Analysis of 977 Long COVID Patients Reveals Prevalent Neuropathy and Association with Anti-Ganglioside Antibodies

BackgroundLong COVID (LC) is a novel condition that is characterized by persistent symptoms that last from months to years following a SARS-CoV-2 infection. While LC symptoms vary widely, neuropathy is one of the most prevalent symptoms and drastically affects patients quality of life. However, the underlying pathophysiology of LC neuropathy remains poorly understood. Here, we investigated the prevalence and potential mechanisms of LC neuropathy in the largest LC neuropathy cohort to date. MethodsWe conducted an observational study of 977 adults with LC at Dell Medical School. Participants underwent clinical assessments, skin punch biopsy, and comprehensive metabolic, endocrine and immunological profiling. A subset of patients received treatment with intravenous immunoglobulin (IVIG). FindingsNeuropathic symptoms were reported by 55% (534/977) participants, with skin biopsy confirming small fiber neuropathy in 56.5% (48/85) cases, affecting both epidermal and autonomic nerve fibers. Common risk factors for neuropathy, including metabolic and endocrine disorders, did not fully explain neuropathic symptoms. While general immunological markers (lymphocyte, T cell, and B cell count and C reactive protein were unremarkable, unexpectedly, we detected anti-ganglioside antibodies (AGAs) in 25% of patients with LC neuropathy, a comparable rate to other AGA-associated neuropathies. Longitudinal testing revealed persistent AGA positivity, and multiple elevated AGAs in a subset of patients. In a pilot treatment cohort of eight patients, IVIG treatment resulted in improvement of patient reported neuropathic symptoms. InterpretationOur findings reveal a high prevalence of small fiber neuropathy in LC, with evidence suggesting an autoimmune mechanism involving AGAs in one in four LC neuropathy patients. The therapeutic response to IVIG further supports an autoimmune pathophysiology, suggesting potential benefits of immunomodulation in LC neuropathy patients.