Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing

Abstract

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7 hi versus IRF7 lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-g. The two phenotypes also produced distinct clinical phenotypes. For IRF7 lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7 hi versus IRF7 lo phenotypes with associated differences in clinical phenotypes.

Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze

“…In the absence of a suitable animal model of asthma or of epithelial dysfunction due to PI3K/Aktintegrin α5β1 downregulation (37), we interrogated published ex vivo pAEC transcriptomic data sets for evidence of these pathways being implicated in early-life wheeze or asthma. We discovered that defective wound repair and dysregulated PI3K/Akt expression were associated with: (a) adult asthma (38), (b) acute wheeze exacerbations, and (c) wheeze recurrence in children presenting to hospital emergency department (39). Our observations of defective epithelial repair contributing to the development of respiratory symptoms are also supported by McErlean and colleagues (16), who identified inadequate nasal epithelial repair to differentiate adult asthmatics that experienced acute respiratory exacerbation.…”

“…We interrogated data sets for evidence of these pathways being implicating in early-life wheeze or asthma, as well as identified who would potentially benefit from celecoxib treatment. Specifically, we targeted our comparisons to data sets using ex vivo nasal samples from adults with physician-diagnosed stable, mild asthma (38) or from viral-induced acute wheeze exacerbations in children (39). Comparison of our defective lower airway pAEC repair signature to the adult stable, mild asthma data set (38) identified more than 80 common DE genes (Supplemental Table 8), including genes associated with integrin and PI3K/Akt pathways like FN1, GRB2, SR, and SHC1 (Supplemental Figure 8).…”

The impact of asthma, toll-like receptors 7 and 8, genetic and clinical determinants on antiviral immune response

“…identified several possible clusters of different cytokine responses to RV in year old children and searched for associations with childhood asthma. Similar to the transcriptome studies(Gomez et al 2018;Khoo et al 2019), they identified two clusters with the lowest and highest IFN response that were associated with asthma. These controversies between studies emphasise the fact that type IFN response variation are not explicit and are most likely influenced by several variables.…”

“…A few recent studies have also challenged the notion that the antiviral immune response in asthma is characterised by type I IFN deficiency. Two transcriptomic studies show that type I IFN production varies between different types of respiratory infection-associated asthma exacerbations but is not necessarily low (Gomez et al 2018;Khoo et al 2019). The third birth-cohort study investigated the association between various cytokine responses to RV and childhood asthma and found that participants with the highest and lowest IFN production were most likely asthmatic compared to other cytokine response types.…”

“…and IFNβ production in response to RV increases in IL4 and IL13 co-culture (Herbert et al 2017). Transcriptome studies of asthma exacerbation types reveal distinct asthma subtypes where IFN production during an exacerbation is either high or low (Gomez et al 2018;Khoo et al 2019). An elaborate study by Custovic et al (2018) The differences between high and low IFNα responders will be examined further in Chapter 4.…”