Hydrocortisone rapidly and significantly reduces the IL-6 level in blood and lungs of patients with COVID-19-related ARDS,Critical Care

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Hydrocortisone rapidly and significantly reduces the IL-6 level in blood and lungs of patients with COVID-19-related ARDS
Critical Care ( IF 15.1 ) Pub Date : 2024-03-28 , DOI: 10.1186/s13054-024-04887-2
Antoine Guillon , Youenn Jouan , Arthur Kassa-Sombo , Christophe Paget , Pierre-François Dequin

Dear Editor,

Increased levels of inflammatory mediators, particularly IL-6, have been observed in conditions like sepsis, acute respiratory distress syndrome (ARDS), and more recently, COVID-19, leading to the exploration of anti-inflammatory treatments. To date, clinical practice guidelines include strong recommendations in favor of a limited number of immunomodulatory for severe COVID-19: corticosteroids, interleukin 6 receptor blockers, and baricitinib [1]. All three may be combined. However, the exact effect of corticosteroids on the main inflammatory cytokines is unknown in critically ill patients with COVID-19. In particular, the pathophysiology of the respiratory failure in COVID-19 is attributed to local immune dysregulation with a lung compartmentalization of inflammatory mediators [2]. The efficacy of corticosteroids to rapidly control the lung inflammation is unknown. The objective of this study was to describe the concentrations in blood and respiratory fluid of IL-6, TNF-α, and IL-1β after a single administration of hydrocortisone, compared to placebo.

We took advantage of two studies performed simultaneously in the same center (CAPE COVID trial and ImPACT study) and performed ancillary analysis of patients included in both studies. The CAPE COVID trial is a randomized, double-blinded, placebo-controlled study assessing the effectiveness of hydrocortisone in patients with COVID-19-related ARDS [3]. The ImPACT study described immunophenotyping in blood and in the supernatants of endotracheal aspirates of severe COVID-19 patients [4]. Briefly, patients aged at least 18 years admitted in ICU and mechanically ventilated for ARDS could be included if they had a biologically confirmed (reverse transcriptase–polymerase chain reaction) COVID-19. The experimental treatment (hydrocortisone or placebo) had to be administered within 24 h of the onset of the first severity criterion (need for mechanical ventilation and/or Pao2/FiO2 < 300 mmHg and/or Pulmonary Severity Index greater than 130) or within 48 h for patients referred from another hospital. Patients receiving vasopressors to correct hypotension related to sedative drugs and mechanical ventilation at high PEEP levels could be included. Principal exclusion criteria were septic shock and do-not-intubate orders. Randomization was centralized and performed electronically. Patients received a continuous intravenous infusion of hydrocortisone at an initial dose of 200 mg/d or its placebo (saline). For the ImPACT study, inflammatory mediators were measured in sera and supernatants of endotracheal aspirates using the Bio-Plex Pro Human cytokines screening panel (Bio-Rad) in a multiplex fluorescent bead assay (Luminex), according to the manufacturer’s instructions. Endotracheal aspirates were collected, then weighed, and incubated in PBS (5 ml/g) with 1 mM dithiothreitol for 30 min at 4 °C under gentle agitation. We thus analyzed samples (from the ImPACT study) that were taken either before or after the start of hydrocortisone or placebo administration (from the CAPE COVID trial).

Twenty patients with COVID-19-related ARDS were enrolled in both studies simultaneously. Patients’ characteristics were (median [quartile 1; quartile 3]), age 64 (57;67) y.o, male/female 2/1, MBI 31 (28;32) kg/m², SAPS2 32 (22;36), and SOFA 4 (2;6). To examine the temporal impact of hydrocortisone or placebo on cytokines concentrations, a linear regression with logarithmic transformation was used. After modeling, trend graphs were generated, along with confidence intervals (Fig. 1). Analysis of these results revealed a statistically significant negative regression coefficient in the hydrocortisone group for IL-6 concentrations. Linear regression was then explored by incorporating an interaction between time and groups. For this purpose, a binary variable was introduced to differentiate between samples taken at negative (before dosing) and positive (after dosing) times. Fitting this regression revealed significant disparities in the temporal influence on hydrocortisone on IL-6 levels, both in blood and in endotracheal aspirate. More specifically, significant tests (p < 0.05) associated with the coefficients confirmed the impact of hydrocortisone on IL-6 measurements; the use of analysis of variance corroborated the significance of the results. Consequently, the IL-6 concentration was barely detectable in the blood after the hydrocortisone administration compared to the placebo group (0.45 [0.45 – 2.2] and 98 [40.5 – 284.6] pg/mL, respectively) and was lower in the endotracheal aspirate (2395 [623 – 2946] and 7854 [5273 – 24,713] pg/mL, respectively). No significant temporal variations were observed for TNF-α and IL1-β after hydrocortisone administration.

Although the relation between steroids and IL-6 is well known, our study provides new insights. (i) It is the first and only demonstration showing the effectiveness of steroids in reducing IL-6 levels in COVID-19-related ARDS with a randomized, double-blinded, placebo-controlled design. (ii) The IL-6 concentration becomes negligible in the blood after the start of hydrocortisone treatment. (iii) There is a reduction of more than two times the initial IL-6 level in the lungs immediately after the intravenous infusion of hydrocortisone. In summary, hydrocortisone rapidly and significantly reduces the IL-6 level in blood and lungs of patients with COVID-19-related ARDS patients.

The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

ARDS:: Acute respiratory distress syndrome
ICU:: Intensive care unit
SAPS:: Simplified Acute Physiology Score
SD:: Standard deviation

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We acknowledge all health care coworkers involved in the ICU department at the Bretonneau Hospital, especially Aurelie Aubrey, Delphine Chartier, Véronique Siméon, and Julien Bontemps, for their excellent management of patient samples and clinical data. Annick Legras, Denis Garot, Emmanuelle Mercier, Charlotte Salmon-Gandonnière, Laetitia Bodet-Contentin, Marlène Morisseau, Stephan Mankikian, and Walid Darwiche are acknowledged for patient inclusions. We also acknowledge Loïc Gonzalez, who conducted the cytokine assays for this study. We thank all patients and their families for their trust and confidence in our work.

The CAPE COVID study was funded by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC) (2014 [CAPE COD parent trial], 2020 [CAPE COVID subtrial]). The ImPACT study was supported by the Agence Nationale de la Recherche “JCJC program” (ANR-19-CE15-0032–01) and by the Fondation du Souffle, with the Fonds de Recherche en Santé Respiratoire. A. KASSA-SOMBO was funded by a grant from Inserm and the French Ministry of Health in the context of MESSIDORE call operated by IReSP (GENIALLY, 2022, Inserm-MESSIDORE N° 72).

Authors and Affiliations

Intensive Care Unit, Tours University Hospital, 2 Bd Tonnellé, 37044, Tours Cedex 9, France
Antoine Guillon & Pierre-François Dequin
Research Center for Respiratory Diseases, INSERM U1100, University of Tours, Tours, France
Antoine Guillon, Youenn Jouan, Arthur Kassa-Sombo, Christophe Paget & Pierre-François Dequin
Cardiac Surgery Department, Tours University Hospital, Tours, France
Youenn Jouan

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Contributions

AG, YJ, CP, and PFD conceived and designed the study and were involved in drafting the manuscript. AKS performed the statistical analysis. AG, YJ, AKS, CP, and PFD were involved in the interpretation of the data and in drafting the manuscript and made critical revisions to the discussion section. AG, YJ, AKS, CP, and PFD read and approved the final version to be published.

Corresponding author

Correspondence to Antoine Guillon.

Consent for publication

The ImPACT study (Clinical Trial.gov identifier: NCT03379207) was approved by the ethics committee (Comité de Protection de Personnes Ile-de- France 8). The CAPE COVID trial (ClinicalTrials.gov Identifier: NCT02517489) was approved by the ethics committee (Comité de Protection des Personnes Ouest 1, France). Each patient or surrogate provided either written or oral informed consent prior to inclusion.

Competing interests

Pr Dequin reported receiving grants from Aerogen and Fisher & Paykel Healthcare and personal fees from Aridis Pharmaceuticals. No other authors reported disclosures.

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Guillon, A., Jouan, Y., Kassa-Sombo, A. et al. Hydrocortisone rapidly and significantly reduces the IL-6 level in blood and lungs of patients with COVID-19-related ARDS. Crit Care 28, 101 (2024). https://doi.org/10.1186/s13054-024-04887-2

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Received: 15 March 2024
Accepted: 22 March 2024
Published: 28 March 2024
DOI: https://doi.org/10.1186/s13054-024-04887-2

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中文翻译：

氢化可的松快速显着降低 COVID-19 相关 ARDS 患者血液和肺部的 IL-6 水平

亲爱的编辑，

在脓毒症、急性呼吸窘迫综合征 (ARDS) 以及最近的 COVID-19 等疾病中观察到炎症介质（尤其是 IL-6）水平升高，从而引发了抗炎治疗的探索。迄今为止，临床实践指南包括强烈建议对严重的 COVID-19 使用有限数量的免疫调节剂：皮质类固醇、白细胞介素 6 受体阻滞剂和巴瑞替尼 [1]。这三者可以结合起来。然而，皮质类固醇对 COVID-19 危重患者主要炎症细胞因子的确切影响尚不清楚。特别是，COVID-19 呼吸衰竭的病理生理学归因于局部免疫失调和肺部炎症介质的区室化[2]。皮质类固醇快速控制肺部炎症的功效尚不清楚。本研究的目的是描述与安慰剂相比，单次给予氢化可的松后血液和呼吸液中 IL-6、TNF-α 和 IL-1β 的浓度。

我们利用同一中心同时进行的两项研究（CAPE COVID 试验和 ImPACT 研究），并对两项研究中纳入的患者进行了辅助分析。 CAPE COVID 试验是一项随机、双盲、安慰剂对照研究，评估氢化可的松对 COVID-19 相关 ARDS 患者的有效性 [3]。 ImPACT 研究描述了重症 COVID-19 患者血液和气管内抽吸物上清液中的免疫表型分析 [4]。简而言之，年龄至少 18 岁入住 ICU 并因 ARDS 接受机械通气的患者，如果他们患有生物学确诊（逆转录酶聚合酶链反应）COVID-19，则可以纳入其中。实验性治疗（氢化可的松或安慰剂）必须在第一个严重性标准（需要机械通气和/或 Pao2/FiO2 < 300 mmHg 和/或肺部严重指数大于 130）开始 24 小时内或在 48 小时内进行h 适用于从另一家医院转诊的患者。可以包括接受血管升压药以纠正与镇静药物和高 PEEP 水平机械通气相关的低血压的患者。主要排除标准是感染性休克和不插管命令。随机化是集中的并以电子方式进行。患者接受连续静脉输注氢化可的松，初始剂量为 200 mg/d 或其安慰剂（生理盐水）。对于 ImPACT 研究，根据制造商的说明，使用 Bio-Plex Pro 人类细胞因子筛选板 (Bio-Rad) 在多重荧光珠测定 (Luminex) 中测量血清和气管内抽吸物上清液中的炎症介质。收集气管内抽吸物，然后称重，并在 PBS (5 ml/g) 和 1 mM 二硫苏糖醇中于 4 °C 温和搅拌下孵育 30 分钟。因此，我们分析了在氢化可的松或安慰剂给药（来自 CAPE COVID 试验）之前或之后采集的样本（来自 ImPACT 研究）。

20 名患有 COVID-19 相关 ARDS 的患者同时参加了这两项研究。患者特征为（中位数[四分位数 1；四分位数 3]），年龄 64 (57;67) 岁，男/女 2/1，MBI 31 (28;32) kg/m ²，SAPS2 32 (22;36)和沙发 4 (2;6)。为了检查氢化可的松或安慰剂对细胞因子浓度的时间影响，使用对数变换的线性回归。建模后，生成了趋势图以及置信区间（图 1）。对这些结果的分析表明，氢化可的松组中 IL-6 浓度存在统计学显着的负回归系数。然后通过结合时间和组之间的相互作用来探索线性回归。为此，引入了二元变量来区分在负时间（给药前）和正时间（给药后）采集的样本。拟合该回归揭示了氢化可的松对血液和气管内抽吸物中 IL-6 水平的时间影响存在显着差异。更具体地说，与系数相关的显着测试 ( p < 0.05) 证实了氢化可的松对 IL-6 测量的影响；方差分析的使用证实了结果的显着性。因此，与安慰剂组相比，给予氢化可的松后，血液中几乎检测不到 IL-6 浓度（分别为 0.45 [0.45 – 2.2] 和 98 [40.5 – 284.6] pg/mL），并且气管内抽吸物中的 IL-6 浓度较低（分别为 2395 [623 – 2946] 和 7854 [5273 – 24,713] pg/mL）。给予氢化可的松后，未观察到 TNF-α 和 IL1-β 的显着时间变化。

尽管类固醇和 IL-6 之间的关系众所周知，但我们的研究提供了新的见解。 (i) 这是第一个也是唯一一个通过随机、双盲、安慰剂对照设计证明类固醇在降低 COVID-19 相关 ARDS 中 IL-6 水平方面的有效性的演示。 (ii) 开始氢化可的松治疗后，血液中的 IL-6 浓度变得可以忽略不计。 (iii) 静脉输注氢化可的松后，肺部的 IL-6 水平立即降低两倍以上。总之，氢化可的松可快速、显着降低 COVID-19 相关 ARDS 患者血液和肺部的 IL-6 水平。

当前研究期间生成和/或分析的数据集不公开，但可根据合理要求从相应作者处获取。

ARDS：: 急性呼吸窘迫综合征
重症监护病房：: 重症监护室
SAPS：: 简化急性生理学评分
标清：: 标准差

Agarwal A、Hunt BJ、Stegemann M 等。世界卫生组织关于 covid-19 药物的现行指南。英国医学杂志。 2020；370：m3379。 https://doi.org/10.1136/bmj.m3379。
文章 PubMed 谷歌学术
Jouan Y、Baranek T、Si-Tahar M 等。 COVID-19 相关 ARDS 中炎症生物标志物的肺区室化。伦敦危重症护理2021；25:120。 https://doi.org/10.1186/s13054-021-03513-9。
文章谷歌学术
Dequin PF、Heming N、Meziani F 等。氢化可的松对 COVID-19 危重患者 21 天死亡率或呼吸支持的影响：一项随机临床试验。贾马。 2020。https://doi.org/10.1001/jama.2020.16761。
文章 PubMed PubMed Central Google Scholar
Jouan Y、Guillon A、Gonzalez L 等。重症 COVID-19 患者非常规 T 细胞的表型和功能改变。 J Exp Med。 2020；217：e20200872。 https://doi.org/10.1084/jem.20200872。
文章 CAS PubMed PubMed Central Google Scholar

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我们感谢 Bretonneau 医院 ICU 部门的所有医疗保健同事，特别是 Aurelie Aubrey、Delphine Chartier、Véronique Siméon 和 Julien Bontemps，他们对患者样本和临床数据进行了出色的管理。 Annick Legras、Denis Garot、Emmanuelle Mercier、Charlotte Salmon-Gandonnière、Laetitia Bodet-Contentin、Marlène Morisseau、Stephan Mankikian 和 Walid Darwiche 因纳入患者而受到认可。我们还要感谢 Loïc Gonzalez，他为本研究进行了细胞因子测定。我们感谢所有患者及其家属对我们工作的信任和信心。

CAPE COVID 研究由法国卫生部的 Program Hospitalier de Recherche Clinique (PHRC) 资助（2014 年 [CAPE COD 家长试验]，2020 年 [CAPE COVID 子试验]）。 ImPACT 研究得到了国家研究机构“JCJC 计划”(ANR-19-CE15-0032-01) 和 Souffle 基金会以及 Santé Respiratoire 基金会的支持。 A. KASSA-SOMBO 的资金来自 Inserm 和法国卫生部在 IReSP 运营的 MESSIDORE 呼叫背景下的拨款（GENIALLY，2022，Inserm-MESSIDORE N° 72）。

作者和单位

重症监护室，图尔大学医院，2 Bd Tonnelle，37044，图尔 Cedex 9，法国
安托万·吉永 & 皮埃尔·弗朗索瓦·德坎
呼吸系统疾病研究中心，INSERM U1100，图尔大学，图尔，法国
Antoine Guillon、Youenn Jouan、Arthur Kassa-Sombo、Christophe Paget 和 Pierre-François Dequin
法国图尔市图尔大学医院心脏外科
尤恩·朱安

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贡献

AG、YJ、CP 和 PFD 构思和设计了本研究，并参与了手稿的起草。 AKS 进行了统计分析。 AG、YJ、AKS、CP 和 PFD 参与了数据解释和手稿起草，并对讨论部分进行了重要修改。 AG、YJ、AKS、CP 和 PFD 阅读并批准了要发布的最终版本。

通讯作者

与安托万·吉永的通讯。

同意发表

ImPACT 研究（Clinical Trial.gov 标识符：NCT03379207）得到了伦理委员会（Comité de Protection de Personnes Ile-de- France 8）的批准。 CAPE COVID 试验（ClinicalTrials.gov 标识符：NCT02517489）获得了伦理委员会（Comité de Protection des Personnes Ouest 1，法国）的批准。每位患者或代理人在纳入之前均提供了书面或口头知情同意书。

利益争夺

Pr Dequin 报告称，获得了 Aerogen 和 Fisher & Paykel Healthcare 的资助以及 Aridis Pharmaceuticals 的个人费用。没有其他作者报告披露情况。

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Guillon, A.、Jouan, Y.、Kassa-Sombo, A.等人。氢化可的松可快速显着降低 COVID-19 相关 ARDS 患者血液和肺部的 IL-6 水平。重症监护 28 , 101 (2024)。 https://doi.org/10.1186/s13054-024-04887-2

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