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. 2022 Mar 14;17(3):e0263580. doi: 10.1371/journal.pone.0263580

Incidence and prognostic value of pulmonary embolism in COVID-19: A systematic review and meta-analysis

Xiaowei Gong 1, Boyun Yuan 1, Yadong Yuan 1,*
Editor: Chiara Lazzeri2
PMCID: PMC8920268  PMID: 35286316

Abstract

Background

Pulmonary embolisms are frequently and prognostically in individuals infected by coronavirus disease 2019 (COVID-19); the incidence of pulmonary embolisms is varied across numerous studies. This study aimed to assess the pooled incidence of pulmonary embolic events and the prognostic value of such events in intensive care unit (ICU) admissions of patients with COVID-19.

Methods

The Cochrane Library, PubMed, and EmBase were systematically searched for eligible studies published on or before October 20, 2021. The pooled incidence of pulmonary embolism was calculated using the random-effects model. Moreover, the prognostic value was assessed by measuring the sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curve (AUC).

Results

Thirty-six studies involving 10,367 COVID-19 patients were selected for the final meta-analysis. The cumulative incidence of pulmonary embolism in patients with COVID-19 was 21% (95% confidence interval [95%CI]: 18−24%; P<0.001), and the incidence of pulmonary embolism in ICU and non-ICU patients was 26% (95%CI: 22−31%; P<0.001) and 17% (95%CI: 14−20%; P<0.001), respectively. The predictive role of pulmonary embolism in ICU admission was also assessed, and the sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.31 (95%CI: 0.21−0.42), 0.84 (95%CI: 0.75−0.90), 1.88 (95%CI: 1.45−2.45), 0.83 (95%CI: 0.75−0.91), 2.25 (95%CI: 1.64−3.08), and 0.61 (95%CI: 0.57−0.65), respectively.

Conclusion

This study found that the incidence of pulmonary embolism was relatively high in COVID-19 patients, and the incidence of pulmonary embolism in ICU patients was higher than that in non-ICU patients.

Introduction

The severe acute respiratory syndrome caused by the novel coronavirus (SARS-CoV-2) was first reported as a cluster of cases in December 2019 [1]. The disease grew into the scale of a global pandemic rapidly, with 93,194,922 confirmed cases, and more than 2 million deaths have been reported as of January 2021 [2]. The clinical presentation of the coronavirus disease 2019 (COVID-19) varies, creating challenges in determining the optimal management of patients infected with COVID-19. The primary cause of fatality in patients with COVID-19 was atypical acute respiratory distress syndrome (ARDS) due to the dissociation between well-conserved lung compliance and severe hypoxemia caused by pulmonary vasoregulation disruption and local thrombogenesis [3, 4]. Moreover, coagulopathy was reported in COVID-19 patients presenting with high levels of D-dimer, which causes inflammation (cytokine storm) and coagulation activation, and is associated with an increased risk of mortality [5–7]. However, the incidence of pulmonary embolism in patients in the intensive care unit (ICU) versus the general ward remains uncertain.

Several systematic reviews and meta-analyses have addressed the incidence of pulmonary embolism in patients with COVID-19 [8–12]. Suh et al. identified studies published before June 15, 2020, and found that the pooled incidence of pulmonary embolism was 16.5% and was significantly higher in ICU patients than in the non-ICU patients (24.7% versus 10.5%) [8]. Malas et al. found that the pooled incidence of pulmonary embolism was 13% in non-ICU and 19% in ICU patients [9]. Liao et al. reviewed 19 studies and found the pooled incidence of pulmonary embolism in COVID-19 patients was 15.3% [10]. Roncon et al. identified 23 studies and found that the pooled in-hospital incidence of pulmonary embolism was 23.4% in COVID-19 patients in the ICU and 14.7% in those in the general wards [11]. Lu et al. found that the pooled incidence of pulmonary embolism was 15% but did not find any significant effect on mortality rate when using anticoagulation therapy in hospitalized COVID-19 patients [12]. However, the pooled incidence for pulmonary embolism varied due to the varying severity of the included COVID-19 cases. Moreover, the most recent data were not included, and the results need to be updated. Therefore, this study was conducted to update the pooled incidence of pulmonary embolism in ICU and non-ICU patients infected with COVID-19. Furthermore, the predictive value of pulmonary embolism for ICU admission was also assessed.

Methods

Data sources, search strategy, and selection criteria

This systematic review and meta-analysis were performed and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement (PRISMA Checklist) [13]. The eligible studies reported the incidence of pulmonary embolism in patients infected by COVID-19 and included whether the patients were admitted to the ICU. PubMed, EmBase, and the Cochrane Library were systematically searched for eligible studies published on or before October 20, 2021, and the following search terms were applied: ((("COVID-19"[Supplementary Concept] OR "Coronavirus"[MeSH Terms]) OR "severe acute respiratory syndrome coronavirus 2"[Supplementary Concept]) OR ((((("Coronavirus"[MeSH Terms] OR "Coronavirus"[All Fields]) OR "coronaviruses" [All Fields]) OR ((((((("COVID-19"[All Fields] OR "covid 2019"[All Fields]) OR "severe acute respiratory syndrome coronavirus 2"[Supplementary Concept]) OR "severe acute respiratory syndrome coronavirus 2"[All Fields]) OR "2019 ncov"[All Fields]) OR "sars cov 2"[All Fields]) OR "2019ncov"[All Fields]) OR (("wuhan"[All Fields] AND ("Coronavirus"[MeSH Terms] OR "Coronavirus"[All Fields])))))) OR (("severe acute respiratory syndrome coronavirus 2"[Supplementary Concept] OR "severe acute respiratory syndrome coronavirus 2"[All Fields]) OR "2019 ncov"[All Fields])) OR (("severe acute respiratory syndrome coronavirus 2"[Supplementary Concept] OR "severe acute respiratory syndrome coronavirus 2"[All Fields]) OR "sars cov 2"[All Fields]))) AND (("embol*"[All Fields] OR "thromb*"[All Fields]) OR ("Embolism"[MeSH Terms] OR "Thrombosis"[MeSH Terms])). The reference lists of the relevant review and original articles were also reviewed manually to identify any new eligible study that met the inclusion criteria.

The literature search and study selection were independently performed by two reviewers, and conflicts between the reviewers were resolved by mutual discussion. The inclusion criteria were as follows: (1) study design: no restrictions placed on study design, including prospective cohort, retrospective cohort, and case series; (2) participants: patients with COVID-19; and (3) exposure and outcomes: pulmonary embolism incidence after admission in ICU or non-ICU patients. Case reports and matched case-control studies were excluded since the incidence of pulmonary embolism was potentially biased.

Data collection and quality assessment

The data items were independently extracted by two authors and included the names of the first authors of the article, publication year, study design, country, sample size, mean age, male proportion, setting, body mass index (BMI) of the patients, diabetes mellitus status (DM), hypertension status, cardiovascular disease status, and the number of pulmonary embolisms. Subsequently, the two authors independently assessed the quality of each individual study using the Newcastle-Ottawa Scale (NOS), which is based on selection (4 items), comparability (1 item), and outcome (3 items) [14]. Any disagreement between the authors regarding data abstracted and/or quality assessment was settled by mutual discussion until a consensus was reached.

Statistical analysis

The incidence of pulmonary embolism was based on the occurrence of the event and the total sample size in the cohort. Pooled incidence with 95% confidence intervals (CIs) was calculated using the random-effects model, which considered the underlying variability among the included studies [15, 16]. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) for the role of pulmonary embolism in subsequent ICU admission were calculated, based on the number of ICU admissions in the patient group with a pulmonary embolism and the group without a pulmonary embolism. The pooled analysis was based on the bivariate generalized linear mixed model and random-effects model [15–17]. The heterogeneity across the included studies was assessed using I2 and Q statistics, and significant heterogeneity was defined as I2>50.0% or P<0.10 [18, 19]. Subgroup analyses were performed for the pooled incidence of pulmonary embolism based on ICU admission or non-admission. Moreover, subgroup analyses were also conducted for the DOR based on the study design, mean age, male proportion, and study quality. Publication biases were assessed by using the funnel plot and Egger and Begg tests [20, 21]. All reported inspection levels were two-sided, and P<0.05 was regarded as statistically significant. All statistical analyses in this study were performed using STATA (version 10.0; Stata Corporation, College Station, TX, USA) and Meta-DiSc (version 1.4; Universidad Complutense, Spain) software.

Results

Literature search

The initial electronic search yielded 8,346 articles, with 5,642 remaining after the duplicate articles were removed. Subsequently, 5,483 articles were excluded because of irrelevant topics. The remaining 159 studies were retrieved for further full-text evaluations, and 123 studies were excluded as they did not report pulmonary embolism (n = 47), had a case-control or case report structure (n = 42), and had no ICU admission information included (n = 34). The cited references included in the articles were reviewed; however, no additional eligible studies were found. Thus, the remaining 36 studies were selected for the final meta-analysis (Fig 1) [22–57].

Fig 1. The flow diagram for the literature search and study selection.

Fig 1

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Study characteristics

The baseline characteristics of the identified and selected studies are shown in Table 1. Of the 36 included studies, six used a prospective design, while the remaining 30 were retrospective studies or case series. All studies were conducted in Europe, and the sample size ranged from 23 to 2,233, with a total of 10,367 patients with COVID-19. Thirty studies reported the incidence of pulmonary embolism in patients with COVID-19 admitted to the ICU, and 25 studies reported the incidence of pulmonary embolism in COVID-19 patients admitted to the general ward. Nine studies were categorized as having a relatively high quality with an NOS of seven stars, while 12 studies were rated as six stars, 11 as five stars, and four as four stars.

Table 1. The baseline characteristics of included studies and participants.

Study Study design Country Sample size Mean age (years) Male (%) Setting BMI (kg/m2) DM (%) Hypertension (%) CVD (%) Number of PE NOS score
Leonard-Lorant 2020 [22] Retrospective France 106 63.3 66.0 ICU (48)/non-ICU (58) 28.4 NA NA NA 32 6
Grillet 2020 [23] Retrospective France 100 66.0 70.0 ICU (39)/non-ICU (61) NA 20.0 NA 39.0 23 6
Helms 2020 [24] Prospective France 150 63.0 81.3 ICU (150) NA 20.0 NA 48.0 25 7
Hékimian 2020 [25] Retrospective France 51 NA NA ICU (8) NA NA NA NA 8 5
Fraissé 2020 [26] Retrospective France 92 61.0 79.0 ICU (92) 30.0 38.0 64.0 10.0 19 5
Van Dam 2020 [27] Retrospective Netherlands 23 63.0 70.0 Non-ICU (23) NA NA NA NA 4 4
Gervaise 2020 [28] Retrospective France 72 62.0 75.0 Non-ICU (72) 26.7 NA NA NA 13 6
Soumagne 2020 [29] Retrospective France 375 63.5 76.8 ICU (375) 29.8 26.4 57.6 9.6 55 7
Longchamp 2020 [30] Retrospective Switzerland 25 68.0 64.0 ICU (25) 27.5 4.0 40.0 12.0 5 5
Klok 2020 [31] Retrospective Netherlands 184 64.0 76.0 ICU (184) NA NA NA NA 65 5
Llitjos 2020 [32] Retrospective France 26 68.0 76.9 ICU (26) NA NA 85.0 NA 6 4
Bompard 2020 [33] Retrospective France 135 64.0 70.0 ICU (24)/non-ICU (111) NA NA NA NA 32 6
Artifoni 2020 [34] Retrospective France 71 64.0 60.6 Non-ICU (71) 27.3 20.0 41.0 NA 7 5
Thomas 2020 [35] Retrospective UK 63 NA 69.0 ICU (63) NA NA NA NA 5 5
Lodigiani 2020 [36] Retrospective Italy 388 66.0 68.0 ICU (61)/non-ICU (327) NA 22.7 47.2 13.9 10 6
Whyte 2020 [37] Retrospective UK 214 61.5 60.2 ICU (78)/non-ICU (136) NA NA NA NA 80 7
Fauvel 2020 [38] Retrospective France 1,240 64.0 58.1 ICU (185)/non-ICU (1,055) 28.1 21.7 45.4 10.7 103 7
Poissy 2020 [39] Retrospective France 107 NA NA ICU (107) NA NA NA NA 22 6
Marone 2020 [40] Retrospective Italy 41 65.0 70.7 ICU (15)/non-ICU (26) NA NA NA NA 24 4
Stoneham 2020 [41] Retrospective UK 274 NA NA Non-ICU (274) NA NA NA NA 16 5
Mestre-Gómez 2020 [42] Retrospective Spain 91 64.7 68.1 Non-ICU (91) 29.5 17.6 51.6 NA 29 4
Middeldorp 2020 [43] Retrospective Netherlands 198 61.0 66.0 ICU (75)/non-ICU (123) 27.0 NA NA NA 13 7
Galeano-Valle 2020 [44] Prospective Spain 785 NA NA Non-ICU (785) NA NA NA NA 15 5
Benito 2020 [45] Prospective Spain 76 62.5 67.1 ICU (25)/non-ICU (51) 27.3 15.8 44.7 NA 32 6
Alonso-Fernandez 2020 [46] Prospective Spain 30 64.5 63.3 ICU (11)/non-ICU (19) 28.2 NA NA 40.0 15 7
Contou 2020 [47] Retrospective France 92 61.0 79.0 ICU (92) NA 38.0 64.0 10.0 16 6
Freund 2020 [48] Retrospective France 974 61.0 48.0 Non-ICU (974) NA NA NA NA 146 5
Scudiero 2020 [49] Retrospective Italy 224 69.0 62.0 ICU (73)/non-ICU (151) NA 28.0 61.0 16.0 32 7
Brüggemann 2020 [50] Retrospective Netherlands 60 68.0 70.0 ICU (13)/non-ICU (47) NA NA NA NA 24 5
Cerda 2020 [51] Retrospective Spain 92 68.0 73.9 ICU (26)/non-ICU (66) 29.2 29.3 56.5 12.0 29 6
Schmidt 2021 [52] Prospective France 2,233 63.0 74.0 ICU (2,233) 28.0 NA NA NA 207 6
García-Ortega 2021 [53] Prospective Spain 73 65.4 71.0 ICU (25)/non-ICU (48) 29.3 18.0 50.0 10.0 26 7
Valle 2021 [54] Retrospective Italy 114 61.0 73.7 ICU (28)/non-ICU (86) NA 14.9 35.9 44.7 65 6
Nordberg 2021 [55] Retrospective Sweden 1,162 64.0 78.0 ICU (252)/non-ICU (910) 27.0 NA NA NA 41 6
Badr 2021 [56] Retrospective Saudi Arabia 159 52.8 69.8 ICU (119)/non-ICU (40) 27.8 42.1 37.1 17.0 51 7
Filippi 2021 [57] Retrospective Italy 267 69.9 64.4 ICU (55)/non-ICU (212) NA NA NA NA 50 5
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Pooled incidence

After pooling all the included studies, we noted that the pooled incidence of pulmonary embolism in patients with COVID-19 was 21% (95%CI: 18−24%; P<0.001; Fig 2), and significant heterogeneity was observed among the included studies (I2 = 95.0%; P<0.001). Subgroup analyses revealed that the incidence of pulmonary embolism in patients with COVID-19 admitted to the ICU was 26% (95%CI: 22−31%; P<0.001), while that in patients with COVID-19 admitted to the general ward was 17% (95%CI: 14−20%; P<0.001).

Fig 2. The pooled incidence of pulmonary embolism in COVID-19 patients.

Fig 2

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Predictive value of pulmonary embolism

Seventeen studies reported the predictive value of pulmonary embolism for ICU admission. The pooled sensitivity and specificity were 0.31 (95%CI: 0.21−0.42) and 0.84 (95%CI: 0.75−0.90), respectively (Fig 3). There was significant heterogeneity in sensitivity (I2 = 92.9%; P<0.01) and specificity (I2 = 96.4%; P<0.01). Moreover, the pooled PLR and NLR were 1.88 (95%CI: 1.45−2.45) and 0.83 (95%CI: 0.75−0.91), respectively (Fig 4). We noted potential significant heterogeneity in the PLR (I2 = 36.8%; P<0.01) and NLR (I2 = 62.4%; P<0.01). Furthermore, the DOR for the predictive value of pulmonary embolism for ICU admission was 2.25 (95%CI: 1.64−3.08; P<0.001; Fig 5), and there was significant heterogeneity in the DOR (I2 = 51.7%; P = 0.007). Lastly, the AUC for the role of pulmonary embolism in ICU admission was 0.61 (95%CI: 0.57−0.65; Fig 6).

Fig 3. Pooled sensitivity and specificity for pulmonary embolism on subsequent ICU admission.

Fig 3

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Fig 4. Pooled PLR and NLR for pulmonary embolism on subsequent ICU admission.

Fig 4

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Fig 5. Pooled DOR for pulmonary embolism on subsequent ICU admission.

Fig 5

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Fig 6. AUC for the role of pulmonary embolism in intensive care unit (ICU) admission.

Fig 6

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Subgroup analysis for DOR

The results of subgroup analyses performed for the DOR are shown in Table 2. Although the DOR of pulmonary embolism for ICU admission was statistically significant in most subgroups, this predictive value was not statistically significant when prospective studies were pooled. Moreover, we noted that the DOR of pulmonary embolism for ICU admission could be affected by the study design (P = 0.046) and male proportion (P = 0.030).

Table 2. Subgroup analyses for the predictive value of pulmonary embolism for ICU admission.

Factors Subgroup DOR and 95%CI P value I2 (%) P value for I2 P value between subgroups
Study design Prospective 1.15 (0.58–2.29) 0.688 0.0 0.543 0.046
Retrospective 2.51 (1.79–3.51) < 0.001 53.4 0.009
Mean age (years) ≥ 65.0 1.88 (1.14–3.11) 0.013 40.4 0.122 0.141
< 65.0 2.50 (1.66–3.74) < 0.001 56.9 0.013
Male (%) ≥ 70.0 3.09 (2.17–4.39) < 0.001 0.0 0.523 0.030
< 70.0 1.81 (1.16–2.82) 0.009 61.2 0.006
Study quality High 1.80 (1.14–2.84) 0.012 54.8 0.039 0.118
Low 2.71 (1.75–4.19) < 0.001 48.3 0.043
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Publication bias

The publication biases for the incidence of pulmonary embolism and the predictive value of pulmonary embolism for ICU admission are listed in Fig 7. We noted significant publication bias for the incidence of pulmonary embolism (P-value for Egger: <0.001; P-value for Begg: <0.001); after adjusting for potential publication bias, the pooled incidence changed to 8% (95%CI: 6%-11%; P<0.001). Moreover, there was no significant publication bias for the predictive value of pulmonary embolism for ICU admission (P = 0.61).

Fig 7.

Fig 7

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Funnel plot for the incidence of pulmonary embolism (A) and the predictive value of pulmonary embolism for ICU admission (B).

Discussion

The incidence of pulmonary embolism in patients with COVID-19 varies, and whether pulmonary embolism could predict ICU admission remains inconclusive. A total of 36 studies involving 10,367 COVID-19 patients was selected in this quantitative analysis, and the characteristics of these studies and patients were broad. This study found that the pooled incidence of pulmonary embolism was 21% (95%CI: 18−24%), and the incidence of pulmonary embolism in ICU patients was higher than that in non-ICU patients with COVID-19. Moreover, we noted a mild predictive value of pulmonary embolism for subsequent ICU admission in patients infected by COVID-19. Lastly, the predictive value of pulmonary embolism for subsequent ICU admission could be affected by the study design and male proportion.

Several systematic reviews and meta-analyses have already illustrated the pooled incidence of pulmonary embolism in COVID-19 patients. However, these previous reviews combined the pooled incidence of pulmonary embolism according to ICU status, while the predictive role of pulmonary embolism for ICU admission was not illustrated [8–12]. Moreover, while the initial phases of COVID-19 yielded numerous new studies, recent meta-analyses and the pooled incidence of pulmonary embolism in this patient group should be updated. Therefore, this systematic review and meta-analysis were performed to update the pooled incidence of pulmonary embolism in patients with COVID-19 patients and assess the predictive role of pulmonary embolism for ICU admission in patients with COVID-19.

This study found that the pooled incidence of pulmonary embolism for COVID-19 patients was 21%, and the incidence in each study ranged from 2−79%. Sensitivity analysis found that the pooled incidence of pulmonary embolism in COVID-19 patients ranged from 20.0−21.9%. The variability of the pooled incidence of pulmonary embolism in individual studies could be explained by the differences in the disease severity and frequency of diagnostic imaging. Several mechanisms could explain the elevated incidence of pulmonary embolism in patients with COVID-19, including that these patients present with abnormally elevated levels of proinflammatory cytokines [5]. The elevated systemic inflammation could be related to endothelial injury by attachment of the virus to the angiotensin-2 receptor of the endothelial cells and viral replication, which could cause prothrombotic endothelial dysfunction [58, 59]. Moreover, the use of central venous catheters, mechanical ventilation, platelet activation, immobilization, and the other characteristics of COVID-19 therapies could play an important role in the prothrombotic state. In addition, these factors could explain the significant heterogeneity in the pooled incidence of pulmonary embolism in patients infected with COVID-19.

This study found that the pooled incidence of pulmonary embolism in patients with COVID-19 in the ICU was higher than that in non-ICU patients. Moreover, we noted that the predictive value of pulmonary embolism for ICU admission was statistically significant, although the predictive value of pulmonary embolism for ICU admission was mild. The higher incidence of pulmonary embolism in ICU patients could be explained by the severe procoagulant state in patients with COVID-19 presenting in a critical condition [60, 61]. However, we noted significant heterogeneity among the included studies in the relationship between pulmonary embolism and ICU admission, which could be explained by the variability in disease status, inflammatory status, and the diagnostic imaging modality used.

The limitations of this study should be acknowledged. This study was both a prospective and retrospective study. Thus, the results may have been affected by the uncontrolled biases from each study design. The diagnostic modality and frequency also differed amongst the studies, which could have affected the number of pulmonary embolisms diagnosed. In addition, the significant heterogeneity was not further analyzed because the number of studies reporting the predictive value of pulmonary embolism for ICU admission was small. Moreover, publication bias was inevitable because of the nature of the review and meta-analysis, which was based on the currently published articles. This study was not registered in PROSPERO, and the transparency of this study could be affected; the analysis used pooled data, and the stratified analyses according to the characteristics of the patients were restricted.

Conclusion

This study found that the pooled incidence of pulmonary embolism was 21% (95%CI: 18−24%). Moreover, the incidence of pulmonary embolism in the ICU patients with COVID-19 was higher than that in the non-ICU patients with COVID-19. Moreover, the predictive value of pulmonary embolism for ICU admission was mild. Further research should be conducted to assess the role of pulmonary embolism in the prognosis of patients with COVID-19.

Supporting information

S1 Checklist. PRISMA checklist.

(DOC)

Click here for additional data file. (62KB, doc)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was supported by Hebei Province Science and Technology Support Program (20277706D) and Scientific Research Fund project of Hebei Provincial Health and Family Planning Commission (20170091). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Chiara Lazzeri

19 Oct 2021

PONE-D-21-15528

Incidence and prognostic value of pulmonary embolism in COVID-19: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Yuan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #2: No

Reviewer #3: Yes

**********

5. Review Comments to the Author

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Reviewer #1: In the present manuscript, Gong and colleagues aimed to assess the pooled incidence of pulmonary embolism (PE) and its prognostic value on ICU admissions of COVID-19 patients. Overall, 31 studies involving more than 8000 patients were included in the metanalysis.

The authors concluded that PE is a common complication in hospitalized COVID-19 patients (cumulative incidence 19%), and its incidence is higher in ICU-patients as compared to patients admitted to general ward.

The topic is of interest since highlights one of most frequent COVID-19 complication, however in the last two years the relationship between COVID-19 and PE was deeply investigated also with large metanalysis.

This reviewer would like that the authors address the following comments:

- The evidence of significant publication bias suggest that the incidence of PE may have influenced the decision whether to publish or not researches on this topic. This finding needs to be interpreted and discussed more extensively in the text.

- The authors should consider reporting how and when PE was assessed among studies, and whether PE has been systematically screened at admission. This information might be included in a separate additional table.

- In a meta-analysis of observational studies, the evidence of high heterogeneity is not just a limitation, but should be interpreted as a result and it needs discussion. The authors may also consider to account for the heterogeneity among studies buy performing multiple meta-regressions for the main patients’ characteristics potentially associated with the risk of PE (i.e. type, dose and timing of anticoagulation therapy, etc).

- Did the authors register this meta-analysis on PROSPERO?

Reviewer #2: Yuan and colleaguesprovided a MA to assess the pooled incidence of PE in COVID-19 patients and their prognostic value on ICU admissions.

They should be thanked for their study, however, this work includes several flaws listed below.

Major comments:

-According to the current pandemic, updated data would be appreciated. However, this study included studies before December 2020, 10 months ago.

-What is the novelty as compared to previous meta-analysis?

-English should be improved.

-Discussion section is poorly understandable.

Minor comments:

-Key word: add pulmonary embolism

-Too many abbreviations in the abstract

-Introduction section, line 47: SARS COV2

-Discussion section, line 208: please reformulate the sentence.

-Figure 2 quality is poor; no legend is available.

Reviewer #3: The authors tried to evaluate the incidence and prognosis of pulmonary embolism in COVID-19 pandemic era using systemic review and meta-analaysis. Although some earlier systemic review and meta-analaysis reports showed similar results, this paper updated this important point and further confirm it. I have no major comments. The English should be revised by a native speaker of English.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PLoS One. 2022 Mar 14;17(3):e0263580. doi: 10.1371/journal.pone.0263580.r002

Author response to Decision Letter 0

22 Dec 2021

PLOS ONE

RE: Manuscript “Incidence and prognostic value of pulmonary embolism in COVID-19: A systematic review and meta-analysis” (PONE-D-21-15528)

Dear editor:

“Incidence and prognostic value of pulmonary embolism in COVID-19: A systematic review and meta-analysis”. We would like to thank PLOS ONE for giving us the opportunity to revise manuscript. We have carefully taken the comments into consideration in preparing our revision, which has resulted in a paper that is clearer and more compelling. The point-by-point responses are attached after this letter. The revisions were highlighted to the text with tracked, have been prepared.

The manuscript has not been published previously, in any language, in whole or in part, and is not currently under consideration elsewhere. None of the authors have any competing financial interest to report.

Thank you for considering our manuscript for publication in your esteemed journal.

Point-By-Point Response

Reviewer #1:

General comments: In the present manuscript, Gong and colleagues aimed to assess the pooled incidence of pulmonary embolism (PE) and its prognostic value on ICU admissions of COVID-19 patients. Overall, 31 studies involving more than 8000 patients were included in the metanalysis.

The authors concluded that PE is a common complication in hospitalized COVID-19 patients (cumulative incidence 19%), and its incidence is higher in ICU-patients as compared to patients admitted to general ward.

The topic is of interest since highlights one of most frequent COVID-19 complication, however in the last two years the relationship between COVID-19 and PE was deeply investigated also with large metanalysis.

This reviewer would like that the authors address the following comments:

Response: As behalf of all co-authors, I would like to appreciate this referee due to thoughtful comments proposed by the peer review. After we revised the manuscript, those significant issues could be changed.

Question 1: The evidence of significant publication bias suggest that the incidence of PE may have influenced the decision whether to publish or not researches on this topic. This finding needs to be interpreted and discussed more extensively in the text.

Response: Thanks for this suggestion, and the following sentence have already added in the revised manuscript: “We noted significant publication bias for the incidence of pulmonary embolism (P value for Egger: < 0.001; P value for Begg: < 0.001), after adjusted potential publication bias, the pooled incidence changed into 8% (95%CI: 6%-11%; P<0.001).”

Question 2: The authors should consider reporting how and when PE was assessed among studies, and whether PE has been systematically screened at admission. This information might be included in a separate additional table.

Response: Thanks for this suggestion. We known the importance of how and when PE was assessed among studies, and all of studies assessed PE after admission. We have already addressed this comment in Methods section.

Question 3: In a meta-analysis of observational studies, the evidence of high heterogeneity is not just a limitation, but should be interpreted as a result and it needs discussion. The authors may also consider to account for the heterogeneity among studies buy performing multiple meta-regressions for the main patients’ characteristics potentially associated with the risk of PE (i.e. type, dose and timing of anticoagulation therapy, etc).

Response: Thanks for this suggestion, and subgroup analysis for DOR were performed to address the potential heterogeneity among included studies. Moreover, the following sentence have already added in Discussion section: “However, we noted significant heterogeneity among included studies for the relationship between pulmonary embolism and ICU admission. This significant heterogeneity could be explained by variability in disease status, inflammatory status, and the diagnostic imaging modality used.”

Question 4: Did the authors register this meta-analysis on PROSPERO?

Response: Thanks for this suggestion, and this study was registered in PROSPERO, which have already addressed in Limitation section.

Reviewer #2:

General comments: Yuan and colleagues provided a MA to assess the pooled incidence of PE in COVID-19 patients and their prognostic value on ICU admissions.

They should be thanked for their study, however, this work includes several flaws listed below.

Response: As behalf of all co-authors, I would like to appreciate this referee due to thoughtful comments proposed by the peer review. After we revised the manuscript, those significant issues could be changed.

Major comments:

Question 1: According to the current pandemic, updated data would be appreciated. However, this study included studies before December 2020, 10 months ago.

Response: Thanks for this suggestion, and the searched data have already updated at October 20, 2021.

Question 2: What is the novelty as compared to previous meta-analysis?

Response: Thanks for this suggestion, and the following sentences have already added in the revised manuscript: “these previous reviews combined the pooled incidence of pulmonary embolism according to ICU status, while the predictive role of pulmonary embolism on ICU admission was not illustrated. Moreover, while the initial phases of COVID-19 yielded numerous new studies, recent meta-analyses and the pooled incidence of pulmonary embolism in this patient group should be updated. Therefore, the current systematic review and meta-analysis was performed to update the pooled incidence of pulmonary embolism in patients with COVID-19 patients, and assess the predictive role of pulmonary embolism on ICU admission in patients with COVID-19. ”

Question 3: English should be improved.

Response: Thanks for this suggestion, and the English revision have already performed by Editage company.

Question 4: Discussion section is poorly understandable.

Response: Thanks for this suggestion, and Discussion section have already changed in the revised manuscript.

Minor comments:

Question 1: Key word: add pulmonary embolism

Response: Thanks for this suggestion, and pulmonary embolism have already added in keywords section.

Question 2: Too many abbreviations in the abstract

Response: Thanks for this suggestion, and the details of abbreviations in the abstract have already changed in the revised manuscript.

Question 3: Introduction section, line 47: SARS COV2

Response: Thanks for this suggestion, and this change have already performed in the revised manuscript.

Question 4: Discussion section, line 208: please reformulate the sentence.

Response: Thanks for this suggestion, and this sentence have already changed into: “Therefore, the current systematic review and meta-analysis was performed to update the pooled incidence of pulmonary embolism in patients with COVID-19 patients, and assess the predictive role of pulmonary embolism on ICU admission in patients with COVID-19. ”

Question 5: Figure 2 quality is poor; no legend is available.

Response: Thanks for this suggestion, and the quality of Figure 2 have already changed.

Reviewer #3:

General comments: The authors tried to evaluate the incidence and prognosis of pulmonary embolism in COVID-19 pandemic era using systemic review and meta-analaysis. Although some earlier systemic review and meta-analaysis reports showed similar results, this paper updated this important point and further confirm it. I have no major comments. The English should be revised by a native speaker of English.

Response: We appreciate the reviewer given this kindly comment, and the English revision have already performed by Editage company.

Attachment

Submitted filename: Response to reviewer.docx

Click here for additional data file. (16.3KB, docx)

Decision Letter 1

Chiara Lazzeri

24 Jan 2022

Incidence and prognostic value of pulmonary embolism in COVID-19: A systematic review and meta-analysis

PONE-D-21-15528R1

Dear Dr. Yuan,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Chiara Lazzeri

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Chiara Lazzeri

4 Mar 2022

PONE-D-21-15528R1

Incidence and prognostic value of pulmonary embolism in COVID-19: A systematic review and meta-analysis

Dear Dr. Yuan:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Chiara Lazzeri

Academic Editor

PLOS ONE

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