Background

Patients with COVID-19-related acute respiratory distress syndrome (ARDS) have been postulated to present with distinct respiratory subphenotypes. However, most phenotyping schema have been limited by sample size, disregard for temporal dynamics, and insufficient validation. We aimed to identify respiratory subphenotypes of COVID-19-related ARDS using unbiased data-driven approaches.

Methods

PRoVENT–COVID was an investigator-initiated, national, multicentre, prospective, observational cohort study at 22 intensive care units (ICUs) in the Netherlands. Consecutive patients who had received invasive mechanical ventilation for COVID-19 (aged 18 years or older) served as the derivation cohort, and similar patients from two ICUs in the USA served as the replication cohorts. COVID-19 was confirmed by positive RT-PCR. We used latent class analysis to identify subphenotypes using clinically available respiratory data cross-sectionally at baseline, and longitudinally using 8-hourly data from the first 4 days of invasive ventilation. We used group-based trajectory modelling to evaluate trajectories of individual variables and to facilitate potential clinical translation. The PRoVENT-COVID study is registered with ClinicalTrials.gov, NCT04346342.

Findings

Between March 1, 2020, and May 15, 2020, 1007 patients were admitted to participating ICUs in the Netherlands, and included in the derivation cohort. Data for 288 patients were included in replication cohort 1 and 326 in replication cohort 2. Cross-sectional latent class analysis did not identify any underlying subphenotypes. Longitudinal latent class analysis identified two distinct subphenotypes. Subphenotype 2 was characterised by higher mechanical power, minute ventilation, and ventilatory ratio over the first 4 days of invasive mechanical ventilation than subphenotype 1, but PaO₂/FiO₂, pH, and compliance of the respiratory system did not differ between the two subphenotypes. 185 (28%) of 671 patients with subphenotype 1 and 109 (32%) of 336 patients with subphenotype 2 had died at day 28 (p=0·10). However, patients with subphenotype 2 had fewer ventilator-free days at day 28 (median 0, IQR 0–15 vs 5, 0–17; p=0·016) and more frequent venous thrombotic events (109 [32%] of 336 patients vs 176 [26%] of 671 patients; p=0·048) compared with subphenotype 1. Group-based trajectory modelling revealed trajectories of ventilatory ratio and mechanical power with similar dynamics to those observed in latent class analysis-derived trajectory subphenotypes. The two trajectories were: a stable value for ventilatory ratio or mechanical power over the first 4 days of invasive mechanical ventilation (trajectory A) or an upward trajectory (trajectory B). However, upward trajectories were better independent prognosticators for 28-day mortality (OR 1·64, 95% CI 1·17–2·29 for ventilatory ratio; 1·82, 1·24–2·66 for mechanical power). The association between upward ventilatory ratio trajectories (trajectory B) and 28-day mortality was confirmed in the replication cohorts (OR 4·65, 95% CI 1·87–11·6 for ventilatory ratio in replication cohort 1; 1·89, 1·05–3·37 for ventilatory ratio in replication cohort 2).

Interpretation

At baseline, COVID-19-related ARDS has no consistent respiratory subphenotype. Patients diverged from a fairly homogenous to a more heterogeneous population, with trajectories of ventilatory ratio and mechanical power being the most discriminatory. Modelling these parameters alone provided prognostic value for duration of mechanical ventilation and mortality.

Funding

Amsterdam UMC.

中文翻译：

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COVID-19 相关急性呼吸窘迫综合征患者的纵向呼吸亚型：来自三个观察队列的结果

背景

据推测，与 COVID-19 相关的急性呼吸窘迫综合征 (ARDS) 患者具有不同的呼吸亚型。然而，大多数表型模式都受到样本量、忽视时间动态和验证不足的限制。我们旨在使用无偏见的数据驱动方法来识别与 COVID-19 相关的 ARDS 的呼吸亚型。

方法

PRoVENT–COVID 是一项研究者发起的、全国性、多中心、前瞻性、观察性队列研究，在荷兰的 22 个重症监护病房 (ICU) 开展。连续接受 COVID-19 有创机械通气的患者（18 岁或以上）作为推导队列，来自美国两个 ICU 的类似患者作为复制队列。COVID-19 通过阳性 RT-PCR 得到证实。我们使用潜在类别分析来识别亚表型，使用基线时临床可用的横断面呼吸数据，并纵向使用有创通气前 4 天的 8 小时数据。我们使用基于组的轨迹建模来评估单个变量的轨迹并促进潜在的临床转化。PRoVENT-COVID 研究已在 ClinicalTrials.gov 注册，NCT04346342。

发现

2020 年 3 月 1 日至 2020 年 5 月 15 日期间，1007 名患者入住荷兰参与的 ICU，并纳入推导队列。复制队列 1 中包括 288 名患者的数据，复制队列 2 中包括 326 名患者的数据。横断面潜在类别分析未发现任何潜在的亚表型。纵向潜在类别分析确定了两种不同的亚表型。亚表型 2 的特点是在有创机械通气的前 4 天机械功率、分钟通气量和通气比高于亚表型 1，但 PaO ₂ /FiO ₂呼吸系统的 pH 值和顺应性在两种亚表型之间没有差异。671 名亚表型 1 患者中的 185 名 (28%) 和 336 名亚表型 2 患者中的 109 名 (32%) 在第 28 天死亡 (p=0·10)。然而，亚表型 2 患者在第 28 天的无呼吸机天数较少（中位数 0，IQR 0–15 vs 5, 0–17；p=0·016）和更频繁的静脉血栓事件（109 [32%] of 336患者对比671 名患者中的 176 名 [26%]；p=0·048) 与亚表型 1 相比。基于组的轨迹建模揭示了通气比和机械功率的轨迹，其动态特性与在潜在类分析衍生的轨迹亚表型中观察到的相似。两条轨迹是：有创机械通气前 4 天的通气比或机械功率稳定值（轨迹 A）或上升轨迹（轨迹 B）。然而，上升轨迹是更好的 28 天死亡率独立预测指标（通气比 OR 1·64，95% CI 1·17–2·29；机械功率 1·82，1·24–2·66）。向上通气比轨迹（轨迹 B）与 28 天死亡率之间的关联在重复队列中得到证实（OR 4·65，重复队列 1 中通气比的 95% CI 1·87–11·6；1·89，

解释

在基线时，与 COVID-19 相关的 ARDS 没有一致的呼吸亚表型。患者从相当同质的人群分化为更加异质的人群，其中通气比和机械功率的轨迹最具歧视性。单独对这些参数进行建模可为机械通气持续时间和死亡率提供预后价值。

资金

阿姆斯特丹联华电子。