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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
ERJ Open Research 2023; DOI: 10.1183/23120541.00702-2022
William Bain
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
2Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA
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  • For correspondence: bainwg@upmc.edu
Mohammadreza Tabary
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Sara R. Moore
3Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
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Xiaojing An
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Georgios D. Kitsios
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Bryan J. McVerry
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Prabir Ray
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Anuradha Ray
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Rama K. Mallampalli
4Department of Medicine, Ohio State University, Columbus, OH, USA
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Viviana P. Ferreira
3Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
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Janet S. Lee
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
5Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
6These authors contributed equally to this work
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S. Mehdi Nouraie
1Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
6These authors contributed equally to this work
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Abstract

Background Effective regulation of complement activation may be crucial to preserving complement function during ARDS. Factor H (FH) is the primary negative regulator of the alternative pathway (AP) of complement. We hypothesized that preserved FH levels are associated with decreased complement activation and reduced mortality during ARDS.

Methods Total AP function was measured by serum hemolytic assay (AH50) using available samples from the ARDSnet LARMA trial (N=218). Factor B (FB) and FH levels were quantified by ELISA using samples from the ARDSnet LARMA and SAILS (N=224) trials. Meta-analyses included previously quantified AH50, FB, and FH values from an observational registry (ALIR). Complement C3, and complement activation products C3a and Ba plasma levels were measured in SAILS.

Results AH50>median was associated with reduced mortality in meta-analysis of LARMA and ALIR [hazard ratio (HR)=0.66, 95% confidence interval (CI) 0.45–0.96]. In contrast, patients in the lowest AH50 quartile demonstrated relative deficiency of both FB and FH. Relative deficiency of FB [HR 1.99, CI 1.44–2.75], or FH [HR 1.52, CI 1.09–2.11], were associated with increased mortality in meta-analysis of LARMA, SAILS, and ALIR. Relative FH deficiency was associated with increased factor consumption as evidenced by lower FB and C3 levels and higher Ba:FB and C3a:C3 ratios. Higher FH levels associated with lower inflammatory markers.

Conclusions Relative FH deficiency, higher Ba:FB and C3a:C3 ratios, and lower FB and C3 levels suggest a subset of ARDS with complement factor exhaustion, impaired AP function, and increased mortality that may be amenable to therapeutic targeting.

Footnotes

This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.

Conflict of interest: The authors declare no competing conflicts of interest with this manuscript.

Conflict of interest: Dr. McVerry discloses grant funding from Bayer Pharmaceuticals and consulting fees from BioAegis, Boehringer Ingelheim, and Synairgen Research for work unrelated to this manuscript.

Conflict of interest: Dr. Mallampalli discloses stock ownership in Koutif Therapeutics, LLC, which is unrelated to this manuscript.

Conflict of interest: Dr. Ferreira discloses a pending patent (60126-US-PSP/D2018-26) as well as grant funding and consulting fees from Apellis Pharmaceuticals for work unrelated to this manuscript.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received December 15, 2022.
  • Accepted April 5, 2023.
  • Copyright ©The authors 2023
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

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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
ERJ Open Research Jan 2023, 00702-2022; DOI: 10.1183/23120541.00702-2022

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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
ERJ Open Research Jan 2023, 00702-2022; DOI: 10.1183/23120541.00702-2022
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