Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design
Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design
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DOI：
10.1164/rccm.201512-2544cp
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发表时间：
2016-07-15
影响因子：
24.7
通讯作者：
Liu, Vincent X.
中科院分区：
文献类型：
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作者：
Prescott, Hallie C.;Calfee, Carolyn S.;Liu, Vincent X.
过去几十年的质量改进和临床研究工作都集中在脓毒症和急性呼吸窘迫综合征（ARDS）的共识定义上。尽管基于现成临床数据的临床定义对广泛的支持性治疗有较高的认识和及时使用，但它们可能会阻碍识别更有针对性的治疗方法，这些治疗方法可以操纵危重疾病背后的特定生物机制。脓毒症和急性呼吸窘迫综合征从定义上来说是异质的，患者的基础生物学和疾病严重程度各不相同。我们长期以来一直能够识别脓毒症和急性呼吸窘迫综合征的亚型，从而赋予不同的预后。关键是我们现在即将确定可能对治疗产生不同反应的亚型。从这个角度来看，受到 2015 年美国胸科学会国际会议题为“肿块和分裂：危重疾病表型分析”研讨会的启发，我们重点介绍了揭示患者亚型的有前景的方法，这些亚型可以预测治疗反应，而不仅仅是预后差异。然后，我们讨论如何通过使用预测丰富和其他设计策略来利用这些信息来提高临床试验的成功率和可转化性。最后，我们讨论了识别生物标志物和内型并将其纳入常规临床实践的挑战和局限性。
Both quality improvement and clinical research efforts over the past fewdecades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.