Identifying organ dysfunction trajectory-based subphenotypes in critically ill patients with COVID-19

Su, C.; Xu, Z.; Hoffman, K.; Goyal, P.; Safford, M. M.; Lee, J.; Alvarez-Mulett, S.; Gomez-Escobar, L.; Price, D. R.; Harrington, J. S.; Torres, L. K.; Martinez, F. J.; Campion, T. R.; Kaushal, R.; Choi, A. M. K.; Wang, F.; Schenck, E. J.

Rationale. COVID-19-associated respiratory failure offers the unprecedented opportunity to evaluate the differential host response to a uniform pathogenic insult. Prior studies of Acute Respiratory Distress Syndrome (ARDS) have identified subphenotypes with differential outcomes. Understanding whether there are distinct subphenotypes of severe COVID-19 may offer insight into its pathophysiology. Objectives. To identify and characterize distinct subphenotypes of COVID-19 critical illness defined by the post-intubation trajectory of Sequential Organ Failure Assessment (SOFA) score. Methods. Intubated COVID-19 patients at two hospitals in New York city were leveraged as development and validation cohorts. Patients were grouped into mild, intermediate, and severe strata by their baseline post-intubation SOFA. Hierarchical agglomerative clustering was performed within each stratum to detect subphenotypes based on similarities amongst SOFA score trajectories evaluated by Dynamic Time Warping. Statistical tests defined trajectory subphenotype predictive markers. Measurements and Main Results. Distinct worsening and recovering subphenotypes were identified within each stratum, which had distinct 7-day post-intubation SOFA progression trends. Patients in the worsening suphenotypes had a higher mortality than those in the recovering subphenotypes within each stratum (mild stratum, 29.7% vs. 10.3%, p=0.033; intermediate stratum, 29.3% vs. 8.0%, p=0.002; severe stratum, 53.7% vs. 22.2%, p<0.001). Worsening and recovering subphenotypes were replicated in the validation cohort. Routine laboratory tests, vital signs, and respiratory variables rather than demographics and comorbidities were predictive of the worsening and recovering subphenotypes. Conclusions. There are clear worsening and recovering subphenotypes of COVID-19 respiratory failure after intubation, which are more predictive of outcomes than baseline severity of illness. Organ dysfunction trajectory may be well suited as a surrogate for research in COVID-19 respiratory failure.