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Predictive scores for the diagnosis of Pulmonary Embolism in COVID-19: A systematic review

  • Lorenzo Vittorio Rindi
    Affiliations
    Department of Systems Medicine, Infectious Disease Clinic, Tor Vergata University, Via Montpellier, 1 – 00133 Rome, Italy
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  • Samir Al Moghazi
    Affiliations
    Clinical and Research Department on Infectious Diseases, National Institute for Infectious Diseases “L. Spallanzani", Via Portuense, 292 - 00147 Rome, Italy
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  • Davide Roberto Donno
    Affiliations
    Clinical and Research Department on Infectious Diseases, National Institute for Infectious Diseases “L. Spallanzani", Via Portuense, 292 - 00147 Rome, Italy
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  • Maria Adriana Cataldo
    Correspondence
    Corresponding author: Dr. Maria Adriana Cataldo. Epidemiology and Pre-clinical Research Department, National Institute for Infectious Diseases "L. Spallanzani", Via Portuense, 292- 00147 Rome, Italy.
    Affiliations
    Epidemiology and Pre-clinical Research Department, National Institute for Infectious Diseases "L. Spallanzani", Via Portuense, 292 - 00147 Rome, Italy
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  • Nicola Petrosillo
    Affiliations
    Clinical and Research Department on Infectious Diseases, National Institute for Infectious Diseases “L. Spallanzani", Via Portuense, 292 - 00147 Rome, Italy
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Open AccessPublished:November 27, 2021DOI:https://doi.org/10.1016/j.ijid.2021.11.038

      Abstract

      Objectives

      During the COVID-19 pandemic, several studies described an increased chance of developing pulmonary embolism (PE). Several scores have been used to predict the occurrence of PE. This systematic review summarizes the literature on predicting rules for PE in hospitalized COVID-19 patients (HCPs).

      Methods

      PUBMED and EMBASE databases were searched to identify articles (1 January 2020-28 April 2021) presenting data pertaining to the use of a prediction rule to assess the risk for PE in adult HCPs. The investigated outcome was the diagnosis of PE. Studies presenting data using a single laboratory assay for PE prediction were excluded. Included studies were appraised for methodological quality using the Newcastle - Ottawa Quality Assessment Scale for Cohort Studies (NOS).

      Results

      We obtained a refined pool of twelve studies for five scoring systems (Wells score, Geneva score, CHADS2/CHA2DS2VASc/M-CHA2DS2VASc, CHOD score, Padua Prediction Score), and 4,526 patients. Only one score was designed explicitly for HCPs. Three and nine included studies were prospective and retrospective cohort studies, respectively. Among the examined scores, the CHOD score seems promising for predictive ability.

      Conclusion

      New prediction rules, specifically developed and validated for estimating the risk of PE in HCP, differentiating ICU from non-ICU patients, and taking into account anticoagulation prophylaxis, comorbidities, and the time from COVID-19 diagnosis are needed.

      Key Words

      Introduction

      One and a half years after the beginning of the coronavirus disease 2019 (COVID-19) pandemic, the high morbidity and mortality across the world is still a concern. To date, more than 255 million confirmed cases have been reported, including more than 5.1 million deaths (

      WHO 2021. - Covid Dashboard (accessed on 11/21/21). https://covid19.who.int/

      ). An extenuating effort in research and clinical efforts led to improvements in diagnostic strategies and therapeutics; however, World Health Organization (WHO) data about the case fatality rate across countries are disturbing (
      • Ioannidis JPA.
      Infection fatality rate of COVID-19 inferred from seroprevalence data.
      ).
      Among factors contributing to a worse prognosis in COVID-19 patients, an important role is the increased chance of developing pulmonary embolism (PE) (
      • Klok FA
      • Kruip MJHA
      • van der Meer NJM
      • Arbous MS
      • Gommers D
      • Kant KM
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.
      ). As already well known, immobility, inflammatory state, and altered coagulation are factors associated with increased chances of developing deep vein thrombosis (DVT) and PE (
      • Elias A
      • Mallett S
      • Daoud-Elias M
      • Poggi J-N
      • Clarke M.
      Prognostic models in acute pulmonary embolism: a systematic review and meta-analysis.
      ). All these factors are common in symptomatic COVID-19 patients, especially during the severe disease state; since the beginning of the pandemic, several studies and case series described the occurrence of PE (
      • Danzi GB
      • Loffi M
      • Galeazzi G
      • Gherbesi E.
      Acute pulmonary embolism and COVID-19 pneumonia: a random association?.
      ;
      • Suh YJ
      • Hong H
      • Ohana M
      • Bompard F
      • Revel M-P
      • Valle C
      • et al.
      Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis.
      ). Indeed, according to the latest meta-analysis by Suh and colleagues, PE and DVT occurred in 16.5% and 14.8% of patients hospitalized for COVID-19, respectively (
      • Liao S-C
      • Shao S-C
      • Chen Y-T
      • Chen Y-C
      • Hung M-J.
      Incidence and mortality of pulmonary embolism in COVID-19: a systematic review and meta-analysis.
      ;
      • Suh YJ
      • Hong H
      • Ohana M
      • Bompard F
      • Revel M-P
      • Valle C
      • et al.
      Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis.
      ). Notably, more than half of the patients with PE lacked DVT (
      • Suh YJ
      • Hong H
      • Ohana M
      • Bompard F
      • Revel M-P
      • Valle C
      • et al.
      Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis.
      ).
      In COVID-19, two distinct pathophysiological mechanisms are believed to independently and simultaneously cause PE: immobility and local immune thrombosis (
      • Van Dam LF
      • Kroft LJM
      • van der Wal LI
      • Cannegieter SC
      • Eikenboom J
      • de Jonge E
      • et al.
      Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: A different phenotype of thrombotic disease?.
      ). The first pathological mechanism is characterized by blood stasis, the leading risk factor for thromboembolic genesis. The second is to be ascribed to pulmonary microvascular endothelial damage, associated with systemic and local proinflammatory factors, in turn leading to a coagulation cascade. Evidence suggests that some patients respond to the infection by an immune overactivation, leading to the so-called “cytokine storm” and to activation of the coagulation system, in turn increasing the risk for Acute Respiratory Distress Syndrome (ARDS), Disseminated Intravascular Coagulation (DIC) and PE (
      • Liu Y
      • Yang Y
      • Zhang C
      • Huang F
      • Wang F
      • Yuan J
      • et al.
      Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.
      ). Of note, COVID-19 related PE most commonly involves the basal lung lobes, precisely in areas of ground-glass opacities (GGO) (
      • Van Dam LF
      • Kroft LJM
      • van der Wal LI
      • Cannegieter SC
      • Eikenboom J
      • de Jonge E
      • et al.
      Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: A different phenotype of thrombotic disease?.
      ;
      • Mueller-Peltzer K
      • Krauss T
      • Benndorf M
      • Lang CN
      • Bamberg F
      • Bode C
      • et al.
      Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS.
      ).
      Thrombotic lesions found in COVID-19-related PE more frequently involve distal, peripheral arteries of the lungs when compared to PE found in non-COVID-19 patients (
      • Van Dam LF
      • Kroft LJM
      • van der Wal LI
      • Cannegieter SC
      • Eikenboom J
      • de Jonge E
      • et al.
      Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: A different phenotype of thrombotic disease?.
      ). Together with a typically decreased total clot burden, as expressed through the Qanadli score (
      • Qanadli SD
      • El Hajjam M
      • Vieillard-Baron A
      • Joseph T
      • Mesurolle B
      • Oliva VL
      • et al.
      New CT Index to Quantify Arterial Obstruction in Pulmonary Embolism.
      ), these elements brought researchers to hypothesize a different PE phenotype in COVID-19 patients (
      • Van Dam LF
      • Kroft LJM
      • van der Wal LI
      • Cannegieter SC
      • Eikenboom J
      • de Jonge E
      • et al.
      Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: A different phenotype of thrombotic disease?.
      ).
      PE in COVID-19 patients is seen at various phases during the illness and can occur despite thromboembolic prophylaxis with low molecular weight heparin (LMWH) (
      • Helms J
      • Tacquard C
      • Severac F
      • Leonard-Lorant I
      • Ohana M
      • Delabranche X
      • et al.
      High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      ). The insidious onset of PE has led to the need for clinicians to frequently monitor D-dimer , inflammatory markers, and clinical symptoms to identify early signs of PE, promptly perform imaging diagnostics, and eventually start anti-thrombotic treatment.
      Before the COVID-19 pandemic, the most used scores to predict PE in the general population were the Geneva and the Wells scores, used either alone or combined with D-dimer (
      • Guo D-J
      • Zhao C
      • Zou Y-D
      • Huang X-H
      • Hu J-M
      • Guo L.
      Values of the Wells and Revised Geneva Scores Combined with D-dimer in Diagnosing Elderly Pulmonary Embolism Patients.
      ). Several scores have been adapted or used after the beginning of the COVID-19 pandemic due to the increasing occurrence of PE in hospitalized COVID-19 patients (HCP). However, several flaws hamper the extensive use of predictive scores, especially in the context of COVID-19: i) the uneven predictive ability of available scores, in terms of sensitivity and specificity; ii) some of these scores contain variables that are not screened outside of a few limited settings, such as in the case of interleukins; iii) predictive scores are often developed in the context of research projects and are seldom validated in clinical settings.
      Despite these limitations, using scores to identify patients at risk for this complication could represent an added value to the clinical management of COVID-19.
      Since a wide variety of predictive scores are available, with different sensitivities and specificities, tested in several settings in patients with heterogeneous clinical characteristics, we performed a systematic review of published data on a prognostic model to predict the risk for PE in COVID-19. We aimed at providing a comprehensive picture of predictive values, including the pros and cons of each score, and to give suggestions on their use in clinical practice.

      Methods

      Article identification

      Studies concerning the use of at least one prediction rule to assess the risk for PE in HCPs were identified through computerized literature searches using free text searching, MEDLINE (National Library of Medicine Bethesda MD), EMBASE, and by reviewing the references of the retrieved articles.
      Index search terms included the Medical Subject Heading "Covid-19," "pulmonary embolism," and "score." The search term lines are available in the supplementary material.
      The search was restricted to English language articles. The literature search period ranged from 1 January 2020 to 28 April 2021. No attempt was made to obtain information about unpublished studies. Reviewed articles were recorded in a master log, and any reason for exclusion from the analysis was documented in the rejected log. The systematic review was reported according to the 2020 Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines (
      • Page MJ
      • McKenzie JE
      • Bossuyt PM
      • Boutron I
      • Hoffmann TC
      • Mulrow CD
      • et al.
      The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.
      ).

      Inclusion and exclusion criteria

      Studies were considered eligible if they presented data about using a prediction rule to assess the risk for PE in adult HCPs with laboratory-confirmed SARS-CoV2 infection. The investigated outcome was the diagnosis of PE. Studies presenting data on using a single laboratory assay for PE prediction, such as D-dimer , C-reactive protein (CRP), ferritin, etc., and imaging diagnostics alone, such as Lung Ultrasound (LUS), were excluded.
      Observational studies were considered eligible if randomized controlled trials (RCTs) were unavailable. Reviews, letters, editorials, abstracts, and case reports were excluded. Studies gathering data for less than ten patients were excluded as well.

      Data extraction

      Data extraction was performed independently by two investigators (S.A.M. and L.V.R). Each investigator was blinded to the other investigator's data extraction. In the case of disagreement between the two reviewers, a third reviewer was consulted (MAC). Data from each study were entered into a standardized form, verified for consistency and accuracy, and entered into a computerized database.
      Abstracted information included: country and period in which patients’ enrollment took place; number and setting of enrolled patients; patient characteristics, including relevant demographic variables; criteria for selecting patients to be assessed with imaging studies; imaging technique used to assess the presence of PE; the number of patients with PE confirmed at imaging; the number of patients completing follow up; type of scores used for the prediction, including the reported threshold, statistical information about the predictive ability of the score used with sensitivity/specificity and/or AUC of the Receiver Operating Characteristic (ROC) when available.
      No automatic tool was used during any phase of the present study.

      Quality assessment

      Included studies were appraised for methodological quality independently by two authors (S.A.M. and L.V.R.) without blinding to journal or study authorship. If required, discrepancies were resolved by discussion or involvement of a third review author.
      The quality of observational studies was assessed using the Newcastle - Ottawa Quality Assessment Scale for Cohort Studies (NOS). Detailed assessment of the risk of bias via NOS table is available in the supplemental material in S1.

      Results

      Our search retrieved 158 articles, of which twelve were eventually included (
      • Whyte MB
      • Kelly PA
      • Gonzalez E
      • Arya R
      • Roberts LN.
      Pulmonary embolism in hospitalised patients with COVID-19.
      ;
      • Baccellieri D
      • Bertoglio L
      • Apruzzi L
      • Ardita V
      • D'Angelo A
      • Bossi M
      • et al.
      Incidence of deep venous thrombosis in COVID-19 hospitalized patients during the first peak of the Italian outbreak.
      ;
      • Monfardini L
      • Morassi M
      • Botti P
      • Stellini R
      • Bettari L
      • Pezzotti S
      • et al.
      Pulmonary thromboembolism in hospitalised COVID-19 patients at moderate to high risk by Wells score: a report from Lombardy, Italy.
      ;
      • Zotzmann V
      • Lang CN
      • Wengenmayer T
      • Bemtgen X
      • Schmid B
      • Mueller-Peltzer K
      • et al.
      Combining lung ultrasound and Wells score for diagnosing pulmonary embolism in critically ill COVID-19 patients.
      ;
      • Kirsch B
      • Aziz M
      • Kumar S
      • Burke M
      • Webster T
      • Immadi A
      • et al.
      Wells Score to Predict Pulmonary Embolism in Patients with Coronavirus Disease 2019.
      ;
      • Melazzini F
      • Colaneri M
      • Fumoso F
      • Freddi G
      • Lenti MV
      • Pieri TC
      • et al.
      Venous thromboembolism and COVID-19: a single-center experience from an academic tertiary referral hospital of Northern Italy.
      ;
      • García-Ortega A
      • Oscullo G
      • Calvillo P
      • López-Reyes R
      • Méndez R
      • Gómez-Olivas JD
      • et al.
      Incidence, risk factors, and thrombotic load of pulmonary embolism in patients hospitalized for COVID-19 infection.
      ;
      • Fang C
      • Garzillo G
      • Batohi B
      • Teo JTH
      • Berovic M
      • Sidhu PS
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      ;
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      ;
      • Polo Friz H
      • Gelfi E
      • Orenti A
      • Motto E
      • Primitz L
      • Donzelli T
      • et al.
      Acute pulmonary embolism in patients presenting pulmonary deterioration after hospitalization for non-critical COVID-19.
      ;
      • Kampouri E
      • Filippidis P
      • Viala B
      • Méan M
      • Pantet O
      • Desgranges F
      • et al.
      Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: an Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital.
      ;
      • Caro-Codón J
      • Lip GYH
      • Rey JR
      • Iniesta AM
      • Rosillo SO
      • Castrejon-Castrejon S
      • et al.
      Prediction of thromboembolic events and mortality by the CHADS2 and the CHA2DS2-VASc in COVID-19.
      ), comprising 4,526 HCPs. Figure 1 shows the selection process of studies included in the systematic review.
      Figre 1
      Figre 1PRISMA chart for identification of studies.

      Study description

      A summary description of the included studies is reported in Table 1 and Table 2. Among the twelve studies, three prospective cohort and nine retrospective cohort studies were included. Eleven studies assessed the presence of PE using CTPA; one used perfusion (Q)-single-photon emission computed tomography (Q/SPECT) instead.
      Table 1Characteristics of studies included in the systematic review.
      Author [ref]Time frame for enrolling patientsCountryStudy designSex (% of males)Age (years, median)Total number of included HCPsTotal number of HCPs with PESelection of cohortSetting
      • Whyte MB
      • Kelly PA
      • Gonzalez E
      • Arya R
      • Roberts LN.
      Pulmonary embolism in hospitalised patients with COVID-19.
      March to May 2020UKRetrospective cohort60.2861.0521480All patients undergoing CTPAMixed, including ICU
      • Baccellieri D
      • Bertoglio L
      • Apruzzi L
      • Ardita V
      • D'Angelo A
      • Bossi M
      • et al.
      Incidence of deep venous thrombosis in COVID-19 hospitalized patients during the first peak of the Italian outbreak.
      April 2020ItalyProspective cohort716220035Consecutive HCPsMixed, including ICU
      Monfardini et al., 2021March 2020ItalyRetrospective cohortNANA3426All patients undergoing CTPAMixed, including ICU
      • Zotzmann V
      • Lang CN
      • Wengenmayer T
      • Bemtgen X
      • Schmid B
      • Mueller-Peltzer K
      • et al.
      Combining lung ultrasound and Wells score for diagnosing pulmonary embolism in critically ill COVID-19 patients.
      March to May 2020GermanyRetrospective cohort7061.62012All patients with ARDS, a CTPA, a LUSICU only
      Kirsch B. et al., 2021February to July 2020USARetrospective cohort54.754.96412All patients undergoing CTPAMixed, including ICU
      Melazzini F. et al., 2020March to April 2020ItalyRetrospective cohort68702594All HCPsMixed, including ICU
      • García-Ortega A
      • Oscullo G
      • Calvillo P
      • López-Reyes R
      • Méndez R
      • Gómez-Olivas JD
      • et al.
      Incidence, risk factors, and thrombotic load of pulmonary embolism in patients hospitalized for COVID-19 infection.
      March to April 2020SpainProspective cohort7165.47326All patients undergoing CTPA + D-dimerMixed, including ICU
      • Fang C
      • Garzillo G
      • Batohi B
      • Teo JTH
      • Berovic M
      • Sidhu PS
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      March to April 2020UKRetrospective cohort64.5159.29341All patients undergoing CTPAMixed, including ICU
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      March to April 2020ItalyRetrospective cohort51.16654315All patients undergoing CTPAWards admitting COVID-19 patients besides ICU
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      March to April 2020ItalyRetrospective cohort51.16654315All patients undergoing CTPAWards admitting COVID-19 patients besides ICU
      H Pol
      • Polo Friz H
      • Gelfi E
      • Orenti A
      • Motto E
      • Primitz L
      • Donzelli T
      • et al.
      Acute pulmonary embolism in patients presenting pulmonary deterioration after hospitalization for non-critical COVID-19.
      April 2020ItalyRetrospective cohort2771.7418All patients undergoing CTPA + reduction in p/f ratio >30%Wards admitting COVID-19 patients besides ICU
      • Kampouri E
      • Filippidis P
      • Viala B
      • Méan M
      • Pantet O
      • Desgranges F
      • et al.
      Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: an Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital.
      February to April 2020SwitzerlandRetrospective cohort57.7868.6844327All HCPsMixed, including ICU
      Caro-Codòn et al., 2021March to April 2020SpainProspective cohort54.962.3304275All COVID-19 patients accessing ERMixed, including ICU
      Key: HCPs= hospitalized COVID-19 patients; PE= Pulmonary embolism; ICU= Intensive care unit; CTPA= CT pulmonary angiogram; ARDS= Acute respiratory distress syndrome; LUS= Lung ultrasound; COVID-19 (coronavirus disease 2019).
      Table 2Prediction ability of scores in included studies
      Author [ref]Score, ThresholdThreshold used in the studySensitivitySpecificityAUC ROCp-value (univariate association between PE and score)Relevant information derived from the study
      • Whyte MB
      • Kelly PA
      • Gonzalez E
      • Arya R
      • Roberts LN.
      Pulmonary embolism in hospitalised patients with COVID-19.
      Wells, > 4>4NANANA0.951Wells score was not able to predict PE in HCPs
      • Baccellieri D
      • Bertoglio L
      • Apruzzi L
      • Ardita V
      • D'Angelo A
      • Bossi M
      • et al.
      Incidence of deep venous thrombosis in COVID-19 hospitalized patients during the first peak of the Italian outbreak.
      Padua, >4>4NANANA0.026Padua score > 4 was significantly associated with PE on univariate analysis
      Monfardini et al., 2021Wells, > 4>4NANANANAAmong patients with Wells > 4, 76% had PE on imaging; 24% had imaging negative for PE
      • Zotzmann V
      • Lang CN
      • Wengenmayer T
      • Bemtgen X
      • Schmid B
      • Mueller-Peltzer K
      • et al.
      Combining lung ultrasound and Wells score for diagnosing pulmonary embolism in critically ill COVID-19 patients.
      Wells + Lung US>2100%80%0.9440.042Wells score >2 + positive lung US is able to predict PE in HCPs
      Kirsch B. et al., 2021Wells, > 4>4NANA0.540.04Wells score was associated with PE in HCPs; nevertheless, it was not able to predict it.
      Melazzini F. et al., 2020Padua, >4>4NANANA0.4100% with PE had Padua >4 (only 4 patients had pulmonary embolism among the sample).
      • García-Ortega A
      • Oscullo G
      • Calvillo P
      • López-Reyes R
      • Méndez R
      • Gómez-Olivas JD
      • et al.
      Incidence, risk factors, and thrombotic load of pulmonary embolism in patients hospitalized for COVID-19 infection.
      CHOD score0-2: 4.5% PE; 3-5: 36.8% PE; 6-7: 100% PENANA0.86HR (p = 0.036); Room-air SatO2 ( p = 0.041); D-dimer (p = 0.022); CRP (p = 0.037)CHOD score was able to predict PE in HCPs
      • Fang C
      • Garzillo G
      • Batohi B
      • Teo JTH
      • Berovic M
      • Sidhu PS
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      Wells, > 4>4NANANA0.801Wells score was not able to predict PE in HCPs
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      Wells, > 4Wells, > 4NANANAWells (0.17)Wells score did not correlate to PE in HCPs
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      Revised Geneva > 4Revised Geneva > 4NANARevised Geneva (0.727)Revised Geneva (p = 0.013)Revised Geneva score was able to predict PE in HCPs
      H Pol
      • Polo Friz H
      • Gelfi E
      • Orenti A
      • Motto E
      • Primitz L
      • Donzelli T
      • et al.
      Acute pulmonary embolism in patients presenting pulmonary deterioration after hospitalization for non-critical COVID-19.
      "Simplified Wells", > 2"Simplified Wells", > 2"Simplified Wells", > 2 + age adjusted D-dimer : 88%"Simplified Wells", > 2 + age adjusted D-dimer : 18%NA0.851"Simplified" Wells score was not able to predict PE in HCPs
      • Kampouri E
      • Filippidis P
      • Viala B
      • Méan M
      • Pantet O
      • Desgranges F
      • et al.
      Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: an Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital.
      Wells > 4 + d dimerWells > 2 + d dimer > 3000 ng/L57.10%91.6%NANAWhen diagnostic imaging for PE is not possible, empiric therapeutic anticoagulation should be considered if Wells score > 2 + D-dimer > 3000 ng/L
      Caro-Codòn et al., 2021CHADS2, CHA2DS2-VASc and the M-CHA2DS2VASc; > 2CHADS2, CHA2DS2-VASc and the M-CHA2DS2VASc; > 2NANA(0.497), CHA2DS2-VASc (0.490) and the M-CHA2DS2VASc (0.541)NANo tested score was able to predict PE in HCPs
      Key: AUC-ROC= Area under curve – receiver operating characteristics; PE= Pulmonary embolism; HCPs= hospitalized COVID-19 patients; NA= Not Available; US= Ultrasound; CHOD = C-reactive protein, Heart rate, Oxygen saturation, D-dimer ; HR= Heart rate; CRP= C-reactive protein; CHA2DS2-VASc= CHF, Hypertension, Age, Diabetes, Stroke, Vascular diseases.
      Table S1 shows the quality appraisal of the included studies.
      In our search, five prediction rules were identified. Only one was explicitly designed for HCPs; the remaining were already in use before the COVID-19 pandemic. Table 3 reports the prediction rules and the variables included in these scoring systems. The Wells score was the most frequently used, found in eight out of twelve studies.
      Table 3Prediction rules for PE in HCPs: included variables and value attributed to each included variable.
      WELLS SCOREREVISED GENEVA SCOREPADUA SCOREM-CHA2DS2-VASCCHOD score
      Variables includedNumeric value attributed to each included variable
      Acute infection/Autoimmune disease1
      D-dimer > 956 ng/mL2
      Thrombophilia3
      O2 Sat < 92%2
      Blood Pressure (↑)/(↓)1
      HR (↑)/(↓)
      Note: In the CHOD score, points for heart rate are attributed when > 90bpm; in the revised Geneva score, the same applies if 75-94bpm (3 points) or > 95bpm (5 points).
      1.53-52
      Diabetes1
      CRP > 50mg/L1
      Cardiac or Respiratory Failure11
      BMI>301
      Lower limb pain3
      Lower limb edema4
      Previous DVT/PE1.5332
      Clinical signs of DVT3
      PE is the most likely diagnosis3
      Surgery/fracture lower limb <1mo prior1.522
      Hypomobility < 3 days prior3
      Hemoptysis12
      Stroke/MI12
      Active malignancy123
      Gender1
      Vasculopathy1
      HRT1
      Age (↑)110-2
      SCORE RANGE0-12.50-220-200-90-7
      THRESHOLD> 4moderate risk > 4; high risk > 11> 4> 2moderate risk > 3; high risk > 5
      Key: CHA2DS2-VASc= CHF, Hypertension, Age, Diabetes, Stroke, Vascular diseases; CHOD = C-reactive protein, Heart rate, Oxygen saturation, D-dimer ; HR = Heart Rate; CRP= C-reactive protein; BMI= Body mass index; DVT = Deep Vein Thrombosis; PE = Pulmonary Embolism; MI= Myocardial Infarction; HRT = Hormone Replacement Therapy.
      low asterisk Note: In the CHOD score, points for heart rate are attributed when > 90bpm; in the revised Geneva score, the same applies if 75-94bpm (3 points) or > 95bpm (5 points).
      Kirsch et al. validated the utility of the Wells score in predicting PE in a retrospective cohort of 64 HCPs (median age 54.9 years, 54.7% males), twelve of whom developed PE. In this study, a Wells score above four was significantly associated with PE development (p= 0.04), even though four out of twelve patients with PE had a score of zero (
      • Kirsch B
      • Aziz M
      • Kumar S
      • Burke M
      • Webster T
      • Immadi A
      • et al.
      Wells Score to Predict Pulmonary Embolism in Patients with Coronavirus Disease 2019.
      ). The AUC-ROC curve for the prediction of PE in HCPs, calculated for an optimal value of Wells score between one and two, was 0.54 (
      • Kirsch B
      • Aziz M
      • Kumar S
      • Burke M
      • Webster T
      • Immadi A
      • et al.
      Wells Score to Predict Pulmonary Embolism in Patients with Coronavirus Disease 2019.
      ).
      Another study found no significant correlation between Wells score and PE in a cohort of 43 HCPs (median age 65 years, 51.16% males) (
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      ). Similar findings were confirmed by Whyte and colleagues in a cohort of 214 HCPs (median age 61 years, 60.28% males). These authors did not find a significant association between the Wells score and the probability of having PE. Of the main components of the Wells score, only the presence of DVT signs and symptoms was found to be significantly associated with PE (p = 0.0017) (
      • Whyte MB
      • Kelly PA
      • Gonzalez E
      • Arya R
      • Roberts LN.
      Pulmonary embolism in hospitalised patients with COVID-19.
      ).
      In a retrospective cohort study of 34 HCPs (median age 61 years, 77% males) with a moderate-to-high pre-test probability of PE, as suggested by Wells score > 4, 76% of the subjects showed signs of PE on a computerized tomographic pulmonary angiogram (CTPA) (n = 26) (
      • Monfardini L
      • Morassi M
      • Botti P
      • Stellini R
      • Bettari L
      • Pezzotti S
      • et al.
      Pulmonary thromboembolism in hospitalised COVID-19 patients at moderate to high risk by Wells score: a report from Lombardy, Italy.
      ).
      In a retrospective study of 443 HCPs (median age 68.68 years, 57.7% males), Kampouri et al. found that a Wells score > 2 in combination with a D-dimer value > 3000 ng/L provided a very specific predictive rule with a sensitivity of 57.1%, and a specificity of 91.6%. A Wells score > 2 combined with a D-dimer value > 1000 ng/L provided a more sensitive prediction rule, with a sensitivity of 92.9% and a specificity of 46.9%. Furthermore, PE was less likely upon admission in cases where the Wells score was ≤ 2 and the D-dimer value was ≤ 1000 ng/ml (
      • Kampouri E
      • Filippidis P
      • Viala B
      • Méan M
      • Pantet O
      • Desgranges F
      • et al.
      Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: an Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital.
      ).
      Zotzmann et al. evaluated all patients retrospectively with SARS-CoV2 associated ARDS admitted to ICU (20 HCPs, median age 61.6 years, 70% males) utilizing the Wells score plus Lung Ultrasound (LUS). The study reports a predictive ability approaching 100% of sensitivity and 80% specificity when a threshold of > 2 for the Wells score was used and predicted PE with an AUC of 0.944. Furthermore, the Wells score was found significantly higher in PE patients than non-PE patients (2.7 + 0.8 vs. 1.7 + 0.5 respectively, p= 0.042) (
      • Zotzmann V
      • Lang CN
      • Wengenmayer T
      • Bemtgen X
      • Schmid B
      • Mueller-Peltzer K
      • et al.
      Combining lung ultrasound and Wells score for diagnosing pulmonary embolism in critically ill COVID-19 patients.
      ).
      Fang and colleagues performed a retrospective analysis of COVID-19 patients undergoing CTPA. In this study, based on a cohort of 93 HCPs (median age 59.2 years, 64.51% males) who underwent a CTPA (41 positive for PE), a high Wells score was not able to predict PE (
      • Fang C
      • Garzillo G
      • Batohi B
      • Teo JTH
      • Berovic M
      • Sidhu PS
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      ).
      Polo Fritz and colleagues performed a similar study, based on 41 HCPs (median age 71.7 years, 73% females) undergoing CTPA. Eight patients were found to have PE at imaging. The Wells score was found not clinically useful (
      • Polo Friz H
      • Gelfi E
      • Orenti A
      • Motto E
      • Primitz L
      • Donzelli T
      • et al.
      Acute pulmonary embolism in patients presenting pulmonary deterioration after hospitalization for non-critical COVID-19.
      ).
      Two studies evaluated the use of the Padua Prediction Score (PPS).
      Baccellieri and colleagues, in a prospective study including 200 consecutive HCPs (median age 62 years, 71% males), found an association between PE and the PPS > 4 by univariate analysis (p= 0.026) (
      • Baccellieri D
      • Bertoglio L
      • Apruzzi L
      • Ardita V
      • D'Angelo A
      • Bossi M
      • et al.
      Incidence of deep venous thrombosis in COVID-19 hospitalized patients during the first peak of the Italian outbreak.
      ).
      Melazzini et al. confirmed similar findings in a retrospective cohort study involving 259 COVID-19 patients (median age 70 years, 68% males); in this study, no patient with PE had a PPS below 4. Nevertheless, it is worth mentioning that only four patients in the examined cohort were diagnosed with PE (
      • Melazzini F
      • Colaneri M
      • Fumoso F
      • Freddi G
      • Lenti MV
      • Pieri TC
      • et al.
      Venous thromboembolism and COVID-19: a single-center experience from an academic tertiary referral hospital of Northern Italy.
      ).
      Scardapane et al. reported the ability of the revised Geneva score in predicting PE in a retrospective cohort with 43 COVID-19 patients, all undergoing CTPA as inclusion criteria. In this cohort, 35% of patients had PE. The Revised Geneva Score was significantly higher in PE patients than in non-PE patients (mean 4+2 vs. 2 + 2, p= 0.01). The AUC-ROC for the predictive ability of the Revised Geneva score was 0.727 (95% CI of 0.525-0.929) (
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      ).
      Caro-Codòn and colleagues published a prospective observational study including 3042 COVID-19 patients (median age 62.3 years, 54.9% males) and assessing the utility of CHADS2, CHA2DS2-VASc, and the M-CHA2DS2VASc, acronyms made of the variables used for its calculation, i.e., congestive heart failure, hypertension, age > 75 years, diabetes, TIA/Stroke/Thromboembolism, vascular disease, age 65-75, gender category; the M version is designed to assign an extra point for male sex (
      • Melgaard L
      • Gorst-Rasmussen A
      • Lane DA
      • Rasmussen LH
      • Larsen TB
      • Lip GYH.
      Assessment of the CHA 2 DS 2 -VASc Score in Predicting Ischemic Stroke, Thromboembolism, and Death in Patients With Heart Failure With and Without Atrial Fibrillation.
      ). No score showed a significant correlation with PE in COVID-19 patients. All three above-mentioned scores showed poor predictive value for PE (AUC 0.497, 0.490, and 0.541, respectively) (
      • Caro-Codón J
      • Lip GYH
      • Rey JR
      • Iniesta AM
      • Rosillo SO
      • Castrejon-Castrejon S
      • et al.
      Prediction of thromboembolic events and mortality by the CHADS2 and the CHA2DS2-VASc in COVID-19.
      ).
      Our search identified only one study designed to predict PE in HCPs, i.e., the CHOD score, acronym of CRP concentration + Heart rate + Oxygen saturation + D-dimer levels. Patients with an elevation in D-dimer were randomly selected from a cohort of 372 HCPs; 73 patients were included (median age 65.4 years, 71% males) and underwent CTPA assessment. PE was diagnosed in 35.6% of them. A multivariate analysis showed that heart rate [Hazard ratio (HR), 1.04], oxygen saturation in room-air (spO2) (HR, 0.87), D-dimer (HR, 1.02), and CRP levels (HR, 1.01) at the time of admission, were independent predictors of PE in HCPs. The AUC-ROC method was used to determine the diagnostic value of each selected quantitative variable, and dichotomized variables were included in another multivariable logistic regression to construct the CHOD score. This score showed a high predictive value (AUC-ROC of 0.86; 95% CI: 0.8 to 0.93) (
      • García-Ortega A
      • Oscullo G
      • Calvillo P
      • López-Reyes R
      • Méndez R
      • Gómez-Olivas JD
      • et al.
      Incidence, risk factors, and thrombotic load of pulmonary embolism in patients hospitalized for COVID-19 infection.
      ). Furthermore, the CHOD score was able to stratify patients into three risk groups, low (0-2 points), moderate (3-5 points), and high risk (more than 5 points), with a PE rate of 4.5%, 36.8%, and 100%, respectively (
      • García-Ortega A
      • Oscullo G
      • Calvillo P
      • López-Reyes R
      • Méndez R
      • Gómez-Olivas JD
      • et al.
      Incidence, risk factors, and thrombotic load of pulmonary embolism in patients hospitalized for COVID-19 infection.
      ).

      Discussion

      The importance of assessing a predictive score for PE stems from the need to promptly diagnose acute thrombotic complications in HCPs, thus reducing an adverse outcome. Indeed, routinely performing CTPA for all HCPs would be costly, time-consuming, poorly feasible, and risky for both patients and operators. Candidate selection for contrast imaging is, therefore, a clinical decision based on experience, observation, and laboratory findings. Ad hoc prediction tools could help select patients who would benefit from CTPA more efficaciously.
      Our systematic review found twelve studies assessing the role of five clinical scores in predicting PE in HCPs.
      The most frequently used score in studies included in our systematic review was the Wells score. It has been extensively used to predict PE for over twenty years and is still used today for stratifying the general population into three groups. i.e., low (1.3% prevalence), moderate (16.2% prevalence), and high risk (37.5% prevalence), according to their pre-test chance of developing PE (
      • Wells PS
      • Anderson DR
      • Bormanis J
      • Guy F
      • Mitchell M
      • Gray L
      • et al.
      value of assessment of pre-test probability of deep-vein thrombosis in clinical management.
      ). The score had an AUC of the ROC calculated for predicting PE in the general population of 0.632 (CI 0.574–0.691) (
      • Coelho J
      • Divernet-Queriaud M
      • Roy P-M
      • Penaloza A
      • Le Gal G
      • Trinh-Duc A
      Comparison of the Wells score and the revised Geneva score as a tool to predict pulmonary embolism in outpatients over age 65.
      ).
      In the studies included in our review, heterogeneous results on the Wells score were obtained. Five studies did not report a significant association between this score and the risk of PE in HCPs. The only study reporting the AUC of the ROC for Wells score predicting ability for PE in HCPs was calculated to be equal to 0.54 when used alone (
      • Kirsch B
      • Aziz M
      • Kumar S
      • Burke M
      • Webster T
      • Immadi A
      • et al.
      Wells Score to Predict Pulmonary Embolism in Patients with Coronavirus Disease 2019.
      ).
      It has been hypothesized that the low prediction ability of the Wells score in HCPs might be correlated with the PE pathophysiological mechanism in HCPs. Indeed, PE might result from direct endothelial cell injury by viral action or from an inflammatory reaction secondary to the alveolar damage (
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      ). Therefore, scores designed for investigating PE as a principal diagnosis, rather than a complication of another pathology (i.e., COVID-19), may not be the best option in these patients (
      • Fang C
      • Garzillo G
      • Batohi B
      • Teo JTH
      • Berovic M
      • Sidhu PS
      • et al.
      Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease.
      ). This hampers the predictive ability of the Wells score, mainly because it stems from the assumption that PE results from a DVT. COVID-19-related PE is most frequently a pulmonary local phenomenon and not a result of immobilization or DVT. In fact, 85% of PE cases were not associated with DVT at US of the lower limbs, as described by Monfardini and colleagues (
      • Monfardini L
      • Morassi M
      • Botti P
      • Stellini R
      • Bettari L
      • Pezzotti S
      • et al.
      Pulmonary thromboembolism in hospitalised COVID-19 patients at moderate to high risk by Wells score: a report from Lombardy, Italy.
      ).
      Regardless of the use in HCPs, the main limitation of the Wells score pertains to the inclusion of a subjective opinion of the physician among variables, i.e., "PE is the most likely diagnosis," as already described by Klok and colleagues (
      • Klok FA
      • Zidane M
      • Djurabi RK
      • Nijkeuter M
      • Huisman M V
      The physician's estimation ‘alternative diagnosis is less likely than pulmonary embolism’ in the Wells rule is dependent on the presence of other required items.
      ). Especially in COVID-19 management, physicians will most often suspect PE if patients present with hypoxemia and tachycardia, de facto limiting the utility of this score in predicting PE (
      • Kirsch B
      • Aziz M
      • Kumar S
      • Burke M
      • Webster T
      • Immadi A
      • et al.
      Wells Score to Predict Pulmonary Embolism in Patients with Coronavirus Disease 2019.
      ).
      A non-accurate history taking could also lead to a miscalculation of the Wells score, as highlighted by Whyte and colleagues, who found a poor predictive ability in HCPs (
      • Whyte MB
      • Kelly PA
      • Gonzalez E
      • Arya R
      • Roberts LN.
      Pulmonary embolism in hospitalised patients with COVID-19.
      ).
      Of note, it has been reported that the concomitant use of the Wells score and D-dimer would enhance the sensitivity and specificity of the test (
      • Zhang L
      • Feng X
      • Zhang D
      • Jiang C
      • Mei H
      • Wang J
      • et al.
      Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan.
      ;
      • Girardi AM
      • Bettiol RS
      • Garcia TS
      • Ribeiro GLH
      • Rodrigues ÉM
      • Gazzana MB
      • et al.
      Wells and Geneva Scores Are Not Reliable Predictors of Pulmonary Embolism in Critically Ill Patients: A Retrospective Study.
      ;
      • Touhami O
      • Ben Marzouk S
      • Bennasr L
      • Touaibia M
      • Souli I
      • Felfel MA
      • et al.
      Are the Wells Score and the Revised Geneva Score valuable for the diagnosis of pulmonary embolism in pregnancy?.
      ;
      • Kampouri E
      • Filippidis P
      • Viala B
      • Méan M
      • Pantet O
      • Desgranges F
      • et al.
      Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: an Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital.
      ).
      Regarding other scores utilized in studies included in our review, the usefulness of PPS in predicting PE in HCPs was evaluated in two studies (
      • Baccellieri D
      • Bertoglio L
      • Apruzzi L
      • Ardita V
      • D'Angelo A
      • Bossi M
      • et al.
      Incidence of deep venous thrombosis in COVID-19 hospitalized patients during the first peak of the Italian outbreak.
      ;
      • Melazzini F
      • Colaneri M
      • Fumoso F
      • Freddi G
      • Lenti MV
      • Pieri TC
      • et al.
      Venous thromboembolism and COVID-19: a single-center experience from an academic tertiary referral hospital of Northern Italy.
      ). The PPS has been validated before COVID-19 to identify the need for anticoagulation in hospitalized patients based on their risk of VTE (
      • Barbar S
      • Noventa F
      • Rossetto V
      • Ferrari A
      • Brandolin B
      • Perlati M
      • et al.
      A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score.
      ). Results appear to confirm the utility of PPS in HCPs only when the score is >4. Nevertheless, a more extensive prospective study would be necessary to clarify the predictive ability of PPS in predicting PE in HCPs.
      The revised Geneva score includes risk factors, such as age, previous PE/DVT, surgery in the month before the admission, active malignant condition, and symptoms, including hemoptysis and unilateral lower-limb pain. In the general population, a score below 4 suggests a low clinical probability of PE (<10%); a score between 4 and 10 defines an intermediate-risk group (10-60%), and a score ≥ 11 a high-risk group (>60%) (
      • Le Gal G
      • Righini M
      • Roy P-M
      • Sanchez O
      • Aujesky D
      • Bounameaux H
      • et al.
      Prediction of Pulmonary Embolism in the Emergency Department: The Revised Geneva Score.
      ;
      • Wicki J
      • Perneger T V
      • Junod AF
      • Bounameaux H
      • Perrier A.
      Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score.
      ). In HCPs, the performance of the revised Geneva score appears to be reasonably satisfactory, with an AUC of the ROC of 0.727; however, the variable with the highest predictivity in this study was the mean D-dimer value (
      • Scardapane A
      • Villani L
      • Bavaro DF
      • Passerini F
      • Ianora AAS
      • Lucarelli NM
      • et al.
      Pulmonary Artery Filling Defects in COVID-19 Patients Revealed Using CT Pulmonary Angiography: A Predictable Complication?.
      ).
      CHA2DS2-VASc is a score used in atrial fibrillation to clinically stratify patients according to their risk of developing ischemic stroke or thromboembolism (
      • Lip GYH
      • Nieuwlaat R
      • Pisters R
      • Lane DA
      • Crijns HJGM.
      Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor-Based Approach.
      ). Caro-Codón and colleagues evaluated these scores in HCPs reporting poor predictive ability and no correlation between CHADS2, CHA2DS2-VASc, and the M-CHA2DS2VASc and PE (
      • Caro-Codón J
      • Lip GYH
      • Rey JR
      • Iniesta AM
      • Rosillo SO
      • Castrejon-Castrejon S
      • et al.
      Prediction of thromboembolic events and mortality by the CHADS2 and the CHA2DS2-VASc in COVID-19.
      ). Thus, their usefulness for predicting PE in HCPs is very limited, and these scores do not deserve to be further assessed in HCPs.
      Among the examined scores, the CHOD score seems promising in terms of predictive ability. This score was developed explicitly for HCPs and is calculated on a few routinely extracted elements. However, only one study described its use, and no validation study was developed yet.
      It is worth highlighting that included studies showed several flaws. First of all, most of these studies enrolled subjects who already underwent CTPA, undermining the correct representation of the at-risk population, thus introducing a potential selection bias. Moreover, most studies were retrospective, and importantly, not designed to evaluate the score's predictive ability. Many of them did not report all relevant data for evaluating the predictive ability of scores and often lacked a multivariate analysis.
      An additional limitation is represented by the study population; most of the studies included a mixed cohort, i.e., ICU and non-ICU patients, hampering the possibility to evaluate the role of scores in predicting PE in critically ill patients. Furthermore, the LMWH prophylaxis effect on preventing PE was not evaluated systematically. Most of the studies were issued in the early period of introduction of LMWH prophylaxis to all HCPs (
      • Kulkarni S
      • Fisk M
      • Kostapanos M
      • Banham-Hall E
      • Bond S
      • Hernan-Sancho E
      • et al.
      Repurposed immunomodulatory drugs for Covid-19 in pre-ICu patients - mulTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19 – Repurposed Drugs (TACTIC-R): A structured summary of a study protocol for a randomised controlled trial.
      ); therefore, LMWH prophylaxis may not have been routinely performed in the clinical practice for HCPs.
      PE is substantially contributing to the severity burden of COVID-19, both in the short and the long term. As the majority of PE cases in COVID-19 do not result from DVT, new prediction rules, specifically developed and validated for estimating the risk of PE in COVID-19, are needed. Findings of the CHOD score seem interesting, but future studies are needed to validate such scores in clinical practice on a larger scale. Scores should differentiate ICU from non-ICU patients and should consider anticoagulation prophylaxis, comorbidities exposing the HCP to an increased risk of developing PE, and the time from COVID-19 diagnosis.

      Authors’ Contributions

      NP and LVR conceived and designed the study. LVR, SAM, and DRD were responsible for data collection. LVR and MAC wrote the initial manuscript. NP, MAC, and LVR critically revised the manuscript. All authors have read and approved the final manuscript.

      Funding

      Work supported by project #32, Donation Grants, INMI Spallanzani.

      Declaration of competing interest

      NP received honoraria for lectures from MSD, Pfizer, Johnson & Johnson, Becton & Dickinson, Shionogi; the other authors have no competing interests.

      Appendix. Supplementary materials

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