EOSINOPHILIC INFLAMMATION IN NASAL POLYPOSIS: REGULATION OF INTERLEUKIN 5 AND INTERLEUKIN 5 RECEPTOR α ISOFORMS

As the vast majority of bilateral nasal polyps (NP) are associated with a prominent eosinophilic inflammation and as eosinophils are well recognised in eliciting tissue damage and subsequent re-modelling, we aimed to investigate the role of eosinophils in the pathogenesis of NP. Especially the regulation of interleukin-5 (IL-5) and the interleukin-5 receptor α (Rα) isoforms were studied with emphasis on future therapeutic strategies in NP. Characterisation of NP suggests a central deposition of plasma proteins (albumin), regulated by the subepithelial, mainly eosinophilic inflammation, as pathogenetic principle of polyp formation and growth. The accumulation and activation of eosinophils is favoured by the low concentrations of TGF- β1 and overproduction of IL-5 and eotaxin in NP tissue. Although elevated IgE levels are found in NP, total IgE and IgE antibodies in NP tissue was unrelated to skin prick tests, but correlated with the degree of eosinophilia. In addition, we demonstrated the organisation of secondary lymphoid tissue in NP tissue and a polyclonal hyper-immunoglobulinemia E associated with the presence of IgE specific to S. aureus enterotoxins (SAEs), colonization with S. aureus, and increased eosinophilic inflammation in a relevant subgroup of NP patients. The ultimate way to test the role of IL-5 and eosinophils in the pathogenesis of nasal polyposis, is by antagonizing IL-5 in an interventional study in NP patients. However, eosinophils show varying IL-5 sensitivity due to a different expression of the IL-5R isoforms according to activation state, maturation and localization in the body. At the local tissue level, the membrane-anchored (TM) IL-5R isoform is down-regulated whereas the secreted (SOL) IL-5R variant is up-regulated in nasal polyp tissue, but eosinophils are still activated. Therefore, strategies to antagonize IL-5 may have to face unexpected difficulties. We demonstrated shrinkage of nasal polyps in half of the verum-treated patients for up to four weeks after intravenous injection of a single dose of an anti-human IL-5 monoclonal antibody. When carefully analysing responders and non-responders, only those nasal polyps with elevated baseline levels of IL-5 in nasal secretions seemed to benefit from anti-IL-5 treatment. Remarkably, the degree of eosinophilia at baseline was not different between responders and non-responders. Our data show that at least in 50% of the nasal polyps, IL-5 and eosinophils play a key role (IL-5-dependent) in sustaining polyp size, whereas in the other group, eosinophilia may be more dependent on other factors (IL-5-independent). Finally, these insights in the regulation of IL-5 and eosinophilia in NP, (re-)open therapeutic perspectives in nasal polyposis based on eosinophil-selective targets

Twelve-year follow-up study after endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyposis

Abstract Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a therapeutic challenge because of the high recurrence rate. Surgical intervention should be considered in patients who fail to improve after medical treatment. We monitored recurrence and revision surgery over 12 years after endoscopic sinus surgery in CRSwNP patients. Methods In this prospective cohort study, 47 patients with CRSwNP, who underwent primary or revision extended endoscopic sinus surgery, were followed. Clinical symptoms and total nasal endoscopic polyp score were evaluated before, 6 years and 12 years after surgery. Results Twelve years after surgery, 38 out of 47 patients (80.9%) were available for examination. There still was a significantly better symptom score and total nasal endoscopic polyp score compared to before surgery (P < 0.001). Within the 12-year follow-up period, 30 out of 38 patients developed recurrent nasal polyps, of which 14 patients underwent additional revision surgery. Comorbid allergic sensitization and tissue IL-5 levels were found to be significant predictors for the need of revision surgery. Conclusions This long-term cohort study, investigating the outcome after surgery in CRSwNP, showed that, despite the low number of patients, 78.9% of patients with CRSwNP were subject to recurrence of the disease and 36.8% to revision surgery over a 12-year period

Monoclonal Antibodies and Airway Diseases

Monoclonal antibodies, biologics, are a relatively new treatment option for severe chronic airway diseases, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS). In this review, we focus on the physiological and pathomechanisms of monoclonal antibodies, and we present recent study results regarding their use as a therapeutic option against severe airway diseases. Airway mucosa acts as a relative barrier, modulating antigenic stimulation and responding to environmental pathogen exposure with a specific, self-limited response. In severe asthma and/or CRS, genome–environmental interactions lead to dysbiosis, aggravated inflammation, and disease. In healthy conditions, single or combined type 1, 2, and 3 immunological response pathways are invoked, generating cytokine, chemokine, innate cellular and T helper (Th) responses to eliminate viruses, helminths, and extracellular bacteria/fungi, correspondingly. Although the pathomechanisms are not fully known, the majority of severe airway diseases are related to type 2 high inflammation. Type 2 cytokines interleukins (IL) 4, 5, and 13, are orchestrated by innate lymphoid cell (ILC) and Th subsets leading to eosinophilia, immunoglobulin E (IgE) responses, and permanently impaired airway damage. Monoclonal antibodies can bind or block key parts of these inflammatory pathways, resulting in less inflammation and improved disease control

Monoclonal Antibodies and Airway Diseases

Monoclonal antibodies, biologics, are a relatively new treatment option for severe chronic airway diseases, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS). In this review, we focus on the physiological and pathomechanisms of monoclonal antibodies, and we present recent study results regarding their use as a therapeutic option against severe airway diseases. Airway mucosa acts as a relative barrier, modulating antigenic stimulation and responding to environmental pathogen exposure with a specific, self-limited response. In severe asthma and/or CRS, genome–environmental interactions lead to dysbiosis, aggravated inflammation, and disease. In healthy conditions, single or combined type 1, 2, and 3 immunological response pathways are invoked, generating cytokine, chemokine, innate cellular and T helper (Th) responses to eliminate viruses, helminths, and extracellular bacteria/fungi, correspondingly. Although the pathomechanisms are not fully known, the majority of severe airway diseases are related to type 2 high inflammation. Type 2 cytokines interleukins (IL) 4, 5, and 13, are orchestrated by innate lymphoid cell (ILC) and Th subsets leading to eosinophilia, immunoglobulin E (IgE) responses, and permanently impaired airway damage. Monoclonal antibodies can bind or block key parts of these inflammatory pathways, resulting in less inflammation and improved disease control

Prevalence, associated factors and management implications of left ventricular outflow tract obstruction in Takotsubo cardiomyopathy: a two-year, two-center experience

Background: Some patients with Takotsubo cardiomyopathy (TTC) develop cardiogenic shock due to left ventricular outflow tract (LVOT) obstruction -there is, however, a paucity of data regarding this condition. Methods: Prevalence, associated factors and management implications of LVOT obstruction in TTC was explored, based on two-year data from two Belgian heart centres. Results: A total of 32 patients with TTC were identified out of 3,272 patients presenting with troponin-positive acute coronary syndrome. In six patients diagnosed with TTC (19%), a significant LVOT obstruction was detected by transthoracic echocardiography. Patients with LVOT obstruction were older and had more often septal bulging, and presented more frequently in cardiogenic shock as compared to those without LVOT obstruction (P < 0.05). Moreover, all patients with LVOT obstruction showed systolic anterior motion (SAM) of the anterior mitral valve leaflet, which was associated with a higher grade of mitral regurgitation (2.2 +/- 0.7 vs. 1.0 +/- 0.6, P< 0.001). Adequate therapeutic management including fluid resuscitation, cessation of inotropic therapy, intravenous beta-blocker, and the use of intra-aortic balloon pump resulted in non-inferior survival in TTC patients with LVOT obstruction as compared to those without LVOT obstruction. Conclusions: TTC is complicated by LVOT obstruction in approximately 20% of cases. Older age, septal bulging, SAM-induced mitral regurgitation and hemodynamic instability are associated with this condition. Timely and accurate diagnosis of LVOT obstruction by echocardiography is key to successful management of these TTC patients with LVOT obstruction and results in a non-inferior outcome as compared to those patients without LVOT obstruction

Development and validation of a standardized double-blind, placebo-controlled food challenge matrix for raw hazelnuts

Background: Double-blind, placebo-controlled food challenge (DBPCFC) is considered the gold standard for food allergy diagnosis. However, this test is rarely performed routinely in clinical practice because of various practical issues, e.g. the lack of a standardized matrix preparation. The aim of this study was to develop and validate a convenient DBPCFC matrix, that can easily be implemented in daily clinical practice. The focus of this study was the blinding of hazelnuts, whereby the hazelnuts retained as much as possible their allergenicity and could be mixed homogenously in low-doses to the matrices. Methods: A basophil-activation test (BAT), microbial tests and an LC-MS/MS test were performed to assess respectively the allergenicity of the used hazelnuts, the microbial stability of the novel developed matrices and the homogeneity of the hazelnuts in the matrices. A sensory test was conducted to validate the blinding of the hazelnuts in the matrices. A pilot DBPCFC study included eight patients as proof of concept. Results: The BAT-test gave the first insights concerning the retained allergenicity of the hazelnuts. The microbial safety could be assured after 12 months of storage. Sufficient masking was assessed by several sensory tests. Homogeneous hazelnut distribution could be achieved for the different hazelnut concentrations. The DBPCFC's results showed diverse allergic responders (from no reactions to distinct objective symptoms). Conclusion: A novel stable and validated DBPCFC matrix using raw hazelnuts has been developed that allows easy preparation in a standardized way for convenient use in daily clinical practice

Enhanced release of IgE-dependent early phase mediators from nasal polyp tissue

Background: The mast cell is a crucial effector cell in allergic rhinitis and other inflammatory diseases. During the acute allergic reaction preformed mediators such as histamine, but also de novo produced mediators such as leukotrienes (LTC4/D-4/E-4) and prostaglandins (PGD(2)) are released. Mast cells represent targets for therapeutic intervention, and thus a human ex-vivo model to stimulate mast cells taken from mucosal sites would be instrumental for drug intervention studies. We have aimed to activate mast cells within ex-vivo human nasal tissue by IgE/anti-IgE specific (epsilon chain specific) stimulations and in this respect to test the usability of nasal polyps versus inferior turbinates Methods: Biopsy samples were collected from patients with nasal polyps and inferior turbinates from patients who underwent sinus or septal surgery. Tissue fragments were primed with IgE 1 mu g/ml for 60 minutes and then stimulated for 30 minutes with tissue culture medium (negative control), anti-IgE 10 mu g/ml, anti-IgE 30 mu g/ml and ionomycin 10 mu M (positive control). Histamine, leukotrienes and PGD2 were measured in supernatants. To help provide an understanding of the extent of the response, the number of tryptase and Fc epsilon RI alpha positive cells was evaluated by means of immunohistochemistry and the Fc epsilon RI alpha-chain was measured by means of quantitative PCR in the nasal polyp and inferior turbinate tissues. Finally, the correlation between IgE concentrations in the nasal tissue and the release of mediators was analysed. Results: Stimulations with anti-IgE on IgE-primed nasal tissue fragments lead to a concentration-dependent release of histamine, leukotrienes and PGD(2). The release of these early phase mediators was significantly higher in nasal polyps compared to inferior turbinates, although tryptase, Fc epsilon RI alpha positive cells and Fc epsilon RI alpha-chain transcripts were equally present in both groups. No correlation was found between baseline concentrations of IgE, and the release of histamine, LTC4/LTD4/LTE4 and PGD2 after stimulation. Conclusion: This human nasal challenge model mimics the allergic early phase reaction. The release of histamine, cys-leukotrienes and PGD(2) was significantly higher in nasal polyps versus inferior turbinates, however, this observation could not be explained by differences in mast cell or Fc epsilon RI+ cell numbers