Global epidemiology of cirrhosis - aetiology, trends and predictions.

Cirrhosis is an important cause of morbidity and mortality in people with chronic liver disease worldwide. In 2019, cirrhosis was associated with 2.4% of global deaths. Owing to the rising prevalence of obesity and increased alcohol consumption on the one hand, and improvements in the management of hepatitis B virus and hepatitis C virus infections on the other, the epidemiology and burden of cirrhosis are changing. In this Review, we highlight global trends in the epidemiology of cirrhosis, discuss the contributions of various aetiologies of liver disease, examine projections for the burden of cirrhosis, and suggest future directions to tackle this condition. Although viral hepatitis remains the leading cause of cirrhosis worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated cirrhosis are rising in several regions of the world. The global number of deaths from cirrhosis increased between 2012 and 2017, but age-standardized death rates (ASDRs) declined. However, the ASDR for NAFLD-associated cirrhosis increased over this period, whereas ASDRs for other aetiologies of cirrhosis declined. The number of deaths from cirrhosis is projected to increase in the next decade. For these reasons, greater efforts are required to facilitate primary prevention, early detection and treatment of liver disease, and to improve access to care.

Hepatobiliary long-term consequences of COVID-19: dramatically increased rate of secondary sclerosing cholangitis in critically ill COVID-19 patients.

BACKGROUND: Increasing evidence suggests that secondary sclerosing cholangitis (SSC), which can lead to cirrhosis or liver failure, may be a hepatobiliary long-term complication of COVID-19. The aim of this study was to estimate the frequency and outcome of this COVID-19 sequela and to identify possible risk factors. METHODS: This observational study, conducted at University Hospital Charité Berlin and Unfallkrankenhaus Berlin, Germany, involved hospitalized patients with COVID-19 pneumonia, including 1082 ventilated COVID-19 patients. We compared COVID-19 patients who developed SSC with a COVID-19 control group by univariate and multivariate analyses. RESULTS: SSC occurrence after COVID-19 was observed exclusively in critically ill patients with invasive ventilation, albeit with extreme clustering among them. One in every 43 invasively ventilated COVID-19 patients developed this complication. Risk factors preceding the development of secondary sclerosing cholangitis in critically ill COVID-19 patients (SSC-CIP) were signs of systemic reduced blood oxygen supply (e.g., low PaO2/FiO2, ischemic organ infarctions), multi-organ failure (high SOFA score) at admission, high fibrinogen levels and intravenous ketamine use. Multivariate analysis confirmed fibrinogen and increased plasma lactate dehydrogenase as independent risk factors associated with cholangiopathy onset. The 1-year transplant-free survival rate of COVID-19-associated SSC-CIP was 40%. CONCLUSIONS: COVID-19 causes SSC-CIP in a substantial proportion of critically ill patients. SSC-CIP most likely develops due to severe tissue hypoxia and fibrinogen-associated circulatory disturbances. A significant increase of patients with SSC-CIP is to be expected in the post-COVID era.

Secreted Frizzled Related Protein 5 (SFRP5) Serum Levels Are Decreased in Critical Illness and Sepsis and Are Associated with Short-Term Mortality.

Sepsis is a major health burden with insufficiently understood mechanisms of inflammation and immune paralysis, leading to a life-threatening critical illness. The secreted frizzled related protein 5 (SFRP5) acts as an anti-inflammatory adipokine by antagonizing the Wnt5a pathway. The aim of this study was to elucidate the role of SFRP5 in critical illness and sepsis and to determine its value as a prognostic biomarker for mortality. We analyzed SFRP5 serum concentrations of 223 critically ill patients at admission to a medical intensive care unit (ICU) and compared those to 24 healthy individuals. SFRP5 serum concentrations were significantly decreased in critical illness as compared to healthy controls (24.66 vs. 100 ng/mL, p = 0.029). Even lower serum concentrations were found in septic as compared to nonseptic critically ill patients (19.21 vs. 32.83 ng/mL, p = 0.031). SFRP5 concentrations correlated with liver disease, age, anti-inflammation, and metabolic parameters. Furthermore, patients with sepsis recovered levels of SFRP5 in the first week of ICU treatment. SFRP5 levels at admission predicted short-term mortality in critically ill but not in septic patients. This study points to the role of the anti-inflammatory mediator SFRP5 not only in sepsis but also in nonseptic critically ill patients and associates high levels of SFRP5 to worse outcomes, predominantly in nonseptic critically ill patients.

Global epidemiology of cirrhosis — aetiology, trends and predictions

Cirrhosis is an important cause of morbidity and mortality in people with chronic liver disease worldwide. In 2019, cirrhosis was associated with 2.4% of global deaths. Owing to the rising prevalence of obesity and increased alcohol consumption on the one hand, and improvements in the management of hepatitis B virus and hepatitis C virus infections on the other, the epidemiology and burden of cirrhosis are changing. In this Review, we highlight global trends in the epidemiology of cirrhosis, discuss the contributions of various aetiologies of liver disease, examine projections for the burden of cirrhosis, and suggest future directions to tackle this condition. Although viral hepatitis remains the leading cause of cirrhosis worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated cirrhosis are rising in several regions of the world. The global number of deaths from cirrhosis increased between 2012 and 2017, but age-standardized death rates (ASDRs) declined. However, the ASDR for NAFLD-associated cirrhosis increased over this period, whereas ASDRs for other aetiologies of cirrhosis declined. The number of deaths from cirrhosis is projected to increase in the next decade. For these reasons, greater efforts are required to facilitate primary prevention, early detection and treatment of liver disease, and to improve access to care. In this Review, Huang et al. highlight global trends in the epidemiology of cirrhosis, including contributions of various aetiologies of liver disease, and consider what needs to be done to address projected increases in the burden of cirrhosis. Key points Hepatitis C virus (HCV) infection remains the leading cause of global deaths related to cirrhosis, followed by alcohol-associated liver disease. The global burden of cirrhosis associated with non-alcoholic fatty liver disease (NAFLD) has increased substantially in the past decade. In the Americas, the dominant cause of cirrhosis is shifting from viral hepatitis to NAFLD and alcohol-associated liver disease. The COVID-19 pandemic has set back progress in the elimination of HCV and hepatitis B virus, and most countries are not on track to meet the WHO viral hepatitis elimination targets. The focus of care should be shifted upstream towards primary prevention and early detection of liver disease to reduce the global burden of cirrhosis.

Versorgung von Lebertransplantierten während der COVID-19-Pandemie : Update der S1-Leitlinie Care of liver transplant patients during the COVID-19 pandemicUpdate of the S1 guideline

Hintergrund Die Pandemie durch Coronavirus Disease 2019 (COVID-19) stellt eine anhaltende Herausforderung für das gesamte Gesundheitssystem dar, darunter auch für die Versorgung von Lebertransplantierten, die eine besondere Risikogruppe darstellen. Fragestellung Ziel der Arbeit ist es, einen praxisnahen Überblick über die aktualisierte S1-Leitlinie zur Versorgung von Lebertransplantierten während der COVID-19-Pandemie zu geben. Material und Methoden Basis dieser Übersicht ist die aktualisierte Leitlinie (Stand 15.06.2022) der Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV). Ergebnisse Während der Pandemie sollen Lebertransplantationsprogramme inklusive Evaluation, Organspenden und Nachsorge möglichst unverändert fortgeführt werden, da sie eine lebensrettende Therapieoption darstellen. Je nach Pandemielage sind jedoch Anpassungen möglich. Die Impfungen gegen „severe acute respiratory syndrome coronavirus type 2" (SARS-CoV-2) sollen entsprechend den Empfehlungen der Ständigen Impfkommission (STIKO) erfolgen, und Antikörperbestimmungen sind sinnvoll. Im Fall einer Infektion stehen verschiedene Therapieoptionen zur Verfügung. Eine präventive Anpassung der Immunsuppression soll nicht erfolgen, eine Anpassung von Mycophenolat-Mofetil-haltigen Regimen sowie eine Anpassung bei SARS-CoV-2-Infektion kann jedoch sinnvoll sein. Schlussfolgerungen Die mittlerweile zur Verfügung stehende Immunisierung sowie die antivirale/immunmodulierende Therapie erlauben eine deutlich verbesserte Prävention und Therapie von COVID-19 bei Lebertransplantierten. Eine frühzeitige Erkennung durch engmaschige Testung ist von hoher Wichtigkeit. Die verbesserten pharmakologischen Optionen ermöglichen unter Risiko-Nutzen-Abwägung auch eine Transplantation von positiven Spendern oder Empfängern.

Cenicriviroc for the treatment of COVID-19: first interim results of a randomised, placebo-controlled, investigator-initiated, double-blind phase II trial.

OBJECTIVES: C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19. METHODS: Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated trial on the CCR2/CCR5-inhibitor Cenicriviroc (CVC) 150 mg BID orally for 28 d in hospitalised patients with moderate to severe COVID-19 are reported. The primary endpoint is the subject's responder status defined by achieving grade 1 or 2 on the 7-point ordinal scale of clinical improvement on day 15. RESULTS: Of the 30 patients randomised, 18 were assigned to receive CVC and 12 to placebo. Efficient CCR2- and CCR5 inhibition was demonstrated through CCL2 and CCL4 elevation in CVC-treated patients (485% and 80% increase on day 3 compared to the baseline, respectively). In the modified intention-to-treat population, 82.4% of patients (14/17) in the CVC group met the primary endpoint, as did 91.7% (11/12) in the placebo group (OR = 0.5, 95% CI = 0.04-3.41). One patient treated with CVC died of progressive acute respiratory distress syndrome, and the remaining had a favourable outcome. Overall, treatment with CVC was well tolerated, with most adverse events being grade I or II and resolving spontaneously. CONCLUSIONS: Our interim analysis provides proof-of-concept data on CVC for COVID-19 patients as an intervention to inhibit CCR2/CCR5. Further studies are warranted to assess its clinical efficacy.

From the Editor’s Desk…Immunogenicity of COVID-19 vaccination in patients with NAFLD and in liver transplant recipients

Despite the large number of clinical trials on COVID-19 vaccines, only a few participants with pre-existing liver diseases were included. In this issue of the Journal, 2 separate studies analyse the safety and efficacy of COVID-19 vaccines in patients with non-alcoholic fatty liver disease (NAFLD) and in liver transplant recipients.

Soluble Urokinase Plasminogen Activator Receptor and Venous Thromboembolism in COVID-19.

Background Venous thromboembolism (VTE) contributes significantly to COVID-19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID-19. Whether suPAR levels identify patients with COVID-19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID-19 with suPAR and D-dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine-Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D-dimer levels. There was a positive association between suPAR and D-dimer (ß=7.34; P=0.002). Adjusted for clinical covariables, including D-dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51-4.75]; P<0.001). Findings were consistent when stratified by D-dimer levels and in survival analysis accounting for death as a competing risk. On the basis of predicted probabilities from random forest, a decision tree found the combined D-dimer <1 mg/L and suPAR <11 ng/mL cutoffs, identifying 41% of patients with only 3.6% VTE probability. Conclusions Higher suPAR was associated with incident VTE independently of D-dimer in patients hospitalized for COVID-19. Combining suPAR and D-dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Rationale of using the dual chemokine receptor CCR2/CCR5 inhibitor cenicriviroc for the treatment of COVID-19.

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created a global pandemic infecting over 230 million people and costing millions of lives. Therapies to attenuate severe disease are desperately needed. Cenicriviroc (CVC), a C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist, an agent previously studied in advanced clinical trials for patients with HIV or nonalcoholic steatohepatitis (NASH), may have the potential to reduce respiratory and cardiovascular organ failures related to COVID-19. Inhibiting the CCR2 and CCR5 pathways could attenuate or prevent inflammation or fibrosis in both early and late stages of the disease and improve outcomes of COVID-19. Clinical trials using CVC either in addition to standard of care (SoC; e.g., dexamethasone) or in combination with other investigational agents in patients with COVID-19 are currently ongoing. These trials intend to leverage the anti-inflammatory actions of CVC for ameliorating the clinical course of COVID-19 and prevent complications. This article reviews the literature surrounding the CCR2 and CCR5 pathways, their proposed role in COVID-19, and the potential role of CVC to improve outcomes.

Outcome of liver cancer patients with SARS-CoV-2 infection: An International, Multicentre, Cohort Study.

BACKGROUND & AIMS: Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population. METHODS: Multicentre retrospective, cross-sectional, international study of liver cancer patients with SARS-CoV-2 infection registered between February and December 2020. Clinical data at SARS-CoV-2 diagnosis and outcomes were registered. RESULTS: Two hundred fifty patients from 38 centres were included, 218 with hepatocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at SARS-CoV-2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow-up of 7.20 (IQR: 1.84-11.24) months, 100 (40%) patients have died, 48% of the deaths were SARS-CoV-2-related. Forty (18.4%) HCC patients died within 30-days. The death rate increase was significantly different according to the BCLC stage (6.10% [95% CI 2.24-12.74], 11.76% [95% CI 4.73-22.30], 20.69% [95% CI 11.35-31.96] and 34.52% [95% CI 17.03-52.78] for BCLC 0/A, B, C and D, respectively; p = .0017). The hazard ratio was 1.45 (95% CI 0.49-4.31; p = .5032) in BCLC-B versus 0/A, and 3.13 (95% CI 1.29-7.62; p = .0118) in BCLC-C versus 0/A in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, and 12 deaths were related to SARS-CoV-2 infection. CONCLUSIONS: This is the largest cohort of liver cancer patients infected with SARS-CoV-2. It characterizes the 30-day mortality risk of SARS-CoV-2 infected patients with HCC during this period.

Severe acute respiratory syndrome coronavirus 2 antibody prevalence in adult patients with short bowel syndrome-A German multicenter cross-sectional study.

BACKGROUND: Not all patients suffer from a severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demanding a definition of groups at risk. Short bowel syndrome (SBS) has been assumed to be a risk factor, because of the complexity of disease, the need for interdisciplinary care, and frequent contact with caretakers. We aimed to establish data on the course of infection and prevalence of SARS-CoV-2 seropositivity in SBS patients in Germany. METHODS: From January 2021 until January 2022 a total of 119 patients from three different tertiary care centers with SBS were included. All patients received an antibody test against the nucleocapsid (N) antigen and were asked to fill out a questionnaire, which included frequency of contact with medical personnel, risk behavior and worries. RESULTS: Sixty-seven percent of SBS patients received parenteral nutrition with a median of 6 days per week. The seroprevalence of SARS-CoV-2 antibodies was 7.6% (n = 9). Seven patients with positive antibodies had coronavirus disease 2019 (COVID-19) with a mild course. None of the patients were hospitalized or needed further treatment. There was no difference in willingness to take risks in SARS-CoV-2 antibody-positive and -negative patients (P = 0.61). Patients were predominantly worried about the economy (61%) and transmitting COVID-19 (52%), less frequent (26%) about receiving insufficient medical treatment. CONCLUSION: These are the first clinical results concerning SARS-CoV-2 seropositivity and COVID-19 disease in patients with SBS. The seropositivity is comparable to national data, which we attribute to increased risk awareness and avoidance. Further studies are warranted to investigate effects of COVID-19 infection in SBS patients.

Updated epidemiology of hepatitis C virus infections and implications for hepatitis C virus elimination in Germany.

In 2014, an analysis was conducted to evaluate the hepatitis C virus (HCV) epidemiology and disease burden in Germany. Since then, there have been considerable developments in HCV management such as the implementation of direct acting antivirals. The aim of this analysis was to assess the recent data available for Germany, establish an updated 2020 HCV prevalence and cascade of care and evaluate the impact of what-if scenarios on the future burden of disease using modelling analysis. A dynamic Markov model was used to forecast the HCV disease burden in Germany. Model inputs were retrieved through literature review, unpublished sources and expert input. Next, three "what-if" scenarios were developed to evaluate the status quo, COVID-19 pandemic, and steps needed to achieve the WHO targets for elimination. At the beginning of 2020, there were 189,000 (95% UI: 76,700-295,000) viremic infections in Germany, a decline of more than 85,000 viremic infections since 2012. Annual treatment starts went down since 2015. Compared with 2019, the COVID-19 pandemic resulted in a further 11% decline in 2020. If this continues for two years, it could result in 110 excess HCC cases and 200 excess liver related deaths by 2030. To achieve the WHO targets, 81,200 people need to be diagnosed, with 118,600 initiated on treatment by 2030. This could also avert 1,020 deaths and 720 HCC cases between 2021 and 2030. Germany has made strides towards HCV elimination, but more efforts are needed to achieve the WHO targets by 2030.

Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19.

OBJECTIVE: Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS: We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS: Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS: Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19.

Background Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. Methods and Results We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36-0.65]). Conclusions In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Haemorrhagic ulcerative duodenitis in a patient with COVID-19 infection: clinical improvement following treatment with budesonide.

We present a case of a male patient in his mid-30s with COVID-19-induced lung failure requiring extracorporeal membrane oxygenation, who needed an emergency oesophagogastroduodenoscopy due to major upper gastrointestinal bleeding. Endoscopy exposed severe ulcerative duodenitis with diffuse mucosal bleeding. While CT angiography did not show any signs of ischaemia, histopathology revealed duodenitis with substantial inflammatory cell infiltrates consisting of neutrophils and CD3+ T lymphocytes with equal CD4+/CD8+ distribution. Since the composition of cell infiltrates coincides with changes in inflammatory patterns of the respiratory mucosa from patients with COVID-19 and in COVID-19-associated enterocolitis, and systemic dexamethasone treatment became standard of care in ventilated intensive care unit patients with COVID-19 infection, we initiated an individualised therapeutic attempt to treat the duodenitis with topical enteral budesonide. Follow-up oesophagogastroduodenoscopies within 4 weeks of enteral budesonide administration revealed a full clinical and histological healing of the duodenal mucosa with marked reduction of neutrophilic and lymphocytic infiltrates.To our knowledge, the current report is the first description of enteral budesonide treatment of duodenitis in a patient with COVID-19 infection and warrants further investigation, whether budesonide might constitute a novel therapeutic strategy for the management of COVID-19-related intestinal mucosal damage.

Circulating Osteopontin Levels and Outcomes in Patients Hospitalized for COVID-19.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is the result of a hyper-inflammatory reaction to the severe acute respiratory syndrome coronavirus 2. The biomarkers of inflammation have been used to risk-stratify patients with COVID-19. Osteopontin (OPN) is an integrin-binding glyco-phosphoprotein involved in the modulation of leukocyte activation; its levels are associated with worse outcomes in patients with sepsis. Whether OPN levels predict outcomes in COVID-19 is unknown. METHODS: We measured OPN levels in serum of 341 hospitalized COVID-19 patients collected within 48 h from admission. We characterized the determinants of OPN levels and examined their association with in-hospital outcomes; notably death, need for mechanical ventilation, and need for renal replacement therapy (RRT) and as a composite outcome. The risk discrimination ability of OPN was compared with other inflammatory biomarkers. RESULTS: Patients with COVID-19 (mean age 60, 61.9% male, 27.0% blacks) had significantly higher levels of serum OPN compared to healthy volunteers (96.63 vs. 16.56 ng/mL, p < 0.001). Overall, 104 patients required mechanical ventilation, 35 needed dialysis, and 53 died during their hospitalization. In multivariable analyses, OPN levels ≥140.66 ng/mL (third tertile) were associated with a 3.5 × (95%CI 1.44-8.27) increase in the odds of death, and 4.9 × (95%CI 2.48-9.80) increase in the odds of requiring mechanical ventilation. There was no association between OPN and need for RRT. Finally, OPN levels in the upper tertile turned out as an independent prognostic factor of event-free survival with respect to the composite endpoint. CONCLUSION: Higher OPN levels are associated with increased odds of death and mechanical ventilation in patients with COVID-19, however, their utility in triage is questionable.

Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin αvß6 upregulation following liver injury.

Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. Using microdissection and next-generation RNA-Seq, we identified 5 genes, including Mapk8ip2, Cdkn1a, Itgb6, Rgs4, and Ccl2, that were most upregulated in proliferating BECs after acute injury. Immunohistochemical analyses confirmed robust upregulation of integrin αvß6 (ITGß6) expression in this BEC injury model, after bile duct ligation, and in patients with chronic cholangiopathies. Deletion of the Itgb6 gene attenuated BEC proliferation after acute bile duct injury. Macrophage depletion or Ccr2 deficiency impaired ITGß6 expression and BEC proliferation. In vitro experiments revealed that bile acid-activated monocytes promoted BEC proliferation through ITGß6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGß6, which work together to promote BEC proliferation and therefore represent potential therapeutic targets for cholangiopathies.