Immune, hormonal, and muscle mitochondrial determinants of recovery in Acute Respiratory Distress Syndrome survivors

PROJECT SUMMARY Prior to COVID-19, over 150,000 Americans survived Acute Respiratory Distress Syndrome (ARDS) each year. To date, more than 500,000 Americans have survived COVID-19 ARDS. At least half of ARDS survivors have persistent muscle weakness that results in increased disability, healthcare costs, and mortality. There are no targeted therapies to improve muscle strength and physical recovery in ARDS survivors, because the mechanisms underlying these physical impairments and poor recovery are not well understood. The overall hypothesis of the project is that multi-systemic dysregulation that occurs in acute ARDS, persists after hospital discharge in those with persistent physical impairment, and resolves in those who recover physically. The overall objective of the project is to determine whether persistent inflammation from dysregulated monocytes, anabolic hormone deficiencies, and muscle mitochondrial dysfunction at 3 months after hospital discharge are each treatment targets for physical disability in ARDS survivors. To achieve our objective, we will conduct a nested case-control study of cohorts. We will prospectively enroll 345 ARDS survivors at hospital discharge with 12- month longitudinal follow-up from Johns Hopkins University and Columbia University hospitals. Three months after hospital discharge, we will conduct an in-person nested case-control study of 180 ARDS survivors, with case status defined as not-recovered from new disability. Inflammation, anabolic hormone deficiencies, and muscle mitochondrial dysfunction increase with aging and comorbidity, and older adult ARDS survivors are less likely to recover than those who are younger and healthier. Therefore, to determine biomarker levels and muscle mitochondrial dysfunction that are associated with ARDS, independent of age or comorbidity, we will compare ARDS survivors with carefully matched community-dwelling adults from the National Heart Lung and Blood Institute (NHLBI) Multi-Ethnic Study of Atherosclerosis (MESA) and the Columbia University Merritt Center muscle biobank. Across the cohorts, we have carefully coordinated sociodemographic, clinical, and functional assessments to facilitate careful matching. We will conduct rigorous serum biomarker assessments, targeted plasma metabolomics, high dimensional flow cytometry of blood, and muscle biopsy mitochondrial function and gene expression analyses to accomplish our three Aims: (1) to determine the role of monocyte function in recovery from disability in ARDS survivors; (2) to determine the role of anabolic hormone deficiencies in recovery from disability in ARDS survivors; and (3), to determine how plasma biomarkers of mitochondrial myopathy associate with skeletal muscle mitochondrial dysfunction and recovery from disability in ARDS survivors. The overall goal is to conduct epi-mechanistic studies that will inform future post-ARDS randomized trials of targeted anti-inflammatory therapies, hormone supplementation therapies, and muscle mitochondrial therapies that aim to improve physical function in ARDS survivors, a NHBLI research priority.