Immunophenotyping patients with sepsis and underlying haematological malignancy reveals defects in monocyte and lymphocyte function,Intensive Care Medicine Experimental

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Immunophenotyping patients with sepsis and underlying haematological malignancy reveals defects in monocyte and lymphocyte function
Intensive Care Medicine Experimental Pub Date : 2024-01-11 , DOI: 10.1186/s40635-023-00578-4
Timothy Arthur Chandos Snow , Aimee Serisier , David Brealey , Mervyn Singer , Nishkantha Arulkumaran , Naveed Saleem , Antonio Cesar , Alessia V. Waller , Francis Ryckaert , Deborah Smyth , Georgia Bercades , Ingrid Hass , Alexandra Zapata Martinez , Laura Gallagher , Gladys Martir ,

To the Editor,

Sepsis is a common reason for intensive care unit (ICU) admission of patients with haematological malignancy [1]. The main focus is placed on neutropenia, with little attention paid to other white cell lineage such as monocytes and lymphocytes. Immune dysfunction in these cells is well-described in non-cancer septic patients and associated with an increased mortality risk [2,3,4]. Features typically associated include impaired monocyte antigen presentation and co-stimulation (HLA-DR, CD80, CD86), increased immune checkpoint inhibition (lymphocyte PD-1 and monocyte PD-L1), impaired lymphocyte proliferation/ maturation (IL-7 receptor), activation (CD28 and CTLA-4), and viability [2,3,4]. The primary objective of this feasibility study was to ascertain whether these cells are similarly affected in haematology patients with sepsis.

We conducted a prospective observational study in patients with or without haematological malignancy admitted to the ICU with sepsis. Peripheral blood mononuclear cells (PBMC) were isolated and assessed by multi-parameter flow cytometry, and serum immune analytes by ELISA (Additional file 1: Methods). A focused analysis was performed of cell surface markers associated with sepsis-induced immunosuppression [2,3,4].

We included 11 haematology ICU patients, 33 non-haematology ICU patients (and 17 healthy volunteers as a reference). Patient demographics are detailed in Additional file 1: Table S2. Compared to non-haematology patients, haematology patients were of similar age and had a similar SOFA score. However, compared to non-haematology patients, haematology patients had lower neutrophils (p < 0.0001), lymphocytes (p = 0.03), and monocytes (p = 0.005). Hospital mortality was similar between both groups (27% non-haematology vs. 36% haematology) (Fig. 1, Additional file 1: Fig. S1).

There was a trend towards decreased monocyte phagocytosis (p = 0.055) among haematology patients. Viability in lymphocyte CD4 and CD8 cell populations and CD4 IL-7R levels were lower among haematology patients (Fig. 1, Additional file 1: Figs. S2, S3). A positive correlation was seen between PD-1 expression and cell death in CD4 lymphocytes in non-haematology patients but not haematology patients (Fig. 1).

Serum TNF-α was higher among haematology patients, although monocyte intracellular TNF-α levels were similar. Following ex vivo whole blood stimulation with LPS, serum IL-1β (p = 0.043) and TNF-α (p = 0.001) increased significantly in non-haematology patients, but not in haematology patients. (Fig. 1).

We present novel data demonstrating immune dysfunction in monocytes and lymphocytes taken from haematology patients with sepsis; over and above that seen in non haematology patients. This included impaired monocyte phagocytosis, and impaired release of TNF-α and IL-1β (canonical cytokines associated with monocyte function) on whole blood stimulation with LPS. Intriguingly, monocyte HLA-DR, a robust functional marker of immunoparesis in critically ill patients [4], was not different in haematology patients.

Mechanisms of lymphocyte death are likely to differ between haematology and non-haematology patient cohorts. The association between CD4 lymphocyte PD-1 expression and cell death is also described in patients with sepsis [4]. We found a positive correlation between PD-1 expression in CD4 lymphocytes in non-haematology patients but not in haematology patients.

Existing therapies to improve clinical outcomes in the critically ill haematology patient with sepsis are limited. Further research is required to gain a better understanding of the immune phenotype in this population, providing a rational for individualized sepsis treatment.

Available upon reasonable request and at discretion of investigators’ institution.

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University College London Hospitals Critical Care Research Team: Naveed Saleem, Antonio Cesar, Alessia V. Waller, Francis Ryckaert, Deborah Smyth, Georgia Bercades, Ingrid Hass, Alexandra Zapata Martinez, Laura Gallagher, Gladys Martir.

Intensive Care Society (ICS) New Investigator Award (TACS), European Society of Intensive Care Medicine (ESICM) Young Investigator Award 2018 (NA). University College London Precision AMR grant 2020 (NA, TACS, and MS). NA acknowledges salary support from UK Medical Research Council (MR/W030489/1).

Authors and Affiliations

Bloomsbury Institute of Intensive Care Medicine, University College London, 1.1 Cruciform Building, Gower Street, London, WC1E 6DH, UK
Timothy Arthur Chandos Snow, Aimee Serisier, David Brealey, Mervyn Singer, Nishkantha Arulkumaran, Naveed Saleem, Antonio Cesar, Alessia V. Waller, Francis Ryckaert, Deborah Smyth, Georgia Bercades, Ingrid Hass, Alexandra Zapata Martinez, Laura Gallagher & Gladys Martir

Authors

Timothy Arthur Chandos SnowView author publications
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David BrealeyView author publications
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Mervyn SingerView author publications
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Nishkantha ArulkumaranView author publications
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Consortia

University College London Hospitals Critical Care Research Team

Naveed Saleem
, Antonio Cesar
, Alessia V. Waller
, Francis Ryckaert
, Deborah Smyth
, Georgia Bercades
, Ingrid Hass
, Alexandra Zapata Martinez
, Laura Gallagher
& Gladys Martir

Contributions

Study design: TACS, DB and NA; Patient recruitment and sample collection: UCLH Critical Care Research Team. Sample processing and experimental acquisition: TACS and UCLH Critical Care Research Team; Clinical data collection: TACS, AS, NA, and UCLH Critical Care Research Team; Statistical analysis: TACS, AS, and NA; Critical Review: MS; All authors approved the manuscript.

Corresponding author

Correspondence to Nishkantha Arulkumaran.

Ethics approval and consent to participate

Ethical approval for obtaining clinical samples and data was received from the London – Queen Square Research Ethics Committee (REC reference 20/LO/1024). Twenty ml samples and clinical data were also taken from healthy volunteers as a reference, with prior approval from the University College London Research Ethics Committee (REC ref 19181/001).

Consent for publication

(Covered in ethics).

Competing interests

The authors declare that they do not have any competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Additional file 1: Table S1.

Flow cytometry fluorochromes used. Table S2. Baseline demographics. Figure S1. Differences in laboratory-measured variables between non-haematology and haematology patients. Figure S2. Differences in classical monocyte and CD4⁺ and CD8⁺ lymphocyte function between non-haematology and haematology patients. Figure S3. Differences in classical monocyte and CD4⁺ and CD8⁺ lymphocyte function between non-haematology and haematology patients.

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Snow, T.A.C., Serisier, A., Brealey, D. et al. Immunophenotyping patients with sepsis and underlying haematological malignancy reveals defects in monocyte and lymphocyte function. ICMx 12, 3 (2024). https://doi.org/10.1186/s40635-023-00578-4

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Received: 13 October 2023
Accepted: 07 December 2023
Published: 11 January 2024
DOI: https://doi.org/10.1186/s40635-023-00578-4

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Keywords

Sepsis
Haematology
Intensive care unit
Monocyte
Lymphocyte

中文翻译：

对脓毒症和潜在血液恶性肿瘤患者进行免疫表型分析发现单核细胞和淋巴细胞功能缺陷

致编辑，

脓毒症是血液系统恶性肿瘤患者入住重症监护病房（ICU）的常见原因[1]。主要关注中性粒细胞减少症，很少关注其他白细胞谱系，例如单核细胞和淋巴细胞。这些细胞的免疫功能障碍在非癌症脓毒症患者中得到了充分描述，并且与死亡风险增加相关[2,3,4]。通常相关的特征包括单核细胞抗原呈递和共刺激受损（HLA-DR、CD80、CD86）、免疫检查点抑制增加（淋巴细胞 PD-1 和单核细胞 PD-L1）、淋巴细胞增殖/成熟受损（IL-7 受体）、激活（CD28 和 CTLA-4）和活力 [2,3,4]。这项可行性研究的主要目的是确定这些细胞在患有脓毒症的血液学患者中是否受到类似的影响。

我们对因脓毒症入住 ICU 的患有或不患有血液恶性肿瘤的患者进行了一项前瞻性观察研究。通过多参数流式细胞术分离和评估外周血单核细胞 (PBMC)，并通过 ELISA 评估血清免疫分析物（附加文件 1：方法）。对与脓毒症诱导的免疫抑制相关的细胞表面标志物进行了集中分析[2,3,4]。

我们纳入了 11 名血液科 ICU 患者、33 名非血液科 ICU 患者（以及 17 名健康志愿者作为参考）。患者人口统计数据详见附加文件 1：表 S2。与非血液科患者相比，血液科患者年龄相似，SOFA 评分相似。然而，与非血液病患者相比，血液病患者的中性粒细胞 ( p < 0.0001)、淋巴细胞 ( p = 0.03) 和单核细胞 ( p = 0.005) 较低。两组之间的医院死亡率相似（非血液学死亡率为 27%，血液学死亡率为 36%）（图 1，附加文件 1：图 S1）。

血液病患者的单核细胞吞噬作用有下降的趋势（p = 0.055）。血液病患者中淋巴细胞 CD4 和 CD8 细胞群的活力以及 CD4 IL-7R 水平较低（图 1，附加文件 1：图 S2、S3）。在非血液病患者中，PD-1 表达与 CD4 淋巴细胞的细胞死亡呈正相关，但在血液病患者中则不然（图 1）。

尽管单核细胞细胞内 TNF-α 水平相似，但血液病患者的血清 TNF-α 较高。用 LPS 进行离体全血刺激后，非血液病患者的血清 IL-1β ( p = 0.043) 和 TNF-α ( p = 0.001) 显着增加，但血液病患者则没有显着增加。（图。1）。

我们提供的新数据证明取自脓毒症血液病患者的单核细胞和淋巴细胞存在免疫功能障碍；超过非血液病患者中所见的情况。这包括单核细胞吞噬作用受损，以及 LPS 刺激全血时 TNF-α 和 IL-1β（与单核细胞功能相关的典型细胞因子）释放受损。有趣的是，单核细胞 HLA-DR 是危重患者免疫麻痹的强大功能标记物 [4]，但在血液病患者中并没有什么不同。

血液学和非血液学患者群体之间的淋巴细胞死亡机制可能有所不同。CD4 淋巴细胞 PD-1 表达与细胞死亡之间的关联也在脓毒症患者中得到描述 [4]。我们发现非血液病患者的 CD4 淋巴细胞中 PD-1 表达呈正相关，但血液病患者则不然。

改善脓毒症危重血液学患者临床结果的现有疗法有限。需要进一步的研究来更好地了解该人群的免疫表型，为个体化脓毒症治疗提供合理依据。

根据合理要求并由调查人员机构酌情提供。

Taccone FS 等人 (2009) 欧洲 ICU 癌症患者的特征和结果。暴击护理 13(1):R15
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Desborough JP (2000) 对创伤和手术的应激反应。Br J 麻醉 85(1):109–117
文章 CAS PubMed 谷歌学术
Boomer JS 等人 (2012) 对急性脓毒症过程中淋巴细胞表型和功能的前瞻性分析。危重护理 16(3):R112
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Boomer JS 等人 (2011) 死于败血症和多器官衰竭的患者的免疫抑制。美国医学会杂志 306(23):2594–2605
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下载参考资料

伦敦大学学院医院重症监护研究团队：Naveed Saleem、Antonio Cesar、Alessia V. Waller、Francis Ryckaert、Deborah Smyth、Georgia Bercades、Ingrid Hass、Alexandra Zapata Martinez、Laura Gallagher、Gladys Martir。

重症监护协会 (ICS) 新研究者奖 (TACS)、欧洲重症监护医学会 (ESICM) 2018 年青年研究者奖 (NA)。伦敦大学学院 Precision AMR 拨款 2020 年（NA、TACS 和 MS）。NA 感谢英国医学研究委员会的薪资支持 (MR/W030489/1)。

作者和单位

伦敦大学学院布鲁姆斯伯里重症监护医学研究所，1.1 Cruciform Building, Gower Street, London, WC1E 6DH, UK
蒂莫西·亚瑟·钱多斯·斯诺、艾米·塞里西尔、大卫·布雷利、默文·辛格、尼什坎塔·阿鲁库马兰、纳维德·萨利姆、安东尼奥·塞萨尔、阿莱西亚·沃勒、弗朗西斯·瑞卡特、黛博拉·史密斯、乔治亚·贝尔卡德斯、英格丽德·哈斯、亚历山德拉·萨帕塔·马丁内斯、劳拉·加拉格尔和格拉迪斯·马蒂尔

作者

Timothy Arthur Chandos Snow查看作者出版物
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财团

伦敦大学学院医院重症监护研究团队

纳维德·萨利姆
, 安东尼奥·塞萨尔
, 阿莱西娅·V·沃勒
, 弗朗西斯·瑞卡特
、黛博拉·史密斯
, 佐治亚州贝尔卡德斯
英格丽德·哈斯
亚历山德拉·萨帕塔·马丁内斯
, 劳拉·加拉格尔
＆格拉迪斯·马蒂尔

贡献

研究设计：TACS、DB 和 NA；患者招募和样本收集：UCLH 重症监护研究团队。样本处理和实验采集：TACS 和 UCLH 重症监护研究团队；临床数据收集：TACS、AS、NA 和 UCLH 重症监护研究团队；统计分析：TACS、AS、NA；批判性评论：MS；所有作者均批准了该手稿。

通讯作者

通讯作者：Nishkantha Arulkumaran。

道德批准并同意参与

获取临床样本和数据的伦理批准已获得伦敦-皇后广场研究伦理委员会（REC 参考号 20/LO/1024）。经伦敦大学学院研究伦理委员会事先批准（REC ref 19181/001），还从健康志愿者身上采集了 20 毫升样本和临床数据作为参考。

同意发表

（包含在道德规范中）。

利益争夺

作者声明他们没有任何竞争利益。

出版商备注

施普林格·自然对于已出版的地图和机构隶属关系中的管辖权主张保持中立。

附加文件 1：表 S1。

使用流式细胞术荧光染料。表S2。基线人口统计数据。图S1。非血液病患者和血液病患者之间实验室测量变量的差异。图S2。非血液病患者和血液病患者之间经典单核细胞以及 CD4 ⁺和 CD8 ⁺淋巴细胞功能的差异。图S3。非血液病患者和血液病患者之间经典单核细胞以及 CD4 ⁺和 CD8 ⁺淋巴细胞功能的差异。

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