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Respiratory Medicine 169 (2020) 106023 Contents lists available at ScienceDirect Respiratory Medicine journal homepage: http://www.elsevier.com/locate/rmed Short communication D-dimer in patients infected with COVID-19 and suspected pulmonary embolism Ignasi Garcia-Oliv�e a, b, c, Helena Sintes a, d, Joaquim Radua e, f, g, h, Jorge Abad Capa a, b, c, d, *, Antoni Rosell a, b, c, d a Servei de Pneumologia. Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain b CibeRes, Ciber de Enfermedades Respiratorias, Bunyola, Spain c Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain d Departament de Medicina. Universitat Aut� onoma de Barcelona, Barcelona, Spain e Imaging of Mood- and Anxiety-Related Disorders (IMARD) group, Institut d’Investigacions Biom�ediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain f CIBERSAM, Madrid, Spain g Early Psychosis: Interventions and Clinical-detection (EPIC) lab, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK h Department of Clinical Neuroscience, Stockholm Health Care Services, Stockholm County Council, Karolinska Institutet, Stockholm, Sweden A R T I C L E I N F O A B S T R A C T Keywords: Objective: To analyze the risk factors for pulmonary embolism (PE) in patients infected with COVID-19. COVID-19 Methods: We conducted an observational, retrospective study. Patients with severe infection with COVID-19 and D-dimer suspected PE were included. Pulmonary embolism Results: Patients with higher levels of D-dimer and those requiring intubation were at a higher risk of developing PE. Higher D-dimer levels were associated with a greater probability of PE 3, 6, 9 and 12 days after determining D-dimer levels with an OR of 1.7, 2.0, 2.4 and 2.4, respectively. Conclusion: In conclusion, patients infected with COVID-19 requiring OTI with higher levels of D-dimer have an increased risk of developing PE. 1. Introduction referral hospital in Badalona (Barcelona, Spain), with 600 beds, covering a population of 700,000 inhabitants. Since the beginning of the COVID-19 pandemic, some authors have suggested that the infection may directly impact cardiovascular disease, 2.2. Study subjects either by increasing the risk of severe disease and death in patients with preexisting cardiovascular disease (CVD) or by the association of Patients hospitalized for severe infection with COVID-19 and sus­ COVID-19 infection with cardiovascular complications including acute pected PE during a two-week period were included. Suspicion was myocardial injury, arrhythmias and venous thromboembolism (VTE) mainly based on a worsening of respiratory symptoms and increases in [1]. D-dimer values. Patients with suspected PE underwent diagnostic pro­ Our objective was to describe our experience with patients infected cedures in order to confirm the diagnosis. with COVID-19 in whom pulmonary embolism (PE) has been suspected and to analyze the associated factors. 2.3. Statistical analysis 2. Methods Categorical variables are expressed as frequencies, while quantita­ tive variables are expressed as the mean and standard deviation (SD). 2.1. Location Qualitative variables were compared with Fisher’s exact test, while quantitative variables were compared using the t-student test. These This was an observational, retrospective study, conducted in a analyses were conducted with version 15 of STATA. * Corresponding author. Servei de Pneumologia. Hospital Universitari Germans Trias i Pujol, Badalona, Carretera del canyet sn, 08916, Badalona, Spain. E-mail address: jabadc.germanstrias@gencat.cat (J. Abad Capa). https://doi.org/10.1016/j.rmed.2020.106023 Received 19 April 2020; Accepted 11 May 2020 Available online 13 May 2020 0954-6111/© 2020 Elsevier Ltd. All rights reserved. I. Garcia-Oliv�e et al. Respiratory Medicine 169 (2020) 106023 Fig. 1. Association between D-dimer levels and probability of PE 3, 6, 9 and 12 days after the determination. We were also interested in assessing whether D-dimer levels might intubated showed a higher risk of PE (p ¼ 0.008). predict the development of PE in the following days. To this end, we first recorded, for each determination of D-dimer levels, whether the patient 3.2. D-dimer had developed PE 3, 6, 9 or 12 days after that determination. Then, separately for each of these time lags (e.g., 3 days), we fitted a mixed- Higher D-dimer levels were associated with a higher probability of effects logistic regression, with the presence of PE as the dependent bi­ PE three days after the determination of the D-dimer levels (OR ¼ 1.7, p nary variable (i.e., the future outcome that we wished to predict), D- ¼ 0.022), 6 days after the determination (OR ¼ 2.0, p ¼ 0.033), 9 days dimer levels as the independent variable (i.e., the variable that we after the determination (OR ¼ 2.4, p ¼ 0.024) and 12 days after the wished to use for predicting), and the subject identification as a random determination (OR ¼ 2.4, p ¼ 0.015) (Fig. 1). factor (to adjust for repeated measures). Initially we also aimed to conduct this analysis using shorter time lags (1 or 2 days), but we could 4. Discussion not correctly fit the corresponding mixed-effects logistic regressions due to singularity. This analysis was conducted with the “lme400 package for Our data show that in severe COVID-19 pneumonia the risk of R [2]. developing PE is associated with higher progressive incremental levels of D-dimer than those observed in the group without PE. The risk of PE 2.4. Ethical considerations increases at day 3 (OR 1.67), day 6 (OR 1.98) and day 9 (OR 2.39) after the first D-dimer determination. The risk does not increase signi­ The research protocol was approved by the regional ethics commit­ ficatively after day 9 (OR 2.38). tee (reference PI-20-131). Potential association between COVID-19 and venous thromboem­ bolism is not new. Several authors have described hematological pa­ 3. Results rameters alterations in patients infected with COVID-19 [3–6]. Among them, some have described an association between the severity of the Twenty-one patients were included in the analysis. Briefly, 48% of disease and levels of D-dimer [4–6]. Zhou and cols, in a retrospective, them were female, with a mean age of 59.9 years (SD 10.9). Days be­ multicentric cohort study conducted in China described increasing odds tween admission and suspicion of PE was 9.7, and mean dimer-D levels of in-hospital death associated with d-dimer greater than 1 μg/mL on on admission and on suspicion of PE were 1.6 μg/mL and 5.1 μg/mL admission [4]. Tang et al. [5], in a series that included 183 patients with respectively, with normal D-dimer values in our laboratory being those confirmed COVID-19 infection, found that patients with abnormal under 0.5 μg/mL. coagulation results, especially markedly elevated D-dimer and fibrin degradation product levels, had a higher risk of death. Furthermore, Gao 3.1. Potential risk factors and cols found that D-dimer levels were closely related to the occurrence of severe COVID-19 disease in adult patients [6]. In line with these Neither age, gender nor days of hospitalization were not associated findings, anticoagulant treatment has been found to be associated with with an increased risk of developing PE. Patients with confirmed PE decreased mortality in patients with severe COVID-19 disease meeting showed higher levels of D-dimer (p ¼ 0.023). Patients who had been the criteria for sepsis-induced coagulopathy or with markedly elevated 2 I. Garcia-Oliv�e et al. Respiratory Medicine 169 (2020) 106023 D-dimer levels [7]. people or organizations that may have inappropriately influenced their Recently, several authors have suggested an association between work in the present article. COVID-19 pneumonia and VTE [8]. Some authors have described the The authors declare that they have no known competing financial prevalence of VTE in severely ill patients [9,10]. In the study by Cui et al. interests or personal relationships that could have appeared to influence [9] the prevalence of VTE was 25%, with a sensitivity, specificity and the work reported in this paper. negative predictive value of D-dimer cut-off value of 1.5 μg/mL of 85, 88.5 and 94.7%, respectively. Klok and cols [10] reported an incidence References of 31% of thrombotic complications in ICU patients with COVID-19 infection. In this study, the authors did not analyze the association be­ [1] E. Driggin, M.V. Madhavan, B. Bikdeli, et al., Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease tween levels of D-dimer and the occurrence of thrombotic events. 2019 (COVID-19) pandemic, J. Am. Coll. Cardiol. (2020 Mar 18), https://doi.org/ Although this is a short analysis it is important to note that it is one of 10.1016/j.jacc.2020.03.031 pii: S0735-1097(20)34637-4. the few studies that has investigated the risk of PE in patients infected [2] D. Bates, M. Maechler, B. Bolker, et al., Fitting linear mixed-effects models using lme4, J. Stat. Software 67 (2015) 1–48, https://doi.org/10.18637/jss.v067.i01. with COVID-19, and analysed the association between D-dimer levels [3] B.E. Fan, V.C.L. Chong, S.S.W. Chan, et al., Hematologic parameters in patients and PE over time. Our data would suggest that despite the high D-dimer with COVID-19 infection, Am Hematol (2020 Mar 4), https://doi.org/10.1002/ value at admission, its rapid increment is associated with a significant ajh.25774. [4] F. Zhou, T. Yu, R. Du, et al., Clinical course and risk factors for mortality of adult risk of PE. Although the ultimate aim of our study would be to use D- inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet dimer levels to predict the development of PE and thus prevent it, we 395 (10229) (2020 Mar 28) 1054–1062, https://doi.org/10.1016/S0140-6736(20) would like to highlight that our results should be taken with caution 30566-3. [5] N. Tang, D. Li, X. Wang, et al., Abnormal Coagulation parameters are associated until they are replicated with other data. with poor prognosis in patients with novel coronavirus pneumonia, J. Thromb. To conclude, patients with severe COVID-19 disease requiring oro­ Haemostasis 18 (4) (2020. Apr) 844–847, https://doi.org/10.1111/jth.14768. tracheal intubation and higher levels of D-dimer have an increased risk [6] Y. Gao, T. Li, M. Han, et al., Diagnostic utility of clinical laboratory data of developing PE. Prospective studies with a larger sample size are determinations for patients with the severe COVID-19, J. Med. Virol. (2020 Mar 17), https://doi.org/10.1002/jmv.25770. required in order to obtain D-dimer cut-off values to create protocols [7] N. Tang, H. Bai, X. Chen, et al., Anticoagulant treatment is associated with both for anticoagulant treatment and diagnostic evaluation when PE is decreased mortality in severe coronavirus disease 2019 patients with suspected. coagulopathy, J. Thromb. Haemostasis (2020 Mar 27), https://doi.org/10.1111/ jth.14817. [8] G.B. Danzi, M. Loffi, G. Galeazzi, et al., Acute pulmonary embolism and COVID-19 Author contribution pneumonia: a random association? Eur. Heart J. (2020) https://doi.org/10.1093/ eurheartj/ehaa254. [9] S. Cui, S. Chen, X. Li, F. Wang, Prevalence of venous thromboembolism in patients Study design: IGO, JAC, AR. with severe novel coronavirus pneumonia, J. Thromb. Haemostasis (2020), Data collecting: IGO, HSP. https://doi.org/10.1111/jth.14830. Statistical analysis: IGO, JR. [10] F.A. Klok, M.J.H.A. Kruip, N.J.M. van der Meer, et al., Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Thromb. Res. (2020), Wrote the manuscript: IGO, HSP. https://doi.org/10.1016/j.thromres.2020.04.13. Read critically the manuscript: IGO, HSP, JR, JAC, AR. Declaration of competing interest The authors do not have any financial or personal relationships with 3