Metabolic-associated fatty liver disease and liver fibrosis scores as COVID-19 outcome predictors: a machine-learning application.

Patients with COVID-19 and metabolic-dysfunction associated fatty liver disease (MAFLD) appear to be at higher risk for severe manifestations, especially in the youngest decades. Our aim was to examine whether patients with MAFLD and/or with increased liver fibrosis scores (FIB-4) are at risk for severe COVID-19 illness, using a machine learning (ML) model. Six hundred and seventy two patients were enrolled for SARS-CoV-2 pneumonia between February 2020 and May 2021. Steatosis was detected by ultrasound or computed tomography (CT). ML model valuated the risks of both in-hospital death and prolonged hospitalizations (> 28 days), considering MAFLD, blood hepatic profile (HP), and FIB-4 score. 49.6% had MAFLD. The accuracy in predicting in-hospital death was 0.709 for the HP alone and 0.721 for HP + FIB-4; in the 55-75 age subgroup, 0.842/0.855; in the MAFLD subgroup, 0.739/ 0.772; in the MAFLD 55-75 years, 0.825/0.833. Similar results were obtained when considering the accuracy in predicting prolonged hospitalization. In our cohort of COVID-19 patients, the presence of a worse HP and a higher FIB-4 correlated with a higher risk of death and prolonged hospitalization, regardless of the presence of MAFLD. These findings could improve the clinical risk stratification of patients diagnosed with SARS-CoV-2 pneumonia.

Evaluation of FIB-4, NFS, APRI and Liver Function Tests as Predictors for SARS-CoV-2 Infection in the Elderly Population: A Matched Case-Control Analysis.

Several investigations have revealed that COVID-19 causes a significant death rate due to acute respiratory distress syndrome, alterations in the quantity of ACE2 receptor expression, or the intensity of cytokine storm. Similarly, patients with hepatic impairment that are co-infected with SARS-CoV-2 are more likely to display upregulations of ACE2 receptors and cytokine storm overload, which exacerbates hepatic impairment, potentially increasing the death rate. Moreover, it is expected that the aging population develops a higher degree of hepatic fibrosis in association with other comorbid conditions that are likely to influence the course of COVID-19. Therefore, this research was developed to describe the differences in liver test parameters in elderly individuals with COVID-19 in relation to other inflammatory markers and outcomes. This current observational single-center research followed a case-control design of elderly patients hospitalized for SARS-CoV-2 infection. The research was conducted at a tertiary emergency hospital in western Romania during a two-year period. There were 632 patients included in the analysis that were split into two equal groups matched 1:1 based on gender and body mass index. Three hundred sixteen patients made the group of cases with COVID-19 patients older than 65 years, while the other half were the 316 patient controls with COVID-19 that were younger than 65 years old. Disease outcomes showed a higher prevalence of ICU admissions (22.8% vs. 12.7%, p-value < 0.001) and in-hospital mortality (17.1% vs. 8.9%, p-value = 0.002) in the group of cases. Specific and non-specific liver biomarkers were identified as risk factors for mortality in the elderly, such as ALP (OR = 1.26), LDH (OR = 1.68), AST (OR = 1.98), and ALT (OR = 2.34). Similarly, patients with APRI and NFS scores higher than 1.5 were, respectively, 2.69 times and, 3.05 times more likely to die from COVID-19, and patients with FIB-4 scores higher than 3.25 were 3.13 times more likely to die during hospitalization for SARS-CoV-2 infection. Our research indicates that abnormally increased liver biomarkers and high liver fibrosis scores are related to a worse prognosis in SARS-CoV-2 infected individuals.

Liver Function Tests and FIB-4 Score as Predictors of Severity in COVID-19 Patients from the South-West of Romania.

BACKGROUND: The coronavirus disease 2019 pandemic (COVID-19) is the most important global health crisis to date. In this study, we performed an analysis to find the association between liver damage, FIB-4 score and the severity of COVID-19 disease. METHODS: We included a total of 580 patients that tested positive for SARS-CoV-2 infection and were hospitalized. No patient included had any known history of liver disease. Liver function tests were performed, and FIB-4 score was calculated in order to assess their involvement in the disease progression. RESULTS: More than half of the patients had elevated liver function tests. Age, high body mass index, associated heart disease and diabetes were associated with poor outcome. Corticosteroids, antibiotics, and anticoagulants strongly correlated with liver injuries. Liver impairment and injury, as well as a FIB-4 score higher than 3.5, also correlated with higher degrees of disease severity. CONCLUSION: Liver injury and elevated FIB-4 score were associated with poor clinical outcome and disease severity, as well as being a valuable tool to predict COVID-19-related mortality.

Usefulness of fibrosis-4 (FIB-4) score and metabolic alterations in the prediction of SARS-CoV-2 severity.

Despite vaccination programs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a public health problem. Identifying key prognostic determinants of severity of the disease may help better focus health resources. The negative prognostic role for metabolic and hepatic alterations is established; however, the interplay among different metabolic comorbidities and their interconnections with the liver have never been explored.The objective of this study is to evaluate the impact of liver alterations in addition to metabolic comorbidities as a predictor of SARS-CoV-2 severity. 382 SARS-CoV-2 patients were enrolled. Severe SARS-CoV-2 was diagnosed according to international consensus. Transaminases > 2 times the upper limit of normality (2ULN), hepatic steatosis (by ultrasound and/or computed tomography in 133 patients), and FIB-4 defined liver alterations. All data were collected on admission. The results are severe SARS-CoV-2 infection in 156 (41%) patients (mean age 65 ± 17; 60%males). Prevalence of obesity was 25%; diabetes, 17%; hypertension, 44%; dyslipidaemia, 29%; with 13% of the cohort with ≥ 3 metabolic alterations. Seventy patients (18%) had transaminases > 2ULN, 82 (62%) steatosis; 199 (54%) had FIB-4 < 1.45 and 45 (12%) > 3.25. At multivariable analysis, ≥ 3 metabolic comorbidities (OR 4.1, CI 95% 1.8-9.1) and transaminases > 2ULN (OR 2.6, CI 95% 1.3-6.7) were independently associated with severe SARS-CoV-2. FIB-4 < 1.45 was a protective factor (OR 0.42, CI 95% 0.23-0.76). Hepatic steatosis had no impact on disease course. The presence of metabolic alterations is associated with severe SARS-CoV-2 infection, and the higher the number of coexisting comorbidities, the higher the risk of severe disease. Normal FIB-4 values are inversely associated with advanced SARS-CoV-2 regardless of metabolic comorbidities, speculating on use of these values to stratify the risk of severe infection.

Fibrosis-4 (FIB-4) Index and mortality in COVID-19 patients admitted to the emergency department.

Liver damage worsens the prognosis of coronavirus 19 disease (COVID-19). However, the best strategy to stratify mortality risk according to liver damage has not been established. The aim of this study is to test the predictive value of the validated Fibrosis-4 (FIB-4) Index and compared it to liver transaminases and to the AST-to-Platelet ratio index (APRI). Multicenter cohort study including 992 consecutive COVID-19 patients admitted to the Emergency Department. FIB-4 > 3.25 and APRI > 0.7 were used to define liver damage. Multivariable Cox regression and ROC curve analysis for mortality were performed. Secondary endpoints were (1) need for high-flow oxygen and (2) mechanical ventilation. 240 (24.2%) patients had a FIB-4 > 3.25. FIB-4 > 3.25 associated with an increased mortality (n = 119, log-rank test p < 0.001 and adjusted hazard ratio (HR) 1.72 (95% confidence interval [95%CI] 1.14-2.59, p = 0.010). ROC analysis for mortality showed that FIB-4 (AUC 0.734, 95% CI 0.705-0.761) had a higher predictive value than AST (p = 0.0018) and ALT (p < 0.0001). FIB-4 > 3.25 was also superior to APRI > 0.7 (AUC 0.58, 95% CI 0.553-0.615, p = 0.0008). Using an optimized cut-off > 2.76 (AUC 0.689, 95% CI 0.659-0.718, p < 0.0001), FIB-4 was superior to FIB-4 > 3.25 (p = 0.0302), APRI > 0.7 (p < 0.0001), AST > 51 (p = 0.0119) and ALT > 42 (p < 0.0001). FIB-4 was also associated with high-flow oxygen use (n = 255, HR 1.69, 95% CI 1.25-2.28, p = 0.001) and mechanical ventilation (n = 39, HR 2.07, 95% CI 1.03-4.19, p = 0.043). FIB-4 score predicts mortality better than liver transaminases and APRI score. FIB-4 score may be an easy tool to identify COVID-19 patients at worse prognosis in the emergency department.

Comprehensive Characterization of PVDF Nanofibers at Macro- and Nanolevel.

This study is focused on the characterization and investigation of polyvinylidene fluoride (PVDF) nanofibers from the point of view of macro- and nanometer level. The fibers were produced using electrostatic spinning process in air. Two types of fibers were produced since the collector speed (300 rpm and 2000 rpm) differed as the only one processing parameter. Differences in fiber's properties were studied by scanning electron microscopy (SEM) with cross-sections observation utilizing focused ion beam (FIB). The phase composition was determined by Fourier-transform infrared spectroscopy (FTIR) and Raman spectroscopy. The crystallinity was determined by differential scanning calorimetry (DSC), and chemical analysis of fiber's surfaces and bonding states were studied using X-ray photoelectron spectroscopy (XPS). Other methods, such as atomic force microscopy (AFM) and piezoelectric force microscopy (PFM), were employed to describe morphology and piezoelectric response of single fiber, respectively. Moreover, the wetting behavior (hydrophobicity or hydrophilicity) was also studied. It was found that collector speed significantly affects fibers alignment and wettability (directionally ordered fibers produced at 2000 rpm almost super-hydrophobic in comparison with disordered fibers spun at 300 rpm with hydrophilic behavior) as properties at macrolevel. However, it was confirmed that these differences at the macrolevel are closely connected and originate from nanolevel attributes. The study of single individual fibers revealed some protrusions on the fiber's surface, and fibers spun at 300 rpm had a core-shell design, while fibers spun at 2000 rpm were hollow.

Liver Injury and Elevated FIB-4 Define a High-Risk Group in Patients with COVID-19.

Liver involvement in Coronavirus Disease 2019 (COVID-19) has been widely documented. However, data regarding liver-related prognosis are scarce and heterogeneous. The current study aims to evaluate the role of abnormal liver tests and incidental elevations of non-invasive fibrosis estimators on the prognosis of hospitalized COVID-19 patients. We conducted a retrospective cohort study to investigate the impact of elevated liver tests, non-invasive fibrosis estimators (the Fibrosis-4 (FIB-4), Forns, APRI scores, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio), and the presence of computed tomography (CT)-documented liver steatosis on mortality in patients with moderate and severe COVID-19, with no prior liver disease history. A total of 370 consecutive patients were included, of which 289 patients (72.9%) had abnormal liver biochemistry on admission. Non-survivors had significantly higher FIB-4, Forns, APRI scores, and a higher AST/ALT ratio. On multivariate analysis, severe FIB-4 (exceeding 3.25) and elevated AST were independently associated with mortality. Severe FIB-4 had an area under the receiver operating characteristic (AUROC) of 0.73 for predicting survival. The presence of steatosis was not associated with a worse outcome. Patients with abnormal liver biochemistry on arrival might be susceptible to a worse disease outcome. An FIB-4 score above the threshold of 3.25, suggestive of the presence of fibrosis, is associated with higher mortality in hospitalized COVID-19 patients.

Integrative Imaging Reveals SARS-CoV-2-Induced Reshaping of Subcellular Morphologies.

Pathogenesis induced by SARS-CoV-2 is thought to result from both an inflammation-dominated cytokine response and virus-induced cell perturbation causing cell death. Here, we employ an integrative imaging analysis to determine morphological organelle alterations induced in SARS-CoV-2-infected human lung epithelial cells. We report 3D electron microscopy reconstructions of whole cells and subcellular compartments, revealing extensive fragmentation of the Golgi apparatus, alteration of the mitochondrial network and recruitment of peroxisomes to viral replication organelles formed by clusters of double-membrane vesicles (DMVs). These are tethered to the endoplasmic reticulum, providing insights into DMV biogenesis and spatial coordination of SARS-CoV-2 replication. Live cell imaging combined with an infection sensor reveals profound remodeling of cytoskeleton elements. Pharmacological inhibition of their dynamics suppresses SARS-CoV-2 replication. We thus report insights into virus-induced cytopathic effects and provide alongside a comprehensive publicly available repository of 3D datasets of SARS-CoV-2-infected cells for download and smooth online visualization.

The Impact of Increased Fib-4 Score in Patients with Type II Diabetes Mellitus on Covid-19 Disease Prognosis.

Background: Emerging evidence suggests that patients with metabolic (dysfunction) associated fatty liver disease (MAFLD) are prone to severe forms of coronavirus disease (COVID-19), especially those with underlying liver fibrosis. The aim of our study is to assess the association of an increased FIB-4 score with COVID-19 disease prognosis. Methods: We performed a prospective study on hospitalized patients with known type II diabetes mellitus (T2DM) and confirmed COVID-19, with imaging evidence of liver steatosis within the last year or known diagnosis of MAFLD. All individuals were screened for liver fibrosis with a FIB-4 index. We evaluated the link between FIB-4 and disease prognosis. Results: Of 138 participants, 91.3% had MAFLD and 21.5% patients had a high risk of fibrosis. In the latter group of patients, the number of severe forms of disease, the hospital stay length, the rate of ICU admissions and the number of deaths reported registered a statistically significant increase. The independent predictors for developing severe forms of COVID-19 were obesity (odds ratio (OR), 3.24; 95% confidence interval (CI), p = 0.003), higher values of ferritin (OR-1.9; 95% CI, 1.17-8.29, p = 0.031) and of FIB-4 ≥ 3.25 (OR-4.89; 95% CI, 1.34-12.3, p = 0.02). Conclusions: Patients with high scores of FIB-4 have poor clinical outcomes and liver fibrosis may have a relevant prognostic role. Although the link between liver fibrosis and the prognosis of COVD-19 needs to be evaluated in further studies, screening for liver fibrosis with FIB-4 index, particularly in patients at risk, such as those with T2DM, will make a huge contribution to patient risk stratification.

Early Elevation of Fibrosis-4 Liver Fibrosis Score Is Associated With Adverse Outcomes Among Patients With Coronavirus Disease 2019.

BACKGROUND: Limited prior data suggest that preexisting liver disease is associated with adverse outcomes among patients with coronavirus disease 2019 (COVID-19). Fibrosis-4 (FIB-4) is a noninvasive index of readily available laboratory measurements that represents hepatic fibrosis. We evaluated the association between FIB-4 at the early stage of infection and COVID-19 outcomes. METHODS: FIB-4 was evaluated at admission in a cohort of 267 patients admitted with early-stage COVID-19 confirmed through reverse-transcription polymerase chain reaction assay. Hazard of ventilator use and of high-flow oxygen was estimated using Cox regression models controlled for covariates. Risks of progression to severe disease and of death/prolonged hospitalization were estimated using multivariable logistic regression models. RESULTS: Forty-one (15%) patients progressed to severe disease, 36 (14%) required high-flow oxygen support, 10 (4%) required mechanical ventilator support, and 1 died. FIB-4 between 1.45 and 3.25 was associated with a greater than 5-fold (95% confidence interval [CI], 1.2-28) increased hazard of high-flow oxygen use, a greater than 4-fold (95% CI, 1.5-14.6) increased odds of progression to severe disease, and an over 3-fold (95% CI, 1.4-7.7) increased odds of death or prolonged hospitalization. FIB-4 >3.25 was associated with a greater than 12-fold (95% CI, 2.3-68. 7) increased hazard of high-flow oxygen use and an over 11-fold (95% CI, 3.1-45) increased risk of progression to severe disease. All associations were independent of sex, number of comorbidities, and inflammatory markers (D-dimer, C-reactive protein). CONCLUSIONS: FIB-4 at the early-stage of COVID-19 had an independent and dose-dependent association with adverse outcomes during hospitalization. FIB-4 provided significant prognostic value for estimating adverse outcomes among COVID-19 patients.

Metabolomics reveals sex-specific metabolic shifts and predicts the duration from positive to negative in non-severe COVID-19 patients during recovery process.

Metabolic profiling in COVID-19 patients has been associated with disease severity, but there is no report on sex-specific metabolic changes in discharged survivors. Herein we used an integrated approach of LC-MS-and GC-MS-based untargeted metabolomics to analyze plasma metabolic characteristics in men and women with non-severe COVID-19 at both acute period and 30 days after discharge. The results demonstrate that metabolic alterations in plasma of COVID-19 patients during the recovery and rehabilitation process were presented in a sex specific manner. Overall, the levels of most metabolites were increased in COVID-19 patients after the cure relative to acute period. The major plasma metabolic changes were identified including fatty acids in men and glycerophosphocholines and carbohydrates in women. In addition, we found that women had shorter length of hospitalization than men and metabolic characteristics may contribute to predict the duration from positive to negative in non-severe COVID-19 patients. Collectively, this study shed light on sex-specific metabolic shifts in non-severe COVID-19 patients during the recovery process, suggesting a sex bias in prognostic and therapeutic evaluations based on metabolic profiling.

FIB-SEM as a Volume Electron Microscopy Approach to Study Cellular Architectures in SARS-CoV-2 and Other Viral Infections: A Practical Primer for a Virologist.

The visualization of cellular ultrastructure over a wide range of volumes is becoming possible by increasingly powerful techniques grouped under the rubric "volume electron microscopy" or volume EM (vEM). Focused ion beam scanning electron microscopy (FIB-SEM) occupies a "Goldilocks zone" in vEM: iterative and automated cycles of milling and imaging allow the interrogation of microns-thick specimens in 3-D at resolutions of tens of nanometers or less. This bestows on FIB-SEM the unique ability to aid the accurate and precise study of architectures of virus-cell interactions. Here we give the virologist or cell biologist a primer on FIB-SEM imaging in the context of vEM and discuss practical aspects of a room temperature FIB-SEM experiment. In an in vitro study of SARS-CoV-2 infection, we show that accurate quantitation of viral densities and surface curvatures enabled by FIB-SEM imaging reveals SARS-CoV-2 viruses preferentially located at areas of plasma membrane that have positive mean curvatures.

Association between electrocardiographic features and mortality in COVID-19 patients.

BACKGROUND: Cardiovascular events have been reported in the setting of coronavirus disease-19 (COVID-19). It has been hypothesized that systemic inflammation may aggravate arrhythmias or trigger new-onset conduction abnormalities. However, the specific type and distribution of electrocardiographic disturbances in COVID-19 as well as their influence on mortality remain to be fully characterized. METHODS: Electrocardiograms (ECGs) were obtained from 186 COVID-19-positive patients at a large tertiary care hospital in Northern Nevada. The following arrhythmias were identified by cardiologists: sinus bradycardia, sinus tachycardia, atrial fibrillation (A-Fib), atrial flutter, multifocal atrial tachycardia (MAT), premature atrial contraction (PAC), premature ventricular contraction (PVC), atrioventricular block (AVB), and right bundle branch block (RBBB). The mean PR interval, QRS duration, and corrected QT interval were documented. Fisher's exact test was used to compare the ECG features of patients who died during the hospitalization with those who survived. The influence of ECG features on mortality was assessed with multivariable logistic regression analysis. RESULTS: A-Fib, atrial flutter, and ST-segment depression were predictive of mortality. In addition, the mean ventricular rate was higher among patients who died as compared to those who survived. The use of therapeutic anticoagulation was associated with reduced odds of death; however, this association did not reach statistical significance. CONCLUSION: The underlying pathogenesis of COVID-19-associated arrhythmias remains to be established, but we postulate that systemic inflammation and/or hypoxia may induce potentially lethal conduction abnormalities in affected individuals. Longitudinal studies are warranted to evaluate the risk factors, pathogenesis, and management of COVID-19-associated cardiac arrhythmias.

The Fibrosis-4 Index Is Associated With Need for Mechanical Ventilation and 30-Day Mortality in Patients Admitted With Coronavirus Disease 2019.

The Fibrosis-4 Index (FIB-4), developed to predict fibrosis in liver disease, was used to identify patients with coronavirus disease 2019 who will require ventilator support as well as those associated with 30-day mortality. Multivariate analysis found obesity (odds ratio [OR], 4.5), diabetes mellitus (OR, 2.55), and FIB-4 ≥2.67 (OR, 3.09) independently associated with need for mechanical ventilation. When controlling for ventilator use, sex, and comorbid conditions, FIB-4 ≥2.67 was also associated with increased 30-day mortality (OR, 8.4 [95% confidence interval, 2.23-31.7]). Although it may not be measuring hepatic fibrosis, its components suggest that increases in FIB-4 may be reflecting systemic inflammation associated with poor outcomes.

Clinical characteristics and laboratory indicator analysis of 67 COVID-19 pneumonia patients in Suzhou, China.

BACKGROUND: Sudden exacerbations and respiratory failure are major causes of death in patients with severe coronavirus disease 2019(COVID-19) pneumonia, but indicators for the prediction and treatment of severe patients are still lacking. METHODS: A retrospective analysis of 67 collected cases was conducted and included approximately 67 patients with COVID-19 pneumonia who were admitted to the Suzhou Fifth People's Hospital from January 1, 2020 to February 8, 2020. The epidemiological, clinical and imaging characteristics as well as laboratory data of the 67 patients were analyzed. RESULTS: The study found that fibrinogen (FIB) was increased in 45 (65.2%) patients, and when FIB reached a critical value of 4.805 g/L, the sensitivity and specificity、DA, helping to distinguish general and severe cases, were 100 and 14%、92.9%, respectively, which were significantly better than those for lymphocyte count and myoglobin. Chest CT images indicated that the cumulative number of lung lobes with lesions in severe patients was significantly higher than that in general patients (P < 0.05), and the cumulative number of lung lobes with lesions was negatively correlated with lymphocyte count and positively correlated with myoglobin and FIB. Our study also found that there was no obvious effect of hormone therapy in patients with severe COVID-19. CONCLUSIONS: Based on the retrospective analysis, FIB was found to be increased in severe patients and was better than lymphocyte count and myoglobin in distinguishing general and severe patients. The study also suggested that hormone treatment has no significant effect on COVID-19.

Elevation of Liver Fibrosis Index FIB-4 Is Associated With Poor Clinical Outcomes in Patients With COVID-19.

BACKGROUND: COVID-19 is a potentially severe disease caused by the recently described SARS-CoV-2. Whether liver fibrosis might be a relevant player in the natural history of COVID-19 is currently unknown. We aimed to evaluate the association between FIB-4 and the risk of progression to critical illness in middle-aged patients with COVID-19. METHODS: In this multicenter, retrospective study with prospective follow-up of 160 patients aged 35-65 years with COVID-19, FIB-4, clinical, and biochemical variables were collected at baseline. FIB-4 ≥2.67 defined patients with risk for advanced liver fibrosis. RESULTS: Risk for advanced fibrosis was estimated in 28.1% of patients. Patients with FIB-4 ≥2.67 more frequently required mechanical ventilation (37.8% vs 18.3%; P = .009). In multivariate analysis, FIB-4 ≥2.67 (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.30-8.92), cardiovascular risk factors (OR, 5.05; 95% CI, 1.90-13.39), previous respiratory diseases (OR, 4.54; 95% CI, 1.36-15.10), and C-reactive protein (OR, 1.01; 95% CI, 1.01-1.02) increased significantly the risk of ICU admission. Bootstrap confirmed FIB-4 as an independent risk factor. CONCLUSIONS: In middle-aged patients with COVID-19, FIB-4 may have a prognostic role. The link between liver fibrosis and the natural history of COVID-19 should be evaluated in future studies.