Mucous Cytokine Levels in Chronic Rhinosinusitis–Associated Olfactory Loss

Abstract

IMPORTANCE Olfactory loss is a frequent symptom of patients with chronic rhinosinusitis (CRS), but our understanding of how inflammatory cytokines affect olfaction is limited. OBJECTIVES To examine whether inflammatory cytokines are present in the olfactory cleft and whether they correlate with objective olfaction. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, patients with CRS underwent quantitative olfactory testing using the Sniffin Sticks test to calculate a composite threshold discrimination identification (TDI) score from October 21, 2013, to November 12, 2015. Nasal mucus was collected using a sponge placed in the olfactory cleft for 5 minutes, and Cytometric Bead Array was used to measure secreted immunomodulatory products. Correlations between TDI score and secreted mediators were then calculated. Data analysis was performed from October 15, 2015, to December 17, 2015. MAIN OUTCOMES AND MEASURES Composite TDI scores and mean secreted mediator levels in mucus from the olfactory cleft. RESULTS Thirty-four patients were enrolled (mean [SD] age, 57.3 [15.7] years; female, 21 [61.8%]; white, 26 [76.5]). The TDI scores were lower in patients with CRS with nasal polyps (CRSwNP) than in patients with CRS without nasal polyps (CRSsNP) (difference, 8.7; 95% CI, 2.5–15.0; P = .007). Interleukin (IL) 5 levels were inversely correlated with TDI scores in patients with CRSwNP and those with CRSsNP (mean [SE] β estimate, −46.56 [15.11]; P = .005), whereas IL-6, IL-7, and vascular endothelial growth factor A were positively correlated with TDI scores only in the CRSwNP cohort. Subscale olfactory TDI scores followed similar correlations to composite TDI scores. CONCLUSIONS AND RELEVANCE In this study, inflammatory cytokines were found in mucus collected from the olfactory cleft. Levels of IL-5, in addition to other cytokines, were associated with objective olfactory function. Further inquiry is needed to establish the source of mucous cytokines and establish whether they play a causal role in olfactory loss.

Olfactory and middle meatal cytokine levels correlate with olfactory function in chronic rhinosinusitis

“…We did, however, find that IL‐6 levels were associated with significantly lower SIT scores. This result is in contrast to that by Schlosser et al, which conversely demonstrated a weak positive correlation between mucus IL‐6 levels and olfactory identification scores . Of note, both IL‐6 and IL‐6 receptor expression have been reported in olfactory mucosa, and elevations in IL‐6 have been associated with reduced neurogenesis …”

“…We did, however, find that the Th2‐associated cytokines IL‐5 and IL‐13 are secreted in high levels within olfactory cleft mucus of patients with CRSwNP. Interestingly, Schlosser et al recently reported that mucus IL‐5 levels were inversely correlated with objective olfactory function in all patients with CRS . We identified this association as well, while noting similar findings for the Th2‐associated cytokine IL‐13, though in our case these associations seemed to be driven primarily by the CRSwNP phenotype.…”

“…Recent evidence from transgenic mouse models have supported this olfactory inflammation hypothesis, with local overexpression of proinflammatory cytokines such as tumor necrosis factor‐α (TNF‐α) and interferon‐γ, resulting in inhibition of olfactory neuron function, turnover, or survival . Likewise, a recent study in patients with CRS found that quantitative olfactory function may be inversely associated with olfactory mucus levels of interleukin (IL)‐5 …”

Mucus T helper 2 biomarkers predict chronic rhinosinusitis disease severity and prior surgical intervention

“…Despite apparent pathophysiological relevance 32-35 , our study found that IL-4 was a poor biomarker for Th2-high CRS, largely because mucus levels were indistinguishable from healthy controls. This is in line with recent studies that have also shown small or no differences in IL-4 levels between individual CRS phenotypes or compared to healthy controls 36-39 , but is in contrast to some prior studies that did confirm elevated levels of IL-4 in CRS compared to controls 40-42 . We suspect that much of these conflicting results may be attributable to differences between assays and variability in approaches for mucus collection and processing.…”

Correlation of mucus inflammatory proteins and olfaction in chronic rhinosinusitis

“…This technique would collect mucus from the OC, although it would not allow one to determine whether it was produced by olfactory mucosa or respiratory mucosa. In a small, single‐institution pilot study, we were able to detect inflammatory proteins in mucus collected from the olfactory cleft and show that some correlate with objective olfactory function . The goal of the current study was to confirm and expand on these findings, utilizing a cohort recruited from several centers across North America.…”