The effect of medical therapy and surgery on the paranasal sinus ecosystem in chronic rhinosinusitis

Abstract

Chronic rhinosinusitis (CRS) is a clinical condition characterised by persistent mucosal inflammation of the nasal cavity and paranasal sinuses. The disease burden is associated with a significant reduction in quality of life for an individual as well as losses in productivity and considerable economic costs. Numerous medical therapies are used to control symptoms (including antibiotics, corticosteroids and sinus rinses) with refractory patients usually proceeding to endoscopic sinus surgery (ESS). Microbiological culture data have implicated Staphylococcus aureus and Pseudomonas aeruginosa in patients with poorer outcomes and perioperative care is often directed towards controlling these organisms. Despite aggressive medical and surgical management, improvements in symptoms are not always sustained long-term and many patients relapse or develop recalcitrant disease, particularly after discontinuing medications. The reasons for this remain unknown. The systematic effects of medical therapies and surgery on bacterial communities, innate immunity, wound healing, drug distribution and the physical sinus environment are not well understood. An improved understanding of the effects of perioperative treatments would allow for the development of more targeted therapies and the rehabilitation of sinus mucosa following surgery. This thesis investigated the histological differences between germ free and pathogen free mice revealing that commensal bacteria contribute significantly to the development of normal mucosa. Doxycycline and prednisone were found to have significant effects on the microbiome, using nonculture dependent molecular microbiological analysis. Using similar methods, ESS and the altered postoperative environment were also found to have a significant effect on the microbiome. The in vitro effect of xylitol was found to reduce biofilm biomass, inhibit biofilm formation and reduce growth of planktonic bacteria in bacterial species associated with CRS. Computational fluid dynamics were used to model changes in the physical sinus environment and found differences in airflow, temperature, humidity and drug distribution following ESS. Finally, using a rabbit model of mucosal injury, perioperative topical therapies were found to have significant effects on parameters of wound healing. This thesis advances the hypothesis that medical therapies and surgery have considerable effects on the paranasal ecosystem and seeks to understand some of the most salient interactions between disease and treatment.