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Objective: To evaluate the association between smell loss and other aspects of disease, and evaluate dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate or severe smell loss. Methods: This post-hoc analysis of the SINUS-24/52 studies (NCT02912468/NCT02898454) analyzed nasal polyp score (NPS, 0−8), nasal congestion/obstruction (NC, 0−3), Lund-Mackay CT-scan score (LMK-CT, 0−24), rhinosinusitis severity visual analog scale (RS-VAS, 0-10), and 22-item Sinonasal Outcome Test (SNOT-22, 0−110) according to baseline monthly average patient-reported loss of smell scores (LoS, 0−3) of >1 to 2 (moderate) or >2 to 3 (severe) in patients randomized to dupilumab 300 mg or placebo every 2 weeks. Results: Of 724 patients randomized, baseline LoS was severe in 601 (83%) and moderate in 106 (15%). At baseline, severe versus moderate LoS was associated with 1-point greater severity of NC (odds ratio [OR] 6.01 [95% confidence interval, (CI) 3.95, 9.15]), 5-point greater severity of LMK-CT (OR 2.19 [1.69, 2.85]), and 8.9-point greater severity of SNOT-22 (OR 1.35 [1.20, 1.49]). At Week 24, least squares mean differences (95% CI) dupilumab versus placebo in change from baseline were: NPS −1.90 (−2.56, −1.25) and −1.95 (−2.20, −1.70) in the moderate and severe baseline LoS subgroups, respectively; NC −.35 (−.64, −.06) and −1.00 (−1.13, −.87); LMK-CT −6.30 (−7.88, −4.72) and −6.22 (−6.82, −5.63); RS-VAS −1.18 (−2.20, −.16) and −3.47 (−3.90, −3.03); and SNOT-22 −7.52 (−14.55, −.48) and −21.72 (−24.63, −18.82); all nominal P <.05 versus placebo. Improvements with dupilumab in NC, RS-VAS, and SNOT-22 were statistically greater in patients with severe versus moderate baseline LoS. Conclusion: Significant smell impairment in severe CRSwNP is associated with significant disease (NC, RS-VAS, LMK), health-related quality of life impairment (SNOT-22), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease. Dupilumab significantly improved NPS, NC, LMK-CT, RS-VAS, and SNOT-22 in subjects with moderate and severe baseline smell loss. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusion\nPLAIN LANGUAGE SUMMARYLoss of sense of smell is a cardinal symptom of chronic rhinosinusitis with nasal polyps (CRSwNP) and significantly impacts health-related quality-of-life. Dupilumab significantly improved smell outcomes (loss of smell [LoS] score; University of Pennsylvania Smell Identification Test [UPSIT]) versus placebo in the phase 3 SINUS-24/-52 studies (clinicaltrials.gov, NCT02898454/NCT02912468) in patients with severe CRSwNP. This post hoc analysis investigated the effect of dupilumab on olfaction using UPSIT smell impairment categories.Patients with baseline smell impairment (UPSIT ≤34/≤33 [women/men; score range 0–40] AND LoS score ≥1 [0–3] AND smell/taste item of the 22-item Sinonasal Outcome Test >0 [SNOT-22; 0–5]) treated with dupilumab 300 mg or placebo once every 2 weeks on background intranasal corticosteroids were analyzed.Of 724 patients, 665 (91.9%) had smell impairment at baseline; most had anosmia (UPSIT 0–18) (dupilumab/placebo: 80.9%/79.8%). At week 24, the proportion of dupilumab-treated patients with anosmia decreased to 28.5%, while 14.9% achieved normosmia; most placebo-group patients (79.2%) remained anosmic and only 1.2% achieved normosmia (odds ratio = 17.3; 95% confidence interval = 5.1–59.0; p <.0001); results were similar at week 52. Improvements in Nasal Polyp Score, nasal congestion, and SNOT-22 total score were moderately correlated with improvements in UPSIT at weeks 24 and 52 (r = −.38 to −.50).Most patients with severe CRSwNP had anosmia at baseline. Dupilumab treatment significantly improved smell versus placebo, with 14.9% achieving normosmia by week 24. There was a trend for better clinical outcomes in patients with greater smell improvement.Chronic rhinosinusitis with nasal polyps (CRSwNP) is a condition that causes partial or complete blockage of the nose, making it difficult to breathe. This has a negative effect on many aspects of a person’s life, with loss of sense of smell one of the most common and troublesome symptoms. A drug called dupilumab, which is injected under the skin every other week, has been approved for use in people with CRSwNP. This article presents results from two studies where dupilumab was tested to see if it helped people with CRSwNP, including whether it could improve sense of smell. At the start of the trial, about 80% of people had completely lost their sense of smell, known as anosmia. After 24 weeks, fewer people taking dupilumab had no sense of smell (28.5%) and more had a completely normal sense of smell (14.9%) compared with people who took a placebo (79.2% had no sense of smell; 1.2% had a normal sense of smell). Smell was assessed again after 52 weeks and dupilumab continued to provide a similar benefit. Dupilumab also improved other aspects of CRSwNP, including reducing polyp size, clearing nose blockage, and improving quality-of-life. In summary, most people with CRSwNP at the start of the dupilumab studies had completely lost their sense of smell, and dupilumab improved smell for most people within 24 weeks. This shows the benefit of dupilumab in dealing with this bothersome and difficult-to-treat symptom of CRSwNP. [ABSTRACT FROM AUTHOR]

This article discusses the effectiveness of dupilumab, a monoclonal antibody, in treating chronic rhinosinusitis with nasal polyposis (CRSwNP). The study examines the relationship between baseline serum total IgE and blood eosinophils levels and the response to dupilumab treatment. The results indicate that dupilumab is effective in improving both objective and subjective measures of CRSwNP severity, regardless of baseline biomarker levels. However, patients with higher blood eosinophil counts showed a greater improvement in treatment outcomes. The findings suggest that dupilumab may be a promising treatment option for CRSwNP patients, particularly those with elevated blood eosinophil levels. The study was funded by Sanofi and Regeneron Pharmaceuticals. [Extracted from the article]

Background: Chronic rhinosinusitis (CRS) is the leading cause of olfactory dysfunction in the general population. Olfactory dysfunction is more common in patients with CRS with nasal polyposis (CRSwNP) compared to those without polyps. Purpose: The present review aims to summarize the current literature on the mechanism behind olfactory dysfunction in CRSwNP and the impact of therapy on olfactory outcomes in this patient population. Methods: A comprehensive review of the available literature on olfaction in CRSwNP was performed. We evaluated the most recent evidence from studies on the mechanisms behind smell loss in CRSwNP and the impact of medical and surgical therapy for CRS on olfactory outcomes. Results: The mechanism behind olfactory dysfunction in CRSwNP is not completely understood, but evidence from clinical research and animal models suggests both an obstructive component causing conductive olfactory loss and an inflammatory response in the olfactory cleft leading to sensorineural olfactory loss. Oral steroids and endoscopic sinus surgery have both shown efficacy in improving olfactory outcomes in CRSwNP in the short term; however, the long-term response of these treatments remains uncertain. Newer targeted biologic therapies, such as dupilumab, have also shown remarkable and durable improvement in smell loss for CRSwNP patients. Conclusion: Olfactory dysfunction is highly prevalent in the CRSwNP population. Although significant advances have been made in our understanding of olfactory dysfunction in the setting of CRS, additional studies are needed to elucidate cellular and molecular changes mediated by type 2-mediated inflammation in the olfactory epithelium with potential downstream effects on the central olfactory system. Further identification of these underlying basic mechanisms will be vital for developing future therapies targeted to improve olfactory dysfunction in patients with CRSwNP. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has been traditionally managed with a combination of topical and systemic medical therapy as well as endoscopic sinus surgery. The emergence of biologic therapies that target specific aspects of the inflammatory cascade has ushered in a potentially new paradigm in the management options available for CRSwNP. Purpose: To summarize the current literature and recommendations supporting the use of available biologic therapies for CRSwNP and to develop an algorithm to aid clinical decision-making regarding treatment selection. Methods: A review of available literature and studies that demonstrated the clinical efficacy of biologic agents for the treatment of CRSwNP informing current CRSwNP consensus algorithms. Results: Current biologic medications target immunoglobulin E, interleukins, or interleukin receptors implicated in the Th2 inflammatory cascade. Institution of biologic therapy is now an option for patients who have disease refractory to topical medical therapy and endoscopic sinus surgery, those who cannot tolerate surgery, or patients with other comorbid Th2 diseases. Response to treatment should be monitored at 4–6 months and 1 year after initiating therapy. Across multiple indirect comparisons, dupilumab appears to have the largest therapeutic benefit across multiple subjective and objective outcomes. The choice of therapeutic agent also depends on drug availability, patient tolerance, presence of comorbid illnesses, and cost. Conclusions: Biologics are emerging as an important option in the management of patients with CRSwNP. While more data is required to fully inform indications, treatment selection, and health economics related to their use, biologics may offer robust symptom relief to patients who have failed other interventions. [ABSTRACT FROM AUTHOR]

In conclusion, our analysis shows that in patients with severe CRSwNP, dupilumab treatment improved patient-reported "taste" versus placebo. Sense of smell was measured using the loss-of-smell score (LoS) - reported daily by patients on a scale of 0-3, similar to how patient-reported taste was measured - UPSIT and the SNOT-22 smell/taste item. Improvement in patient-reported "taste" and association with smell in dupilumab-treated patients with severe chronic rhinosinusitis with nasal polyps from the SINUS-24 and SINUS-52 trials Post-hoc analysis showed dupilumab significantly improves patient-reported "taste" versus placebo in patients with severe CRSwNP. [Extracted from the article]

Summary: Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) can be a severe and debilitating disease associated with significant morbidity, loss of smell, sinus pressure and asthma exacerbations. Eosinophils play a role in the majority (85%) of patients. Benralizumab, an afucosylated monoclonal antibody directed against the IL‐5 receptor, has powerful apoptotic effects on eosinophils. Objective: We sought to investigate the therapeutic benefit of inhibiting the IL‐5 receptor using benralizumab to treat severe rhinosinusitis with nasal polyps. Methods: Patients with severe NP (defined by endoscopic grade 5 or more out of 8) with elevated eosinophils and a history of previous surgical or endoscopic polypectomy met entry criteria and were randomized in a double‐blind fashion to receive 30 mg benralizumab SC or placebo. Endoscopic NP score was assessed at baseline and at treatment week 20. CT scan, SNOT‐22 survey and UPSIT smell test score changes were also evaluated. Results: Thirty‐three patients were screened, and twenty‐four (n = 24) were enrolled in the study. Compared with baseline, benralizumab significantly improved NP score (−0.9 ± 0.2, P = 0.004) whereas placebo did not (−0.3 ± 0.3, P = 0.166). Benralizumab induced polyp size reduction compared with placebo did not reach statistical significance (P = 0.103). Five of 12 benralizumab‐treated patients (42%) had improvements in all major outcomes (polyp score, CT, SNOT‐22 and smell test) versus 2 out of 12 placebo (17%). The ratio of blood eosinophil count to allergen skin test positivity correlated with polyp reduction. Conclusion: Benralizumab was well‐tolerated and compared with baseline achieved a statistically significant reduction in nasal polyp size, sinus occupancy, symptoms and improved sensation of smell for most patients (83%). [ABSTRACT FROM AUTHOR]

Objective: Chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilia is a disease of the upper respiratory tract for which few therapies are available. Because the oral investigational drug dexpramipexole serendipitously decreased blood eosinophils in amyotrophic lateral sclerosis studies, we assessed its safety, eosinophil-lowering activity, and preliminary clinical efficacy in patients with CRSwNP and eosinophilia.Methods: Sixteen subjects with CRSwNP, absolute eosinophil count (AEC) ≥ 0.300 × 109 /L, and polyp tissue eosinophils were evaluable for efficacy in a 6-month open-label, multi-center study of dexpramipexole 150 mg twice daily. The coprimary endpoints were change in AEC and change in total polyp score (TPS) from baseline to month 6, with additional clinical and histologic endpoints assessed.Results: Thirteen of 16 subjects completed 6 months of dexpramipexole treatment. Geometric mean baseline AEC was 0.525 ± 0.465 eosinophils × 109 /L and decreased to 0.031 ± 0.019 after 6 months of dexpramipexole treatment, a 94% reduction (P < 0.001). Ten of 16 subjects had eosinophil counts reduced to ≤ 0.020 × 109 /L at month 6. In 12 subjects with nasal polyp biopsies at baseline and month 6, tissue eosinophils were reduced from a mean of 168 ± 134 to 5 ± 2 per high-power field (HPF) (P = 0.001), a 97% reduction from baseline. There was no significant reduction in TPS or improvement in other clinical endpoints. Dexpramipexole was well tolerated, with no drug-related serious adverse events.Conclusion: Dexpramipexole treatment produced profound eosinophil-lowering in peripheral blood and nasal polyp tissue. Despite the near-elimination of polyp eosinophils, decreased TPS and nasal symptom improvement were not observed.Level Of Evidence: 2 Laryngoscope, 129:E61-E66, 2019. [ABSTRACT FROM AUTHOR]

7 Carney S. Current understanding of the role of eosinophils in CRSwNP and implications for treatment with mepolizumab and benralizumab. The past several years have been extraordinary in the advancement of our understanding of chronic rhinosinusitis with nasal polyps (CRSwNP) and the management options we have to benefit the lives of patients. 8 Tan B. B lineage cells and IgE in allergic rhinitis and CRSwNP and the role of omalizumab treatment. [Extracted from the article]

Background: Eosinophilic inflammation is a hallmark of chronic rhinosinusitis with nasal polyps. To model this disease process experimentally, nasal sensitization of mice with ovalbumin or aspergillus has been described. Here, we describe a genetically mutant mouse that develops robust spontaneous nasal eosinophilic inflammation. These mice lack the enzyme SHP-1 that down-regulates the IL-4Rαstat6 signaling pathway. We compared nasal inflammation and inflammatory mediators in SHP-1 deficient mice (mev) and an ovalbumin-induced nasal allergy model. Methods: A novel technique of trans-pharyngeal nasal lavage was developed to obtain samples of inflammatory cells from the nasal passages of allergic and mev mice. Total and differential cell counts were performed on cytospin preparations. Expression of tissue mRNA for IL-4, IL-13, and mouse beta-defensin-1 (MBD-1) was determined by quantitative PCR. Eotaxin in the lavage fluid was assessed by ELISA. Results: Allergic and mev mice had increased total cells and eosinophils compared with controls. Expression of IL-4 was similarly increased in both allergic and mev mice, but expression of IL-13 and eotaxin was significantly greater in the allergic mice than mev mice. Eotaxin was significantly up-regulated in both allergic rhinitis and mev mice. In both models of eosinophilic inflammation, down-regulation of the innate immune marker MBD-1 was observed. Conclusions: The mev mice display spontaneous chronic nasal eosinophilic inflammation with potential utility for chronic rhinosinusitis with nasal polyps research. The eosinophilic infiltrate is more robust in the mev mice than allergic mice, but Th2 cytokine expression is not as pronounced. Decreased MBD-1 expression in both models supports the concept that Th2- cytokines down-regulate sinonasal innate immunity in humans, and suggests a role for mouse models in investigating the interaction between adaptive and innate immunity in the sinonasal mucosa. [ABSTRACT FROM AUTHOR]

Background: Hepatocyte growth factor (HGF) is a growth factor thought to attenuate Th2-driven eosinophilic airway inflammatory responses. Increased expression of HGF and its receptor c-Met in nasal polyps suggests a role in disease pathogenesis. The effect of HGF on human sinonasal epithelial cell (SNEC) responses to Th2 inflammatory cytokines in chronic rhinosinusitis with nasal polyps (CRSwNP) has not been explored. Methods: SNECs isolated from patients with CRSwNP and control subjects were grown in cell culture at the air-liquid interface. The Th2 cytokine IL-13 was applied for 24 hours in the presence or absence of HGF. Eotaxin-3 and c-Met expression was assessed using real-time PCR, immunohistochemistry, and flow cytometry. Results: SNECs obtained from both CRSwNP and control subjects showed markedly increased expression of eotaxin-3 after exposure to IL-13. HGF significantly blocked IL-13-induced expression of eotaxin-3 in control SNECs, but not in SNECs derived from CRSwNP subjects. Conclusion: SNECs are active participants in sinonasal mucosal immunity, expressing inflammatory mediators in response to potential pathogens and endogenous cytokines. Although Th2 cytokines can elicit expression of proeosinophilic mediators by SNECs, HGF appears to have a down-regulating effect on this response. In patients with CRSwNP, SNECs are resistant to this attenuation, showing continued IL-13-induced eotaxin-3 expression despite HGF treatment. Abnormalities in the regulation of epithelial cell responses to endogenous cytokines and growth factors may contribute to the persistent eosinophilic inflammatory state in CRSwNP. [ABSTRACT FROM AUTHOR]

Background: Abnormalities in host mucosal immunity exist in chronic rhinosinusitis with nasal polyps (CRSwNPs), but it is unclear whether this is a cause or an effect of the eosinophilic inflammation and frequent microbial colonization that characterizes the disease. Sinonasal epithelial cells (SNECs) are critical participants in healthy antimicrobial innate immune defense. They also can promote Th2 inflammation with various mediators, including interleukin (IL)-33, which induces T helper cells to produce Th2 cytokines. Methods: CRSwNP SNECs were obtained during sinus surgery and stored. Patients were subsequently classified as either treatment responsive or treatment recalcitrant, based on long-term outcomes of medical and surgical therapy. Epithelial cells from these patients were grown in air-liquid interface (ALI) culture and treated with IL-13, as well as the bacteria-associated molecule, CpG. Expression of IL-33 mRNA was determined by real-time polymerase chain reaction. Results: Recalcitrant CRSwNP epithelial cells had increased baseline expression of IL-33 compared with responsive CRSwNPs, which was further increased by 24-hour exposure to CpG. Treatment-responsive epithelial cells were not induced by CpG to express IL-33. Prolonged treatment with IL-13 during differentiation at the ALI diminished the baseline expression of IL-33 and prevented the subsequent induction of IL-33 by CpG. Conclusion: Mucosal innate immunity likely plays an important role in CRSwNP pathogenesis. A definitive link between infectious triggers and the development of Th2 inflammation has been elusive. We have found constitutive IL-33 expression by SNECs in recalcitrant CRSwNPs, which can be further induced by a bacteria-associated molecular pattern. Dysregulated epithelial cell immune interactions between host and environment may contribute to Th2 inflammation in CRSwNPs. [ABSTRACT FROM AUTHOR]

Key points: A persistent type 2 endotype signature exists in recalcitrant chronic rhinosinusitis with nasal polyps mucosa on dupilumab.Revision sinus surgery immediately prior to dupilumab reduces long‐term interleukin (IL)‐4/IL‐13 tissue mRNA.Pre‐dupilumab revision surgery is associated with reduced tissue eosinophils and GATA‐3+ cells. [ABSTRACT FROM AUTHOR]

Background: While essential to the normal differentiation of ciliated airway epithelial cells, upregulated Wnt signaling in chronic rhinosinusitis with nasal polyps (CRSwNP) has been proposed to result in abnormal epithelial morphology and dysfunctional mucociliary clearance. The mechanism of epithelial Wnt signaling dysregulation in CRSwNP is unknown, and importantly cellular sources of Wnt ligands in CRSwNP have not yet been investigated. Methods: Human sinonasal epithelial cells (hSNECs) and human sinonasal fibroblasts (hSNFs) were collected from 34 human subjects (25 control and 9 CRSwNP) and differentiated as primary air‐liquid interface (ALI) and organoid co‐cultures. hSNECs were isolated to the apical compartment of the transwell and hSNFs were isolated to the basolateral compartment. After 21 days of ALI culture, ciliary expression and sinonasal epithelial morphology were examined by immunohistochemistry (IHC) and quantitative real‐time polymerase chain reaction (qRT‐PCR). An organoid model was used to evaluate proliferation of basal cells in presence of hSNFs. Results: Epithelial cells co‐cultured with CRSwNP‐hSNFs revealed significantly decreased ciliated cells, altered epithelial cell morphology, and increased colony forming efficiency compared to epithelial cells co‐cultured with control‐hSNFs. CRSwNP‐hSNFs showed significantly higher messenger RNA (mRNA) expression of canonical WNT3A. A Wnt agonist, CHIR99021, replicated CRSwNP‐hSNF co‐cultures, and treatment with the Wnt inhibitor IWP2 prevented abnormal morphologies. Conclusion: These results suggest that abnormal interactions between epithelial cells and fibroblasts may contribute to CRSwNP pathogenesis and supports the concept that dysregulated Wnt signaling contributes impairment to epithelial function in CRSwNP. [ABSTRACT FROM AUTHOR]

Background: Bitter and sweet taste receptors (T2Rs and T1Rs), respectively, are involved in the innate immune response of the sinonasal cavity and associated with chronic rhinosinusitis (CRS). Growing evidence suggests extraoral TRs as relevant biomarkers, but the current understanding is incomplete. This systematic review synthesizes current evidence of extraoral taste receptors in CRS. Methods: PubMed, Embase, Cochrane, Web of Science, and Scopus were reviewed in accordance with Preferred Reporting Items for Systemic Reviews and Meta‐Analyses guidelines and included studies of genotypic and phenotypic T2R/T1R status in CRS patients. Results: Twenty‐two studies with 3845 patients were included. Seventeen studies evaluated genotype and 10 evaluated taste phenotypes. Four of 6 studies examining the haplotype distribution of the T2R, TAS2R38, demonstrated increased AVI/AVI haplotype ("nontaster") frequency in CRS. Meanwhile, 2 studies demonstrated decreased bitter sensitivity in CRS with nasal polyposis (CRSwNP), whereas 3 other studies reported decreased bitter sensitivity only in CRS without nasal polyposis (CRSsNP). Findings regarding sweet sensitivity were mixed. Three studies with cystic fibrosis patients (n = 1393) were included. Studies investigating the association between clinical outcomes and TAS2R38 alleles were limited, but the nonfunctional combination of AVI/AVI was associated with increased utilization of sinus surgery and, in CRSsNP patients, with poorer improvement of symptoms postoperatively. Conclusion: Both genotypic and phenotypic assessments of T2Rs suggest a potential association with CRS, particularly CRSsNP. However, limited evidence and mixed conclusions cloud the role of T2Rs in CRS. Future investigations should aim to increase diverse populations, broaden institutional diversity, examine T1Rs, and utilize uniform assessments. [ABSTRACT FROM AUTHOR]

Keywords: chronic rhinosinusitis; corticosteroid implant; endoscopic sinus surgery; nasal polyps; T2 biologic; topical corticosteroid; treatment algorithm EN chronic rhinosinusitis corticosteroid implant endoscopic sinus surgery nasal polyps T2 biologic topical corticosteroid treatment algorithm 1407 1416 10 11/02/21 20211001 NES 211001 SUMMARY Chronic rhinosinusitis (CRS) represents a significant health care problem in the United States and CRS patients have a significant decreased quality of life. Only FDA-approved treatment options were considered in this stepwise approach for CRSwNP because these therapies had undergone rigorous safety and efficacy evaluation. The value of these therapies compared with those of time tested and better studied therapies such as ESS and aspirin desensitization certainly need to be considered on an individual basis. Most otolaryngologists and allergists would agree that this patient would require a host of interventions including a complete ESS, oral and topical corticosteroids, endotype-specific therapies such as type 2 targeting biologics and consideration for aspirin desensitization in aspirin triad (also known as AERD) patients. [Extracted from the article]

Background: Interleukin 13 (IL‐13) is a pleiotropic cytokine that has been shown to be important in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and other type 2 inflammation–related diseases. Increased IL‐13 expression can elicit several pro‐inflammatory effects, including eosinophilia, and pathology such as increased mucus secretion. Polypogenesis in chronic rhinosinusitis (CRS) can be caused by hypoxia, which can also lead to hyperpermeability of airway epithelium and epithelium‐to‐mesenchymal translation through the upregulation of hypoxia‐associated genes, such as HIF1. Whether T‐helper 2 (Th2) inflammatory cytokines, such as IL‐13, can also induce sinonasal epithelial hypoxia‐associated genes is currently unknown. Methods: Human air‐liquid interface (ALI) sinonasal epithelial cell cultures treated with recombinant IL‐13 were analyzed by real‐time polymerase chain reaction (PCR) and flow cytometry to determine the effect on epithelial cells. Results: Whole tissue from CRSwNP subjects showed increased HIF1A gene expression. Treatment of fully differentiated human ALI cultures with IL‐13 resulted in a concurrent increase in HIF1A and ARNT messenger RNA (mRNA) expression. However, the level of EPAS1 expression was significantly reduced. IL‐13 also had a dose‐dependent response on the expression of HIF genes and the time course experiment showed peak expression of HIF1A and ARNT at 5 to 7 days poststimulation. Remarkably, CD73 surface expression also peaked at day 5 poststimulation. Conclusion: Our data suggests that IL‐13 can induce hypoxia signaling pathway genes leading to surface expression of CD73, which has an anti‐inflammatory effect. [ABSTRACT FROM AUTHOR]