Preprint Analysis of 977 Long COVID Patients Reveals Prevalent Neuropathy and Association with Anti-Ganglioside Antibodies, 2025, Maguire et al.

Analysis of 977 Long COVID Patients Reveals Prevalent Neuropathy and Association with Anti-Ganglioside Antibodies
Cole Maguire; Kristina Kashyap; Elizabeth Williams; Aziz Rija; Maisey Schuler; Cheyenne Ahamed; Chumeng Wang; Aurelia Mena; Jeffrey Saniuk; Johanna Busch; Sara Austin; Mary Kelley; W. Michael Brode; Esther Melamed

BACKGROUND
Long 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 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.

METHODS
We 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) treatment.

FINDINGS
Neuropathic symptoms were reported by 55% (534/977) participants, with skin biopsy confirming small fiber neuropathy in 57.7% (49/85) 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 CRP) were unremarkable, unexpectedly, we detected anti-ganglioside antibodies (AGAs) in 25% of patients with LC neuropathy. 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.

INTERPRETATION
Our 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.

COMPETING INTEREST STATEMENT
EM is a principal investigator on a subcutaneous immunoglobulin clinical trial (CSL-Behring) for post-COVID Postural Orthostatic Tachycardia Syndrome. WMB and JB are co-investigators on the same study. The other authors declare no competing interests.

FUNDING STATEMENT
This work was supported by philanthropic funds from Tom Bonney, NIH R01AI104870-S1 (E.M.), NIAAA K08AA027837-05 (E.M.), The University of Texas at Austin Graduate School Continuing Fellowship (C.M.), The University of Texas at Austin Research and Creative Grant Award (E.M.), and institutional Dell Medical School Startup funding (E.M.). Funding sources did not have a direct role in design, analysis, or approval of this manuscript.

Link | PDF (Preprint: MedRxiv) [Open Access]