ERJ open research

2312-0541932023MayERJ open researchERJ Open ResFactor H preserves alternative complement function during ARDS, linked to improved survival.00702-202210.1183/23120541.00702-2022Effective regulation of complement activation may be crucial to preserving complement function during acute respiratory distress syndrome (ARDS). Factor H is the primary negative regulator of the alternative pathway of complement. We hypothesised that preserved factor H levels are associated with decreased complement activation and reduced mortality during ARDS.Total alternative pathway function was measured by serum haemolytic assay (AH50) using available samples from the ARDSnet Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) trial (n=218). Factor B and factor H levels were quantified using ELISA using samples from the ARDSnet LARMA and Statins for Acutely Injured Lungs from Sepsis (SAILS) (n=224) trials. Meta-analyses included previously quantified AH50, factor B and factor H values from an observational registry (Acute Lung Injury Registry and Biospecimen Repository (ALIR)). Complement C3, and complement activation products C3a and Ba plasma levels were measured in SAILS.AH50 greater than the median was associated with reduced mortality in meta-analysis of LARMA and ALIR (hazard ratio (HR) 0.66, 95% CI 0.45-0.96). In contrast, patients in the lowest AH50 quartile demonstrated relative deficiency of both factor B and factor H. Relative deficiency of factor B (HR 1.99, 95% CI 1.44-2.75) or factor H (HR 1.52, 95% CI 1.09-2.11) was associated with increased mortality in meta-analysis of LARMA, SAILS and ALIR. Relative factor H deficiency was associated with increased factor consumption, as evidenced by lower factor B and C3 levels and Ba:B and C3a:C3 ratios. Higher factor H levels associated with lower inflammatory markers.Relative factor H deficiency, higher Ba:B and C3a:C3 ratios and lower factor B and C3 levels suggest a subset of ARDS with complement factor exhaustion, impaired alternative pathway function, and increased mortality, that may be amenable to therapeutic targeting.Copyright ©The authors 2023.BainWilliamW0000-0001-8506-0552Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA.TabaryMohammadrezaMAcute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.MooreSara RSRDepartment of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.AnXiaojingXAcute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.KitsiosGeorgios DGD0000-0002-1018-948XAcute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.McVerryBryan JBJ0000-0002-1175-4874Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.RayPrabirPAcute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.RayAnuradhaAAcute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.MallampalliRama KRKDepartment of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.FerreiraViviana PVPDepartment of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.LeeJanet SJS0000-0002-6812-6043Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.Department of Medicine, Ohio State University, Columbus, OH, USA.Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University in St Louis, St Louis, MO, USA.NouraieS MehdiSM0000-0001-7465-0581Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.These authors contributed equally to this work.engK24 HL143285HLNHLBI NIH HHSUnited StatesR01 HL136143HLNHLBI NIH HHSUnited StatesR01 HL142084HLNHLBI NIH HHSUnited StatesP01 HL114453HLNHLBI NIH HHSUnited StatesR21 HL148088HLNHLBI NIH HHSUnited StatesIK2 BX004886BXBLRD VAUnited StatesR01 HL112937HLNHLBI NIH HHSUnited StatesJournal Article20230626