Functional Activity of the Complement System in Hospitalized COVID-19 Patients: A Prospective Cohort Study

Abstract

AimsAlthough the exact factors promoting disease progression in COVID-19 are not fully elucidated, unregulated activation of the complement system (CS) seems to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by SARS-CoV-2. In particular, the lectin pathway (LP) has been implicated in previous autopsy studies. The primary purpose of our study is to investigate the role of the CS in hospitalized COVID-19 patients with varying degrees of disease severity.MethodsIn a single-center prospective observational study, 154 hospitalized patients with PCR-confirmed SARS-CoV-2 infection were included. Serum samples on admission to the COVID-19 ward were collected for analysis of CS pathway activities and concentrations of LP proteins [mannose-binding lectin (MBL) and ficolin-3 (FCN-3)] & C1 esterase inhibitor (C1IHN). The primary outcome was mechanical ventilation or in-hospital death.ResultsThe patients were predominately male and had multiple comorbidities. ICU admission was required in 16% of the patients and death (3%) or mechanical ventilation occurred in 23 patients (15%). There was no significant difference in LP activity, MBL and FCN-3 concentrations according to different peak disease severities. The median alternative pathway (AP) activity was significantly lower (65%, IQR 50-94) in patients with death/invasive ventilation compared to patients without (87%, IQR 68-102, p=0.026). An optimal threshold of <65.5% for AP activity was derived from a ROC curve resulting in increased odds for death or mechanical ventilation (OR 4,93; 95% CI 1.70-14.33, p=0.003) even after adjustment for confounding factors. Classical pathway (CP) activity was slightly lower in patients with more severe disease (median 101% for death/mechanical ventilation vs 109%, p=0.014). C1INH concentration correlated positively with length of stay, inflammatory markers and disease severity on admission but not during follow-up.ConclusionOur results point to an overactivated AP in critically ill COVID-19 patients in vivo leading to complement consumption and consequently to a significantly reduced AP activity in vitro. The LP does not seem to play a role in the progression to severe COVID-19. Apart from its acute phase reaction the significance of C1INH in COVID-19 requires further studies.

Secondary Complement Deficiency Impairs Anti-Microbial Immunity to Klebsiella pneumoniae and Staphylococcus aureus During Severe Acute COVID-19

“…A loss of complement functional activity in sera of patients with severe COVID-19 has also been reported by Charitos et al. ( 53 ), showing a correlation between COVID-19 severity and a loss of complement functional activity via the classical and the alternative pathway. A study by Defendi et al.…”

Targeting thromboinflammation in COVID-19 – A narrative review of the potential of C1 inhibitor to prevent disease progression

“…Interestingly, a MASP-2 inhibitory monoclonal antibody was able to block this LP-mediated complement activation ( Ali et al, 2021 ). On the other hand, analyses of patient samples from our and other centers did not confirm an active role of the lectin pathway in disease progression to severe COVID-19 and pointed mainly towards an overactivated alternative pathway, at least in critically ill COVID-19 patients ( Charitos et al, 2021 , Sinkovits et al, 2021 ). In line, the S protein of SARS-CoV-2 was shown to directly activate the alternative pathway ( Yu et al, 2020 ), and recent data from Canadian ICU patients suggested markers of the alternative pathway to correlate with hypoxemia and predict in-hospital mortality, and a history of macular degeneration (often associated with complement-activating genetic polymorphisms in alternative pathway genes) was identified as risk factors for SARS-Cov-2-associated mortality ( Leatherdale et al, 2022 , Ramlall et al, 2020 ).…”

“…These haplotypes are often grouped according to their associated MBL protein concentrations into high, medium and low activity haplotypes. Conflicting results regarding the association of MBL activity and SARS-CoV-2 outcome have been reported ( Charitos et al, 2021 , Hultstrom et al, 2022 ; Stravalaci et al, 2022). Recently, Hultström M et al described a U-shaped association between MBL haplotypes and thrombotic complications/pulmonary embolism.…”

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

“…MBL levels in plasma were in general higher in COVID-19 patients compared with healthy controls [ 134 , 137 , 138 ]. Overactivation of the alternative pathway was observed as well, especially in critically ill COVID-19 patients [ 12 , 16 , 43 , 122 , 139 ]. In a prospective cohort study of 219 hospitalized COVID-19 patients, including those admitted to the ICU, increase in concentrations over time of C3a, C5a and factor Bb were associated with death [ 43 ].…”