McDunn Jonathan E, Husain Kareem D, Polpitiya Ashoka D, Burykin Anton, Ruan Jianhua, Li Qing, Schierding William, Lin Nan, Dixon David, Zhang Weixiong, Coopersmith Craig M, Dunne W Michael, Colonna Marco, Ghosh Bijoy K, Cobb J Perren
Center for Critical Illness and Health Engineering, Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA.
PLoS One. 2008 Feb 13;3(2):e1564. doi: 10.1371/journal.pone.0001564.
Diagnosis of acute infection in the critically ill remains a challenge. We hypothesized that circulating leukocyte transcriptional profiles can be used to monitor the host response to and recovery from infection complicating critical illness.
METHODOLOGY/PRINCIPAL FINDINGS: A translational research approach was employed. Fifteen mice underwent intratracheal injections of live P. aeruginosa, P. aeruginosa endotoxin, live S. pneumoniae, or normal saline. At 24 hours after injury, GeneChip microarray analysis of circulating buffy coat RNA identified 219 genes that distinguished between the pulmonary insults and differences in 7-day mortality. Similarly, buffy coat microarray expression profiles were generated from 27 mechanically ventilated patients every two days for up to three weeks. Significant heterogeneity of VAP microarray profiles was observed secondary to patient ethnicity, age, and gender, yet 85 genes were identified with consistent changes in abundance during the seven days bracketing the diagnosis of VAP. Principal components analysis of these 85 genes appeared to differentiate between the responses of subjects who did versus those who did not develop VAP, as defined by a general trajectory (riboleukogram) for the onset and resolution of VAP. As patients recovered from critical illness complicated by acute infection, the riboleukograms converged, consistent with an immune attractor.
CONCLUSIONS/SIGNIFICANCE: Here we present the culmination of a mouse pneumonia study, demonstrating for the first time that disease trajectories derived from microarray expression profiles can be used to quantitatively track the clinical course of acute disease and identify a state of immune recovery. These data suggest that the onset of an infection-specific transcriptional program may precede the clinical diagnosis of pneumonia in patients. Moreover, riboleukograms may help explain variance in the host response due to differences in ethnic background, gender, and pathogen. Prospective clinical trials are indicated to validate our results and test the clinical utility of riboleukograms.
对危重症患者进行急性感染的诊断仍然是一项挑战。我们推测,循环白细胞转录谱可用于监测宿主对危重症并发感染的反应以及从感染中恢复的情况。
方法/主要发现:采用了转化研究方法。15只小鼠接受气管内注射活的铜绿假单胞菌、铜绿假单胞菌内毒素、活的肺炎链球菌或生理盐水。在损伤后24小时,对循环血沉棕黄层RNA进行基因芯片微阵列分析,确定了219个基因,这些基因可区分肺部损伤以及7天死亡率的差异。同样,每两天从27名机械通气患者中获取血沉棕黄层微阵列表达谱,持续长达三周。由于患者的种族、年龄和性别,观察到呼吸机相关性肺炎(VAP)微阵列谱存在显著异质性,但在VAP诊断前后的七天内,确定了85个丰度有一致变化的基因。对这85个基因进行主成分分析,似乎可以区分发生VAP和未发生VAP的受试者的反应,这由VAP发生和消退的一般轨迹(核糖白细胞图)来定义。随着患者从并发急性感染的危重症中康复,核糖白细胞图趋同,这与免疫吸引子一致。
结论/意义:在此,我们展示了一项小鼠肺炎研究的成果,首次证明从微阵列表达谱得出的疾病轨迹可用于定量追踪急性疾病的临床进程并确定免疫恢复状态。这些数据表明,感染特异性转录程序的启动可能早于患者肺炎的临床诊断。此外,核糖白细胞图可能有助于解释由于种族背景、性别和病原体差异导致的宿主反应差异。需要进行前瞻性临床试验来验证我们的结果并测试核糖白细胞图的临床实用性。