key: cord-1031833-my02g4vc
authors: Mouhat, Basile; Besutti, Matthieu; Bouiller, Kevin; Grillet, Franck; Monnin, Charles; Ecarnot, Fiona; Behr, Julien; Capellier, Gilles; Soumagne, Thibaud; Pili-Floury, Sébastien; Besch, Guillaume; Mourey, Guillaume; Lepiller, Quentin; Chirouze, Catherine; Schiele, François; Chopard, Romain; Meneveau, Nicolas
title: Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients
date: 2020-09-09
journal: Eur Respir J
DOI: 10.1183/13993003.01811-2020
sha: 3cc18c48328c517d296861ec8e4eed1fef440328
doc_id: 1031833
cord_uid: my02g4vc

BACKGROUND: COVID-19 may predispose to venous thromboembolism. We determined factors independently associated with computed tomography pulmonary angiography (CTPA)-confirmed pulmonary embolism (PE) in hospitalised severe COVID-19 patients. METHODS: Among all (N=349) patients hospitalised for COVID-19 in a university hospital in a French region with a high rate of COVID-19, we analysed patients who underwent CTPA for clinical signs of severe disease (SpO2≤93% or breathing rate≥30/min); or rapid clinical worsening. Multivariable analysis was performed using Firth penalised maximum likelihood estimates. RESULTS: In total, 162 patients (46.4%) underwent CTPA (mean age 65.6±13.0; 67.3% males (95% confidence interval (CI) 59.5–75.5%)). PE was diagnosed in 44 patients (27.2%). Most PE were segmental and the rate of PE-related right ventricular dysfunction was 15.9%. By multivariable analysis, the only two significant predictors of CTPA-confirmed PE were D-dimer level and the lack of any anticoagulant therapy (odds ratio (OR) 4.0 (95%CI 2.4–6.7) per additional quartile, and OR 4.5 (95%CI 1.1–7.4) respectively). ROC curve analysis identified a D-dimer cut-off value of 2590 ng·mL(−1) to best predict occurrence of PE (AUC: 0.88, p<0.001, sensitivity 83.3%, specificity 83.8%). D-dimer level >2590 ng·mL(−1) was associated with a 17-fold increase in the adjusted risk of PE. CONCLUSION: Elevated D-dimers (>2590 ng·mL(−1)) and absence of anticoagulant therapy predict PE in hospitalised COVID-19 patients with clinical signs of severity. These data strengthen the evidence base in favour of systematic anticoagulation, and suggest wider use of D-dimer guided CTPA to screen for PE in acutely ill hospitalised patients with COVID-19.

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may predispose patients to venous thromboembolic (VTE) complications [1] .

Preliminary reports suggest that the severe inflammatory response and other features of critical illness contribute to a procoagulant profile that predisposes to thrombotic events [2, 3] . Possible forms of coagulopathy include hemostatic abnormalities, notably with increased levels of D-dimers [2] [3] [4] [5] .

Incident pulmonary embolism (PE) has been reported in 20.6% to 30% of severe COVID-19 patients [6] [7] [8] [9] [10] . However, given the clinical presentation of patients with concomitant COVID-19

pneumonia, it is difficult to identify patients in whom PE should be suspected. In this regard, the indications for computed tomography pulmonary angiography (CTPA) remain to be defined. [11] [12] [13] [14] Furthermore, the efficacy of VTE prophylaxis in patients with COVID-19 is poorly documented. [15] In this context, this study aimed to: (1) determine the independent predictors of PE; and (2) evaluate whether anticoagulant therapy is effective for PE prevention in severe COVID-19 patients undergoing computed-tomography pulmonary angiography (CTPA) imaging.

Retrospective, single-centre study in a university tertiary care hospital in Besançon, France, with a high rate of COVID-19 [16] . We included all patients hospitalized from 15

March to 16 April 2020 with biologically proven COVID-19 pneumonia and CTPA performed due to clinical signs of severity, namely: SpO2 ≤ 93% in room air, breathing rate of ≥30/min; or rapid clinical worsening [17] . Patients were followed until death or 5th May 2020, even if discharged before. In the context of the COVID-19 pandemic, the French national commission for the protection of personal data (CNIL) considers that, for single-centre observational research, the need for information of patients and families is waived. Our protocol followed the ethical guidelines of the declaration of Helsinki and was approved by our institutional review board. Results are reported in accordance with the STROBE guidelines. [19] 

Baseline characteristics, in-hospital therapies, CTPA findings, and adverse events were recorded by research physicians in an anonymous case report form. For each patient, demographic data, medical history, and home treatments were collected prospectively at admission. Each patient had a blood sample drawn at admission, and then at least once daily thereafter.

Multidetector CTPA was performed on a Revolution CT machine (GE Healthcare, Milwaukee, WI, USA) after intravenous injection of 60 ml iodinated contrast agent (Iomeprol 400 Mg I/mL, Bracco Imaging, Milan, IT) at a flow rate of 4 mL/s, triggered in the pulmonary trunk.

Imaging results were reviewed by two chest radiologists. Readers were blinded to clinical and biological features. Readers were asked to assess the COVID-19 pattern by quantitative visual CT evaluation, which consisted in grading acute COVID-19-related lung inflammatory lesions for each lobe, scored as 0 (0%), 1 (1-25%), 2 (26-50%), 3 (51-75%), or 4 (76-100%), respectively. The total severity score was reached by summing the five lobe scores [20] .

Readers were also asked to detect presence or absence on CTPA of PE, defined as a filling defect within pulmonary vessels [21] . When PE present, readers reported extent of PE; topography of PE; and signs of right ventricular (RV) dysfunction (i.e. enlargement of the pulmonary artery >35mm, abnormal position of the interventricular septum, right ventricular dilation (defined by a RV/left ventricular (LV) ratio >1 measured in the transverse or four-chamber view on CTPA [22] ), or the presence of pulmonary infarction). In case of discordance between readers, scans were re-assessed to reach consensus.

The primary objective was to determine independent predictors of PE in COVID-19 patients with clinical signs of severity who underwent CTPA. The secondary objective was to evaluate whether anticoagulant therapy is effective for PE prevention in these patients.

Continuous variables are expressed as mean±standard deviation or median [Q1-Q3] as appropriate.

Categorical variables are expressed as number (percentage). Unadjusted differences between patients with and without CTPA-confirmed PE were compared using the chi square or Student t-test, as appropriate. To identify independent predictors of CTPA-confirmed PE in severe COVID-19 patients, we used Firth penalized maximum likelihood estimates to adjust our cohort study that includes a small sample size (n=162), to overcome the substantial bias linked to logistic regression [23] .

Multivariable models included site of care (conventional ward vs ICU) as a random effect to account for patient clustering within departments. In multivariable models, continuous co-variates were categorized per quartile. All variables with a p-value<0.10 by univariate analysis were included in multivariable analysis. Linearity of significant co-variates in the multivariable model was verified before computing the Receiver Operating Characteristic (ROC) curve to determine the optimal cutoff value. The multivariable model was then repeated, including independent continuous variables dichotomized based on ROC curve results. The accuracy of the multivariable models was assessed by: (1) global model fit (Akaike Information Criteria and Bayes Information Criteria); (2) discrimination, using Harrell's C-statistic index; and calibration by visually plotting the mean of model-predicted CTPA-confirmed PE in each decile against observed PE.

All tests were two-sided. A p-value <0.05 was considered significant. Analyses were performed using SAS 9.4 (SAS institute Inc., Cary, NC). Table 1 summarizes the demographic and clinical characteristics of the population at admission.

Mean age was 65.57±13 years, 67.3% (95%CI, 59.5-75.5) were male. The most common comorbidities were hypertension, dyslipidemia, obesity, diabetes mellitus, and a history of any heart disease. There were no significant differences between patients with vs without PE, except more men had PE. Factors known to be associated with an increased risk of VTE, such as history of VTE, cancer, and recent surgery did not differ between groups (Table 1) .

There was no difference in home treatment between groups. Thirteen patients (8.0% (95%CI, 4.3-13.3)) were taking anticoagulant therapy at admission for a history of VTE or atrial fibrillation, (Table   1 ).

In total, during follow-up, 21 Regarding the COVID-19-related CT pattern, half of the patients had more than 50% of affected lung parenchyma. There was an unadjusted difference in the extent of COVID-19-related CT abnormality between patients with and without PE (p=0.001), whereby forms with >50% extension were predominantly found in patients with PE.

Unadjusted comparisons of biological results from blood samples drawn on the day of CTPA are summarized in Table 3 Figures S2 and S3 ).

To the best of our knowledge, this study is the first to identify independent predictors of the occurrence of PE, from a cohort of 162 COVID-19 patients with clinical signs of severity. Our data show that PE was frequent in these patients, while elevated D-dimer levels and the absence of any anticoagulant therapy were both found to be independent predictors of PE. Specifically, a D-dimer level >2590 ng/mL was associated with a 17-fold increase, and lack of anticoagulation with a 4-fold The increased thrombo-embolic risk in COVID-19 patients could be enhanced by a procoagulant state generated by the severity of the infection,[2] the magnitude of the inflammatory response [3] and liver dysfunction [24] [25] [26] . The most frequently reported biological anomalies in COVID-19 patients include elevations of inflammatory markers such as CRP, D-dimers, ferritin and IL-6. [27, 28] In our population, D-dimer levels were four times higher in PE patients than in non-PE patients. This elevation of D-dimer levels has been established as being associated with severity of disease and mortality in COVID-19 patients and should be considered to reflect activation of the coagulation system in this setting. [3, 9, [28] [29] [30] In a Chinese study of 183 patients with COVID-19, D-dimer levels were 3.5 times higher in patients who died compared to patients who survived. [3] Similarly, COVID-19 patients with increased D-dimer concentration at admission (>1000 ng/mL) were reported to have an 18-times higher risk of in-hospital mortality than those with normal D-dimer levels. [28] Our data confirm this finding, and strengthen the evidence underpinning the relation between elevated D-dimers and the risk of PE in COVID-19 patients. [1] The threshold for D-dimers that we identified, i.e. 2590 ng/mL, was the stronger independent predictor of PE in our population. To the best of our knowledge, this study is the first to identify a threshold for D-dimer levels that is an independent predictor of PE in COVID-19 patients after multivariable adjustment. Therefore, particular attention should be paid to search for potential PE in patients with clinical criteria of severity and with a D-dimer level above 2590 ng/mL, since PE is a life-threatening but potentially treatable condition [22] .

Our data confirm that anticoagulation for the prevention of VTE is absolutely crucial in the most severe COVID-19 patients, and administration of anticoagulants reduces the risk of PE by 4. The relatively high proportion of patients who did not receive preventive anticoagulation in our study can likely be explained by the fact that 20.5% of patients had a diagnosis of PE at admission and were thus admitted directly from home with no anticoagulation in place. A recently published short report including 2773 COVID-19 patients showed that longer duration of anticoagulant treatment was associated with a reduced risk of in-hospital mortality (adjusted hazard ratio 0.86 per day, 95% CI 0.82-0.89). [31] In our study, regardless of the regimen used, the prevalence of PE remained high. However, our data do not enable us to determine the most appropriate prophylactic strategy, or to answer the question of whether curative doses are more effective than preventive doses in averting PE. This question was the subject of some debate during the development of a recent consensus on the prevention, antithrombotic therapy, and follow-up of thrombotic or thromboembolic disease in COVID-19 patients. [15] Indeed, in this document, the authors were unable to reach consensus on the optimal dosing of anticoagulant therapy, stipulating that "the majority of panel members consider prophylactic anticoagulation, although a minority consider intermediate-dose or therapeutic dose to be reasonable". [15] There is thus a compelling need for prospective studies investigating the optimal dosing in patients with severe COVID-19. In practice, pluridisciplinary discussion is warranted to evaluate the patient's hemorrhagic risk, and to weigh it against the risk of VTE. In light of our results, this point is of paramount importance in COVID-19 patients with severe forms of disease and evidence of activation of the coagulation system (e.g. elevated D-dimers) in whom

prophylactic anticoagulant treatment appears to be essential for the prevention of PE. This is in accordance with a study of 449 patients with severe COVID-19 from China, where a reduction in mortality of around 20% was observed with heparin treatment in patients who had D-dimers exceeding 3000 ng/mL (6 times the upper limit of normal, ULN). [32] Furthermore, a recent expert panel document from the Global COVID-19 Thrombosis Collaborative Group postulates that LMWH and UFH may have anti-inflammatory and antiviral properties [33] , although there is no established link between these properties and the course of COVID-19 disease.

Although current guidelines from professional societies of radiology recommend performing noncontrast chest CT to assess the COVID-19 pattern and its extension, [11] [12] [13] our data plead in favour of a wider screening strategy for PE by performing CTPA in COVID-19 patients who have signs of clinical severity and D-dimer levels > 2590 ng/mL. Indeed, the utility of CTPA over non-contrast CT is that it covers the whole spectrum of possible COVID-19-related complications, including COVID-19related lung injuries, parenchymal bacterial infection, pleural effusion, pneumothorax, as well as enabling diagnosis of PE thanks to contrast injection. The high prevalence of PE in patients receiving anticoagulation is an additional argument in favour of this approach. The D-dimer cut-off identified in this study could be used to guide CTPA use, particularly in patients at risk of contrast-induced acute kidney injury. Indeed, it has recently been shown that acute kidney injury was associated with unfavourable outcome in hospitalized COVID-19 patients [34, 35] . Further prospective studies with larger sample sizes are warranted to externally validate the optimal D-dimer cut-off value related to PE in acutely ill hospitalized COVID-19 patients.

Our study has some limitations. Firstly, it is a retrospective study from a single-centre, and we cannot exclude the possible presence of unmeasured confounders. The sample size is relatively small, although it is nonetheless the largest series of COVID-19 patients undergoing CTPA reported to date. Only patients undergoing CTPA were included, and it is thus possible that the actual rate of PE was even higher than reported here. The selection of patients to undergo CTPA was based on clinical criteria of severity that may be debatable. Furthermore, most patients did not have compression ultrasonography screening during the study period. Our data do not make it possible to identify the most appropriate prophylactic anticoagulation strategy, and notably, do not provide answer the question of whether curative anticoagulation is more effective than preventive anticoagulation in averting PE. Finally, transthoracic echocardiographic data was not recorded in the present study to assess RV function in COVID-19-associated PE patients. However, current guidelines stipulate that CTPA is a validated alternative for the evaluation of RV dysfunction in acute PE [22] .

Despite these limitations, this study is the first to identify independent predictors of PE, using robust statistical methods, and to report exhaustive biological and radiological findings as well as details of anticoagulant therapy in COVID-19 patients at the peak of the epidemic in France.

Pulmonary embolism is frequent in patients with clinically severe COVID-19 disease. Elevated Ddimer levels (>2590 ng/mL) and a lack of anticoagulation were found to be independent predictors of PE in these patients. These data strengthen the evidence base in favour of systematic anticoagulation, and suggest wider use of D-dimer guided CTPA to screen for PE in acutely ill hospitalized patients with COVID-19. The optimal dosing of anticoagulants remains unknown and warrants further prospective investigation.

No author has any conflict of interest to declare.

This work received no funding. 

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COPD, chronic obstructive pulmonary disease

ACEI, angiotensin-converting enzyme inhibitors

defined as any history of coronary artery disease, valvular heart disease, arrhythmia, dilated or hypertrophic cardiomyopathy ‡Cancer

3% (95%CI, 2.6-21

Alkaline Phosphatase

Supplementary