Respiratory syncytial virus (RSV) infection has been associated with the subsequent development of recurrent wheezing and asthma, although the mechanisms involved are still unknown. We investigate the role of epigenetics in the respiratory morbidity after infection by comparing methylation patterns from children who develop recurrent wheezing (RW-RSV), subsequent asthma (AS-RVS), and those experiencing complete recovery (CR-RSV).

This is a prospective, observational study of infants aged < 2 years with RSV respiratory infection admitted to hospital and followed-up after discharge for at least three years. According to their clinical course, patients were categorized into subgroups: RW-RSV, AS-RSV, and CR-RSV. The DNA genome-wide methylation pattern was analyzed in whole blood samples, collected during the acute phase of the infection, using the Illumina Infinium Methylation EPIC BeadChip.

Patients who developed respiratory sequelae showed a statistically significant higher proportion of NK and CD8T cells than those with complete recovery. We identified 5,097 significant differentially methylated positions (DMPs) when comparing RW-RSV and AS-RVS together against CR-RSV. The most significant DMPs, affecting several genes involved in airway inflammation processes, were found to be hypomethylated in cases and therefore generally leading to overexpression of affected genes. Logistic regression analysis resulted in a diagnostic epigenetic signature of 3-DMPsthat allows to efficiently differentiate sequelae cases from CR-RSV patients.

Epigenetic mechanisms might play a fundamental role in the long-term sequelae after RSV infection, contributing to explain the different phenotypes observed.