Background There is little scientific evidence to support the current practice of using oral glucocorticosteroids and antibiotics to treat patients with chronic rhinosinusitis and nasal polyps. ...Objective We evaluated the effects of oral glucocorticoids and doxycycline on symptoms and objective clinical and biological parameters in patients with chronic rhinosinusitis and nasal polyps. Methods In a double-blind, placebo-controlled, multicenter trial, we randomly assigned 47 participants with bilateral nasal polyps to receive either methylprednisolone in decreasing doses (32–8 mg once daily), doxycycline (200 mg on the first day, followed by 100 mg once daily), or placebo for 20 days. Participants were followed for 12 weeks. Patients were assessed for nasal peak inspiratory flow and symptoms and by nasal endoscopy. Markers of inflammation such as eosinophilic cationic protein (ECP), IL-5, myeloperoxidase, matrix metalloproteinase 9, and IgE were measured in nasal secretions. Concentrations of eosinophils, ECP, and soluble IL-5 receptor α were measured in peripheral blood samples. Results Methylprednisolone and doxycycline each significantly decreased nasal polyp size compared with placebo. The effect of methylprednisolone was maximal at week 3 and lasted until week 8, whereas the effect of doxycycline was moderate but present for 12 weeks. Methylprednisolone significantly reduced levels of ECP, IL-5, and IgE in nasal secretions, whereas doxycycline significantly reduced levels of myeloperoxidase, ECP, and matrix metalloproteinase 9 in nasal secretions. Conclusion This is the first double-blind, placebo-controlled study to show a significant effect of oral methylprednisolone and doxycycline on size of nasal polyps, nasal symptoms, and mucosal and systemic markers of inflammation.
Background
Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are chronic type 2 inflammatory diseases that are frequently associated with each other. Dupilumab inhibits the dual signaling ...pathways of interleukin (IL)-4 and IL-13, which are key and central drivers of type 2 inflammation in CRSwNP. Omalizumab blocks the action of immunoglobulin E. Head-to-head studies are required to investigate the comparative efficacy and safety of these interventions. EVEREST (EValuating trEatment RESponses of dupilumab vs omalizumab in Type 2 patients) trial is designed to evaluate whether the efficacy of dupilumab is superior to omalizumab in treating patients with CRSwNP and comorbid asthma (ClinicalTrials.gov Identifiers: NCT04998604).
Objective
Here, we describe the EVEREST study design to compare the efficacy and safety of dupilumab compared to omalizumab over 24 weeks of treatment in patients with severe CRSwNP and comorbid asthma.
Methods
EVEREST is a global, phase 4 multicenter, randomized (1:1), double-blind, active-controlled trial. Approximately 422 adult patients with severe CRSwNP, symptoms of nasal congestion and loss of smell, and coexisting asthma will be recruited across 15 countries. The primary objective is to assess the efficacy of dupilumab compared to omalizumab in reducing the nasal polyp size and improving the sense of smell. The key secondary objectives are to evaluate the comparative efficacy in improving CRSwNP symptoms (eg, nasal congestion) and lung function. The safety will be evaluated in terms of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest.
Conclusions
EVEREST is the first head-to-head trial assessing the comparative efficacy and safety of 2 biologics in patients with severe CRSwNP and comorbid asthma. The study will provide evidence to help optimize treatment plans for patients that suffer from severe CRSwNP and comorbid asthma.
Background Nasal polyps often are associated with asthma. The phenotype of these patients is unknown. Objective To identify the mucosal factors associated with asthma comorbidity, we analyzed the ...inflammatory patterns of nasal polyps. Methods Nasal polyps from 70 Belgian patients, 34% with asthma, were analyzed for type of inflammation, T-cell cytokines, and IgE antibodies to Staphylococcus aureus enterotoxins. The same investigations were repeated in 93 Chinese patients with polyps, a group with a low asthma comorbidity rate (8%). Results In Belgian patients with polyps, 54% of samples showed eosinophilic inflammation. A classification tree evaluation identified IL-5 as the main positive determinant. Enterotoxin IgE in tissue (37%) was associated with significantly increased total IgE and eosinophil cationic protein concentrations. Expression of enterotoxin IgE, total IgE at greater than 1,442 kU/L, and eosinophil cationic protein at greater than 17,109 μg/L in samples with a total IgE concentration of greater than 246 kU/L significantly predicted asthma (odds ratio, 5.8-13). Only 7.5% of the samples from Chinese patients with polyps showed eosinophilic inflammation. IL-5 was confirmed as a positive determinant of eosinophilic inflammation, and enterotoxin IgE in tissue (17% of patients) was associated with significantly increased total IgE and eosinophil cationic protein concentrations. The expression of IL-5 or total IgE at greater than 790 kU/L in samples with an IL-5 concentration of greater than 194 pg/mL significantly predicted comorbid asthma (odds ratio, 17.2-96). Conclusion Mucosal inflammation in nasal polyps orchestrated by TH 2 cytokines and amplified by S aureus enterotoxins is characterized by an increased eosinophilic inflammation and formation of IgE antibodies. This phenotype is associated with comorbid asthma in white and Asian patients with nasal polyps.
The last year has seen great progress in the understanding of upper airway disease and in its management. For allergic rhinitis, authors focused on the prediction of and effect on the natural course ...of disease. New evidence was published for the disease-modifying effect of allergen immunotherapy in terms of avoidance of new sensitizations and prevention of asthma in either randomized or real-life studies. Specifically, for patients with house dust mite allergies, which are often underestimated and difficult to diagnose, the efficacy of SQ house dust mite sublingual immunotherapy tablets has been demonstrated in patients with allergic rhinitis and asthma. For the first time, allergen immunotherapy significantly reduced asthma exacerbations. In patients with chronic rhinosinusitis, a novel endotyping approach purely based on T helper cell biomarkers has been developed and has shown clinical relevance through associations with asthma comorbidity and recurrence after surgery. Severe nasal polyposis with high risk for asthma comorbidity and disease recurrence is characterized by type 2 inflammatory patterns, including IgE antibodies to staphylococcal superantigens; several studies using biologic agents have targeted exactly this spectrum of mediators. This goes in parallel with new knowledge on even more type 2 mediators derived from epithelial cells, which will expand the number of possible candidates for innovative intervention.
Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the accumulation of inflammatory cells; however, an eosinophil predominance is seen in white (Belgian), but not Asian ...(south Chinese), patients with polyps. Objective We sought to investigate the association of inflammatory cell predominance with regulatory T-cell and T-effector cell patterns. Methods Nasal mucosal tissue was obtained from 26 consecutive Belgian patients with CRSwNP and 21 Belgian control subjects and 29 south Chinese patients with CRSwNP and 29 south Chinese control subjects, who all underwent phenotyping, including nasal endoscopy and computed tomographic scanning. Tissues were investigated for granulocytes and their products and T-effector/regulatory T cells and related cytokines. Results Both CRSwNP groups were comparable in terms of symptoms, computed tomographic scan results, and nasal endoscopy results, but asthma comorbidity was significantly higher in white patients. Tissue from white patients with CRSwNP was characterized by eosinophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio > 2), whereas samples from Asian patients were biased toward neutrophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio = 0.25). Both CRSwNP groups demonstrated significant upregulation of the T-cell activation marker soluble IL-2 receptor α and significant downregulation of Foxp3 expression and TGF-β1 protein content versus their respective control groups. However, whereas white patients displayed a significant increase in TH 2 cytokine and related marker levels versus control subjects and versus Asian patients, the latter showed a TH 1/TH 17 cell pattern versus control tissue. Conclusion Nasal polyps (CRSwNP) from white and Asian patients are both characterized by T-cell activation and impaired regulatory T-cell function; however, T-effector cells in the samples from white patients were TH 2-biased, whereas samples from their Asian counterparts demonstrated a TH 1/TH 17 polarization.
Background There is little evidence on the efficacy of glucocorticoid transnasal nebulization therapy in patients with eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP). Objective We ...sought to evaluate the immunologic and remodeling effects of budesonide transnasal nebulization in patients with eosinophilic CRSwNP. Methods Sixty patients with eosinophilic CRSwNP were randomized to receive budesonide or placebo treatment for 14 days by means of transnasal nebulization in a double-blind manner. Endoscopic polyp size scores (maximum = 6 points, Kennedy score) and visual analog scale scores for nasal symptoms were assessed before and after treatment. Similarly, polyp samples were evaluated for inflammatory cytokines, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) by using an immunoassay; collagen by using histochemistry; eosinophils by using hematoxylin and eosin stain; and T-cell subsets by using flow cytometry. Results Budesonide transnasal nebulization significantly reduced polyp size compared with placebo (mean difference between groups, −0.73 units; 95% CI, −1.15 to −0.32 units; P = .002) and improved symptoms. Polyp IL-5 and eotaxin expression decreased significantly, whereas TGF-β and IL-10 expression increased. Expression of IFN-γ and IL-17 was not altered. Budesonide transnasal nebulization consistently reduced eosinophil infiltration and TH 2 cell frequency and increased natural regulatory T-cell and type 1 regulatory T-cell frequencies. Indices of remodeling, including albumin, MMP-2, MMP-7, MMP-8, and MMP-9, were significantly decreased, whereas collagen deposition and TIMP-1, TIMP-2, and TIMP-4 levels were significantly increased. Budesonide transnasal nebulization did not suppress the hypothalamic-pituitary-adrenal axis or cause any serious side effects. Conclusion Short-term budesonide transnasal nebulization is an effective and safe treatment option in patients with eosinophilic CRSwNP, achieving clinical improvement by regulating remodeling, cytokine expression, and T-cell subset distribution.
Background Increasing evidence points toward a modifying role of Staphylococcus aureus and its products in the pathogenesis of nasal polyposis. Objective The aim of this study was to investigate ...cytokine and mediator production after stimulation with S aureus –derived proteins enterotoxin B, protein A, and lipoteichoic acid in nasal polyp and control inferior turbinate tissue. Methods Tissue fragments were stimulated with RPMI (negative control), enterotoxin B, protein A, and lipoteichoic acid for 30 minutes and 24 hours. Supernatants were measured by multiplex for proinflammatory cytokines (IL-1β, TNF-α) and T-cell and subset–related cytokines (IFN-γ, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13). Histamine, TGF-β1, cysteinyl leukotrienes, and prostaglandin D2 were analyzed by ELISA. Results Thirty minutes of protein A stimulation resulted in a significant increase of histamine, leukotrienes, and prostaglandin D2 . Enterotoxin B stimulation over a period of 24 hours induced a significant increase of IL-1β, TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-10, and IL-13 in both groups, with this increase significantly higher in nasal polyps compared with controls. Conclusion We here show that S aureus products have various effects on mucosal tissues: surface protein A induces mast cell degranulation, whereas enterotoxins induce the release of cytokines, with a TH 2-skewed pattern in nasal polyps, supporting the stimulatory role of superantigens in the development of this inflammatory disease.
Background To date there is no information on the expression of mediators associated with tissue remodeling in Asian patients with chronic rhinitis with (CRSwNP) or without (CRSsNP) nasal polyps. ...Objectives To study the expression of TGF-β1, matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), collagen, and regulatory T cells in Chinese patients with CRSwNP and CRSsNP. Methods Thirty-six male and female subjects (12 patients with CRSwNP, 12 patients with CRSsNP, and 12 control subjects), age 17 to 60 years, were recruited into the study. Samples were collected from polyp and sinusoidal mucosal, ethmoidal mucosal, or inferior turbinate in the respective groups and assessed for TGF- β1, MMP-2, MMP-7, MMP-9, TIMP-1, TIMP-2, TIMP-3, and TIMP-4 by immunoassay; collagen by histochemistry; and forkhead box P3 (FOXP3) mRNA by real-time PCR. Results Patients with CRSwNP showed significantly lower concentrations of TGF-β1, TIMP-1, TIMP-4, FOXP3, and collagen compared with patients with CRSsNP. Although there were no significant differences between the concentrations of MMP-7 and MMP-9 in patients with CRSwNP and CRSsNP, these were significantly increased compared with control patients. MMP-2 and TIMP-2 concentrations were not significantly different in any patient group, whereas TIMP-3 was not detectable. Conclusion Chronic rhinosinusitis with nasal polyps is characterized by a relative lack of TGF-ß expression versus CRSsNP. This finding may be causal for decreased collagen, TIMP-1/4, and FOXP3 expression in CRSwNP versus CRSsNP. TGF-ß serves as a main switch for different remodeling patterns in sinus disease.
Although the majority of patients with chronic upper airway diseases have controlled symptoms during treatment, many patients have severe chronic upper airway diseases (SCUADs). SCUAD defines those ...patients whose symptoms are inadequately controlled despite adequate (ie, effective, safe, and acceptable) pharmacologic treatment based on guidelines. These patients have impaired quality of life, social functioning, sleep, and school/work performance. Severe uncontrolled allergic rhinitis, nonallergic rhinitis, chronic rhinosinusitis, aspirin-exacerbated respiratory diseases, or occupational airway diseases are defined as SCUADs. Pediatric SCUADs are still unclear. In developing countries SCUADs exist, but risk factors can differ from those seen in developed countries. Comorbidities are common in patients with SCUADs and might increase their severity. The present document is the position of a group of experts considering that SCUADs should be considered differently from mild chronic upper airway diseases. It reviews the state of the art, highlighting gaps in our knowledge, and proposes several areas for a better understanding, prevention, and management of SCUADs. This document can also serve to optimize the pharmacoeconomic evaluation of SCUADs by means of comparison with mild chronic upper airway diseases.
Periostin expression has been shown to be regulated by several mediators, including TGF-β1, TGF-β2, and TGF-β4; bone morphogenic proteins 2 and 4; vascular endothelial growth factor; and IL-3, ...IL-4, IL-6, and IL-13.5 Our study showed that concomitant with the significantly increased periostin expression in nasal tissue of IL-5high patients with CRSwNP, expression of IL-4 and IL-13, but not IFN-γ, IL-17, and TGF-β1 (Fig 1, E), was also significantly increased in IL-5high patients with CRSwNP compared with that seen in IL-5low patients with CRSwNP and control subjects, with a significant correlation between periostin and IL-4 expression (r = 0.342, P = .038). Periostin has been reported to interact with extracellular matrix (ECM) proteins, such as type 1 collagen, fibronectin, tenascin C, and heparin.10 Accordingly, our results showed that the expression patterns of fibronectin and tenascin C were similar to that of periostin (Fig 1, F), with tenascin C expression correlated with periostin expression (r = 0.397, P = .015) in patients with CRSwNP and fibronectin and tenascin C expression colocalized with eosinophil counts and periostin expression in the subepithelial region of NP tissue (Fig 2, A). ...eosinophils adhered to fibronectin and tenascin C (Fig 2, D).
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