Background Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic ...challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a TH 2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma. Objective The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma. Methods A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels. Results There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (−2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy. Conclusion Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways.
Background To date, no study has evaluated the diversity of TH cell cytokine patterns of patients with chronic rhinosinusitis (CRS) among centers in different continents using identical methods. ...Objective We sought to assess TH cytokine profiles in patients with CRS from Europe, Asia, and Australia. Methods Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP; n = 435) and control subjects (n = 138) were recruited from centers in Adelaide, Benelux, Berlin, Beijing, Chengdu, and Tochigi. Nasal mucosal concentrations of TH 2, TH 17, and TH 1 cytokines; eosinophilic cationic protein (ECP); myeloperoxidase (MPO); IL-8; and tissue total and Staphylococcus aureus enterotoxin (SE)–specific IgE were measured by using identical tools. Results Combinations of TH 1/TH 2/TH 17 cytokine profiles in patients with CRSwNP varied considerably between regions. CRSwNP tissues from patients from Benelux, Berlin, Adelaide, and Tochigi were TH 2 biased, whereas those from Beijing mainly demonstrated TH 2/TH 1/TH 17 mixed patterns, and patients from Chengdu showed an even lower TH 2 expression. Concentrations of IL-8 and tissue total IgE in patients with CRSwNP were significantly higher than those in control subjects in all regions. More than 50% of patients with CRSwNP in Benelux, Berlin, Adelaide, and Tochigi showed a predominantly eosinophilic endotype compared with less than 30% of patients in Beijing and Chengdu. SE-specific IgE was found in significantly greater numbers in patients with CRSwNP from Benelux, Adelaide, and Tochigi and significantly lower numbers in patients from Beijing and Chengdu. Moreover, the TH 1/TH 2/TH 17 cytokine profiles in patients with CRSsNP showed diversity among the 6 regions. Conclusion TH cytokine levels, eosinophilic/neutrophilic patterns, and SE-specific IgE expressions show extreme diversity among patients with CRS from Europe, Asia, and Oceania.
Background Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately ...reflect the pathophysiologic diversity within patients with CRS. Objective We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes. Methods In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-β1, IgE, Staphylococcus aureus enterotoxin–specific IgE, and albumin. We used partition-based clustering. Results Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5–negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a TH 17 profile and had mixed CRSsNP/CRSwNP. The IL-5–positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin–specific IgE. Conclusion Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only.
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 is characterized by TH 2-biased eosinophilic inflammation. Eosinophils have been shown to generate so-called extracellular eosinophilic traps ...(EETs) under similar pathologic conditions. Objective Our aim was to investigate a possible link between EET formation and the presence of Staphylococcus aureus , an organism frequently colonizing the upper airways, at the human mucosal site of the disease. Methods Tissue slides were investigated for the presence of EETs and S aureus by using immunofluorescent staining and the PNA-Fish assay, respectively. An ex vivo human mucosal disease tissue model was used for artificial infection with S aureus . Cell markers were analyzed by using immunohistochemistry, the Luminex Multiplex assay, ELISA, PCR, and immunoblotting and linked to the presence of EETs. Results About 8.8% ± 4.8% of the infiltrating eosinophils exhibited EETs in patients' nasal polyp tissues. Formation of EETs was associated with increased IL-5 ( P < .05) and periostin ( P < .05) tissue levels and colonization with S aureus ( P < .05). By using an ex vivo human mucosal disease tissue model, EET formation was induced (4.2 ± 0.9–fold) on exposure to S aureus but not Staphylococcus epidermidis . Eosinophils were shown to migrate ( P < .01) toward S aureus and entrap the bacteria both inside and outside the mucosal tissue. Blocking NAPDH oxidase activity led to a complete inhibition ( P < .05) of EET formation by S aureus. Conclusion Eosinophils are likely to be specifically recruited to S aureus and possibly other microorganisms and form EETs at sites of airway epithelial damage to protect the host from infections in patients with chronic rhinosinusitis with nasal polyps.
Background The role of IgE in patients with severe asthma is not fully understood. Objective We sought to investigate whether IgE to Staphylococcus aureus enterotoxins might be relevant to disease ...severity in adult asthmatic patients. Methods Specific IgE antibody concentrations in serum against enterotoxins, grass pollen (GP), and house dust mite allergens and total IgE levels were measured in adult cohorts of 69 control subjects, 152 patients with nonsevere asthma, and 166 patients with severe asthma. Severe asthma was defined as inadequately controlled disease despite high-dose inhaled corticosteroids plus at least 2 other controller therapies, including oral steroids. Results Enterotoxin IgE positivity was significantly greater in patients with severe asthma (59.6%) than in healthy control subjects (13%, P < .001). Twenty-one percent of patients with severe asthma with enterotoxin IgE were considered nonatopic. Logistic regression analyses demonstrated significantly increased risks for enterotoxin IgE–positive subjects to have any asthma (OR, 7.25; 95% CI, 2.7-19.1) or severe asthma (OR, 11.09; 95% CI, 4.1-29.6) versus enterotoxin IgE–negative subjects. The presence of GP or house dust mite IgE antibodies was not associated with either significantly increased risk for asthma or severity. Oral steroid use and hospitalizations were significantly increased in patients with enterotoxin IgE and nonatopic asthma. GP IgE was associated with a higher FEV1 percent predicted value, and enterotoxin IgE was associated with a lower FEV1 percent predicted value. Conclusions Staphylococcal enterotoxin IgE antibodies, but not IgE against inhalant allergens, are risk factors for asthma severity. We hypothesize that the presence of enterotoxin IgE in serum indicates the involvement of staphylococcal superantigens in the pathophysiology of patients with severe asthma.
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 Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. Objective We ...sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. Methods Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. Results Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. Conclusion Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.
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.
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.
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