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INTRODUCTION
Since the emergence of coronavirus disease 2019 (COVID-19), various clinical manifestations ranging from asymptomatic disease to symptomatic presentations, including interstitial pneumonia, severe acute respiratory distress syndrome (ARDS), multi-organ failure, and death, have been reported [1]. The respiratory pattern of COVID-19 clinical evolution can be explained in three forms: mild symptomatic involvement of the upper respiratory tract, non-life-threatening pneumonia, and severe pneumonia with ARDS, which initially presents as non-severe symptoms in the first 7–8 days and rapidly progresses until advanced respiratory support is required [2].
Numerous investigations in the literature have described a hypercoagulable state in patients infected with COVID-19, which leads to thromboembolic events, including pulmonary thromboembolism, coronary artery disease, arterial thrombosis, and ischemic strokes [3-5]. In addition, abnormal coagulation-related parameters have been frequently noted and are associated with a poor prognosis [6, 7].
The cytopathic reaction is one of the substantial theories regarding COVID-19 infection pathogenesis; however, from another point of view, the virus induces an unrelenting cascade of local cytokine release, inflammatory response, and a potentially detrimental immune reaction [8]. Excessive inflammatory response, in addition to hypoxia, immobilization, and diffuse intravascular coagulation in the setting of COVID-19 infection, contributes to the prothrombotic state [9].
Pulmonary thromboembolism (PTE) is one of the critical thrombotic conditions estimated to occur in 1.1–3.4% of COVID-19 patients, regardless of hospital admission. However, the data may have been influenced by the severity of the infection and the short-term follow-up of the patients. Additionally, there is an ongoing debate regarding the necessity for prophylactic and therapeutic anticoagulant use for patients with COVID-19. The current study aimed to assess the characteristics of patients with PTE to determine which COVID-19 patients are at an increased risk for PTE development and to provide subsequent anticoagulation therapy.
MATERIALS AND METHODS
Study population
This was a cross-sectional study of patients admitted to Amin and Alzahra Hospitals (affiliated with Isfahan University of Medical Sciences) due to COVID-19 pneumonia from May to June 2020. This case-control investigation was conducted on 231 patients suspected of PTE in two groups, including 99 patients with confirmed PTE according to computed tomography pulmonary angiography (CTPA) and 132 patients whose imaging was negative for PTE.
This study adhered to the tenets of the Declaration of Helsinki. The Institutional Ethical Committee at Isfahan University of Medical Sciences approved the study and all related protocols (IR.MUI.MED.REC.1399.692).
This was an observational study derived from an ongoing cohort study of a large population of COVID-19 pneumonia patients. Accordingly, the patients (or their legal guardian if needed) were informed about the protocols, reassured regarding the confidentiality of their personal information, and written informed consent was obtained from all participants before any intervention.
The study population was gathered from suspected PTE patients hospitalized due to COVID-19 pneumonia, which was confirmed by a positive polymerase chain reaction (PCR) test. Patients with pregnancy, immune deficiency, history of coagulopathies, and thromboembolic events within a month before hospitalization regardless of its type (deep vein thrombosis, pulmonary thromboembolism, cerebrovascular accidents, arterial thrombosis, or myocardial infarction), were excluded from the study. The included patients received anti-COVID-19 infection and anticoagulation therapy according to Iran’s national guidelines [10].
Diagnosis of PTE
Patients with clinical manifestations suggestive of PTE (sudden dyspnea, pleuritic chest pain, hemoptysis, sudden hemodynamic instability, sudden general condition exacerbation, sudden loss of consciousness, and inconsistency of hypoxemia with the severity of lung involvement on computed tomography) were evaluated using D-dimer testing. CTPA was performed to confirm PTE in patients with elevated D-dimer levels [11].
Data collection
Demographic characteristics, including age, sex, smoking, comorbidities [diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), end-stage renal disease (ESRD), malignancy, cerebrovascular accident (CVA), ischemic heart disease (IHD), history of PTE], current smoking, and medical history (antiplatelet or anticoagulant administration prior to PTE assessments), were entered into the study checklist.
On admission, hemodynamic information [oxygen saturation (O2 saturation), pulse rate, systolic and diastolic blood pressure, respiratory rate, and mobility] and laboratory assessments [complete blood count with differential (CBC diff), albumin, ferritin, C-reactive protein (CRP), D-dimer, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), fibrinogen, troponin, and lactate dehydrogenase (LDH)] were recorded in the study checklist. A reference laboratory performed all assessments to minimize potential bias.
CRP and LDH levels were measured every other day during hospital admission, while D-dimer levels were measured twice a week. The greatest difference between the on-admission measurements and the highest parameter level was calculated.
Patients with on-admission oxygen saturation below 90% and a respiratory rate above 30 breaths per minute were determined to have a severe course of COVID-19 pneumonia.
The patients who were given medications including hydroxychloroquine, antibiotics, remdesivir, interferon, favipiravir, corticosteroids, and kaletra prior to PTE diagnosis, were recruited as well.
Anticoagulation therapy administration status prior to PTE assessment was classified as no anticoagulant therapy, prophylactic, intermediate dose, or therapeutic dose. Anticoagulants were initiated before the incidence of thrombosis. Prophylactic doses included 5,000 IU subcutaneous unfractionated heparin (UFH) (three times a day) [for BMI >40 kg/m2: 7,500 IU subcutaneous UFH (three times a day)] or 40 mg subcutaneous enoxaparin (once daily) [for BMI >40 kg/m2: 40 mg subcutaneous enoxaparin (twice daily)]. Intermediate doses included 7,500 IU subcutaneous UFH (three times a day) or 60 mg subcutaneous enoxaparin (daily). The therapeutic doses were determined as 80 IU/kg UFH bolus infusion, followed by 18 IU/kg/h UFH infusion, or 1 mg/kg subcutaneous enoxaparin (twice daily). The doses were defined according to national protocols [10]. Anticoagulantrelated adverse effects, including gastrointestinal (GI) bleeding, hemoptysis, and hematuria, were recorded. Other probable side effects, such as easy bruising, petechiae, or purpura, were categorized as “other”.
The latter outcomes were ICU admission requirement, discharge/death, and non-invasive ventilation (NIV)/intubation.
Data analysis
The data were entered into the Statistical Package for Social Sciences (SPSS, version 22.0, SPSS Inc., Chicago, IL, USA). The descriptive data were presented as mean and standard deviation or median and range for the continuous variables, and frequency and percentages for categorical variables. The chi-square test or Fisher’s exact test was used to compare categorical variables between the groups. Continuous variables were compared using the Mann–Whitney U test. Binary logistic regression analysis was applied to estimate the odds ratio and determine the association between the assessed factors and thrombotic events in the crude and adjusted models for age and sex. Statistical significance was set at P<0.05.
RESULTS
Among the 13,099 patients admitted to the reference hospitals due to COVID-19 pneumonia, 690 (5.26%) were suspected of having PTE according to the clinical manifestations. CTPA was performed for suspected cases (N=690), among which PTE was confirmed in 132 patients (19.13%). Ninety-nine (75%) out of the 132 confirmed PTE patients had complete medical records. Eventually, they were randomly matched with 132 suspected PTE patients with negative CTPA reports.
The PTE patients were predominantly male, had poorer on-admission oxygen saturation levels, higher neutrophil-to-lymphocyte ratios (NLR), higher troponin, D-dimer, CRP, and LDH levels, and lower hemoglobin, fibrinogen, PTT, and albumin levels (P<0.05). Detailed information is presented in Table 1.
The hospital-related characteristics of the study population are shown in Table 2. According to this table, the two groups were remarkably different in terms of hydroxychloroquine, interferon, and corticosteroid use. The use of anticoagulants before PTE diagnosis, anticoagulant-related adverse effects, hospitalization outcomes, and the period between admission and discharge were the other parameters that were different between the two groups.
According to logistic regression, the requirement for NIV was significantly increased by PTE in both crude (OR, 3.37; 95% CI, 1.60–7.12) and adjusted models (OR, 3.40; 95% CI, 1.59–7.25); however, the other hospitalization outcomes were not associated with PTE incidence (Table 3).
Furthermore, corticosteroid administration was significantly associated with PTE development in crude (OR, 2.14; 95% CI, 1.11–4.13) and an adjusted model for severe COVID-19 (O2 saturation <90 and respiratory rate >30) (OR, 2.17; 95% CI, 1.12–4.19).
Logistic regression analysis revealed that male sex and decreased O2 saturation, hemoglobin, and albumin levels were independent predictors of PTE development as shown in Table 4.
DISCUSSION
The present investigation, which is a secondary study derived from an ongoing report of a large population of hospitalized patients with COVID-19 pneumonia, tried to assess the characteristics of patients with PTE due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We found that male sex and lower oxygen saturation, hemoglobin, and albumin levels were independently associated with the risk of PTE development. Interestingly, corticosteroid administration led to an approximately 2.5-fold increased risk of PTE.
Respiratory tract infection is a well-known predisposing factor for PTE among hospitalized patients. Previous studies have shown that roughly 23–30% of COVID-19 patients were positive for PTE based on CTPA [12, 13], a statistic that is in line with the present study in which approximately 20% of the patients who underwent CTPA had PTE.
Searching the literature shows an increasing body of evidence regarding the increased risk of PTE due to COVID-19. This viral infection predisposes a person to venous thromboembolism due to the activation of a systemic inflammatory response, leading to an imbalance between procoagulant and anticoagulant effects [14].
Higher levels of biomarkers related to the hypercoagulable state induced by COVID-19, including fibrinogen, PTT, INR, and D-dimer, have been noted in our study, which is consistent with data from other studies conducted on PTE patients with COVID-19 pneumonia [4, 6]. Some studies have attempted to present a cut-off for D-dimer levels to distinguish PTE [15], although most of the recent guidelines did not favor routinely assessing this biomarker to diagnose venous thromboembolism [16]. Likewise, we did not detect D-dimer as a standalone predictor of PTE incidence among patients with SARS-CoV-2.
Male sex was accompanied by a 2-fold increased risk of PTE. Most previous studies have highlighted more severe lung involvement among men than among women [17, 18]. However, gender-based assessments of PTE due to COVID-19 are inadequate. In line with our study, Grillet and colleagues demonstrated that the male gender was a significant risk factor for both PTE development and its severity [12]. Nevertheless, a cohort study by Cavagna et al. [19] was opposed. Generally, it is assumed that male sex hormones and the modulatory role of estrogen in immune response intensity and endothelial function are factors associated with a higher risk of complications in males. Similar logic has been noted for other conditions associated with inflammatory processes, such as atherosclerosis. On the other hand, males may consult physicians when in more deteriorated states than females. In addition, males usually have more predisposing factors, such as smoking or other comorbidities [17].
An on-admission oxygen saturation level of less than 93% was an independent predictor of PTE incidence associated with a 2.33-fold increased risk of PTE. Oxygenation status is a mainstay in the determination of COVID-19 severity, prognosis, and complications. Although PTE itself may lead to a V/Q mismatch, a decreased oxygen saturation level represents a more severe disease course that is accompanied by a storm of cytokine release, oxidative stress, and endothelial dysfunction, and therefore, an increased risk for thromboembolism [1, 20, 21].
Albumin is a well-known marker of health status in medicine. Accordingly, some researchers have tried to assess its value in predicting COVID-19 prognosis. In this regard, Li et al. [22] presented albumin as an independent predictor of mortality in critically ill patients, and Violi et al. [23] confirmed this theory in a general population of COVID-19 patients that was not limited to critically ill patients. In this study, we have shown up to a 20% decrease in the risk of PTE by each unit increase in albumin. Nevertheless, no data in this regard, a 4-fold increase in D-dimer levels among patients with hypoalbuminemia reinforces the theory about the association between decreased serum albumin level and hypercoagulable state [16]. Further investigations for the generalization of the data are required.
Hemoglobin was another hematological factor associated with PTE incidence due to COVID-19 pneumonia. Most studies reported insignificant differences between those with thromboembolic events and the control groups [24, 25]. Low levels of hemoglobin negatively affect blood viscosity, which in turn inhibits the function of anti-thrombotic mechanisms due to the reduction of stress formation on endothelial bed dysfunction [26, 27].
Most studies have unanimously described a poor prognosis of PTE in patients with COVID-19 [28, 29]. Surprisingly, we found that PTE independently did not affect any factor related to in-hospital outcomes, including ICU admission, intubation, discharge, and death, except for NIV requirement, which increased up to 3.5 times. Since the emergence of COVID-19, NIV has been considered as a key intervention to preserve a patient’s appropriate oxygenation and minimize the requirement for invasive strategies. On the other hand, it was assumed that patients under mechanical ventilation were predisposed to PTE development due to their more severe disease course [30]. Thus, the generalization of this outcome requires further investigation.
According to the findings of this study, PTE was confirmed in one-fifth of suspected patients who underwent CTPA imaging. Male sex, decreased oxygen saturation, and lower levels of hemoglobin and albumin were independent predictors of PTE in patients with COVID-19 pneumonia. Further investigations to provide an inexpensive, accessible, non-invasive, and safe scoring system to predict PTE development and initiate anticoagulation therapy for patients with COVID-19 are strongly recommended.
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