Acute hypoxemic respiratory failure (HRF) is associated with high morbidity and mortality, but its heterogeneity challenges the identification of effective therapies. Defining subphenotypes with distinct prognoses or biologic features can improve therapeutic trials, but prior work has focused on ARDS, which excludes many acute HRF patients. We aimed to characterize persistent and resolving subphenotypes in the broader HRF population. In this secondary analysis of 2 independent prospective ICU cohorts, we included adults with acute HRF, defined by invasive mechanical ventilation and PaO2-to-FIO2 ratio ≤ 300 on cohort enrollment (n = 768 in the discovery cohort and n = 1715 in the validation cohort). We classified patients as persistent HRF if still requiring mechanical ventilation with PaO2-to-FIO2 ratio ≤ 300 on day 3 following ICU admission, or resolving HRF if otherwise. We estimated relative risk of 28-day hospital mortality associated with persistent HRF, compared to resolving HRF, using generalized linear models. We also estimated fold difference in circulating biomarkers of inflammation and endothelial activation on cohort enrollment among persistent HRF compared to resolving HRF. Finally, we stratified our analyses by ARDS to understand whether this was driving differences between persistent and resolving HRF. Over 50% developed persistent HRF in both the discovery (n = 386) and validation (n = 1032) cohorts. Persistent HRF was associated with higher risk of death relative to resolving HRF in both the discovery (1.68-fold, 95% CI 1.11, 2.54) and validation cohorts (1.93-fold, 95% CI 1.50, 2.47), after adjustment for age, sex, chronic respiratory illness, and acute illness severity on enrollment (APACHE-III in discovery, APACHE-II in validation). Patients with persistent HRF displayed higher biomarkers of inflammation (interleukin-6, interleukin-8) and endothelial dysfunction (angiopoietin-2) than resolving HRF after adjustment. Only half of persistent HRF patients had ARDS, yet exhibited higher mortality and biomarkers than resolving HRF regardless of whether they qualified for ARDS. Patients with persistent HRF are common and have higher mortality and elevated circulating markers of lung injury compared to resolving HRF, and yet only a subset are captured by ARDS definitions. Persistent HRF may represent a clinically important, inclusive target for future therapeutic trials in HRF.

中文翻译：

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两个独立队列中急性低氧血症性呼吸衰竭持续性和缓解性亚表型的鉴定


急性低氧性呼吸衰竭（HRF）与高发病率和死亡率相关，但其异质性对有效治疗的确定提出了挑战。定义具有不同预后或生物学特征的亚表型可以改善治疗试验，但之前的工作主要集中在 ARDS 上，这排除了许多急性 HRF 患者。我们的目的是表征更广泛的 HRF 人群中持续且可解决的亚表型。在对 2 个独立的前瞻性 ICU 队列进行的二次分析中，我们纳入了患有急性 HRF 的成人，定义为有创机械通气且队列入组时 PaO2 与 FIO2 比率≤ 300（发现队列中 n = 768 例，验证队列中 n = 1715 例）队列）。如果患者入院后第 3 天仍需要机械通气且 PaO2 与 FIO2 比率≤ 300，我们将患者归类为持续性 HRF；否则，我们将患者归类为解决 HRF。我们使用广义线性模型估算了与解决 HRF 相比，与持续 HRF 相关的 28 天医院死亡率的相对风险。我们还估计了持续性 HRF 与缓解性 HRF 队列入组时炎症和内皮激活循环生物标志物的倍数差异。最后，我们通过 ARDS 对分析进行分层，以了解这是否导致持续性 HRF 和解决性 HRF 之间存在差异。在发现组 (n = 386) 和验证组 (n = 1032) 中，超过 50% 的人出现了持续性 HRF。调整年龄后，在发现组（1.68 倍，95% CI 1.11, 2.54）和验证组（1.93 倍，95% CI 1.50, 2.47）中，持续 HRF 与解决 HRF 相关的死亡风险更高，性别、慢性呼吸道疾病和入组时的急性疾病严重程度（发现中的 APACHE-III，验证中的 APACHE-II）。 与调整后 HRF 消退的患者相比，持续性 HRF 患者显示出更高的炎症生物标志物（白细胞介素 6、白细胞介素 8）和内皮功能障碍（血管生成素 2）。只有一半的持续性 HRF 患者患有 ARDS，但无论他们是否符合 ARDS 的条件，其死亡率和生物标志物都比解决 HRF 更高。与解决 HRF 相比，持续性 HRF 患者很常见，死亡率更高，肺损伤循环标志物升高，但 ARDS 定义只捕获了一小部分患者。持续性 HRF 可能代表了未来 HRF 治疗试验的一个临床上重要的、包容性的目标。