key: cord-0799108-woif3hi5 authors: Hamam, O.; Goda, A.; Awad, R.; Ussama, A.; Eldalal, M.; Fayez, A.; Baral, S.; Elyamany, K.; Bhandari, R.; Egbe, A.; Sharina, I. title: Pulmonary Embolism in Patients with COVID-19: A Systematic review and Meta-analysis date: 2020-10-09 journal: nan DOI: 10.1101/2020.10.09.20209965 sha: 440c07e5c9c310b166bf1757a754da5b1a66082d doc_id: 799108 cord_uid: woif3hi5 Background: There is an increasing evidence that COVID-19 could be complicated by coagulopathy which may lead to death; especially in severe cases. Hence, this study aimed to build concrete evidence regarding the incidence and mortality of pulmonary embolism (PE) in patients with COVID-19. Methods: We performed a systematic search for trusted databases/search engines including PubMed, Scopus, Cochrane library and web of science. After screening, the relevant data were extracted and the incidences and mortality rates from the different included studies were pooled for meta-analysis. Results: Twenty studies were finally included in our study consisting of 1896 patients. The results of the meta-analysis for the all included studies showed that the incidence of PE in patients with COVID-19 was 17.6% with the 95% confidence interval (CI) of 12.7 to 22.5%. There was significant heterogeneity. Additionally, the results of meta-analysis including 8 studies showed that the mortality in patients with both PE and COVID-19 was 43.1% with the 95% confidence interval (CI) of 19 to 67.1%. There was significant heterogeneity. Conclusion: PE was highly frequent in patients with COVID-19. The mortality in patients with both COVID-19 and PE was remarkable representing almost half of the patients. Appropriate prophylaxis and management are vital for better outcomes Coronavirus disease 2019 (COVID-19); caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a global health pandemic that threatens the lives of millions everywhere 1 . COVID-19 manifestations vary from mild respiratory symptoms to severe multi-organ failure and death 2, 3 . Moreover, there is an increasing evidence that COVID-19 could be complicated by coagulopathy which may lead to death; especially in severe cases 4,5 . The viral infection, respiratory deterioration, and the use of central venous catheter may provide major risk factors for the occurring thromboembolism 6 . Likewise, the activation of coagulation and thrombo-inflammation with local vascular damage may enhance the process 4-6 . Among the associated complications, pulmonary embolism (PE) has been reported 7 . Studies showed different estimates for the epidemiological aspects PE with COVID-19. For instance, a study by Grillet et al 8 showed that PE incidence; detected by pulmonary CT angiography was 23%. Additionally, many studies showed incidences of venous thrombosis reaching up to 80% even with thromboprophylaxis [9] [10] [11] . However, the exact incidence of PE in COVID-19 patients is still not clear being based on few observational studies without large sample sizes. Therefore, this systematic review and meta-analysis aimed to build a concrete evidence about the incidence and mortality of PE among patients with COVID-19. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Cochrane's handbook of systematic reviews to conduct this study 12, 13 . We combined the following keywords and conducted our search: "COVID-19", "SARS-CoV-2", "pulmonary embolism" and "venous thromboembolism". We searched PubMed, Web of Science, Scopus, and Cochrane Library for relevant articles to be included. An additional online and manual search was performed on Google Scholar and Preprint Servers to ensure adequate inclusion of all studies. Results were imported into Endnote X8 (Thompson Reuter, CA, USA) for duplicates deletion. We included valid case series (>10 patients) and cohort studies including adults with COVID-19 with pulmonary embolism. Review articles, editorial, commentaries were excluded. The first author (O.H) divided other authors into two teams; each team independently performed title and abstract screening. Then, each team obtained the full-text of the included papers and performed full-text screening. Any disagreement between the two teams was resolved through consultation with the study seniors (A.E and I.S). . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint The two teams extracted the data; one team performed extraction of selected outcomes and the other team extracted baseline data, then, data were revised in a cross-revision manner. Extracted data include author, country, year, study design, age, sex, total number of patients, and number of patients with PE, PE diagnosis, prophylactic treatment, and mortality rate from PE patients. We used the Newcastle-Ottawa scale (NOS) which is available at (https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp) for assessing the risk of bias for our included studies. The possible scores of this scale range from 0 to 9. Studies with a score of seven to nine, four to six, and zero to three were classified as studies with low, moderate, and high risk of bias, respectively. The meta-analysis of the included studies was performed using OpenMeta [Analyst] version 1.15 for conducting single-arm meta-analysis. Meta-analysis for proportions was utilized to pool the incidence and mortality of PE in the groups. Dichotomous data were calculated to obtain risk ratios along with their 95% confidence intervals (CIs). Heterogeneity among studies was assessed using the I 2 test and P-value from the chi-squared test of heterogeneity. Values of I 2 >50 and P<0.1 are significant markers of heterogeneity among studies according to Cochrane's handbook 13 . Random effect models were used to avoid the effect heterogeneity. The statistical significance was set with P-value at 0.05. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint We searched the aforementioned search engines/databases and found 1452 studies after duplicate removal. We excluded 1432 studies as they were not eligible for inclusion according to eligibility criteria, and a total of 20 studies were finally included in our study consisting of 1896 patients [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] . Figure (1) shows a summary of our search and table (1) shows the summary of the included studies. Baseline characteristics are shown in table 1. Most of the included studies were conducted in Europe with only one report from USA. Among the included studies, the highest mean age was 73 years while the lowest was 60.5 years. Most of the included studies have a male predominance reaching 83% of the total included patients. CT pulmonary angiography was used for diagnosis of PE in most of the included studies. Among our twenty included studies evaluated for the risk of bias, all of our studies had a low risk of bias with score of six or higher (Table 1) . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint The results of meta-analysis including the 20 studies showed that the incidence of PE in patients with COVID-19 was 17.6% with the 95% confidence interval (CI) of 12.7 to 22.5%. There was significant heterogeneity (I 2 = 91.17%) which can be attributed to the variability of reported incidences among the different included studies (Figure 2 ). The results of pooled analysis including 8 studies showed that the mortality in patients with both PE and COVID-19 was 43.1% with the 95% confidence interval (CI) of 19 to 67.1%. There was significant heterogeneity (I 2 = 86.96%) as shown in figure 3 . Previous studies have showed that coagulation could be a common complication among patients with COVID-19 5-8 . The results of this systematic review and meta-analysis showed that PE occurred frequently in patients with COVID-19 with incidence exceeding 17% of the total cases . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint We noticed significant heterogeneity while performing this meta-analysis. This can be explained by the different and variable estimates among the included studies and different settings and severity degrees among COVID-19 patients in the different included studies. It is also worth noting that most our included studies did not separate by the severity degrees and progress which prevent us from subgrouping in our meta-analysis. This study can be considered the most updated and comprehensive study to assess the incidence and mortality of PE with COVID-19 in a suitable number of patients. However, this study suffered from several limitations. The included studies were all observational retrospective cohort studies and case series and this type of studies has its own known limitations. Additionally, there was a wide variation among the reported items in the included studies which leaded to limitation in pooling more of the expected common data for analysis. To recapitulate, PE was highly frequent in patients with COVID-19 and observed in 17.6% of them. The mortality in patients with both PE and COVID-19 was remarkable reaching 43.1%. Appropriate prophylaxis and management are vital for better outcomes. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 9, 2020. . Authors declare no Conflict of Interests for this article. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 9, 2020. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.09.20209965 doi: medRxiv preprint World Health Organization Clinical characteristics of coronavirus disease 2019 in China Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring Acute pulmonary embolism associated with COVID-19 pneumonia detected by pulmonary CT Angiography Acute complications and mortality in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement Cochrane Handbook for Systematic Reviews of Interventions Heparininduced Thrombocytopenia with Thrombosis in COVID-19 Adult Respiratory Distress None