Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Alabama at Birmingham and Children's of Alabama, Birmingham, AL, USA.
Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Hepatology. 2021 Jan;73(1):233-246. doi: 10.1002/hep.31271.
Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim was to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome.
Among 47 PALF study participants, 12 IAMs collected ≤6 days after enrollment were measured by flow cytometry and IMMULITE assay on blood natural killer and cluster of differentiation 8-positive (CD8 ) lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort using 4 of 12 IAMs which were available in all participants (percent perforin-positive and percent granzyme-positive CD8 cells, absolute number of CD8 cells, soluble interleukin-2 receptor level) were sufficient to define high (n = 10), medium (n = 15), and low IAM (n = 22) cohorts. High IAM was more frequent among those with indeterminate etiology than those with defined diagnoses (80% versus 20%, P < 0.001). High IAM was associated with higher peak serum total bilirubin levels than low IAM (median peak 21.7 versus 4.8 mg/dL, P < 0.001) and peak coma grades. The 21-day outcomes differed between groups, with liver transplantation more frequent in high IAM participants (62.5%) than those with medium (28.2%) or low IAM (4.8%) (P = 0.002); no deaths were reported. In an independent validation cohort (n = 71) enrolled in a prior study, segregation of IAM groups by etiology, initial biochemistries, and short-term outcomes was similar, although not statistically significant. High serum aminotransferases, total bilirubin levels, and leukopenia at study entry predicted a high immune activation profile.
Four circulating T-lymphocyte activation markers identify a subgroup of PALF participants with evidence of immune activation associated with a distinct clinical phenotype and liver transplantation; these biomarkers may identify PALF participants eligible for future clinical trials of early targeted immunosuppression.
免疫失调导致小儿急性肝衰竭（PALF）的发病机制。我们的目的是确定与特定临床表型和结果相关的 PALF 中的免疫激活标志物（IAM）。
在 47 名 PALF 研究参与者中，在入组后≤6 天内通过流式细胞术和 IMMULITE 测定收集了 12 个 IAM，这些 IAM 来自于血液自然杀伤和分化群 8 阳性（CD8）淋巴细胞，并进行了无监督层次分析。使用所有参与者中可用的 4 个 IAM（穿孔素阳性和颗粒酶阳性 CD8 细胞的百分比、CD8 细胞的绝对数、可溶性白细胞介素-2 受体水平）的衍生队列足以定义高（n=10）、中（n=15）和低 IAM（n=22）队列。不定原因组中高 IAM 的频率高于明确诊断组（80%比 20%，P<0.001）。高 IAM 与较高的血清总胆红素峰值水平相关，而与低 IAM 相比，高 IAM 的峰值更高（中位数峰值 21.7 比 4.8 mg/dL，P<0.001）和峰值昏迷程度。21 天的结果在各组之间有所不同，高 IAM 组中肝移植的频率更高（62.5%），而中 IAM 组（28.2%）和低 IAM 组（4.8%）（P=0.002）；没有死亡报告。在之前研究中招募的独立验证队列（n=71）中，病因、初始生物化学和短期结果的 IAM 分组分离相似，尽管没有统计学意义。研究入组时血清转氨酶、总胆红素水平和白细胞减少症升高预测高免疫激活谱。
四种循环 T 淋巴细胞激活标志物可识别出具有免疫激活证据的 PALF 参与者亚组，其与特定的临床表型和肝移植相关；这些生物标志物可能识别出适合未来早期靶向免疫抑制治疗 PALF 参与者的临床试验的生物标志物。
