Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.
Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.
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DOI：
10.1073/pnas.2010540117
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发表时间：
2020-10-06
影响因子：
11.1
通讯作者：
Mollnes TE
中科院分区：
文献类型：
--
作者：
Holter JC;Pischke SE;de Boer E;Lind A;Jenum S;Holten AR;Tonby K;Barratt-Due A;Sokolova M;Schjalm C;Chaban V;Kolderup A;Tran T;Tollefsrud Gjølberg T;Skeie LG;Hesstvedt L;Ormåsen V;Fevang B;Austad C;Müller KE;Fladeby C;Holberg-Petersen M;Halvorsen B;Müller F;Aukrust P;Dudman S;Ueland T;Andersen JT;Lund-Johansen F;Heggelund L;Dyrhol-Riise AM;Mollnes TE
新的SARS-CoV-2大流行导致COVID-19伴有呼吸衰竭、高发病率和高死亡率。固有免疫反应的过度激活被认为会引发这一有害的过程。补体系统在先天免疫中起着关键作用。尽管有一些关于局部补体激活的报道，但缺乏证据表明，系统性补体激活的程度在COVID-19患者中早期发生，以及这是否与呼吸衰竭有关。本研究表明，从入院和住院期间，一些补体激活产品系统地、一致地、持久地增加。值得注意的是，终末sC5b-9补体复合体与呼吸衰竭有关。因此，补体抑制是治疗covid -19的一种有吸引力的治疗方法。据推测，急性呼吸综合征冠状病毒2 （SARS-CoV-2）大流行中的呼吸衰竭是由过度反应的先天免疫反应驱动的，其中补体系统是关键角色。在这项针对39名住院冠状病毒病COVID-19患者的前瞻性队列研究中，我们描述了全身补体激活及其与呼吸衰竭发展的关系。入院时、第3 ~ 5天和第7 ~ 10天分别获取临床资料和生物样本。PO2/FiO2比值≤40 kPa为呼吸衰竭。采用酶免疫法分析经典/凝集素（C4d）、替代途径（C3bBbP）和共同途径（C3bc、C5a和sC5b-9）、凝集素途径识别分子MBL和抗体血清学的补体激活产物；通过PCR检测病毒载量。对照组包括健康的献血者。在住院期间，大多数COVID-19患者观察到持续增加的全身补体激活。入院时，有呼吸衰竭患者sC5b-9和C4d明显高于无呼吸衰竭患者（P = 0.008和P = 0.034）。Logistic回归显示sC5b-9患者发生呼吸衰竭的几率增加（优势比31.9,95% CI 1.4 ~ 746, P = 0.03）， C4d患者需要氧疗的几率增加（11.7,1.1 ~ 130,P = 0.045）。入院sC5b-9和C4d与铁蛋白显著相关（r = 0.64, P < 0.001; r = 0.69, P < 0.001）。C4d、sC5b-9和C5a与抗病毒抗体相关，但与病毒载量无关。系统性补体激活与COVID-19患者呼吸衰竭有关，为未来临床试验中研究补体抑制剂提供了依据。
The new SARS-CoV-2 pandemic leads to COVID-19 with respiratory failure, substantial morbidity, and significant mortality. Overactivation of the innate immune response is postulated to trigger this detrimental process. The complement system is a key player in innate immunity. Despite a few reports of local complement activation, there is a lack of evidence that the degree of systemic complement activation occurs early in COVID-19 patients, and whether this is associated with respiratory failure. This study shows that a number of complement activation products are systemically, consistently, and long-lastingly increased from admission and during the hospital stay. Notably, the terminal sC5b-9 complement complex was associated with respiratory failure. Thus, complement inhibition is an attractive therapeutic approach for treatment of COVD-19. Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.
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