Derivation and validation of clinical phenotypes and associated treatment responses in critically ill COVID-19 patients

ABSTRACT

Introduction: Due to variability in the host response, a uniform treatment strategy for severe COVID-19 may be inadequate. We applied unsupervised clustering methods to large cohorts of COVID-19 ICU patients to derive and validate clinical phenotypes, and to explore treatment responses in these phenotypes. Method(s) Phenotypes were derived in 13.279 critically ill COVID-19 patients admitted to 82 Dutch ICUs from September 2020 to February 2022. Twenty-one features were selected from clinical characteristics measured within 24 h after ICU admission. Phenotypes were assigned using consensus k means clustering. External validation was performed in 6225 critically ill COVID-19 patients admitted to 55 Spanish ICUs from February 2020 to December 2021. Individual patient data on corticosteroids therapy enabled us to investigate phenotype-specific responses in this cohort. Result(s) Three distinct clinical phenotypes were derived (Fig. 1A). Patients with phenotype 1 (43%) were younger, had lower APACHE IV scores, higher BMI as well as a lower P/F ratio and 90-day in-hospital mortality (18%, Fig. 1A). Phenotype 2 patients (37%) were older and had slightly higher APACHE IV scores compared with phenotype 1, a lower BMI, and higher mortality compared to phenotype 1 (24%, p = 2.95e-07). Phenotype 3 (20%) included the oldest patients with the most comorbidities and highest APACHE IV scores, severe renal and metabolic impairment, and the worst outcome (47% mortality, p = 6.6e-16 and p = 6.6e-16 versus phenotypes 1 and 2, respectively). Phenotype distribution and outcome were very similar in the validation cohort (Fig. 1B). This cohort also revealed that corticosteroid therapy only benefited phenotype 3 (65% vs. 54% mortality, p = 2.5e-03, Fig. 1C). Conclusion(s) COVID-19 ICU phenotypes based on clinical data are related to outcome and treatment responses. This can inform treatment decisions as well as randomized trials employing precision medicine approaches.