{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:22:29Z","timestamp":1788056549864,"version":"build-2784847793"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Many patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience neurologic changes post-infection, which has been hypothesized to be due to dysregulation in the infectious-immune axis that leads to a neuro-immune response. This immune dysfunction has been termed \u201cAlzheimer\u2019s of the Immune System\u201d or AIS and there are several immune factors that may play a key role. These include, among others, complement activation due to low levels of C1-esterase inhibitor (C1-INH) and function, and a decrease in signaling of Toll-like receptor (TLR)-3. We propose that C1-INH replacement may upregulate the immune dysfunction, thereby improving neurological symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this randomized, double-blind, placebo-controlled, crossover, proof-of-concept study, adults experiencing SARS-CoV-2 post-viral fatigue syndrome for &amp;gt;4\u202fweeks post-recovery from coronavirus disease 2019 (COVID-19) infection were randomized 1:1 to two arms: Arm 1 (C1-INH for 8\u202fweeks, then placebo for 8\u202fweeks) or to Arm 2 (placebo for 8\u202fweeks, then C1-INH for 8\u202fweeks). Patients were assessed for adult executive function, abnormal cognitive decline, depression [Beck Depression Inventory-II (BDI-II)], migraine, fatigue [Fatigue Severity Scale (FSS)] and pain (Short-form McGill Pain Questionnaire). Percent change in TLR signaling in response to zymosan was compared with controls at baseline, Week 8 and Week 16. Safety was assessed throughout.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At this interim analysis, 36 patients with SARS-CoV-2 post-viral fatigue syndrome had completed the two 8-week treatment periods. In Arm 1, trends toward improvements from baseline at Week 8 of C1-INH therapy were observed in BDI-II score (\u22128.7 points), mean FSS score (0.6 points), and mean McGill Pain Questionnaire score (\u22120.4 points). These improvements were either sustained or worsened at Week 16, following crossover to placebo. The outcomes in Arm 2 were compatible with those in Arm 1. Patients with SARS-CoV-2 post-viral fatigue syndrome had low levels of TLR-related signaling biomarkers compared with healthy controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This proof-of-concept study demonstrates sustained dysregulation of the immune system after COVID-19 infection. Improvements in depression, fatigue, and pain were observed with C1-INH treatment in patients with SARS-CoV-2 post-viral fatigue syndrome, indicating C1-INH may be a potential therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:related-object>The study was registered on September 21, 2024, with the identifier number NCT04705831.<\/jats:related-object>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2025.1523814","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T06:23:40Z","timestamp":1762410220000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Does C1 esterase inhibitor play a role in post COVID-19 neurological symptoms? 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