TY - JOUR
T1 - Factor H preserves alternative complement function during ARDS, linked to improved survival
AU - Bain, William
AU - Tabary, Mohammadreza
AU - Moore, Sara R.
AU - An, Xiaojing
AU - Kitsios, Georgios D.
AU - McVerry, Bryan J.
AU - Ray, Prabir
AU - Ray, Anuradha
AU - Mallampalli, Rama K.
AU - Ferreira, Viviana P.
AU - Lee, Janet S.
AU - Nouraie, S. Mehdi
N1 - Publisher Copyright:
© The authors 2023.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85163813256&partnerID=8YFLogxK
U2 - 10.1183/23120541.00702-2022
DO - 10.1183/23120541.00702-2022
M3 - Article
C2 - 37377659
AN - SCOPUS:85163813256
SN - 2312-0541
VL - 9
JO - ERJ Open Research
JF - ERJ Open Research
IS - 3
M1 - 00702-2022
ER -