Does hospitalisation of older patients with severe community acquired pneumonia and sepsis lead to long term immunoparesis?

患有严重社区获得性肺炎和败血症的老年患者住院是否会导致长期免疫麻痹？

• 批准号: MR/S002782/1
• 负责人: David Thickett
• 金额: $ 66.85万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS002782%2F1
• 关键词: Does; hospitalisation; older; patients; severe

Pneumonia is a serious lung infection. The 5th leading cause of death, each year 11 in every 1000 adults develop pneumonia outside of hospital, and 1 in 100 of those die. If the person is ill enough to be admitted to hospital, the death rate is much higher, and this rises considerably if a complication called sepsis develops. Sepsis is a syndrome whereby the infection causes changes to the body's natural immune system and ultimately cause damage to organs such as the lungs, brain and heart. Older people are more likely to develop pneumonia, have a higher risk of sepsis, and have worse outcomes (30 in 100 dying within 6 months). The main treatment for pneumonia is antibiotics. Older adults often do not make a full recovery. An episode of pneumonia can lead to increased frailty, with the older person needing more social support or admission to a care home. Following pneumonia, older people are more susceptible to developing a subsequent (secondary) infection. These include another pneumonia, but also infections elsewhere in the body. Secondary infections have even worse outcomes but the reason older people are prone to them is unclear.There are no treatments that help the immune system overcome pneumonia. Given that our population is ageing, this is an area of huge unmet need.Neutrophils are white blood cells crucial for fighting infections. They leave the blood, moving (migrating) accurately to areas of infection, where they ingest bacteria, killing them with an arsenal of proteins contained within the cell. These proteins cause damage and inflammation if they are released outside of the cell into the body's tissues. In the face of overwhelming infection, neutrophils release their intracellular contents either directly into tissues (degranulation) or by releasing injurious proteins on a web of their own internal contents (like a fishing net) to trap and kill bacteria. Neutrophils contain genes that control the cell by dictating what proteins are expressed. These proteins could be enzymes, controlling chemical reactions within the neutrophil, or structural proteins, controlling how they move.Other white blood cells help coordinate our immune system, by increasing neutrophil responses to make them clear infection or release their injurious contents more aggressively or dampening down their responses to promote healing. Cells involved in these controlling processes include B cell and T cell lymphocytes, which act as a memory of infections we have experienced in the past. B cells produce antibodies that promote the ingestion of bacteria and T cells coordinate local tissue responses, increasing inflammation and neutrophil activity at the start of an infection and promoting tissue healing after infection is cleared. How immune cells function deteriorates with age. With ageing, our immune system becomes less able to differentiate "friend" (things that are safe) from "foe" (bacteria that will damage us). Our research shows that neutrophil migration, ingestion of bacteria and NET production become indiscriminate and inaccurate. Immune memory fades and our ability to respond quickly to infection but then heal, is blunted. When older people develop pneumonia, immune function is compromised even further. Our research suggests that neutrophil migration and bacterial clearance is severely impaired for up to 6 weeks after pneumonia. We believe this paralysis of the immune system may lead to secondary infections. We wish to investigate the long-term relevance of injurious neutrophil behaviours in pneumonia, using immune cells from patients with pneumonia and following recovery, and in models of infection. By studying B and T cells and how they interact with neutrophils, we will be able to determine the cause of the prolonged defective neutrophil behaviour, including the genes that control these cells. This will provide a new understanding of how our immune cells function in pneumonia and how we can improve outcome.

肺炎是一种严重的肺部感染。第五大死因，每年每1000名成年人中就有11人在医院外患肺炎，其中1/100死亡。如果患者的病情足以入院，死亡率就会高得多，如果出现一种称为败血症的并发症，死亡率就会大幅上升。败血症是一种综合征，感染会导致身体自然免疫系统的变化，最终导致肺、脑和心脏等器官的损害。老年人更容易患肺炎，有更高的脓毒症风险，结果更差(每100人中有30人在6个月内死亡)。肺炎的主要治疗方法是抗生素。老年人通常不会完全康复。肺炎的发作可能会导致身体虚弱，老年人需要更多的社会支持或进入疗养院。继肺炎之后，老年人更容易继发(继发)感染。这些包括另一种肺炎，但也包括身体其他部位的感染。继发性感染的结果甚至更糟，但老年人容易患上继发性感染的原因尚不清楚。目前还没有帮助免疫系统战胜肺炎的治疗方法。考虑到我们的人口正在老龄化，这是一个巨大的未得到满足的需求领域。中性粒细胞是对抗感染的关键白细胞。它们离开血液，准确地移动(迁移)到感染区域，在那里它们摄取细菌，用细胞内包含的大量蛋白质杀死它们。如果这些蛋白质从细胞外释放到身体组织中，就会造成损伤和炎症。面对压倒性的感染，中性粒细胞将其细胞内内容物直接释放到组织中(脱颗粒)，或者通过释放自身内部内容物的网(如渔网)释放有害蛋白质来捕获和杀灭细菌。中性粒细胞含有控制细胞表达的蛋白质的基因。这些蛋白质可能是酶，控制中性粒细胞内的化学反应，或者结构蛋白，控制它们的移动方式。其他白细胞帮助协调我们的免疫系统，通过增加中性粒细胞的反应，使它们清除感染，或更积极地释放其有害内容，或抑制它们的反应，以促进愈合。参与这些控制过程的细胞包括B细胞和T细胞淋巴细胞，它们作为我们过去经历过的感染的记忆。B细胞产生抗体，促进细菌的摄取，T细胞协调局部组织反应，在感染开始时增加炎症和中性粒细胞的活性，并在感染清除后促进组织愈合。免疫细胞的功能如何随着年龄的增长而恶化。随着年龄的增长，我们的免疫系统越来越不能区分“朋友”(安全的东西)和“敌人”(伤害我们的细菌)。我们的研究表明，中性粒细胞的迁移、细菌的摄取和净生产变得不分青红皂白和不准确。免疫记忆消失，我们对感染快速反应但随后痊愈的能力变得迟钝。当老年人患上肺炎时，免疫功能会进一步受损。我们的研究表明肺炎后中性粒细胞迁移和细菌清除严重受损长达6周。我们认为，这种免疫系统的瘫痪可能会导致继发性感染。我们希望使用肺炎患者和康复后的免疫细胞以及感染模型来研究肺炎患者中性粒细胞损害性行为的长期相关性。通过研究B和T细胞以及它们如何与中性粒细胞相互作用，我们将能够确定中性粒细胞行为长期缺陷的原因，包括控制这些细胞的基因。这将对我们的免疫细胞如何在肺炎中发挥作用以及我们如何改善预后提供新的理解。

项目成果

Predicting the pulmonary effects of long-term e-cigarette use: are the clouds clearing?

• DOI: 10.1183/16000617.0121-2021
• 发表时间: 2022-03-31
• 期刊: EUROPEAN RESPIRATORY REVIEW
• 影响因子: 7.5
• 作者: Davis, Lauren C.;Sapey, Elizabeth;Thickett, David R.;Scott, Aaron
• 通讯作者: Scott, Aaron

Dysregulated Neutrophil Phenotype and Function in Hospitalised Non-ICU COVID-19 Pneumonia.

• DOI: 10.3390/cells11182901
• 发表时间: 2022-09-16
• 期刊: CELLS
• 影响因子: 6
• 作者: Belchamber, Kylie B. R.;Thein, Onn S.;Hazeldine, Jon;Grudzinska, Frances S.;Faniyi, Aduragbemi A.;Hughes, Michael J.;Jasper, Alice E.;Yip, Kay Por;Crowley, Louise E.;Lugg, Sebastian T.;Sapey, Elizabeth;Parekh, Dhruv;Thickett, David R.;Scott, Aaron
• 通讯作者: Scott, Aaron

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

• DOI: 10.1164/rccm.202007-2794oc
• 发表时间: 2020-12-15
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Drake TM;Docherty AB;Harrison EM;Quint JK;Adamali H;Agnew S;Babu S;Barber CM;Barratt S;Bendstrup E;Bianchi S;Villegas DC;Chaudhuri N;Chua F;Coker R;Chang W;Crawshaw A;Crowley LE;Dosanjh D;Fiddler CA;Forrest IA;George PM;Gibbons MA;Groom K;Haney S;Hart SP;Heiden E;Henry M;Ho LP;Hoyles RK;Hutchinson J;Hurley K;Jones M;Jones S;Kokosi M;Kreuter M;MacKay LS;Mahendran S;Margaritopoulos G;Molina-Molina M;Molyneaux PL;O'Brien A;O'Reilly K;Packham A;Parfrey H;Poletti V;Porter JC;Renzoni E;Rivera-Ortega P;Russell AM;Saini G;Spencer LG;Stella GM;Stone H;Sturney S;Thickett D;Thillai M;Wallis T;Ward K;Wells AU;West A;Wickremasinghe M;Woodhead F;Hearson G;Howard L;Baillie JK;Openshaw PJM;Semple MG;Stewart I;Jenkins RG;ISARIC4C Investigators
• 通讯作者: ISARIC4C Investigators