Severe acute respiratory distress syndrome (ARDS) during SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection, manifests as uncontrolled lung inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies can reduce COVID-19 severity if administered in the early viremic phase, but treatments for later stage immuno-thrombotic syndrome and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases during thrombotic, thrombolytic and immune responses. The myxoma poxvirus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated coagulation and complement protease pathways as part of a self-defense strategy to combat viral clearance by the innate immune system. When purified and utilized as an anti-immune therapeutic, Serp-1 is effective as an anti-inflammatory drug in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 (PEGSerp-1) as a therapy for immuno-thrombotic complications during ARDS. Treatment with PEGSerp-1 in two distinct mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved clinical outcomes. PEGSerp-1 significantly reduced M1 macrophage invasion in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR) and complement membrane attack complex (MAC). Sequential changes in urokinase-type plasminogen activator receptor (uPAR) and serpin gene expression were observed in lung and heart with PEGSerp-1 treatment. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for treatment of severe viral ARDS with additional potential to reduce late SARS-CoV-2 complications related to immune-thrombotic events that persist during long COVID. Significance: Severe acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection manifests as uncontrolled tissue inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies reduce COVID-19 severity if administered early, but treatments for later stage immuno-thrombosis are limited. Serine protease inhibitors (SERPINS) regulate thrombotic, thrombolytic and complement pathways. We investigate here systemic treatment with purified poxvirus-derived PEGSerp-1 as a therapeutic for immuno-thrombotic complications in viral ARDS. PEGSerp-1 treatment in two mouse-adapted SARS-CoV-2 models (C57Bl/6 and BALB/c) significantly reduced lung and heart inflammation and improved clinical outcomes, with sequential changes in thrombolytic (uPAR) and complement expression. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for immune-thrombotic complications in severe viral ARDS and has potential benefit for long COVID.

Introduction: Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is an uncommon cause of colonic ischemia for which surgical treatment is recommended. We describe the clinical, radiologic and endoscopic findings in IMHMV patients to provide clinicians with a framework for the identification of this rare disease. Methods: We performed a systematic review of seven databases for cases of IMHMV and identified additional cases from Yale New Haven Hospital records. To identify features specifically associated with colonic ischemia due to IMHMV, we performed multivariate logistic regression analysis incorporating data from a large, well-characterized multicenter cohort of biopsy-proven ischemic colitis (n5923). Results: A total of 123 patients with IMHMV were identified from 58 publications and 3 unpublished cases at Yale New Haven Hospital (80% male, mean age 53, 56% Caucasian). Symptoms at presentation were most commonly abdominal pain (87%) and diarrhea (67%). The most affected areas were the sigmoid colon (89%) and rectum (66%). Median time from symptom onset to diagnosis was 4 months. Complications, including obstruction and perforation due to diagnostic delay occurred in 33% of patients. The most common radiologic feature was thickening of the affected segment of colon (97%). Anatomic vascular abnormalities including non-opacification of the inferior mesenteric vein were observed in 38% of patients. 97% of patients ultimately underwent curative segmental colectomy. Mean follow-up time was 23.6 months. Compared to biopsy-proven non-IMHMV colonic ischemia, IMHMV was significantly associated with younger age (p50.010), male sex (p50.002), rectal involvement on imaging (p50.027) and on endoscopic evaluation (p50.004), mucosal ulcerations on endoscopy (p50.049) and absence of rectal bleeding on presentation (p, 0.001) (Table ). Conclusion: IMHMV is a rare, underreported cause of colonic ischemia that predominantly involves the left colon. Using the largest IMHMV cohort to date and comparing to a multicenter cohort of patients with ischemic colitis, we identify clinical, endoscopic, and radiologic characteristics of this entity. Our findings suggest younger age, rectal involvement, and absence of rectal bleeding as clinical features to help identify select patients presenting with colonic ischemia as having higher likelihood of IMHMV and therefore consideration of upfront surgical management. Diabetesmellitus 61 13.1% (8) 921 30.0% (276) 0.005 Stroke 61 4.9% (3) 920 10.8% (99) 0.193