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.
Highlights
In December 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China
Given the paucity of data regarding the lectin pathway of complement in SARS-CoV-2 infection, we aimed to investigate serum concentrations of two important pattern-recognition receptors (PRR) of the LP and of its predominant inhibitor (i.e. C1 esterase inhibitor (C1INH)) as well as to clarify the role of complement pathway activities in a well-characterized cohort of COVID-19 patients with respect to severity and outcome
Patients who deteriorated with a C-reactive protein (CRP) above 70 mg/L and/or progressive lung involvement on repeat chest computed tomography (CT) scan were treated with tocilizumab (8 mg/kg body weight up to 800 mg with a repeat dose after 24 to 48 hours if required) on a compassionate use basis
Summary
In December 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. The clinical spectrum of COVID-19 ranges from asymptomatic carriers to respiratory failure requiring respiratory support in the intensive care unit (ICU). In the latter setting, a dysregulated immune response characterized by a decrease in suppressor T cell counts, excessive release of pro-inflammatory cytokines, and activation of several inflammatory cascades including the contact activation, coagulation and complement cascade, contributes to the observed organ dysfunction [2,3,4]
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