Mechanisms underlying the SARS-CoV-2-triggered hyperacute thrombo-inflammatory response that causes multi-organ damage in coronavirus disease 2019 (COVID-19) are poorly understood. Several lines of evidence implicate overactivation of complement. To delineate the involvement of complement in COVID-19, we prospectively studied 25 ICU-hospitalized patients for up to 21 days. Complement biomarkers in patient sera and healthy controls were quantified by enzyme-linked immunosorbent assays. Correlations with respiratory function and mortality were analyzed. Activation of complement via the classical/lectin pathways was variably increased. Strikingly, all patients had increased activation of the alternative pathway (AP) with elevated levels of activation fragments, Ba and Bb. This was associated with a reduction of the AP negative regulator, factor (F) H. Correspondingly, terminal pathway biomarkers of complement activation, C5a and sC5b-9, were significantly elevated in all COVID-19 patient sera. C5a and AP constituents Ba and Bb, were significantly associated with hypoxemia. Ba and FD at the time of ICU admission were strong independent predictors of mortality in the following 30 days. Levels of all complement activation markers were sustained throughout the patients’ ICU stays, contrasting with the varying serum levels of IL-6, C-reactive protein, and ferritin. Severely ill COVID-19 patients have increased and persistent activation of complement, mediated strongly via the AP. Complement activation biomarkers may be valuable measures of severity of lung disease and the risk of mortality. Large-scale studies will reveal the relevance of these findings to thrombo-inflammation in acute and post-acute COVID-19.

SARS-CoV-2 引发的超急性血栓炎症反应导致 2019 年冠状病毒病 (COVID-19) 中的多器官损伤的机制知之甚少。几条证据表明补体过度激活。为了描述补体在 COVID-19 中的作用，我们对 25 名 ICU 住院患者进行了长达 21 天的前瞻性研究。通过酶联免疫吸附测定对患者血清和健康对照中的补体生物标志物进行量化。分析了与呼吸功能和死亡率的相关性。通过经典/凝集素途径的补体激活不同程度地增加。引人注目的是，所有患者的旁路途径 (AP) 激活增加，激活片段 Ba 和 Bb 水平升高。这与 AP 负调节因子 (F) H 的减少有关。相应地，补体激活的终末通路生物标志物 C5a 和 sC5b-9 在所有 COVID-19 患者血清中均显着升高。C5a 和 AP 成分 Ba 和 Bb 与低氧血症显着相关。入住 ICU 时的 Ba 和 FD 是接下来 30 天内死亡率的强独立预测因子。所有补体激活标志物的水平在患者入住 ICU 期间均保持不变，这与不同的血清 IL-6、C 反应蛋白和铁蛋白水平形成对比。重症 COVID-19 患者的补体激活增加且持续存在，通过 AP 强烈介导。补体激活生物标志物可能是衡量肺部疾病严重程度和死亡风险的重要指标。