PDF(Pubmed)
Abstract：
UNASSIGNED: Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, there is no curative intent therapy able to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerging neutrophil heterogeneity, the study of subsets of circulating NET-forming neutrophils [NET + Ns] as mediators of multi-organ failure progression among patients with COVID-19 is critical to identification of therapeutic targets.
UNASSIGNED: We conducted a prospective observational study of circulating levels of CD11b + [NET + N] immunotyped for dual endothelin-1/signal peptide receptor (DEspR ±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)-ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET + N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted.
UNASSIGNED: Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA (rho r S = 0.80) and ICUFD (r S = -0.76); circulating DEspR + [NET + Ns] with t1-SOFA (r S = 0.71), t2-SOFA (r S = 0.62), and ICUFD (r S = -0.63), and ANC with t1-SOFA (r S = 0.71), and t2-SOFA (r S = 0.61).Causal mediation analysis identified DEspR + [NET + Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR + [NET + Ns] were theoretically reduced to zero. Concordantly, DEspR + [NET + Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR + [NET + Ns] were reduced to zero. In patients with t1-SOFA > 1, the indirect effect of a hypothetical treatment eliminating DEspR + [NET + Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR + [NET + Ns], and no significant mediation of SOFA-score through ANC.
UNASSIGNED: Despite equivalent correlations, DEspR + [NET + Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR + [NET + Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19.
UNASSIGNED: The online version contains supplementary material available at 10.1186/s41231-023-00143-x.
UNASSIGNED: We conducted a prospective observational study of circulating levels of CD11b + [NET + N] immunotyped for dual endothelin-1/signal peptide receptor (DEspR ±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)-ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET + N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted.
UNASSIGNED: Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA (rho r S = 0.80) and ICUFD (r S = -0.76); circulating DEspR + [NET + Ns] with t1-SOFA (r S = 0.71), t2-SOFA (r S = 0.62), and ICUFD (r S = -0.63), and ANC with t1-SOFA (r S = 0.71), and t2-SOFA (r S = 0.61).Causal mediation analysis identified DEspR + [NET + Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR + [NET + Ns] were theoretically reduced to zero. Concordantly, DEspR + [NET + Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR + [NET + Ns] were reduced to zero. In patients with t1-SOFA > 1, the indirect effect of a hypothetical treatment eliminating DEspR + [NET + Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR + [NET + Ns], and no significant mediation of SOFA-score through ANC.
UNASSIGNED: Despite equivalent correlations, DEspR + [NET + Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR + [NET + Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19.
UNASSIGNED: The online version contains supplementary material available at 10.1186/s41231-023-00143-x.
摘要：
■累积研究表明，在严重的COVID-19中，中性粒细胞和中性粒细胞胞外陷阱（NETs）与不良预后相关。然而,到目前为止,目前尚无治愈性治疗能够阻断中性粒细胞/NETs介导的多器官功能障碍进展.由于中性粒细胞异质性的出现，在COVID-19患者中，循环形成NET的中性粒细胞[NET+Ns]亚群作为多器官衰竭进展的介质的研究对于确定治疗靶点至关重要。
■我们通过定量免疫荧光细胞学和因果介导分析对双重内皮素-1/信号肽受体（DEspR±）表达进行了CD11b[NETN]免疫分型的循环水平进行了前瞻性观察研究。在2020年5月至9月因MOD-重度COVID-19住院的36名同意成年人中，我们在时间点t1（ICU/入院后平均5.5天）和t2（ICU出院或死亡前一天）通过SOFA评分测量急性多器官衰竭，并通过SaO2/FiO2（SF）比率测量呼吸衰竭，第28天无ICU天数（ICUFD）。在t1时测量循环中性粒细胞绝对计数（ANC）和[NETN]子集特异性计数。进行了Spearman相关性和因果中介分析。
■Spearman相关性分析显示t1-SOFA与t2-SOFA（rhorS=0.80）和ICUFD（rS=-0.76）的相关性；循环DEspR[NETNs]与t1-SOFA（rS=0.71）的相关性，t2-SOFA(rS=0.62)，和ICUFD(rS=-0.63)，和具有t1-SOFA(rS=0.71)的ANC，和t2-SOFA(rS=0.61)。因果中介分析确定DEspR[NETNs]为t1-SOFA（暴露）和t2-SOFA（结果）之间因果路径的44.1%[95%CI：16.5,110.6]的中介，当DEspR+[NET+Ns]理论上降低到零时，消除了46.9%[15.8,124.6]。和谐地，DEspR+[NET+Ns]将t1-SOFA的47.1%[22.0,72.3%]介导到ICUFD因果路径，如果DEspR+[NET+Ns]降低到零，则消除51.1%[22.8,80.4%]。在t1-SOFA>1的患者中，消除DEspR[NETNs]的假设治疗的间接效果预计t2-SOFA减少0.98[0.29,2.06]点，ICUFD减少3.0[0.85,7.09]天。相比之下,通过DESPR+[NET+Ns]，SF比率没有显著的中介作用，SOFA评分通过ANC没有显著的中介作用。
■尽管有等效的相关性，DEspR+[NET+Ns]，但不是非国大,急性COVID-19多器官衰竭的介导进展，其假设的减少预计将改善ICUFD。这些转化发现需要进一步研究DEspR+[NET+Ns]作为COVID-19多器官衰竭的潜在患者分层和可行的治疗靶标。
■在线版本包含补充材料，可在10.1186/s41231-023-00143-x获得。
■我们通过定量免疫荧光细胞学和因果介导分析对双重内皮素-1/信号肽受体（DEspR±）表达进行了CD11b[NETN]免疫分型的循环水平进行了前瞻性观察研究。在2020年5月至9月因MOD-重度COVID-19住院的36名同意成年人中，我们在时间点t1（ICU/入院后平均5.5天）和t2（ICU出院或死亡前一天）通过SOFA评分测量急性多器官衰竭，并通过SaO2/FiO2（SF）比率测量呼吸衰竭，第28天无ICU天数（ICUFD）。在t1时测量循环中性粒细胞绝对计数（ANC）和[NETN]子集特异性计数。进行了Spearman相关性和因果中介分析。
■Spearman相关性分析显示t1-SOFA与t2-SOFA（rhorS=0.80）和ICUFD（rS=-0.76）的相关性；循环DEspR[NETNs]与t1-SOFA（rS=0.71）的相关性，t2-SOFA(rS=0.62)，和ICUFD(rS=-0.63)，和具有t1-SOFA(rS=0.71)的ANC，和t2-SOFA(rS=0.61)。因果中介分析确定DEspR[NETNs]为t1-SOFA（暴露）和t2-SOFA（结果）之间因果路径的44.1%[95%CI：16.5,110.6]的中介，当DEspR+[NET+Ns]理论上降低到零时，消除了46.9%[15.8,124.6]。和谐地，DEspR+[NET+Ns]将t1-SOFA的47.1%[22.0,72.3%]介导到ICUFD因果路径，如果DEspR+[NET+Ns]降低到零，则消除51.1%[22.8,80.4%]。在t1-SOFA>1的患者中，消除DEspR[NETNs]的假设治疗的间接效果预计t2-SOFA减少0.98[0.29,2.06]点，ICUFD减少3.0[0.85,7.09]天。相比之下,通过DESPR+[NET+Ns]，SF比率没有显著的中介作用，SOFA评分通过ANC没有显著的中介作用。
■尽管有等效的相关性，DEspR+[NET+Ns]，但不是非国大,急性COVID-19多器官衰竭的介导进展，其假设的减少预计将改善ICUFD。这些转化发现需要进一步研究DEspR+[NET+Ns]作为COVID-19多器官衰竭的潜在患者分层和可行的治疗靶标。
■在线版本包含补充材料，可在10.1186/s41231-023-00143-x获得。
