• Niklas Bruse, Anna Motos, Rombout van Amstel, Eckart de Bie, Emma J Kooistra, Aron Jansen, Dirk van Lier, Jason Kennedy, Daniel Schwarzkopf, Daniel Thomas-Rüddel, Jesus F Bermejo-Martin, Ferran Barbe, Nicolette F de Keizer, Michael Bauer, Johannes G van der Hoeven, Antoni Torres, Christopher Seymour, Lonneke van Vught, Peter Pickkers, and Matthijs Kox.
• Department of Intensive Care Medicine, Radboud university medical center, Nijmegen, The Netherlands.
• Intensive Care Med. 2024 Nov 1; 50 (11): 188418961884-1896.

PurposeDisease heterogeneity in coronavirus disease 2019 (COVID-19) may render the current one-size-fits-all treatment approach suboptimal. We aimed to identify and immunologically characterize clinical phenotypes among critically ill COVID-19 patients, and to assess heterogeneity of corticosteroid treatment effect.MethodsWe applied consensus k-means clustering on 21 clinical parameters obtained within 24 h after admission to the intensive care unit (ICU) from 13,279 COVID-19 patients admitted to 82 Dutch ICUs from February 2020 to February 2022. Derived phenotypes were reproduced in 6225 COVID-19 ICU patients from Spain (February 2020 to December 2021). Longitudinal immunological characterization was performed in three COVID-19 ICU cohorts from the Netherlands and Germany, and associations between corticosteroid treatment and survival were assessed across phenotypes.ResultsWe derived three phenotypes: COVIDICU1 (43% of patients) consisted of younger patients with the lowest Acute Physiology And Chronic Health Evaluation (APACHE) scores, highest body mass index (BMI), lowest PaO2/FiO2 ratio, and a 90-day in-hospital mortality rate of 18%. COVIDICU2 patients (37%) had the lowest BMI, were older and had higher APACHE scores and mortality rate (24%) than COVIDICU1. Patients with COVIDICU3 (20%) were the eldest with the most comorbidities, the highest APACHE scores, acute kidney injury and metabolic dysregulations, and the highest mortality rate (47%). These patients also displayed the most pronounced inflammatory response. Corticosteroid therapy started at day 5 [2-9] after ICU admission and administered for 5 [3-7] days was associated with an increased risk for 90-day mortality in patients with the COVIDICU1 and COVIDICU2 phenotypes (hazard ratio [HR] 1.59 [1.09-2.31], p = 0.015 and HR 1.79 [1.42-2.26], p < 0.001, respectively), but not in patients with the COVIDICU3 phenotype (HR 1.08 [0.76-1.54], p = 0.654).ConclusionOur multinational study identified three distinct clinical COVID-19 phenotypes, each exhibiting marked differences in demographic, clinical, and immunological features, and in the response to late and short-term corticosteroid treatment.© 2024. The Author(s).

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