Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7–8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.

正确管理COVID-19有助于更好地了解疾病的发病机理。初始症状发作后7-8天，临床突然恶化表明，COVID-19中的严重呼吸衰竭（SRF）是由独特的免疫功能障碍引起的。我们研究了54例COVID-19患者的免疫反应，其中28例患有SRF。所有患有SRF的患者均表现出巨噬细胞活化综合征（MAS）或极低的人类白细胞抗原D相关（HLA-DR）表达，并伴有CD4淋巴细胞，CD19淋巴细胞和自然杀伤（NK）细胞的大量消耗。循环单核细胞产生的肿瘤坏死因子-α（TNF-α）和白细胞介素6（IL-6）得以持续，这种模式不同于细菌性败血症或流感。SARS-CoV-2患者血浆抑制HLA-DR表达，IL-6阻滞剂Tocilizumab可以部分恢复这种作用；病人的标签外Tocilizumab治疗伴随着循环淋巴细胞的增加。因此，重度COVID-19中免疫失调的独特模式的特征在于IL-6介导的低HLA-DR表达和淋巴细胞减少，与持续的细胞因子产生和过度炎症有关。