Increased Alternative Complement Pathway Function and Improved Survival during Critical Illness

Abstract

Rationale: Complement is crucial for host defense but may also drive dysregulated inflammation. There is limited understanding of alternative complement function, which can amplify all complement activity, during critical illness. Objectives: We examined the function and key components of the alternative complement pathway in a series of critically ill patients and in a mouse pneumonia model. Methods: Total classical (CH50) and alternative complement (AH50) function were quantified in serum from 321 prospectively enrolled critically ill patients and compared with clinical outcomes. Alternative pathway (AP) regulatory factors were quantified by ELISA ( n = 181) and examined via transcriptomics data from external cohorts. Wild-type, Cfb −/− , and C3 −/− mice were infected intratracheally with Klebsiella pneumoniae (KP) and assessed for extrapulmonary dissemination. Measurements and Main Results: AH50 greater than or equal to median, but not CH50 greater than or equal to median, was associated with decreased 30-day mortality (adjusted odds ratio [OR], 0.53 [95% confidence interval (CI), 0.31–0.91]), independent of chronic liver disease. One-year survival was improved in patients with AH50 greater than or equal to median (adjusted hazard ratio = 0.59 [95% CI, 0.41–0.87]). Patients with elevated AH50 had increased levels of AP factors B, H, and properdin, and fewer showed a “hyperinflammatory” subphenotype (OR, 0.30 [95% CI, 0.18–0.49]). Increased expression of proximal AP genes was associated with improved survival in two external cohorts. AH50 greater than or equal to median was associated with fewer bloodstream infections (OR, 0.67 [95% CI, 0.45–0.98). Conversely, depletion of AP factors, or AH50 less than median, impaired in vitro serum control of KP that was restored by adding healthy serum. Cfb −/− mice demonstrated increased extrapulmonary dissemination and serum inflammatory markers after intratracheal KP infection compared with wild type. Conclusions: Elevated AP function is associated with improved survival during critical illness, possibly because of enhanced immune capacity.

COVID-19–associated Acute Respiratory Distress Syndrome Clarified: A Vascular Endotype?

“…Cytokine release and complement activation have long been implicated in organ failure and ARDS in sepsis ( 11 ). Although cytokine levels are comparable with non-COVID ARDS (medRxiv preprint DOI: https://doi.org/10.1101/2020.05.15.20103549 ), complement-mediated damage to the lung microvascular endothelial cells appears to be a predominant feature of COVID-ARDS, whereas direct comparisons with non-COVID ARDS have not been published as of this writing ( 6 ).…”

Status of mannose-binding lectin (MBL) and complement system in COVID-19 patients and therapeutic applications of antiviral plant MBLs

“…5). During critical illness, the alternative pathway amplifies all complement activity and improves survival, likely due to improved immune capacity [108]. Thus, complement is a "dual-edged sword" which is critical for innate immunity against pathogens.…”

COVID-19 and Respiratory System Disorders

“…An exaggerated immune or inflammatory response may activate the complement cascade, further propagating endothelial damage as leukocytes are recruited and elaborate inflammatory cytokines and other signaling molecules. 27 Although complement activation may be harmful in COVID-19, it is also critical in host response to infection 67 ; its net effect in COVID-19 remains to be determined. In situ microthrombus formation instigated by local inflammation and endothelial damage would contribute to abnormal V/Q matching and gas exchange abnormalities.…”