Vissing Nadja Hawwa, Larsen Jeppe Madura, Rasmussen Morten Arendt, Chawes Bo Lund Krogsgaard, Thysen Anna Hammerich, Bønnelykke Klaus, Brix Susanne, Bisgaard Hans
From the *Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark; and †Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
Pediatr Infect Dis J. 2016 May;35(5):561-6. doi: 10.1097/INF.0000000000001092.
Neonatal colonization of the airways with respiratory pathogens is associated with increased risk of lower respiratory infections (LRI) in early childhood. Therefore, we hypothesized that children developing LRI have an aberrant immune response to pathogenic bacteria in infancy. The objective was to characterize in vitro the early life systemic immune response to pathogenic bacteria and study the possible association with incidence of LRI during the first 3 years of life.
The Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) is a clinical birth cohort study of 411 children born of mothers with asthma. LRI incidence was prospectively captured from 6-monthly planned visits and visits at acute respiratory episodes. The in vitro systemic immune response to Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was characterized by the production of TNF-α, IFN-γ, IL-2, IL-5, IL-10, IL-13 and IL-17 in peripheral blood mononuclear cells isolated at age 6 months from 291 infants. Data were analyzed by Poisson regression against incidence of LRI in infancy.
A multivariable model including all cytokine responses from the 3 different bacterial stimulations significantly identified children at risk of LRI (P = 0.006). The immune response pattern associated with LRI was characterized by perturbed production of several cytokines rather than production of one specific cytokine, and was independent of concurrent asthma. TNF-α and IL-5 were key drivers but did not explain the entire variation in LRI susceptibility.
Children at risk of future LRI present a perturbed systemic immune response upon exposure to common airway pathogens in early life.
呼吸道病原体在新生儿气道中的定植与儿童早期下呼吸道感染（LRI）风险增加有关。因此，我们推测发生LRI的儿童在婴儿期对病原菌有异常的免疫反应。目的是在体外表征生命早期对病原菌的全身免疫反应，并研究其与生命最初3年LRI发病率的可能关联。
哥本哈根儿童哮喘前瞻性研究2000（COPSAC2000）是一项对411名母亲患有哮喘的儿童进行的临床出生队列研究。LRI发病率通过每6个月的定期访视以及急性呼吸道发作时的访视进行前瞻性记录。从291名6个月大婴儿的外周血单个核细胞中分离出的肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）、白细胞介素-2（IL-2）、白细胞介素-5（IL-5）、白细胞介素-10（IL-10）、白细胞介素-13（IL-13）和白细胞介素-17（IL-17）的产生来表征对流感嗜血杆菌、卡他莫拉菌和肺炎链球菌的体外全身免疫反应。通过泊松回归分析针对婴儿期LRI发病率的数据。
一个包含来自3种不同细菌刺激的所有细胞因子反应的多变量模型显著识别出有LRI风险的儿童（P = 0.006）。与LRI相关的免疫反应模式的特征是几种细胞因子的产生受到干扰，而不是一种特定细胞因子的产生，并且与同时存在的哮喘无关。TNF-α和IL-5是关键驱动因素，但不能解释LRI易感性的全部差异。
未来有LRI风险的儿童在生命早期接触常见气道病原体时会出现全身免疫反应紊乱。
