Chronic rhinosinusitis (CRS) affects more than 10% of the population in the United States and Europe. Recent findings point to a considerable variation of inflammatory subtypes in patients with CRS ...with nasal polyps and patients with CRS without nasal polyps. According to current guidelines, glucocorticosteroids and antibiotics are the principle pharmacotherapeutic approaches; however, they fail in a group of patients who share common clinical and laboratory markers. Several clinical phenotypes often leading to uncontrolled disease, including adult nasal polyposis, aspirin-exacerbated respiratory disease, and allergic fungal rhinosinusitis, are characterized by a common endotype: a TH 2 bias is associated with a higher likelihood of comorbid asthma and recurrence after surgical treatment. As a consequence, several innovative approaches targeting the TH 2 bias with humanized mAbs have been subjected to proof-of-concept studies in patients with CRS with nasal polyps with or without comorbid asthma: omalizumab, reslizumab, mepolizumab, and recently dupilumab. Future concepts using upstream targets, such as GATA-3, also focus on this endotype. This current development might result in advantages in the treatment of patients with the most severe CRS.
Chronic rhinosinusitis (CRS) is a complex disease consisting of several disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is ...possibly the greatest obstacle in understanding the causes of CRS and improving treatment. It is generally agreed that there are clinically relevant CRS phenotypes defined by an observable characteristic or trait, such as the presence or absence of nasal polyps. Defining the phenotype of the patient is useful in making therapeutic decisions. However, clinical phenotypes do not provide full insight into all underlying cellular and molecular pathophysiologic mechanisms of CRS. Recognition of the heterogeneity of CRS has promoted the concept that CRS consists of multiple groups of biological subtypes, or “endotypes,” which are defined by distinct pathophysiologic mechanisms that might be identified by corresponding biomarkers. Different CRS endotypes can be characterized by differences in responsiveness to different treatments, including topical intranasal corticosteroids and biological agents, such as anti–IL-5 and anti-IgE mAb, and can be based on different biomarkers that are linked to underlying mechanisms. CRS has been regarded as a single disease entity in clinical and genetic studies in the past, which can explain the failure to identify consistent genetic and environmental correlations. In addition, better identification of endotypes might permit individualization of therapy that can be targeted against the pathophysiologic processes of a patient's endotype, with potential for more effective treatment and better patient outcomes.
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 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 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.
Chronic rhinosinusitis can be differentiated into several phenotypes based on clinical criteria; however, these phenotypes do not teach us much about the underlying inflammatory mechanisms. Thus, the ...use of nasal endoscopy and CT scanning, and eventually taking a swab or a biopsy, may not be sufficient to fully appreciate the individual patient's pathology. Endotyping of chronic rhinosinusitis on the basis of pathomechanisms, functionally and pathologically different from others by the involvement of specific molecules or cells, may in contrast provide us with information on the risk of disease progression or recurrence and on the best available treatment, and also helps us identifying innovative therapeutic targets for treatment. Endotyping may best be structured around T helper cells and their downstream events, such as tissue eosinophilia or neutrophilia; this approach involves the cytokines and chemokines related to specific T helper cell populations, and related markers such as IgE. Endotyping is of specific interest at the time of the arrival of new biologicals, confronting us with the challenge of the selection of eligible patients for treatment and predicting their therapeutic response; defining suitable biomarkers is therefore an urgent task. Failure to appreciate the underlying mechanisms and endotypes of chronic rhinosinusitis may limit progress in the management of the disease at present.
Pathogenesis of chronic rhinosinusitis: Inflammation Van Crombruggen, Koen, PhD; Zhang, Nan, MD; Gevaert, Philippe, MD ...
Journal of allergy and clinical immunology,
10/2011, Letnik:
128, Številka:
4
Journal Article
Recenzirano
Chronic rhinosinusitis (CRS) is a heterogeneous group of inflammatory diseases of the nasal and paranasal cavities either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP ...and CRSwNP are prevalent medical conditions associated with substantial impaired quality of life, reduced workplace productivity, and serious medical treatment costs. Despite recent research evidence that contributes to further unveiling the pathophysiology of these chronic airway conditions, the cause remains poorly understood and appears to be multifactorial. A diverse spectrum of alterations involving histopathology, inflammatory cell and T-cell patterns, remodeling parameters (eg, TGF-β), eicosanoid and IgE production, microorganisms, and epithelial barrier malfunctions is reported in the search to describe the pathogenesis of this heterogeneous group of upper airway diseases. Furthermore, novel evidence indicates considerable heterogeneity within the CRSwNP subgroup determining the risk of comorbid asthma. The characterization of specific disease subgroups is a challenging scientific and clinical task of utmost importance in the development of diagnostic tools and application of individualized treatments. This review focuses on recent evidence that sheds new light on our current knowledge regarding the inflammatory process of CRS to further unravel its pathogenesis.
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 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 Moderate-to-severe allergic rhinitis (AR) is a challenge to treat, with many patients using multiple therapies and achieving limited symptom control. More effective therapies must be ...developed and tested in well-controlled, randomized, prospective studies with a direct comparison to current standards. Objectives The aim of these studies was to investigate the efficacy of MP29-02 (a novel formulation of azelastine and fluticasone propionate FP) in patients with moderate-to-severe seasonal allergic rhinitis (SAR) and to compare its efficacy with 2 first-line therapies (ie, intranasal azelastine and intranasal FP) in this population. Methods Three thousand three hundred ninety-eight patients (≥12 years old) with moderate-to-severe SAR were enrolled into 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group trials (MP4002 NCT00651118, MP4004 NCT00740792, and MP4006 NCT00883168). Each trial was conducted for 14 days during different allergy seasons. The primary efficacy variable was the sum of the morning and evening change from baseline in reflective total nasal symptom score (range, 0-24) over the treatment period. Outcomes for the meta-analysis included efficacy according to disease severity and time to response in relevant responder criteria. Results In the meta-analysis MP29-02 reduced the mean reflective total nasal symptom score from baseline (−5.7 SD, 5.3) more than FP (−5.1 SD, 4.9, P < .001), azelastine (−4.4 SD, 4.8, P < .001), or placebo (−3.0 SD, 4.2, P < .001). This benefit was observed from the first day of assessment, with improvement in each individual nasal symptom, even in the patients with the most severe disease. MP29-02 achieved response consistently days earlier and showed greater efficacy in patients with moderate-to-severe rhinitis than FP and azelastine. Conclusions MP29-02 represents a novel therapy that demonstrated superiority to 2 first-line therapies for AR. Patients with moderate-to-severe SAR achieved better control, and their symptoms were controlled earlier with MP29-02 than with recommended medications according to guidelines.
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