ORIGINAL RESEARCH published: 25 August 2020 doi: 10.3389/fmed.2020.00557 Pulmonary Thrombosis or Embolism in a Large Cohort of Hospitalized Patients With Covid-19 Natividad Benito 1,2,3*† , David Filella 2,3† , Jose Mateo 4 , Ana M. Fortuna 5 , Juan E. Gutierrez-Alliende 6 , Nerea Hernandez 2,3 , Ana M. Gimenez 6 , Virginia Pomar 1,2,3 , Ivan Castellvi 2,7 , Hector Corominas 2,7 , Jordi Casademont 2,3 and Pere Domingo 1,3 1 Infectious Disease Unit, Hospital de la Santa Creu i Sant Pau - Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain, 2 Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, 3 Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau - Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain, 4 Thrombosis and Hemostasis Unit, Hospital de la Santa Creu i Sant Pau - Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain, 5 Department of Respiratory Diseases, Hospital de la Santa Creu i Sant Pau - Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain, 6 Department of Radiology, Hospital de la Santa Creu i Sant Pau - Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain, 7 Department of Rheumatology, Hospital de la Santa Creu i Sant Pau - Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain Edited by: Manuel Jesús Núñez Fernández, Complejo Hospitalario de Objective: We set out to analyze the incidence and predictive factors of pulmonary Pontevedra, Spain embolism (PE) in hospitalized patients with Covid-19. Reviewed by: Alejandro Lazo-Langner, Methods: We prospectively collected data from all consecutive patients with University of Western Ontario, Canada Gianpaolo Vidili, laboratory-confirmed Covid-19 admitted to the Hospital de la Santa Creu i Sant Pau, University of Sassari, Italy a university hospital in Barcelona, between March 9 and April 15, 2020. Patients *Correspondence: with suspected PE, according to standardized guidelines, underwent CT pulmonary Natividad Benito angiography (CTPA). nbenito@santpau.cat † These Results: A total of 1,275 patients with Covid-19 were admitted to hospital. CTPA was authors have contributed equally to this work performed on 76 inpatients, and a diagnosis of PE was made in 32 (2.6% [95%CI 1.7–3.5%]). Patients with PE were older, and they exhibited lower PaO2 :FiO2 ratios Specialty section: and higher levels of D-dimer and C-reactive protein (CRP). They more often required This article was submitted to Hematology, admission to ICU and mechanical ventilation, and they often had longer hospital stays, a section of the journal although in-hospital mortality was no greater than in patients without PE. High CRP Frontiers in Medicine and D-dimer levels at admission (≥150 mg/L and ≥1,000 ng/ml, respectively) and a Received: 11 June 2020 peak D-dimer ≥6,000 ng/ml during hospital stay were independent factors associated Accepted: 05 August 2020 Published: 25 August 2020 with PE. Prophylactic low molecular weight heparin did not appear to prevent PE. Citation: Increased CRP levels correlated with increased D-dimer levels and both correlated with Benito N, Filella D, Mateo J, a lower PaO2 :FiO2 . Fortuna AM, Gutierrez-Alliende JE, Hernandez N, Gimenez AM, Pomar V, Conclusions: The 2.6% incidence of PE in Covid-19 hospitalized patients is clearly Castellvi I, Corominas H, high. Higher doses of thromboprophylaxis may be required to prevent PE, particularly Casademont J and Domingo P (2020) Pulmonary Thrombosis or Embolism in patients at increased risk, such as those with high levels of CRP and D-dimer at in a Large Cohort of Hospitalized admission. These findings should be validated in future studies. Patients With Covid-19. Front. Med. 7:557. Keywords: COVID-19, pulmonary thrombosis, pulmonary embolism (MeSH), thromboprophylaxis, anticoagulant doi: 10.3389/fmed.2020.00557 (MeSH), thromboinflammation Frontiers in Medicine | www.frontiersin.org 1 August 2020 | Volume 7 | Article 557 Benito et al. Pulmonary Embolism in Covid-19 Patients INTRODUCTION TABLE 1 | Characteristics of patients with Covid-19 with and without pulmonary embolism. Since December 2019, the rapid spread of the novel Variable Pulmonary NO P-value betacoronavirus, named SARS-CoV-2, has led to a global embolism pulmonary pandemic of coronavirus disease 2019 (Covid-19). Several recent N = 32 embolism studies have shown that patients with Covid-19 frequently N = 44 have coagulation disorders, especially a marked increase in Age, years—median (IQR) 66 (13) 60 (17) 0.110 D-dimer (1–5). These abnormal coagulation parameters have Age ≥ 60 years—no. (%) 24 (75) 22 (50) 0.028 been associated with worse outcomes (1, 2). It is also suggested Male gender—no. (%) 20 (62.5) 31 (70.5) 0.466 that Covid-19 predisposes patients to a higher risk of thrombotic Diabetes mellitus—no. (%) 6 (18.8) 6 (13.6) 0.546 disorders, including both venous and arterial thromboembolic Hypertension—no. (%) 15 (46.9) 19 (43.2) 0.749 disease (3, 4). Several scientific societies and authors have already Chronic lung disease—no. (%) 4 (12.5) 12 (27.3) 0.119 proposed specific guidelines and recommendations on the use of Active cancer—no. (%) 5 (15.6) 2 (4.5) 0.124 thromboprophylaxis in patients with Covid-19 (6–11), although BMI—median (IQR) 28.1 (5.4) 26.7 (8) 0.527 the best thromboprophylaxis regimen (dosing and duration), BMI ≥ 25—no. (%) 22 (75.9) 27 (71.1) 0.660 taking into account the characteristics of different groups of Obesity—no. (%) 8 (27.6) 13 (32.5) 0.661 patients, has not been established. Area of admission in the hospital at the time 0.938 To date, a few case series studies (12–19) and some case of performing CTPA—no. (%) reports (17, 20–30) have investigated the incidence and features - emergency department 4 (12.5) 6 (13.6) of pulmonary thrombosis or embolism (PE) in patients with - inpatient ward 23 (71.9) 30 (68.2) - intensive care unit 5 (15.6) 8 (18.2) Covid-19. All studies included small numbers of cases, and Days from admission until CTPA 7 (10.5) 5 (10) 0.398 most of them were conducted in ICU patients (12, 16–19), as performed—median (IQR) they constitute a particular group with an increased risk of PE LMWH administration before CTPA—no. (%) 28 (87.5) 39 (88.6) 1 (14). Other studies have been based on patients who underwent Days of LMWH administration before 6 (9) 5 (9) 0.922 computed tomography pulmonary arteriography (CTPA) but did CTPA—median (IQR) not provide clear information on the baseline population (14, 15). LMWH doses—no. (%) 0.823 These limitations make it difficult to know the true incidence, - prophylactic doses 26 (92.9) 34 (87.2) characteristics, and risk factors of PE in patients with Covid-19. - “higher risk” prophylactic doses 2 (7.1) 4 (10.3) Using a large cohort of consecutive patients with laboratory- - therapeutic doses 0 (0) 1 (2.6) confirmed Covid-19 admitted to a single university hospital, we Pneumonia in the CTPA—no. (%) 31 (96.9) 41 (93.2) 0.634 sought to analyze the incidence, clinical features, and predictive PaO2 :FiO2 at the time of performing CTPA 222 (163.5) 250 (181.8) 0.102 factors of PE in patients with Covid-19. Invasive mechanical ventilation at the time of 7 (21.9) 6 (13.6) 0.346 CTPA—no. (%) Worst PaO2 :FiO2 –median (IQR) 158.5 228.5 0.017 METHODS (134.8) (170.5) Patients needing ICU admission during their 15 (46.9) 10 (22.7) 0.027 Setting hospital stay—no. (%) We conducted this study at the Hospital de la Santa Creu i Sant Patients requiring invasive mechanical 14 (43.8) 8 (18.2) 0.015 Pau, a tertiary acute care university hospital in Barcelona, Spain. ventilation during their hospital stay—no. (%) The hospital’s Institutional Review Board approved the study. D-dimer at admission, ng/mL—median (IQR) 5,274.5 1,045.5 0.017 (16,419) (6,287.8) We collected data prospectively from all consecutive patients D-dimer at admission ≥ 1,000 ng/mL—no. 26 (81.3) 23 (52.3) 0.009 with laboratory-confirmed Covid-19 diagnosed at our hospital (%) between March 9 and April 15, 2020, and we included those who Peak D-dimer, ng/mL—median (IQR) 22,791 6039.5 0.001 were admitted to hospital. (42,552) (15,982.3) Specific guidance based on the International Society of Peak D-dimer ≥ 3,000 ng/mL—no. (%) 31 (96.9) 29 (65.9) 0.001 Thrombosis and Hemostasis interim guidelines (6) was Peak D-dimer ≥ 6,000 ng/mL—no. (%) 29 (90.6) 23 (52.3) <0.001 developed at our center and distributed on March 18 to all C-reactive protein at admission, 161.5 (65) 83.5 (126) 0.007 attending staff. It was recommended to start prophylactic mg/L—median (IQR) doses of subcutaneous low molecular weight heparin (LMWH) C-reactive protein at admission ≥ 150 24 (75) 14 (31.8) <0.001 (enoxaparin 4,000 IU/24 h, bemiparin 3,500 IU/24 h or mg/L—no. (%) Peak C-reactive protein, mg/L—median (IQR) 221.5 183 (236.4) 0.059 tinzaparin 4,500 IU/24 h) for all patients (including the non- (169.4) critically ill) who required hospital admission for Covid-19 Hospital stay, days—median (IQR) 15.5 (9.8) 7 (11) 0.010 in the absence of contraindications. Doses were adjusted to In-hospital death—no. (%) 3 (9.4) 5 (11.4) 1 body weight. On April 3, 2020, the guidance was subsequently amplified by adding the use of high-dose prophylaxis for patients BMI, body mass index; CTPA, computed tomography pulmonary arteriography; FiO2 , Fraction of inspired oxygen; IQR, interquartile range; LMWH, low molecular weight at increased thrombotic risk, including those with D-dimer heparin; PaO2 partial pressure of arterial oxygen. >3,000 ng/mL (enoxaparin 100 IU/kg/ 24 h, bemiparin 75–80 Bold values refer to P-values that are statistically significant (< 0.05); the idea is to make IU/kg/24 h, or tinzaparin 100 IU/Kg/ 24 h). easer the identification of statistically significant variables in this large table. Frontiers in Medicine | www.frontiersin.org 2 August 2020 | Volume 7 | Article 557 Benito et al. Pulmonary Embolism in Covid-19 Patients FIGURE 1 | Receiver operating characteristic (ROC) curve for D-dimer and C-reactive protein as predictors of pulmonary embolism in patients with Covid-19. AUC, area under the ROC curve. Hospital guidance on when to suspect possible PE and request high) according to a modified Qanadli Score (31) were evaluated. a CTPA in Covid-19 patients was also developed and distributed Right ventricle overload was also assessed (right ventricle to all attending staff. Suspicion of having PE included those diameter to left ventricle diameter ratio >1.3). Following the patients whose partial pressure of arterial oxygen to fraction clinical guidelines developed at our medical center and the of inspired oxygen (PaO2 :FiO2 ) ratio worsened or failed to recommendations of the Spanish Agency for Medicinal Products improve, associated with an increasing or persistently high and Medical Devices (AEMPS), a single dose of intravenous D-dimer (>3,000 ng/mL) and/or hemodynamic deterioration tocilizumab (600 mg for patients ≥75 kg; 400 mg for those or other “classic” symptoms of PE, such as pleuritic chest <75 kg) was suggested as treatment for hospitalized patients with pain, hemoptysis, syncope, and/or signs of right ventricular Covid-19 and data for cytokine release syndrome. strain. Patients with suspicion of PE had a CTPA and started anticoagulant therapy with full-dose LMWH if PE was diagnosed. Variables Assessed All CTPA scans were performed using a 16-slice multi- We collected information on patients who underwent detector CT (Philips Brilliance CT 16 C Slice) after intravenous CTPA for suspected PE. Variables included demographic injection of 60 ml iodinated contrast agent (Optiray Ultraject data, preexisting chronic medical conditions, body mass 350 mg/mL Ioversol, Guerbet, France) at a flow rate of 4 mL/s, index, thrombosis prophylaxis with LMWH and dosing, triggered on the main pulmonary artery. The CT scan settings diagnosis and characteristics of PE, PaO2 :FiO2 ratio, were 120 kVp, slice thickness 2 mm, increment 1 mm, pitch estimated using methods developed by Brown and 0.688, rotation time 0.28 s, and average tube current 300 mA. colleagues (32, 33) (PaO2 :FiO2 at the time of CTPA and The location of embolus (main pulmonary, lobar, segmental, worst ratio during hospital stay), evolution of D-dimer and subsegmental artery) and clot burden (low, moderate, and and C-reactive protein (at admission and peak level), and Frontiers in Medicine | www.frontiersin.org 3 August 2020 | Volume 7 | Article 557 Benito et al. Pulmonary Embolism in Covid-19 Patients FIGURE 2 | Correlation between D-dimer and C-reactive protein at admission in patients with Covid-19 and suspected pulmonary embolism (rs = 0.146; p = 0.208). clinical outcomes, including need for invasive mechanical RESULTS ventilation, ICU admission, length of hospital stay, and in-hospital death. Of 1,863 consecutive patients diagnosed with laboratory- confirmed Covid-19 between March 9 and April 15, 2020, at our center, a total of 1,275 patients (68.4%) were admitted to hospital. Statistical Analysis A total of 146 inpatients (12.4%; 95% CI 10.5–14.4%) died during We summarized continuous variables as medians and their hospital stay [101 patients (7.9%) were still hospitalized at interquartile ranges and categorical variables as percentages the time of data analysis]. of the total sample for that variable. The incidence of PE During this period, a CTPA was indicated for suspicion of was estimated with a 95% confidence interval (CI). We used PE in 76 inpatients (6% of patients with Covid-19 admitted the Wilcoxon rank-sum and chi-square tests (or Fisher’s to hospital). CTPA confirmed a diagnosis of PE in 32 patients exact tests when appropriate) to evaluate group differences (42.1% of tests), which represents a cumulative incidence of (Covid-19 patients with and without PE in the CTPA) 2.6% (95 CI 1.7–3.5%) for PE among Covid-19 inpatients. Most for continuous and categorical variables, respectively. A CTPAs were requested for patients admitted to conventional multivariable logistic regression model was used to identify wards (70%); in fact, a similar percentage of patients with (71.9%) factors independently associated with a higher risk of and without PE (68.2%) were hospitalized in the wards at the time developing PE. Any variable tested in univariate analysis of diagnosis (Table 1). with a p < 0.25, together with all variables of known Table 1 shows the characteristics of Covid-19 inpatients clinical importance, were selected as candidates for the with and without PE in the CTPA. Patients with PE were first multivariate model. We then followed the purposeful more often ≥60 years old, had lower PaO2 :FiO2 ratios, and selection of covariates method described by Hosmer et al. had higher levels of D-dimer and C-reactive protein. The D- (34) Final parameter estimates are shown as odds ratios (OR) dimer levels of these patients were therefore more than five with their corresponding 95% CIs. Correlations between times higher at hospital admission, and the peak D-dimer quantitative variables were examined using the Spearman rank level during hospital stay was more than three times higher correlation test. P < 0.05 were considered to be significant for than in patients without PE. Moreover, C-reactive protein at all statistical tests. Data were analyzed using IBM R SPSS R , admission was almost twice as high among PE patients. Covid- version 26.0. 19 inpatients with PE more often required ICU admission Frontiers in Medicine | www.frontiersin.org 4 August 2020 | Volume 7 | Article 557 Benito et al. Pulmonary Embolism in Covid-19 Patients and invasive mechanical ventilation than those without PE and followed by C-reactive protein at admission had the largest area had longer hospital stays, although in-hospital mortality was under the ROC curve (Figure 1). not statistically significantly different between the two groups We examined a possible linear correlation between levels of (9.4% vs. 11.4%). There were also no significant differences D-dimer and C-reactive protein at admission (Figure 2) and at between in-hospital mortality in PE patients and mortality in their highest levels during hospital stay (Figure 3). A positive all admitted Covid-19 patients (p = 0.604). A high proportion linear correlation was observed in both cases and was statistically of patients with and without PE (87.5% and 88.6, respectively) significant for peak D-dimer and peak C-reactive protein values were receiving LMWH prior to CTPA, mostly at prophylactic during hospitalization. We also found statistically significant doses, with no statistically significant differences between the negative correlations between peak D-dimer levels and worst two groups. PaO2 :FiO2 ratio (Figure 4) and between peak C-reactive protein We did not investigate deep vein thrombosis (DVT), except in levels and worst PaO2 :FiO2 ratio (Figure 5) during hospital stay. symptomatic patients. We found DVT in two patients with PE, In patients with PE, the CTPA showed mainly affection of one of whom was a patient with gastric cancer. the segmental and subsegmental branches of pulmonary arteries, Candidate variables for the first multivariable model were: predominantly with a low thrombus load (Table 2). age ≥ 60 years, sex, chronic lung disease, active cancer, BMI, LMWH administration, D-dimer at admission ≥ 1,000 ng/mL, DISCUSSION C-reactive protein at admission ≥ 150 mg/L, ICU admission, worst PaO2 :FiO2 , and peak D-dimer ≥ 6,000. Multivariate In this analysis involving a large sample of consecutive patients analysis found the following independent factors as associated hospitalized with Covid-19, we found a high incidence of PE of with an increased risk of having PE: C-reactive protein at 2.6% despite the wide use of thromboprophylaxis. Patients with admission ≥ 150 mg/L (OR 7.9, 95% CI 2.4–26.7), D-dimer at PE were older and had lower PaO2 :FiO2 ratios and markedly admission ≥ 1,000 ng/mL (OR 4.5, 95% CI 1.2–17.2, p = 0.026), higher levels of D-dimer and C-reactive protein. They more and peak D-dimer ≥ 6,000 ng/mL during hospital stay (OR 5.6, often required admission to ICU, invasive mechanical ventilation, 95% CI 1.3–24.5) (Nagelkerke R2 = 0.439). and longer hospital stays, although in-hospital mortality was We analyzed D-dimer and C-reactive protein as predictors of no greater than in patients without PE. We identified high C- PE using ROC curves. The peak D-dimer during hospital stay reactive protein and D-dimer at admission (≥150 mg/L and FIGURE 3 | Correlation between peak D-dimer and peak C-reactive protein during hospital stay in patients with Covid-19 and suspected pulmonary embolism (rs = 0.279; p = 0.015). Frontiers in Medicine | www.frontiersin.org 5 August 2020 | Volume 7 | Article 557 Benito et al. Pulmonary Embolism in Covid-19 Patients FIGURE 4 | Correlation between peak D-dimer and worst PaO2 :FiO2 during hospital stay in patients with COVID-19 and suspected pulmonary embolism (rs = −0.471; p < 0.001). ≥1,000 ng/ml, respectively) and a peak D-dimer during hospital PE close to 3% (which may be underestimated by the number stay ≥6,000 ng/ml as independent factors associated with PE. of patients undergoing CTPA) is certainly high, particularly Prophylactic doses of LMWH did not, however, appear to when compared with the figure of 1.4% for PE found in a large prevent PE. prospective study of critically ill patients in the ICU (36). Most of the studies on PE in patients with Covid-19 have In most of the studies mentioned above, as was the case been conducted in ICU patients, who are at greater risk of in the present study, patients developed PE even though venous thromboembolism and have shown incidences ranging most of them were receiving anticoagulant thromboprophylaxis. from 17 to 35% (12, 16–19, 35). Interestingly, one of these These findings raise the need to increase thromboprophylaxis studies demonstrated that patients with acute respiratory distress doses, particularly in higher risk patients (5, 16, 18). The syndrome (ARDS) due to Covid-19 developed PE significantly predictive factors for PE found in the present study can help more often than patients with ARDS due to other diseases (11.7% identify patients who may benefit from high prophylactic doses. vs. 2.1%) (18). Another study showed a much higher frequency Patients with C-reactive protein ≥ 150 mg/L and D-dimer of PE in ICU patients with Covid-19 (21%) than during the ≥ 1,000 could therefore be candidates for increased doses same time interval in 2019 (6%), and it was also higher than the of thromboprophylaxis; if these patients continue to have a incidence of PE in patients with influenza admitted to the same persistently elevated or increasing D-dimer, however, CTPA ICU in 2019 (8%) (12). It seems clear therefore that the incidence should be considered to diagnose possible PE. of PE in patients admitted to ICU with Covid-19 is much higher When analyzing all patients with suspicion of PE, we than in other critically ill non-Covid-19 patients, including those found that increased C-reactive protein levels (an acute with ARDS and other respiratory infections, despite the fact that phase protein whose serum concentrations increase during these patients are already at an increased risk of PE (10). inflammatory states and whose expression is driven by IL- The only previous study that has addressed the incidence of 6) (37) correlated with increased D-dimer levels, suggesting PE in all patients admitted to hospital with Covid-19 found a a link between inflammation and procoagulant changes, as percentage of 2.8% (13). Despite the smaller sample size, this proposed by other authors (5, 38). In fact, increased C-reactive proportion is remarkably similar to that found in the present protein (≥150 mg/mL) at admission was the strongest predictor study (2.6%). In both studies, the vast majority of patients of developing PE in multivariable analysis, although peak D- (>70%) were admitted to conventional wards. An incidence of dimer had greater diagnostic capacity according to the ROC Frontiers in Medicine | www.frontiersin.org 6 August 2020 | Volume 7 | Article 557 Benito et al. Pulmonary Embolism in Covid-19 Patients FIGURE 5 | Correlation between highest C-reactive protein and worst PaO2 :FiO2 during hospital stay in patients with COVID-19 and suspected pulmonary embolism (rs = −0.473; p < 0.001). curve. This supports the hypothesis that inflammation associated TABLE 2 | Characteristics of pulmonary embolism in the computed tomography with Covid-19 leads to subsequent activation of coagulation pulmonary angiogram of patients with Covid-19. and a higher risk of thrombotic disease (4, 38). Furthermore, Variable Patients with pulmonary we also demonstrated that both high levels of D-dimer embolism (n = 32) and C-reactive protein correlated with increased hypoxemia, evidenced by a decrease in the PaO2 :FiO2 ratio. This provides Location of embolus - no. (%) further important information about the hypercoagulability and - Main pulmonary artery 0 thromboinflammatory response associated with Covid-19 and - Lobar artery 7 (21.9) - Segmental artery 16 (50) their association with acute lung injury. - Subsegmental artery 9 (28.1) A relevant debate has arisen recently about whether Thrombus load - no. (%) thrombosis or pulmonary embolism is the most critical aspect - High 4 (12.5) of pulmonary thromboembolic events in Covid-19 patients (16, - Moderate 8 (25) 39, 40). These patients are clearly at increased risk for venous - Low 20 (62.5) thromboembolic disease (41), and it is therefore not surprising Right ventricular overload - no. (%) 5 (15.6) that they may also develop pulmonary embolisms. Pulmonary thrombosis in Covid-19 patients found at autopsy (42) and, remarkably, in all studied patients in one very recent study (40), however, suggests that pulmonary thrombosis may play a together with the association between inflammation, coagulation, role in the pathogenesis of more severe cases. Our study does and hypoxemia, would also support this hypothesis. not permit to differentiate between thrombosis and pulmonary Our study has limitations that are mainly associated with its embolism. Nevertheless, some of our findings would support the observational study design. With such a large number of patients predominance of pulmonary thrombosis. First, the low frequency and the high demand for care during this period, systematic of patients with DVT is worthy of note, which is consistent with performance of CTPA in all patients was not possible, which may other studies (12, 16). Likewise, the predominant involvement in have led to underestimating the true incidence of PE. Either way, our study of the segmental and subsegmental pulmonary arteries, any large prospective study including all Covid-19 hospitalized Frontiers in Medicine | www.frontiersin.org 7 August 2020 | Volume 7 | Article 557 Benito et al. Pulmonary Embolism in Covid-19 Patients patients should probably be based on establishing criteria by a correlation between increased levels of C-reactive protein which to evaluate CTPA requests since it does not seem feasible and D-dimer and increased hypoxemia, which supports the for all patients to have a CTPA. To enable the standardization of role of thromboinflammation in acute lung injury observed in criteria, our institution developed hospital guidelines on when to patients with Covid-19. We need more information on the most suspect PE and request a CTPA. On the other hand, we compared appropriate thromboprophylactic doses and duration to prevent the features of patients with and without PE on the basis of PE in patients with Covid-19. their CTPA results so that our findings cannot be extrapolated to the entire cohort of inpatients with Covid-19. In order to obtain results that apply to all hospitalized patients with Covid- DATA AVAILABILITY STATEMENT 19, we are currently planning a nested case-cohort study that will The data that support the findings of this study are available from include all PE patients diagnosed by CTPA as cases and a random the corresponding author upon reasonable request. sample of all Covid-19 inpatients as controls. The CT unit used in our study was a Phillips Brilliance CT 16-slice scanner, which is the one reserved at our center for emergencies. During the ETHICS STATEMENT Covid-19 pandemic, this CT unit was reserved for the study of all patients with Covid-19 in order to spare the other CT The studies involving human participants were reviewed units. While better CT image resolution would be obtained with and approved by Clinical Research Ethics Committee other more technologically up-to-date units, we think that the of the Hospital de la Santa Creu i Sant Pau. Written quality of the image, even in subsegmental arteries, is sufficient informed consent for participation was not required for for cases of PE. Even so, while the frequency of PE found is this study in accordance with the national legislation and the high, it is probably underestimated, as the data from autopsies institutional requirements. of patients with Covid-19 suggest (40, 43). In an autopsy study of 12 consecutive patients who died from Covid-19, PE was AUTHOR CONTRIBUTIONS found in five of them even though no preclinical evidence of PE had been reported (43). In another study, meticulous autopsies NB, DF, and JM conceived the study, searched the literature, of 11 deceased patients (10 of whom were selected at random) and designed the study. NB analyzed the data and drafted the observed thrombosis in small to mid-sized pulmonary arteries in report. NB, DF, JM, and AF interpreted the results. DF, VP, JG-A, all cases (40). and AG collected the data and critically revised the report for In conclusion, patients admitted to hospital with Covid- important intellectual content. DF, JM, and AF critically revised 19 have a high incidence of PE, estimated at 2.6%. Our the report. JC and PD supervised the study, interpreted the study identified predictors of PE able to select patients results, and critically revised the report for important intellectual at increased risk of developing PE, making them possible content. All authors gave final approval of the version to candidates for thromboprophylaxis at higher doses. There is be published. REFERENCES 8. Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: a comment. J 1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course Thromb Haemost. (2020) 18:2060–63. doi: 10.1111/jth.14860 and risk factors for mortality of adult inpatients with COVID-19 in 9. Zhai Z, Li C, Chen Y, Gerotziafas G, Zhang Z, Wan J, et al. Prevention and Wuhan, China: a retrospective cohort study. Lancet. 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The use, distribution or reproduction in other forums is permitted, Diagn Interv Imaging. (2020) 101:321–2. doi: 10.1016/j.diii.2020.04.003 provided the original author(s) and the copyright owner(s) are credited and that the 30. Martinelli I, Ferrazzi E, Ciavarella A, Erra R, Iurlaro E, Ossola M, et al. original publication in this journal is cited, in accordance with accepted academic Pulmonary embolism in a young pregnant woman with COVID-19. Thromb practice. No use, distribution or reproduction is permitted which does not comply Res. (2020) 191:36–7. doi: 10.1016/j.thromres.2020.04.022 with these terms. Frontiers in Medicine | www.frontiersin.org 9 August 2020 | Volume 7 | Article 557