Factor H preserves alternative complement function during ARDS, linked to improved survival

William Bain; Mohammadreza Tabary; Sara R Moore; Xiaojing An; Georgios D Kitsios; Bryan J McVerry; Prabir Ray; Anuradha Ray; Rama K Mallampalli; Viviana P Ferreira; Janet S Lee; S Mehdi Nouraie

doi:10.1183/23120541.00702-2022

Factor H preserves alternative complement function during ARDS, linked to improved survival

ERJ Open Res. 2023 Jun 26;9(3):00702-2022. doi: 10.1183/23120541.00702-2022. eCollection 2023 May.

Authors

William Bain^{1

2}, Mohammadreza Tabary¹, Sara R Moore³, Xiaojing An¹, Georgios D Kitsios¹, Bryan J McVerry¹, Prabir Ray^{1

4}, Anuradha Ray^{1

4}, Rama K Mallampalli⁴, Viviana P Ferreira³, Janet S Lee^{1

5

6}, S Mehdi Nouraie^{1

7}

Affiliations

¹ Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
² Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA.
³ Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
⁴ Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Department of Medicine, Ohio State University, Columbus, OH, USA.
⁶ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University in St Louis, St Louis, MO, USA.
⁷ These authors contributed equally to this work.

Abstract

Background: Effective 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Abstract

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