Complement Activation in the Disease Course of Coronavirus Disease 2019 and Its Effects on Clinical Outcomes

Abstract

Background: Excessive activation of immune responses in coronavirus disease 2019 (COVID-19) is considered to be related to disease severity, complications, and mortality rate. The complement system is an important component of innate immunity and can stimulate inflammation, but its role in COVID-19 is unknown.

Methods: A prospective, longitudinal, single center study was performed in hospitalized patients with COVID-19. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed.

Results: Complement factors C3a, C3c, and TCC were significantly increased in plasma of patients with COVID-19 compared with healthy controls (P < .05). These complement factors were especially elevated in intensive care unit patients during the entire disease course (P < .005 for C3a and TCC). More intense complement activation was observed in patients who died and in those with thromboembolic events.

Conclusions: Patients with COVID-19 demonstrate activation of the complement system, which is related to disease severity. This pathway may be involved in the dysregulated proinflammatory response associated with increased mortality rate and thromboembolic complications. Components of the complement system might have potential as prognostic markers for disease severity and as therapeutic targets in COVID-19.

Keywords: ARDS; COVID-19; Coagulation; Complement; Inflammation; SARS-CoV-2.

Figure 1.

Simplified overview of the complement pathway. Activation of the complement system commences via the classical, lectin, and/or alternative pathway, resulting in the formation of C3 convertase, which cleaves C3 into C3a and C3b. C3b further degrades to C3c but also activates C5 convertase, which cleaves C5 into C5a and C5b. C5b combined with other complement factors forms the terminal complement complex (TCC) or membrane attack complex (MAC). C3a and C5a are anaphylatoxins and are inducers of inflammation and coagulation. TCC leads to cell lysis and can also activate the coagulation pathway. The complement factors measured in this study are highlighted with a black outline.

Figure 2.

Circulating concentrations of complement factors C3a (A), C3c (B), and terminal complement complex (TCC) (C) in healthy controls (n = 10), patients with coronavirus disease 2019 (COVID-19) (n = 122), and patients with sepsis (n = 39). Data are presented as medians with interquartile range. Dotted line in B represents upper detection limit. P values between all groups were <.001 for all complement factors. *P < .05; †P < .01; ‡P < .001.

Figure 3.

Longitudinal course of C3a (A), C3c (B), and terminal complement complex (TCC) (C) plasma concentrations during hospital admission in non–intensive care unit (non-ICU) patients (n = 115) and ICU patients (n = 75) with coronavirus disease 2019. P values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with interquartile range.

Figure 4.

Longitudinal course of C3a (A), C3c (B), and terminal complement complex (TCC) (C) plasma concentrations during hospital admission in patients with coronavirus disease 19 who survived (n = 164) and in those who died (n = 27). P values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with interquartile range.

Figure 5.

Longitudinal course of C3a (A), C3c (B), and terminal complement complex (TCC) (C) plasma concentrations during hospital admission in patients with coronavirus disease 2019 with (n = 28) or without (n = 169) thromboembolic events (TEEs). P values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with interquartile range.

Figure 6.

Correlation of complement activation with inflammatory markers in patients with coronavirus disease 2019.. Correlation coefficients (r values, shown in the figure) and P values were calculated using the Spearman rank correlation test. *P < .004 (considered significant after Bonferroni correction for multiple testing). Abbreviations: CRP, C-reactive protein; IL-6, interleukin 6; TCC, terminal complement complex.