Keywords
Pulmonary Embolism, Coronavirus, COVID-19, Venous thromboembolism, Incidence, Meta-analysis
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Munner MS, Ritchie CA, Elkhidir IH et al. Incidence of acute pulmonary embolism among patients hospitalized with COVID-19: a systematic review and meta-analysis [version 1; peer review: 1 not approved]. F1000Research 2020, 9:1489 (https://doi.org/10.12688/f1000research.27425.1)
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Systematic Review
Incidence of acute pulmonary embolism among patients hospitalized with COVID-19: a systematic review and meta-analysis
[version 1; peer review: 1 not approved]
PUBLISHED 18 Dec 2020
OPEN PEER REVIEW
REVIEWER STATUS
This article is included in the Emerging Diseases and Outbreaks gateway.
This article is included in the Coronavirus collection.
Abstract
Corresponding author:
Hussein J. Ahmed
Competing interests:
No competing interests were disclosed.
Grant information:
The author(s) declared that no grants were involved in supporting this work.
Copyright:
© 2020 Munner MS et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Munner MS, Ritchie CA, Elkhidir IH et al. Incidence of acute pulmonary embolism among patients hospitalized with COVID-19: a systematic review and meta-analysis [version 1; peer review: 1 not approved]. F1000Research 2020, 9:1489 (https://doi.org/10.12688/f1000research.27425.1)
First published: 18 Dec 2020, 9:1489 (https://doi.org/10.12688/f1000research.27425.1)
Latest published: 26 Apr 2021, 9:1489 (https://doi.org/10.12688/f1000research.27425.2)
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of this article available.
Introduction
In December 2019, pneumonia of unknown cause was detected in Wuhan, China1. The causative agent was identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)2. On March 11th, 2020, the World Health Organization characterized the coronavirus disease of 2019 (COVID-19) as a pandemic1,3, resulting in 53,507,282 and 1,305,164 COVID-19-related cases and deaths, respectively, as of November 15th, 20204. While COVID-19 is primarily a pulmonary disease, there are multiple other pathologic manifestations and complications, including pulmonary embolism (PE)5.
The relationship between COVID-19 and thromboembolism is becoming established in the literature5. Thromboembolism has been previously associated with zoonotic coronaviruses6 and may be attributed to several factors including; a hypercoagulable state associated with severe infection or inflammation7, COVID-19 associated hemostatic abnormalities8,9, recumbence7,10–12, and possible drug interactions between investigational COVID-19 therapies (Lopinavir/ritonavir) and antithrombotics5.
This systematic review and meta-analysis analyzed and estimated the pooled PE incidence from published literature of patients hospitalized with COVID-19 who developed PE.
Methods
This meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline13,14. Institutional review board approval was not required for this study.
Search strategy
A systematic literature search was performed on May 19th, 2020 using Medline/PubMed, Cochrane, OpenGrey, and ScienceDirect. PubMed, Cochrane, and OpenGrey were queried for the following strategy: ("COVID 19" OR "SARS-CoV-2” OR "coronavirus disease 2019" OR "2019-nCoV" OR "Wuhan coronavirus") AND (“Pulmonary embolism” OR "pulmonary thromboembolism" OR “Pulmonary embol*” OR “pulmonary thrombo*” OR “PE”). ScienceDirect was queried using the same variables only without asterisks.
Duplicate citations and older versions of the same study population were removed. All included study bibliographies were screened for additional articles investigating PE in patients hospitalized with COVID-19. All eligible studies underwent full-text screening.
Eligibility criteria
Studies reporting data sufficient to estimate PE incidence of patients hospitalized with COVID-19 were included in the analysis. Only English and published studies were included. Studies with insufficient data, case reports, editorials, proposals, and abstracts without full-text were excluded. The title and abstract of retrieved articles were screened by two independent reviewers for potential inclusion. Any discrepancy between the reviewers was resolved by consensus with two additional reviewers.
Quality appraisal and data extraction
Appraisal of individual study quality was performed by two independent reviewers using the Newcastle–Ottawa scale, AXIS tool, and quality assessment tool for observational cohort and case-control, cross-sectional, and case series, respectively15–17. Articles were deemed of good quality if they scored 50% or more using an arbitrary cut-off.
Information was sought from each included study are: characteristics of participants (including age, gender, BMI, D dimer of patient with COVID-19,, and total patients in the study), summary about included studies (first author, country, year of publication, study period, study design, method of diagnosing COVID-19) and the main data for meta-analysis (total patients in each study i.e., sample size and number of patients developing PE from the total). The data was subsequently extracted by five independent reviewers utilizing Microsoft Excel® 2016 (Microsoft Corporation, Redmond, WA).
Analysis
Due to skewed proportions, the random effect model was used to pool the individual estimates through LOGIT transformation instead of double arcsine transformation to avoid a paradoxical effect upon back-transformation18,19.
Statistical analysis was performed using R language v.420, using “meta” and ”metafor” packages21–23. Random effects models were utilized to accommodate for the heterogeneity in the reported pooled incidences. Statistical heterogeneity was estimated using I2 statistics and further assessed using subgroup analysis, meta-regression, influence analysis, and Gosh analysis. Publication bias was evaluated by both the Egger test and funnel plot visual analysis.
Results
Study characteristics
The search yielded 81 and 47 records in both Medline/PubMed and ScienceDirect, respectively. No records were identified in OpenGrey and Cochrane databases. After eliminating duplicate data, 125 studies were included for abstract screening, of which 76 were excluded due to insufficient data. Full-text screening of the remaining 49 studies excluded 38 records with an agreement kappa of 0.813. Of the remaining studies, one scored <50% on the quality assessment tool, leaving ten studies for pooled analysis (Table 1). Nine studies were from Europe and one study was from North America (Table 1). Studies were divided into descriptive and analytic categories for subgroup analysis (Table 1). The reported PE incidence among patients hospitalized with COVID-19 in all included studies ranged from 3–35% (Table 2). Details of the selection process are summarized in (Figure 1).
Table 1. Patient characteristics of the included studies.
| First author | Publication year | Region | Country | Study period MM/DD/YYYY | Study design type | Design (analytic or descriptive) | Method of COVID-19 diagnosis |
|---|---|---|---|---|---|---|---|
| Lodigiani et al., 202024 | 2020 | Europe | Italy | 02/13/2020 To 04/10/2020 | Retrospective Cohort | Analytic | Laboratory |
| Middeldorp et al., 202025 | 2020 | Europe | Netherlands | 03/02/2020 To 04/30/2020 | Retrospective Cohort | Analytic | RT-PCR/ CT/ Clinical |
| Helms et al., 202026 | 2020 | Europe | France | 03/03/2020 To 04/07/2020 | Prospective Cohort | Analytic | RT-PCR |
| Bompard et al., 202027 | 2020 | Europe | France | 03/01/2020 To 04/16/2020 | Retrospective Cohort | Analytic | NA |
| Poyiadi et al., 202028 | 2020 | North America | Detroit | 03/16/2020 To 04/18/2020 | Case Control | Analytic | RT-PCR |
| Grillet et al., 202029 | 2020 | Europe | France | 03/15/2020 To 04/14/2020 | Retrospective Cross Sectional | Descriptive | RT-PCR / Strong Clinical Suspicion |
| Leonard-Lorant et al., 202030 | 2020 | Europe | France | 03/01/2020 To 03/31/2020 | Retrospective Cross Sectional | Descriptive | RT-PCR / CT and Clinical |
| Possiy et al., 202031 | 2020 | Europe | France | 02/27/2020 To 04/09/2020 | Case Series | Descriptive | PCR |
| Klok et al., 202032 | 2020 | Europe | Netherlands | 03/07/2020 To 04/22/2020 | Case Series | Descriptive | NA |
| Llitjos et al., 202033 | 2020 | Europe | France | 03/19/2020 To 04/11/2020 | Retrospective cross sectional | Descriptive | PCR |
Table 2. Primary data for calculation of the incidence of patients hospitalized with COVID-19.
| First author | Sample size | Number of CTPA | Number of PE | PE proportion |
|---|---|---|---|---|
| Lodigiani et al., 202024 | 388 | 30 | 10 | 0.03 |
| Middeldorp et al., 202025 | 198 | NA | 13 | 0.07 |
| Helms et al., 202026 | 150 | 99 | 25 | 0.17 |
| Bompard et al., 202027 | 135 | 135 | 32 | 0.24 |
| Poyiadi et al., 202028 | 328 | 328 | 72 | 0.22 |
| Grillet et al., 202029 | 100 | 100 | 23 | 0.23 |
| Leonard-Lorant et al., 202030 | 106 | 106 | 32 | 0.30 |
| Possiy et al., 202031 | 107 | 34 | 22 | 0.21 |
| Klok et al., 202032 | 184 | NA | 65 | 0.35 |
| Llitjos et al., 202033 | 26 | NA | 6 | 0.23 |
Figure 1. The study selection process depicted using the PRISMA flowchart.
Patients had a mean age of 63 years. The incidence of PE was noted to be higher in males (Table 3). The D-dimer levels were specified between PE group and non-PE group in only three studies, while the remaining either reported it improperly or had missing data (Table 3).
Table 3. Characteristics of patients hospitalized with COVID-19 and those who developed pulmonary embolism (PE).
| First author | Age of patients with PE (years) | Male patients with PE (n (%)) | BMI of patients with PE (kg/m2) | D-dimer of patients with PE | Age of total patients (years) | Male total patients (n (%)) | BMI of total patients (kg/m2) | D-dimer of total patients |
|---|---|---|---|---|---|---|---|---|
| Lodigiani et al., 202024 | Mean = 69.3 | 7 (70) | NA | Mean = 10669.9 ng/ml | Median (IQR)= 66 (55-75) | 264 (68) | >30 =24.1% | NA |
| Middeldorp et al., 202025 | NA | NA | NA | NA | Mean±SD = 61±14 | 130 (66) | Median (IQR) = 27 (24-31) | Median (IQR)= 1.1 (0.7-2.3) mg/l |
| Helms et al., 202026 | Mean = 62 | 24 (96) | NA | NA | Median (IQR)= 63 (53-71) | 122 (81.3) | NA | Median (IQR) = 2.27 (1.16-20) mg/l |
| Bompard et al., 202027 | Median (IQR) = 70 (59-77) | 26 (81) | NA | Median (IQR) = 9841 (2921-10000) u/l | Median (IQR)= 64 (54-76) | 94 (70) | NA | Median (IQR) = 1285 (891 - 2742) u/l* |
| Poyiadi et al., 202028 | Mean±SD = 59±15 | 35 (49) | 42 (58%) >30 | Mean±SD = 9.33±7 mg/ml | Mean = 61.3 | 150 (45.7) | 155 (47.2%) >30 | Mean±SD = 2.54±3.67 mg/ml* |
| Grillet et al., 202029 | Mean±SD = 67±11 | 21 (91) | NA | NA | Mean±SD = 66±13 | 70 (70) | NA | NA |
| Leonard-Lorant et al., 202030 | Mean±SD = 64±22 | 25 (78) | Median (IQR) = 27±8 | Median (IQR) = 15385±14410ug/l | Mean= 63.3 | 70 (66) | Mean= 28.4 | Mean±SD = 1940 ± 3060 ug/l* |
| Possiy et al., 202031 | Median (range) = 57 (29-80) | 13 (59.1) | Median (range) = 30 (22-53) | NA | NA | NA | NA | NA |
| Klok et al., 202032 | NA | NA | NA | NA | Mean±SD= 64±12 | 139 (76) | NA | NA |
| Llitjos et al., 202033 | NA | NA | NA | NA | Mean±SD= 68±11.5 | 20 (77) | NA | NA |
Though anatomical distribution of PE was mentioned in most studies (except Lorant et al. and Grillet et al.)29,30, the clinical classification of PE into massive and sub-massive was not mentioned.
Meta-analysis
The pooled incidence of PE in hospitalized patients with COVID-19 was 17% (95% CI: 11-26%) (Figure 2). I2 test revealed significant study heterogeneity (I2= 94%, p<0.01). The risk of publication bias was tested for by Egger test (t-value = -1.867, p=0.0989) and examined visually using a funnel plot (Figure 3).
Figure 2. Forest plot of included studies and their pooled estimate.
Figure 3. Funnel plot for assessment of any potential publication bias.
Subgroup analysis
The pooled PE incidence was estimated at 11% (95% CI: 5-23%) and 27% (95% CI 22-34%) in the analytic and descriptive studies, respectively. Higher heterogeneity was detected among the analytic group (I2= 95%, p<0.01), compared to the descriptive group (I2= 48%, p=0.05) (Figure 4).
Figure 4. Forest plot of subgroup analysis.
Meta-regression
When categorizing the included studies into analytic or descriptive, the meta-regression model showed that the study design was significantly associated with the difference in PE incidence (p<0.05) (Figure 5).
Figure 5. Meta-regression plot showing both LOGIT and back-transformation.
Discussion
PE is the most common thromboembolic complication occurring in patients with COVID-1924,30,32. This systematic review and meta-analysis estimated a pooled PE incidence among patients hospitalized with COVID-19 at 17% (95% CI: 10-26%) (Figure 2)24–33. This pooled PE incidence is higher than the PE incidence of the general population, and most importantly, higher than that of hospitalized patients with other medical conditions34–40.
This reported PE incidence could represent an over or under estimation of the true incidence. The increasing knowledge of higher incidences of venous thromboembolism in patients with COVID-19 may have led to a selection bias due to lower threshold of CT pulmonary angiography (CTPA) utilization41. An underestimation is known to occur in the general population for the diagnosis of PE related to the majority of massive PE being diagnosed on post-mortem examination. Similarly, patients with COVID-19 could be assumed to have a lower reported incidence of PE diagnosis due to; limited CT scan availability, patients instability, concern over hospital exposure to others related to transportation, early hospital mortality and death outside of healthcare5,42–44.
Most of the patients included in this meta-analysis were males and aged sixty years and above. Not only was PE higher in elderly and males patients hospitalized with COVID-19, but also other COVID-19 related complications and death were seen more in this population45,46. This observation is consistent with the higher PE incidence across the elderly in the general population as well47. Therefore, hospitalized male and elderly patients with COVID-19 could be at a higher risk of developing PE compared to their COVID-19-afflicted female and young counterparts, respectively.
To account for the variability of CTPA timing effect on PE incidence, a study assigned each patient with COVID-19 two time points in the CTPA and demonstrated a higher incidence at the later time point27. Such an observation may help in interpreting the variation in PE incidence across different studies with similar population characteristics and may also highlight underestimation of PE incidence in population with single time CTPA.
PE mortality was reported in only 3 out of the 10 studies using different formats24,25,27,28,33. Therefore, the estimated pooled mortality could not be calculated.
Strength, limitations, and recommendations
This study was designed and executed in accordance with PRISMA guidelines. The heterogonous severity of the included COVID-19 cohort included the complete spectrum of hospitalized patients with COVID-19. Therefore, this estimated incidence could apply to any hospitalized patients with COVID-19, regardless of disease acuity. However, these findings need to be interpreted in the context of some limitations. First, neither articles in non-indexed journals nor non-published papers were searched, which may have introduced some publication bias. Second, the inclusion of studies published only in English literature may have led to language bias. Third, the presence of a subpopulation in whom PE was suspected and CTPA could not be performed for various reasons, such as allergy to contrast material, and could result in skewed incidence. Fourth, both clinical indications for CTPA and PE classification or risk stratification were not specified in the different studies. Sixth, due to variability of the way of reporting specific data on some variables (d-dimer, mortality data), it was difficult to make meaningful predictions. Lastly, some relevant clinical and para-clinical variables were not mentioned.
Further research is warranted to accurately characterize the patients hospitalized with COVID-19 who develop PE in terms of; risk factors profile, PE diagnostic indications, CTPA timing, PE prophylaxis and management, and PE pathogenesis.
Conclusion
This systematic review and meta-analysis reported a pooled PE incidence among patients hospitalized with COVID-19 at 17%, suggesting that almost in every five hospitalized patients with COVID-19, one may develop PE. This represents around a 243-fold increase in incidence when compared to the general population. Healthcare professionals should be aware of this observed increase in risk of PE incidence among patients hospitalized with COVID-19. Development of accurate and precise risk stratification scores and point of care biomarkers to guide prophylactic and therapeutic strategies in this vulnerable population are warranted.
Data availability
Underlying data
All data underlying the results are available as part of the article and no additional source data are required.
Extended data
Open Science Framework: Codes and PRISMA checklist, https://doi.org/10.6084/m9.figshare.13347473.v248.
This project contains the following extended data:
Reporting guidelines
Open Science Framework: PRISMA checklist for ‘Incidence of acute pulmonary embolism among patients hospitalized with COVID-19: a systematic review and meta-analysis’, https://doi.org/10.6084/m9.figshare.13347473.v248.
Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).
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CITE
how to cite this article
Munner MS, Ritchie CA, Elkhidir IH et al. Incidence of acute pulmonary embolism among patients hospitalized with COVID-19: a systematic review and meta-analysis [version 1; peer review: 1 not approved] F1000Research 2020, 9:1489 (https://doi.org/10.12688/f1000research.27425.1)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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PUBLISHED 18 Dec 2020
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How to cite this report:
Qi X and An Y. Reviewer Report For: Incidence of acute pulmonary embolism among patients hospitalized with COVID-19: a systematic review and meta-analysis [version 1; peer review: 1 not approved]. F1000Research 2020, 9:1489 (https://doi.org/10.5256/f1000research.30307.r77814)
The direct URL for this report is:
https://f1000research.com/articles/9-1489/v1#referee-response-77814
https://f1000research.com/articles/9-1489/v1#referee-response-77814
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 10 Mar 2021
Xingshun Qi, Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
Yang An, Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
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VIEWS 35
This paper is too simple, especially the Results section focusing on the pooled incidence of PE. Data analysis should be expanded to explore the risk factors and impact of PE. Can the relationship between PE and COVID-19 severity be established?
... Continue reading
CITE
HOW TO CITE THIS REPORT
Qi X and An Y. Reviewer Report For: Incidence of acute pulmonary embolism among patients hospitalized with COVID-19: a systematic review and meta-analysis [version 1; peer review: 1 not approved]. F1000Research 2020, 9:1489 (https://doi.org/10.5256/f1000research.30307.r77814)
The direct URL for this report is:
https://f1000research.com/articles/9-1489/v1#referee-response-77814
https://f1000research.com/articles/9-1489/v1#referee-response-77814
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Author Response 26 Apr 2021Hussein Ahmed, University of Khartoum, Khartoum, Sudan26 Apr 2021Author ResponseDear reviewer,
Thank you for your valuable comments, we did a systematic review and meta-analysis regarding the incidence of PE among patients hospitalized due to COVID-19.
Our ultimate aim ... Continue reading
COMMENTS ON THIS REPORT
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Author Response 26 Apr 2021Hussein Ahmed, University of Khartoum, Khartoum, Sudan26 Apr 2021Author ResponseDear reviewer,
Thank you for your valuable comments, we did a systematic review and meta-analysis regarding the incidence of PE among patients hospitalized due to COVID-19.
Our ultimate aim ... Continue reading
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