Breathing pattern disorder in chronic rhinosinusitis with severe asthma: nasal obstruction and polyps do not increase prevalence.

OBJECTIVES: Chronic rhinosinusitis (CRS) with severe asthma are associated with breathing pattern disorder (BPD). Mouth breathing is a sign of breathing pattern disorder, and nose breathing a fundamental part of breathing pattern retraining for BPD. The prevalence of BPD in relation to CRS subtypes and the relationship of nasal obstruction to BPD in CRS and associated severe asthma is unknown. The breathing pattern assessment tool (BPAT) can identify BPD. Our objective was to thus investigate the prevalence of BPD, nasal airflow obstruction and measures of airway disease severity in CRS with (CRSwNP) and without nasal polyps (CRSsNP) in severe asthma. METHODS: We determined whether CRS status, peak nasal inspiratory flow (PNIF) or polyp disease increased BPD prevalence. Demographic factors, measures of airway function and breathlessness in relation to BPD status and CRS subtypes were also evaluated. RESULTS: 130 Patients were evaluated (n = 69 had BPD). The prevalence of BPD in CRS with severe asthma was 53.1%. There was no difference between BPD occurrence between CRSwNP and CRSsNP. The mean polyp grade and PNIF were not statistically different between the BPD and non-BPD group. The presence of nasal polyps did not increase breathlessness. CONCLUSIONS: BPD and CRS are commonly co-associated. CRS status and nasal obstruction per se does not increase BPD prevalence.

Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial.

BACKGROUND: Patients with eosinophilic nasal polyposis frequently require surgery, and recurrence rates are high. OBJECTIVE: We sought to assess the efficacy and safety of mepolizumab versus placebo for severe bilateral nasal polyposis. METHODS: This randomized, double-blind, placebo-controlled trial recruited patients aged 18 to 70 years with recurrent nasal polyposis requiring surgery. Patients received 750 mg of intravenous mepolizumab or placebo every 4 weeks for a total of 6 doses in addition to daily topical corticosteroid treatment. The primary end point was the number of patients no longer requiring surgery at Week 25 based on a composite end point of endoscopic nasal polyp score and nasal polyposis severity visual analog scale (VAS) score. Secondary end points included change in nasal polyposis severity VAS score, endoscopic nasal polyp score, improvement in individual VAS symptoms (rhinorrhea, mucus in throat, nasal blockage, and sense of smell), patient-reported outcomes, and safety. RESULTS: One hundred five patients received mepolizumab (n = 54) or placebo (n = 51). A significantly greater proportion of patients in the mepolizumab group compared with the placebo group no longer required surgery at Week 25 (16 [30%] vs 5 [10%], respectively; P = .006). There was a significant improvement in nasal polyposis severity VAS score, endoscopic nasal polyp score, all individual VAS symptom scores, and Sino-Nasal Outcome Test patient-reported outcome score in the mepolizumab compared with placebo groups. Mepolizumab's safety profile was comparable with that of placebo. CONCLUSION: In patients with recurrent nasal polyposis receiving topical corticosteroids who required surgery, mepolizumab treatment led to a greater reduction in the need for surgery and a greater improvement in symptoms than placebo.

Antibodies and superantibodies in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps is associated with local immunoglobulin hyperproduction and the presence of IgE antibodies against Staphylococcus aureus enterotoxins (SAEs). Aspirin-exacerbated respiratory disease is a severe form of chronic rhinosinusitis with nasal polyps in which nearly all patients express anti-SAEs. OBJECTIVES: We aimed to understand antibodies reactive to SAEs and determine whether they recognize SAEs through their complementarity-determining regions (CDRs) or framework regions. METHODS: Labeled staphylococcal enterotoxin (SE) A, SED, and SEE were used to isolate single SAE-specific B cells from the nasal polyps of 3 patients with aspirin-exacerbated respiratory disease by using fluorescence-activated cell sorting. Recombinant antibodies with "matched" heavy and light chains were cloned as IgG1, and those of high affinity for specific SAEs, assayed by means of ELISA and surface plasmon resonance, were recloned as IgE and antigen-binding fragments. IgE activities were tested in basophil degranulation assays. RESULTS: Thirty-seven SAE-specific, IgG- or IgA-expressing B cells were isolated and yielded 6 anti-SAE clones, 2 each for SEA, SED, and SEE. Competition binding assays revealed that the anti-SEE antibodies recognize nonoverlapping epitopes in SEE. Unexpectedly, each anti-SEE mediated SEE-induced basophil degranulation, and IgG1 or antigen-binding fragments of each anti-SEE enhanced degranulation by the other anti-SEE. CONCLUSIONS: SEEs can activate basophils by simultaneously binding as antigens in the conventional manner to CDRs and as superantigens to framework regions of anti-SEE IgE in anti-SEE IgE-FcεRI complexes. Anti-SEE IgG1s can enhance the activity of anti-SEE IgEs as conventional antibodies through CDRs or simultaneously as conventional antibodies and as "superantibodies" through CDRs and framework regions to SEEs in SEE-anti-SEE IgE-FcεRI complexes.

IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and TH2 cytokine expression. Type 2 innate lymphoid cells from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33, although the relevance of this axis to local mucosal T-cell responses is unknown. OBJECTIVE: We sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP. METHODS: Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T-cell surface phenotype/intracellular cytokines were assessed by means of flow cytometry. T-cell receptor variable ß-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis. RESULTS: IL-25 receptor (IL-17RB)-expressing TH2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB(+)CD4(+) polyp-derived TH2 cells coexpressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB(+)CD4(+) T cells, several identical T-cell receptor variable ß-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17-producing T cells were observed in both healthy nasal mucosal and polyp populations, with TH17-related genes the most overexpressed compared with peripheral blood T cells. CONCLUSION: IL-25 and IL-33 can interact locally with IL-17RB(+)ST2(+) polyp T cells to augment TH2 responses in patients with CRSwNP. A local TH17 response might be important in healthy nasal mucosal immune homeostasis.

Activin-A is overexpressed in severe asthma and is implicated in angiogenic processes.

Activin-A is a pleiotropic cytokine that regulates allergic inflammation. Its role in the regulation of angiogenesis, a key feature of airways remodelling in asthma, remains unexplored. Our objective was to investigate the expression of activin-A in asthma and its effects on angiogenesis in vitro.Expression of soluble/immunoreactive activin-A and its receptors was measured in serum, bronchoalveolar lavage fluid (BALF) and endobronchial biopsies from 16 healthy controls, 19 patients with mild/moderate asthma and 22 severely asthmatic patients. In vitro effects of activin-A on baseline and vascular endothelial growth factor (VEGF)-induced human endothelial cell angiogenesis, signalling and cytokine release were compared with BALF concentrations of these cytokines in vivo.Activin-A expression was significantly elevated in serum, BALF and bronchial tissue of the asthmatics, while expression of its protein receptors was reduced. In vitro, activin-A suppressed VEGF-induced endothelial cell proliferation and angiogenesis, inducing autocrine production of anti-angiogenic soluble VEGF receptor (R)1 and interleukin (IL)-18, while reducing production of pro-angiogenic VEGFR2 and IL-17. In parallel, BALF concentrations of soluble VEGFR1 and IL-18 were significantly reduced in severe asthmatics in vivo and inversely correlated with angiogenesis.Activin-A is overexpressed and has anti-angiogenic effects in vitro that are not propagated in vivo, where reduced basal expression of its receptors is observed particularly in severe asthma.

Chronic rhinosinusitis with nasal polyps: eosinophils versus B lymphocytes in disease pathogenesis.

PURPOSE OF REVIEW: To highlight the current evidence that supports the view that eosinophils may not drive disease in chronic rhinosinusitis with nasal polyps (CRSwNP) and the emerging evidence for B cells as an important player in this disease. RECENT FINDINGS: Eosinophil depletion studies in CRSwNP do not fully support a critical role for eosinophils in CRSwNP. Almost complete eosinophil depletion with dexpramipexole had no impact on polyp size reduction or clinical improvement. Anti-interleukin (IL)-5 and IL-5Rα inhibition were more effective though with less clinical impact when compared to anti-immunoglobulin E (IgE) or IL-4Rα inhibition strategies. As IL-5Rα is also expressed on CRSwNP derived IgE+ and IgG4+ plasma cells to the same extent as eosinophils, improvements in CRSwNP with IL-5 inhibition may suggest a role for B cells over eosinophils in CRSwNP. We review both eosinophils and B cells in the context of CRSwNP and highlight the current evidence that supports an emerging role for B cells. SUMMARY: Despite many aspects of immunopathology in CRSwNP explainable by B cell dysfunction, B cells have so far been ignored in CRSwNP. Further work is needed, as targeting B cells may offer an exciting new therapeutic option in the future.

Mepolizumab Reduces Systemic Corticosteroid Use in Chronic Rhinosinusitis With Nasal Polyps.

BACKGROUND: Systemic corticosteroids (SCSs) are associated with short- and long-term adverse effects. OBJECTIVE: To assess mepolizumab efficacy according to prior SCS use and characterize mepolizumab's SCS-sparing capabilities, in patients with severe chronic rhinosinusitis with nasal polyps. METHODS: In the randomized, double-blind, phase III SYNAPSE trial (NCT03085797), adults with severe chronic rhinosinusitis with nasal polyps eligible for repeat sinus surgery despite standard of care treatment received mepolizumab (100 mg subcutaneously) or placebo every 4 weeks for 52 weeks. The impact of prior SCS courses (0/1/>1) on mepolizumab versus placebo treatment responses (changes from baseline in total endoscopic nasal polyp [week 52], nasal obstruction visual analog scale [weeks 49-52], and 22-item Sino-Nasal Outcome Test total [week 52] scores) was analyzed post hoc. To characterize mepolizumab's SCS-sparing capabilities, time-to-first SCS course for nasal polyps (prespecified) and total prednisolone-equivalent oral corticosteroid dose by patient baseline characteristics (post hoc, in patients with ≥1 SCS course during SYNAPSE) were assessed up to week 52. RESULTS: Mepolizumab versus placebo improved treatment responses, irrespective of prior SCS use. By week 52, the probability of requiring SCSs for nasal polyps (Kaplan-Meier estimate [95% CI]) was lower with mepolizumab (25.4% [20.0-32.1]) versus placebo (37.5% [31.1-44.6]). In patients requiring 1 or more dose of SCSs, total (mean ± SD mg/y) prednisolone-equivalent oral corticosteroid dose was lower with mepolizumab (438.9 ± 350.40) versus placebo (505.2 ± 455.091), overall and irrespective of prior sinus surgeries, blood eosinophil count, or comorbidities. CONCLUSIONS: Mepolizumab is associated with clinical benefits in patients with severe chronic rhinosinusitis with nasal polyps regardless of prior SCS use and has an SCS-sparing effect.

The effects of an anti-IL-13 mAb on cytokine levels and nasal symptoms following nasal allergen challenge.

BACKGROUND: IL-13 is a key T(H)2 cytokine that is implicated in allergic responses. OBJECTIVE: We evaluated the effects of an anti-IL-13-blocking antibody compared with placebo on repeated nasal allergen challenge responses in hay fever patients out of season. METHODS: We performed a parallel group double-blind study of anti-IL-13 (single dose, 6 mg/kg intravenously, n = 16) and placebo (n = 15), with an additional open label group given a topical nasal corticosteroid (n = 5). Subjects received intranasal timothy grass pollen (Phleum pratense P5 allergen), and serial samples of nasal mucosal lining fluid were taken by using synthetic absorptive matrix and by nasal lavage. RESULTS: Administration of anti-IL-13 on day 1 resulted in a significant decrease in IL-13 levels in synthetic absorptive matrix eluates compared with placebo (area under the curve 0-8 hours, change from baseline) during the late phase after nasal allergen challenge on day 5 (P < .05) and day 7 (P < .01). There were no apparent effects of anti-IL-13 treatment on nasal lavage eosinophil numbers or total nasal symptom scores versus placebo. However, in a subgroup with high late-phase IL-13 levels at screening, there was a trend for a decrease in total nasal symptom scores after nasal allergen challenge on day 5, when compared with subjects with low IL-13 levels (P < .10). Nasal fluticasone caused suppression of IL-13 (P < .05 on day 5) as well as IL-5 (P < .01 on day 5) levels in the late phase compared with placebo. CONCLUSIONS: Anti-IL-13 had specific pharmacodynamic action in this nasal allergen challenge model, causing profound inhibition of nasal lining fluid IL-13 responses. In addition, there was a possible effect of anti-IL-13 treatment on total nasal symptom scores in a subgroup with high late-phase nasal IL-13 levels at screening.

Expression of functional receptor activity modifying protein 1 by airway epithelial cells with dysregulation in asthma.

BACKGROUND: Epithelial cell expression of calcitonin gene-related peptide (CGRP) is a feature of provoked asthma. Receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor combine to form the CGRP1 receptor. OBJECTIVE: To determine whether functional RAMP1 is expressed by airway epithelial cells and whether there are alterations in asthma. METHODS: BEAS-2B and A549 cells lines were studied by RT-PCR, confocal microscopy, a quantitative immunofluorescence assay, and ELISA. Bronchial biopsies from normal subjects and subjects with asthma were examined by immunohistochemistry and in situ hybridization. RESULTS: Inflammatory cytokines induced CGRP release and CGRP mRNA in BEAS-2B and A549 epithelial cell lines. RAMP1 was highly expressed by resting, unstimulated BEAS-2B and A549 cells. CGRP induced internalization of RAMP1 and IL-6 production, both of which were inhibited by the CGRP antagonist, CGRP(8-37). Activation of BEAS-2B and A549 cells by inflammatory cytokines induced CGRP secretion, binding of CGRP to RAMP1, and RAMP1 internalization, which was blocked by CGRP (8-37). RAMP1 immunoreactivity and RAMP1 mRNA expression in bronchial biopsies from subjects with asthma were significantly lower than in normal subjects (P = .002 and P = .007, respectively). Inhalational challenge of atopic subjects with asthma with allergen-derived peptides produced a significant decrease in the numbers of RAMP1-positive epithelial cells in responders (P = .027) but not nonresponders. CONCLUSION: Receptor activity modifying protein 1 was expressed both by airway epithelial cells in culture and in bronchial biopsies from normal subjects and internalized after epithelial cell activation through autocrine feedback of CGRP. There is an apparent dysregulation of RAMP1 in asthmatic epithelium, suggesting continuous stimulation of pathways involving CGRP.

B cells and upper airway disease: allergic rhinitis and chronic rhinosinusitis with nasal polyps evaluated.

Introduction: The first mucosal site to encounter inhaled allergen, antigen, and microbes is the upper airway. It must perforce have a rapid system of environmental threat recognition and self-defense. B cells play a critical role in such airway host-defense, tissue surveillance, and immune modulation. Several common upper airway diseases can be defined in the expression of either exaggerated or dysregulated B-cell function within T2-high mucosal inflammatory states.Areas covered: In this review, the authors discuss the immunology of allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) in the context of highlighting key aspects of B-cell biology and function. The review is based on the findings of a literature search using the terms B cells, rhinitis, nasal polyps, and rhinosinusitis.Expert opinion: Despite the emerging role of B-cell overdrive and dysfunction in upper airway disease, studies are lacking specifics to B cells, particularly in association with sinonasal infection and mucosal inflammation. There is a pressing need to focus on how respiratory inflammation, alongside impaired or exaggerated B-cell function, amplifies and further dysregulates immune signaling pathways in the disease setting of AR and CRSwNP.

Chronic rhinosinusitis with and without nasal polyps and asthma: Omalizumab improves residual anxiety but not depression.

BACKGROUND: Chronic rhinosinusitis (CRS) has a high prevalence of anxiety and depression. It is currently uncertain if treatment in patients with CRS with or without nasal polyps (CRSwNP and CRSsNP) has any impact on improving mental health outcomes. The aims here were to document anxiety and depression in patients with severe CRS and asthma already treated with appropriate medical therapy. We then evaluated whether further maximal treatment with omalizumab improved anxiety and/or depression alongside improvements in CRS and coassociated asthma. METHODS: Hospital Anxiety and Depression Scale (HADS) scores along with measures of CRS and asthma severity were recorded according to CRSwNP and CRSsNP status in n = 95 patients with severe CRS and asthma. Of this group, a further n = 23 had omalizumab for associated allergic asthma. Follow-up measures were collected 16 weeks after omalizumab treatment. RESULTS: HADS anxiety and depression prevalence in CRS were 49.47 % and 38.95%, respectively. Within the CRSwNP and CRSsNP group 53.06% and 45.66% had raised HADS-anxiety scores. Abnormal HADS-depression scores were present in 40.82% and 36.95% of the CRSwNP and CRSsNP groups, respectively. Correlations for sinonasal outcome test-22 (SNOT-22) versus HADS total was r = 0.59 p < 0.0001, HADS-anxiety r = 0.56 p < 0.0001 and HADS-depression r = 0.49 p < 0.0001. Omalizumab improved anxiety in CRS (p < 0.0001) regardless of nasal polyp status (CRSwNP p = 0.0042 and CRSsNP p = 0.0078). Depression scores did not improve in either group. SNOT-22 (p = 0.0006), asthma control questionnaire-7 (p = 0.0019) and mini-asthma quality of life questionnaire including emotional function (p = 0.0003 and p = 0.0009, respectively) all improved in both subgroups. CONCLUSION: In CRS and asthma, anxiety scores but not depression improved after omalizumab treatment. Anxiety may be closely related to airway disease severity, but depression may be independent of airway disease itself. If so, a separate mental health care pathway is needed for CRS patients with depression.

The role of eosinophils in airway tissue remodelling in asthma.

There is an increasing evidence that airway structural change (termed remodelling) is associated with the severity and chronicity of asthma. Recent studies support an important role for eosinophils in the remodelling process. In particular eosinophil depletion studies have demonstrated that several aspects of remodelling are attenuated. Eosinophils have been confirmed as an important source of TGF-beta(1) as well as other important cytokines that can lead to the direct activation of epithelium and mesenchymal cells that are considered to drive airway remodelling. The current studies that support a role for eosinophils in airway remodelling are reviewed in article.

Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma.

BACKGROUND: Both transforming growth factor (TGF)-beta(1) and activin-A have been implicated in airway remodeling in asthma, but the modulation of their specific signaling pathways after disease activation remains undefined. OBJECTIVE: To define the expression kinetics of TGF-beta(1), activin-A ligands, and follistatin (a natural activin inhibitor), their type I and type II receptors (activin-like kinase[ALK]-1, ALK-5, ALK-4, TbetaRII, and ActRIIA/RIIB) and activation of signaling (via phosphorylated (p) Smad2), in the asthmatic airway after allergen challenge. METHODS: Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic patients with asthma (median age, 25 years; median FEV(1)% predicted, 97%) at baseline and 24 hours after allergen inhalation. Functional effects of activin-A were evaluated by using cultured normal human bronchial epithelial (NHBE) cells. RESULTS: pSmad2(+) epithelial cells increased at 24 hours (P = .03), and pSmad2 was detected in submucosal cells. No modulation of activin-A, follistatin, or TGF-beta(1) expression was demonstrated. Activin receptor(+) cells increased after allergen challenge: ALK-4 in epithelium (P = .04) and submucosa (P = .04), and ActRIIA in epithelium (P = .01). The TGF-beta receptor ALK-5 expression was minimal in the submucosa at baseline and after challenge and was downregulated in the epithelium after challenge (P = .02), whereas ALK-1 and TbetaRII expression in the submucosa increased after allergen challenge (P = .03 and P = .004, respectively). ALK-1 and ALK-4 expression by T cells was increased after allergen challenge. Activin-A induced NHBE cell proliferation, was produced by NHBE cells in response to TNF-alpha, and downregulated TNF-alpha and IL-13-induced chemokine production by NHBE cells. CONCLUSION: Both TGF-beta and activin signaling pathways are activated on allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.

Chronic rhinosinusitis with nasal polyps: mechanistic insights from targeting IL-4 and IL-13 via IL-4Rα inhibition with dupilumab.

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex immunological upper airway disease . CRSwNP, particularly in Caucasians, often has a more distinct T2 inflammatory endotype. IL-4 and IL-13 are key upstream cytokines that help establish and sustain T2 inflammation as well as strongly influencing tissue remodeling. They have a shared signaling receptor IL-4Rα. An attractive and novel therapeutic approach is by way of blocking IL-4 and IL-13 simultaneously via inhibiting IL-4Rα. Dupilumab is a murine derived fully human monoclonal inhibitory antibody directed against IL-4Rα which thereby prevents IL-4/IL-13 cell signaling. Following successful Phase 3 studies dupilumab has become the first licensed biologic for treating CRSwNP. Areas covered: This review covers the essential immunology of CRSwNP in the context of IL-4 and IL-13 signaling via IL-4Rα. The potential mechanisms by which therapeutic improvements occur with dupilumab are evaluated. IL-4, IL-13, dupilumab and rhinosinusitis were used as the search terms in PubMed and Google Scholar through to August 2020. Expert commentary: Dupilumab has the potential to transform the care for patients with CRSwNP. It is essential that further studies are conducted promptly to identify disease-specific biomarkers and clinical traits to guide clinicians on best patient selection thereby ensuring optimal dupilumab outcomes.

Chronic Rhinosinusitis with Nasal Polyps: Targeting IgE with Anti-IgE Omalizumab Therapy.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex, clinically heterogeneous and persistent inflammatory disorder of the upper airway. Detailed mechanistic insights into disease pathogenesis are lacking, but it is now accepted that local tissue IgE driven T2-high inflammatory pathways are critical to disease. The recent CRSwNP Phase 3 POLYP1 and POLYP2 replicate studies of blocking IgE with omalizumab confirmed rapid improvements in all clinical parameters of sinonasal disease, confirming a pivotal role for IgE driven inflammatory pathways in CRSwNP. This review summarises the biology of IgE in relation to CRSwNP. Insight into how IgE may drive CRSwNP is evaluated in the context of clinical improvements seen with omalizumab. The need for further studies using a broader patient and biomarker specific groups to aid more precise drug-patient selection alongside more detailed mechanistic studies of omalizumab in CRSwNP is highlighted.

Dupilumab: Clinical Efficacy of Blocking IL-4/IL-13 Signalling in Chronic Rhinosinusitis with Nasal Polyps.

In September 2019, The Lancet published details of two large Phase III double-blind placebo-controlled studies (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52) confirming the clinical efficacy of the biologic dupilumab in simultaneously blocking both IL-4/IL-13 signalling in chronic rhinosinusitis with nasal polyps (CRSwNP). The studies demonstrated that dupilumab (Dupixent®, Sanofi and Regeneron) 300mg subcutaneously administered was clinically effective when added for patients with moderate to severe CRSwNP already maintained on the standard intranasal steroid mometasone furoate. Duration of treatment ranged from injections either 2 weekly for 24 weeks (SINUS-24) or every 2 weeks for 52 weeks or finally every 2 weeks for 24 weeks stepping down thereafter to every 4 weeks for a further 28 weeks (SINUS-52). Rapid improvements in all important parameters of disease burden were seen with such improvement maintained even where the frequency of injections was decreased. In patients with co-existent asthma, lung function and asthma control scores improved. This is consistent with the one airway hypothesis of shared T2 inflammatory programmes driving both disease syndromes. The studies formed the basis for FDA registration and clinical launch in the US, and EMA approval in Europe. Dupilumab presents a significant new treatment option in an area of urgent unmet therapeutic need in CRSwNP. Should dupilumab prove to be as effective in the real-life clinical environment as it has been in the studies, then a paradigm shift from sinonasal surgery to medical treatment of CRSwNP may need to occur in the ENT community. Questions in relation to best patient selection, combined upper and lower airway therapeutic pathways, long-term safety along with health economics and cost constraints ought now to be addressed.

Basal expression of bone morphogenetic protein receptor is reduced in mild asthma.

RATIONALE: Despite increasing recognition of bone morphogenetic protein (BMP) signaling in tissue remodeling, the expression pattern of ligands and signaling pathways remain undefined in the asthmatic airway. OBJECTIVES: To determine expression of BMP ligands (BMP-2, BMP-4, and BMP-7) and type I and type II receptors (ALK-2, ALK-3, ALK-6, and BMPRII) as well as evidence for activation of BMP signaling via detection of phosphorylated Smad1/5 (pSmad1/5) expression in asthmatic airways at baseline (compared with nonasthmatic controls), and after allergen challenge. METHODS: Bronchial biopsies were obtained from 6 nonasthmatic control volunteers, and 15 atopic patients with asthma (median age, 25 yr; median FEV(1)% predicted, 97%) at baseline, then at 24 hours and 7 days after allergen challenge. Expression of BMP ligands, receptors, and signaling was analyzed using immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: BMP ligand expression did not differ between asthmatic and control airways at baseline. Compared with the normal airway, there was significant down-regulation of ALK-2 (P = 0.001), ALK-6 (P = 0.0009), and BMPRII (P = 0.009) expression in asthma. Allergen challenge was associated with marked and sustained up-regulation of BMP-7 in airway epithelium (P = 0.017) and infiltrating inflammatory cells (P = 0.071) (predominantly in eosinophils, but also CD4(+) T cells, mast cells, and macrophages). Up-regulation of pSmad1/5 expression (P = 0.031), ALK-2 (P = 0.002), and ALK-6 (P < 0.001) was observed indicating active signaling. CONCLUSIONS: BMP receptor expression is down-regulated in the asthmatic airway, which may impede repair responses. Allergen provocation increases expression of the regulatory ligand BMP-7, activates BMP signaling, and increases receptor expression, all of which may contribute to repair and control of inflammation.

Chronic rhinosinusitis with nasal polyps: insights into mechanisms of disease from emerging biological therapies.

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex disease of the upper airway, with long-term morbidity. With detailed mechanistic studies currently lacking, understanding of the immunopathogenesis is still limited. However, outcomes from CRSwNP clinical studies using biologics that block key mediators or cells may provide some insights into how immune signaling pathways potentially integrate and modulate each other and contribute to disease. Current treatments are often ineffective and there is an urgent unmet clinical need for effective therapeutic strategies. Emerging biologics hold promise. Areas covered: This review covers the biology of CRSwNP in terms of the clinical outcomes reported from blocking immune cascades with available biologics. Immune amplification mechanisms and how biologics can potentially modulate such 'master' cytokines and signaling proteins that drive inflammation and contribute to tissue remodeling in CRSwNP are discussed. Expert commentary: Biologics have the potential to transform CRSwNP treatment. The ability to predict clinical response in a complex disease as CRSwNP to a biologic cannot necessarily be predicted by measuring a single protein or cell as a biomarker of disease. Further studies with biologics must be carefully undertaken to fully evaluate wider biomarker associated pheno-endotype responses along with any associated asthma outcome measures.