A randomized, double-blind, placebo-controlled trial of IL-7 in critically ill patients with COVID-19.

IF 6.1 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2025-02-04 DOI:10.1172/jci.insight.189150

Manu Shankar-Hari, Bruno Francois, Kenneth E Remy, Cristina Gutierrez, Stephen Pastores, Thomas Daix, Robin Jeannet, Jane Blood, Andrew H Walton, Reinaldo Salomao, Georg Auzinger, David Striker, Robert S Martin, Nitin J Anand, James Bosanquet, Teresa Blood, Scott Brakenridge, Lyle L Moldawer, Vidula Vachharajani, Cassian Yee, Felipe Dal-Pizzol, Michel Morre, Frederique Berbille, Marcel van den Brink, Richard Hotchkiss

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Abstract

Background: Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients' ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function.

Methods: We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically ill, patients with lymphopenia who have COVID-19. The primary endpoint was to assess CYT107's effect on lymphocyte recovery with secondary clinical endpoints including safety, ICU and hospital length-of-stay, incidence of secondary infections, and mortality.

Results: CYT107 was well tolerated without precipitating a cytokine storm or worsening pulmonary function. Absolute lymphocyte counts increased in both groups without a significant difference between CYT107 and placebo. Patients with COVID-19 receiving CYT107 but not concomitant antiviral medications, known inducers of lymphopenia, had a final lymphocyte count that was 43% greater than placebo (P = 0.067). There were significantly fewer treatment-emergent adverse events in CYT107 versus placebo-treated patients (P < 0.001), consistent with a beneficial drug effect. Importantly, CYT107-treated patients had 44% fewer hospital-acquired infections versus placebo-treated patients (P = 0.014).

Conclusion: Given that hospital-acquired infections are responsible for a large percentage of COVID-19 deaths, this effect of CYT107 to decrease nosocomial infections could substantially reduce late morbidity and mortality in this highly lethal disease. The strong safety profile of CYT107 and its excellent tolerability provide support for trials of CYT107 in other potential pandemic respiratory viral infections.

Trial registration: NCT04379076, NCT04426201, NCT04442178, NCT04407689, NCT04927169.

Funding: Funding for the trial was provided by RevImmune and the Cancer Research Institute.

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IL-7在危重症COVID-19患者中的随机、双盲、安慰剂对照试验

背景：淋巴细胞减少和淋巴细胞早期IFN-γ反应失败与COVID-19死亡率增加相关。考虑到CD4辅助细胞和CD8细胞毒性细胞在消除病毒病原体中的重要作用，淋巴细胞的严重损失可能会损害患者消除病毒的能力。白细胞介素-7是一种多效性细胞因子，是淋巴细胞生存和最佳功能所必需的。方法：我们对109例危重淋巴细胞减少症COVID-19患者进行了一项前瞻性、双盲、随机、安慰剂对照试验。主要终点是评估CYT107对淋巴细胞恢复的影响，次要临床终点包括安全性、ICU和住院时间、继发感染发生率和死亡率。结果：CYT107耐受性良好，未引起细胞因子风暴或肺功能恶化。两组的绝对淋巴细胞计数均有所增加，CYT107与安慰剂之间无显著差异。接受CYT107但未同时服用抗病毒药物（已知的淋巴细胞减少诱导剂）的COVID-19患者的最终淋巴细胞计数比安慰剂高43% （p=0.067）。与安慰剂治疗的患者相比，CYT107治疗后出现的不良事件显著减少(p结论：鉴于医院获得性感染是COVID-19死亡的主要原因，CYT107降低医院感染的效果可以显著降低这种高致死率疾病的晚期发病率和死亡率。CYT107强大的安全性及其良好的耐受性为CYT107在其他潜在的大流行性呼吸道病毒感染中的试验提供了支持。试验注册：NCT04379076、NCT04426201、NCT04442178、NCT04407689；NCT04927169。

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来源期刊

JCI insight Medicine-General Medicine

CiteScore

13.70

自引率

1.20%

发文量

543

审稿时长

6 weeks

期刊介绍： JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.