\u003cli\u003eESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). European Heart Journal (2019)00,161\u003c/li\u003e\n\u003cli\u003eMcFadyen JD, Stevens H, Peter K. The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications. Circulation Research. 2020 Jul 31;127(4):571\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eSmilowitz NR, Kunichoff D, Garshick M, Shah B, Pillinger M, Hochman JS, Berger JS. C-reactive protein and clinical outcomes in patients with COVID-19. Eur Heart J. 2021 Jun 14;42(23):2270-2279. doi: 10.1093/eurheartj/ehaa1103. PMID: 33448289; PMCID: PMC7928982.\u003c/li\u003e\n\u003cli\u003eDi Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies. Semin Thromb Hemost. 2020 ;46(7):763-771. doi: 10.1055/s-0040-1715456. \u003c/li\u003e\n\u003cli\u003eMiro O, Jimenez S, Mebazaa A et al. Pulmonary embolism in patients with COVID-19: incidence, risk factors, clinical characteristics and outcome, Eur Heart J 2021;42:3127-3142. doi 10.1093/eurheartj/ehab314\u003c/li\u003e\n\u003cli\u003eZhang L., Feng X., Zhang D et al. Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome. Circulation. 2020 Jul 14;142(2):114-110.\u003c/li\u003e\n\u003cli\u003eCerd\u0026agrave; P, Ribas J, Iriarte A, et al. Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis. PLoS One. 2020 Dec 28;15(12):e0243533. doi: 10.1371/journal.pone.0243533. \u003c/li\u003e\n\u003cli\u003eKwee RM, Adams HJA, Kwee TC. Pulmonary embolism in patients with COVID-19 and value of D-dimer assessment: a meta-analysis. Eur Radiol. 2021;31(11):8168-8186. doi: 10.1007/s00330-021-08003-8. \u003c/li\u003e\n\u003cli\u003eMahmoud AA, Abd El-Hafeez HA, Ali AO et al. Plasma brain natriuretic peptide, D-Dimer, and serum troponin-I as predictors for in-hospital death in patients with COVID-19. Egypt J Immunol. 2023;30(3):32-43\u003c/li\u003e\n\u003cli\u003eVan den Boom W, Hoy M, Sankaran J et al. The search for optimal oxygen saturation targets in critically ill patients: observational data from large ICU databases. Chest. 2020;157:566\u0026ndash;573.\u003c/li\u003e\n\u003cli\u003eSiemieniuk RAC, Chu DK, Kim LH et al. Oxygen therapy for acutely ill medical patients: a clinical practice guideline. BMJ. 2018;363:k4169.\u003c/li\u003e\n\u003cli\u003eNiculae C, Hristea A, Mororti R. Mechanisms of COVID-19 associated pulmonary thrombosis: narrative review. Biomedicines 2023;11:99 doi.org /10.3390/ biomedicines 11030929\u003c/li\u003e\n\u003cli\u003eZuin M, Rigatelli G, Bilato C et al. COVID-19 patients with acute pulmonary embolism have a higher mortality risk: systematic review and meta-analysis based on Italian cohorts. J Cardiovasc Med (Hagerstown). 2022;23(12):773-778. doi: 10.2459/JCM.0000000000001354. \u003c/li\u003e\n\u003cli\u003eRoncon L, Zuin M, Barco S et al. Incidence of acute pulmonary embolism in COVID-19 patients: Systematic review and meta-analysis. Eur J Intern Med. 2020;82:29-37. doi: 10.1016/j.ejim.2020.09.006.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":true,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5767328/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5767328/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e COVID-19 disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is characterized by hypercoagulable state that results in an increased risk for embolic and thrombotic vascular complications. Incidence of pulmonary embolism (PE) in COVID-19 varies between 20-30%.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e To determine predictors for treatment outcome in patients with COVID-19 and its associations with clinical and laboratory parameters.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and methods:\u003c/strong\u003e A retrospective observational single-center study was conducted between 1\u003csup\u003est\u003c/sup\u003e of September 2021 and 24\u003csup\u003eth\u003c/sup\u003e of December 2021 involving 2111 patients admitted to the COVID Hospital \"Batajnica\", University Clinical Center of Serbia, Belgrade. Among them, 100 patients (4.74%) got diagnosis of pulmonary embolism by computed tomography pulmonary angiography (CTPA). Patients were divided in two groups. Study group (100 patients) with COVID-19 and PE and control group (100 patients) with COVID-19 but without PE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e According to multivariate regression analysis, predictors of impaired outcome in COVID-19 patients are age (p\u0026lt;0.001, OR 1.134, 95% HR 1.062-1.211), C reactive protein level (CRP) (p=0.043, OR 1.006, 95% 1.000-1.013), invasive mechanical ventilation (p\u0026lt;0.001, OR 58.72, 95%HR 13.784-254.189), pulmonary embolism (p=0.025, OR 3.718, 95% HR 1.183-11.681), and hospitalization in intensive care unit (p=0.012, OR 9.673, 95% 1.660-56.363).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eWe report increased mortality and mechanical ventilation rates in COVID-19 patients with acute PE. Older age, elevated level of CRP, hospitalization in ICU, and PE present independent predictors for impaired outcome in COVID-19 patients.\u003c/p\u003e","manuscriptTitle":"Predictors of Impaired Treatment Outcome in COVID-19 Patients with Acute Pulmonary Embolism - Single Center Observational Study From Serbia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-28 15:52:42","doi":"10.21203/rs.3.rs-5767328/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8bd5de88-fbae-4c21-933f-138b25d5fbaa","owner":[],"postedDate":"January 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-04T06:23:59+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-28 15:52:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5767328","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5767328","identity":"rs-5767328","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}