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.

Defining Age-specific Relationships of Respiratory Syncytial Virus and Rhinovirus Species in Hospitalized Children With Acute Wheeze.

BACKGROUND: Acute wheezing is one of the most common hospital presentations for young children. Respiratory syncytial virus (RSV) and rhinovirus (RV) species A, B and the more recently described species C are implicated in the majority of these presentations. However, the relative importance and age-specificities of these viruses have not been defined. Hence, this study aimed to establish these relationships in a large cohort of prospectively recruited hospitalized children. METHODS: The study cohort was 390 children 0-16 years of age presenting with acute wheezing to a children's emergency department, 96.4% being admitted. A nonwheezing control population of 190 was also recruited. Nasal samples were analyzed for viruses. RESULTS: For the first 6 months of life, RSV was the dominant virus associated with wheezing (P < 0.001). From 6 months to 2 years, RSV, RV-A and RV-C were all common but none predominated. From 2 to 6 years, RV-C was the dominant virus detected (50-60% of cases), 2-3 times more common than RV-A and RSV, RSV decreasing to be absent from 4 to 7 years. RV-B was rare at all ages. RV-C was no longer dominant in children more than 10 years of age. Overall, RV-C was associated with lower mean oxygen saturation than any other virus (P < 0.001). Controls had no clear age distribution of viruses. CONCLUSION: This study establishes a clear profile of age specificity of virus infections causing moderate to severe wheezing in children: RSV as the dominant cause in the first 6 months and RV-C in preschool-age children.

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-γ. 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.

Prospective Assessment of Rhinovirus Symptoms and Species Recurrence in Children With and Without an Acute Wheezing Exacerbation.

To assess if the difference in species-specific immune response to RV-C correlates with a higher frequency of reinfection, shorter time to reinfection, or different symptom severity than infections with RV-A or RV-B. Forty-three patients were enrolled of which 34 were successfully tracked longitudinally over 3 months, with nasal swabs and symptom questionnaires provided every 2 weeks to identify rhinovirus (RV) strains and the concurrent symptomatology. No difference was found in the time to reinfection with an RV species between RV-C and RV-A or RV-B (p = 0.866). There was a trend toward more rapid reinfection with the same species in RV-C than RV-A (55.1 days vs. 67.9 days), but this failed to reach statistical significance (p = 0.105). RV infections were generally associated with only minor symptoms, with rhinorrhea being the only significantly associated symptom (p = 0.01). RV-C was shown to have higher levels of lethargy and wheeze than other RV species. Time to reinfection with subsequent RV is not influenced by the species of the preceding RV.