Risk factors for pulmonary embolism in patients with COVID-19: a systemic review and meta-analysis

Open AccessPublished:August 18, 2021DOI:https://doi.org/10.1016/j.ijid.2021.08.017

      Highlights

      • Risk factors for PE in COVID-19 are different from the classic PE risk factors.
      • Risk factors in COVID-19 are likely to be associated with the severity of illness.
      • Risk factors for PE are likely to differ in diverse study populations.

      Abstract

      Purpose

      To detect the risk factors for pulmonary embolism (PE) in patients with COVID-19.

      Methods

      Studies were searched for in PubMed, Cochrane Library, Web of Science, and EMBASE. Two authors independently screened articles and extracted data. The data were pooled by meta-analysis and three subgroup analyses were performed.

      Results

      Of the 2210 articles identified, 27 studies were included. Pooled analysis suggested that males (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.26−1.75, P = 0.000), obesity (OR 1.37, 95% CI 1.03−1.82, P = 0.033), mechanical ventilation (OR 3.34, 95% CI 1.90−5.86, P = 0.000), severe parenchymal abnormalities (OR 1.92, 95% CI 1.43−2.58, P = 0.000), ICU admission (OR 2.44, 95% CI 1.48−4.03, P = 0.000), and elevated D-dimer and white blood cell values (at two time points: hospital admission or closest to computed tomography pulmonary angiography) (P = 0.000) correlated with a risk for PE occurrence in COVID-19 patients. However, age and common comorbidities had no association with PE occurrence. Computed tomography pulmonary angiography, unclear-ratio/low-ratio, and hospitalization subgroups had consistent risk factors with all studies; however, other subgroups had fewer risk factors for PE.

      Conclusions

      Risk factors for PE in COVID-19 were different from the classic risk factors for PE and are likely to differ in diverse study populations.

      Keywords

      Introduction

      Since December 2019, coronavirus disease 2019 (COVID-19) has rapidly spread worldwide and caused more than 1 billion infections and 2 million deaths to date (
      • Ackermann M
      • Verleden SE
      • Kuehnel M
      • et al.
      Pulmonary vascular endotheliitis, thrombosis, and angiogenesis in COVID-19.
      ). The pathophysiology of COVID-19 has not yet been fully revealed. However, the direct viral toxicity (
      • Alonso-Fernández A
      • Toledo-Pons N
      • Cosío BG
      • et al.
      Prevalence of pulmonary embolism in patients with COVID-19 pneumonia and high D-dimer values: A prospective study.
      ), endothelial cell damage, and dysregulation of the immune response (
      • Ameri P
      • Inciardi RM
      • Di Pasquale M
      • et al.
      Pulmonary embolism in patients with COVID-19: characteristics and outcomes in the Cardio-COVID Italy multicenter study.
      ) are widely believed to participate in the process (
      • Artifoni M
      • Danic G
      • Gautier G
      • et al.
      Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors.
      ). Emerging evidence has revealed that pulmonary embolism (PE) is a common complication in patients with COVID-19, with a higher incidence rate of 5−19% (
      • Bavaro DF
      • Poliseno M
      • Scardapane A
      • et al.
      Occurrence of acute pulmonary embolism in COVID-19—a case series.
      ,
      • Benito N
      • Filella D
      • Mateo J
      • et al.
      Pulmonary thrombosis or embolism in a large cohort of hospitalized patients with COVID-19.
      ,
      • Bilaloglu S
      • Aphinyanaphongs Y
      • Jones S
      • Iturrate E
      • Hochman J
      • Berger JS.
      Thrombosis in hospitalized patients with COVID-19 in a New York city health system.
      ) and mortality rate of 8.7−45.1% (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      ,
      • BujaL M
      • Wolf DA
      • Bihong Z
      • et al.
      The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities.
      ,
      • Bunce PE
      • High SM
      • Nadjafi M
      • Stanley K
      • Liles WC
      • Christian MD.
      Pandemic H1N1 influenza infection and vascular thrombosis.
      ) than that in patients without COVID-19 (
      • Ceriani E
      • Combescure C
      • Gal GL
      • et al.
      Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis.
      ,
      • Chen J
      • Wang X
      • Zhang S
      • et al.
      Characteristics of acute pulmonary embolism in patients with COVID-19 associated pneumonia from the city of Wuhan.
      ) (incidence: 1.7−7.5%, mortality: 6.8%). Importantly, PE in patients with COVID-19 has been found to be different from classic PE in patients without COVID-19 in demographic, clinical, and laboratory characteristics (
      • Chi G
      • Lee JJ
      • Jamil A
      • Gunnam V
      • Najafi H.
      Venous Thromboembolism among hospitalized patients with COVID-19 undergoing thromboprophylaxis: a systematic review and meta-analysis.
      ,
      • Choi JJ
      • Wehmeyer GT
      • Li HA
      • et al.
      D-dimer cut-off points and risk of venous thromboembolism in adult hospitalized patients with COVID-19.
      ). Even the traditional etiology of PE – venous thrombi dislodging and traveling as emboli to the pulmonary arteries (
      • Connors JM
      • Levy JH.
      COVID-19 and its implications for thrombosis and anticoagulation.
      ) – has been suspected in COVID-19 patients (
      • Contou D
      • Pajot O
      • Cally R
      • et al.
      Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study.
      ,
      • Egger M
      • Davey Smith G
      • Schneider M
      • Minder C
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
      ,
      • Fang C
      • Garzillo G
      • Batohi B
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      ). Some researchers have proposed a new hypothesis of pulmonary microvascular thrombosis, according to the unusual autopsy finding in COVID-19 that thrombosis and microangiopathy are common in the small vessels and capillaries of the lungs (
      • Contou D
      • Pajot O
      • Cally R
      • et al.
      Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study.
      ,
      • Egger M
      • Davey Smith G
      • Schneider M
      • Minder C
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
      ,
      • Fang C
      • Garzillo G
      • Batohi B
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      ). Therefore, the risk factors for PE in patients with COVID-19 may differ from the classic ones and this is supported by several studies (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      ,
      • Fauvel C
      • Weizman O
      • Trimaille A
      • et al.
      Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.
      ,
      • Flumignan RLG
      • JDDSá Tinôco
      • Pascoal PIF
      • et al.
      Prophylactic anticoagulants for people hospitalised with COVID-19.
      ,
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • Li G
      • Quincy Brown J
      • Vander Heide RS
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ). However, the results on this issue have been inconsistent. One systemic review without sub-analysis of PE recently stated the risk factors of venous thrombus embolism (VTE) in COVID-19, and they were different from the classic ones (
      • Gervaise A
      • Bouzad C
      • Peroux E
      • Helissey C.
      Acute pulmonary embolism in non-hospitalized COVID-19 patients referred to CTPA by emergency department.
      ). Considering that PE in COVID-19 may not only originate from deep vein thrombosis, the detection of risk factors for PE is necessary.
      At present, as clinical judgment lacks standardization (such as Wells, the revised Geneva prediction rule, or risk factors), the screening of suspected PE for computed tomography pulmonary angiography (CTPA) in patients with COVID-19 is mostly based on the empirical evaluation of clinicians. The common reasons are unexplained: respiratory deterioration, a rapid increase in D-dimer, or clinical symptoms of PE (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      ,
      • Choi JJ
      • Wehmeyer GT
      • Li HA
      • et al.
      D-dimer cut-off points and risk of venous thromboembolism in adult hospitalized patients with COVID-19.
      ,
      • Flumignan RLG
      • JDDSá Tinôco
      • Pascoal PIF
      • et al.
      Prophylactic anticoagulants for people hospitalised with COVID-19.
      ,
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • Li G
      • Quincy Brown J
      • Vander Heide RS
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ). These make a low PE judgment rate with high heterogeneity between studies in COVID-19 (positive CTPA: 8−44%) (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      ,
      • Fauvel C
      • Weizman O
      • Trimaille A
      • et al.
      Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.
      ,
      • Grillet F
      • Behr J
      • Calame P
      • Aubry S
      Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography.
      ) compared with the classic PE judgment using Wells or the revised Geneva prediction rule (confirmed PE expected to be 0−10% in the low-probability category and 65% in the high-probability category) (
      • Ceriani E
      • Combescure C
      • Gal GL
      • et al.
      Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis.
      ,
      • Gupta A
      • Madhavan MV.
      Extrapulmonary manifestations of COVID-19.
      ). Also, this rate may be overestimated because of the cautious screening strategy of suspected PE adopted to reduce cross-infection (
      • Hajra A
      • Mathai SV
      • Ball S
      • et al.
      Management of thrombotic complications in COVID-19: an update.
      ,
      • Jalaber C
      • Revel MP
      • Chassagnon G
      • et al.
      Role of upfront CT pulmonary angiography at admission in COVID-19 patients.
      ). Therefore, it is essential to assess the risk factors for PE in COVID-19 and, aside from improving PE detection, risk factors can also promote the prevention and management of PE.
      Therefore, this meta-analysis was conducted to detect the risk factors for PE in patients with COVID-19, along with subgroup analyses, considering the clinical practicability. It is believed that this is the first systematic review to do this and it is hoped that it can help physicians in diagnosing and managing PE. At the same time, it can promote an awareness of the clinical prediction rules for PE in patients with COVID-19, which is similar to the Geneva or Wells score.

      Methods

      This study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and registered with PROSPERO (CRD42020207652).

       Citation search and selection

      The PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched from 01 January 2019 to 28 December 2020, with no publication language limited. The following search strategy was used: ("pulmonary embolism" OR "lung embolism" OR "pulmonary thromboembolism" OR "lung thromboembolism") AND ("COVID-19" OR "coronavirus disease 2019” OR "2019-nCoV Disease" OR "2019-nCoV Infection" OR "SARS-CoV-2 Disease" OR "SARS-CoV-2 Infection"). The authors also manually screened the reference lists of reviews to guarantee that all relevant articles were included.
      Two authors (YLC, WWC) independently screened out the full-text articles and included studies according to the following criteria. They reached a consensus on inclusion criteria: (1) cohort, case-control, case-series, or cross-sectional study; (2) consecutive COVID-19 patients. The exclusion criteria were: (1) patients aged < 18 years, and pregnant women; (2) a sample size < 10. If an institution published several similar articles, only the one with the largest sample size was included. The differences were resolved by an arbitrator (ZMC).

       Data extraction and quality assessment

      Data extraction and quality assessment of the included studies were conducted by two authors (DX and YYL), respectively. The data involved study design, publishing location, reasons for CTPA examination, and prophylactic anticoagulation ratio. The demographic, clinical, and laboratory features were also extracted. The study quality was assessed by the Newcastle Ottawa Score checklist (
      • Jevnikar M
      • Sanchez O
      • Andronikov M
      • et al.
      Prevalence of pulmonary embolism in patients at the Time of Hospital Admission for COVID-19.
      ).

       Statistical analysis

      Weighted mean difference (WMD) with 95% confidence intervals (CI) was chosen as the effect size of a continuous variable, and odds ratio (OR) with 95% CI for a dichotomous variable. All analyses were executed using Stata MP version 14.0 (Stata Corporation, College Station, TX, USA), with heterogeneities assessed by I2 (
      • Jiménez HS
      • Lozano PL
      • Suñen CG
      • et al.
      Clinical findings, risk factors, and final outcome in patients diagnosed with pulmonary thromboembolism and COVID-19 in hospital emergency departments.
      ). An I2 of 25%, 50%, and 75% indicates low, moderate, and high heterogeneity, respectively. When I2 < 50%, inverse variance weights (fixed-effect model) were used. If I2 > 50%, the DerSimonian-Laird procedure (random-effect model) was used. At the same time, a further sensitivity analysis was performed with subgroup analyses for every parameter in three categories. According to the different study populations, the included studies were divided into: CTPA vs. COVID-19 subgroup (COVID-19 patients who were suspected of PE and underwent CTPA vs. all COVID-19 patients); unclear-ratio vs. low-ratio (ratio < 80%) vs. high-ratio subgroup (ratio > 80%) (the patients with different ratios of thromboprophylaxis); and the hospitalization vs. ICU-stay subgroup. The publication bias (studies ≥ 10) was evaluated using Egger's test (
      • Higgins JP
      • Thompson SG
      • Deeks JJ
      • Altman DG.
      Measuring inconsistency in meta-analyses.
      ). P < 0.05 was considered as statistical significance.

      Results

       Study selection and quality assessment

      The search strategy identified 2210 articles. After the exclusion of duplicates, 1270 articles were screened. Seventy-nine were considered eligible for full-text evaluation. Finally, 27 studies were included according to the inclusion and exclusion criteria (Figure 1). The risk of bias was judged as low for all included studies (Table 1).
      Table 1Characteristics of the included studies.
      Study IDRegion, countryStudy designNo. of COVID-19
      No. of COVID-19, number of patients with COVID-19
      Diagnosis of COVID-19Reasons for PE screeningRatio
      Ratio, ratio of prophylactic anticoagulation
      No. of CTPA
      No. of CTPA, number of patients with CTPA examination or suspicion of PE
      No.of PE
      No. of PE, number of patients with confirmed PE
      Quality
      Quality, all studies were assessed by the Newcastle Ottawa Score (NOS); –, not available
      Fauvel C (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      )
      Franceretrospective, multi-center, multi-hospital2878RT-PCR+, clinical criteriaunexplained respiratory deterioration67.5%12401038
      Poyiadji N (
      • Fauvel C
      • Weizman O
      • Trimaille A
      • et al.
      Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.
      )
      Detroit, USAretrospective, multi-hospitalRT-PCR+328728
      Mestre-Gómez B (
      • Flumignan RLG
      • JDDSá Tinôco
      • Pascoal PIF
      • et al.
      Prophylactic anticoagulants for people hospitalised with COVID-19.
      )
      Madrid, Italyretrospective, single non-critical ward452RT-PCR +, clinical criteriaunexplained respiratory deterioration, elevation of D-dimer91299
      Alonso-Fernánde A (
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • Li G
      • Quincy Brown J
      • Vander Heide RS
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      )
      Palma de Mallorca, Spainprospective, single hospital127RT-PCR +, clinical criteriaD-dimer > 1 mg/L96.7%30158
      Fang C (
      • Grillet F
      • Behr J
      • Calame P
      • Aubry S
      Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography.
      )
      London, UKretrospective, single hospital1200RT-PCR+93418
      Chen JP (
      • Jalaber C
      • Revel MP
      • Chassagnon G
      • et al.
      Role of upfront CT pulmonary angiography at admission in COVID-19 patients.
      )
      Wuhan, Chinaretrospective, single hospital100815 RT-PCR+, 10 clinical criteriaelevated D-dimer, PE symptom(s)25109
      Leonard-Lorant I (
      • Huisman MV
      • Barco S
      • Cannegieter SC
      • et al.
      Pulmonary embolism.
      )
      Strasbourg, FranceRetr ospective, 2 hospitals97 RT-PCR+, 9 clinical criteria46.2%106328
      Bompard F (
      • Kim KD
      • Zhao J
      • Auh S
      • et al.
      Adaptive immune cells temper initial innate responses.
      )
      Paris, Franceretrospective, 2 hospitalsrespiratory deterioration100%135328
      Ooi MWX (
      • Kirsch B
      • Aziz M
      • Kumar S
      • et al.
      Wells score to predict pulmonary embolism in patients with coronavirus disease 2019.
      )
      GreaterManchester, UKretrospective, 5 hospitals974RT-PCR+, clinical criteriarespiratory deterioration, elevation of D-dimer84329
      Ventura-Diaz S (
      • 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): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
      )
      Madrid, Spainretrospective, single hospitalRT-PCR+, clinical criteria242738
      Kirsch B (
      • Kosior DA
      • Undas A
      • Kopec G
      • et al.
      Guidance for anticoagulation management in venous thromboembolism during the coronavirus disease 2019 pandemic in Poland an expert opinion of the section on pulmonary circulation of the polish cardiac society.
      )
      Houston, USAretrospective, single hospital45964127
      Planquette B (
      • Kunutsor SK
      • Laukkanen JA.
      Incidence of venous and arterial thromboembolic complications in COVID-19: A systematic review and meta-analysis.
      )
      Paris, Franceretrospective, 2 hospitalsRT-PCR +, clinical criteria34.6%269598
      Mouhat B (
      • Lax SF
      • Skok K
      • Zechner P
      • et al.
      Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center.
      )
      Besançon, Franceretrospective, single hospital349RT-PCR+unexplained respiratory deterioration87%162449
      Whyte MB (
      • Léonard-Lorant I
      • Delabranche X.
      Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to d-dimer levels.
      )
      London, UKretrospective, single hospital145 RT-PCR, 69 Clinical criteriaunexplained clinical deterioration100%214809
      Grillet F (
      • Liao SC
      • Shao SC
      • Chen YT
      • Chen YC
      • Hung MJ.
      Incidence and mortality of pulmonary embolism in COVID-19: a systematic review and meta-analysis.
      )
      Besancon Cedex, Franceretrospective, single hospital280RT-PCR+, clinical criteria100238
      Bavaro DF (
      • Llitjos JF
      • Leclerc M
      • Chochois C
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      )
      Bari, Italyretrospective, single hospitalD-dimer > 1 mg/L and clinically suspected PE85%2088
      Benito N (
      • Mestre-Gómez B
      • Lorente-Ramos RM
      • Rogado J
      • et al.
      Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis.
      )
      Barcelona, Spainprospective, single hospital1275RT-PCR+unexplained circulatory/ respiratory deterioration, elevation of D-dimer88.2%76329
      Gervaise A (
      • Mouhat B
      • Besutti M
      • Bouiller K
      • et al.
      Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients.
      )
      Saint Mandé, Franceretrospective, single ED58 RT-PCR +, 14 clinical criteriarespiratory deterioration, elevation of D-dimer72139
      Contou D (
      • Mueller-Peltzer K
      • Krauss T
      • Benndorf M
      • et al.
      Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS.
      )
      Argenteuil, Franceretrospective, single ICU92RT-PCR +unexplained circulatory/ respiratory deterioration100%26169
      Zotzmann V (
      • Nopp S
      • Janata-Schwatczek K
      • Prosch H
      • Shulym I
      • Königsbrügge O.
      Pulmonary embolism during the COVID-19 pandemic: Decline in diagnostic procedures and incidence at a university hospital.
      )
      Freiburg, Germanyretrospective, single ICU113RT-PCR +severe ARDS20129
      Soumagne T (
      • Ooi MWX
      • Rajai A
      • Patel R
      • et al.
      Pulmonary thromboembolic disease in COVID-19 patients on CT pulmonary angiography−Prevalence, pattern of disease and relationship to D-dimer.
      )
      Besancon, Franceretrospective, single ICURT-PCR +respiratory deterioration81.8%44179
      Taccone FS (
      • Pandey P
      • Agarwal S
      Rajkumar. Lung pathology in COVID-19: A systematic review.
      )
      Brussels, Belgiumretrospective, single ICU82RT-PCR +mechanical ventilation100%40139
      Jevnikar M (
      • Planquette B
      • Le Berre A
      • Khider L
      • et al.
      Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.
      )
      Le Kremlin-Bicêtre, Franceprospective, multi-center, multi-hospital135RT-PCR +systematic screening107169
      Jalaber C (
      • Rodriguez-Sevilla J
      • Rodó-Pin A
      • Espallargas I
      • et al.
      Pulmonary embolism in patients with Covid-19 pneumonia: the utility of d-dimer.
      )
      Saint Priest en Jarez, Franceprospective, single ED7065 RT-PCR+, 5 clinical criteriasystematic screening7049
      Ameri P (
      • Poyiadji N
      • Cormier P
      • Patel PY
      • et al.
      Acute pulmonary embolism and COVID-19.
      )
      Italyretrospective, multi-center, 13 cardiology units689RT-PCR +, clinical criteria528
      Lascarrou JB (
      • Salje H
      • Kiem CT
      • Lefrancq N
      • et al.
      Estimating the burden of SARS-CoV-2 in France.
      )
      France and Belgiumretrospective, multi-center, 21 ICU375RT-PCR +100%558
      Scudiero F (
      • Scudiero F
      • Silverio A
      • Di Maio M
      • et al.
      Pulmonary embolism in COVID-19 patients: Prevalence, predictors and clinical outcome.
      )
      Seriate, Italyretrospective, multi-center, 7 hospitals224RT-PCR +18.8%328
      Abbreviations: COVID-19, coronavirus disease 2019; PE, pulmonary embolism; CTPA, computed tomography pulmonary angiography; RT-PCR+, positive reverse transcription-polymerase chain reaction; ICU, intensive care unit; ED, emergency department
      a No. of COVID-19, number of patients with COVID-19
      b Ratio, ratio of prophylactic anticoagulation
      c No. of CTPA, number of patients with CTPA examination or suspicion of PE
      d No. of PE, number of patients with confirmed PE
      e Quality, all studies were assessed by the Newcastle Ottawa Score (NOS); –, not available

       Characteristics of included studies

      All 27 included studies involved 927 PE patients and 3927 non-PE patients (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      ,
      • Fauvel C
      • Weizman O
      • Trimaille A
      • et al.
      Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.
      ,
      • Flumignan RLG
      • JDDSá Tinôco
      • Pascoal PIF
      • et al.
      Prophylactic anticoagulants for people hospitalised with COVID-19.
      ,
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • Li G
      • Quincy Brown J
      • Vander Heide RS
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Grillet F
      • Behr J
      • Calame P
      • Aubry S
      Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography.
      ,
      • Jalaber C
      • Revel MP
      • Chassagnon G
      • et al.
      Role of upfront CT pulmonary angiography at admission in COVID-19 patients.
      ,
      • Huisman MV
      • Barco S
      • Cannegieter SC
      • et al.
      Pulmonary embolism.
      ,
      • Kim KD
      • Zhao J
      • Auh S
      • et al.
      Adaptive immune cells temper initial innate responses.
      ,
      • Kirsch B
      • Aziz M
      • Kumar S
      • et al.
      Wells score to predict pulmonary embolism in patients with coronavirus disease 2019.
      ,
      • 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): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
      ,
      • Kosior DA
      • Undas A
      • Kopec G
      • et al.
      Guidance for anticoagulation management in venous thromboembolism during the coronavirus disease 2019 pandemic in Poland an expert opinion of the section on pulmonary circulation of the polish cardiac society.
      ,
      • Kunutsor SK
      • Laukkanen JA.
      Incidence of venous and arterial thromboembolic complications in COVID-19: A systematic review and meta-analysis.
      ,
      • Lax SF
      • Skok K
      • Zechner P
      • et al.
      Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center.
      ,
      • Léonard-Lorant I
      • Delabranche X.
      Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to d-dimer levels.
      ,
      • Liao SC
      • Shao SC
      • Chen YT
      • Chen YC
      • Hung MJ.
      Incidence and mortality of pulmonary embolism in COVID-19: a systematic review and meta-analysis.
      ,
      • Llitjos JF
      • Leclerc M
      • Chochois C
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      ,
      • Mestre-Gómez B
      • Lorente-Ramos RM
      • Rogado J
      • et al.
      Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis.
      ,
      • Mouhat B
      • Besutti M
      • Bouiller K
      • et al.
      Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients.
      ,
      • Mueller-Peltzer K
      • Krauss T
      • Benndorf M
      • et al.
      Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS.
      ,
      • Nopp S
      • Janata-Schwatczek K
      • Prosch H
      • Shulym I
      • Königsbrügge O.
      Pulmonary embolism during the COVID-19 pandemic: Decline in diagnostic procedures and incidence at a university hospital.
      ,
      • Ooi MWX
      • Rajai A
      • Patel R
      • et al.
      Pulmonary thromboembolic disease in COVID-19 patients on CT pulmonary angiography−Prevalence, pattern of disease and relationship to D-dimer.
      ,
      • Pandey P
      • Agarwal S
      Rajkumar. Lung pathology in COVID-19: A systematic review.
      ,
      • Planquette B
      • Le Berre A
      • Khider L
      • et al.
      Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.
      ,
      • Rodriguez-Sevilla J
      • Rodó-Pin A
      • Espallargas I
      • et al.
      Pulmonary embolism in patients with Covid-19 pneumonia: the utility of d-dimer.
      ,
      • Poyiadji N
      • Cormier P
      • Patel PY
      • et al.
      Acute pulmonary embolism and COVID-19.
      ,
      • Salje H
      • Kiem CT
      • Lefrancq N
      • et al.
      Estimating the burden of SARS-CoV-2 in France.
      ,
      • Scudiero F
      • Silverio A
      • Di Maio M
      • et al.
      Pulmonary embolism in COVID-19 patients: Prevalence, predictors and clinical outcome.
      ), of which 23 were retrospective case-control studies and four were prospective cohort studies (
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • Li G
      • Quincy Brown J
      • Vander Heide RS
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Mestre-Gómez B
      • Lorente-Ramos RM
      • Rogado J
      • et al.
      Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis.
      ,
      • Planquette B
      • Le Berre A
      • Khider L
      • et al.
      Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.
      ,
      • Rodriguez-Sevilla J
      • Rodó-Pin A
      • Espallargas I
      • et al.
      Pulmonary embolism in patients with Covid-19 pneumonia: the utility of d-dimer.
      ) (Table 1). Among these studies, 24 were from Europe (833 PEs vs. 3604 non-PEs), two were from America (
      • Fauvel C
      • Weizman O
      • Trimaille A
      • et al.
      Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.
      ,
      • Kosior DA
      • Undas A
      • Kopec G
      • et al.
      Guidance for anticoagulation management in venous thromboembolism during the coronavirus disease 2019 pandemic in Poland an expert opinion of the section on pulmonary circulation of the polish cardiac society.
      ), and one was from China (
      • Jalaber C
      • Revel MP
      • Chassagnon G
      • et al.
      Role of upfront CT pulmonary angiography at admission in COVID-19 patients.
      ). The CTPA subgroup consisted of 22 articles involving 768 PEs and 2621 non-PEs, with 15 articles stating the reason for CTPA examination, of which unexplained respiratory deterioration or a rapid increase in D-dimer counted the most (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      ,
      • Flumignan RLG
      • JDDSá Tinôco
      • Pascoal PIF
      • et al.
      Prophylactic anticoagulants for people hospitalised with COVID-19.
      ,
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • Li G
      • Quincy Brown J
      • Vander Heide RS
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Jalaber C
      • Revel MP
      • Chassagnon G
      • et al.
      Role of upfront CT pulmonary angiography at admission in COVID-19 patients.
      ,
      • Kim KD
      • Zhao J
      • Auh S
      • et al.
      Adaptive immune cells temper initial innate responses.
      ,
      • Kirsch B
      • Aziz M
      • Kumar S
      • et al.
      Wells score to predict pulmonary embolism in patients with coronavirus disease 2019.
      ,
      • Lax SF
      • Skok K
      • Zechner P
      • et al.
      Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center.
      ,
      • Léonard-Lorant I
      • Delabranche X.
      Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to d-dimer levels.
      ,
      • Llitjos JF
      • Leclerc M
      • Chochois C
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      ,
      • Mestre-Gómez B
      • Lorente-Ramos RM
      • Rogado J
      • et al.
      Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis.
      ,
      • Mouhat B
      • Besutti M
      • Bouiller K
      • et al.
      Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients.
      ,
      • Mueller-Peltzer K
      • Krauss T
      • Benndorf M
      • et al.
      Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS.
      ,
      • Nopp S
      • Janata-Schwatczek K
      • Prosch H
      • Shulym I
      • Königsbrügge O.
      Pulmonary embolism during the COVID-19 pandemic: Decline in diagnostic procedures and incidence at a university hospital.
      ,
      • Ooi MWX
      • Rajai A
      • Patel R
      • et al.
      Pulmonary thromboembolic disease in COVID-19 patients on CT pulmonary angiography−Prevalence, pattern of disease and relationship to D-dimer.
      ,
      • Pandey P
      • Agarwal S
      Rajkumar. Lung pathology in COVID-19: A systematic review.
      ) (Table 1). The COVID-19 subgroup consisted of five articles involving 159 PEs and 1306 non-PEs (
      • Planquette B
      • Le Berre A
      • Khider L
      • et al.
      Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.
      ,
      • Rodriguez-Sevilla J
      • Rodó-Pin A
      • Espallargas I
      • et al.
      Pulmonary embolism in patients with Covid-19 pneumonia: the utility of d-dimer.
      ,
      • Poyiadji N
      • Cormier P
      • Patel PY
      • et al.
      Acute pulmonary embolism and COVID-19.
      ,
      • Salje H
      • Kiem CT
      • Lefrancq N
      • et al.
      Estimating the burden of SARS-CoV-2 in France.
      ,
      • Scudiero F
      • Silverio A
      • Di Maio M
      • et al.
      Pulmonary embolism in COVID-19 patients: Prevalence, predictors and clinical outcome.
      ). In the subgroup analysis of prophylactic anticoagulation, unclear, low-ratio (18.8−67.5%), and high-ratio (82−100%) subgroups contained 13 (389 PEs vs. 1596 non-PEs) (
      • Fauvel C
      • Weizman O
      • Trimaille A
      • et al.
      Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.
      ,
      • Flumignan RLG
      • JDDSá Tinôco
      • Pascoal PIF
      • et al.
      Prophylactic anticoagulants for people hospitalised with COVID-19.
      ,
      • Grillet F
      • Behr J
      • Calame P
      • Aubry S
      Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography.
      ,
      • Jalaber C
      • Revel MP
      • Chassagnon G
      • et al.
      Role of upfront CT pulmonary angiography at admission in COVID-19 patients.
      ,
      • Kirsch B
      • Aziz M
      • Kumar S
      • et al.
      Wells score to predict pulmonary embolism in patients with coronavirus disease 2019.
      ,
      • 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): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
      ,
      • Kosior DA
      • Undas A
      • Kopec G
      • et al.
      Guidance for anticoagulation management in venous thromboembolism during the coronavirus disease 2019 pandemic in Poland an expert opinion of the section on pulmonary circulation of the polish cardiac society.
      ,
      • Liao SC
      • Shao SC
      • Chen YT
      • Chen YC
      • Hung MJ.
      Incidence and mortality of pulmonary embolism in COVID-19: a systematic review and meta-analysis.
      ,
      • Mouhat B
      • Besutti M
      • Bouiller K
      • et al.
      Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients.
      ,
      • Nopp S
      • Janata-Schwatczek K
      • Prosch H
      • Shulym I
      • Königsbrügge O.
      Pulmonary embolism during the COVID-19 pandemic: Decline in diagnostic procedures and incidence at a university hospital.
      ,
      • Planquette B
      • Le Berre A
      • Khider L
      • et al.
      Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.
      ,
      • Rodriguez-Sevilla J
      • Rodó-Pin A
      • Espallargas I
      • et al.
      Pulmonary embolism in patients with Covid-19 pneumonia: the utility of d-dimer.
      ,
      • Poyiadji N
      • Cormier P
      • Patel PY
      • et al.
      Acute pulmonary embolism and COVID-19.
      ), four (226 PEs vs. 1521 non-PEs) (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      ,
      • Huisman MV
      • Barco S
      • Cannegieter SC
      • et al.
      Pulmonary embolism.
      ,
      • Kunutsor SK
      • Laukkanen JA.
      Incidence of venous and arterial thromboembolic complications in COVID-19: A systematic review and meta-analysis.
      ,
      • Scudiero F
      • Silverio A
      • Di Maio M
      • et al.
      Pulmonary embolism in COVID-19 patients: Prevalence, predictors and clinical outcome.
      ), and 10 studies (312 PEs vs. 810 non-PEs) (
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • Li G
      • Quincy Brown J
      • Vander Heide RS
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Kim KD
      • Zhao J
      • Auh S
      • et al.
      Adaptive immune cells temper initial innate responses.
      ,
      • Lax SF
      • Skok K
      • Zechner P
      • et al.
      Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center.
      ,
      • Léonard-Lorant I
      • Delabranche X.
      Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to d-dimer levels.
      ,
      • Llitjos JF
      • Leclerc M
      • Chochois C
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      ,
      • Mestre-Gómez B
      • Lorente-Ramos RM
      • Rogado J
      • et al.
      Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis.
      ,
      • Mueller-Peltzer K
      • Krauss T
      • Benndorf M
      • et al.
      Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS.
      ,
      • Ooi MWX
      • Rajai A
      • Patel R
      • et al.
      Pulmonary thromboembolic disease in COVID-19 patients on CT pulmonary angiography−Prevalence, pattern of disease and relationship to D-dimer.
      ,
      • Pandey P
      • Agarwal S
      Rajkumar. Lung pathology in COVID-19: A systematic review.
      ,
      • Salje H
      • Kiem CT
      • Lefrancq N
      • et al.
      Estimating the burden of SARS-CoV-2 in France.
      ). Eighteen studies (716 PEs vs. 2710 non-PEs) were carried on the hospitalization of the study population and five studies (113 PEs vs. 393 non-PEs) were carried on the ICU stay (Contou et al., 2020; Zotzmann et al., 2020; Soumagne and Winiszewski, 2020; Taccone et al., 2020; Soumagne and Lascarrou, 2020).

       Risk factors

       Demographic risk factors

      Nearly all included studies reported information about age and sex. The pooled estimates indicated that males developed PE more easily than females (OR 1.49, 95% CI 1.26−1.75, I2 = 0.0%, P = 0.000) (Table 2, Figure 2A). Age had no significant influence on the occurrence of PE (WMD 1.57, 95% CI -0.31−3.45, I2 = 64.9%, P = 0.101), excluding one study by sensitivity analysis (
      • Léonard-Lorant I
      • Delabranche X.
      Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to d-dimer levels.
      ) (Table 2). Eleven studies reported information about BMI, and the pooled data showed that obesity (BMI > 30) was associated with PE occurrence (OR 1.37, 95% CI 1.03−1.82, P = 0.033, I2 = 0%) (Table 2, Figure 2B). Estimates for eight comorbidities were also pooled, including previous VTE, chronic heart failure, cancer, diabetes, hypertension, recent surgery, cardiovascular disease, and chronic obstructive pulmonary disease. All comorbidities were found to have no association with PE occurrence (P > 0.068), with low heterogeneity (I2 = 0−35.3%). Among all the demographic parameters, only age had publication bias (P = 0.002).
      Table 2Meta-analysis results of the whole studies on PE risk factors in COVID-19.
      VariablesNstudies
      Nstudies, number of studies
      PE, n/PE
      PE, n/PE, number of PE patients, number of PE patients with variable/number of PE patients
      non-PE, n/non-PE
      non-PE, n/non-PE, number of non-PE patients, number of non-PE patients with variable/number of non-PE patients; I2, index for the degree of heterogeneity; P value, significant at P < 0.05 and present in bold; Egger's, index for the degree of publication bias; –, not available
      WMD/OR95% CII2 (%)P-valueEgger's
      Demographic risk factors
      Age, years (WMD)2684737931.57-0.31−3.4564.9%0.1010.002
      Male, % (OR)26627/9112356/38361.491.26−1.760.0%0.0000.606
      Obesity (BMI > 30%)11123/329237/7061.371.03−1.820.0%0.0330.238
      Comorbidities, % (OR)
      Previous VTE847/457168/21601.370.96−1.950.0%0.079
      Chronic heart failure725/358248/26190.850.55−1.3135.3%0.456
      Cancer1356/530325/24300.810.59−1.1032.4%0.1750.473
      Diabetes18146/578746/30730.980.78−1.210.0%0.8190.136
      Hypertension17288/5991615/30990.840.70−1.010.0%0.0680.159
      Recent surgery34/12610/3890.970.30−3.120.0%0.955
      Cardiovascular disease1258/381383/25730.950.69−1.320.0%0.7650.613
      COPD834/381224/24660.910.62−1.350.0%0.651
      Clinical risk factors, % (OR)
      Mechanical ventilation552/11961/2663.341.90−5.8610.8%0.000
      Severe parenchymal abnormalities on chest CT (> 50%)7170/2881183/15551.921.43−2.580.0%0.000
      ICU admission7118/272177/6762.651.48−4.7466.0%0.001
      Laboratory risk factors, (WMD)
      D-dimer, ug/ml (closest to the CTPA)102746346.035.14−6.9238.0%0.0000.872
      D-dimer, ug/ml (hospital admission)931020892.101.10−3.1073.8%0.000
      WBC, × 109/L (closest to the CTPA)52164571.460.77−2.150.0%0.000
      WBC, × 109/L (hospital admission)316317862.101.21−3.000.0%0.000
      Lymphocytes, × 109/L (closest to the CTPA)33857-0.09-0.62−0.4351.6%0.734
      Lymphocytes, × 109/L (hospital admission)422919070.009-0.09−0.100.0%0.855
      Fibrinogen, g/L (closest to the CTPA)4136268-0.10-0.77−0.5622.1%0.759
      Fibrinogen, g/L (hospital admission)317712700.27-0.07−0.600.0%0.122
      Abbreviations: PE, pulmonary embolism; COVID-19, coronavirus disease 2019; WMD, weighted mean difference; OR, odds ratio; 95% CI, 95% confidence interval; VTE, venous thrombus embolism; COPD, chronic obstructive pulmonary disease; CT, computed tomography; WBC, white blood cells
      a Nstudies, number of studies
      b PE, n/PE, number of PE patients, number of PE patients with variable/number of PE patients
      c non-PE, n/non-PE, number of non-PE patients, number of non-PE patients with variable/number of non-PE patients; I2, index for the degree of heterogeneity; P value, significant at P < 0.05 and present in bold; Egger's, index for the degree of publication bias; –, not available
      Fig. 2
      Fig. 2Meta-analysis of demographical factors associated with PE occurrence in COVID-19. A, Male; B, Obesity.

       Clinical risk factors

      Five studies (119 PEs vs. 266 non-PEs) reported the relationship between mechanical ventilation (MV). The result indicated that patients with MV had a significantly higher rate of PE (OR 3.34, 95% CI 1.90−5.86, P = 0.000) with low heterogeneity (I2 = 10.8%) (Table 2, Figure 3A). Seven studies (288 PEs vs. 1555 non-PEs) evaluated the extent of parenchymal damage on chest computed tomography (CT) (
      • Bompard F
      • Monnier H
      • Saab I
      • et al.
      Pulmonary embolism in patients with COVID-19 pneumonia.
      ,
      • Grillet F
      • Behr J
      • Calame P
      • Aubry S
      Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography.
      ,
      • Kim KD
      • Zhao J
      • Auh S
      • et al.
      Adaptive immune cells temper initial innate responses.
      ,
      • Kirsch B
      • Aziz M
      • Kumar S
      • et al.
      Wells score to predict pulmonary embolism in patients with coronavirus disease 2019.
      ,
      • Kunutsor SK
      • Laukkanen JA.
      Incidence of venous and arterial thromboembolic complications in COVID-19: A systematic review and meta-analysis.
      ,
      • Ooi MWX
      • Rajai A
      • Patel R
      • et al.
      Pulmonary thromboembolic disease in COVID-19 patients on CT pulmonary angiography−Prevalence, pattern of disease and relationship to D-dimer.
      ,
      • Rodriguez-Sevilla J
      • Rodó-Pin A
      • Espallargas I
      • et al.
      Pulmonary embolism in patients with Covid-19 pneumonia: the utility of d-dimer.
      ). The pooled estimates showed that severe parenchymal damage (> 50% of lung) had a higher PE incidence rate (OR 1.92, 95% CI 1.43−2.58, P = 0.000) with no heterogeneity (I2 = 0%) (Table 2, Figure 3B). The data pooled from seven studies indicated that ICU admission had a higher rate of PE than conventional wards (OR 2.65, 95% CI 1.48−4.74, P = 0.000), with a high heterogeneity (I2 = 66%) (Table 2, Figure 3C) (Fang et al., 2020; Léonard-Lorant et al., 2020; Bompard et al., 2020; Whyte et al., 2020; Grillet et al., 2020; Benito et al., 2020; Scudiero et al., 2021).
      Fig. 3
      Fig. 3Meta-analysis of clinical factors associated with PE occurrence in COVID-19. A, Mechanical Ventilation; B, pulmonary parenchymal damage; C, ICU admission.
      Fig. 4
      Fig. 4Meta-analysis of laboratory factors associated with PE occurrence in COVID-19. A, D-dimer closet to the CTPA examination; B, D-dimer at hospital admission; C, WBC values closet to the CTPA examination; D, WBC values at hospital admission. Abbreviations:CTPA, computer tomography pulmonary angiography; WBC, white blood cell

       Laboratory risk factors

      Laboratory parameters were obtained at two time points: hospital admission and closest to the CTPA examination (within 24−48 hours). The D-dimer (P = 0.000, I2 < 73.8%) and white blood cell (WBC) values (P = 0.000, I2 = 0%) in PE patients were significantly higher than that in non-PE patients at both time points (Table 2, Figure 4 A, B, C, D). Lymphocytes (P > 0.73, I2 < 51.6%) and fibrinogen (P > 0.12, I2 < 22.1%) had no significant influence on the occurrence of PEs, no matter at which time point (Table 2).

       Subgroup analysis

      There was no significant difference between the CTPA and COVID-19 subgroup (P > 0.073). The CTPA subgroup accounted for the majority of the included studies (22 vs. 27 studies, 768 PEs vs. 927 PEs). It had the same results as whole studies in analyses of each parameter (Supplementary Table 1). However, the COVD-19 subgroup differed from the CTPA and whole studies in males (P = 0.072), previous VTE (P = 0.005), severe parenchymal damage (> 50% of the lung) (P = 0.468), ICU admission (P = 0.816), and D-dimer value at hospital admission (P = 0.107) (Supplementary Table 1, Supplementary Figure 1).
      Three subgroups of prophylactic anticoagulation had no difference (P > 0.078). Risk factors of the unclear and low-ratio subgroups were almost consistent with the results of the whole included studies, including male, MV, D-dimer (two time points), WBC (two time points), severe parenchymal damage (> 50% of the lung) (P< 0.035), and ICU admission (P < 0.035) (Supplementary Table 1). However, in the high-ratio subgroup, D-dimer (hospital admission), WBC (hospital admission), severe parenchymal damage, and ICU admission were non-risk factors (P > 0.055) (Supplementary Table 1).
      The hospitalization subgroup, which contained 18 studies, had consistent PE risk factors with the overall studies. The ICU-stay subgroup had distinctly different results from them in age, obesity, previous VTE, hypertension, MV, severe parenchymal damage, D-dimer, and WBC (two time points) (Supplementary Table 1).

      Discussion

      This review analyzed several demographical, clinical, and laboratory indicators of COVID-19 patients for risk factors of PE. The whole included studies revealed that males, obesity, MV, severe parenchymal abnormalities of chest CT, ICU admission, and elevated D-dimer or WBC value (at both hospital admission and closest to CTPA) were risk factors for PE in COVID-19. Age and common comorbidities had no association with PE occurrence. PE risk factors might be different between the subgroups of these three subgroup analyses. The subgroups (the CTPA, unclear-ratio, hospitalization) that accounted for most of the included studies had consistent PE risk factors with the overall studies. Common comorbidities had no significant influence on the occurrence of PEs in all subgroups.
      This systemic review revealed that risk factors for PE occurrence in COVID-19 were different from the classic risk factors. First, old age is a weak risk factor for classic PE (OR < 2), and male sex is not (
      • Ceriani E
      • Combescure C
      • Gal GL
      • et al.
      Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis.
      ). However, in COVID-19, male sex was a weak risk factor (OR 1.49, P = 0.000) for PE occurrence, and age was not associated with PE (OR 1.57, P = 0.101). Second, the classic PE risk factors from comorbidities, including previous VTE with strong risk (OR > 10), chronic heart failure, cancer history with moderate risk (OR 2−9), diabetes, and hypertension with weak risk (OR < 2) (
      • Ceriani E
      • Combescure C
      • Gal GL
      • et al.
      Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis.
      ) all had no association with PE in COVID-19 patients. A recent meta-analysis of risk factors for VTE in COVID-19 showed similar results to the current ones except in age (
      • Gervaise A
      • Bouzad C
      • Peroux E
      • Helissey C.
      Acute pulmonary embolism in non-hospitalized COVID-19 patients referred to CTPA by emergency department.
      ). Several other studies showed that classic PE and PE in COVID-19 were different in certain characteristics (
      • Chi G
      • Lee JJ
      • Jamil A
      • Gunnam V
      • Najafi H.
      Venous Thromboembolism among hospitalized patients with COVID-19 undergoing thromboprophylaxis: a systematic review and meta-analysis.
      ,
      • Choi JJ
      • Wehmeyer GT
      • Li HA
      • et al.
      D-dimer cut-off points and risk of venous thromboembolism in adult hospitalized patients with COVID-19.
      ,
      • Shi L
      • Jie X
      • Guang CD
      • Hai YY
      • Ya DW.
      The pooled prevalence of pulmonary embolism in patients with COVID-19.
      ). More interestingly, some studies stated that old age, male, and comorbidities were risk factors for severe COVID-19 (
      • Soumagne T
      • Lascarrou JB
      • Hraiech S
      • et al.
      Factors associated with pulmonary embolism among coronavirus disease 2019 acute respiratory distress syndrome: a multicenter study among 375 patients.
      ,
      • Soumagne T
      • Winiszewski H
      • Besch G
      • et al.
      Pulmonary embolism among critically ill patients with ARDS due to COVID-19.
      ) and they partly overlapped with the risk factors for PE or VTE in COVID-19. These indicate that PE or VTE in COVID-19 is affected to a certain extent by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection.
      Mechanical ventilation (OR 3.72, P = 0.000), severe parenchymal damage (OR 1.92, P = 0.000), and ICU admission (OR 2.44, P = 0.000), which represented the severity of COVID-19 pneumonia, were associated with PE occurrence, with low heterogeneity. One imaging study found that pulmonary thrombi in COVID-19 were located in opacitated lung segments and supported this (
      • Sungnak W
      • Huang N
      • Bécavin C
      • et al.
      SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.
      ). It can also be explained by the pathological findings from autopsy: in COVID-19, distinct thrombosis and microangiopathy are common in the small vessels and pulmonary capillaries, along with classic diffuse alveolar damage (
      • Contou D
      • Pajot O
      • Cally R
      • et al.
      Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study.
      ,
      • Egger M
      • Davey Smith G
      • Schneider M
      • Minder C
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
      ,
      • Fang C
      • Garzillo G
      • Batohi B
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      ,
      • Taccone FS
      • Gevenois PA
      • Peluso L
      • et al.
      Higher intensity thromboprophylaxis regimens and pulmonary embolism in critically ill coronavirus disease 2019 patients.
      ,
      • van Dam LF
      • Kroft LJM
      • van der Wal LI
      • et al.
      Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: A different phenotype of thrombotic disease?.
      ). These findings are consistent with the plausible pathophysiological changes of lung lesions in COVID-19: widespread pulmonary endothelial dysfunction associated with direct viral tissue damage (ACE2 as the entry receptor for SARS-CoV-2) or immune-mediated inflammation leads to inflammatory thrombosis and microvascular dysfunction (
      • Artifoni M
      • Danic G
      • Gautier G
      • et al.
      Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors.
      ,
      • Varga Z
      • Flammer AJ
      • Steiger P
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ). Therefore, even if the pulmonary infection is also a moderate risk factor for classic PE (
      • Ceriani E
      • Combescure C
      • Gal GL
      • et al.
      Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis.
      ), the new hypothesis − the etiology of PE in COVID-19 may be local microthrombosis −cannot be ruled out (
      • Contou D
      • Pajot O
      • Cally R
      • et al.
      Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study.
      ,
      • Egger M
      • Davey Smith G
      • Schneider M
      • Minder C
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
      ,
      • Fang C
      • Garzillo G
      • Batohi B
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      ).
      Elevated D-dimer and WBC levels were risk factors for PE occurrence in COVID-19 patients (at both hospital admission and closet to CTPA) (P = 0.000). The reason may be that they are closely related to excessive inflammation and severe COVID-19 (
      • Soumagne T
      • Winiszewski H
      • Besch G
      • et al.
      Pulmonary embolism among critically ill patients with ARDS due to COVID-19.
      ). D-dimer has widely been deemed a marker of COVID-19-associated coagulopathy (
      • Artifoni M
      • Danic G
      • Gautier G
      • et al.
      Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors.
      ,
      • Ventura-Diaz S
      • Quintana-Perez JV
      • Gil-Boronat A
      • et al.
      A higher D-dimer threshold for predicting pulmonary embolism in patients with COVID-19: a retrospective study.
      ). Several studies have also proposed that D-dimer level is a good predictor for embolic events in patients with COVID-19. However, more studies are needed to assess the cut-off value, as it is inconsistent among studies (
      • Watchmaker JM
      • Goldman DT
      • Lee JY.
      Increased incidence of acute pulmonary embolism in emergency department patients during the COVID-19 pandemic.
      ,
      • Whyte MB
      • Kelly PA
      • Gonzalez E
      • Arya R
      • Roberts LN.
      Pulmonary embolism in hospitalised patients with COVID-19.
      ,

      Worldometer COVID-19 Data, Available at https://www.worldometers.info/coronavirus/, [Accessed September 30, 2020].

      ). Other studies have reported more laboratory indicators related to severe COVID-19 and VTE (
      • Gervaise A
      • Bouzad C
      • Peroux E
      • Helissey C.
      Acute pulmonary embolism in non-hospitalized COVID-19 patients referred to CTPA by emergency department.
      ,
      • Soumagne T
      • Winiszewski H
      • Besch G
      • et al.
      Pulmonary embolism among critically ill patients with ARDS due to COVID-19.
      ) than the current review, liking activated partial thromboplastin time, platelets, fibrinogen, C-reactive protein, lower lymphocyte, and so on. The reason may be that the current review separated the collection time of laboratory indicators at hospital admission or closest to the CTPA examination, which was more accurate and less heterogeneous; the small sample size may be another reason. More original articles about the clinical and laboratory characteristics of PE in detail are needed to detect the risk factors.
      Although the heterogeneity of most parameters of this systematic review was low, it also performed subgroup analyses according to clinical application. Apparently, both the CTPA vs. COVID-19 and the hospitalization vs. ICU-stay subgroup analyses had distinctly different study populations. The management of thrombus in COVID-19 has always been a hot topic. Studies recommend that the use of preventive anticoagulants above conventional doses may reduce thrombotic events for patients with severe COVID-19 or those at high risk of thrombosis (
      • Wu T
      • Zuo Z
      • Yang D
      • et al.
      Venous thromboembolic events in patients with COVID-19: A systematic review and meta-analysis.
      ,
      • Zeng X
      • Zhang Y
      • Kwong JS
      • et al.
      The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review.
      ). However, whether prophylactic anticoagulation should apply to all patients with COVID-19 remains controversial (
      • Zheng Z
      • Peng F
      • Xu B
      • et al.
      Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis.
      ,
      • Zotzmann V
      • Lang CN
      • Wengenmayer T
      • et al.
      Combining lung ultrasound and Wells score for diagnosing pulmonary embolism in critically ill COVID-19 patients.
      ). Therefore, this review attempted to conduct an unclear-ratio vs. low-ratio vs. high-ratio subgroup analysis on this issue. The CTPA, unclear-ratio, or hospitalization subgroup was the group with the largest sample size in the three subgroup analyses and they had consistent results with the overall studies in low heterogeneities. This emphasized that the currently reported PE risk factors were calculated based on the population of the CTPA, unclear-ratio, or hospitalization patients. In the remaining subgroups, they had different PE risk factors, with low heterogeneities in most parameters. They had fewer risk factors than the CTPA, unclear-ratio, and hospitalization subgroups. While, given the vast gap in sample size between the subgroups, these differences in PE risk factors between subgroups require more evidence. Most interestingly, the three subgroup analyses only had consistent results in common comorbidities, and these traditional PE risk factors had no significant influence on the occurrence of PEs. This indicated that PE risk factors were different between COVID-19 and non-COVID-19. Moreover, PE risk factors in COVID-19 were more likely to be associated with the severity of illness, for example, MV, severe parenchymal abnormalities, ICU admission, and elevated D-dimer and WBC values.
      This review had several limitations. First, due to the limitations of the original studies, several ORs had a small sample size. Also, the number of studies on COVID-19 or low-ratio subgroup was small. Fortunately, the heterogeneities of most results were acceptable. Second, 24 out of 27 included studies were from Europe, and whether the risk factors differ between regions is unclear. Third, risk factors may vary due to different subgroup analyses, and this subgroup analysis was incomplete. Subgroup analysis based on race, country, anticoagulant dose, or severity of illness can provide more comprehensive information about risk factors for PE in COVID-19. Finally, most of the included studies were retrospective case-controls. More accurate relative risks calculated from prospective cohorts are hard to obtain. Therefore, more multicenter, better-designed original studies are needed to ascertain the risk factors for PE in COVID-19 patients.

      Conclusion

      In conclusion, this review presented different risk factors for PE in COVID-19 from the classic risk factors in non-COVID-19. PE risk factors in COVID-19 were more likely to be associated with the severity of illness. Three subgroup analyses revealed that the currently reported risk factors for PE are mostly based on the population of COVID-19 patients with CTPA, unclear-ratio/low-ratio thromboprophylaxis, or hospitalization; these might be different in other study populations.

      Funding support

      This study received salary support from "National Key Research and Development Project"(2020YFC2005700) and “High-level Hospital Construction Research Project of Maoming People’s Hospital” during the conduct of the study.

      Conflicts of interest

      All authors declare that there are no competing interests in the research, authorship, and publication of this article.

      Ethical Approval

      Not applicable.

      Authors' contributions

      LYC and WWC were responsible for study design, screening, data extraction, data analysis, and writing the article. And they contributed equally. ZWM, DX, and YYL helped extract and dispose of data. JYL and TWL participated in the data analysis and revision of the article. ZMC designed and revised the article.

      Acknowledgements

      We are grateful to Jie-ming Shi, who gave us some suggestions in statistical methods.

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