key: cord-1054401-u3edrz71 authors: Polo Friz, Hernan; Gelfi, Elia; Orenti, Annalisa; Motto, Elena; Primitz, Laura; Donzelli, Tino; Intotero, Marcello; Scarpazza, Paolo; Vighi, Giuseppe; Cimminiello, Claudio; Boracchi, Patrizia title: Acute pulmonary embolism in patients presenting pulmonary deterioration after hospitalization for non‐critical COVID‐19. date: 2021-04-08 journal: Intern Med J DOI: 10.1111/imj.15307 sha: d138f5acd30f9781a5670166430ec1a95baa1fb0 doc_id: 1054401 cord_uid: u3edrz71 BACKGROUND: Emerging evidence suggests an association between COVID‐19 and acute pulmonary embolism (APE). AIMS: To assess the prevalence of APE in patients hospitalized for non‐critical COVID‐19 who presented clinical deterioration, and to investigate the association of clinical and biochemical variables with a confirmed diagnosis of APE in these subjects. METHODS: All consecutive patients admitted to the internal medicine department of a general hospital with a diagnosis of non‐critical COVID‐19, who performed a Computer Tomography Pulmonary Angiography (CTPA) for respiratory deterioration in April 2020, were included in this retrospective cohort study. RESULTS: Study populations: 41 subjects, median(IRQ)age:71.7(63‐76)years, CPTA confirmed APE=8(19.51%,CI95%:8.82%‐34.87%). Among patients with and without APE, no significant differences were found with regards symptoms, comorbidities, treatment, Wells score and outcomes. The optimal cut‐off value of D‐dimer for predicting APE was 2454 ng/mL, sensitivity(CI95%):63(24‐91), specificity:73(54‐87), Positive Predictive Value:36(13‐65), Negative Predictive Value: 89(71‐98) and AUC:0.62(0.38‐0.85). The standard and age‐adjusted D‐dimer cut‐offs, and the Wells score >2 did not associate with confirmed APE, albeit a cut‐off value of D‐dimer=2454 ng/mL showed an RR:3.21;CI95%:0.92‐13.97;p=0.073. Heparin at anticoagulant doses was used in 70.73% of patients before performing CTPA. CONCLUSION: Among patients presenting pulmonary deterioration after hospitalization for non‐critical COVID‐19, the prevalence of APE is high. Traditional diagnostic tools to identify high APE pre‐test probability patients do not seem to be clinically useful. These results support the use of a high index of suspicion for performing CTPA to exclude or confirm APE as the most appropriate diagnostic approach in this clinical setting. This article is protected by copyright. All rights reserved. The study was conducted at the Vimercate Hospital, a 500 bed General Hospital located in Lombardy, northern Italy. From February to May 2020, 712 patients with a confirmed diagnosis of COVID-19 were hospitalized in our institution. Among them, in April 2020 218 subjects were admitted to the internal medicine department wards after been evaluated in the Emergency Department. In the first months of 2020, different reports suggesting an increasing risk of APE in COVID-19 patients were published [6] . Thus, in late march, a multidisciplinary group from our hospital issued an internal protocol with some recommendations to prevent and treat thrombotic complications in COVID-19 patients. The protocol strongly recommended performing a diagnostic CTPA to confirm or rule out APE in COVID-19 patients admitted to the internal medicine department wards presenting respiratory deterioration after admission, defined by a PaO2/FiO2 ratio reduction of > 30%. Therefore, in the present retrospective cohort study we included all COVID-19 patients admitted to the internal medicine department (sub intensive and acute general beds of the internal medicine department wards) who had CTPA examinations performed from April 1 st to April 31 st for respiratory deterioration after admission, defined by a reduction of > 30% of the PaO2/FiO2 ratio. The exclusion criteria were: subjects with a story of bleeding diathesis and/or current use of anticoagulant therapy before hospitalization; age < 18, and critical COVID19 infection, defined by any of the following criteria a. respiratory failure needing mechanical assistance, b. shock c. "extra pulmonary" organ failure needing intensive care unit. Electronic charts of all included patients were retrieved for evaluation. Trained study personnel retrospectively recorded relevant clinical, laboratory and treatment data. The diagnosis of COVID-19 was confirmed by RNA detection of the SARS-CoV-2. Data of the following laboratory test performed 24-48 hours before performing CPTA were collected: D-dimer, international normalized ratio (INR), c-reactive protein (CRP), white blood cell count (WBCC), lactate dehydrogenase (LDH), alanine transaminase (ALT), aspartate transaminase (ALT), Creatinine (Cr), arterial partial pressure of carbon dioxide (PaCO2), arterial oxygen partial pressure (PaO2), fraction of inspired oxygen (FiO2). Albumin, Interleukin 6, and Antithrombin III were measured within 24 hours of performing CTPA. D-dimer was measured by using HemosIL D-Dimer HS, a latex-enhanced turbidimetric immunoassay from Instrumentation Laboratory, on the fully automated coagulometer ACL TOP analyzer [15] . The normal value declared by the producer is less than 243 ng/mL [15] . Based on a retrospective chart review of clinical symptoms and patient history factors Wells score simplified version was calculated for each patient, and it was referred to the day when CPTA was performed. One point was To evaluate the diagnostic accuracy of D-dimer to predict APE, a ROC curve was fitted and the Area Under the ROC Curve (AUC) with pertinent 95% confidence interval (CI95%) was estimated. Optimal cut-off was obtained as the D-dimer value which maximizes both the specificity and the sensitivity. The diagnostic performance of different Ddimer cut-offs (standard cut-off: > 243 ng/mL, age adjusted cut off: patients' age x 5, ROC curve best discriminating value: 2454 ng/mL) and Wells score (standard cut off: >2) was evaluated by computing the corresponding values of sensitivity and specificity, positive predictive value, negative predictive value with pertinent CI95%. Furthermore, four generalized linear regression models with binomial error and link log were fitted: the response was APE and the explanatory variable was a dichotomous variable discriminating patients with D-dimer value over the different cut offs or Wells score over 2. Results were reported as Relative Risk (RR) with corresponding CI95% and p-values. All analyses were performed using R software version 4.0.0, with packages OptimalCutpoints, pROC and epiR added. From 1 st to 30 th April 2020, 41 patients admitted to internal medicine department wards underwent a CTPA because respiratory deterioration after admission, defined by a PaO2/FiO2 ratio reduction of > 30%, and represent the study population. The median (IRQ) age of the cohort was 71.7 (63-76) years, 30 (73%) were females, the median days (IRQ) since onset of symptoms to hospitalization was 8 (4) (5) (6) (7) (8) (9) (10) (11) (12) and the median days (IRQ) since onset of symptoms to CTPA was 11 (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) . By the end of May 2020 in-hospital mortality of the cohort was 4.88%, with 2 patients still hospitalized and 90% already discharged. Clinical characteristics, treatment and outcomes of the study population are shown in Table 1 . Most frequent symptoms were fever (98%), dyspnea (73%) and cough (63%), and more than 70% of subjects were hypertensive (29 cases). Most patients have been treated empirically with hydroxychloroquine (95%) and steroids (80%), more than 70% with full anticoagulant doses of heparin before performing CTPA, and 61% with continuous positive airway pressure. /L, p = 0.007), and a trend for a lower value of alanine aminotransferase were found. The results of laboratory test in patients with APE confirmed and excluded are shown in Table 2 . The Table 3 . This article is protected by copyright. All rights reserved. Although emerging data suggest that acutely ill patients with COVID-19 have an increased risk for APE, the actual prevalence of APE in this clinical setting is not well known. Most information on the thrombotic complications of COVID-19 derives from studies including critical ill patients and data on non-critical acutely ill subjects are lacking. In the present study we found that among patients who presented respiratory deterioration after been admitted to the internal medicine department with a diagnosis of non-critical COVID-19, near 20% presented a confirmed APE. In these subjects the best discriminating cut-off value of D-dimer for predicting APE was approximately 10 fold the standard threshold (2454 ng/mL), showing a trend to be associated with confirmed APE, albeit not statistically significant (RR: 3.21; CI95%: 0.92-13.97; p = 0.073). The values of D-dimer, when the standard and the age adjusted cut-offs were applied, the simplified Wells score, and other laboratory test did not appear to be clinically useful to identify patients with confirmed APE. Moreover, more than 70% have been empirically treated with full anticoagulant doses of heparin before performing CTPA. Some points are worth discussing. Firstly, the prevalence of APE we found in this clinical setting was high. This finding is even more noticeable when considering that most patients were receiving heparin at anticoagulant doses. As mentioned, most data on prevalence of APE and thrombotic events in general, are from COVID-19 ICU critical patients [8, [10] [11] [12] [13] [14] [15] . COVID-19 patients admitted to the ICUs of 3 Dutch hospitals, Klok and colleagues found a cumulative incidence of the composite thromboembolic outcome of 31% (CI95%: 20-41%) with APE representing 81% of all these thrombotic complication (n = 25) [10] . The rate of thromboembolic complications, mainly APE, was higher (11.7%) in COVID-19 patients referred to ICU from a French hospital, than that observed in a historical control group of non-COVID-19 ARDS patients (2.1%) [14] . These figures are much higher than the rates of APE observed in non COVID-19 ICU patients with sepsis or shock receiving guideline-recommended thromboprophylaxis [17] . In one of the few studies which describing thromboembolic events in non ICU COVID-19 patients, 29 out of 91 subjects (31.9%) who underwent CTPA presented APE, after admission to the internal medicine department [18] . Moreover, in the meta-analysis by Malas as arterial blood gas analysis, interleukin-6, antithrombin III, AST, ALT, LDH, and serum creatinine. Our results suggest that a very high D-dimer cut-off (approximately 10 fold the standard threshold) may be associated to a confirmed APE. These data are in keeping with the results of a study reporting that a D-dimer threshold of 2660 μg/L detected all subject with APE among hospitalized COVID-19 patients [20] . These cut-off values are much higher than those used to exclude pulmonary embolus in non-ICU patients [21] . Even though a diagnostic strategy for APE suspicion based on a single variable (D-dimer) presents evident limitations and guidelines recommend multivariable predicting algorithms for non-COVID19 patients [21] , the diagnostic value of a sharp increase of D-dimer as marker of increased risk of APE in COVID-19 patients remains to be established. Some authors have proposed using age-adjusted D-dimer cut-off levels to rule out venous thromboembolism in COVID-19 patients [22] . Yet, in our study the age adjusted threshold did Accepted Article not show to be clinically useful.Thirdly, in our study, among acutely ill patients presenting respiratory deterioration after admission to the internal medicine department wards with a diagnosis of COVID-19 during the so-called "first wave", most have been treated with full anticoagulant doses of heparin before performing CTAP. The fact that these patients have been certainly considered at a very high risk of having APE probably lead physicians to prescribe full anticoagulation instead of prophylaxis with heparin, also because at the time of the study period (April 2020), no clear expert clinical guidance had been issued on this subject. Interestingly, also in the study by Klok et al [10] it was described as heparin regimes differed between hospitals and the doses increased over time, presumably reflecting an increasing concern on the risk of developing APE in COVID-19 patients. However, empirical use of anticoagulant doses of heparin may not only be ineffective but deleterious since it has been well established that high-dose LMWH administration may be associated with increased incidence of major and fatal bleeding [23] . In fact, pending the results of randomized clinical trials, in patients without a confirmed diagnosis of APE, most authors recommend thromboprophylaxis with LMWH for non-ICU COVID-19 patients [24] . Finally, in COVID-19 patients, given the high prevalence of APE, the unavailability of satisfactory tools for estimating pretest probability and the potential high risk of complications associated with the use of empirical anticoagulation, a high index of suspicion for performing CTPA should be strongly recommended, in order to exclude or to confirm APE. Main contraindications for CTPA are an impaired renal function and hemodynamic instability to undergo the test. Our results show that these conditions are relatively rare among non-ICU COVID-19 patients. The main limitations of our study are retrospective and monocentric design and small sample size, with large CI95% limiting the precision of estimates and the generalizability of results. Yet, we included all consecutive subjects fulfilling the inclusion criteria, to reduce selection bias. Thus, our study population would represent a real world sample severe COVID-19 patients admitted to internal medicine department wards who presented respiratory deterioration. Nevertheless, to confirm our findings, larger and multicenter studies are needed. Moreover, our study population was limited to 41 subjects who presented respiratory deterioration after hospitalization thus performing CPAP, from a total of 218 non-ICU COVID19 patients admitted to the internal medicine department wards of our hospital in the study period (April 2020). No data may be provided on the rates of AP in patients who did not presented respiratory deterioration, because CPAP was not performed in these subjects. Among patients hospitalized in the internal medicine department with a diagnosis of non-critical COVID-19, in whom a CTPA was performed because of respiratory deterioration after admission, the prevalence of confirmed APE is high (20%). Some validated tools used in the APE diagnostic workup of non COVID-19 patients, such as D-dimer (standard and age-adjusted cutoffs) and Wells score, along with other commonly used laboratory test, do not seem to be clinically useful to identify patients with confirmed APE. Most subjects have been treated empirically with full anticoagulant doses of heparin before performing CTPA, even though in many cases CTPA did not confirmed the diagnosis of APE. While awaiting additional evidence and the development of new diagnostic and therapeutic algorithms, our results support the use of a high index of suspicion for performing CTPA to exclude or to confirm APE, as the most appropriate diagnostic approach in this clinical setting. This article is protected by copyright. All rights reserved. PaCO2=arterial partial pressure of carbon dioxide; PaO2=arterial oxygen partial pressure;SO2=oxygen saturation; PaO2: arterial oxygen partial pressure; FiO2: fraction of inspired oxygen Table 3 . Diagnostic performance of different D-dimer cut-offs and Wells score for the diagnosis of APE. APE: acute pulmonary embolism. RR: relative risk. This article is protected by copyright. All rights reserved. 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APE: acute pulmonary embolism; IQR: interquartile range; INR: international normalized ratio; CRP:c-reacted protein WBCC:white blood cell count; LDH: lactate dehydrogenase; ALT: alanine aminotransferase; AST:aspartate transaminase; Cr: Creatinine; PaCO2: arterial partial pressure of carbon dioxide FiO2: fraction of inspired oxygen This article is protected by copyright. All rights reserved. Time since hospitalization to CTPA, median days (IQR) 11 (7 -17) 11 (1.2 -13.5) 11 (8 -17) This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.