C1-esterase Inhibitor Treatment is Associated with Immune and Vascular Pathway Modulation in PASC with Neurological Symptoms: Longitudinal Plasma Proteomics.

Post-acute sequelae of SARS-CoV-2 infection (PASC), particularly neurological manifestations, remain a significant therapeutic challenge, likely driven by persistent inflammation, immune dysregulation, and endothelial dysfunction. In a randomized, double-blind, placebo-controlled crossover trial, 10 patients with post-COVID-19 neurological symptoms received C1-esterase inhibitor (C1-INH; RUCONEST®) or placebo over two eight-week phases. Longitudinal plasma proteomics (SomaScan®) profiled molecular dynamics during and after C1-INH treatment. C1-INH administration was associated with distinct, phase-specific proteomic signatures, including lower levels of inflammatory-associated proteins such as CRP and IL-6, increased levels of neuroimmune and endothelial repair proteins (Neuropilin-2, CD83, C1QTNF5), and modulation of bradykinin-kinin and extracellular matrix pathways. These molecular shifts were evaluated in relation to clinical change scores during the active treatment windows. Several proteomic changes were observed at timepoint 26 after treatment cessation, describing candidate post-treatment molecular trajectories. In conclusion, these results provide exploratory mechanistic insights and support the need for validation in larger, prospective cohorts. Together, these findings prioritize immune and vascular pathways for further investigation in PASC and may have relevance to other post-infectious neuroimmune conditions.