Basophil levels in PBMC population during childhood acute wheeze/asthma are associated with future exacerbations

Our data suggest that a basophil level above 0.18% of the PBMC population during an acute respiratory exacerbation is associated with an increased risk for future exacerbations in children with asthma and/or wheeze

Personal Network Inference Unveils Heterogeneous Immune Response Patterns to Viral Infection in Children with Acute Wheezing

Human rhinovirus (RV)-induced exacerbations of asthma and wheeze are a major cause of emergency room presentations and hospital admissions among children. Previous studies have shown that immune response patterns during these exacerbations are heterogeneous and are characterized by the presence or absence of robust interferon responses. Molecular phenotypes of asthma are usually identified by cluster analysis of gene expression levels. This approach however is limited, since genes do not exist in isolation, but rather work together in networks. Here, we employed personal network inference to characterize exacerbation response patterns and unveil molecular phenotypes based on variations in network structure. We found that personal gene network patterns were dominated by two major network structures, consisting of interferon-response versus FCER1G-associated networks. Cluster analysis of these structures divided children into subgroups, differing in the prevalence of atopy but not RV species. These network structures were also observed in an independent cohort of children with virus-induced asthma exacerbations sampled over a time course, where we showed that the FCER1G-associated networks were mainly observed at late time points (days four–six) during the acute illness. The ratio of interferon- and FCER1G-associated gene network responses was able to predict recurrence, with low interferon being associated with increased risk of readmission. These findings demonstrate the applicability of personal network inference for biomarker discovery and therapeutic target identification in the context of acute asthma which focuses on variations in network structure

Viral respiratory infections and the oropharyngeal bacterial microbiota in acutely wheezing children.

Acute viral wheeze in children is a major cause of hospitalisation and a major risk factor for the development of asthma. However, the role of the respiratory tract microbiome in the development of acute wheeze is unclear. To investigate whether severe wheezing episodes in children are associated with bacterial dysbiosis in the respiratory tract, oropharyngeal swabs were collected from 109 children with acute wheezing attending the only tertiary paediatric hospital in Perth, Australia. The bacterial community from these samples was explored using next generation sequencing and compared to samples from 75 non-wheezing controls. No significant difference in bacterial diversity was observed between samples from those with wheeze and healthy controls. Within the wheezing group, attendance at kindergarten or preschool was however, associated with increased bacterial diversity. Rhinovirus (RV) infection did not have a significant effect on bacterial community composition. A significant difference in bacterial richness was observed between children with RV-A and RV-C infection, however this is likely due to the differences in age group between the patient cohorts. The bacterial community within the oropharynx was found to be diverse and heterogeneous. Age and attendance at day care or kindergarten were important factors in driving bacterial diversity. However, wheeze and viral infection were not found to significantly relate to the bacterial community. Bacterial airway microbiome is highly variable in early life and its role in wheeze remains less clear than viral influences

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

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 IRF7hi versus IRF7lo 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-?. The two phenotypes also produced distinct clinical phenotypes. For IRF7lo 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 IRF7hi versus IRF7lo phenotypes with associated differences in clinical phenotypes