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

肺部疾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。由呼吸道合胞病毒（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RSV的婴儿住院治疗，许多人发展为长期呼吸道疾病，如哮喘，超过100，000人死亡;其中99%的死亡发生在发展中国家。许多患有早期RSV疾病的儿童进展为复发性喘息和哮喘，尽管其他人没有。事实上，已经提出易感儿童的RSV感染可能导致哮喘。反复喘息和哮喘降低生活质量，产生显著的医疗保健成本，并可能影响儿童期以后的呼吸系统健康和肺功能。青年期肺功能低下会增加各种原因导致的早期死亡的可能性，并且是慢性阻塞性肺疾病发展的重要风险因素，慢性阻塞性肺疾病占全球所有死亡人数的5%。其中90%的死亡发生在低收入或中等收入地区。早期识别婴儿在以后的生活中具有慢性呼吸道症状和低肺功能的高风险，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。虽然这是世界范围内的迫切需求，但在低收入人群中尤为紧迫，因为婴儿会经历更严重的RSV感染和更严重的长期肺部疾病。我们的计划旨在解决这个终身问题在生命的最初几个月。我们认为，严重的RSV感染会导致特定的哮喘亚型（而不是其他亚型），不同的喘息轨迹和哮喘亚型与不同类型的病毒免疫反应有关，这些免疫反应可以在呼吸道分泌物中测量，从而可以早期识别处于风险中的儿童。我们的总体目标是使用新的数学模型在经历过严重RSV感染的儿童中识别儿童期喘息疾病的不同模式（或亚型），并发现早期生命风险因素和预测这些不同喘息亚型的分子。我们将利用阿根廷低收入地区1,153名儿童的独特研究。其中，419例婴儿期严重RSV感染，344例严重非RSV感染，390例为健康对照。通过首次入院收集了大量临床数据，并获得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推导出喘息的亚型，并对4-6岁儿童的肺功能进行详细评估。与此同时，我们将对保存的气道生物样本进行一系列研究，以确定婴儿严重感染期间的抗病毒免疫反应类型及其与临床结局的关系。将在呼吸道样本中评估由免疫系统的某些细胞分泌并对其他细胞有影响的多种分子的浓度。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独特的机会，以确定RSV特异性慢性喘息和哮喘亚型，并定义亚型特异性指标进展为长期呼吸道疾病。重要的是，这些信息来自一个极易患呼吸道疾病的人群：一群生活在极端贫困中的婴儿。早期识别有进展为长期喘息性疾病风险的婴儿可能有助于采取干预措施，避免未来疾病持续存在和肺功能丧失。

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.