ABSTRACT
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis. OBJECTIVE: We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP. METHODS: NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing. RESULTS: Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA, IGHE, and cell cycle- and proliferation-related transcripts (CCND2, MKI67, CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes. CONCLUSION: NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP.
Subject(s)
Asthma, Aspirin-Induced , Nasal Polyps , Rhinitis , Sinusitis , Humans , Nasal Polyps/metabolism , Interleukin-5 , Rhinitis/metabolism , Asthma, Aspirin-Induced/metabolism , Aspirin/adverse effects , Chronic Disease , Antibody-Producing Cells/metabolism , Sinusitis/metabolism , Cell Proliferation , Neoplasm Proteins , Protein Tyrosine PhosphatasesABSTRACT
BACKGROUND: Responder analyses of SINUS phase 3 study data have shown clinically meaningful improvements across multiple chronic rhinosinusitis with nasal polyps (CRSwNP) outcomes with dupilumab. OBJECTIVE: To gain a better understanding of dupilumab response dynamics over 52 weeks. METHODS: Post hoc analysis using data from the SINUS-52 (NCT02898454) intention-to-treat population, of patients with severe CRSwNP who received dupilumab 300 mg once every 2 weeks (q2w) or placebo. Response, defined as an improvement from baseline of ≥ 1 point for Nasal Polyp Score (NPS), nasal congestion (NC), and loss of smell (LoS), and ≥ 8.9 points for 22-item Sino-Nasal Outcome Test (SNOT-22), was assessed for rapidity, maintenance, and durability. RESULTS: 303 patients (dupilumab, n = 150; placebo, n = 153) were included. For each outcome measure, a greater proportion of patients achieved first response by Week 16 (rapidity) with dupilumab vs placebo: NPS, 75.3% vs 39.2%; NC, 60.0% vs 24.2%; LoS, 60.7% vs 15.7%; and SNOT-22, 83.3% vs 66.0%. Among dupilumab patients with a response by Week 16, more than 80% maintained response at Week 52 (maintenance). Over 52 weeks, greater proportions of dupilumab patients were responders at ≥ 80% of time points: NPS, 46.7% vs 2.6%; NC, 46.7% vs 9.2%; LoS, 47.3% vs 3.9%; and SNOT-22, 62.0% vs 21.6% (durability). CONCLUSION: Most CRSwNP patients achieve clinically meaningful responses to dupilumab by Week 16, and most of these patients had maintenance and durability of response with continued treatment over time.
ABSTRACT
Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus with latent and lytic cycles. EBV replicates in the stratified epithelium but the nasopharynx is also composed of pseudostratified epithelium with distinct cell types. Latent infection is associated with nasopharyngeal carcinoma (NPC). Here, we show with nasopharyngeal conditionally reprogrammed cells cultured at the air-liquid interface that pseudostratified epithelial cells are susceptible to EBV infection. Donors varied in susceptibility to de novo EBV infection, but susceptible cultures also displayed differences with respect to pathogenesis. The cultures from one donor yielded lytic infection but cells from two other donors were positive for EBV-encoded EBERs and negative for other lytic infection markers. All cultures stained positive for the pseudostratified markers CK7, MUC5AC, α-tubulin in cilia, and the EBV epithelial cell receptor Ephrin receptor A2. To define EBV transcriptional programs by cell type and to elucidate latent/lytic infection-differential changes, we performed single cell RNA-sequencing on one EBV-infected culture that resulted in alignment with many EBV transcripts. EBV transcripts represented a small portion of the total transcriptome (~0.17%). All cell types in the pseudostratified epithelium had detectable EBV transcripts with suprabasal cells showing the highest number of reads aligning to many EBV genes. Several restriction factors (IRF1, MX1, STAT1, C18orf25) known to limit lytic infection were expressed at lower levels in the lytic subcluster. A third of the differentially-expressed genes in NPC tumors compared to an uninfected pseudostratified ALI culture overlapped with the differentially-expressed genes in the latent subcluster. A third of these commonly perturbed genes were specific to EBV infection and changed in the same direction. Collectively, these findings suggest that the pseudostratified epithelium could harbor EBV infection and that the pseudostratified infection model mirrors many of the transcriptional changes imposed by EBV infection in NPC.
Subject(s)
Epithelial Cells/virology , Epstein-Barr Virus Infections/virology , Host-Pathogen Interactions/immunology , Nasopharyngeal Neoplasms/virology , Carcinoma/metabolism , Carcinoma/virology , Epithelial Cells/metabolism , Epithelium/metabolism , Epithelium/virology , Epstein-Barr Virus Infections/metabolism , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/pathogenicity , Humans , Nasopharyngeal Carcinoma/virology , RNA, Viral/geneticsABSTRACT
INTRODUCTION: Biologics are used in the treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of this retrospective study was to evaluate the effects of biologics initiated for asthma on coexistent CRS and the influence of comorbid factors, including aspirin-exacerbated respiratory disease (AERD) and secretory otitis media (SOM). METHODS: A review of electronic health records (2009-2020) at a Finnish tertiary center was conducted to identify CRS patients treated with biologics for their asthma. We identified the type of biologic and treatment response, by comparing nasal polyp score (NPS), sinonasal outcome test (SNOT)-22, need for oral corticosteroids (OCS) and antibiotics, frequency of visits, and endoscopic sinus surgeries (ESS) pretreatment and during treatment. RESULTS: 55 patients were treated with anti-immunoglobulin E (IgE) (n = 18) or anti-interleukin-5/5-receptor (IL-5/5R) (n = 37) biologics. Treatment lasted for an average of 4.1 years. Seventy-five percent (n = 41) had CRSwNP and 25% (n = 14) had CRSsNP. Of all patients, 24% (n = 13) had comorbid AERD and 22% (n = 12) had SOM. Biologic therapy reduced the need for OCS courses (anti-IgE, n = 17, p = 0.03; anti-IL-5/5R, n = 35, p = 0.01) and for daily OCS in anti-IL-5/5R (n = 35, p = 0.001) but not in anti-IgE patients (n = 16, p = 0.07). Biologics also improved NPS by 0.5 point (n = 32, p = 0.009) and SNOT-22 by 14 points (n = 7, p = 0.02) in CRSwNP patients. The overall discontinuation rate was 37.7% (n = 20) and was independent of type of biologic. CONCLUSION: Treatment with anti-IgE and/or anti-IL-5/5R biologics reduced the overall need for OCS medication in individuals with asthma and concomitant CRS, but despite this, the discontinuation rate was high.
Subject(s)
Asthma, Aspirin-Induced , Asthma , Biological Products , Nasal Polyps , Rhinitis , Sinusitis , Humans , Adrenal Cortex Hormones/therapeutic use , Asthma/complications , Asthma/drug therapy , Asthma/epidemiology , Asthma, Aspirin-Induced/complications , Biological Products/therapeutic use , Chronic Disease , Finland/epidemiology , Immunoglobulin E , Nasal Polyps/drug therapy , Nasal Polyps/epidemiology , Retrospective Studies , Rhinitis/drug therapy , Rhinitis/epidemiology , Rhinitis/complications , Sinusitis/drug therapy , Sinusitis/epidemiologyABSTRACT
PURPOSE OF REVIEW: With increasing industrialization, exposure to ambient and wildfire air pollution is projected to increase, necessitating further research to elucidate the complex relationship between exposure and sinonasal disease. This review aims to summarize the role of ambient and wildfire air pollution in chronic rhinosinusitis (CRS) and olfactory dysfunction and provide a perspective on gaps in the literature. RECENT FINDINGS: Based on an emerging body of evidence, exposure to ambient air pollutants is correlated with the development of chronic rhinosinusitis in healthy individuals and increased symptom severity in CRS patients. Studies have also found a robust relationship between long-term exposure to ambient air pollutants and olfactory dysfunction. Ambient air pollution exposure is increasingly recognized to impact the development and sequelae of sinonasal pathophysiology. Given the rising number of wildfire events and worsening impacts of climate change, further study of the impact of wildfire-related air pollution is a crucial emerging field.
Subject(s)
Air Pollutants , Air Pollution , Olfaction Disorders , Rhinosinusitis , Wildfires , Humans , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Air Pollution/adverse effects , Air Pollutants/adverse effects , Particulate Matter/adverse effectsABSTRACT
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently remains uncontrolled despite maximal medical therapy and sinonasal surgery, presenting several unmet needs and challenges. Omalizumab previously demonstrated efficacy in CRSwNP in duplicate phase 3, randomized, placebo-controlled trials (POLYP 1, POLYP 2). OBJECTIVE: This open-label extension evaluated the continued efficacy, safety, and durability of response of omalizumab in adults with CRSwNP who completed POLYP 1 or 2. METHODS: After 24 weeks of omalizumab or placebo in POLYP 1 and 2, patients (n = 249) received open-label omalizumab plus background nasal mometasone therapy for 28 weeks and were subsequently followed for 24 weeks after omalizumab discontinuation. Efficacy end points assessed change from baseline for the coprimary end points, Nasal Polyp Score and Nasal Congestion Score, and the secondary end points of Sino-Nasal Outcome Test 22, Total Nasal Symptom Score and its components, and University of Pennsylvania Smell Identification Test scores. Safety objectives included incidence of adverse events and adverse events leading to omalizumab discontinuation. RESULTS: Patients who continued omalizumab experienced further improvements across coprimary end points and secondary end points through 52 weeks. Patients who switched from placebo to omalizumab experienced favorable responses across end points through week 52 that were similar to POLYP 1 and 2 at week 24. After omalizumab discontinuation, scores gradually worsened over the 24-week follow-up, but remained improved from pretreatment levels for both groups. The safety profile was similar to previous reports. CONCLUSIONS: The efficacy and safety profile from this study supports extended omalizumab treatment up to 1 year for CRSwNP with inadequate response to nasal corticosteroids.
Subject(s)
Nasal Polyps , Omalizumab , Adult , Chronic Disease , Humans , Nasal Polyps/drug therapy , Omalizumab/adverse effects , Rhinitis/drug therapy , Sinusitis/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Shotgun sequencing of cultured microbial isolates/individual eukaryotes (whole-genome sequencing) and microbial communities (metagenomics) has become commonplace in biology. Very often, sequenced samples encompass organisms spanning multiple domains of life, necessitating increasingly elaborate software for accurate taxonomic classification of assembled sequences. RESULTS: While many software tools for taxonomic classification exist, SprayNPray offers a quick and user-friendly, semi-automated approach, allowing users to separate contigs by taxonomy (and other metrics) of interest. Easy installation, usage, and intuitive output, which is amenable to visual inspection and/or further computational parsing, will reduce barriers for biologists beginning to analyze genomes and metagenomes. This approach can be used for broad-level overviews, preliminary analyses, or as a supplement to other taxonomic classification or binning software. SprayNPray profiles contigs using multiple metrics, including closest homologs from a user-specified reference database, gene density, read coverage, GC content, tetranucleotide frequency, and codon-usage bias. CONCLUSIONS: The output from this software is designed to allow users to spot-check metagenome-assembled genomes, identify, and remove contigs from putative contaminants in isolate assemblies, identify bacteria in eukaryotic assemblies (and vice-versa), and identify possible horizontal gene transfer events.
Subject(s)
Metagenome , Microbiota , Bacteria/genetics , Metagenomics , Microbiota/genetics , SoftwareABSTRACT
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2-mediated inflammatory disease with high symptom burden and reduced health-related quality of life (HRQoL). This report aimed to comprehensively understand the effects of dupilumab on domains of HRQoL, their individual elements, and health status in patients with severe CRSwNP from phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) trials. METHODS: Patients were randomized to dupilumab (n = 438) or placebo (n = 286) for 24 weeks (SINUS-24), or 52 weeks (SINUS-52). Disease-specific HRQoL using 22-item sino-nasal outcome test (SNOT-22), and health status using EuroQoL-visual analog scale (EQ-VAS) was evaluated in the pooled intention-to-treat (ITT) population (Week 24), SINUS-52 ITT (Week 52) and in the subgroups with/without asthma; non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD); and prior sinus surgery. RESULTS: At baseline, patients had poor disease-specific HRQoL and general health status and identified "Decreased sense of smell/taste" and "Nasal blockage" as the most important symptoms. Dupilumab significantly improved SNOT-22 total, domain (Nasal, Sleep, Function, Emotion, and Ear/facial), and 22-item scores, and EQ-VAS, at Week 24 vs placebo (all p < .0001), with continued improvements to Week 52 in SINUS-52. Improvements occurred irrespective of comorbid asthma, NSAID-ERD, or prior surgery. A significantly greater proportion of dupilumab-treated patients exceeded clinically meaningful thresholds for SNOT-22 total score and EQ-VAS vs placebo (all subgroups p < .05 except patients without surgery at Week 24). CONCLUSIONS: Dupilumab treatment led to significant clinically meaningful improvements across all aspects of disease-specific HRQoL, and general health status in patients with severe CRSwNP.
Subject(s)
Antibodies, Monoclonal, Humanized , Nasal Polyps , Quality of Life , Rhinitis , Sinusitis , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Asthma/epidemiology , Chronic Disease , Humans , Nasal Polyps/drug therapy , Rhinitis/drug therapy , Sinusitis/drug therapy , Treatment OutcomeABSTRACT
Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is the most bothersome phenotype of chronic rhinosinusitis; it is typically characterized by a type 2 inflammatory reaction and by comorbidities, including asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, and allergies. Here, the European Forum for Research and Education in Allergy and Airway Diseases proposes structured definitions to enable communication between clinicians and provides a practical algorithm to define type 2 inflammation in CRSwNP in daily clinical practice. A rational approach for the treatment of uncontrolled severe CRSwNP is discussed; it consists of evaluating the perspective and risks of surgery and efficacy and adverse events of biologics on the basis of currently available data. Further, possible combinations of surgery and biologics are discussed, and a rationale is provided. Here, it is of importance to adequately counsel the patient about both approaches to enable a decision-making process with an informed patient. Criteria for the selection of a biologic drug are provided, as several biologics for uncontrolled severe CRSwNP will be available in many countries within a short time. Further, suggestions for monitoring of the drug effects that support recognition of responders to the therapy and, subsequently, the decision regarding continuation or discontinuation of the biologic are proposed.
Subject(s)
Nasal Polyps , Rhinitis , Sinusitis , Chronic Disease , Congresses as Topic , Humans , Nasal Polyps/classification , Nasal Polyps/diagnosis , Nasal Polyps/immunology , Nasal Polyps/therapy , Practice Guidelines as Topic , Rhinitis/classification , Rhinitis/diagnosis , Rhinitis/immunology , Rhinitis/therapy , Severity of Illness Index , Sinusitis/classification , Sinusitis/diagnosis , Sinusitis/immunology , Sinusitis/therapyABSTRACT
PURPOSE OF REVIEW: Over half of all patients with severe asthma have chronic rhinosinusitis (CRS). Although distinct and specialized in function and form, the upper and lower airways share similar and inter-related pathophysiologic mechanisms. The severity of CRS particularly in patients with nasal polyps can correlate with that of asthma and vice versa. The purpose of this review is to elucidate the relationship between these conditions and summarize key elements in the management of these patients. RECENT FINDINGS: Several advances have been made in the evaluation and treatment of patients with CRS and asthma. Further understanding of inflammatory endotypes common to both CRS and severe asthma hopefully will provide appropriate and effective treatments and improve patient outcomes. SUMMARY: CRS significantly impairs quality of life, and therapies are targeted toward improving patient symptoms, and hopefully in the future, treating the underlying immune dysfunction. Management of CRS and severe asthma requires a multidisciplinary approach. Further real-world studies are necessary to determine the best treatment algorithm for these patients.
Subject(s)
Asthma/therapy , Rhinitis/therapy , Sinusitis/therapy , Asthma/complications , Chronic Disease , Comorbidity , Humans , Nasal Polyps , Quality of Life , Rhinitis/complications , Sinusitis/complicationsABSTRACT
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously. OBJECTIVE: Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2). METHODS: Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events. RESULTS: Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P < .0001) and -0.90 versus -0.31 (P = .0140); Nasal Congestion Score, -0.89 versus -0.35 (P = .0004) and -0.70 versus -0.20 (P = .0017); and SNOT-22 score, -24.7 versus -8.6 (P < .0001) and -21.6 versus -6.6 (P < .0001). Adverse events were similar between groups. CONCLUSION: Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.
Subject(s)
Anti-Allergic Agents/therapeutic use , Nasal Polyps/drug therapy , Omalizumab/therapeutic use , Rhinitis/drug therapy , Sinusitis/drug therapy , Adrenal Cortex Hormones/therapeutic use , Adult , Anti-Allergic Agents/adverse effects , Chronic Disease , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Mometasone Furoate/therapeutic use , Omalizumab/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both. METHODS: LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454. FINDINGS: Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was -2·06 (95% CI -2·43 to -1·69; p<0·0001) in SINUS-24 and -1·80 (-2·10 to -1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was -0·89 (-1·07 to -0·71; p<0·0001) in SINUS-24 and -0·87 (-1·03 to -0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was -7·44 (-8·35 to -6·53; p<0·0001) in SINUS-24 and -5·13 (-5·80 to -4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo. INTERPRETATION: In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options. FUNDING: Sanofi and Regeneron Pharmaceuticals.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Nasal Polyps/drug therapy , Sinusitis/drug therapy , Adrenal Cortex Hormones/therapeutic use , Adult , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Asthma/drug therapy , Asthma/epidemiology , Chronic Disease , Female , Humans , Injections, Subcutaneous , Male , Middle Aged , Nasal Polyps/complications , Nasal Polyps/epidemiology , Nasal Polyps/psychology , Placebos/administration & dosage , Quality of Life , Severity of Illness Index , Sinusitis/epidemiology , Sinusitis/psychology , Treatment OutcomeABSTRACT
BACKGROUND: 15-Lipoxygenase 1 (15LO1) is expressed in airway epithelial cells in patients with type 2-high asthma in association with eosinophilia. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also associated with type 2 inflammation and eosinophilia. CCL26/eotaxin 3 has been reported to be regulated by 15LO1 in lower airway epithelial cells. However, its relation to 15LO1 in patients with CRSwNP or mechanisms for its activation are unclear. OBJECTIVE: We sought to evaluate 15LO1 and CCL26 expression in nasal epithelial cells (NECs) from patients with CRSwNP and healthy control subjects (HCs) and determine whether 15LO1 regulates CCL26 in NECs through extracellular signal-regulated kinase (ERK) activation. METHODS: 15LO1, CCL26, and phosphorylated ERK were evaluated in NECs from patients with CRSwNP and HCs. 15LO1/CCL26 and CCL26/cytokeratin 5 were colocalized by means of immunofluorescence. IL-13-stimulated NECs were cultured at an air-liquid interface with or without 15-lipoxygenase 1 gene (ALOX15) Dicer-substrate short interfering RNAs (DsiRNA) transfection, a specific 15LO1 enzymatic inhibitor, and 2 ERK inhibitors. Expression of 15LO1 and CCL26 mRNA and protein was analyzed by using quantitative RT-PCR, Western blotting, and ELISA. RESULTS: 15LO1 expression was increased in nasal polyp (NP) epithelial cells compared with middle turbinate epithelial cells from patients with CRSwNP and HCs. 15LO1 expression correlated with CCL26 expression and colocalized with CCL26 expression in basal cells of the middle turbinate and NPs from patients with CRSwNP. In primary NECs in vitro, IL-13 induced 15LO1 and CCL26 expression. 15LO1 knockdown and inhibition decreased IL-13-induced ERK phosphorylation and CCL26 expression. ERK inhibition (alone) similarly decreased IL-13-induced CCL26. Phosphorylated ERK expression was increased in NECs from CRSwNP subjects and positively correlated with both 15LO1 and CCL26 expression. CONCLUSIONS: 15LO1 expression is increased in NP epithelial cells and contributes to CCL26 expression through ERK activation. 15LO1 could be considered a novel therapeutic target for CRSwNP.
Subject(s)
Arachidonate 15-Lipoxygenase/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Nasal Polyps/metabolism , Respiratory Mucosa/metabolism , Rhinitis/metabolism , Sinusitis/metabolism , Turbinates/metabolism , Adult , Arachidonate 15-Lipoxygenase/genetics , Cells, Cultured , Chemokine CCL26/metabolism , Chronic Disease , Enzyme Activation , Female , Humans , Male , Middle Aged , Nasal Polyps/complications , RNA, Small Interfering/genetics , Respiratory Mucosa/pathology , Rhinitis/complications , Sinusitis/complications , Up-RegulationABSTRACT
Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2-targeting biologics such as anti-IgE, anti-IL4Rα, anti-IL5, and anti-IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma.
Subject(s)
Asthma/complications , Biological Products/therapeutic use , Nasal Polyps/complications , Rhinitis/complications , Rhinitis/drug therapy , Sinusitis/complications , Sinusitis/drug therapy , Biological Products/administration & dosage , Biological Products/adverse effects , Chronic Disease , Clinical Decision-Making , Comorbidity , Disease Management , Health Services Needs and Demand , Humans , Research , Treatment OutcomeSubject(s)
Air Pollutants/toxicity , Air Pollution/adverse effects , Environmental Exposure/adverse effects , Particulate Matter/toxicity , Rhinitis/etiology , Sinusitis/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Air Pollutants/analysis , Air Pollution/analysis , Air Pollution/statistics & numerical data , Case-Control Studies , Chronic Disease , Environmental Exposure/analysis , Environmental Exposure/statistics & numerical data , Female , Humans , Logistic Models , Male , Maryland , Middle Aged , Particulate Matter/analysis , Retrospective Studies , Risk Factors , Young AdultABSTRACT
OBJECTIVE: Provide clinicians with current evidence for biologic therapy in children with chronic rhinosinusitis with nasal polyposis (CRSwNP). DATA SOURCES: PubMed, MEDLINE, Cochrane, and clinical trial registries. REVIEW METHODS: Key search terms related to biologic therapy in pediatric CRSwNP were identified via a structured query of current medical literature and clinical trial databases. CONCLUSIONS: There is a dearth of active clinical trials and research studies for biologics targeting pediatric CRSwNP. There is an ongoing compassionate-use clinical trial involving Dupilumab for children with nasal polyps as well as only 1 published work specifically focused on Dupilumab for pediatric CRSwNP in the setting of aspirin-exacerbated respiratory disease. IMPLICATIONS FOR PRACTICE: For children with atopic dermatitis, asthma, and chronic idiopathic urticaria, biologic therapies such as Omalizumab, Dupilumab, and Mepolizumab have gained Food and Drug Administration approval. The role of biologic therapy in pediatric CRSwNP demonstrates significant promise in the comprehensive management of the unified airway. Additional Phase III trials are necessary to broaden clinical indications for children with comorbid conditions and complex sinonasal disease.
Subject(s)
Biological Therapy , Rhinitis , Sinusitis , Humans , Sinusitis/drug therapy , Chronic Disease , Rhinitis/drug therapy , Child , Biological Therapy/methods , Nasal Polyps/drug therapy , Nasal Polyps/complications , Omalizumab/therapeutic use , Rhinosinusitis , Antibodies, Monoclonal, HumanizedABSTRACT
Background: The adoption of avoidance diets by adult-onset asthmatics has not previously been studied. We hypothesized that avoidance diets would associate with adult-onset asthma, allergy, and aspirin-exacerbated respiratory disease (AERD). Methods: A total of 1247 subjects with adult-onset asthma (age range: 31-91) from the Finnish national registry, and age- and sex-matched controls (n = 1970) participated in a questionnaire study in 1997. We estimated the association between asthma/allergy/AERD and avoidance diets, adjusting for potential confounding factors and validated the results in two retrospective cohorts of 5080 rhinitis/rhinosinusitis patients and 167 AERD patients from 2019 to 2020. Results: The presence of asthma positively associated with adoption of any avoidance diet (adjusted OR [CI95%] 1.24 [1.02-1.51], p = 0.029) as did allergic disease and self-reported AERD within the asthmatic group (1.79 [1.29-2.48], p = 0.001 and 1.69 [1.15-2.49], p = 0.007, respectively). Asthmatics and allergic asthmatics were more likely to report avoidance of fish, fruits and vegetables, and spices (p ≤ 0.03) compared to controls and non-allergic asthmatics. The adjusted OR for multiple diets among AERD patients was 2.57 [1.34-4.95] p = 0.005. In the validation, 26.2% of the allergic asthmatics and 10.8% of AERD patients had documented avoidance diets. Conclusions: Our study shows a positive association between avoidance diets and adult-onset asthma, and with allergic disease or AERD within asthmatic patients. Although we lack information on the reason patients chose to observe a specific diet, our results reinforce the importance of asking patients about their diet and if needed, giving dietary advice for adult asthma patients to help them avoid the adoption of unnecessarily restrictive diets.
ABSTRACT
KEY POINTS: IL-5, CCL2, and CXCL8 in sinus mucous are higher in patients with AERD relative to aspirin-tolerant patients with CRS These mediators are pleiotropic, leading to widescale inflammatory processes contributing to AERD AERD is not only a T2 disease but heterogeneous: this may explain the refractory nature of AERD.