Immune biomarker discovery in children susceptible to recurrent otitis media

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Project Summary/Abstract Viral-bacterial co-infections are often the most serious infectious events in young children, leading to unplanned office and hospital visits as well as significant morbidity. Acute otitis media (AOM) is a canonical viral-bacterial co-infection, where an opportunistic nasopharyngeal colonizer ascends the Eustachian tube to infect the middle ear during a concurrent viral upper respiratory infection. In a cohort study of >1000 children over the last 14 years, we have studied AOM pathogenesis, epidemiology, and immunity from six months to five years of age. Children prone to multiple AOMs, termed stringently-defined otitis prone (sOP) children in our cohort, comprise approximately 10% of the total child population but account for the majority of the health care burden due to AOM and are more likely to undergo surgery for tympanostomy tube insertion. It is clear that sOP children are colonized early in life with one or more potential otopathogens compared to non-otitis prone (NOP) children, but this predictive feature of susceptibility requires continuous monitoring throughout early life in order to determine. Preliminary data suggests that, in addition to changes in nasopharyngeal (NP) otopathogen colonization and demographic risk factors, sOP children have a pro-inflammatory phenotype in the NP after one year of age. Immune network modeling of the NP immune response to AOM comparing sOP and NOP children suggests an IL-6, IL-10, IL-17A, and CCL5 immune network may be responsible for the immune differences observed in sOP children. From these data, our hypothesis is that early life colonization with otopathogens alters NP immunity, thus leaving some children susceptible to recurrent AOM. Further, soluble NP factors can be identified that, when measured in early life, will be a predictor of recurrent AOM and inform individualized care. Aim 1 will employ LC-MS based proteomics in matched sOP and NOP samples to determine the NP proteome at defined ages before, during, and after AOM susceptibility for biomarker identification. Aim 2 will measure the candidate biomarkers from Aim 1 in 400 nasal wash samples across the child cohort to determine robustness of the biomarkers across child age and covariates. Therefore, this grant proposal focuses on the determination of a bio-signature predictive of severe recurrent AOM and therefore the need for tympanostomy tube insertion versus watchful waiting that will be measured before or during the onset of AOM infections in children under two years of age.