Supplementary Material for: ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients

Background: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. Methods: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. Results: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. Conclusion: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

背景：新型冠状病毒肺炎（COVID-19）患者并发急性呼吸窘迫综合征（ARDS，acute respiratory distress）的常见潜在诱因是巨噬细胞活化样综合征（Macrophage activation-like syndrome, MALS）与复杂性免疫失调（complex immune dysregulation, CID）。本研究旨在探讨个性化免疫治疗对重症COVID-19患者临床转归的改善作用。
方法：本研究为开放标签前瞻性临床试验，共纳入102例经严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染引发ARDS的患者，按临床指标分层筛查出MALS患者（铁蛋白＞4420 ng/mL）与CID患者（铁蛋白≤4420 ng/mL，且CD14+单核细胞表面人类白细胞抗原（human leukocyte antigen, HLA）-DR表达降低）。合并氨基转移酶升高的MALS或CID患者接受静脉注射阿那白滞素治疗；CID且氨基转移酶水平正常的患者则予以托珠单抗治疗。本研究的主要终点为第8天时序贯器官衰竭评分（Sequential Organ Failure Assessment, SOFA）较基线下降≥25%，或呼吸比值升高≥50%；次要终点包括28天死亡率、第28天时SOFA评分变化、血清生物标志物水平以及单核细胞的细胞因子生成能力。
结果：阿那白滞素治疗组中58.3%的患者达成主要研究终点，托珠单抗治疗组的达标率为33.3%（P=0.01）。两组多数患者均接受了作为标准治疗的地塞米松。组间在次要终点、死亡率及SOFA评分变化方面均未观察到显著差异。阿那白滞素治疗组患者的血清铁蛋白水平有所下降；托珠单抗治疗组患者的白细胞介素-6、可溶性尿激酶型纤溶酶原激活物受体水平及CD14+单核细胞HLA-DR表达均有所升高。第28天时仍存活的阿那白滞素治疗患者，在世界卫生组织（WHO）临床进展量表中分布于更低的严重程度层级。托珠单抗治疗组的继发感染发生率更高。
结论：免疫评估结果显示，重症COVID-19合并MALS特征的患者对阿那白滞素治疗应答良好。