PROJECT SUMMARY/ABSTRACT Dysautonomia, or autonomic nervous system dysfunction, is a common and disabling post-infectious syndrome that can occur following COVID-19 and Lyme disease. Dysautonomia accounts for many of the symptoms in Post-Acute Sequelae of COVID-19 (PASC, also called Long COVID) and Post-Treatment Lyme Disease (PTLD, also called Chronic Lyme). Dysautonomia has a wide variety of manifestations, including POTS (Postural orthostatic tachycardia syndrome), gastrointestinal dysmotility, interstitial cystitis, and neuropathic pain. A small- fiber neuropathy is also often present. The mechanisms of dysautonomia in patients with PASC and PTLD are not well understood. A subset of patients with dysautonomia have ganglionic acetylcholine receptor (gAchR) autoantibodies and often respond to immunomodulatory therapy with intravenous immunoglobulin (IVIG), implicating autoimmune destruction of small nerve fibers as a potential mechanism of dysautonomia. Some patients without gAchR antibodies still respond to IVIG, suggesting that some autoantibodies remain to be discovered. This project will leverage the clinical resources of the Johns Hopkins post-Acute COVID Clinic, the Lyme Disease Research Center, and the POTS Clinic to identify patients with post-infectious dysautonomia. Patients with confirmed PASC and PTLD dysautonomia will prospectively undergo objective autonomic testing in the Autonomic Lab, histopathological examination of small-fiber nerve density on skin biopsy, and clinical phenotyping using patient-reported outcome measures. In Aim 1, we will identify distinct clinical subgroups using unbiased latent variable cluster analysis. In Aim 2, we will determine the clinical significance of small-fiber neuropathy in post-infectious dysautonomia by investigating the association with disease severity, and will correlate clinical outcomes with changes in nerve fiber density over time. In Aim 3, we will perform immunoprecipitation and mass spectrometry to identify novel autoantibodies targeting the sympathetic ganglia in post-infectious dysautonomia. This Award will help the candidate, who is currently an Assistant Professor at Johns Hopkins University, develop her career as an independent physician-scientist with a focus on dysautonomia. Throughout the Award period, she will enhance her clinical research and biostatistical skills through hands-on experience and formal coursework. A key focus of the proposal is for Dr. Adler to refine her skills in autonomic testing and learn how to perform transcranial doppler ultrasound which is currently being integrated into the Autonomic Lab and will be a key skill that she will utilize throughout her research career. She has assembled an exceptional mentorship team that each provides complementary skills to ensure the success of this project, and includes experts in autonomic neuroscience and peripheral neuropathies, PASC and PTLD, immunology and autoantibody discovery, and biostatistics. With the guidance of her mentorship team, the candidate will develop an independent translational research program and a track-record that will lead to a successful R01 application.

PROJECT NARRATIVE A subset of patients develop chronic disabling symptoms of autonomic dysfunction such as fatigue and dizziness following infection with COVID-19 (Long Covid) or Lyme disease (Chronic Lyme), but the mechanisms through which this occurs are not understood. We will study a group of patients with chronic post-infectious autonomic symptoms to understand the markers and subtypes of this syndrome, and to test whether it is driven by an autoimmune attack on the nerves leading to chronic nerve damage.