Complement activation correlates with impaired olfactory function in patients with chronic rhinosinusitis with nasal polyps

The mechanisms that contribute to CRSwNP-related olfactory loss are poorly characterized. We have previously shown in middle meatus mucus that levels of C3, a component of the complement system, are elevated and correlate with worse disease severity. Excessive complement activation has been shown to impact the severity and progression of injury in the visual and auditory sensory systems but has yet to be investigated in the context of olfaction and thus is the focus of this study. Mucus from the olfactory cleft was sampled from CRSwNP patients (n=22) undergoing endoscopic sinus surgery. Olfactory status was determined by UPSIT. Patients were categorized into two groups: normosmic/mild microsmic (n=10) and moderate microsomia/total anosmia (n=12). Mucus concentrations of classical (C1q), lectin (MBL), alternative pathways (fB, Adipsin), complement proteins (C2, 4, 3, and 5), activation fragments (C4b, C3a, C3b, C5a), and soluble regulators (Factor I and H) were assessed by multiplex or ELISA. With regards to findings, CRSwNP patients with olfactory dysfunction had higher MBL, C4, C3, fB, and Adipsin levels, suggesting lectin and alternative pathway involvement. Complement activation was present and significantly increased in microsomia/total anosmia patients as determined by the presence C3a and C3b complement cleavage fragments. No differences in terminal pathway proteins, C5 or C5a, were noted. Fluid phase complement inhibitor, factor H, was elevated, representative of increased complement activity. In conclusion, Elevated complement activation is linked to more severe olfactory dysfunction. These findings highlight the potential role of complement pathways in the pathogenesis of olfactory impairment related to CRSwNP.