■急性呼吸窘迫综合征(ARDS)是严重COVID-19的常见并发症,并导致患者的发病率和死亡率。ARDS是由各种侮辱引起的异质性综合征,并导致急性低氧性呼吸衰竭。来自COVID-19的ARDS患者可能代表ARDS患者的一个亚组,具有不同的分子谱,可驱动疾病结局。这里,我们假设纵向转录组分析可能在COVID-19ARDS过程中识别出不同的动态病理生物学途径。
■我们从现有的ICU生物储存库中确定了一个患者队列,并建立了三组进行比较:1)住院存活的COVID-19ARDS患者(COVID幸存者,n=4),2)住院期间未能存活的COVID-19ARDS患者(COVID非幸存者,n=5),和3)其他原因引起的ARDS患者作为对照组(ARDS对照,n=4)。在4个时间点(ICU入院后第1、3、7和10天)从外周血单核细胞(PBMC)中分离RNA,并通过批量RNA测序进行分析。
■我们首先在各个时间点比较了组间的转录组,并观察到差异表达基因(DEGs)的显着异质性。接下来,我们利用似然比检验来识别3组之间随时间变化的不同模式的基因,并在时间上识别出341个DEG,包括血红蛋白亚基α2(HBA1,HBA2),血红蛋白亚基β(HBB),血管性血友病因子C和EGF域(VWCE),和碳酸酐酶1(CA1),与COVID幸存者相比,COVID非幸存者均表现出持续的上调。在341个DEG中,314显示,与幸存者相比,COVID非幸存者的基因表达持续增加的模式相似,与铁稳态信号传导的经典途径相关,红细胞与氧气和二氧化碳的相互作用,促红细胞生成素信号,血红素生物合成,卟啉的代谢,以及铁的吸收和运输。
■这些发现描述了COVID-19ARDS幸存者和非幸存者在患者ICU过程中基因调控的显着差异。我们确定了表明血红素和红细胞代谢有助于疾病结局的多种途径。这种方法可推广到更大的队列,并支持ARDS分子谱分析研究中的纵向采样方法。这可能会发现新的可靶向的损伤和解决途径。
UNASSIGNED: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS.
UNASSIGNED: We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing.
UNASSIGNED: We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport.
UNASSIGNED: These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution.