key: cord-0776437-79t71vt2
authors: Planquette, Benjamin; Le Berre, Alice; Khider, Lina; Yannoutsos, Alexandra; Gendron, Nicolas; de Torcy, Marie; Mohamedi, Nassim; Jouveshomme, Stéphane; Smadja, David M.; Lazareth, Isabelle; Goudot, Guillaume; Fournier, Laure; Bruel, Cédric; Diehl, Jean Luc; Mourad, Jean-Jacques; Meyer, Guy; Priollet, Pascal; Messas, Emmanuel; Sanchez, Olivier; Beaussier, Hélène; Mirault, Tristan; Zins, Marc; Chatelier, Gilles; Emmerich, Joseph
title: Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study
date: 2020-11-07
journal: Thromb Res
DOI: 10.1016/j.thromres.2020.11.001
sha: 3baccaea333603509c96781255b3ba480c060ed1
doc_id: 776437
cord_uid: 79t71vt2

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Previous studies reported pulmonary embolism (PE) in severe COVID-19 patients. Aim of the study was to estimate the prevalence of symptomatic PE in COVID-19 patients and to identify the clinical, radiological or biological characteristics associated with PE. PATIENTS/METHODS: We conducted a retrospective nested case-control study in 2 French hospitals. Controls were matched in a 1:2 ratio on the basis of age, sex and center. PE patients with COVID-19 were compared to patients in whom PE was ruled out (CTPA controls) and in whom PE has not been investigated (CT controls). RESULTS: PE was suspected in 269 patients among 1042 COVID-19 patients, and confirmed in 59 patients (5.6%). Half of PE was diagnosed at COVID-19 diagnosis. PE patients did not differ from CT and CTPA controls for thrombosis risk factors. PE patients more often required invasive ventilation compared to CTPA controls (odds ratio (OR) 2.79; 95% confidence interval (CI) 1.33–5.84) and to CT controls (OR 8.07; 95% CI 2.70–23.82). PE patients exhibited more extensive parenchymal lesions (>50%) than CT controls (OR 3.90; 95% CI 1.54–9.94). D-dimer levels were 5.1 (95% CI 1.90–13.76) times higher in PE patients than CTPA controls. CONCLUSIONS: Our results suggest a PE prevalence in COVID-19 patients close to 5% in the whole population and to 20% of the clinically suspected population. PE seems to be associated with more extensive lung damage and to require more frequently invasive ventilation.

In December 2019, China reported the first cluster of severe acute respiratory syndrome due to a new coronavirus (SARS-CoV-2). 1 The disease rapidly spread into a global pandemic of public health worldwide leading to more than 617 000 deaths (data from July 22, 2020) . The main failure in COVID-19 was atypical acute respiratory distress syndrome (ARDS) because of the dissociation between well-conserved lung compliance and severe hypoxemia, attributed to pulmonary vasoregulation disruption and local thrombogenesis. 2, 3 Furthermore, COVID-19 outbreak coagulopathy has been described with unusual high levels of D-dimer in a large majority of patients 1,4-6 . High D-dimer levels, caused by both inflammation storm and coagulation activation have been associated with increased mortality. 4, 5, [7] [8] [9] Taking together, these reports have led to several therapeutic proposals in terms of anticoagulant therapy from scientific societies. [10] [11] [12] Publications recently reported thrombotic complications in series of severe COVID-19 patients admitted in intensive care unit (ICU), but the frequency of pulmonary embolism (PE) remains uncertain. [13] [14] [15] [16] [17] [18] [19] [20] Earlier during the European COVID-19 outbreak, the European Society of Radiology and the European Society of Thoracic Imaging suggested to performed CT-scan in COVID-19 patients with respiratory symptoms such as dyspnea and desaturation 21 . Additional pulmonary CT angiogram (CTPA) could be performed if COVID-19 patient has symptoms susceptible to be associated with PE such as worsening of oxygen requirement and occurrence of ARDS. Hence, a nested-case control seems an appropriate methodology to compare PE patients to all COVID-19 in-patients with CT-scan requiring or not CTPA.

In the present analysis, we aimed to 1) evaluate the prevalence of PE among a large population of all consecutive patients admitted for COVID-19 pneumonia in two centers and 2) identify the characteristics associated with PE in those patients by using a nested case-

We conducted a retrospective study that included, from March 1 to April 20, 2020, all consecutive patients with COVID-19 pneumonia who had a CT scan for diagnosis and/or evaluation of the severity of lung lesions. All patients were recorded in a database in two large university hospitals in Paris, France: Groupe Hospitalier Paris Saint-Joseph (GHPSJ) and

Hôpital Européen Georges Pompidou (HEGP).

Patients were included according to the following inclusion criteria: patients over 18 years of age, admitted for acute COVID-19 pneumonia and who underwent a chest CT at baseline for rapid triage assessment at the emergency room and/or in wards during their hospitalization.

Diagnosis of SARS-CoV-2 infection was confirmed by a positive result of a reversetranscriptase-polymerase-chain-reaction (RT-PCR) assay and/or typical CT findings of COVID-19 pneumonia. Exclusion criteria were patient's refusal to participate and respiratory distress syndrome explained by another cause.

Patients were hospitalized in medical wards or ICU, if required, to receive usual supportive care including oxygen therapy, antibiotics, as well as prophylactic anticoagulation by lowmolecular weight heparin (enoxaparin 4000 IU) or unfractionated heparin in case of glomerular filtration rate <30 mL/min. The study sponsor is GHPSJ. The cohort protocol has been approved by the institutional ethics committee (IRB number IRB00012157 and registered on national institute of health data platform INDS n° MR 4516150520). The patients' non-opposition to the use of their data for research was also collected in accordance with European regulations (General Data Protection Regulation, GDPR). We followed requirement of the STROBE statement, on observational studies in epidemiology (https://www.strobe-statement.org).

All data were extracted from our computed medical record (Dx-Care® MEDASYS, France) by distinct investigators independently. All data were confidentially collected and coded according to the local cohort IRB-approved statements. The database was frozen for statistical analysis on May 20, 2020. The computed file used for this research was implemented in accordance with French regulations and European regulations (GDPR). Demographic and medical characteristics, including age, sex, body mass index (BMI), history of venous or arterial thrombosis, tobacco use, and anticoagulant treatment at admission and before the diagnosis of PE were available in medical records. During follow-up, maximal oxygen flow required or the need of invasive mechanical ventilation (IMV) were recorded. Time from COVID-19 illness onset to hospital admission and to PE diagnosis have been recorded.

Patients status at the end of the inclusion period was recorded as discharged from hospital, still hospitalized or deceased.

Biological parameters at admission including complete blood count, aspartate and alanine aminotransferase (ASAT, ALAT), plasma creatinine were recorded. We report D-dimer values in PE patients and CTPA controls, using the STA®-Liatest® D-Di (Diagnostica Stago, Asnières, France) (GHPSJ) or the Vidas D-Dimer® assay (Biomérieux, Marcy-Etoile, France) (HEGP). During follow-up, highest values of C-reactive protein (CRP) and fibrinogen were J o u r n a l P r e -p r o o f Journal Pre-proof also noted. Nasopharyngeal swabs were collected in universal transport medium (Xpert® nasopharyngeal sample collection kit) at hospital admission. SARS CoV-2 was detected using Allplex™ 2019-nCoV Assay (Seegene), a multiplex Real-time PCR assay that detects three target genes (E gene, RdRP gene and N gene) in a single tube, as previously described. 22 Only qualitative data were available.

The main purpose of our study was to estimate the prevalence of symptomatic PE in a large population of consecutive COVID-19 patients presenting with respiratory symptoms.

Secondary objectives were to identify the clinical, radiological or biological characteristics associated with PE. We also analyzed whether or not PE was associated with a worse outcome in hospitalized COVID-19 patients. Finally, we evaluated the diagnostic performance of Ddimer for the diagnosis of PE in COVID-19 patients.

Cases and controls were matched in a 1:2 ratio on the basis of age, sex and center. For each patient of the PE group, a greedy-matching algorithm was used to select the control patients who most closely matched that patient in terms of the three matching factors. 23 Table 1 . BMI, history of venous or arterial thrombosis, were not associated with the occurrence of PE in this population. Interestingly, active smoking was uncommon in this COVID-19 population and was not associated with the occurrence of PE. Therapeutic anticoagulation and hydroxychloroquine treatment were not associated with a decreased risk of PE.

IMV was associated with an increased risk of PE with an OR of 2.79 (95% CI 1. 33 

The main radiological and biological characteristics of the cases and controls are summarized in Table 2 . There was no difference between PE patients and the two control groups in terms of CT findings suggestibility for COVID-19 on the first CT scan, with highly suggestive features found in a majority of patients in all groups. PE patients exhibited more extensive lesions than the CT controls (OR 3.9; 95% CI 1.54-9.94, for a parenchymal involvement >50%). At admission, there was no difference among PE patients and the two control groups regarding hemoglobin level, platelet count, lymphocyte count, creatinine, ASAT and ALAT levels. Regarding inflammation during the hospitalization, assessed by both CRP and J o u r n a l P r e -p r o o f fibrinogen, PE diagnosis tends to be associated with increased levels of these biomarkers. The risk of PE was significantly associated with CRP elevation (OR 3.36; 95% CI 1.58-7.14) compared to CT controls.

Among COVID-19 patients with suspected PE, the risk of being diagnosed with PE was 5.11 times higher in patients with D-dimer level above 2605 ng/mL (95% CI 1.90-13.76). The ROC curve for D-dimer as a predictive marker for PE is shown in Supplemental figure 1.

According to the Youden index, the optimal D-dimer level cut-off was 1500 ng/mL ( Table 3 ).

The sensitivity of the test is 76.1% and the specificity is 65.0%. With this test, in our population, the NPV was 97.8% and 91.1% according to a PE prevalence of 5.6% (whole population) or 21.2% (population with CTPA). On the other hand, we also assessed if a higher threshold of D-dimer would have a good PPV for the diagnosis of PE. In our population of 1042 COVID-19 patients, thresholds of 2500 ng/mL and 3500 ng/mL, were associated with a PPV of 15.9% and 20.3% respectively. In the suspected PE group (CTPA group), PPV were of 45.4% and 53.3% respectively.

Our study evaluates the prevalence of PE in 1042 COVID-19 patients consecutively admitted in 2 large French hospitals for acute respiratory symptoms, during the main period of the pandemic in France. We found a prevalence of PE of 5.6% in this large population. This rate could be considered as a high prevalence of PE in such unselected population. Considering that 24.7% of patients required ICU, our study highlight that PE prevalence is 3 times higher than the 1.7% prevalence observed in the ICU population of the PROTECT study (dalteparin versus unfractionated heparin prophylaxis of thromboembolism in critical care) that included 60% of patients for respiratory or sepsis conditions. 24 In a study of 198 consecutive Dutch patients a similar prevalence of PE was observed (6.6%) 17 and a prevalence of 2.8% in 388 Italian patients. 18 Recently a French multicentric study found a prevalence of 8.3% in large population of COVID-19 patients hospitalized in medical wards 20 .

Furthermore, compared to recent prevention studies in acutely ill medical patients, the prevalence of PE in our population is 10 times higher than the prevalence observed in these randomized trials, demonstrating the high thrombotic risk associated with COVID-19. [25] [26] [27] [28] Nevertheless, it remains difficult to draw definite conclusions by comparing incidence measured in randomized studies in ICU to prevalence observed in our retrospective series. In COVID-19 patients who had CTPA performed, we found a PE prevalence of 21.2%.

Recently, 4 studies of less than 200 COVID-19 patients, mainly hospitalized in ICU, found a similar prevalence of PE between 13.5% and 30%. 14-17 Interestingly, almost half of the PE episodes were diagnosed at hospital admission as previously described 18 , suggesting that PE should be suspected at COVID-19 diagnosis in patients with respiratory symptoms. population. 29 We did not find a higher prevalence for VTE risk factors in PE patients compared to both control groups. IMV was strongly associated with the occurrence of PE, compared to both control groups. The association remains true considering high flow oxygen therapy (≥6 L/min) compared to lower flow oxygen therapy. Therefore, PE patients seemed more severe than controls.

Interestingly and in accordance with another report 30 , the mortality did not differs between groups suggesting that PE does not impact patient's survival in this COVID-19 population.

Patients with PE tended to have a higher CRP than patients in the 2 control groups and to present more extensive COVID-19 lung damages. Those findings have been related to a more severe COVID-19 associated coagulopathy. 10 Two other French studies showed that PE was more frequent in ICU COVID-19 patients when compared to ARDS non-COVID-19 patients 16 or patients with influenza infection. 14 Finally, our data are concordant with the hypothesis of a specific effect of the SARS-CoV-2 infection in thrombosis and inflammation.

A recent autopsy study demonstrated a high incidence of thromboembolic events associated with COVID-19 coagulopathy (58%), but histology also demonstrated microvascular thrombosis. 31 Clinical and pathology studies demonstrated endothelial injury 32 associated with intracellular SARS-CoV-2 infection, widespread microangiopathy of alveolar capillaries and angiogenesis, features that appeared different from influenza A (H1N1) infection. 33 Furthermore, recently, our team showed that therapeutic anticoagulation at admission could prevent COVID-19-associated endothelial injury. 6 Previous reports 1, 4, 8, 7, 5, 6 have shown that D-dimer levels are increased during COVID-19associated coagulopathy and higher D-dimer levels at admission are associated with VTE J o u r n a l P r e -p r o o f during follow-up. 17 The use of high D-dimer thresholds, such as 3500 ng/mL, is not effective enough to diagnose PE or initiate therapeutic anticoagulation, as we showed that the D-dimer positive predictive value in patients with suspected PE was only 50%. As previously published D-dimer are increased in pneumonia and associated with radiologic pneumonia extension 34 Furthermore, in patients diagnosed with community-acquired pneumonia, Ddimers where more elevated in patients with high probability PE 35 .

Our study results suggest that D-dimer measurement has a poor performance for PE diagnosis that should be only driven by CTPA or V/Q lung scan use as suggested by the recent ISTH guidance 36 . The main limitation of this strategy is the prevalence of renal impairment 37 and the risk of contrast-induced nephropathy in COVID-19 patients especially in ICU.

Considering that PE could be frequently suspected at COVID-19 diagnosis or when respiratory condition gets worse, majority of patients would require CTPA. A specific clinical probability score, a specific D-dimer threshold or an adjusted strategy pending damage lung extent could help in reducing CTPA use in COVID-19 patients Our study has a few limitations. First this is a retrospective series due to the emergency of the health crisis. Second outcomes analysis may be biased because some patients were still hospitalized at the time of data collection and other patients were transferred to other hospitals. Thus, it may lead to immortal time bias, potentially affecting the PE prevalence. 146 a Two prevalences were tested considering prevalence of PE in our cohort (5.6%) and prevalence of PE in patients for whom it has been suspected (21.2%); b Optimal D-dimer according to the ROC curve. PE = pulmonary embolism; Se = sensitivity; Sp = specificity; NPV = negative predictive value; PPV = positive predictive value.

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All percentages were calculated for available data for each variable. a PE patients versus CTPA controls

We would like to acknowledge all nurses, technicians and physicians involved in the Vascular medicine, Radiology, Internal medicine, Respiratory medicine, Intensive care and Hematology departments of GHPSJ and HEGP for their help in taking care of patients and including them in the study. We thank Andréanne Durivage for the English editing.J o u r n a l P r e -p r o o f