Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA.
Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, PA.
Pediatr Crit Care Med. 2020 Dec;21(12):e1084-e1093. doi: 10.1097/PCC.0000000000002531.
To identify and compare serum and lower respiratory tract fluid biomarkers of lung injury using well-characterized mouse models of lung injury. To explore the relationship between these preclinical biomarkers and clinical outcomes in a discovery cohort of pediatric patients with acute respiratory failure from pneumonia.
Prospective, observational cohort study.
A basic science laboratory and the PICU of a tertiary-care children's hospital.
PICU patients intubated for respiratory failure from a suspected respiratory infection.
Prospective enrollment and collection of lower respiratory tract fluid samples.
C57BL6/J mice were intranasally inoculated with escalating doses of influenza A virus or toll-like receptor agonists to simulate varying degrees of lung injury. Serum and bronchoalveolar lavage fluid were measured for the presence of cytokines using commercially available multiplex cytokine assays. Elevated levels of C-C motif chemokine ligand 7 at the peak of inflammation in both bronchoalveolar lavage fluid and serum correlated with lethality, with the bronchoalveolar lavage fluid ratio of C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 providing the best prediction in the mouse models. These preclinical biomarkers were examined in the plasma and lower respiratory tract fluid of a discovery cohort of pediatric patients with acute respiratory failure from pneumonia. The primary clinical outcome measure was ventilator-free days, with secondary outcomes of pediatric acute respiratory distress syndrome severity and mortality. Elevation in peak lower respiratory tract fluid C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratios demonstrated a significant negative correlation with ventilator-free days (r = -0.805; p < 0.02).
This study provides evidence that lung immune profiling via lower respiratory tract fluid cytokine analysis is feasible and may provide insight into clinical outcomes. Further validation of markers, including the C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratio in this limited study, in a larger cohort of patients is necessary.
使用经过充分验证的肺损伤小鼠模型，鉴定和比较血清和下呼吸道液中的肺损伤生物标志物。探索这些临床前生物标志物与肺炎所致急性呼吸衰竭患儿发现队列中临床结局之间的关系。
前瞻性观察队列研究。
基础科学实验室和三级儿童医院的 PICU。
因疑似呼吸道感染而接受呼吸衰竭插管的 PICU 患者。
前瞻性入组和下呼吸道液样本采集。
C57BL6/J 小鼠经鼻内接种递增剂量的流感病毒或 Toll 样受体激动剂，以模拟不同程度的肺损伤。使用市售的多因子细胞因子检测试剂盒测量血清和支气管肺泡灌洗液中细胞因子的存在。在支气管肺泡灌洗液和血清中，炎症高峰期 C 型趋化因子配体 7 的水平升高与死亡率相关，支气管肺泡灌洗液中 C 型趋化因子配体 7 与 C 型趋化因子配体 22 的比值对小鼠模型的预测最佳。在肺炎所致急性呼吸衰竭的儿科患者发现队列的血浆和下呼吸道液中检查了这些临床前生物标志物。主要临床结局指标为无呼吸机天数，次要结局指标为儿科急性呼吸窘迫综合征严重程度和死亡率。下呼吸道液中 C 型趋化因子配体 7 与 C 型趋化因子配体 22 峰值比值升高与无呼吸机天数显著负相关（r = -0.805；p < 0.02）。
这项研究提供了证据，表明通过下呼吸道液细胞因子分析进行肺部免疫分析是可行的，并且可能对临床结局提供深入了解。需要在更大的患者队列中进一步验证标志物，包括在这项有限研究中的 C 型趋化因子配体 7 与 C 型趋化因子配体 22 的比值。
