To the Editor

We highly appreciate Korppi and Riikonen's comment to our article regarding trajectories of lung function and bronchial hyper‐reactivity (BHR) during puberty in children with bronchiolitis in infancy.1, 2 The comment offers an overview of the published literature based on three Finnish and Norwegian cohorts following children hospitalized for bronchiolitis in early age. Our published study is actually a substudy of a larger study of approximately 200 young adults with previous bronchiolitis and matched controls, performed at 17‐20 years of age. This main study is now under preparation and will focus on differences between groups and associations with risk factors. The published substudy represents the subjects who have undergone lung function testing at both 11 and 18 years of age.1, 3

We have learned from longitudinal cohort studies that there is a distribution of lung function trajectories throughout a lifespan.4 This has been shown both in unselected populations and after other infant respiratory diseases such as bronchopulmonary dysplasia associated with extreme prematurity.4 These developmental processes are controlled and modulated by a range of genetic and environmental factors that vastly influence individual respiratory health and disease.5 It has been hypothesized that chronic obstructive pulmonary disease (COPD) begins in childhood, either as a result of an early respiratory insult or precipitated by a disadvantageous intrauterine environment.5 To what extent, in what way, and importantly, which early childhood events have an impact on lung function trajectories, is therefore a highly prioritized research agenda.

Bronchial hyper‐reactivity is a hallmark of asthma, but also reported in individuals without respiratory symptoms, even in infants, and may precede the development of severe bronchiolitis, asthma, and possible COPD.6 Pike and colleagues argue for a causal role of early fetal growth restriction in the development of BHR, substantiated by findings in a mouse model,7 and also found in a study of children born extremely preterm.8 Persisting BHR is also shown after bronchiolitis.3 In our study, we found stable BHR during puberty, with neither improvements toward the normal range nor any signs of further deterioration.1 Moreover, we found that BHR at age 11 was independently associated with asthma at age 18.1 The results support a notion that increased BHR is a feature that is established in early life, either due to airway damage caused by the respiratory insult during bronchiolitis, or already present prior to the respiratory event. Is it possible that BHR is an inborn feature leading to both a severe course of bronchiolitis in infancy, asthma during childhood and young adulthood, and finally COPD in later adulthood? Larger population‐based cohort studies with early measurements of lung function and BHR will be necessary to answer this question.

Korppi and Riikonen argue that future follow‐up studies after bronchiolitis should focus on the development of irreversible airflow obstruction by including reversibility testing rather than assessments of BHR.2 However, testing of reversibility cannot reliably be performed at the same day as tests for BHR. Based on the considerations above, we chose to prioritize tests of BHR.

We agree that the Norwegian and Finnish studies published so far have relatively few participants, and are therefore hampered by low statistical power. Sufficiently powered studies are certainly welcome in this area of respiratory medicine and important to confirm our results suggesting stable predicted lung function and no changes of BHR during puberty after bronchiolitis in infancy.

致编辑

我们高度赞赏Korppi和Riikonen对我们关于婴儿期毛细支气管炎儿童青春期肺功能和支气管高反应性（BHR）轨迹的评论。1，2该评论概述了已发表的文献，该文献基于在早期因支气管炎住院的儿童后的三个芬兰和挪威队列。我们发表的研究实际上是对17至20岁进行的大约200例先前患有细支气管炎和相匹配的对照的年轻人进行的一项大型研究的子研究。这项主要研究目前正在准备中，将侧重于具有危险因素的群体和协会之间的差异。已发表的子研究代表已在11岁和18岁接受肺功能测试的受试者。一三

我们从纵向队列研究中获悉，整个生命周期中肺功能轨迹存在分布。4这在未选人群和其他婴儿呼吸道疾病（如与极端早产相关的支气管肺发育异常）中均已显示。4这些发育过程受广泛影响个体呼吸系统健康和疾病的一系列遗传和环境因素控制和调节。5据推测，慢性阻塞性肺疾病（COPD）可能是由于早期呼吸道感染或由于不利的宫内环境而在儿童期开始的。5因此，在何种程度上，以何种方式，以及重要的是，哪些幼儿事件对肺功能轨迹有影响，是高度优先的研究议程。

支气管高反应性是哮喘的标志，但在没有呼吸道症状的个体中也有报道，即使在婴儿中，也可能在严重的细支气管炎，哮喘和可能的COPD发生之前出现。[6]派克（Pike）及其同事争辩说，早期胎儿生长受限在BHR发生中起因果作用，这一作用已在小鼠模型[ 7]中得到证实，并且在一项针对极早产儿的研究中也得到证实。8细支气管炎后也显示持续性BHR。3在我们的研究中，我们发现青春期期间的BHR稳定，既没有向正常范围的改善，也没有进一步恶化的迹象。1此外，我们发现11岁时的BHR与18岁时的哮喘独立相关。1结果支持这样一种观点，即BHR升高是早年确立的一种特征，这可能是由于细支气管炎期间呼吸道感染引起的气道损伤或在呼吸道事件之前就已经存在。BHR是否可能是一种先天性特征，导致婴儿期严重的细支气管炎病程，儿童期和成年后的哮喘病以及成年后的最终COPD？为了对这个问题进行回答，有必要对早期的肺功能和BHR进行更大规模的队列研究。

Korppi和Riikonen认为，毛细支气管炎后的未来随访研究应通过包括可逆性测试而不是BHR评估来关注不可逆性气流阻塞的发展。2但是，可逆性测试无法与BHR测试同时可靠地进行。基于上述考虑，我们选择对BHR的测试进行优先排序。

我们同意，迄今为止发表的挪威和芬兰研究参与者相对较少，因此受制于较低的统计能力。在呼吸道医学领域，足够强大的研究无疑是受欢迎的，并且对证实我们的结果表明婴儿期毛细支气管炎后青春期期间稳定的预测肺功能和BHR没有变化非常重要。