PROJECT SUMMARY Medical teams globally are consumed in caring for patients with respiratory failure and acute comorbidities caused by Coronavirus Disease 2019 (COVID-19). To understand the full impact of this pandemic on the lives of survivors and the magnitude of this emerging public health crisis, we must study the brain. We helped define the plague of disabling features suffered by millions of intensive care unit (ICU) survivors called Post-Intensive Care Syndrome (PICS), characterized by an acquired Alzheimer's disease and related dementia (ADRD), post- traumatic stress disorder (PTSD), and depression. Approximately 10% to 15% of COVID-19 patients develop hypoxemia requiring hospitalization, which can lead to acute respiratory distress syndrome and the need for life support, including mechanical ventilation. Up to 26% of hospitalized patients with COVID-19 require ICU admission. We hypothesize that COVID-19 survivors who are hospitalized will have a high burden of PICS- related acquired-ADRD, PTSD, and depression. To test this hypothesis, we propose this NIH Administrative Supplement to the BRAIN-ICU-2 Study (R01AG058639). This Administrative Supplement will allow us to use the BRAIN-ICU-2 long-term follow-up infrastructure to collect 6-month cognition, PTSD, and depression data for a NHLBI-sponsored randomized trial (ORCHID) that is evaluating hydroxychloroquine versus placebo on 15-day death, mechanical ventilation, or oxygen supplementation. We will ascertain these 6-month outcomes using a comprehensive phone battery that incorporates robust neuropsychological tests for memory, attention, language, reasoning, and executive function, and diagnostic evaluations for PTSD and depression. Our Administrative Supplement is titled “Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease - Brain Outcomes and Psychological Distress (ORCHID-BUD)” and will conduct 6-month follow-up assessments in 270 adults who are hospitalized with COVID-19 infection and survive. ORCHID-BUD has the following specific aims: (1) To determine the epidemiology (i.e., prevalence) of cognitive impairment (i.e., acquired-dementia) at 6 months and if hydroxychloroquine administration is associated with improvement in these same outcomes; (2) To determine the epidemiology of PTSD and depression at 6-months, and if hydroxychloroquine administration is associated with improvement in these same outcomes, and (3) To identify modifiable risk factors (e.g., sedatives, isolation, intravenous fluids, pressor, ACE-inhibitor or ARB use, etc.) associated with worse long-term cognitive impairment, PTSD, and depression at 6 months. To our knowledge, this investigation will be the first ever to conduct robust neuropsychological assessments for SARS, MERS or COVID-19 survivors, and the first among COVID-19 to conduct diagnostic PTSD and depression assessments. This Administrative Supplement will leverage BRAIN- ICU-2 and ORCHID's resources to conduct a high impact and novel investigation at relatively low cost and help provide a comprehensive evaluation of COVID-19's effect on long-term cognitive and psychological outcomes.

Project Narrative To understand the full impact of the COVID-19 pandemic on the lives of survivors and the magnitude of this emerging public health crisis, we must study how it impacts the brain. Our proposal will evaluate if hospitalized adult COVID-19 survivors have a high burden of Post-Intensive Care Syndrome (PICS)-related acquired Alzheimer's disease and related dementia (ADRD), post-traumatic stress disorder (PTSD), and depression at 6-months. Secondarily, we will also determine if hydroxychloroquine versus placebo improves these outcomes.