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G Model ARBRES-2543; No. of Pages 2 ARTICLE IN PRESS Arch Bronconeumol. 2020;xxx(xx):xxx–xxx www.archbronconeumol.org Scientific Letter Pulmonary Embolism in Patients With Covid-19 CTPA assessment were clinical worsening (85%) and/or elevated Pneumonia: The Utility of D-dimer D-dimer (15%). Only two patients had right ventricle dilatation at the time of PE diagnosis. Dyslipidaemia and obesity were Embolia pulmonar en pacientes con neumonia por covid-19: more frequent in patients with PE, but there were no signifi- utilidad del dímero-d cant differences found between groups when analysing with other variables. Forty-nine patients received low weight molecular hep- Dear Editor, arin (LWMH) as thromboprophylaxis at standard dose (40 mg/day, n = 25) or intermediate dose (1 mg/kg/day, n = 18) according D- D-dimer levels are increased in pulmonary embolism (PE) dimer value (≤2000 and >2000, respectively) or therapeutic LWMH but also in many other conditions including inflammation, (1 mg/kg/12 h, n = 6) for medical conditions (atrial fibrillation and cancer, pregnancy, trauma, and sepsis.1 D-dimer is a useful others). Three patients (2 with PE and 1 non-PE) did not receive rule-out test for avoiding imaging in several clinical settings.2 thromboprophylaxis. In fact, in patients with low or intermediate clinical proba- At the time of admission, D-dimer levels were not dif- bility, D-dimer has negative predictive value to exclude deep ferent among patients that developed PE [(median (P5–P75) vein thrombosis or PE without further testing in the outpatient 2350 (1070–10500) mcg/L] and those who did not [3030 setting.3 Nevertheless, its usefulness in hospitalized patients with (650–12415) mcg/L], (P = .87). We found significant differences in suspected thromboembolism is less well established. Only few the highest values of D-dimer before performing CTPA only in studies have evaluated the predictive value of quantification of D- patients with PE [14,240 (5140–31550) mcg/L, P = .007]. The mean dimers in hospitalized patients with PE,4 and there are no studies changes from the baseline to the highest values before CTPA for addressing this topic in patients with COVID-19. Thus, in the con- patients with PE was 9406 (2917) mcg/L. In Table 1, we set out text of the COVID pandemic, in which seriously ill patients have estimates of sensitivity, specificity, Positive Predicted Value (PPV), respiratory symptoms, it is even more convenient to find an ade- Negative Predicted Value (NPV), Positive Likelihood Ratio (LR+), and quate value of D-dimer that can help when requesting imaging (LR−) values to predict the diagnosis of PE. D-dimer of 2000 mcg/L studies, such as computed tomography pulmonary angiography resulted in the best cut-off point of sensitivity for patients with PE: (CTPA). sensitivity, 1.00; PPV, 0.60; specificity, 0.44; and, NPV, 1.00; LR−, A retrospective study was performed to analyze the predictive 0. Using this threshold there were zero negative false cases; how- value of D-dimer to assess CTPA for diagnosis of PE in patients ever, there were 18 (35%) positive false cases. By contrast, D-dimer with COVID-19 pneumonia during their hospitalization. The local of 30,000 mcg/L or higher was the best threshold for the diagnosis Clinical Research Ethical approved the study. of PE; sensitivity, 0.26; PPV, 0.75; specificity, 0.93; NPV, 0.61, and All patients included in current study were COVID-19 positive LR+, 3.78; but we found only 2 (3.8%) positive false cases at this cut- according to present diagnostic criterion.5 They had undergone off. In addition, we found that a variation in D-dimer of 4000 mcg/L CTPA scans due to suspected PE and underwent D-dimer tests or more from admission to the highest value before CPTA was pre- according guidelines.6 D-dimers were checked at least at the time dictive of PE with a sensitivity, 0.48; PPV, 0.79; specificity, 0.90; of admission and prior to CTPA. D-dimer (local reference range: NPV, 0.68; LR+ 4.62, and LR− 0.58. This magnitude showed only <500 mcg/L FEU), was measured by a commercial latex-enhanced 3 positive false cases. Among the subjects included in the study, immunoturbidimetric assay (Siemens AG SYSMEX CS-5100). CTPA only 2 deaths were confirmed to be caused by severe respiratory examinations were obtained in a multidetector CT scanner (Dis- syndrome, with no evidence of PE. covery CT750 HD, GE Healthcare, Milwaukee, USA) by using a The current retrospective study identified that a D-dimer value Dual-Energy CTPA protocol (Gemstone Spectral Imaging GSI). High- of 2000 mcg/L was the best sensitivity cut-off point to rule out PE est observed values of D-dimer (of at least one assessment during in patients with COVID-19 pneumonia. Besides, we recognized a hospitalization) before CTPA for each patient were used as diagnos- D-dimer level of 30,000 mcg/L as the best value of specificity to pre- tic threshold and their sensitivity and specificity was estimated. dict PE. Also, an increase of D-dimer of 4000 mcg/L from admission Positive predictive (PPV)- and negative predictive (NPV)-values to the highest determination during hospitalization was found to were calculated to evaluate the correct positive and correct neg- be the best value to detect PE. ative test procedure results.7 The calculations were made with To our knowledge, this is the first report with the aim to iden- SPSS/PC for Windows (version 25.0, SPSS Inc., Chicago, IL, USA) and tify specific D-dimer cut-off values in patients with COVID-19 MedCalc (version 9.3.9.0; MedCalc, Mariakerke, Belgium). P values pneumonia to predict PE. Several studies have shown that the of <.05 were considered statistically significant. risk of thrombotic events increases with rising D-dimer concen- A total of 52 patients with a confirmed diagnosis of COVID-19 tration in acutely ill-hospitalized patients.4,8 A recent study has pneumonia and suspected PE were included. The main causes for demonstrated that despite systematic thrombosis prophylaxis, the https://doi.org/10.1016/j.arbres.2020.06.013 0300-2896/© 2020 SEPAR. Published by Elsevier España, S.L.U. All rights reserved. Please cite this article in press as: Rodriguez-Sevilla J, et al. Pulmonary Embolism in Patients With Covid-19 Pneumonia: The Utility of D-dimer. Arch Bronconeumol. 2020. https://doi.org/10.1016/j.arbres.2020.06.013 G Model ARBRES-2543; No. of Pages 2 ARTICLE IN PRESS 2 Scientific Letter / Arch Bronconeumol. 2020;xxx(xx):xxx–xxx Table 1 Sensitivity, specificity, PPV, LR+, LR− and NPV with 95% confidence interval for highest levels of D-dimer (mcg/L) at different cut-off points for prediction pulmonary embolism in patients with COVID-19 during hospitalization. D-dimer cut-off Sensitivity LR+ PPV Specificity LR− NPV 2000 1.00 (1.00–1.00) 1.79 (1.26–2.53) 0.60 (0.44–0.76) 0.44 (0.25–0.63) 0.00 1.00 (1.00–1.00) 3000 0.90 (0.77–1.00) 1.88 (1.22–2.89) 0.60 (0.42–0.78) 0.52 (0.32–0.72) 0.19 (0.05–0.75) 0.87 (0.69–1.00) 5000 0.76 (0.58–0.94) 1.90 (1.11–3.26) 0.62 (0.43–0.80) 0.60 (0.41–0.79) 0.40 (0.17–0.91) 0.75 (0.56–0.94) 10,000 0.57 (0.36–0.78) 2.38 (1.08–5.25) 0.67 (0.45–0.88) 0.76 (0.59–0.93) 0.56 (0.32–0.99) 0.68 (0.51–0.85) 15,000 0.48 (0.26–0.69) 2.98 (1.09–8.18) 0.71 (0.48–0.95) 0.84 (0.70–0.98) 0.62 (0.39–1.00) 0.66 (0.49–0.82) 30,000 0.26 (0.08–0.44) 3.78 (0.84–17.02) 0.75 (0.45–1.00) 0.93 (0.84–1.00) 0.79 (0.58–1.00) 0.61 (0.47–0.76) Definition of abbreviations: LR+, positive likelihood ratio; LR−, negative likelihood ratio; PPV, positive predicted value; NPV, negative predicted value. incidence of thrombotic complications (mainly PE) in ICU patients medical patients with recently reduced mobility: a randomized trial. Ann Intern with COVID-19 infections is notably high.9 Med. 2010;153:8–18. 9. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant It has been stated that viral infections could lead to a prothrom- KM, et al. Incidence of thrombotic complications in critically ill ICU patients botic state. Dengue virus has been stated to give rise to increased with COVID-19. Thromb Res. 2020. Interleukin-6 (IL-6), which in turn leads to an increase in Plas- 10. Wills BA, Oragui EE, Stephens AC, Daramola OA, Dung NM, Loan HT, et al. Coagulation abnormalities in dengue hemorrhagic Fever: serial investigations minogen activator inhibitor-1 (PAI-1)10 a decrease in tPA which in 167 Vietnamese children with Dengue shock syndrome. Clin Infect Dis. leads to a pro-thrombotic state. Likewise, severe cases of COVID-19 2002;35:277–85. and original SARS virus were associated with an increase IL-6 level 11. Gong J, Dong H, Xia SQ, Huang YZ, Wang D, Zhao Y, et al. Correlation analysis between disease severity and inflammation-related parameters in (and other inflammatory markers),11 and elevated PAI-1 levels,12 patients with COVID-19 pneumonia. medRxiv. 2020, http://dx.doi.org/10.1101/ respectively. 2020.02.25.20025643. Our study presents several limitations: its retrospective nature 12. Liu ZH, Wei R, Wu YP, Lisman T, Wang ZX, Han JJ, et al. Elevated plasma tissue- type plasminogen activator (t-PA) and soluble thrombomodulin in patients and a sample size is small. These shortcomings are however coun- suffering from severe acute respiratory syndrome (SARS) as a possible index terbalanced by two strengths. First, the wide range of D-dimer for prognosis and treatment strategy. Biomed Environ Sci. 2005;18:260–4. values both at admission and during hospitalization, second, 40% incidence when PE is suspected suggests a considerable frequent Juanjo Rodriguez-Sevilla a , Anna Rodó-Pin b , occurrence. Irene Espallargas c , Judit Villar-García d , Lluis Molina e , In conclusion, D-dimer monitoring helps in the evaluation of PE Purificación Pérez Terán f , Antonia Vázquez Sanchez f , in patients with COVID-19 pneumonia and they should be consid- Joan Ramón Masclans f , Carmen Jiménez a , ered in the clinical management of these patients. Our study opens Raúl Millan Segovia e , Flavio Zuccarino c , Antonio Salar a , the venue to future multicenter studies with a larger sample size Diego A. Rodriguez-Chiaradía b,∗ for adequate validation. a Department of Hematology, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain References b Pulmonology Department, Hospital del Mar, Institut Hospital del 1. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. Mar d’Investigacions Mèdiques (IMIM), Universitat Pompeu Fabra 2019 ESC Guidelines for the diagnosis and management of acute pulmonary (UPF), CIBERES, (ISCiii), Barcelona, Spain embolism developed in collaboration with the European Respiratory Society c Department of Radiology, Hospital del Mar, Institut Hospital (ERS). Eur Heart J. 2020;41:543–603. 2. Righini M, Perrier A, De Moerloose P, Bounameaux H. D-Dimer for venous throm- del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain boembolism diagnosis: 20 years later. J Thromb Haemost. 2008;6:1059–71. d Department of Infectious Diseases, Hospital del Mar, Barcelona, 3. Pasha SM, Klok FA, Snoep JD, Mos IC, Goekoop RJ, Rodger MA, et al. Safety of Spain, IMIM (Hospital del Mar Medical Research Institute, Institut excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: a meta-analysis. Thromb Hospital del Mar d’Investigacions Mediques), Barcelona, Spain, Res. 2010;125:e123–7. Department of Medicine, Universitat Autònoma de Barcelona, Spain 4. Cohen AT, Spiro TE, Spyropoulos AC, Desanctis YH, Homering M, Buller HR, et al. e Cardiology Department, Hospital del Mar, Institut Hospital del Mar D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb d’Investigacions Mèdiques (IMIM), Barcelona, Spain f Critical Care Department, Hospital del Mar, GREPAC Institut Haemost. 2014;12:479–87. 5. Spanish Health Ministery Guidelines. Action procedure against cases of infection Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat with the new coronavirus (SARS-CoV-2). 6. Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, Syrigos K. Pompeu Fabra (UPF), Barcelona, Spain Thromboembolic risk and anticoagulant therapy in COVID-19 patients: Emerg- ing evidence and call for action. Br J Haematol. 2020. ∗ Corresponding author. 7. Altman DG, Bland JM. Diagnostic tests 2: predictive values. BMJ. 1994;309:102. 8. Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, E-mail address: darodriguez@parcdesalutmar.cat et al. Extended-duration venous thromboembolism prophylaxis in acutely ill (D.A. Rodriguez-Chiaradía). Please cite this article in press as: Rodriguez-Sevilla J, et al. Pulmonary Embolism in Patients With Covid-19 Pneumonia: The Utility of D-dimer. Arch Bronconeumol. 2020. https://doi.org/10.1016/j.arbres.2020.06.013