Heterogeneity within and across Pediatric Pulmonary Infections: From Bipartite Networks to At-Risk Subphenotypes

Although influenza (flu) and respiratory syncytial virus (RSV) infections are extremely common in children under two years and resolve naturally, a subset develop severe disease resulting in hospitalization despite having no identifiable clinical risk factors. However, little is known about inherent host-specific genetic and immune mechanisms in this at-risk subpopulation. We therefore conducted a secondary analysis of statistically significant, differentially-expressed genes from a whole genome-wide case-control study of children less than two years of age hospitalized with flu or RSV, through the use of bipartite networks. The analysis revealed three clusters of cases common to both types of infection: core cases with high expression of genes in the network core implicated in hyperimmune responsiveness; periphery cases with lower expression of the same set of genes indicating medium-responsiveness; and control-like cases with a gene signature resembling that of the controls, indicating normal-responsiveness. These results provide testable hypotheses for at-risk subphenotypes and their respective pathophysiologies in both types of infections. We conclude by discussing alternate hypotheses for the results, and insights about how bipartite networks of gene expression across multiple phenotypes can help to identify complex patterns related to subphenotypes, with the translational goal of identifying targeted therapeutics.