Julien Poissy, MD, PhD¹; Julien Goutay, MD ²; Morgan Caplan, MD²; Erika Parmentier, MD²; Thibault Duburcq, MD²; Fanny Lassalle, PharmD³; Emmanuelle Jeanpierre, PharmD³; Antoine Rauch, MD, PhD³; Julien Labreuche, BST⁴; Sophie Susen, MD, PhD³; and the Lille ICU Haemostasis COVID-19 group

1 Univ. Lille, Inserm U1285, CHU Lille, Pôle de Réanimation, CNRS, UMR 8576 – UGSF -Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France;

2 CHU Lille, Pôlede réanimation, F-59000, Lille, France;

3 Univ. Lille, Inserm, CHU Lille, Departement of Hematology and Transfusion, Pôle de Biologie Pathologie Génétique, Institut Pasteur de Lille,UMR1011-EGID, 59000, Lille, France;

4 Univ. Lille, CHU Lille, ULR 2694 – METRICS:
Évaluation des technologies de santé et des pratiques médicales, F-59000 Lille, France

Abstract

We report a case-series of COVID-19 patients with pulmonary embolism (PE) in our institution. Lille University Hospital is the tertiary care center for the North-of-France, the 2nd French region in population density (189 p/km2), also considered as a “metabolic” area with high number of overweight patients.

The study was approved by the Institutional data protection authority of Lille University Hospital.

Introduction

Among the 107 first consecutive confirmed COVID-19 patients admitted in ICU for pneumonia from Feb 27th to March 31th, we noticed an unexpected high number of PE during their stay in ICU, 22(20.6%) at the time of analysis (April 9th), within a median time from ICU admission of 6 days (range 1 to 18 days).

To determine whether this represents an increase in the expected incidence of PE over a similar time interval, we analyzed the files of 196 patients hospitalized in our ICU during the same time interval in 2019.

Despite a similar severity score at entrance in ICU, the frequency of PE in our COVID-19 series was twice higher than the frequency we found in this control period, (20.6% vs 6.1%; absolute increase risk of 14.4%, 95%CI 6.1 to 22.8%).

It was also twice higher than the 7.5% frequency of PE in the 40 Influenza ICU patients admitted between 1stJanuary to 31thDecember 2019 (3PE, absolute increase risk 13.1%, 95%CI 1.9 to 24.3%).

A qualitative description of main characteristics of PE cases in the different periods are reported in the Table.

Taking into account the ICU duration at time of analysis, we estimated the cumulative incidence of PE using Kalbfleisch and Prentice-method by taking into account death (n=15) and discharge alive (n=48) as competing events; the 22 patients still hospitalized in ICU without PE at the time of analysis (median[range] ICU length of stay=15 days [10 to 30] days) were treated as censored observations.

At 15 day of ICU admission, cumulative incidence of PE in COVID-19 ICU patients was estimated to 20.4% (95%CI, 13.1 to 28.7%).

Regarding main data at ICU admission (using univariable Fine and Gray model to estimate subhazard ratios (SHRs) of PE), D-Dimers (SHR per log-SD increase=1.81; 95%CI,1.03 to 3.16), plasma factor VIII activity (SHR per log-SD increase,1.73; 95%CI,1.10 to 2.72), and factor Willebrand antigen levels (SHR per log-SD increase,1.69; 95%CI,1.12 to 2.56) values seem to be associated with a greater PE risk.

At the time of PE diagnosis, 20/22 patients were receiving prophylactic antithrombotic treatment (UFH or LWMH) according to the current guidelines in critically ill patients1,2.

One patient with a history of DVT was receiving fluindione with INR in the therapeutic range and one patient was receiving therapeutic UFH because of atrial fibrillation.

The criteria for decision to perform Computed Tomography Pulmonary Angiography (CTPA) were suspicion of PE upon admission and/or acute degradation of hemodynamic or respiratory status. All CTPA were performed with multi-bar CT with no difference in the injection protocol whether the CTPA was performed for PE diagnosis or not.

The number of CTPA was higher in COVID19 patients than in the ICU patients hospitalized during the same time period in 2019.

This historical control group reflects the global practice in our ICU. Because only 34% of patients from this group suffer from respiratory failure requiring CTPA (see Table), a potential bias of an increased detection of PE in COVID-19 patients could have been generated.

That is why we compared COVID-19 patients to Influenza patients admitted in ICU for respiratory failure in 2019. Even if the number of CTPA performed in Influenza patients was higher than in patients with COVID-19, less PE were identified, reinforcing the increase risk of PE in COVID-19 patients.

The low number of associated DVT in COVID-19 patients may suggest that they have pulmonary thrombosis rather than embolism.

Pulmonary embolism frequency has not yet been reported in the different series of COVID-19 patients. All our patients received thromboprophylaxis according to the current recommendations for critically ill medical patient.

However, we suspect that the high obesity prevalence in our patient-group contributes to the increased PE frequency3 specific studies in this population, the recommendations do not mention an adaptation of prophylaxis regimen in overweight patients nor a need for monitoring of anti-factor concentration.

Furthermore, heparin could have benefic impacts in COVID-19 infection, but the effective dose and monitoring is discussed, in particular in very high-risk patients, with high BMI or according to other criteria such as D-dimers4 Indeed, during the H1N1-flupandemic, some centers reported an increased thrombotic risk in severe patients with ARDS and suggested the use of higher doses of heparin5.

In conclusion, there is an urgent need for replication in a much larger scale of our data on PE frequency in COVID-19 infection in ICU-patients.

Failure to identify and accurately managethis risk could worsen the prognosis of patients with COVID-19.

References

1. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S, Murad MH. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e195S-e226S.

2. Schünemann HJ, Cushman M, Burnett AE, Kahn SR, Beyer-Westendorf J, Spencer FA, Rezende SM, Zakai NA, Bauer KA, Dentali F, Lansing J, Balduzzi S, Darzi A, Morgano GP, Neumann I, Nieuwlaat R, Yepes-Nuñez JJ, Zhang Y, Wiercioch W. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv. 2018;2:3198–3225.

3. Simonnet A, Chetboun M, Poissy J, Raverdy V, Noulette J, Duhamel A, Labreuche J, Mathieu D, Pattou F, Jourdain M, Lille Intensive Care COVID-19 and Obesity study group. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) requiring invasive mechanical ventilation. Obesity (Silver Spring). April 9, 2020. doi:10.1002/oby.22831. [epub ahead of print].

4. Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. April 2, 2020. doi:10.1111/jth.14821. [epub ahead of print].

5. Obi AT, Tignanelli CJ, Jacobs BN, Arya S, Park PK, Wakefield TW, Henke PK, Napolitano LM. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. J Vasc Surg Venous Lymphat Disord. 2019;7:317–324.

Affiliations

Julien Poissy, MD, PhD
Pôle de Réanimation, Hôpital Roger Salengro,
Rue Emile Laine, CHU Lille, 59037 Lille cedex, France.
Tel: +33320444084
Fax: +33320446504
Email: julien.poissy@chru-lille.fr

Sophie Susen, MD, PhD
Institut Cœur-Poumon (Heart and Lung Institute)
Hemostasis Department, Bd du Pr Leclercq
CHU Lille, 59037 Lille cedex, France
Tel: +33320444891
Fax: +33320446504
Email: sophiesusen@aol.com