Abstract
There is growing interest for studying how early-life influences the development of respiratory diseases. Our aim was to apply metabolomic analysis to urine collected at birth, to evaluate whether there is any early metabolic signatures capable to distinguish children who will develop acute bronchiolitis and/or recurrent wheezing. Urine was collected at birth in healthy term newborns. Children were followed up to the age of 3 years and evaluated for the development of acute bronchiolitis and recurrent wheezing (≥3 episodes). Urine were analyzed through a liquid-chromatography mass-spectrometry based untargeted approach. Metabolomic data were investigated applying univariate and multivariate techniques. 205 children were included: 35 had bronchiolitis, 11 of whom had recurrent wheezing. Moreover, 13 children had recurrent wheezing not preceded by bronchiolitis. Multivariate data analysis didn’t lead to reliable classification models capable to distinguish children with and without bronchiolitis or with recurrent wheezing preceded by bronchiolitis neither by PLS for classification (PLS2C) nor by Random Forest (RF). However, a reliable signature was discovered to distinguish children who later develop recurrent wheezing not preceded by bronchiolitis, from those who do not (MCCoob = 0.45 for PLS2C and MCCoob = 0.48 for RF). In this unselected birth cohort, a well-established untargeted metabolomic approach found no biochemical-metabolic dysregulation at birth associated with the subsequent development of acute bronchiolitis or recurrent wheezing post-bronchiolitis, not supporting the hypothesis of an underlying predisposing background. On the other hand, a metabolic signature was discovered that characterizes children who develop wheezing not preceded by bronchiolitis.
Highlights
Even if the association between acute bronchiolitis and subsequent recurrent wheezing is well known [1,2], the mechanism by which this may occur is poorly understood.There is an historical debate whether the viral acute infection causes the subsequent recurrent wheezing, by affecting airway structure or by inducing a long-term aberrant immune response to different triggers, or if the viral acute infection is just the first sign of a long-term airway morbidity related to host pre-existing susceptibility factors [2,3]
We obtained a mass accuracy for the standard mix of less than 3 ppm for the 9 metabolites used, a change in retention times in a 0.20 min window and a coefficient of variation in ion intensity, both for the standards and for most of the identified metabolites in the Quality Control samples (QC) (85 metabolites), less than 20%, both in positive and in negative
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Summary
There is an historical debate whether the viral acute infection causes the subsequent recurrent wheezing, by affecting airway structure or by inducing a long-term aberrant immune response to different triggers, or if the viral acute infection is just the first sign of a long-term airway morbidity related to host pre-existing susceptibility factors [2,3]. These perspectives are not mutually exclusive, being both relevant in recurrent wheeze development. A recent birth cohort study demonstrated that early-life environmental exposures (such as maternal psychological state, tobacco smoke, allergens and microbes) show specific association with different childhood respiratory phenotypes, defined by wheezing and sensitization patterns [6]
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