严重 COVID-19 中肺纤维化的分子机制和治疗反应。

Molecular mechanisms and treatment responses of pulmonary fibrosis in severe COVID-19.

机构信息

Department of Intensive Care Medicine, Radboud University Medical Center, Postbus 9101, 6500 HB, Nijmegen, The Netherlands.

Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.

出版信息

Respir Res. 2023 Aug 9;24(1):196. doi: 10.1186/s12931-023-02496-1.

BACKGROUND

Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients.

METHODS

We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA- (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts.

RESULTS

Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4, PDE4D, MMP8, CRISP3, and BCL2L15. Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay (pre-DEXA: 42 [29-49] vs. 18 [13-27] days, p < 0.001; DEXA: 42 [28-57] vs. 13 [7-24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes.

CONCLUSIONS

ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.

背景

2019 年冠状病毒病（COVID-19）患者可发展为肺纤维化（PF），这与预后不良有关。我们评估了与 PF 相关的特定白细胞转录组谱，并研究了早期地塞米松（DEXA）治疗对危重症 COVID-19 患者 PF 临床病程的影响。

方法

我们对入住重症监护病房（ICU）的 191 例 COVID-19 患者进行了前后设计研究，分为两个治疗队列：DEXA 前（n=67）和 DEXA 后（n=124）。PF 通过影像学发现、通气参数恶化和循环 PIIINP 水平升高来确定。对 52 例 DEXA 前患者进行了 RNA 测序的纵向转录组谱分析。在两个队列中，我们分析了 PF 患者和非 PF 患者之间泼尼松治疗对临床纤维化参数和结局的影响。

结果

与非 PF 患者相比，PF 患者的转录组分析显示炎症、凝血和中性粒细胞细胞外陷阱相关途径上调。涉及的关键基因包括 PADI4、PDE4D、MMP8、CRISP3 和 BCL2L15。在特发性肺纤维化患者的外部队列中，几个已确定途径的富集与生存不良相关。在泼尼松治疗后，PF 相关的特征向非 PF 组观察到的特征逆转。同样，PIIINP 水平在泼尼松治疗后显著降低。DEXA 前和 DEXA 队列的 PF 发生率分别为 28%和 25%（p=0.61）。DEXA 前组 ICU 住院时间（42[29-49] vs. 18[13-27]天，p<0.001；DEXA 组：42[28-57] vs. 13[7-24]天，p<0.001）和死亡率（DEXA 前组：47% vs. 15%，p=0.009；DEXA 组：61% vs. 19%，p<0.001）在 PF 组中均高于非 PF 组。在两个队列中，DEXA 前和 DEXA 治疗组的 PF 患者 ICU 住院时间和死亡率均较高。早期地塞米松治疗并未影响这些结局。