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Baricitinib therapy in critical COVID-19: plenty of promise, but no hard evidence yet
Critical Care ( IF 8.8 ) Pub Date : 2024-12-18 , DOI: 10.1186/s13054-024-05191-9
Seung-Hun You, Moon Seong Baek, Tae Wan Kim, Sun-Young Jung, Won-Young Kim

Dear Editor,

We would like to thank Wei et al. [1] for their interest in our recently published correspondence in Critical Care [2]. The authors share our enthusiasm for the comparison of baricitinib and tocilizumab therapies in patients with coronavirus disease 2019 (COVID-19) receiving mechanical ventilation (MV) and agree that the study findings are important. However, they raised several issues with respect to the methodology regarding confounding by indication.

The authors commented that the tocilizumab group had a higher severity of illness, which might have led to a bias in the outcome assessment of the baricitinib and tocilizumab groups, even after propensity score (PS) matching. Indeed, the tocilizumab group was more likely to exhibit higher Charlson Comorbidity Index and renal dysfunction, along with a greater frequency of renal replacement therapy than those of the baricitinib group (Table S1 in the paper) [2]. However, contrary to the authors’ concerns, the patients in the baricitinib group were more likely to receive neuromuscular blocking agents and extracorporeal membrane oxygenation. Hence, we respectfully disagree, at least in part, with their claim that tocilizumab was preferentially administered to patients with rapidly progressing or refractory conditions. In the Korean National Health Insurance Service database [3], it is not feasible to temporarily associate MV with drug administration (baricitinib or tocilizumab) during hospitalization due to the lack of timestamps. Hence, it was not possible to assess whether the duration of MV prior to drug administration was associated with the outcomes in our study.

We agree with the authors’ opinion that the study design was vulnerable to unmeasured confounders, although the groups were balanced with regard to the measured confounders using a robust model such as PS analysis. However, the current guidelines are based on the results of analyses that do not include direct comparison between the two drugs [4, 5]. Thus, observational studies are useful for providing data regarding the effectiveness of baricitinib and tocilizumab in patients with critical COVID-19. We also agree that the differences in treatment duration and pharmacodynamics may have resulted in a more favorable response to baricitinib. In fact, multiple oral administrations of baricitinib may potentially exhibit consistent drug concentrations, even in cases of gastrointestinal dysfunction commonly observed in critically ill patients [6].

Since the intolerance to enteral nutrition might reflect a more critical condition, we conducted a subgroup analysis of 30-day mortality according to total parenteral nutrition (TPN) therapy (yes or no) in response to the authors’ suggestion regarding the exclusion of patients who received TPN. TPN use was identified using the relevant procedure codes (aseptic preparation fee of parenteral nutrition [J0042] and/or nutrition support team consultation fee [AI600 and AI700]) [7]. A higher percentage of patients in the tocilizumab group received TPN than that in the baricitinib group (239/557 [42.9%] vs 188/557 [33.8%], respectively; standardized mean difference = 1.01). However, regardless of TPN use, patients who received baricitinib exhibited significantly lower mortality rates than of those who received tocilizumab (Fig. 1). Notably, patients who received TPN experienced lower mortality rates, thereby indicating that intravenous therapies may not be ideal surrogates of disease severity. This finding may also be attributed to the difficulties in providing active nutritional support during the COVID-19 pandemic [8].

In conclusion, our study demonstrates that baricitinib may be a promising therapy for the treatment of patients with COVID-19 on MV. However, we agree with the authors’ observation that future studies would require more granular data, such as vital signs and laboratory values, to evaluate the association with baseline severity between the baricitinib and tocilizumab groups. Additionally, data on the timing of MV initiation and drug administration would be helpful in assessing the effects of early or late administration of baricitinib in patients requiring oxygen or MV. Finally, baricitinib or tocilizumab concentrations and inflammatory cytokine levels should be measured to enhance our understanding of the relationship between drugs and clinical response.

All data generated or analyzed during this study are included in this published article.

COVID-19:: Coronavirus disease 2019
MV:: Mechanical ventilation
PS:: Propensity score
TPN:: Total parenteral nutrition

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This study used the database of the Korea Disease Control and Prevention Agency and the National Health Insurance Service for policy and academic research (KDCA-NHIS-2023-1-488).

This research was supported by the National Research Foundation of Korea grant funded by the Korea government (Ministry of Science, ICT & Future Planning) (2022R1F1A1067609). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Authors and Affiliations

Department of Global Innovative Drugs, The Graduate School of Chung-Ang University, Chung-Ang University, Seoul, Republic of Korea
Seung-Hun You & Sun-Young Jung
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
Moon Seong Baek, Tae Wan Kim & Won-Young Kim
College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
Sun-Young Jung

Authors

Seung-Hun YouView author publications
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Moon Seong BaekView author publications
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Tae Wan KimView author publications
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Sun-Young JungView author publications
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Won-Young KimView author publications
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Corresponding authors

Correspondence to Sun-Young Jung or Won-Young Kim.

Ethics approval and consent to participate

The study protocol for the utilization of de-identified patient data was exempt from review by the Institutional Review Board of Chung-Ang University (1041078-20230306-HR-055).

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Not applicable.

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The authors declare that they have no competing interests.

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You, SH., Baek, M.S., Kim, T.W. et al. Baricitinib therapy in critical COVID-19: plenty of promise, but no hard evidence yet. Crit Care 28, 409 (2024). https://doi.org/10.1186/s13054-024-05191-9

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Received: 23 November 2024
Accepted: 25 November 2024
Published: 18 December 2024
DOI: https://doi.org/10.1186/s13054-024-05191-9

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中文翻译：

Baricitinib 治疗危重 COVID-19：前景光明，但尚无确凿证据

尊敬的编辑：

我们要感谢 Wei 等人 [1] 对我们最近发表的重症监护 [2] 信件的关注。作者与我们一样热衷于比较 baricitinib 和托珠单抗疗法在接受机械通气（MV）的 2019 冠状病毒病（COVID-19）患者中的疗效，并同意研究结果很重要。然而，他们提出了关于适应症混杂的方法的几个问题。

作者评论说，托珠单抗组的疾病严重程度更高，这可能导致巴瑞替尼组和托珠单抗组的结局评估出现偏倚，即使在倾向评分（PS）匹配后也是如此。事实上，与巴瑞克替尼组相比，托珠单抗组更可能表现出更高的查尔森合并症指数和肾功能不全，以及更高的肾脏替代治疗频率（论文中的表 S1）[2]。然而，与作者的担忧相反，巴瑞替尼组的患者更有可能接受神经肌肉阻滞剂和体外膜肺氧合。因此，我们尊重地至少部分地不同意他们的说法，即托珠单抗优先用于病情快速进展或难治性的患者。在韩国国家健康保险服务数据库 [3] 中，由于缺乏时间戳，在住院期间暂时将 MV 与药物管理（baricitinib 或 tocilizumab）相关联是不可行的。因此，无法评估给药前 MV 的持续时间是否与我们研究中的结局相关。

我们同意作者的观点，即研究设计容易受到未测量的混杂因素的影响，尽管各组使用稳健的模型（如 PS 分析）在测量的混杂因素方面是平衡的。然而，目前的指南基于分析结果，不包括两种药物之间的直接比较 [4， 5]。因此，观察性研究有助于提供有关 baricitinib 和 tocilizumab 对危重 COVID-19 患者有效性的数据。我们还同意，治疗持续时间和药效学的差异可能导致对 baricitinib 的反应更有利。事实上，多次口服巴瑞替尼可能表现出一致的药物浓度，即使在危重患者中常见的胃肠道功能障碍病例中也是如此 [6]。

由于对肠内营养的不耐受可能反映了更危急的病情，我们根据全肠外营养（TPN）治疗（是或否）对 30 天死亡率进行了亚组分析，以响应作者关于排除接受 TPN 的患者的建议。使用相关程序代码（肠外营养无菌制备费 [J0042] 和/或营养支持团队咨询费 [AI600 和 AI700]）确定 TPN 的使用[7]。托珠单抗组接受 TPN 的患者百分比高于巴瑞替尼组（分别为 239/557 [42.9%] 和 188/557 [33.8%];标准化均数差 = 1.01）。然而，无论 TPN 的使用如何，接受巴瑞替尼治疗的患者的死亡率明显低于接受托珠单抗的患者（图 1）。值得注意的是，接受 TPN 的患者死亡率较低，这表明静脉注射治疗可能不是疾病严重程度的理想替代指标。这一发现也可能归因于 COVID-19 大流行期间难以提供积极的营养支持 [8]。

总之，我们的研究表明，巴瑞克替尼可能是一种很有前途的疗法，用于治疗 MV 上的 COVID-19 患者。然而，我们同意作者的观察，即未来的研究将需要更精细的数据，例如生命体征和实验室值，以评估巴瑞替尼组和托珠单抗组与基线严重程度的相关性。此外，有关 MV 开始时间和药物给药的数据将有助于评估早期或晚期给予巴瑞克替尼对需要氧气或 MV 的患者的影响。最后，应测量巴瑞替尼或托珠单抗浓度和炎性细胞因子水平，以增强我们对药物与临床反应之间关系的理解。

本研究期间生成或分析的所有数据都包含在这篇已发表的文章中。

COVID-19 冠状病毒：: 2019 冠状病毒病
MV：: 机械通气
附言：: 倾向评分
TPN：: 全胃肠外营养

Wei JCC， Kuo P， Shih PC.评论 baricitinib 与托珠单抗在机械通气 COVID-19 患者中的对比：一项全国性队列研究。暴击护理。2024;28:357.

PubMed PubMed Central 谷歌学术搜索
You SH， Baek MS， Kim TW， Jung SY， Kim WY.Baricitinib 与托珠单抗在机械通气 COVID-19 患者中的对比：一项全国性队列研究。暴击护理。2024;28:282.

PubMed PubMed Central 谷歌学术搜索
国民健康保险共享服务。https://nhiss.nhis.or.kr/en/z/a/001/lpza001m01en.do （2024 年）。2024 年 11 月 23 日访问。
美国食品药品监督管理局：冠状病毒（COVID-19）更新：FDA 授权联合药物用于治疗 COVID-19。https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19 （2020 年）。2024 年 11 月 23 日访问。
美国食品药品监督管理局：冠状病毒（COVID-19）更新：FDA 授权用于治疗 COVID-19 的药物。https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-treatment-covid-19 （2021 年）。2024 年 11 月 23 日访问。
Reintam Blaser A、Poeze M、Malbrain ML、Bjorck M、Oudemans-van Straaten HM、Starkopf J 等人。重症监护第一周的胃肠道症状与不良结局相关：一项前瞻性多中心研究。重症监护医学 2013;39:899–909.

PubMed PubMed Central 谷歌学术搜索
Cheon S， Oh SH， Kim JT， Choi HG， Park H， Chung JE.营养支持团队的营养治疗：住院患者多腔袋和定制肠外营养的比较。营养素。2023;15:2531.

PubMed PubMed Central 谷歌学术搜索
Tetamo R， Fittipaldi C， Buono S， Umbrello M. COVID-19 大流行期间对危重病人的营养支持：意大利 SIAARTI 调查。J Anesth Analg Crit Care。2022;2:35.

PubMed PubMed Central 谷歌学术搜索

下载参考资料

本研究使用韩国疾病控制和预防局和国家健康保险公团的数据库进行政策和学术研究（KDCA-NHIS-2023-1-488）。

这项研究得到了由韩国政府（科学、信息通信技术和未来规划部）（2022R1F1A1067609）资助的韩国国家研究基金会资助的支持。资助者在研究的设计和实施中没有作用;数据的收集、管理、分析和解释;手稿的准备、审查或批准;或决定提交手稿出版。

作者和单位

中央大学研究生院全球创新药系，中央大学，首尔，韩国
Seung-Hun You & Sun-Young Jung
韩国首尔中央大学医学院中央大学医院内科肺与重症监护医学科

Moon Seong Baek， Tae Wan Kim & Won-Young Kim
中央大学药学院，首尔，大韩民国
Sun-Young Jung

作者

Seung-Hun You （柳承勋）查看作者出版物

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通讯作者

与 Sun-Young Jung 或 Won-Young Kim 的通信。

道德批准和参与同意

中央大学机构审查委员会（1041078-20230306-HR-055）免于审查利用去识别化患者数据的研究方案。

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