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Respiratory Medicine 178 (2021) 106325 Contents lists available at ScienceDirect Respiratory Medicine journal homepage: http://www.elsevier.com/locate/rmed Short communication Incidence of pulmonary embolism in patients with non-invasive respiratory support during COVID-19 outbreak Jose Gregorio González-García a, b, Sergi Pascual-Guardia a, b, c, Ricardo J. Aguilar Colindres a, Pilar Ausín Herrero a, b, Mariela Alvarado Miranda a, Mariela Arita Guevara a, Diana Badenes Bonet a, b, Salome Bellido Calduch a, Oswaldo A. Caguana Vélez a, b, Cinta Cumpli Gargallo a, Marisol Dominguez-Alvarez a, c, Joaquim Gea a, b, c, Nuria Grau a, b, c, Karys Khilzi a, Juana Martínez-Llorens a, c, Mónica Sánchez Ortiz a, Albert Sánchez-Font a, c, d, Antonio Sancho-Muñoz a, c, Francisco José Parrilla-Gómez e, Judith Marín Corral e, Purificación Pérez Terán e, Juan José Rodríguez-Sevilla f, Roberto Chalela a, b, c, *, 1, Diego Rodríguez-Chiaradia a, c, d, 1 a Respiratory Medicine Department, Hospital del Mar (PSMAR) - IMIM. Barcelona, Spain b School of Health & Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain c CIBER, Área de Enfermedades Respiratorias (CIBERES), ISCIII, Spain d Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain e Intensive Care Unit, Hospital del Mar (PSMAR) - IMIM. Barcelona, Spain f Hematology Department, Hospital del Mar (PSMAR) - IMIM. Barcelona, Spain A R T I C L E I N F O A B S T R A C T Keywords: While the incidence of thrombotic complications in critically ill patients is very high, in patients under non- Non-invasive respiratory support (NIS) invasive respiratory support (NIS) is still unknown. The specific incidence of thrombotic events in each of the CPAP clinical scenarios within the broad spectrum of severity of COVID-19, is not clearly established, and this has not Severe COVID-19 allowed the implementation of thromboprophylaxis or anticoagulation for routine care in COVID-19. Patients Pulmonary embolism COVID-19 pneumonia admitted in a semi-critical unit treated initially with NIS, especially Continuous-Positive Airway Pressure (CPAP), COVID-19 were included in the study. The cumulative incidence of pulmonary embolism was analyzed and compared between patients with good response to NIS and patients with clinical deterioration that required orotracheal intubation. 93 patients were included and 16% required mechanical ventilation (MV) after the NIS. The crude cumulative incidence of the PE was 14% (95%, CI 8–22) for all group. In patients that required orotracheal intubation and MV, the cumulative incidence was significantly higher [33% (95%, CI 16–58)] compared to patients that continued with non-invasive support [11% (CI 5–18)] (Log-Rank, p = 0.013). Patients that required mechanical ventilation were at higher risk of PE for a HR of 4.3 (95%CI 1.2–16). In conclusion, cumulative incidence of PE is remarkably higher in critically patients with a potential impact in COVID-19 evolution. In this context, patients under NIS are a very high-risk group for developing PE without a clear strategy regarding thromboprophylaxis. 1. Introduction especially acute pulmonary embolism (PE), is a well-recognized complication of severe COVID-19 [1,2]. In contrast to findings from Several reports have shown that acute respiratory distress syndrome ARDS secondary to influenza A (H1N1), SARS-CoV-2 infection induce (ARDS) is the most common respiratory complication in patients with endothelial injury, widespread vascular thrombosis with micro­ severe infection by SARS-CoV-2 and is widely accepted that thrombosis, angiopathy, and occlusion of alveolar capillaries with a significant new * Corresponding author. Respiratory Medicine Department, Hospital del Mar (PSMAR) – IMIM. Barcelona, Spain. Pg. Marítim 25-27, E-08003, Barcelona, Spain. E-mail address: rchalela@parcdesalutmar.cat (R. Chalela). 1 The authors had equal contributions and credit in the article. https://doi.org/10.1016/j.rmed.2021.106325 Received 17 July 2020; Received in revised form 25 January 2021; Accepted 27 January 2021 Available online 4 February 2021 0954-6111/© 2021 Elsevier Ltd. All rights reserved. J.G. González-García et al. Respiratory Medicine 178 (2021) 106325 vessel growth through a mechanism of intussusceptive angiogenesis [3]. Table 1 Moreover, in patients with severe COVID-19, different grades of coa­ Baseline characteristics, microbiological diagnosis and outcomes. gulopathy associated with disseminated intravascular coagulopathy Variable NIS + MV n = NIS n = 78 p (DIC) have been observed. In this population, the presentation of the 15 value severe disease has a characteristic pattern that include high levels of BASELINE CHARACTERISTICS D-dimer and fibrinogen [4,5]. Age, mean (SD) (months) 64.1 [12] 60.8 [12] 0.350 In line with this, while the incidence of thrombotic complications in Sex: Male/Female, n (%) 9/6 (60/40) 54/24 (69/ 0.484 critically ill patients is very high, in patients under non-invasive respi­ 31) Smoking status, current or former, n 8 (53.3) 23 (30) 0.073 ratory support (NIS) is still unknown [6,7]. The specific incidence of (%) thrombotic events in each of the clinical scenarios within the broad Comorbidities, n (%) spectrum of severity of COVID-19, is not clearly established, and this has Diabetes mellitus 6 (40) 16 (20.5) 0.104 not allowed the implementation of thromboprophylaxis or anti­ Obesity 7 (46.7) 27 (35) 0.375 Coronary disease 1 (6.7) 2 (2.6) 0.410 coagulation for routine care in COVID-19 [8,9]. In this context, the Dyslipidemia 7 (47) 31 (40) 0.617 purpose of the present study was to investigate the cumulative incidence Hypertension 10 (66.7) 35 (45) 0.122 of PE in COVID-19 patients receiving NIS for respiratory failure during Atrial fibrillation 2 (13.3) 4 (5.1) 0.236 their hospitalization. COPD 3 [20] 5 (6.4) 0.086 Asthma 0 (0) 4 (5.1) 0.370 Obstructive sleep apnea 1 (6.7) 3 (3.8) 0.622 2. Methods Previous cancer 2 (13.3) 1 (14.1) 0.640 Immunosuppression 1 (6.7) 3 (3.8) 0.622 We designed a retrospective study based in a severe COVID-19 Previous deep venous thrombosis 0 (0) 2 (2.2) 0.531 cohort, to analyze the patients admitted in our respiratory unit from Days symptoms-NIS, mean (SD). 10.2 (4.4) 10.3 [6] 0.979 Symptoms, n (%) March 2020 to May 2020 treated with NIS (ie. Continuous-Positive Fever 10 (67) 70 (90) 0.018 Airway Pressure (CPAP), Bi-level Positive Airway Pressure (BiPAP) Cough 13 (87) 59 (82) 0.350 and/or High-flow Oxygen Therapy (HFO). We decided on a selected Dyspnea 9 (60) 46 (59) 0.941 group of patients to treat with NIS, mainly CPAP, as initial treatment, as Headache 2 (13.3) 18 (23.4) 0.388 a bridge to orotracheal intubation or as definitive treatment. In all cases, Diarrhea 5 (33.3) 23 (29.5) 0.766 Nausea 0 (0) 7 [9] 0.228 there was an immediate re-evaluation, to decide if they continued with Arthromyalgia 3 [20] 32 (41) 0.124 the NIS or required orotracheal intubation. This strategy has been Dysgeusia 2 (13.3) 17 (21.8) 0.457 adopted by various European groups with positive results [10,11]. Anosmia 2 (13.3) 14 [18] 0.664 The patients were COVID-19 positive according to the actual diag­ Weight, mean (SD), kgs 88.2 (28) 81.2 (15.7) 0.218 Height, mean (SD), cms 166 [10] 165 (10.9) 0.889 nostic criterion [12]. All patients with moderate or severe COVID-19 underwent serial D-dimer since it is an accepted marker of prognosis. CLINICAL FEATURES If there was an elevation of the same along with clinical suspicion of PE Vital signs at admission, mean (SD) Respiratory rate,/min 29.6 [7] 27.4 (7.7) 0.319 based on current guidelines, a multidetector computed tomography Heart rate,/min 94 (21.7) 96.4 (17.5) 0.661 pulmonary angiography (CTPA) was performed [13]. The study was Median arterial pressure, mmHg 92.7 [15] 94.7 [14] 0.469 approved by the local Clinical Research Ethical Committee. Results are Oxygen saturation, % 93 (7.7) 93.6 (6.3) 0.805 expressed as means ± standard deviation (SD), for normally distributed PAFI mmHg, mean (SD) 283 (240) 273 (94) 0.802 Temperature, Celsius◦ 36.8 (1.1) 37.2 (1.1) 0.251 variables, or as medians and 25th-75th percentiles, for non-normal Blood test analysis variables. Student t-test was used to compare continuous variables be­ Total lymphocytes at admission 986 (609) 935 (456) 0.706 tween groups. Abnormally distributed variables were compared with Hemoglobin at admission 13.1 (1.5)7 13.5 (1.5) 0.416 Mann-Whitney U test. Qualitative variables are described as counts and Platelets at admission, 103 221 (120) 200 (86) 0.416 percentages. We calculated the cumulative incidence of the PE. The Lactate dehydrogenase (LDH), 376 (104) 344 (126) 0.359 higher index date was the first day of symptoms. Patients were censored upon Interleukin 6, higher 163 (45) 119 (175) 0.390 hospital discharge, if they died, or at 30 days from the beginning of Ferritin, higher 1182 (864) 1596 (1327) 0.250 symptoms, whichever came first. Reactive C protein (PCR), higher 18.6 (8.8) 13.7 (8.4) 0.042 Procalcitonin, higher 0.41 (0.5) 0.65 (2.8) 0.749 D-dimer, higher 11,664 6314 0.078 3. Results (11,832) (40,431) CURB-65 score ≥ 2, n (%) 8 (29.1) 39 (51.3) 0.880 We analyzed 93 patients with severe COVID-19 under NIS. Fifteen Deaths, n (%) 3 (5.1) 1 (2.9) 0.624 patients (16%) required mechanical ventilation (MV) after the NIS, while in 78 (84%) the treatment with NIS was considered definitive. All patients received pharmacological thromboprophylaxis or anti­ of them having central filling defects and the other two lobar or coagulation based on current guidelines [14]. Their comparative char­ segmental arteries affected. acteristics are summarized in Table 1. In the patients who a CTPA was performed and the presence of PE The crude cumulative incidence of the PE was 14% (95%, CI 8–22) was confirmed, the D-dimer was 6.8-fold higher than the patients in for all group. However, in patients that required orotracheal intubation whom PE was ruled out (27,076 ng/mL vs 3943 ng/mL, p = 0.002). No and MV, the cumulative incidence was significantly higher [33% (95%, differences were found in terms of age, sex or comorbidities, and CI 16–58)] compared to patients that continued with non-invasive regarding the biomarkers of severity, the patients who presented clinical support [11% (CI 5–18)] (Log-Rank, p = 0.013) (Fig. 1). The median worsening after NIS, had only significant differences in levels of CRP. D- days from initial symptoms to PE diagnosis was 21 days (IQR 13–25). dimer was almost the double in patients requiring MV, regardless of Patients that required mechanical ventilation were at higher risk of PE whether they presented PE or not. However, only four patients died, this for a HR of 4.3 (95%CI 1.2–16). Three patients (18%) had central PE and means a global mortality of 4.3% (no differences were found between 4 patients (26%) had lobar PE, while 9 patients (60%) had purely both groups). segmental (5, 33%) or subsegmental (4, 26%) PE. The right lung was involved in 14 cases (93%) and in 9 cases (60%) the left lung was affected. Three patients had CT signs of right cardiac overload, with one 2 J.G. González-García et al. Respiratory Medicine 178 (2021) 106325 Fig. 1. Cumulative Incidence of Pulmonary Embolism during follow-up. 4. Discussion prevalence between 26 and 77% depending on whether they were in the emergency room, a general ward or ICU [22]. Despite the absence of Our study in patients with respiratory failure by COVID-19 under NIS clinical trials evaluating the efficacy of systematic anticoagulation in has provided three relevant findings. First, the cumulative incidence of patients with severe COVID-19, Nadkarni G et al. conclude from a large PE in our patients under NIS was almost 10-fold higher than in patients retrospective analysis that anticoagulation was associated with lower in ward according to previous reports [15]. Second, the cumulative mortality and intubation among hospitalized COVID-19 patients [23]. incidence of PE for patients that required orotracheal intubation after The current study also has several limitations. In the majority of the the NIS was more than 3-fold higher than patients that responded to patients in whom a CTPA was performed, no other thrombotic compli­ initial treatment. Third, our study confirms that patients under me­ cations beyond PE were evaluated. Although it is possible that throm­ chanical ventilation represent a high-risk group to develop PE during botic disease was underestimated, we have evaluated two large COVID-19 evolution. homogeneous groups at the same level of severity at the beginning of the The high cumulative incidence of PE in critically ill patients with study, since they all were under NIS. COVID-19 has been demonstrated during the last months [6,15], how­ In conclusion, cumulative incidence of PE is remarkably higher in ever the incidence in patients receiving NIS has not been evaluated to critically patients with a potential impact in COVID-19 evolution. In this our knowledge. The main reasons for the development of thrombotic context, patients under NIS are a very high-risk group for developing PE complications in COVID-19 are uncontrolled inflammatory reaction and without a clear strategy regarding thromboprophylaxis. coagulopathy in the context of significant endothelial dysfunction [16]. These physio-pathological processes are present in all the stages of the CRediT authorship contribution statement disease with special relevance in patients requiring intensive care unit (ICU) [8,9]. However, up to the present time, there are no studies clearly Jose Gregorio González-García: Conceptualization, Methodology, identifying patients at high risk in early stages of SARS-CoV-2 infection. Investigation, Formal analysis, Writing - original draft, Writing - review Our results indicate that severity of the disease can be related with & editing. Sergi Pascual-Guardia: Formal analysis, Visualization, the increased incidence of PE but is less clear that thrombotic events Methodology, Investigation, Visualization. Ricardo J. Aguilar Col­ play an independent role in the prognosis of patients, or if is a direct indres: Investigation, Recruitment. Pilar Ausín Herrero: Investigation, consequence of the disease. In line with this, it has been hypothesized Recruitment. Mariela Alvarado Miranda: Investigation, Recruitment. that the origin of the increased d-Dimer is intra-alveolar fibrin deposi­ Mariela Arita Guevara: Investigation, Recruitment. Diana Badenes tion in the context of severe acute lung injury [17]. Also, our study Bonet: Investigation, Recruitment, Visualization, Resources. Salome confirm that CRP is probably the best biomarker to follow-up patients Bellido Calduch: Investigation, Recruitment. Oswaldo A. Caguana with severe respiratory failure and COVID-19 pneumonia [18,19]. In our Vélez: Investigation, Recruitment. Cinta Cumpli Gargallo: Investiga­ cohort IL6 was elevated in all patients, as expected because all of them tion, Recruitment. Marisol Dominguez-Alvarez: Investigation, had severe disease, but no difference was found between both groups. Recruitment. Joaquim Gea: Conceptualization, Formal analysis, Finally, hypertension, obesity, dyslipidemia and diabetes were highly Writing - original draft, Writing - review & editing. Nuria Grau: incident among both groups of patients [20]. It is noteworthy that Investigation, Recruitment. Karys Kilhzi: Álvarez, Investigation, despite analyzing a cohort of patients with severe respiratory disease, Recruitment. Juana Martínez-Llorens: Investigation, Recruitment, where bilateral pneumonia and pulmonary thromboembolism even Resources. Mónica Sánchez Ortiz: Investigation, Recruitment. Albert coexist, more than 40% of patients did not report dyspnea at the time of Sánchez-Font: Investigation, Recruitment. Antonio Sancho-Muñoz: admission. This finding known as “happy hypoxia” is being debated in Investigation, Recruitment. Francisco José Parrilla-Gómez: Investi­ the scientific community and has already been described by some groups gation, Recruitment. Marín Corral Judith: Investigation, Recruitment. [21]. Our results are in line with recently published evidence where Purificación Pérez Terán: Investigation, Recruitment. Juan José Brüggemann R et al. described the number of PE diagnosis among pa­ Rodríguez-Sevilla: Investigation, Methodology. tients with COVID-19 and respiratory deterioration, and found a 3 J.G. González-García et al. Respiratory Medicine 178 (2021) 106325 Declaration of competing interest [10] D. Radovanovic, M. Rizzi, S. Pini, M. Saad, D.A. Chiumello, P. Santus, Helmet CPAP to treat acute hypoxemic respiratory failure in patients with COVID-19: a management strategy proposal, J. Clin. Med. 9 (2020) 1191. The authors declare that they have no known competing financial [11] M. Oranger, Gonzalez-Bermejo Jésus, P. Dacosta-Noble, et al., Continuous positive interests or personal relationships that could have appeared to influence airway pressure to avoid intubation in SARS-CoV-2 pneumonia: a two period the work reported in this paper. retrospective case-control study, Eur. Respir. J. 56 (2020 Aug), 2001692 in press. [12] World Health Organization, Surveillance Strategies for COVID-19 Human Infection, 10 May 2020 on June 22 2020, https://www.who.int/publications/i/it Appendix A. Supplementary data em/surveillance-strategies-for-covid-19-human-infection. [13] S.V. Konstantinides, G. Meyer, C. Becattini, et al., ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with Supplementary data to this article can be found online at https://doi. the European Respiratory Society (ERS): the Task Force for the diagnosis and org/10.1016/j.rmed.2021.106325. management of acute pulmonary embolism of the European Society of Cardiology (ESC), Eur. Heart J. 41 (2020) 543–603. [14] H.J. Schünemann, M. Cushman, A.E. Burnett, et al., American Society of References Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients, Blood Adv 2 [1] World Health Organization, Coronavirus disease 2019 (COVID-19): situation report (2018) 3198–3225. – 82. 11 april 2020, on, https://www.who.int/docs/default-source/coronavir [15] S. Middeldorp, M. Coppens, T.F. van Haaps, et al., Incidence of venous use/situation-reports/20200411-sitrep-82-covid- 19.pdf?sfvrsn=74a5d15_2. thromboembolism in hospitalized patients with COVID-19, J. Thromb. (Accessed 11 April 2020). Haemostasis (2020 May 5), https://doi.org/10.1111/jth.14888 (Online ahead of [2] D.A. Berlin, R.M. Gulick, F.J. Martinez, Severe Covid-19 [published online ahead of print). print, 2020 May 15], N. Engl. J. Med. (2020), https://doi.org/10.1056/ [16] Z. Varga, A.J. Flammer, P. Steiger, M. Haberecker, R. Andermatt, A.S. Zinkernagel, NEJMcp2009575, 10.1056/NEJMcp.2009575. M.R. Mehra, R.A. Schuepbach, F. Ruschitzka, H. Moch, Endothelial cell infection [3] M. Ackermann, S.E. Verleden, M. Kuehnel, et al., Pulmonary vascular and endotheliitis in COVID-19, Lancet 395 (2020) 1417–1418. endothelialitis, thrombosis, and angiogenesis in covid-19, N. Engl. J. Med. 383 [17] Beverley J. Hunt, Marcel Levi, The source of elevated plasma D-dimer levels in (2020) 120–128. COVID-19 infection, Br. J. Haematol. (2020 Jun 18), https://doi.org/10.1111/ [4] R.J. Jose, A. Manuel, COVID-19 cytokine storm: the interplay between bjh.16907, 10.1111/bjh.16907 [Epub ahead of print]. inflammation and coagulation, Lancet Respir Med 8 (2020) e46–e47. [18] B.M. Henry, M.H.S. de Oliveira, S. Benoit, M. Plebani, G. Lippi, Hematologic, [5] A.D. Makatsariya, K.N. Grigoreva, M.A. Mingalimov, V.O. Bitsadze, J.K. Khizroeva, biochemical and immune biomarker abnormalities associated with severe illness M.V. Tretyakova, I. Elalamy, A.S. Shkoda, V.B. Nemirovskiy, D.V. Blinov, D. and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis, Clin. V. Mitryuk, Coronavirus disease (COVID-19) and disseminated intravascular Chem. Lab. Med. 58 (7) (2020) 1021–1028. coagulation syndrome, Obstetrics, Gynecology and Reproduction 14 (2) (2020) [19] F. Liu, L. Li, M. Xu, et al., Prognostic value of interleukin-6, C-reactive protein, and 123–131. procalcitonin in patients with COVID-19, J. Clin. Virol. 127 (2020) 104370. [6] F.A. Klok, M.J.H.A. Kruip, N.J.M. van der Meer, et al., Incidence of thrombotic [20] W.J. Guan, W.H. Liang, Y. Zhao, et al., Comorbidity and its impact on 1590 complications in critically ill ICU patients with COVID-19, Thromb. Res. 191 patients with COVID-19 in China: a nationwide analysis, Eur. Respir. J. 55 (2020) (2020) 145–147, https://doi.org/10.1016/j.thromres.2020.04.013. 2000547. [7] F. Bompard, H. Monnier, I. Saab, et al., Pulmonary embolism in patients with [21] J. Couzin-Frankel, The mystery of the pandemic’s ’happy hypoxia, Science 368 Covid-19 pneumonia [published online ahead of print, 2020 May 12], Eur. Respir. (6490) (2020 May 1) 455–456. J. (2020) 2001365, https://doi.org/10.1183/13993003.01365-2020. [22] R. Brüggemann, B. Spaetgens, H. Gietema, et al., The prevalence of pulmonary [8] C. Fernández-Capitán, R. Barba, M.D.C. Díaz-Pedroche, et al., Presenting embolism in patients with COVID-19 and respiratory decline: a three-setting characteristics, treatment patterns, and outcomes among patients with venous comparison, Thromb. Res. 196 (2020) 486–490. thromboembolism during hospitalization for COVID-19, Semin. Thromb. Hemost. [23] G. Nadkarni, A. Lala, E. Bagiella, et al., Anticoagulation, bleeding, mortality, and (2020 Oct 21), https://doi.org/10.1055/s-0040-1718402 (Online ahead of print). pathology in hospitalized patients with COVID-19, J. Am. Coll. Cardiol. 76 (2020) [9] M.M. Daughety, A. Morgan, E. Frost, C. Kao, J. Hwang, R. Tobin, B. Patel, 1815–1826. M. Fuller, I. Welsby, T.L. Ortel, COVID-19 associated coagulopathy: thrombosis, hemorrhage and mortality rates with an escalated-dose thromboprophylaxis strategy, Thromb. Res. 196 (2020 Dec) 483–485. 4