Acute Pulmonary Embolism in Coronavirus Disease 2019

Background Pulmonary embolism is a severe condition prone to misdiagnosis given its nonspecic signs and symptoms. Previous studies on the pneumonia outbreak caused by coronavirus disease 2019 (COVID-19) showed a number of patients with elevated d-dimer, whether those patients combined with pulmonary embolism got our attention. Methods Data on clinical manifestations, laboratory and radiological ndings, treatment, and disease progression of 19 patients with laboratory-conrmed COVID-19 pneumonia,who completed computed tomographic pulmonary angiography (CTPA) during hospitalization in the Central Hospital of Wuhan from January 2 to March 26, 2020, were reviewed. Results Of the 19 suspected pulmonary embolism and subjected to CTPA patients, six were diagnosed with pulmonary embolism. The Wells’ score of the six patients with pulmonary embolism was 0–1, which suggested a low risk of pulmonary embolism. The median level of d-dimers collected at the day before or on the day of CTPA completion in the patients with pulmonary embolism was 18.36 (interquartile range [IQR]: 6.69–61.46) µg/mL, which was much higher than that in the patients without pulmonary embolism (median 9.47 [IQR: 4.22–28.02] µg/mL). Of the 6 patients diagnosed with pulmonary embolism, all patients received anticoagulant therapy, 5 of which survived and were discharged and 1 died. whether The clinical manifestations who developed pulmonary prompting challenge on differential

Conclusion A potential causal relationship exists between COVID-19 infection and pulmonary embolism, but whether this phenomenon is common remains uncertain. The clinical manifestations of COVID-19 patients who developed pulmonary embolism are similar to those of patients with increased d-dimer alone, prompting a signi cant challenge on differential diagnoses.

Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a highly infectious type of pneumonia that has reached global pandemic status as declared by the WHO [1,2]. Recent studies have focused on the clinical characteristics, prognostic risk factors, disease progression, and imaging features of patients with COVID-19 [3,4]. Common symptoms of COVID-19 include fever, fatigue, dry cough, dyspnea, hemoptysis, chest pain, and diarrhea [5,6]. Chest computed tomographic scans show bilateral patchy shadows or ground glass opacity in the lungs of all patients [7]. The potential risk factors of older age, high sequential organ failure assessment score, and d-dimer greater than 1 µg/L could help clinicians identify patients with poor prognosis at an early stage [8,9]. Elevating ddimer triggered by COVID-19 might shed an important indicator for clinicians to evaluate whether patients need to be screened for pulmonary embolism (PE) [10]. The symptoms of acute PE include chest pain, shortness of breath, palpitations, fainting, and signs of shock and hypotension [11], which are similar to those of COVID-19 infection. Therefore, whether the elevated d-dimers in COVID-19 patients are associated with PE needs to be identi ed. However, few studies have reported PE in hospitalized COVID-19 patients during the epidemic. In the present case series, we aim to report the clinical manifestations, laboratory ndings, treatment, and progression of 19 laboratorycon rmed COVID-19 patients who were suspected to develop PE and underwent computed tomographic pulmonary angiography (CTPA) during hospitalization at the Central Hospital of Wuhan, Wuhan, China.

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A retrospective case series was conducted on 19 COVID-19 patients with suspected PE for CTPA on the basis of clinical signs and elevated d-dimers in the Central Hospital of Wuhan from January 10 to March 26, 2020. COVID-19 was diagnosed in accordance with the interim guidance of the WHO [11]. Only patients with laboratory-con rmed SARS-CoV-2 infection from throat swab specimens were enrolled. All patients were followed up until discharge or death. The requirement for informed consent was waived due to the urgency to collect data on the emerging SARS-CoV-2. This study was approved by the Ethics Committees of the Central Hospital of Wuhan.

Data Collection
The clinical electronic medical records of 19 patients with SARS-CoV-2 infection were reviewed by three rst-line clinical physicians (Y.G, W.S, and Y.L) and double-checked by a fourth researcher (Y.Lv.). Demographic, clinical, laboratory, treatment, and outcome data were extracted using a standardized data collection form modi ed in accordance with the WHO/International Severe Acute Respiratory and Emerging Infection Consortium case record forms.
We collected data on clinical records, laboratory ndings, chest CT, and CTPA scans. Information on demographic characteristics (gender and age), comorbidities (chronic obstructive pulmonary disease, hypertension, diabetes, cardiovascular disease, cerebrovascular disease, and chronic kidney disease), clinical manifestations, treatment, and outcomes (discharge or death) were extracted from electronic medical records. Laboratory ndings, including white blood cell count, neutrophil count, lymphocyte count, hemoglobin, platelet count, C-reactive protein, procalcitonin, blood urea, creatinine, total bilirubin, alanine aminotransferase, aspartate aminotransferase, brinogen, d-dimer, lactate dehydrogenase, creatine kinase, and arterial blood gases (lactate and PaO 2 /FiO 2 [the ratio of partial pressure of oxygen to fraction of inspired oxygen]), were collected at admission and the day before or on the day of CTPA completion. Acute Physiology and Chronic Health Evaluation II scores (APACHE II), sequential organ failure assessment (SOFA), CURB-65 criteria and Simpli ed were determined within 24 h after admission. Wells' scores [12] were determined at the day before or on the day of CTPA completion. Data on all treatment measures, including antibiotic, antivirus, glucocorticoid, and intravenous immunoglobulin therapy, anticoagulation therapy, and respiratory support, were acquired during hospitalization. Throat swab samples were collected from all suspected patients, and the laboratory con rmation of SARS-CoV-2 was performed using real-time reverse transcription polymerase chain reaction in accordance with the manufacturer's protocol (Shanghai ZJ Bio-Tech Co., Ltd. Or Xi'an Tianlong Science and Technology Co., Ltd).
De nitions PE is a form of venous thromboembolism (VTE) in which an embolus (a travelling blood clot) blocks the blood vessels of the pulmonary artery tree, which can ultimately result in sudden death [13]. Acute respiratory distress syndrome (ARDS) was determined by the consensus of two trained physician reviewers using the Berlin de nition, that is, the development of acute, bilateral pulmonary in ltrates, and hypoxemia (PaO2/FiO2 ≤ 300 mm Hg) not primarily due to heart failure or volume overload [14].

Statistical analysis
We summarized continuous variables as medians with interquartile rages (IQR) and categorical variables with n (%). Since our study is a case series study, statistical comparison is not necessary. All analyses were performed by using SPSS, version 20.0.

Results
All 19 patients with signi cantly elevated d-dimers were suspected with acute PE and subjected to CTPA. The clinical characteristics of all patients strati ed by the result of CTPA are presented in Table 1. Six patients were diagnosed with PE by CTPA (Fig. 1). The laboratory ndings were collected at the day before or on the day of CTPA completion. The age of the patients was 65 (IQR: 57-70) years, and 12 (63%) of them were male. Eight (42%) patients had chronic hypertension, and none of the patients had underlying diseases, such as diabetes, COPD, or cardiovascular disease. Sixteen (84.2%) patients had different degrees of ARDS at admission. The APACHE II score in the patients with PE was 7 (4-9) and 5 (4-6) for those without PE. The Wells' score of two patients without PE was ≥ 2. The median levels of d-dimers in the patients with PE were 18.36 (IQR: 6.69-61.46) µg/mL, which were much higher than those in the patients without PE  The clinical characteristics on admission of six COVID-19 patients who were diagnosed with PE are presented in Table 2. These patients were admitted to the hospital with u-like symptoms, including fever (n = 3), myalgia (n = 2), fatigue (n = 4), cough (n = 2), dyspnea (n = 3), and only one presented with diarrhea. All patients had no leg swelling and no pain on calf palpation. Three patients (patients 2, 3, and 5) were screened for venous vessels in the lower extremities, and the presence of venous thrombosis has not been observed. Three of the six patients had lymphopenia (< 1 × 10 cells per L). Four patients had increased d-dimers at admission. The Wells' score of six patients was 0-1, suggesting low risk of PE. The six patients were treated with anticoagulation (low-molecularweight heparin [LMWH]). Patient 3 stopped anticoagulant treatment because of gastrointestinal bleeding during hospitalization, and LMWH was given after gastrointestinal bleeding stabilized. The changes in d-dimers of the six patients are presented in Fig. 2. During the treatment, the coagulation function of the six patients was within normal range, including prothrombin time, international normalized ratio, prothrombin time activity, brinogen, and activated partial thromboplastin time (Fig. 2). After treatment of anticoagulation, the three patients (patients 2, 3, and 4) underwent CTPA again, and the embolism of three PE patients disappeared or signi cantly relieved (Fig. 3). Patient 6 developed critical COVID-19 pneumonia and died on the 11th day of hospitalization. Discussion COVID-19 is commonly complicated with signi cant abnormality of coagulation function [15,16]. The occurrence of embolic events has aroused the attention of clinicians, such as cerebral infarctions and PE [17,18]. A case report with a 75-year-old woman hospitalized for COVID-19 proposed a possible precipitant role of SARS-CoV-2 infection in the development of acute venous thrombo-embolism [18]. In our treatment of patients with COVID-19, we found ddimers elevated in many patients, especially those who developed severe cases, which was similar to previous studies [5,9]. PE is a form of VTE in which an embolus blocks the blood vessels of the pulmonary artery tree; massive PE is life threatening and can present as cardiogenic shock and cardiac arrest [11,19]. Survivors of acute PE can develop post-PE syndrome, characterized by dyspnea and exercise intolerance, who had lower quality of life. A negative d-dimer assay allows the physician to safely rule out the diagnosis of PE. However, a positive d-dimer test is not an absolute diagnostic criterion for PE because elevated d-dimers could be observed in other clinical situations (e.g., infection, in ammation, malignancy, postsurgical status, or pregnancy) [20,21]. Acute infections are associated with a transient increased risk of venous thromboembolic events. In our cases, the clinical characteristics of COVID-19 patients with PE were similar to those of common patients who developed COVID-19 pneumonia, which further complicates the differential diagnosis of COVID-19 from PE. CTPA is the preferred method of diagnosis [22].
In our study, 19 patients completed CTPA, of whom only six patients were diagnosed with PE. This result may be related not only to the limitation of CTPA's evaluation value for pulmonary embolus below the subsegment due to its spatial resolution but also to the characteristics of patients. The levels of d-dimers, PaO2/FiO2, lactate, and APACHE II score were much higher in the patients with PE than in those without PE. These results may provide clinicians some indications when screening patients with elevated d-dimer for CTPA. The clinical application of CTPA is also subject to certain limitations, such as the high cost, contrast agent allergy, renal insu ciency, and pregnancy, and contrast agents may cause renal injury [22]. During the outbreak of SARS-CoV-2, the transfer of patients presents with considerable di culties and risks. For critically ill patients, bedside ultrasound may be used as an option. Echocardiographic evaluation showed a dilated and hypokinetic right ventricle with an increased mean derived pulmonary arterial pressure, which suggests PE [23].
PE is easy to be neglected in COVID-19 patients with highly elevated d-dimer because of the similar clinical symptoms between PE and severe or critical pneumonia. Especially, in these PEs are not associated with hemodynamic instability (i.e., shock or hypotension). Wells' score is often used to assess the risk of PE [24,25]. In patients with low, moderate, and high Wells' scores, the incidence rates of PE are 6%, 23%, and 49%, respectively [26]. The Wells' score of the six PE patients in our study was 0-1, suggesting a low risk of PE for these patients. In our study, the six patients had PE but without strong predisposing risk factors for venous thrombo-embolism, such as recent surgery or immobilization, previous history of PE or deep vein thrombosis, hemoptysis, and malignancy. Therefore, the absence of major predisposing factors in those COVID-19 patients with PE seems to con rm the role of COVID-19 infection as a factor for acute PE and the causal relationship.
Parenteral anticoagulation is a common treatment for PE. LMWH carries a low risk of inducing major bleeding and heparin-induced thrombocytopenia and prefers initial anticoagulation in PE [27]. Anticoagulation should be initiated even prior to the con rmed diagnosis when the clinical suspicion of acute PE is high and the bleeding risk is low [28]. Anticoagulant therapy mainly with LMWH is associated with good prognosis in severe COVID-19 patients with markedly elevated D-dimer [16,29]. In our study, we also recommend prophylactic anticoagulation in the absence of bleeding risk or contraindications. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Funding Not available.

Figure 1
Computed tomographic pulmonary angiography scans (CTPA) of 6 patients with pulmonary embolism A-F was the CTPA scans of patients 1 to patients 6, respectively. The red arrows indicate the location of the pulmonary artery thrombosis.