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.

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.

Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study.

BACKGROUND: Management strategies for non-alcoholic steatohepatitis (NASH) are based predominantly on lifestyle modification, with no approved disease-modifying drugs yet available. We aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of pegozafermin (BIO89-100), a glycoPEGylated FGF21 analogue, in participants with NASH. METHODS: This randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study enrolled adults (aged 21-75 years) who had NASH with stage F1-F3 fibrosis, or non-alcoholic fatty liver disease and a high risk of NASH (referred to in this study as phenotypic NASH) due to central obesity with type 2 diabetes, or central obesity with increased alanine aminotransferase (ALT) or a Fibroscan score of 7 kPa or greater, across 12 specialist centres and clinics in the USA. Patients were centrally randomised by use of an interactive web response system to receive subcutaneously administered pegozafermin (3, 9, 18, or 27 mg once weekly; 18 or 36 mg once every 2 weeks) or placebo for 12 weeks. The primary endpoints were the safety, tolerability, and pharmacokinetics of pegozafermin. This trial is registered with ClinicalTrials.gov (NCT04048135). FINDINGS: Between July 29, 2019, and Aug 3, 2020, 275 participants were screened and 81 (15 [19%] with biopsy-confirmed NASH) were randomly assigned: 62 to pegozafermin (six to 3 mg once weekly, 12 to 9 mg once weekly, 11 to 18 mg once weekly, ten to 27 mg once weekly, 14 to 18 mg once every 2 weeks, and nine to 36 mg once every 2 weeks) and 19 to placebo; 63 received pegozafermin and 18 received placebo, as one participant in the placebo group inadvertently received 3 mg pegozafermin once weekly. Adverse events were reported in eight (44%) of 18 participants in the pooled placebo group, six (86%) of seven in the 3 mg once weekly pegozafermin group, four (33%) of 12 in the 9 mg once weekly group, seven (64%) of 11 in the 18 mg once weekly group, seven (70%) of ten in the 27 mg once weekly group, eight (57%) of 14 in the 18 mg once every 2 weeks group, and eight (89%) of nine in the 36 mg once every 2 weeks group. The most common treatment-related adverse event was mild increased appetite (in ten [16%] of 63 participants in the pooled pegozafermin group vs none of 18 in the pooled placebo group), which was not associated with bodyweight gain. Two patients discontinued treatment due to an adverse event (one each in the 27 mg once weekly and 18 mg once every 2 weeks groups). No treatment-related serious adverse events or deaths occurred. Dose-proportional pharmacokinetics were observed. Anti-drug antibodies were detected in 41 (65%) of 63 participants treated with pegozafermin. By week 13, pegozafermin significantly reduced the least squares mean (LSM) absolute differences in hepatic fat fraction versus pooled placebo (-8·9% [95% CI -14·8 to -3·1; p=0·0032] for 3 mg once weekly, -11·5% [-16·1 to -6·9; p<0·0001] for 9 mg once weekly, -8·9% [-13·7 to -4·2; p=0·0004] for 18 mg once weekly, -14·9% [-20·1 to -9·7; p<0·0001] for 27 mg once weekly, -10·4% [-14·7 to -6·1; p<0·0001] for 18 mg once every 2 weeks, and -11·1% [-16·2 to -6·0; p<0·0001] for 36 mg once every 2 weeks). At week 13, significant LSM relative reductions versus pooled placebo in ALT were observed for pegozafermin 9 mg once weekly, 18 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. At week 13, significant LSM relative reductions versus pooled placebo in aspartate aminotransferase were observed for pegozafermin 3 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. Significant improvements were also observed with pegozafermin treatment for triglycerides (9 mg once weekly, 27 mg once weekly, and 18 mg once every 2 weeks), LDL-C (9 mg once weekly and 27 mg once weekly), HDL-C (3 mg once weekly and 18 mg once every 2 weeks), non-HDL-C (9 mg once weekly and 27 mg once weekly), adiponectin (all doses except for 36 mg once every 2 weeks), PRO-C3 (27 mg once weekly), and bodyweight (27 mg once weekly). Changes in insulin resistance and HbA1c were not significant. INTERPRETATION: Pegozafermin was generally well tolerated and associated with clinically meaningful reductions in liver fat, measures of liver function, and circulating lipids. Further evaluation of pegozafermin in individuals with NASH is warranted. FUNDING: 89bio.

Social and Demographic Disparities in the Severity of Multisystem Inflammatory Syndrome in Children.

Social constructs are known risk factors for multisystem inflammatory syndrome in children. A review of 206 patients demonstrated that children who were non-Hispanic Black, over the age of 12 years or living in a disadvantaged neighborhood associated with severe multisystem inflammatory syndrome in children (intensive care unit admission, intubation and/or vasopressor use).

Serum biomarkers for prediction of mortality in patients with COVID-19.

BACKGROUND: There is limited information regarding the role of biomarker levels at predicting mortality in patients with the coronavirus disease (COVID-19) pandemic. The purpose of this study is to determine the differences in serum biomarker levels in adults with COVID-19 who survived hospitalization from those who did not. METHODS: A comprehensive search was completed on PubMed, EMBASE and Cochrane libraries to identify studies of interest. Endpoints of interest were blood counts, hepatic function test, acute phase reactants, cytokines and cardiac biomarkers. RESULTS: A total of 10 studies with 1584 patients were included in the pooled analyses. Biomarkers that were noted to be significantly higher in those who died from coronavirus disease included: white blood cell count, neutrophil count, C-reactive protein, high sensitivity C-reactive protein, procalcitonin, ferritin, D-dimer, interleukin-6, lactate dehydrogenase, creatine kinase, prothrombin time, aspartate aminotransferase, alanine aminotransferase, total bilirubin and creatinine. Lymphocyte count, platelet count and albumin were significantly lower in patients who died. CONCLUSION: This pooled analysis of 10 studies including 1584 patients identified significant differences in biomarkers on admission in patients who survived from those who did not. Further research is needed to develop risk stratification models to help with judicious use of limited health-care resources.

MYOCARDITIS POST-SARS-COV-2 VACCINE ERA: A RETROSPECTIVE CASE SERIES

B Introduction: b Centers for Disease Control has received reports of myocarditis temporally associated with SARS CoV-2 vaccination in teenagers. Further studies are needed to better understand if mRNA SARS CoV-2 vaccination is associated with an increased risk of developing myocarditis compared to baseline and if the course differs from those with non-vaccine related myocarditis. There was no in-hospital mortality and median hospital length of stay (LOS) was 2.5 days (1.2-3.2). [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Disparities in case frequency and mortality of coronavirus disease 2019 (COVID-19) among various states in the United States.

OBJECTIVE: To utilize publicly reported, state-level data to identify factors associated with the frequency of cases, tests, and mortality in the USA. MATERIALS AND METHODS: Retrospective study using publicly reported data collected included the number of COVID-19 cases, tests and mortality from March 14th through April 30th. Publicly available state-level data was collected which included: demographics comorbidities, state characteristics and environmental factors. Univariate and multivariate regression analyses were performed to identify the significantly associated factors with percent mortality, case and testing frequency. All analyses were state-level analyses and not patient-level analyses. RESULTS: A total of 1,090,500 COVID-19 cases were reported during the study period. The calculated case and testing frequency were 3332 and 19,193 per 1,000,000 patients. There were 63,642 deaths during this period which resulted in a mortality of 5.8%. Factors including to but not limited to population density (beta coefficient 7.5, p < .01), transportation volume (beta coefficient 0.1, p < .01), tourism index (beta coefficient -0.1, p = .02) and older age (beta coefficient 0.2, p = .01) are associated with case frequency and percent mortality. CONCLUSIONS: There were wide variations in testing and case frequencies of COVID-19 among different states in the US. States with higher population density had a higher case and testing rate. States with larger population of elderly and higher tourism had a higher mortality. Key messages There were wide variations in testing and case frequencies of COVID-19 among different states in the USA. States with higher population density had a higher case and testing rate. States with larger population of elderly and higher tourism had a higher mortality.

RAMIC: Design of a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of ramipril in patients with COVID-19.

BACKGROUND AND AIMS: Retrospective studies have shown that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk of complications and mortality in persons with novel coronavirus disease 2019 (COVID-19). Thus, we aimed to examine the efficacy of ramipril, an ACE-inhibitor, in preventing ICU admission, mechanical ventilation and/or mortality while also minimizing the risk of transmission and use of personal protective equipment (PPE). METHODS: RAMIC is a multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial comparing the efficacy of treatment with ramipril 2.5 mg orally daily compared to placebo for 14 days. The study population includes adult patients with COVID-19 who were admitted to a hospital or assessed in an emergency department or ambulatory clinic. Key exclusion criteria include ICU admission or need for mechanical ventilation at screening, use of an ACE inhibitor or angiotensin-receptor-II blocker within 7 days, glomerular filtration rate < 40 mL/min or a systolic blood pressure (BP) < 100 mmHg or diastolic BP < 65 mmHg. Patients are randomized 2:1 to receive ramipril (2.5 mg) or placebo daily. Informed consent and study visits occur virtually to minimize the risk of SARS-CoV-2 transmission and preserve PPE. The primary composite endpoint of ICU admission, invasive mechanical ventilation and death are adjudicated virtually. CONCLUSIONS: RAMIC is designed to assess the efficacy of treatment with ramipril for 14 days to decrease ICU admission, mechanical ventilator use and mortality in patients with COVID-19 and leverages virtual study visits and endpoint adjudication to mitigate risk of infection and to preserve PPE (ClinicalTrials.gov, NCT04366050).

Covid-19 in an infant with systemic to pulmonary artery shunt dependent functionally univentricular physiology.

We report a case of two-month old with a functionally univentricular heart and parallel circulation who presented to the emergency department with Covid-19 and subsequently developed acute respiratory distress syndrome. The course of illness, clinical values, and laboratory markers are characterized in this report.

Pediatric Intensive Care Unit Admissions for COVID-19: Insights Using State-Level Data.

INTRODUCTION: Intensive care has played a pivotal role during the COVID-19 pandemic as many patients developed severe pulmonary complications. The availability of information in pediatric intensive care units (PICUs) remains limited. The purpose of this study is to characterize COVID-19 positive admissions (CPAs) in the United States and to determine factors that may impact those admissions. MATERIALS AND METHODS: This is a retrospective cohort study using data from the COVID-19 Virtual Pediatric System (VPS) dashboard containing information regarding respiratory support and comorbidities for all CPAs between March and April 2020. The state-level data contained 13 different factors from population density, comorbid conditions, and social distancing score. The absolute CPA count was converted to frequency using the state's population. Univariate and multivariate regression analyses were performed to assess the association between CPA frequency and admission endpoints. RESULTS: A total of 205 CPAs were reported by 167 PICUs across 48 states. The estimated CPA frequency was 2.8 per million children in a one-month period. A total of 3,235 tests were conducted of which 6.3% were positive. Children above 11 years of age comprised 69.7% of the total cohort and 35.1% had moderated or severe comorbidities. The median duration of a CPA was 4.9 days (1.25-12.00 days). Out of the 1,132 total CPA days, 592 (52.2%) involved mechanical ventilation. The inpatient mortalities were 3 (1.4%). Multivariate analyses demonstrated an association between CPAs with greater population density (beta coefficient 0.01, p < 0.01). Multivariate analyses also demonstrated an association between pediatric type 1 diabetes mellitus with increased CPA duration requiring advanced respiratory support (beta coefficient 5.1, p < 0.01) and intubation (beta coefficient 4.6, p < 0.01). CONCLUSIONS: Inpatient mortality during PICU CPAs is relatively low at 1.4%. CPA frequency seems to be impacted by population density. Type 1 DM appears to be associated with increased duration of HFNC and intubation. These factors should be included in future studies using patient-level data.

Factors associated with deep venous thrombosis in patients infected with coronavirus disease 2019: a meta-analysis.

Coronavirus disease 2019 (COVID-19) has affected more than 6 million patients worldwide. Deep venous thrombosis (DVT) has been increasingly recognized complication in these patients and is associated with increased morbidity and mortality. However, the factors associated with development of DVT in patients with COVID-19 have not been elucidated due to the novelty of the virus. We performed a meta-analysis of published studies comparing laboratory results in COVID-19 patients with and without DVT with the aim of identifying risk factors. We searched major databases for studies evaluating DVT in COVID-positive patients and performed a meta-analysis of baseline laboratory markers associated with development of DVT. A total of six studies with 678 patients were included in the pooled analyses. Of the 678 patients, 205 of patients had a DVT. Patients diagnosed with DVT were more likely to be older [mean difference 4.59 years, 95% confidence interval (CI) 1.25-7.92], and needing admission to ICU (relative risk 1.96, 95% CI 1.09-3.51). Patients with DVT had significantly higher white cell count (mean difference 1.36 × 109/l, 95% CI 0.33-2.40) and d-dimer levels (mean difference 3229.8, 95% CI 1501.5-4958.1). Lymphocyte count was lower in patients with DVT (mean difference -0.19 × 109/l, 95% CI -0.37 to -0.02). Patients with COVID-19 who develop DVT are more likely to be older and have leukocytosis with lymphopenia. Moreover, d-dimer is statistically higher and patients that are admitted to the ICU are at great risk to develop DVT.

Targeting the renin-angiotensin signaling pathway in COVID-19: Unanswered questions, opportunities, and challenges.

The role of the renin-angiotensin signaling (RAS) pathway in COVID-19 has received much attention. A central mechanism for COVID-19 pathophysiology has been proposed: imbalance of angiotensin converting enzymes (ACE)1 and ACE2 (ACE2 being the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] virus "receptor") that results in tissue injury from angiotensin II (Ang II)-mediated signaling. This mechanism provides a rationale for multiple therapeutic approaches. In parallel, clinical data from retrospective analysis of COVID-19 cohorts has revealed that ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may be beneficial in COVID-19. These findings have led to the initiation of clinical trials using approved drugs that target the generation (ACEIs) and actions (ARBs) of Ang II. However, treatment of COVID-19 with ACEIs/ARBs poses several challenges. These include choosing appropriate inclusion and exclusion criteria, dose optimization, risk of adverse effects and drug interactions, and verification of target engagement. Other approaches related to the RAS pathway might be considered, for example, inhalational administration of ACEIs/ARBs (to deliver drugs directly to the lungs) and use of compounds with other actions (e.g., activation of ACE2, agonism of MAS1 receptors, ß-arrestin-based Angiotensin receptor agonists, and administration of soluble ACE2 or ACE2 peptides). Studies with animal models could test such approaches and assess therapeutic benefit. This Perspective highlights questions whose answers could advance RAS-targeting agents as mechanism-driven ways to blunt tissue injury, morbidity, and mortality of COVID-19.

COVID-19 and Hyperinflammatory Syndrome in Children: Kawasaki Disease with Macrophage Activation Syndrome in Disguise?

A hyperinflammatory syndrome has been described in times of COVID-19 in children. In the setting of uncertainty due to a new virus, the so-called hyperinflammatory syndrome has been coined as a novel entity by some and is being referred to as pediatric inflammatory multisystem syndrome (PIMS). However, the characteristics of the syndrome resemble those of Kawasaki disease (KD), an inflammatory syndrome in children that can lead to coronary artery abnormalities due to a subsequent vasculitis. Furthermore, Kawasaki disease may occasionally trigger macrophage activation syndrome (MAS), a condition in which there is uncontrolled activation and proliferation of macrophages and other cell types, and could lead to multiorgan system dysfunction. This study provides a review of the data regarding COVID-19, Kawasaki disease, and macrophage activation syndrome to demonstrate the similarities and differences between the inflammatory syndrome seen with COVID-19 and KD. In addition, a framework for diagnosis and evaluation is provided that focuses on the pathway previously established for KD and MAS. The authors believe that based on current knowledge, KD treatment delays may carry deleterious effects in the near future for children with COVID-19-related Kawasaki disease.

Clinical Research in Hepatology in the COVID-19 Pandemic and Post-Pandemic Era: Challenges and the Need for Innovation.

The severe acute respiratory syndrome coronavirus 2 pandemic has drastically altered all facets of clinical care and research. Clinical research in hepatology has had a rich tradition in several domains, including the discovery and therapeutic development for diseases such as hepatitis B and C and studying the natural history of many forms of chronic liver disease. National Institutes of Health, foundation, and industry funding have provided important opportunities to advance the academic careers of young investigators while they strived to make contributions to the field. Instantaneously, however, all nonessential research activities were halted when the pandemic started, forcing those involved in clinical research to rethink their research strategy, including a shift to coronavirus disease 2019 research while endeavoring to maintain their preexisting agenda. Strategies to maintain the integrity of ongoing studies, including patient follow-up, safety assessments, and continuation of investigational products, have included a shift to telemedicine, remote safety laboratory monitoring, and shipping of investigational products to study subjects. As a revamp of research is being planned, unique issues that face the research community include maintenance of infrastructure, funding, completion of studies in the predetermined time frame, and the need to reprogram career path timelines. Real-world databases, biomarker and long-term follow up studies, and research involving special groups (children, the homeless, and other marginalized populations) are likely to face unique challenges. The implementation of telemedicine has been dramatically accelerated and will serve as a backbone for the future of clinical research. As we move forward, innovation in clinical trial design will be essential for conducting optimized clinical research.

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.

Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.