Complex immune deregulation in severe COVID-19: More than a mechanism of pathogenesis.
Complex immune deregulation in severe COVID-19: More than a mechanism of pathogenesis.
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DOI：
10.1016/j.ebiom.2021.103673
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发表时间：
2021-11
期刊：
影响因子：
11.1
通讯作者：
Giamarellos-Bourboulis EJ
中科院分区：
文献类型：
--
作者：
Giamarellos-Bourboulis EJ
在SARS-CoV-2(也称为新冠肺炎)大流行初期产生的印象是，严重的新冠肺炎是由于一场以白细胞介素6过度产生为主要特征的细胞因子风暴[1]。随着经验的积累和IL-6成为许多国家的常规生物标志物，人们认识到尽管IL-6升高，但并不能达到细胞因子风暴综合征(CS)的程度。CS又称巨噬细胞激活综合征(MAS)，具有高热、肝功能障碍、细胞减少和凝血障碍等临床特征，表现为迅速演变的器官功能障碍导致早期死亡[2]。感染性疾病，包括SARS-CoV-2，被认为是病因。然而，并不是所有严重新冠肺炎的患者都患有MAS。MAS使用美国风湿病学会推出的HScore进行分类，并对核心温度、细胞减少数量、器官肿大、天冬氨酸氨基转移酶、甘油三酯、纤维蛋白原、铁蛋白、免疫抑制病史和骨髓吞噬功能提供单独的评分[2]。HScore 169或以上对MAS的敏感性为82%。通过应用HScore作为诊断希腊细菌性败血症的金标准，将其分为一个测试和一个验证队列，并对109名瑞典患者中的一个队列进行测试，引入血清铁蛋白作为诊断工具；血清铁蛋白浓度高于ng/ml具有98%的特异度和97.1%的阴性预测值[3]。然而，只有3%到4%的参与者发现了MAS。在新冠肺炎流行之初，我们寻求在机械通气(MV)下治疗严重呼吸衰竭(SRF)患者的铁蛋白。我们还分离了外周血单个核细胞(PBMC)以刺激细胞因子的产生，并测定了CD14单核细胞表面人类白细胞抗原DR(人类白细胞DR)分子的数量。结果与细菌性社区获得性肺炎(CAP)和脓毒症患者进行比较；低于5000 mhla-DR被诊断为免疫抑制。在SRF患者中可识别出两种免疫学实体；25%的患者患有MAS，75%的患者患有低于5000 mhla-DR的复杂免疫失调(CID)。重症新冠肺炎的CID与脓毒症诱导的免疫抑制不同，因为PBMC维持其产生细胞因子的功能，主要是肿瘤坏死因子-α(TNFa)和IL-6；在脓毒症免疫抑制中，这一功能丧失[4]。来自挪威的一小群患者也描述了严重新冠肺炎患者的低mhla-DR[5]。这些发现被Bonnet等人的研究证实了。在当前的EBioMedicine文章中[6]。作者研究了134名接受MV治疗的SRF患者，将其分为2020年3月至6月和9月至11月两个时期，对应于法国新冠肺炎的前两波。这两个时期在护理标准(SOC)管理方面也不同，因为在康复试验结果之后的第二波患者的SOC中加入了地塞米松[7]。作者发现了CID的强烈特征，即低mhla-DR和中等水平的IL-6循环。不良结局与mhla-DR分子数低于5000和易发生二次感染有关。作者试图使其更适用于患者的常规评估，并介绍了IL-6/mhla-DR的系列测定。这一比率在前三天内高于18.1值，以及在第7天和第10天之间超过48.6时与…相关
The generated impression early at the beginning of the pandemic by SARS-CoV-2 (also called COVID-19) was that severe COVID-19 is due to a cytokine storm with the over-production of interleukin (IL)-6 as the predominant feature [1]. As more and more experience was acquired and IL-6 became a routine biomarker in many countries, it was realized that although IL-6 was increased this was not at the extent found in cytokine storm syndrome (CSS). CSS, also known as macrophage activation syndrome (MAS), bears clinical features of high fever, hepatic dysfunction, cytopenias and coagulopathy and is manifested by rapidly evolving organ dysfunction leading to early death (2). Infectious disorders, amongst which SARS-CoV-2, are considered aetiological factors. However, not all patients with severe COVID-19 are suffering from MAS. MAS is classified using the HScore introduced by the American College of Rheumatology and provides separate scoring for core temperature, number of cytopenias, organomegaly, aspartate aminostransferase, triglycerides, fibrinogen, ferritin, history of immunosuppression and bone marrow hemophagocytosis [2]. HScore 169 or more is linked with 82% sensitivity for MAS. By applying the HScore as gold standard for diagnosis in 5121 Greek patients with bacterial sepsis split into one test and one validation cohorts and by also testing one cohort of 109 Swedish patients, serum ferritin was introduced as diagnostic tool; serum concentrations above 4420 ng/ml had 98% specificity and 97.1% negative predictive value [3]. However, MAS was found in only 3 to 4% of participants. At the beginning of COVID-19 pandemic, we sought for ferritin in patients with severe respiratory failure (SRF) under mechanical ventilation (MV). We also isolated peripheral blood mononuclear cells (PBMCs) for stimulation for cytokine production and we measured the number of HLA-DR (Human leukocyte Antigen DR) molecules on CD14-monocytes (mHLA-DR). Results were compared to patients with bacterial community-acquired pneumonia (CAP) and sepsis; less than 5000 mHLA-DR was diagnostic of immunosuppression. Two immunological entities were recognized in patients with SRF; 25% had MAS and 75% had complex immune dysregulation (CID) with less than 5000 mHLA-DR. The CID of severe COVID-19 was distinct from sepsis-induced immunosuppression since PBMCs maintained their functionality for cytokine production, mainly for tumour necrosis factor-alpha (TNFa) and IL-6; in sepsis immunosuppression this functionality was lost [4]. Low mHLA-DR in severe COVID-19 has also been described in a small cohort of patients from Norway [5]. These findings were solidified by the study of Bonnet et al. in the current article of EBioMedicine [6]. The authors studied a cohort of 134 patients with SRF under MV split into two periods, March-June and September-November 2020, corresponding to the first two waves of COVID-19 in France. The two periods were also different regarding the standard-of-care (SOC) management since dexamethasone was added in the SOC of patients in the second wave following the results of the RECOVERY trial [7]. The authors identified strong traits of CID ie low mHLA-DR and moderate circulating levels of IL-6. Unfavourable outcome was associated with less than 5000 molecules of mHLA-DR and predisposition for secondary infections. The authors tried to make this more applicable for the routine evaluation of patients and introduced the serial measurement of the ratio of IL-6 to mHLA-DR. Values of this ratio above 18.1, within the first three days, and above 48.6 between days 7 and 10 were associated …
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影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
13.3
作者：
Fardet, Laurence;Galicier, Lionel;Hejblum, Gilles
通讯作者：
Hejblum, Gilles
影响因子：
9.3
作者：
Kyriazopoulou E;Leventogiannis K;Norrby-Teglund A;Dimopoulos G;Pantazi A;Orfanos SE;Rovina N;Tsangaris I;Gkavogianni T;Botsa E;Chassiou E;Kotanidou A;Kontouli C;Chaloulis P;Velissaris D;Savva A;Cullberg JS;Akinosoglou K;Gogos C;Armaganidis A;Giamarellos-Bourboulis EJ;Hellenic Sepsis Study Group
通讯作者：
Hellenic Sepsis Study Group
DOI：
10.1016/j.medj.2021.09.003
发表时间：
2021-10-08
期刊：
Med (New York, N.Y.)
影响因子：
--
作者：
van Laarhoven A;Kurver L;Overheul GJ;Kooistra EJ;Abdo WF;van Crevel R;Duivenvoorden R;Kox M;Ten Oever J;Schouten J;van de Veerdonk FL;van der Hoeven H;Rahamat-Langendoen J;van Rij RP;Pickkers P;Netea MG
通讯作者：
Netea MG
影响因子：
158.5
作者：
Horby, Peter;Lim, Wei Shen;Landray, Martin J.
通讯作者：
Landray, Martin J.