Clinical phenotyping uncovers heterogeneous associations between corticosteroid treatment and survival in critically ill COVID-19 patients,Intensive Care Medicine

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Clinical phenotyping uncovers heterogeneous associations between corticosteroid treatment and survival in critically ill COVID-19 patients
Intensive Care Medicine ( IF 27.1 ) Pub Date : 2024-08-26 , DOI: 10.1007/s00134-024-07593-3
Niklas Bruse ₁ , Anna Motos _{2,

3} , Rombout van Amstel ₄ , Eckart de Bie ₁ , Emma J Kooistra ₁ , Aron Jansen ₁ , Dirk van Lier ₁ , Jason Kennedy ₅ , Daniel Schwarzkopf ₆ , Daniel Thomas-Rüddel ₆ , Jesus F Bermejo-Martin ₂ , Ferran Barbe ₂ , Nicolette F de Keizer _{7,

8,

9} , Michael Bauer ₆ , Johannes G van der Hoeven ₁ , Antoni Torres _{2,

10} , Christopher Seymour ₅ , Lonneke van Vught ₄ , Peter Pickkers ₁ , Matthijs Kox ₁

Affiliation

Department of Intensive Care Medicine, Radboud university medical center, Nijmegen, The Netherlands.
CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain.
IDIBAPS, University of Barcelona, Barcelona, Spain.
Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
National Intensive Care Evaluation (NICE) Foundation, Amsterdam, The Netherlands.
Department of Medical Informatics, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
Amsterdam Public Health, Quality of Care and Digital Health, Amsterdam, The Netherlands.
Pneumology Service, Respiratory Institute, Hospital Clinic of Barcelona, Barcelona, Spain.

Purpose

Disease 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.

Methods

We 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.

Results

We 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).

Conclusion

Our 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.

中文翻译：

临床表型揭示了皮质类固醇治疗与危重 COVID-19 患者生存率之间的异质性关联

目的

2019 冠状病毒病（COVID-19）的疾病异质性可能使目前的一刀切治疗方法不理想。我们旨在识别和免疫学表征危重症 COVID-19 患者的临床表型，并评估皮质类固醇治疗效果的异质性。

方法

我们对 2020 年 2 月至 2022 年 2 月入住 82 个荷兰 ICU 的 13,279 名 COVID-19 患者在重症监护病房（ICU）入院后 24 小时内获得的 21 个临床参数应用共识 k-means 聚类。在来自西班牙的 6225 名 COVID-19 ICU 患者（2020 年 2 月至 2021 年 12 月）中复制了衍生表型。在来自荷兰和德国的三个 COVID-19 ICU 队列中进行了纵向免疫学表征，并评估了皮质类固醇治疗与生存之间的关联。

结果

我们得出了三种表型： COVIDICU1 （43% 的患者）由急性生理学和慢性健康评估（APACHE）评分最低、体重指数（BMI）最高、PaO₂/FiO₂ 比率最低和 90 天院内死亡率为 18% 的年轻患者组成。COVIDICU2 名患者（37%）的 BMI 最低，年龄较大，APACHE 评分和死亡率（24%）高于 COVIDICU1。COVIDICU3 患者（20%）是合并症最多的年龄最大、APACHE 评分最高、急性肾损伤和代谢失调以及最高死亡率（47%）。这些患者还表现出最明显的炎症反应。皮质类固醇治疗在入住 ICU 后第 5 天 [2-9] 开始并给药 5 [3-7] 天与COVIDICU1 和 COVIDICU2 表型患者的 90 天死亡风险增加相关（风险比 [HR] 分别为 1.59 [1.09–2.31]，p = 0.015 和 HR 1.79 [1.42–2.26]，p < 0.001），但在COVIDICU3表型患者中则不然（HR 1.08 [0.76–1.54]， p = 0.654）。