Progranulin is a widely expressed pleiotropic growth factor with a central regulatory effect during the early immune response in sepsis. Progranulin signaling has not been systematically studied and compared between sepsis, community-acquired pneumonia (CAP), COVID-19 pneumonia and a sterile systemic inflammatory response (SIRS). We delineated molecular networks of progranulin signaling by next-generation sequencing (NGS), determined progranulin plasma concentrations and quantified the diagnostic performance of progranulin to differentiate between the above-mentioned disorders using the established biomarkers procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) for comparison. The diagnostic performance of progranulin was operationalized by calculating AUC and ROC statistics for progranulin and established biomarkers in 241 patients with sepsis, 182 patients with SIRS, 53 patients with CAP, 22 patients with COVID-19 pneumonia and 53 healthy volunteers. miRNAs and mRNAs in blood cells from sepsis patients (n = 7) were characterized by NGS and validated by RT-qPCR in an independent cohort (n = 39) to identify canonical gene networks associated with upregulated progranulin at sepsis onset. Plasma concentrations of progranulin (ELISA) in patients with sepsis were 57.5 (42.8–84.9, Q25–Q75) ng/ml and significantly higher than in CAP (38.0, 33.5–41.0 ng/ml, p < 0.001), SIRS (29.0, 25.0–35.0 ng/ml, p < 0.001) and the healthy state (28.7, 25.5–31.7 ng/ml, p < 0.001). Patients with COVID-19 had significantly higher progranulin concentrations than patients with CAP (67.6, 56.6–96.0 vs. 38.0, 33.5–41.0 ng/ml, p < 0.001). The diagnostic performance of progranulin for the differentiation between sepsis vs. SIRS (n = 423) was comparable to that of procalcitonin. AUC was 0.90 (95% CI = 0.87–0.93) for progranulin and 0.92 (CI = 0.88–0.96, p = 0.323) for procalcitonin. Progranulin showed high discriminative power to differentiate bacterial CAP from COVID-19 (sensitivity 0.91, specificity 0.94, AUC 0.91 (CI = 0.8–1.0) and performed significantly better than PCT, IL-6 and CRP. NGS and partial RT-qPCR confirmation revealed a transcriptomic network of immune cells with upregulated progranulin and sortilin transcripts as well as toll-like-receptor 4 and tumor-protein 53, regulated by miR-16 and others. Progranulin signaling is elevated during the early antimicrobial response in sepsis and differs significantly between sepsis, CAP, COVID-19 and SIRS. This suggests that progranulin may serve as a novel indicator for the differentiation between these disorders. Trial registration: Clinicaltrials.gov registration number NCT03280576 Registered November 19, 2015.

中文翻译：

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脓毒症、社区获得性细菌性肺炎和 COVID-19 中的颗粒蛋白前体信号传导：一项比较观察性研究

颗粒蛋白前体是一种广泛表达的多效性生长因子，在脓毒症的早期免疫反应中具有中枢调节作用。尚未对脓毒症、社区获得性肺炎 (CAP)、COVID-19 肺炎和无菌全身炎症反应 (SIRS) 之间的颗粒蛋白前体信号传导进行系统研究和比较。我们通过下一代测序 (NGS) 描绘了颗粒蛋白前体信号传导的分子网络，确定了颗粒蛋白前体的血浆浓度并量化了颗粒体蛋白前体的诊断性能，以使用已建立的生物标志物降钙素原 (PCT)、白细胞介素-6 (IL- 6) 和 C 反应蛋白 (CRP) 进行比较。通过计算颗粒蛋白前体的 AUC 和 ROC 统计数据并在 241 名败血症患者、182 名 SIRS 患者、53 名 CAP 患者、22 名 COVID-19 肺炎患者和 53 名健康志愿者中建立生物标志物，对颗粒蛋白原的诊断性能进行了操作。脓毒症患者（n = 7）血细胞中的 miRNA 和 mRNA 由 NGS 表征，并在独立队列（n = 39）中通过 RT-qPCR 验证，以鉴定与脓毒症发作时上调的颗粒蛋白前体相关的规范基因网络。脓毒症患者的颗粒蛋白前体 (ELISA) 血浆浓度为 57.5 (42.8–84.9, Q25–Q75) ng/ml，显着高于 CAP (38.0, 33.5–41.0 ng/ml, p < 0.001)、SIRS (29.0, 25.0–35.0 ng/ml, p < 0.001) 和健康状态 (28.7, 25.5–31.7 ng/ml, p < 0.001)。COVID-19 患者的颗粒蛋白前体浓度明显高于 CAP 患者（67.6、56.6-96.0 与 38.0、33.5-41.0 ng/ml，p < 0.001）。颗粒蛋白前体区分脓毒症与 SIRS（n = 423）的诊断性能与降钙素原的诊断性能相当。颗粒蛋白原的 AUC 为 0.90（95% CI = 0.87–0.93），降钙素原的 AUC 为 0.92（CI = 0.88–0.96，p = 0.323）。颗粒蛋白前体在区分细菌 CAP 与 COVID-19 方面表现出很高的辨别力（敏感性 0.91，特异性 0.94，AUC 0.91（CI = 0.8-1.0）并且表现明显优于 PCT、IL-6 和 CRP。NGS 和部分 RT-qPCR 确认显示免疫细胞的转录组网络，具有上调的颗粒蛋白前体和分拣蛋白转录物以及 Toll 样受体 4 和肿瘤蛋白 53，受 miR-16 等调节。颗粒蛋白前体信号在脓毒症的早期抗菌反应期间升高，并且在脓毒症、CAP、COVID-19 和 SIRS 之间存在显着差异。这表明颗粒蛋白前体可以作为区分这些疾病的新指标。试验注册：Clinicaltrials.gov 注册号 NCT03280576，2015 年 11 月 19 日注册。