Background Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with systemic changes in immune response which might be associated with COVID-19 severity. The aim of this study was to investigate the impact of NAFLD on COVID-19 severity and outcomes. Methods A prospective observational study included consecutively hospitalized adult patients with severe COVID-19 between March and June 2021. Patients were screened for fatty liver by ultrasound and subsequently diagnosed with NAFLD. Patients were daily followed until discharge, and demographic, clinical and laboratory data were collected and correlated to clinical outcomes. Results Of the 216 patients included, 120 (55.5%) had NAFLD. NAFLD group had higher C-reactive protein (84.7 mg/L, IQR 38.6-129.8 vs 66.9, 32.2-97.3, p=0.0340), Interleukin-6 (49.19 ng/L, IQR 22.66-92.04 vs 13.22, IQR 5.29-39.75, p<0.0001), aspartate aminotransferase (58 IU/L, IQR 40-81 vs 46, IQR 29-82, p=0.0123), alanine aminotransferase (51 IU/L, IQR 32-73 vs 40, IQR 23-69, p=0.0345) and lactate dehydrogenase (391 IU/L, IQR 285-483 vs 324, IQR 247-411, p= 0.0027). The patients with NAFLD had higher disease severity assessed by seven-category ordinal scale, more frequently required HFNC or NIV (26, 21.66% vs 10, 10.42%, p=0.0289), had longer duration of hospitalization (10, IQR 8-15 vs. 9, IQR 6-12 days, p=0.0018) and pulmonary thromboembolism (26.66% vs. 13.54%, p=0.0191). On multivariable analyses, NAFLD was negatively associated with time to recovery (HR 0.64, 95%CI 0.48-0.86) and was identified as a risk factor for pulmonary thrombosis (OR 2.15, 95%CI 1.04-4.46). Conclusions NAFLD is associated with higher COVID-19 severity, adverse outcomes and pulmonary thrombosis.

Recurrent Clostridioides difficile infections (rCDI) have a substantial impact on healthcare systems, with limited and often expensive therapeutic options. Nonalcoholic fatty liver disease (NAFLD) affects about 25% of the adult population and is associated with metabolic syndrome, changes in gut microbiome and bile acids biosynthesis, all possibly related with rCDI. The aim of this study was to determine whether NAFLD is a risk factor associated with rCDI. A retrospective cohort study included patients ≥ 60 years hospitalized with CDI. The cohort was divided into two groups: those who were and were not readmitted with CDI within 3 months of discharge. Of the 329 patients included, 107 patients (32.5%) experienced rCDI. Patients with rCDI were older, had higher Charlson Age–Comorbidity Index (CACI) and were more frequently hospitalized within 3 months. Except for chronic kidney disease and NAFLD, which were more frequent in the rCDI group, there were no differences in other comorbidities, antibiotic classes used and duration of antimicrobial therapy. Multivariable Cox regression analysis showed that age >75 years, NAFLD, CACI >6, chronic kidney disease, statins and immobility were associated with rCDI. In conclusion, our study identified NAFLD as a possible new host-related risk factor associated with rCDI.

Non-alcoholic fatty liver disease (NAFLD) is identified as a risk factor for developing severe COVID-19. While NAFLD is associated with chronic low-grade inflammation, mechanisms leading to immune system hyperactivation remain unclear. The aim of this prospective observational study is to analyze cytokine profiles in patients with severe COVID-19 and NAFLD. A total of 94 patients with severe COVID-19 were included. Upon admission, clinical and laboratory data were collected, a liver ultrasound was performed to determine the presence of steatosis, and subsequently, 51 were diagnosed with NAFLD according to the current guidelines. There were no differences in age, sex, comorbidities, and baseline disease severity between the groups. Serum cytokine concentrations were analyzed using a multiplex bead-based assay by flow cytometry. Upon admission, the NAFLD group had higher C-reactive protein, procalcitonin, alanine aminotransferase, lactate dehydrogenase, and fibrinogen. Interleukins-6, -8, and -10 and CXCL10 were significantly higher, while IFN-γ was lower in NAFLD patients. Patients with NAFLD who progressed to critical illness had higher concentrations of IL-6, -8, -10, and IFN-β, and IL-8 and IL-10 appear to be effective prognostic biomarkers associated with time to recovery. In conclusion, NAFLD is associated with distinct cytokine profiles in COVID-19, possibly associated with disease severity and adverse outcomes.

Nonalcoholic fatty liver disease (NAFLD) is associated with systemic changes in immune response linked with chronic low-grade inflammation and disease progression. Semaphorins, a large family of biological response modifiers, were recently recognized as one of the key regulators of immune responses, possibly also associated with chronic liver diseases. The aim of this study was to identify semaphorins associated with NAFLD and their relationship with steatosis and fibrosis stages. In this prospective, case-control study, serum semaphorin concentrations (SEMA3A, -3C, -4A, -4D, -5A and -7A) were measured in 95 NAFLD patients and 35 healthy controls. Significantly higher concentrations of SEMA3A, -3C and -4D and lower concentrations of SEAMA5A and -7A were found in NAFLD. While there was no difference according to steatosis grades, SEMA3C and SEMA4D significantly increased and SEMA3A significantly decreased with fibrosis stages and had better accuracy in predicting fibrosis compared to the FIB-4 score. Immunohistochemistry confirmed higher expression of SEMA4D in hepatocytes, endothelial cells and lymphocytes in NAFLD livers. The SEMA5A rs1319222 TT genotype was more frequent in the NAFLD group and was associated with higher liver stiffness measurements. In conclusion, we provide the first evidence of the association of semaphorins with fibrosis in patients with NAFLD.

Background Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with a prevalence up to 30%. NAFLD is strongly associated with components of metabolic syndrome, already recognized as risk factors for worse outcomes in COVID-19. However, the impact of NAFLD on COVID-19 is not well characterized. The aim of this study was to investigate a possible association between NAFLD and COVID-19 severity and outcomes. Methods A prospective observational study included consecutively hospitalized adult patients with severe COVID-19 at the University Hospital for Infectious Diseases in Zagreb, Croatia between March and June 2021. On admission patients were screened for fatty liver by the ultrasound and subsequently diagnosed with NAFLD according to current guidelines. Demographic, clinical and laboratory data was collected and correlated to clinical outcomes. Results Of the 112 patients included in the study, 77 (68.7%) had NAFLD (59.7% males; median age of 62, IQR 54-66 years). Except for higher prevalence of obesity in NAFLD group (61.0% vs 17.1%) there were no differences in other comorbidities. NAFLD group had higher inflammatory markers CRP (96, IQR 51-138 vs 59, IQR 29-99mg/L) and IL-6 (129, IQR 44-169 vs 25, IQR 8-56pg/mL). Steatosis stage showed positive correlation with BMI, waist/hip ratio, CRP, PCT, IL-6, AST, ALT, LDH and fibrinogen. Steatosis stage correlated with clinical status at the 7-category scale on admission and at days 7, 14 and 28. Patients with NAFLD had longer duration of hospitalization (9, IQR 6-15 vs 6, IQR 5-11 days, p=0.024), more frequently required noninvasive ventilation or high-flow oxygen (24.7% vs 5.7%, p=0.018) and had higher rate of pulmonary embolism (22.1% vs 5.7%, p=0.024). There was no difference in mortality. The median value for clinical status on the ordinal scale at day 7 was significantly higher in NAFLD group at days 7 and 14, as presented in Fig. 1. Multivariable analysis identified age > 65 (OR 3.6, 95%CI 1.3-10.9), LDH > 350 (OR 8.1, 95%CI 2.7-29.4), NAFLD (OR 3.9, 1.1-20.5) and pulmonary embolism (OR 10.4, 2.7-48.3) associated with adverse outcomes at day 28. The figure shows the patients’ clinical status as assessed on the seven-category ordinal scale on admission and at day 7, 14 and 28, according to the presence of NAFLD. Categories on the ordinal scale were as follows: 1, discharged or ready for discharge; 2, hospitalization in a non–intensive care unit (ICU) without supplemental oxygen; 3, non–ICU hospitalization with supplemental oxygen; 4, ICU or non–ICU hospitalization with noninvasive ventilation or high-flow oxygen; 5, ICU hospitalization with mechanical ventilation; 6, ICU hospitalization with extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; and 7, death. Conclusion Our data suggests that NAFLD is associated with COVID-19 severity and might be linked to adverse outcomes in hospitalized patients. Disclosures All Authors: No reported disclosures