Journal Article

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

Bassetti, Stefano, Heijnen, Ingmar A. F. M., Charitos, Panteleimon, Osthoff, Michael, Egli, Adrian, Trendelenburg, Marten

2021

Overview

Although 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. In 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. The 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. Our results point to an overactivated AP in critically ill COVID-19 patients leading to complement consumption and consequently to a significantly reduced AP activity 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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Adult / Aged / Alternative pathway / Autopsy / C1 esterase inhibitor / Classical pathway / Clinical outcomes / Cohort analysis / Comorbidity / Complement activation / Complement C1 Inhibitor Protein - immunology / Complement system / Complement System Proteins - immunology / COVID-19 / COVID-19 - blood / COVID-19 - immunology / COVID-19 - mortality / COVID-19 - therapy / Critical Illness / Death / Epidemics / Female / Hospital Mortality / Hospitalization / Humans / Immunology / Infections / inflammation / Laboratories / Lectins / Lectins - immunology / Lungs / Male / Mannose / Mannose-binding lectin / Mechanical ventilation / Middle Aged / Mortality / Patients / Prospective Studies / Respiration, Artificial / Respiratory failure / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Severity of Illness Index / Software / Statistical analysis / Variables / Ventilators