Complement activation in severely ill patients with sepsis: no relationship with inflammation and disease severity

The results of this study point toward profound activation of the complement pathway in sepsis patients, reflected by a decrease in complement components C3 and C5 and an increase in C3a, C3c, C5a, as well as the end product sTCC. We did not observe differences in complement factor concentrations between patients with the different immunological endotypes: hyperinflammation or immunoparalysis. In line with this, no correlation with other inflammatory parameters, disease severity, or mortality was observed. Therefore, we conclude that in this cohort of sepsis patients with very severe illness, the degree of complement activation is not related to dysregulation of the immune response and clinical outcomes.

Our findings are in contrast to previous research demonstrating associations between activation of the complement pathway and mortality in sepsis patients. Studies have shown decreased circulating concentrations of C3 and C5 in non-surviving patients compared to survivors [8,9,10]. Subsequently, C3a and C5a concentrations were increased in non-survivors, suggesting that in these patients the complement pathway is more extensively activated [8,9,10,11]. This difference is likely to be explained by differences in timing of sample collection, sample type, pre-analytical sample handling, method of complement assessment, and disease severity between cohorts. The current study included patients based on the new Sepsis-3 criteria [1], whereas the other studies used older sepsis criteria [12, 13], hence selecting a different selection of ‘sepsis’ patients. Therefore, our results might indicate that in severely ill patients with sepsis, the complement pathway is activated to such an extent that a ceiling is reached and relationships with inflammatory or clinical parameters can no longer be identified. Since large amounts of the C3 and C5 proteins are present in the blood in homeostasis, the limiting factor(s) for additional activation of the pathway is likely upstream of these factors. However, we have only investigated the terminal complement pathway in this study, so these limiting factors remain to be elucidated. Moreover, whether this saturation of the complement pathway also leads to functional impairment of the complement system needs to be investigated.

This study has limitations that need to be addressed. First, we only measured complement factors at a single timepoint within 24 h after sepsis diagnosis. Since the complement system reacts very early in the disease course, the 24-h sampling window could already induce variation in the actual status of complement activation. We cannot exclude that repeated measurements during the disease course with strict timing intervals could provide additional insight into the relationships between complement, inflammation, and outcomes. Moreover, we cannot exclude that in sepsis patients with less severe disease, associations between complement activation and disease severity may be present. Therefore, caution is needed when extrapolating these data to other (sepsis) populations and future studies are warranted. Second, the higher age of sepsis patients compared to healthy controls could have affected our results. However, as C5 concentrations appear to increase with age [14], the already significantly lower C5 concentrations observed in sepsis patients compared to healthy controls may be an underestimation of the true difference. Therefore, this does not affect our overall conclusions. Third, as this study focused on plasma concentrations of terminal complement markers, no conclusions can be drawn regarding complement functionality or complement activity in the tissues. Fourth, due to the observational nature of this study, no causation can be inferred.

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