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 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.
Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2).
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.
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.
Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.
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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.
Pathogenesis of chronic rhinosinusitis: Inflammation Van Crombruggen, Koen, PhD; Zhang, Nan, MD; Gevaert, Philippe, MD ...
Journal of allergy and clinical immunology,
10/2011, Volume:
128, Issue:
4
Journal Article
Peer reviewed
Open access
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.
The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription ...factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA).
We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1).
After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo.
Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.).
Background
Real‐world evidence is sparse on the benefits of allergen immunotherapy AIT; subcutaneous/sublingual immunotherapy (SCIT/SLIT), the only disease‐modifying intervention for allergic ...rhinitis (AR) with long‐term efficacy. This real‐life study evaluated the effect of six AITs (native pollen SLIT/SCIT, four allergoid SCITs) vs symptomatic medication use, on AR symptoms and asthma symptoms/onset, in patients with birch pollen‐associated AR and/or asthma.
Methods
In this retrospective cohort analysis of a German longitudinal prescription database, AIT patients received ≥2 successive seasonal treatment cycles; non‐AIT patients had ≥3 AR prescriptions in three seasons or previous month. Patients were matched for: index year, age, gender, main indication at index, number of seasonal cycles within treatment period, baseline AR/asthma treatment prescriptions. Multiple regression analysis compared prescription data in AIT and non‐AIT groups as proxy for clinical status/disease progression.
Results
Up to 6 years of follow‐up, significantly more AIT (65.4%) vs non‐AIT (47.4%) patients were AR medication‐free; odds ratio (OR) 95% confidence interval (CI): 0.51 (0.48‐0.54); P < 0.001 (28.6% covariate‐adjusted reduction vs non‐AIT; P < 0.001), and significantly more AIT (49.1%) vs non‐AIT (35.1%) patients were asthma medication‐free OR (95% CI): 0.59 (0.55‐0.65); P < 0.001 (32% reduction vs non‐AIT; P < 0.001), or reduced existing asthma medication use (32% covariate‐adjusted reduction vs non‐AIT; P < 0.001). During treatment, new‐onset asthma risk was significantly reduced in the AIT vs non‐AIT group (OR: 0.83; P = 0.001).
Conclusions
Birch pollen AIT demonstrated real‐world benefits up to 6 years post‐treatment cessation through significantly reduced AR and asthma medication intake, and significantly decreased risk of new‐onset asthma medication use on‐treatment.
In this retrospective, real‐world study in Germany, birch pollen allergen immunotherapy (AIT) demonstrated significant benefits up to 6 years post‐treatment in patients with birch pollen‐associated allergic rhinitis (AR) and/or asthma. AIT was associated with significantly improved AR and asthma symptoms as the medication dispensing decreased; nearly two‐thirds and one‐half of patients initially using AR or asthma medications, respectively, no longer required them at study end. During the period in which they were receiving AIT, patients with AR but not asthma had a significantly decreased risk of new‐onset asthma medication dispensing.
Objectives
Nasal polyps are often characterized by type 2 inflammation and disease recurrence. We developed a new surgical technique, referred to as reboot approach, which aims to maximally remove ...all sinus mucosa and allow healthy re‐epithelialization from the preserved nasal mucosa. We here review type 2 endotype chronic rhinosinusitis with nasal polyps (CRSwNP) patients who underwent classical mucosa‐sparing endoscopic sinus surgery (ESS) or the reboot approach.
Methods
Retrospective case‐control study of 50 consecutive CRSwNP patients who underwent endoscopic sinus surgery between 2015 and 2017, either as a classical non‐reboot ESS (n = 20); a partial reboot approach removing the mucosa of the ethmoidal, sphenoidal, and maxillary sinuses (n = 18); or a complete reboot approach including Draf III and removal of all frontal sinus mucosa (n = 12). Polyp recurrence over the follow‐up period of 2 years served as the primary outcome.
Results
All patients demonstrated a type 2 inflammation of the mucosal tissue harvested during surgery. In the classical approach group (n = 20), nine patients relapsed within 2 years (45%); in the partial reboot group, three out of 18 patients (17%) relapsed; and in the full reboot group one out of 12 patients (8%) relapsed. The relapse rates were significantly different between the non‐reboot and the reboot groups (P = 0.02) but also between all treatment groups (P = 0.038).
Conclusion
Complete removal of diseased mucosa from the paranasal sinuses (reboot approach) significantly reduces the recurrence of nasal polyps for 30 months postoperatively compared to the current mucosa‐sparing approach in type 2 inflammatory CRSwNP.
Level of Evidence
3b
Laryngoscope, 129:1286–1292, 2019
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 Chronic airway inflammatory diseases, such as chronic rhinosinusitis with nasal polyps and asthma, show increased nasal Staphylococcus aureus colonization. Staphylococcus aureus –derived ...serine protease–like protein (Spl) D and other closely related proteases secreted by S aureus have recently been identified as inducers of allergic asthma in human subjects and mice, but their mechanism of action is largely unknown. Objective We investigated the role of recombinant SplD in driving TH 2-biased responses and IgE formation in a murine model of allergic asthma. Methods Allergic asthma was induced in C57BL/6 J wild-type mice, Toll-like receptor (TLR) 4 knockout (Tlr4 −/− ) mice, and recombination-activating gene (Rag2) knockout (Rag2 −/− ) mice by means of repeated intratracheal applications of SplD. Inflammatory parameters in the airways were assessed by means of flow cytometry, ELISA, Luminex, and immunohistochemistry. Serum SplD-specific IgE levels were analyzed by using ELISA. Results We observed that repeated intratracheal exposure to SplD led to IL-33 and eotaxin production, eosinophilia, bronchial hyperreactivity, and goblet cell hyperplasia in the airways. Blocking IL-33 activity with a soluble ST2 receptor significantly decreased the numbers of eosinophils, IL-13+ type 2 innate lymphoid cells and IL-13+ CD4+ T cells and IL-5 and IL-13 production by lymph node cells but had no effect on IgE production. SplD-induced airway inflammation and IgE production were largely dependent on the presence of the functional adaptive immune system and independent of TLR4 signaling. Conclusion The S aureus –derived protein SplD is a potent allergen of S aureus and induces a TH 2-biased inflammatory response in the airways in an IL-33–dependent but TRL4-independent manner. The soluble ST2 receptor could be an efficient strategy to interfere with SplD-induced TH 2 inflammation but does not prevent the allergic sensitization.
Following the trend in asthma, endotypes for chronic rhinosinusitis with nasal polyps have been established, with type 2 immune reactions representing >80% of nasal polyp cases in Europe and the ...United States. Endotyping is without doubt useful to predict the natural course of disease, to determine pharmacotherapy and the extent of surgery, and lately also to select patients for treatment with type 2 biologics. However, with the opening of this new era of treatment, limitations of the current possibilities in subgrouping patients also became apparent, as (1) mixed endotypes often can be found and (2) predictions as to the best biologic to be used in an individual patient are not yet possible. Some of the questions to address in the near future are discussed.
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