Patients with COVID-19-related acute respiratory distress syndrome (ARDS) are assumed to have consistent respiratory subphenotypes at presentation. However, the results of a clinical trial recently reported in Lancet Respiratory Medicine have refuted that assumption.1 Notably, some questions have been raised regarding findings of the recently completed trial.2

The PRactice ­VENTilation in COVID-19 Patients (PRoVENT–COVID) trial ( Identifier: NCT04346342) was a national, investigator-initiated, multicenter, prospective, observational cohort study that followed 1007 patients admitted to 22 intensive care units (ICUs) in the Netherlands. The researchers found no statistical evidence of respiratory subphenotypes existing at the beginning of invasive mechanical ventilation or at cross-sectional analysis over the next 4 days. However, using time-dependent analysis, they discovered 2 distinct trajectories that developed during the initial 4 days of mechanical ventilation. These trajectories represent 2 distinct subphenotypes.1

The 2 trajectories were defined as trajectory A, a stable value for ventilatory ratio or mechanical power over the first 4 days of invasive mechanical ventilation; and  trajectory B, an upward trajectory showing increasing minute ventilation, higher mechanical power, and a greater ventilatory ratio. Upward trajectories were better independent predictors of 28-day mortality.1

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In all, 185 (28%) of 671 patients with subphenotype 1 and 109 (32%) of 336 patients with subphenotype 2 had died at day 28 (P =.10). Patients with subphenotype 2 had fewer ventilator-free days at day 28 (median 0, IQR, 0-15 vs 5, 0-17; P =.016) and more frequent venous thrombotic events (109 [32%] of 336 patients vs 176 [26%] of 671 patients; P =.048) compared with patients having subphenotype 1. Ventilatory ratio and mechanical power were the most discriminatory trajectories. Modelling these 2 parameters alone enabled the researchers to predict the duration of mechanical ventilation and mortality.1

The researchers concluded that, at baseline, patients with COVID-19-related ARDS have no consistent respiratory subphenotype. Over time, however, the patient population diverges from a homogenous to a more heterogeneous one. “This finding reveals the importance of including time as a key variable in future efforts towards subphenotyping COVID-19,” the researchers noted.1

The authors said theirs was the first study to systematically evaluate the existence of respiratory subphenotypes in patients with COVID-19-related ARDS using unbiased, data-driven, statistical methods. They found no earlier studies describing such subphenotypes in a multicenter setting.1

In a subsequent response to this reported research that was also published in Lancet Respiratory Medicine, another researcher acknowledged the study’s high quality but pointed to some potential shortcomings of the study, including the possible relation of phenotypes to treatment heterogeneity in ICUs and the researchers’ inability to study biomarkers—the chief determinants of previously investigated ARDS phenotypes.2

Disclosure: The primary author reports receipt of several grants unrelated to this research from non-industry sources.1


1. Bos LDJ, Sjoding M, Sinha P, et al; PRoVENT-COVID collaborative group. Longitudinal respiratory subphenotypes in patients with COVID-19-related acute respiratory distress syndrome: results from three observational cohorts. Lancet Respir Med. 2021;9(12):1377-1386. doi:10.1016/S2213-2600(21)00365-9

2. Lascarrou JB. COVID-19-related ARDS: one disease, two trajectories, and several unanswered questions. Lancet Respir Med. 2021;9(12):1345-1347. doi:10.1016/S2213-2600(21)00381-7