Longitudinal analysis of chest Q-SPECT/CT in patients with severe COVID-19.

INTRODUCTION: Patients with COVID-19 have an increased risk for microvascular lung thrombosis. In order to evaluate the type and prevalence of perfusion defects, we performed a longitudinal analysis of combined perfusion single-photon emission and low-dose computed tomography (Q-SPECT/CT scan) in patients with COVID-19 pneumonia. METHODS: Consecutive patients with severe COVID-19 (B.1.1.7 variant SARS-CoV-2) and respiratory insufficiency underwent chest Q-SPECT/CT during hospitalization, and 3 months after discharge. At follow-up (FU), Q-SPECT/CT were analyzed and compared with pulmonary function tests (PFT), blood analysis (CRP, D-dimers, ferritin), modified Medical Research Council (mMRC) dyspnea scale, and high-resolution CT scans (HRCT). Patients with one or more segmental perfusion defects outside the area of inflammation (PDOI) were treated with anticoagulation until FU. RESULTS: At baseline, PDOI were found in 50 of 105 patients (47.6 %). At FU, Q-SPECT/CT scans had improved significantly (p < 0.001) and PDOI were recorded in 14 of 77 (18.2 %) patients. There was a significant correlation between mMRC score and the number of segmental perfusion defects (r = 0.511, p < 0.001), and a weaker correlation with DLCO (r = -0.333, p = 0.002) and KCO (r = -0.373, p = 0.001) at FU. Neither corticosteroid therapy nor HRCT results showed an influence on Q-SPECT/CT changes (p = 0.94, p = 0.74). CRP, D-Dimers and ferritin improved but did not show any association with the FU Q-SPECT/CT results (p = 0.08). CONCLUSION: Segmental mismatched perfusion defects are common in severe COVID-19 and are correlated with the degree of dyspnea. Longitudinal analyses of Q-SPECT/CT scans in severe COVID-19 may help understand possible mechanisms of long COVID and prolonged dyspnea.

Preliminary Comparison of Molecular Antioxidant and Inflammatory Mechanisms Determined in the Peripheral Blood Granulocytes of COVID-19 Patients.

The aim of this study was to evaluate selected parameters of redox signaling and inflammation in the granulocytes of COVID-19 patients who recovered and those who died. Upon admission, the patients did not differ in terms of any relevant clinical parameter apart from the percentage of granulocytes, which was 6% higher on average in those patients who died. Granulocytes were isolated from the blood of 15 healthy people and survivors and 15 patients who died within a week, and who were selected post hoc for analysis according to their matching gender and age. They differed only in the lethal outcome, which could not be predicted upon arrival at the hospital. The proteins level (respective ELISA), antioxidant activity (spectrophotometry), and lipid mediators (UPUPLC-MS) were measured in the peripheral blood granulocytes obtained via gradient centrifugation. The levels of Nrf2, HO-1, NFκB, and IL-6 were higher in the granulocytes of COVID-19 patients who died within a week, while the activity of cytoplasmic Cu,Zn-SOD and mitochondrial Mn-SOD and IL-2/IL-10 were lower in comparison to the levels observed in survivors. Furthermore, in the granulocytes of those patients who died, an increase in pro-inflammatory eicosanoids (PGE2 and TXB2), together with elevated cannabinoid receptors 1 and 2 (associated with a decrease in the anti-inflammatory 15d-PGJ2), were found. Hence, this study suggests that by triggering transcription factors, granulocytes activate inflammatory and redox signaling, leading to the production of pro-inflammatory eicosanoids while reducing cellular antioxidant capacity through SOD, thus expressing an altered response to COVID-19, which may result in the onset of systemic oxidative stress, ARDS, and the death of the patient.

Incidence, Risk Factors and Mortality Associated with Major Bleeding Events in Hospitalized COVID-19 Patients.

Thromboprophylaxis is a mainstay of treatment of hospitalized COVID-19 patients, due to the high occurrence of thrombotic events. This increases the risk of bleeding. However, data on bleeding events and associated risk factors are scarce. Thus, we aimed to investigate the incidence, predictors and clinical outcomes associated with major bleeding in hospitalized COVID-19 patients. We retrospectively evaluated a cohort of 4014 consecutively hospitalized COVID-19 patients treated in a tertiary-level institution in the period 3/2020-3/2021. Bleeding of any kind was documented in 322 (8%) and major bleeding in 129 (3.2%) patients. A total of 129 (40.1%) bleeding events were present at the time of hospital admission, and 193 (59.9%) occurred during hospitalization. In the multivariate logistic regression analysis, intensive-care-unit treatment (adjusted odds ratio (aOR) 6.55; p < 0.001), atrial fibrillation (aOR 2.55; p = 0.029), higher white-blood-cell count (WBC) (aOR 1.03; p = 0.021), lower hemoglobin (aOR 0.97; p = 0.002) and history of bleeding (aOR 17.39; p < 0.001) were recognized as mutually independent predictors of major bleeding. Major bleeding was significantly associated with increased in-hospital mortality compared to non-major-bleeding patients (59.7% vs. 34.8%, p < 0.001), especially if occurring during hospitalization. Median time from major bleeding to death was 5 days. Bleeding events are frequent in hospitalized COVID-19 patients, with a significant proportion of patients presenting at the time of hospital admission, and others almost universally exposed to anticoagulant and corticosteroid therapies. Major bleeding is associated with high mortality, especially if occurring during hospitalization. The recognition of patients at risk and implementation of timely interventions are of high clinical importance.

Proton pump inhibitors use prior to COVID-19 hospitalization is associated with higher Clostridioides difficile infection rate.

BACKGROUND: There are uncertainties regarding associations of prior proton pump inhibitor (PPI) use with susceptibility for COVID-19 and risks associated with SARS-CoV-2 infection. We aimed to evaluate the associations of prior PPI use with outcomes in hospitalized patients with COVID-19. RESEARCH DESIGN AND METHODS: We have retrospectively evaluated a total of 5959 consecutively hospitalized patients with COVID-19 from a tertiary-level institution in the period 3/2020-6/2021. Associations of prior PPI use with outcomes of in-hospital mortality, mechanical ventilation, intensive care unit stay, venous thromboembolism, arterial thrombosis, major bleeding, bacteremia, and Clostridioides difficile infection (C. diff.) were evaluated in entire and case-matched cohorts. RESULTS: Among 5959 evaluated patients, there were 1967 (33%) PPI users. In an entire cohort, prior PPI use was associated with higher in-hospital mortality and higher occurrence of C. diff. Association of prior PPI use with mortality diminished, whereas association with C. diff. persisted after multivariable adjustments. In a matched cohort, prior PPI use was associated only with higher risk of C. diff. but not other outcomes in line with multivariable analysis. CONCLUSIONS: Although prior PPI use might not have a significant impact on clinical course and mortality of SARS-CoV-2 infection, it may predispose patients to the development of complications like higher occurrence of C. diff. and thus substantially impact the course of treatment.

Ability of presepsin concentrations to predict mortality in adult patients with sepsis.

Background: Early diagnosis of sepsis is essential for a favorable disease outcome. The aim of this study was to evaluate the association of initial and subsequent presepsin concentrations with sepsis outcomes. Methods: One hundred sepsis patients were enrolled in the study from two different university centers. Four times during study, concentrations of presepsin, procalcitonin (PCT), and C-reactive protein (CRP) were measured, and Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score were calculated. Patients were grouped into survivors and nonsurvivors. A sandwich ELISA kit was used to measure presepsin concentrations. To test the changes in biomarkers concentrations and SOFA score and APACHE II score during the disease course and to estimate the differences between outcome groups, generalized linear mixed effects model was used. Receiver operating characteristic curve analysis was performed to determine the prognostic value of presepsin concentrations. Results: Initial values of presepsin, SOFA score, and APACHE II score were significantly higher in nonsurvivors compared to survivors. Concentrations of PCT and CRP did not differ significantly between outcome groups. ROC curve analyses show a greater predictive ability of initial presepsin concentrations for predicting mortality compared to subsequent measurements of presepsin concentrations. Conclusions: Presepsin has a good ability to predict mortality. Initial presepsin concentrations better reflects poor disease outcome compared to presepsin concentrations 24 and 72 hours after admission.

The performance of the WHO COVID-19 severity classification, COVID-GRAM, VACO Index, 4C Mortality, and CURB-65 prognostic scores in hospitalized COVID-19 patients: data on 4014 patients from a tertiary center registry.

AIM: To evaluate the predictive properties of several common prognostic scores regarding survival outcomes in hospitalized COVID-19 patients. METHODS: We retrospectively reviewed the medical records of 4014 consecutive COVID-19 patients hospitalized in our tertiary level institution from March 2020 to March 2021. Prognostic properties of the WHO COVID-19 severity classification, COVID-GRAM, Veterans Health Administration COVID-19 (VACO) Index, 4C Mortality Score, and CURB-65 score regarding 30-day mortality, in-hospital mortality, presence of severe or critical disease on admission, need for an intensive care unit treatment, and mechanical ventilation during hospitalization were evaluated. RESULTS: All of the investigated prognostic scores significantly distinguished between groups of patients with different 30-day mortality. The CURB-65 and 4C Mortality Score had the best prognostic properties for prediction of 30-day mortality (area under the curve [AUC] 0.761 for both) and in-hospital mortality (AUC 0.757 and 0.762, respectively). The 4C Mortality Score and COVID-GRAM best predicted the presence of severe or critical disease (AUC 0.785 and 0.717, respectively). In the multivariate analysis evaluating 30-day mortality, all scores mutually independently provided additional prognostic information, except the VACO Index, whose prognostic properties were redundant. CONCLUSION: Complex prognostic scores based on many parameters and comorbid conditions did not have better prognostic properties regarding survival outcomes than a simple CURB-65 prognostic score. CURB-65 also provides the largest number of prognostic categories (five), allowing more precise risk stratification than other prognostic scores.

Diversified Effects of COVID-19 as a Consequence of the Differential Metabolism of Phospholipids and Lipid Peroxidation Evaluated in the Plasma of Survivors and Deceased Patients upon Admission to the Hospital.

As a result of SARS-CoV-2 infection, inflammation develops, which promotes oxidative stress, leading to modification of phospholipid metabolism. Therefore, the aim of this study is to compare the effects of COVID-19 on the levels of phospholipid and free polyunsaturated fatty acids (PUFAs) and their metabolites produced in response to reactions with reactive oxygen species (ROS) and enzymes (cyclooxygenases-(COXs) and lipoxygenase-(LOX)) in the plasma of patients who either recovered or passed away within a week of hospitalization. In the plasma of COVID-19 patients, especially of the survivors, the actions of ROS and phospholipase A2 (PLA2) cause a decrease in phospholipid fatty acids level and an increase in free fatty acids (especially arachidonic acid) despite increased COXs and LOX activity. This is accompanied by an increased level in lipid peroxidation products (malondialdehyde and 8-isoprostaglandin F2α) and lipid mediators generated by enzymes. There is also an increase in eicosanoids, both pro-inflammatory as follows: thromboxane B2 and prostaglandin E2, and anti-inflammatory as follows: 15-deoxy-Δ-12,14-prostaglandin J2 and 12-hydroxyeicosatetraenoic acid, as well as endocannabinoids (anandamide-(AEA) and 2-arachidonylglycerol-(2-AG)) observed in the plasma of patients who recovered. Moreover, the expression of tumor necrosis factor α and interleukins (IL-6 and IL-10) is increased in patients who recovered. However, in the group of patients who died, elevated levels of N-oleoylethanolamine and N-palmitoylethanolamine are found. Since lipid mediators may have different functions depending on the onset of pathophysiological processes, a stronger pro-inflammatory response in patients who have recovered may be the result of the defensive response to SARS-CoV-2 in survivors associated with specific changes in the phospholipid metabolism, which could also be considered a prognostic factor.

Lipidomics Revealed Plasma Phospholipid Profile Differences between Deceased and Recovered COVID-19 Patients.

Thorough understanding of metabolic changes, including lipidome alteration, associated with the development of COVID-19 appears to be crucial, as new types of coronaviruses are still reported. In this study, we analyzed the differences in the plasma phospholipid profiles of the deceased COVID-19 patients, those who recovered and healthy people. Due to identified abnormalities in plasma phospholipid profiles, deceased patients were further divided into two subgroups (D1 and D2). Increased levels of phosphatidylethanolamines (PE), phosphatidylcholines (PC) and phosphatidylserines (PS) were found in the plasma of recovered patients and the majority of deceased patients (first subgroup D1) compared to the control group. However, abundances of all relevant PE, PC and PS species decreased dramatically in the plasma of the second subgroup (D2) of five deceased patients. These patients also had significantly decreased plasma COX-2 activity when compared to the control, in contrast to unchanged and increased COX-2 activity in the plasma of the other deceased patients and recovered patients, respectively. Moreover, these five deceased patients were characterized by abnormally low CRP levels and tremendous increase in LDH levels, which may be the result of other pathophysiological disorders, including disorders of the immune system, liver damage and haemolytic anemia. In addition, an observed trend to decrease the autoantibodies against oxidative modifications of low-density lipoprotein (oLAb) titer in all, especially in deceased patients, indicate systemic oxidative stress and altered immune system that may have prognostic value in COVID-19.

Survival after hospital discharge in patients hospitalized for acute coronavirus disease 2019: data on 2586 patients from a tertiary center registry.

AIM: To assess the long-term survival after hospital discharge of patients hospitalized due to coronavirus disease 2019 (COVID-19). METHODS: We retrospectively reviewed data on post-discharge survival of 2586 COVID-19 patients hospitalized in our tertiary hospital from March 2020 to March 2021. RESULTS: Among 2586 patients, 1446 (55.9%) were men. The median age was 70 years, interquartile range (IQR, 60-80). The median Charlson comorbidity index was 4 points, IQR (2-5). The median length of hospital stay was 10 days, IQR (7-16). During a median follow-up of 4 months, 192 (7.4%) patients died. The median survival time after hospital discharge was not reached, and 3-month, 6-month, and 12-month survival rates were 93%, 92%, and 91%, respectively. In a multivariate analysis, mutually independent predictors of worse mortality after hospital discharge were age >75 years, Eastern Cooperative Oncology Group status 4, white blood cell count >7 ×109/L, red cell distribution width >14%, urea on admission >10.5 mmol/L, mechanical ventilation during hospital stay, readmission after discharge, absence of obesity, presence of chronic obstructive pulmonary disease, dementia, and metastatic malignancy (P<0.05 for all). CONCLUSION: Substantial risk of death persists after hospital admission due to COVID-19. Factors related to an increased risk are older age, higher functional impairment, need for mechanical ventilation during hospital admission, parameters indicating more pronounced inflammation, impaired renal function, and particular comorbidities. Interventions aimed at improving patients' functional capacity may be needed.

The Impact of Severe COVID-19 on Plasma Antioxidants.

Several studies suggested the association of COVID-19 with systemic oxidative stress, in particular with lipid peroxidation and vascular stress. Therefore, this study aimed to evaluate the antioxidant signaling in the plasma of eighty-eight patients upon admission to the Clinical Hospital Dubrava in Zagreb, of which twenty-two died within a week, while the other recovered. The differences between the deceased and the survivors were found, especially in the reduction of superoxide dismutases (SOD-1 and SOD-2) activity, which was accompanied by the alteration in glutathione-dependent system and the intensification of the thioredoxin-dependent system. Reduced levels of non-enzymatic antioxidants, especially tocopherol, were also observed, which correlated with enhanced lipid peroxidation (determined by 4-hydroxynonenal (4-HNE) and neuroprostane levels) and oxidative modifications of proteins assessed as 4-HNE-protein adducts and carbonyl groups. These findings confirm the onset of systemic oxidative stress in patients with severe SARS-CoV-2, especially those who died from COVID-19, as manifested by strongly reduced tocopherol level and SOD activity associated with lipid peroxidation. Therefore, we propose that preventive and/or supplementary use of antioxidants, especially of lipophilic nature, could be beneficial for the treatment of COVID-19 patients.

Short-term outcomes of patients with chronic liver disease hospitalised with COVID-19.

BACKGROUND: Patients with chronic liver disease (CLD) might have an aggravated course after acquisition of coronavirus disease 2019 (COVID-19). AIMS: To analyse the outcomes of patients with CLD who were hospitalised due to COVID-19. METHODS: The medical records of 4014 patients hospitalised because of COVID-19 in a regional referral hospital over a 12-month period were analysed. Patients with CLD were identified based on discharge diagnoses according to the International Classification of Diseases-10th Revision. Patients were followed for 30 days from admission and their outcomes (intensive care unit (ICU) admission, mechanical ventilation (MV) or death) were analysed. RESULTS: Of the 4014 patients, 110 (2.7%) had CLD and 49 (1.2%) had cirrhosis. The median age of CLD patients was 67.5 years, 79 (71.8%) were males, 224 (23.5%) were obese, 56 (50.9%) reported alcohol abuse, 24 (21.8%) had non-alcoholic fatty liver disease, 11 (10%) had viral hepatitis and 98 (89.1%) had pneumonia. The median length of hospitalisation was 12 days; 32 (29.1%) patients required ICU admission and 23 (20.9%) patients required MV, while 43 (39.1%) died. In univariate analysis, patients with cirrhosis (45% vs 73%, hazard ratio (HR) = 2.95; P < 0.001), but not those with non-cirrhotic CLD (74% vs 73%; P > 0.05), experienced worse 30-day survival when compared with age, sex and COVID-19 duration-matched cohorts. In a logistic regression analysis conducted on the overall and matched cohorts, liver cirrhosis, but not CLD, predicted inferior survival independently of age, comorbidities and severity of COVID-19, with a fourfold higher adjusted risk of 30-day mortality. CONCLUSION: Cirrhosis is independently associated with higher 30-day mortality of hospitalised patients with COVID-19.

Incidence and risk factors for venous and arterial thromboses in hospitalized patients with coronavirus disease 2019: data on 4014 patients from a tertiary center registry.

AIM: To evaluate the burden and predictors of thromboembolic complications in a large real-life cohort of hospitalized patients with established coronavirus disease 2019 (COVID-19). METHODS: We retrospectively reviewed the records of 4014 consecutive adult patients admitted to a tertiary-level institution because of COVID-19 from March 2020 to March 2021 for the presence of venous and arterial thrombotic events. RESULTS: Venous-thromboembolic (VTE) events were present in 5.3% and arterial thrombotic events in 5.8% patients. The majority of arterial thromboses occurred before or on the day of admission, while the majority of VTE events occurred during hospitalization. The majority of both types of events occurred before intensive care unit (ICU) admission, although both types of events were associated with a higher need for ICU use and prolonged immobilization. In multivariate logistic regression, VTE events were independently associated with metastatic malignancy, known thrombophilia, lower mean corpuscular hemoglobin concentration, higher D-dimer, lower lactate dehydrogenase, longer duration of disease on admission, bilateral pneumonia, longer duration of hospitalization, and immobilization for at least one day. Arterial thromboses were independently associated with less severe COVID-19, higher Charlson comorbidity index, coronary artery disease, peripheral artery disease, history of cerebrovascular insult, aspirin use, lower C reactive protein, better functional status on admission, ICU use, immobilization for at least one day, absence of hyperlipoproteinemia, and absence of metastatic malignancy. CONCLUSION: Among hospitalized COVID-19 patients, venous and arterial thromboses differ in timing of presentation, association with COVID-19 severity, and other clinical characteristics.

The associations of age, sex, and comorbidities with survival of hospitalized patients with coronavirus disease 2019: data from 4014 patients from a tertiary-center registry.

AIM: To investigate how age, sex, and comorbidities affect the survival of hospitalized coronavirus disease 2019 (COVID-19) patients. METHODS: We retrospectively analyzed the records of 4014 consecutive adults hospitalized for COVID-19 in a tertiary-level institution from March 2020 to March 2021. RESULTS: The median age was 74 years. A total of 2256 (56.2%) patients were men. The median Charlson-comorbidity-index (CCI) was 4 points; 3359 (82.7%) patients had severe or critical COVID-19. A significant interaction between age, sex, and survival (P<0.05) persisted after adjustment for CCI. In patients <57 years, male sex was related to a favorable (odds ration [OR] 0.50, 95% confidence interval [CI] 0.29-0.86), whereas in patients ≥57 years it was related to an unfavorable prognosis (OR 1.19, 95% CI 1.04-1.37). Comorbidities associated with inferior survival independently of age, sex, and severe/critical COVID-19 on admission were chronic heart failure, atrial fibrillation, acute myocardial infarction, acute cerebrovascular insult, history of venous thromboembolism, chronic kidney disease, major bleeding, liver cirrhosis, mental retardation, dementia, active malignant disease, metastatic malignant disease, autoimmune/rheumatic disease, bilateral pneumonia, and other infections on admission. CONCLUSION: Among younger patients, female sex might lead to an adverse prognosis due to undisclosed reasons (differences in fat tissue distribution, hormonal status, and other mechanisms). Patient subgroups with specific comorbidities require additional considerations during hospital stay for COVID-19. Future studies focusing on sex differences and potential interactions are warranted.

Red cell distribution width is a potent prognostic parameter for in-hospital and post-discharge mortality in hospitalized coronavirus disease 2019 patients: a registry-based cohort study on 3941 patients.

AIM: To investigate clinical and prognostic associations of red cell distribution width (RDW) in hospitalized coronavirus disease 2019 (COVID-19) patients. METHODS: We retrospectively analyzed the records of 3941 consecutive COVID-19 patients admitted to a tertiary-level institution from March 2020 to March 2021 who had available RDW on admission. RESULTS: The median age was 74 years. The median Charlson comorbidity index (CCI) was 4. The majority of patients (84.1%) on admission presented with severe or critical COVID-19. Patients with higher RDW were significantly more likely to be older and female, to present earlier during infection, and to have higher comorbidity burden, worse functional status, and critical presentation of COVID-19 on admission. RDW was not significantly associated with C-reactive protein, occurrence of pneumonia, or need for oxygen supplementation on admission. During hospital stay, patients with higher RDW were significantly more likely to require high-flow oxygen therapy, mechanical ventilation, intensive care unit, and to experience prolonged immobilization, venous thromboembolism, bleeding, and bacterial sepsis. Thirty-day and post-hospital discharge mortality gradually increased with each rising RDW percent-point. In a series of multivariate Cox-regression models, RDW demonstrated robust prognostic properties at >14% cut-off level. This cut-off was associated with inferior 30-day and post-discharge survival independently of COVID-19 severity, age, and CCI; and with 30-day survival independently of COVID severity and established prognostic scores (CURB-65, 4C-mortality, COVID-gram and VACO-index). CONCLUSION: RDW has a complex relationship with COVID-19-associated inflammatory state and is affected by prior comorbidities. RDW can improve the prognostication in hospitalized COVID-19 patients.

Vaccination provides protection from respiratory deterioration and death among hospitalized COVID-19 patients: Differences between vector and mRNA vaccines.

Outcomes of 109 hospitalized COVID-19 patients who received at least one vaccine dose 14 or more days prior the disease onset were retrospectively compared to control cohort of 109 age, sex, and Charlson comorbidity index-matched patients chosen among 2990 total hospitalized patients in our tertiary-level institution in a period from January to June 2021. Among 109 vaccinated patients, 84 patients were partially and 25 fully vaccinated. Vaccinated patients experienced significantly lower 30 days mortality (30% vs. 49%; hazard ratio [HR]: 0.56 [0.37-0.85]; p = 0.008), less frequently required high flow oxygen therapy (17% vs. 34%; HR: 0.45 [0.26-0.76]; p = 0.005), and mechanical ventilation (8% vs. 18%; HR: 0.41 [0.20-0.88]; p = 0.027) in comparison to the matched cohort of unvaccinated patients. More favorable survival was observed in patients receiving vector in comparison to messenger RNA (mRNA) vaccine types in unadjusted analysis (30 days mortality 18% vs. 40%; HR: 0.45 [0.25-0.79]; p = 0.034). In the multivariable Cox regression analysis model both mRNA (HR: 0.59 [0.36-0.98]; p = 0.041) and vector vaccine types (HR: 0.30 [0.15-0.60]; p < 0.001) were associated with improved survival in comparison to unvaccinated patients, independently of age (HR: 1.03 [1.01-1.06]; p = 0.011), male sex (HR: 1.78 [1.14-2.76]; p = 0.010), severity of illness (HR: 2.06 [1.36-3.10]; p < 0.001) and functional status on admission (HR: 1.42 [1.07-1.85]; p = 0.013).

Real-life experience with remdesivir for treatment of hospitalized coronavirus disease 2019 patients: matched case-control study from a large tertiary hospital registry.

AIM: To evaluate the association of remdesivir use and the survival of hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: We retrospectively reviewed the medical records of 5959 COVID-19 patients admitted to our tertiary-level hospital from March 2020 to June 2021. A total of 876 remdesivir-treated patients were matched with 876 control patients in terms of age, sex, Charlson comorbidity index (CCI), WHO-defined COVID-19 severity on admission, and oxygen requirement at the time of remdesivir use. RESULTS: Among 1752 COVID-19 patients (median age 66 years, 61.8% men), 1405 (80.2%) had severe and 311 (17.8%) had critically severe COVID-19 on admission. Remdesivir was given at a median of one day after hospital admission and at a median of eight days from the onset of symptoms. Overall, 645 (73.6%) patients received remdesivir before high-flow oxygen therapy (HFOT) or mechanical ventilation (MV), 198 (22.6%) after HFOT institution, and 83 (9.5%) after MV institution. Remdesivir use was associated with improved survival in the entire cohort (hazard ratio 0.79, P=0.006). Survival benefit was evident among patients receiving remdesivir during low-flow oxygen requirement (hazard ratio 0.61, P<0.001) but not among patients who received it after starting HFOT (P=0.499) or MV (P=0.380). CONCLUSION: Remdesivir, if given during low-flow oxygen therapy, might be associated with survival benefit in hospitalized COVID-19 patients.

Asymptomatic deep vein thromboses in prolonged hospitalized COVID-19 patients.

High incidence of venous thromboembolic (VTE) events in coronavirus disease 2019 (COVID-19) patients has been reported despite pharmacologic thromboprophylaxis. We performed prospective bilateral lower extremity ultrasound evaluation of prolonged hospitalized COVID-19 ward patients from our institution without clinical suspicion of deep vein thrombosis (DVT).A total of 102 patient were included in the study. All patients were receiving pharmacologic thromboprophylaxis, the majority in intermediate or therapeutic doses. Asymptomatic DVT was detected in 26/102 (25.5%) patients: 22 had distal and four had proximal DVT, six had bilateral leg involvement. Pulmonary embolism was highly prevalent (17/70, 24.3%) but similarly grouped among patients with and without asymptomatic DVT. In total 37.2% of patients included in the study were recognized as having VTE.Asymptomatic DVT events were more common in intensive care unit (ICU) survivors (60% in postmechanically ventilated ICU survivors, 21.2% in ward patients, 22% in high-flow oxygen treated patients; P = 0.031), in patients with higher modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk-score (median 3 vs. 2 points with and without DVT; P = 0.021) and higher body temperature on admission (median 38.7 °C vs. 37.7 °C with and without DVT; P = 0.001). No clear associations with Padua VTE risk score, demographic and other clinical characteristics, intensity of thromboprophylaxis, severity of other COVID-19 symptoms, degree of systemic inflammation or D­dimers on admission were found (P > 0.05 for all analyses).Systematic ultrasound assessment in prolonged hospitalized severe COVID-19 patients prior to hospital discharge is needed, especially in ICU survivors, to timely recognize and appropriately treat patients with asymptomatic DVT.

Prevalence and Prognostic Impact of Deranged Liver Blood Tests in COVID-19: Experience from the Regional COVID-19 Center over the Cohort of 3812 Hospitalized Patients.

BACKGROUND: Derangement of liver blood tests (LBT) is frequent in patients with Coronavirus disease 2019 (COVID-19). We aimed to evaluate (a) the prevalence of deranged LBT as well as their association with (b) clinical severity at admission and (c) 30-day outcomes among the hospitalized patients with COVID-19. METHODS: Consecutive patients with COVID-19 hospitalized in the regional referral center over the 12-month period were included. Clinical severity of COVID-19 at hospital admission and 30-day outcomes (need for intensive care, mechanical ventilation, or death) were analyzed. RESULTS: Derangement of LBT occurred in 2854/3812 (74.9%) of patients, most frequently due to elevation of AST (61.6%), GGT (46.1%) and ALT (33.4%). Elevated AST, ALT, GGT and low albumin were associated with more severe disease at admission. However, in multivariate Cox regression analysis, when adjusted for age, sex, obesity and presence of chronic liver disease, only AST remained associated with the risk of dying (HR 1.5081 and 2.1315, for elevations 1-3 × ULN and >3 × ULN, respectively) independently of comorbidity burden and COVID-19 severity at admission. Patients with more severe liver injury more frequently experienced defined adverse outcomes. CONCLUSIONS: Deranged LBTs are common among patients hospitalized with COVID-19 and might be used as predictors of adverse clinical outcomes.

Preliminary Findings on the Association of the Lipid Peroxidation Product 4-Hydroxynonenal with the Lethal Outcome of Aggressive COVID-19.

Major findings of the pilot study involving 21 critically ill patients during the week after admission to the critical care unit specialized for COVID-19 are presented. Fourteen patients have recovered, while seven passed away. There were no differences between them in respect to clinical or laboratory parameters monitored. However, protein adducts of the lipid peroxidation product 4-hydroxynonenal (HNE) were higher in the plasma of the deceased patients, while total antioxidant capacity was below the detection limit for the majority of sera samples in both groups. Moreover, levels of the HNE-protein adducts were constant in the plasma of the deceased patients, while in survivors, they have shown prominent and dynamic variations, suggesting that survivors had active oxidative stress response mechanisms reacting to COVID-19 aggression, which were not efficient in patients who died. Immunohistochemistry revealed the abundant presence of HNE-protein adducts in the lungs of deceased patients indicating that HNE is associated with the lethal outcome. It seems that HNE was spreading from the blood vessels more than being a consequence of pneumonia. Due to the limitations of the relatively small number of patients involved in this study, further research on HNE and antioxidants is needed. This might allow a better understanding of COVID-19 and options for utilizing antioxidants by personalized, integrative biomedicine approach to prevent the onset of HNE-mediated vitious circle of lipid peroxidation in patients with aggressive inflammatory diseases.