Immune Checkpoint Inhibitor Use in Sepsis: Monitoring Immune Checkpoint Inhibitor Toxicity.
Immune Checkpoint Inhibitor Use in Sepsis: Monitoring Immune Checkpoint Inhibitor Toxicity.
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免疫检查点抑制剂在脓毒症中的应用：监测免疫检查点抑制剂的毒性。
DOI：
10.1097/ccm.0000000000003813
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发表时间：
2019
影响因子：
8.8
通讯作者：
D'Alessio,Franco
中科院分区：
文献类型：
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作者：
Suresh,Karthik;D'Alessio,Franco
我们怀着极大的兴趣阅读了霍奇基斯等人（1）在最近一期《重症监护医学》上发表的文章，该文章研究了免疫检查点抑制剂（ICI）在脓毒症患者中的安全性。然而，我们担心可能接受ICI的脓毒症患者肺部免疫相关不良事件的发展。在癌症背景下，检查点抑制剂肺炎（CIP）是一种严重的，高度病态的疾病，诊断也具有挑战性。我们（2-4）和其他人（5）报告了非小细胞肺癌中CIP的发生率上升，特别是在临床试验之外使用ICI和患有既往肺部疾病的患者中。我们担心，如果在所有脓毒症患者中使用ICI，则CIP可能诊断不足，而不考虑病因（例如，肺源vs非肺源），也不考虑共病肺部疾病。作者如何在高危人群中筛查CIP？即使在没有败血症的患者中，CIP诊断也具有挑战性;症状是非特异性的，可以模仿心力衰竭或病毒感染。当观察到呼吸困难、咳嗽或去饱和时，接受ICI治疗的患者是否接受胸部成像和/或重新评估新的肺损伤来源？治疗组中至少有1起严重不良事件（[1]中的补充表S2）继发于呼吸窘迫，但被认为与治疗无关;在这种情况下如何排除CIP？由于迄今为止没有可靠的生物标志物可以区分CIP与败血症人群中的医疗保健相关性肺炎和其他常见实体共病，我们仍然高度关注ICI在败血症患者中的使用，因为诊断不足的CIP可能会增加死亡率。临床前研究中确实有证据表明程序性细胞死亡蛋白-1可能是脓毒症免疫调节的靶点（6）。然而，我们认为，在确认ICI疗法用于人体脓毒症试验之前，需要在转化和临床前研究中仔细检查其他因素，包括病原体特异性差异（脓毒症的细菌与病毒来源）、肺损伤机制（即间接损伤与直接损伤）和潜在宿主合并症。例如，在大多数评价ICI的临床前研究中，脓毒症的来源是间接的（即，非肺部来源-通常是盲肠结扎/穿刺）。我们知道，直接和间接肺损伤在病理生理学上有很大的不同（7），因此，我们认为，ICI治疗肺源性脓毒症患者并不容易得到临床前文献的支持。我们同意作者的观点，即对脓毒症免疫调节的热情很高，这一领域的研究已经成熟。然而，鉴于脓毒症的异质性，我们对ICI使用的热情受到我们对人群中可能的肺毒性的担忧的影响，在这些人群中，此类毒性的诊断本身可能证明是非常困难的。
We read with great interest the article published in a recent issue of Critical Care Medicine by Hotchkiss et al (1), examining safety of immune checkpoint inhibitors (ICIs) in humans with sepsis. However, we are concerned about the development of pulmonary immune-related adverse events in septic patients who may receive ICI. In cancer settings, checkpoint inhibitor pneumonitis (CIP) is a serious, highly morbid condition that is also challenging to diagnose. We (2–4) and others (5) have reported rising incidence of CIP in non-small cell lung cancer, especially in the context of ICI use outside of clinical trials and in patients with preexisting lung disease. We are concerned that CIP may be underdiagnosed if ICIs were to be used in all patients with sepsis, regardless of etiology (eg, pulmonary source vs nonpulmonary source) and without consideration of comorbid lung disease. How did the authors screen for CIP in their high-risk population? Even in patients without sepsis, CIP diagnosis is challenging; symptoms are nonspecific and can mimic those of heart failure or viral infection. Did patients who received ICI therapy undergo chest imaging and/or re-evaluation for new sources of lung injury when dyspnea, cough, or desaturation was observed? At least one serious adverse event (Supplementary Table S2 in [1]) in the treatment group was secondary to respiratory distress but was deemed not related to therapy; how was CIP excluded in this scenario? Since no reliable biomarkers to date can distinguish CIP from healthcare-associated pneumonia and other common entities comorbid in the sepsis population, we remain highly concerned about ICI use in septic patients due to the possibility of increasing mortality from underdiagnosed CIP. There is certainly evidence in preclinical studies to suggest that programmed cell death protein-1 could be a target for the immunomodulation of sepsis (6). However, in our opinion, additional factors including pathogen-specific differences (bacterial vs viral source of sepsis), mechanism of lung injury (ie, indirect injury vs direct injury) and underlying host comorbidities need to be carefully examined in translational and preclinical studies before credentialing ICI therapy for use in human sepsis trials. As one example, the source of sepsis in the majority of preclinical studies evaluating ICIs was indirect (ie, nonpulmonary source—typically cecal ligation/puncture). We know that direct and indirect lung injuries are very different pathophysiologically (7), and thus, ICI therapy for sepsis patients with a pulmonary source is, in our opinion, not as readily supported by the preclinical literature. We agree with the authors that enthusiasm for immune modulation in sepsis is high, and this area is ripe for investigation. However, given the heterogeneity of sepsis, our enthusiasm for ICI use is tempered by our concern for possible pulmonary toxicities in a population where the diagnosis of such toxicities may itself prove very difficult.
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM