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
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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.
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- Received December 15, 2022.
- Accepted April 5, 2023.
- Copyright ©The authors 2023
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