Endotypes of childhood wheezing after severe RSV lower respiratory tract illness in infancy in socially vulnerable Argentinian children

社会弱势阿根廷儿童婴儿期严重 RSV 下呼吸道疾病后儿童喘息的内型

• 批准号: MR/T031565/1
• 负责人: Adnan Custovic
• 金额: $ 116.42万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT031565%2F1
• 关键词: Endotypes; childhood; wheezing; after; severe

Lung diseases are a major cause of ill health and premature death globally, and particularly in low- and middle-income countries. Lower respiratory tract infection caused by respiratory syncytial virus (RSV) is the main cause of hospital admissions in infants worldwide. Every year, millions of infants who are infected with RSV are hospitalised, many progress to experience long-term respiratory illnesses such as asthma, and >100,000 die; 99% of these deaths occur in developing countries. Many children with early-life RSV illness progress to develop recurrent wheezing and asthma, although others do not. In fact, it has been proposed that RSV infection in susceptible children may cause asthma. Recurrent wheezing and asthma reduce quality of life, create significant health care costs, and may affect respiratory health and lung function beyond childhood. Low lung function in young adulthood increases the likelihood of early death from all causes and is an important risk factor for development of chronic obstructive pulmonary disease, which is responsible for 5% of all deaths worldwide. About 90% of those deaths occur in low or middle-income regions. Early identification of infants at high-risk for chronic respiratory symptoms and low lung function in later life may allow us to develop new interventions to avert persistent illness and the serious consequences from loss of lung function. While this is an urgent need worldwide, it is particularly pressing in low-income populations, where infants experience more severe RSV infections and long-term lung illness of greater severity. Our program aims to tackle this lifelong problem in the early months of life. We propose that severe RSV infection causes specific subtype(s) of asthma (but not others), and that different wheeze trajectories and asthma subtypes are linked with different types of immune responses to viruses which can be measured in respiratory secretions, thereby allowing early recognition of children at risk. Our overarching goal is to identify different patterns (or subtypes) of wheezing illness through childhood among children who experienced a severe RSV infection using novel mathematical modelling, and to discover early-life risk factors and molecules which predict these different subtypes of wheezing. We will leverage a unique study of 1,153 children in a low-income region of Argentina. Of these, 419 had severe RSV infection in infancy, 344 a severe non-RSV infection, and 390 are healthy controls. Extensive clinical data has been collected through the initial hospital admission, and biological samples were obtained for future analyses. Participants attended several follow-ups to age 3 years, with excellent retention (91%). We will extend follow up to the age of 6 years. We will derive subtypes of wheeze using sophisticated machine learning techniques, and conduct detailed assessments of lung function at ages 4-6 years. In parallel, we will conduct a series of studies in saved biological samples from the airways to identify types of antiviral immune responses during severe infection in infancy and their relationship with clinical outcomes. Concentrations of multiple molecules which are secreted by certain cells of the immune system and have an effect on other cells will be assessed in respiratory samples. We will identify patterns of immune responses and compare clinical outcomes between different patterns. This study represents a unique opportunity to identify RSV-specific subtype(s) of chronic wheezing and asthma, and define subtype-specific indicators of progression to long-term respiratory illness. Importantly, this information comes from a population highly susceptible to respiratory illness: a group of infants living in extreme poverty. Early identification of infants at risk for progression to long-term wheezing illness may allow interventions to avert persistent disease and loss of lung function in the future.

肺病是全球健康状况不佳和过早死亡的主要原因，特别是在低收入和中等收入国家。呼吸道合胞病毒(RSV)引起的下呼吸道感染是全球婴儿住院的主要原因。每年有数百万感染呼吸道合胞病毒的婴儿住院，其中许多进展是经历哮喘等长期呼吸道疾病，并导致10万人死亡；其中99%的死亡发生在发展中国家。许多患有早期呼吸道合胞病毒病的儿童进展为反复喘息和哮喘，尽管其他人没有。事实上，已经有人提出，易感儿童中的RSV感染可能会导致哮喘。反复出现的喘息和哮喘降低了生活质量，造成了巨大的医疗费用，并可能影响儿童以后的呼吸健康和肺功能。青年时期的低肺功能增加了各种原因导致的早期死亡的可能性，也是慢性阻塞性肺疾病发展的一个重要风险因素，慢性阻塞性肺疾病占全球所有死亡人数的5%。其中约90%的死亡发生在低收入或中等收入地区。及早识别患有慢性呼吸道症状和肺功能低下的高危婴儿，可能使我们能够开发新的干预措施，以避免持续性疾病和肺功能丧失的严重后果。虽然这是全世界的迫切需要，但在低收入人口中尤其紧迫，因为在低收入人口中，婴儿经历更严重的RSV感染和更严重的长期肺部疾病。我们的计划旨在在生命的最初几个月解决这个终生问题。我们认为，严重的呼吸道合胞病毒感染会导致特定的哮喘亚型(S)(而不是其他亚型)，不同的喘息轨迹和哮喘亚型与对病毒的不同类型的免疫反应有关，这些免疫反应可以从呼吸道分泌物中检测到，从而使早期识别处于危险之中的儿童。我们的首要目标是使用新的数学模型在经历过严重呼吸道合胞病毒感染的儿童中识别不同的儿童喘息疾病模式(或亚型)，并发现预测这些不同亚型喘息的早期生命风险因素和分子。我们将利用一项独特的研究，对阿根廷低收入地区的1153名儿童进行研究。在这些人中，419人在婴儿时期有严重的呼吸道合胞病毒感染，344人有严重的非呼吸道合胞病毒感染，390人是健康对照。在首次入院期间收集了大量临床数据，并获取了生物样本用于未来分析。参与者参加了几次随访，直到3岁，保持良好(91%)。我们将延长随访至6岁。我们将使用复杂的机器学习技术得出喘息的亚型，并对4-6岁儿童的肺功能进行详细评估。同时，我们将从呼吸道保存的生物样本中进行一系列研究，以确定婴儿在严重感染期间的抗病毒免疫反应类型及其与临床结果的关系。由免疫系统的某些细胞分泌并对其他细胞产生影响的多种分子的浓度将在呼吸道样本中进行评估。我们将确定免疫反应的模式，并比较不同模式之间的临床结果。这项研究提供了一个确定呼吸道合胞病毒特异性亚型(S)慢性喘息和哮喘的独特机会，并确定了发展为长期呼吸道疾病的亚型特异性指标。重要的是，这一信息来自一个高度易患呼吸道疾病的人群：一群生活在极端贫困中的婴儿。及早识别有发展为长期喘息性疾病的风险的婴儿可能会允许干预措施，以避免未来持续疾病和肺功能的丧失。

项目成果

Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK.

• DOI: 10.1016/s2213-2600(21)00013-8
• 发表时间: 2021-07
• 期刊: The Lancet. Respiratory medicine
• 作者: Bloom CI;Drake TM;Docherty AB;Lipworth BJ;Johnston SL;Nguyen-Van-Tam JS;Carson G;Dunning J;Harrison EM;Baillie JK;Semple MG;Cullinan P;Openshaw PJM;ISARIC investigators
• 通讯作者: ISARIC investigators

Data-driven research on eczema: systematic characterization of the field and recommendations for the future

数据驱动的湿疹研究：该领域的系统特征和未来建议

• DOI: 10.1101/2022.01.14.22269294
• 发表时间: 2022
• 作者: Duverdier A

Data-driven research on eczema: Systematic characterization of the field and recommendations for the future.

• DOI: 10.1002/clt2.12170
• 发表时间: 2022-06
• 期刊: Clinical and translational allergy
• 影响因子: 4.4
• 作者: Duverdier A;Custovic A;Tanaka RJ
• 通讯作者: Tanaka RJ

Allergy Essentials

过敏必需品

• DOI: 10.1016/b978-0-323-80912-2.00003-2
• 发表时间: 2022
• 作者: Custovic A

Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study.

• DOI: 10.1016/s2665-9913(21)00104-1
• 发表时间: 2021-07
• 期刊: The Lancet. Rheumatology
• 作者: Drake TM;Fairfield CJ;Pius R;Knight SR;Norman L;Girvan M;Hardwick HE;Docherty AB;Thwaites RS;Openshaw PJM;Baillie JK;Harrison EM;Semple MG;ISARIC4C Investigators
• 通讯作者: ISARIC4C Investigators