ALCOHOLIC HEPATITIS CLINICAL AND TRANSLATIONAL NETWORK: LATE PHASE CLINICAL TRIALS AND OBSERVATIONAL STUDIES 6/9

摘要 尽管具有很高的临床意义，但对COVID的管理和治疗知识有限- 19.酒精相关性肝病（ALD）和COVID-19患者患严重疾病的风险增加， 发病率和死亡率。也有数据表明，在隔离期间，酒精消费量会增加， 由于在COVID-19大流行期间实施的社交距离措施， ALD可能会增加。目前针对严重COVID-19患者的治疗方法包括抗病毒治疗 代理和支持性护理。在我们的初步和初步研究中，我们观察到肌肉减少症或骨骼丢失， ALD患者的肌肉质量和肌肉力量受损。肌肉减少症和伴随的收缩 功能障碍导致住院和重症监护时间更长，更需要辅助支持， 急性呼吸窘迫综合征（ARDS）的结果，这是严重COVID-19的标志。“细胞因子风暴” 新出现的数据表明，COVID-19患者发生的这种疾病伴随着循环中IL-6的升高， IL-6抑制剂改善了严重COVID-19患者的生存率。尽管对IL-6的兴趣很大， 随着多项正在进行的临床试验，这些药物增加了继发感染的风险 （在COVID-19中常见），并且在血浆浓度显著升高的患者中禁用 转氨酶β-羟基-β-丁酸甲酯（HMB），一种非氮亮氨酸代谢产物， 此外，它还抑制血浆IL-6，同时改善肌肉质量和收缩功能。因此我们 假设COVID-19影响ALD患者临床结局和肌肉损失， HMB通过IL-6依赖性方式造成的肌肉损失将改善ALD患者的临床结果。这 假设将通过两个相互关联，但独立的具体目标进行测试：（1）建立自然的 ALD患者的COVID-19感染过程，通过确定COVID-19是否在 ALD和COVID-19是否会导致ALD的肝损伤;（2）确定是否使用HMB治疗 改善COVID-19在骨骼肌质量、骨骼肌张力、骨骼肌张力、 肌肉功能和ALD患者的临床结果。我们将使用临床和生物样本来确定 结果和对针对这些患者骨骼肌的干预的反应。我们预计HMB将 减少炎症标志物，包括循环IL-6，改善住院临床结局，逆转 肌肉减少症，并改善长期临床结果。这些人类研究有可能立即 转化为临床实践，以快速改善ALD患者的即时和长期结局， 2019冠状病毒病。这些研究将补充申请人正在进行的酒精性肝炎网络赠款支持 ”吴彦祖说。

ABSTRACT Despite the high clinical significance, there is limited knowledge of the management and treatment of COVID- 19. Patients with alcohol associated liver disease (ALD) and COVID-19 are at increased risk for severe disease, morbidity and mortality. There are also data that alcohol consumption increases during isolation, like that caused by social distancing measures enacted during the COVID-19 pandemic, therefore the incidence and severity of ALD is likely to increase. Current treatment approaches for patients with severe COVID-19 include antiviral agents and supportive care. In our preliminary and pilot studies we have observed sarcopenia or loss of skeletal muscle mass and impaired muscle strength in patients with ALD. Sarcopenia and accompanying contractile dysfunction contribute to longer hospital and intensive care stay, greater need for ventilatory support and poor outcomes in acute respiratory distress syndrome (ARDS), a hallmark of severe COVID-19. The “cytokine storm” that occurs in patients with COVID-19 is accompanied by elevated circulating IL-6, and emerging data suggests that IL-6 inhibitors improve survival in patients with severe COVID-19. Despite the significant interest in IL-6 inhibitors with multiple ongoing clinical trials underway, these agents increase the risk for secondary infections (a common occurrence in COVID-19) and are contraindicated in those with significant elevated plasma transaminases. β-hydroxy β-methyl butyrate (HMB), a non-nitrogenous leucine metabolite with anabolic properties, also inhibits plasma IL-6 while improving muscle mass and contractile function. We therefore hypothesize that COVID-19 worsens clinical outcomes and muscle loss in ALD patients, and that reversal of muscle loss by HMB through an IL-6 dependent manner will improve clinical outcomes in ALD patients. This hypothesis will be tested through two interrelated, but independent specific aims: (1) establish the natural course of COVID-19 infection in patients with ALD by determining whether COVID-19 is more severe in ALD and whether COVID-19 worsens liver injury in ALD; (2) determine whether treatment with HMB improves the acute and long-term consequences of COVID-19 in terms of skeletal muscle mass, skeletal muscle function, and clinical outcomes in ALD patients. We will use clinical and biosamples to determine outcomes and responses to intervention targeting the skeletal muscle in these patients. We anticipate HMB will reduce inflammatory markers including circulating IL-6, improve clinical outcomes in-hospital, reverse sarcopenia, and improve long-term clinical outcomes. These human studies have the potential for immediate translation into clinical practice to rapidly improve immediate and long-term outcomes in ALD patients with COVID-19. These studies will supplement the applicant’s ongoing alcoholic hepatitis network grant supported by the NIAAA.