In vivo imaging of the airway wall in asthma: fibered confocal fluorescence microscopy in relation to histology and lung function

<p>Abstract</p> <p>Background</p> <p>Airway remodelling is a feature of asthma including fragmentation of elastic fibres observed in the superficial elastin network of the airway wall. Fibered confocal fluorescence microscopy (FCFM) is a new and non-invasive imaging technique performed during bronchoscopy that may visualize elastic fibres, as shown by <it>in vitro </it>spectral analysis of elastin powder. We hypothesized that FCFM images capture <it>in vivo </it>elastic fibre patterns within the airway wall and that such patterns correspond with airway histology. We aimed to establish the concordance between the bronchial elastic fibre pattern in histology and FCFM. Second, we examined whether elastic fibre patterns in histology and FCFM were different between asthmatic subjects and healthy controls. Finally, the association between these patterns and lung function parameters was investigated.</p> <p>Methods</p> <p>In a cross-sectional study comprising 16 subjects (8 atopic asthmatic patients with controlled disease and 8 healthy controls) spirometry and bronchoscopy were performed, with recording of FCFM images followed by endobronchial biopsy at the airway main carina. Elastic fibre patterns in histological sections and FCFM images were scored semi-quantitatively. Agreement between histology and FCFM was analysed using linearly weighted kappa κ_w.</p> <p>Results</p> <p>The patterns observed in histological sections and FCFM images could be divided into 3 distinct groups. There was good agreement between elastic fibre patterns in histology and FCFM patterns (κ_w0.744). The semi-quantitative pattern scores were not different between asthmatic patients and controls. Notably, there was a significant difference in post-bronchodilator FEV₁%predicted between the different patterns by histology (p = 0.001) and FCFM (p = 0.048), regardless of asthma or atopy.</p> <p>Conclusion</p> <p>FCFM captures the elastic fibre pattern within the airway wall in humans <it>in vivo</it>. The association between post-bronchodilator FEV₁%predicted and both histological and FCFM elastic fibre patterns points towards a structure-function relationship between extracellular matrix in the airway wall and lung function.</p> <p>Trial registration</p> <p>Netherlands Trial Register <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=NTR1306">NTR1306</a></p

Refractory&quot; eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids

It has been suggested that patients with refractory eosinophilic airway inflammation represent a separate &quot;eosinophilic&quot; asthma phenotype associated with increased morbidity and a poor prognosis. To investigate whether persistent eosinophilia in these patients is a fixed feature or can still be modified by treatment, we investigated the effect of high-dose intramuscular corticosteroids on eosinophils in induced sputum. Twenty-two patients with stable severe asthma (15 women, aged 21-73 years) participated in this double-blind, placebo-controlled study. All were using inhaled corticosteroids (у 1,600 g/day) or chronic oral prednisone. They were included if the percentage of eosinophils in induced sputum was above the upper limit of normal (у 2%). Two weeks after treatment with triamcinolone, but not placebo, sputum eosinophils almost completely disappeared from a median of 12.6-0.2% (p Ͻ 0.001). In 82% of patients, no eosinophils could be observed at all. In addition, the rescue medication score decreased from 1.4 to 0.8 (p ϭ 0.01), and FEV 1 improved from a median of 73.8-88.3% predicted (p ϭ 0.001). We conclude that persistent sputum eosinophilia despite extensive antiasthma treatment is not a refractory phenomenon but is still sensitive to high-dose systemic corticosteroids. This implies that these patients with severe asthma need additional or alternative antiinflammatory treatment to combat the eosinophilia and associated poor prognosis. Keywords: asthma; eosinophilia; glucocorticoids; phenotype; sputum; severity of illness index There is now accumulating evidence that patients with bronchial asthma are heterogeneous with respect to the type of inflammation in the airways and the response to antiinflammatory therapy (1-4). Most patients with asthma have eosinophilic airway inflammation with good response to treatment with inhaled corticosteroids (5). However, a relatively large proportion of adult asthma cases is characterized by neutrophilic airway inflammation (4, 6), in particular those with severe disease (7-9). These patients are more difficult to treat and often require high doses of inhaled or oral corticosteroids to control their disease. Remarkably, bronchial biopsy and bronchoalveolar lavage studies have shown that in a subgroup of patients with severe asthma such neutrophilic airway inflammation is accompanied by persistent eosinophilic inflammation (10, 11). Eosinophilic inflammation in the airway mucosa that persists despite the use of high doses of inhaled corticosteroids or oral corticosteroids has been observed in several studies Correspondence and requests for reprints should be addressed to Elisabeth H. and has been implicated by Wenzel and colleagues as a feature of a separate asthma phenotype, associated with poor asthma prognosis (10, 12). Indeed, studies have shown that eosinophilic inflammation despite vigorous antiasthma treatment is associated with remodeling of the airways, impaired lung function, and near-fatal asthma attacks Why eosinophilia is persisting in these patients is unknown. Moreover, it has not been investigated whether persistent eosinophilia is a permanent characteristic of a specific phenotype of severe asthma or can be modulated by more intensive treatment. In this study, we investigated the effect of high-dose intramuscular corticosteroids on sputum eosinophilia in a subgroup of patients with severe asthma featuring persistent eosinophilia despite extensive antiinflammatory treatment. In addition, the effect of intramuscular corticosteroids on asthma symptoms, lung function, peripheral blood eosinophils, and nitric oxide in exhaled breath was examined. The results of this study have been published previously in the form of an abstract (21). METHODS Patients The patients in this study were part of a cohort of severe asthma patients participating in studies aimed at identifying risk factors of asthma severity Design The study had a randomized, parallel, double-blind, placebo-controlled design. At baseline (Visit 1), patients&apos; characteristics were documented, and Borg score, postbronchodilator FEV 1 , and level of exhaled nitric oxide were assessed. A blood sample was taken, and sputum was induced. If the sputum eosinophil percentage exceeded 2%, patients were randomized to one of the two treatments, with stratification for daily use of oral steroids (strata yes/no), and level of sputum eosinophil percentage (strata 2-10% or Ͼ 10%). After 1 week (Visit 2), one single intramuscular injection of 3 ml (40 mg/ml) long-acting triamcinolone acetonide (Kenacort-A40; Bristol-Myers Squibb, Woerden, The Netherlands) or matched placebo (3 ml NaCl 0.9%) was given. Intramuscular administration was chosen instead of a course of oral corticosteroids to avoid any confounding by noncompliance with therapy. Two weeks thereafter (Visit 3), the measurements performed at Visit 1 were repeated. A diary was completed by the patients during the first and third weeks of the study. Measurements Postbronchodilator FEV 1 was assessed (24) 30 minutes after the inhalation of 400 g salbutamol, and exhaled nitric oxide measurements wer

Cumulative Corticosteroid Sparing Effect of Anti-Interleukin-5/5Ra In Eosinophilic Asthma

BACKGROUND: Anti-interleukin (IL)-5/IL-5 receptor α (IL-5Ra) therapy has been shown to reduce maintenance oral corticosteroid (OCS) dose in severe eosinophilic asthma. However, the effect on cumulative OCS exposure is currently unknown. Neither is it known how prior OCS exposure affects response to anti-IL-5/5Ra treatment. We aimed primarily to compare the cumulative OCS exposure over a 2-year period before and after anti-IL-5/5Ra initiation, and secondarily to investigate whether duration and cumulative OCS exposure prior to anti-IL-5/5Ra influence the ability to discontinue OCS within 2 years of anti-IL-5/5Ra therapy. METHODS: This real-world nationwide observational registry-based study evaluated all dispensed OCS from 389 adults with severe eosinophilic asthma included in the Dutch Severe Asthma Registry (RAPSODI) 2 years before and 2 years after initiating anti-IL-5/5Ra. The Wilcoxon signed-rank test and multivariable regression analyses were used. RESULTS: Median (interquartile range) cumulative OCS exposure in the 2 years before and after anti-IL-5/5Ra initiation decreased from 2.715 (1.150–5.539) to 1.050 (0.300–3.640) g (p<0.001). 52% of patients were able to discontinue OCS within 2 years after anti-IL-5/5Ra therapy, which was independently predicted by lower and shorter prior OCS exposure. CONCLUSIONS: This real-world study showed that anti-IL-5/5Ra therapy leads to a significant reduction in cumulative OCS exposure over a 2-year period. Patients with lower and shorter OCS exposure were more likely to completely eliminate OCS. Since cumulative exposure increased progressively prior to anti-IL-5/5Ra initiation, our data suggest that early intervention leads to a better long-term prognosis in patients with severe eosinophilic asthma

Bronchial Thermoplasty Induced Airway Smooth Muscle Reduction and Clinical Response in Severe Asthma:The TASMA Randomized Trial

RATIONALE: Bronchial Thermoplasty (BT) is a bronchoscopic treatment for severe asthma targeting airway smooth muscle (ASM). Observational studies have shown ASM mass reduction after BT but appropriate control groups are lacking. Furthermore, as treatment response is variable, identifying optimal candidates for BT treatment is important. AIMS: First, to assess the effect of BT on ASM mass and second, to identify patient characteristics that correlate with BT-response. METHODS: Severe asthma patients (n=40) were randomized to immediate (n=20) or delayed (n=20) BT-treatment. Prior to randomization, clinical, functional, blood and airway biopsy data were collected. In the delayed control group, re-assessment, including biopsies, was performed after 6 months of standard clinical care, followed by BT. In both groups, post-BT data including biopsies were obtained after 6 months. ASM mass (% positive desmin or α-smooth muscle actin area in the total biopsy) was calculated with automated digital analyses software. Associations between baseline characteristics and Asthma Control and Asthma Quality of Life Questionnaire (ACQ/AQLQ) improvement were explored. RESULTS: Median ASM mass decreased by >50% in the immediate BT group (n=17) versus no change in the delayed control group (n=19) (p=0.0004). In the immediate group ACQ scores improved with -0.79 (-1.61;0.02 IQR) compared to 0.09 (-0.25;1.17 IQR) in the delayed group (p=0.006). AQLQ scores improved with 0.83 (-0.15;1.69 IQR) versus -0.02 (-0.77;0.75 IQR) (p=0.04). Treatment response in the total group (n=35) was positively associated with serum IgE and eosinophils, but not with baseline ASM mass. CONCLUSION: ASM mass significantly decreases after BT when compared to a randomized non-BT treated control group. Treatment response was associated with serum IgE and eosinophil levels but not with ASM mass. Clinical trial registration available at www.clinicaltrials.gov, ID:NCT0222539

OCS Reduction According to the Presence of Nasal Polyps or Atopic Status in the PONENTE Study

Peer reviewedPostprin

Adrenal Insufficiency is Not a Barrier to OCS Elimination in the PONENTE Study

Peer reviewedPostprin

Extinction and Positivity for the Evolution P-Laplacian Equation

AbstractThe aim of this paper is to discuss the extinction and positivity for the evolution P-Laplacian equation [formula] with p > 1. In particular, the necessary and sufficient condition for extinction is obtained

Corticosteroid tapering with benralizumab treatment for eosinophilic asthma: PONENTE Trial.

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody approved in several countries for the add-on maintenance treatment of patients with severe eosinophilic asthma aged 12 years and older. In the 28-week Phase III ZONDA trial (ClinicalTrials.gov identifier: NCT02075255), benralizumab produced a median 75% reduction from baseline in oral corticosteroid (OCS) dosage (versus 25% for placebo) while maintaining asthma control for patients with OCS-dependent severe asthma. This manuscript presents the detailed protocol for the Phase IIIb PONENTE (ClinicalTrials.gov identifier: NCT03557307), a study that will build on the findings from ZONDA. As the largest steroid-sparing study undertaken in severe asthma, PONENTE has a faster steroid tapering schedule for prednisone dosages ≥7.5 mg·day-1 than previous studies, and it includes an evaluation of adrenal insufficiency and an algorithm to taper OCS dosage when prednisone dosage is ≤5 mg·day-1. It also has a longer maintenance phase to assess asthma control for up to 6 months after completion of OCS tapering. The two primary endpoints are whether patients achieve 100% reduction in daily OCS use and whether patients achieve 100% reduction in daily OCS or achieve OCS dosage ≤5 mg·day-1, if adrenal insufficiency prevented further reduction, both sustained over ≥4 weeks without worsening of asthma. Safety and change from baseline in health-related quality of life will also be assessed. PONENTE should provide valuable guidance for clinicians on tapering OCS dosage, including the management of adrenal insufficiency, following benralizumab initiation for the treatment of patients who are OCS-dependent with severe, uncontrolled eosinophilic asthma

Prospective observational study in patients with obstructive lung disease : NOVELTY design

Peer reviewedPublisher PD

Heterogeneity within and between physician-diagnosed asthma and/or COPD : NOVELTY cohort

Copyright ©The authors 2021. For reproduction rights and permissions contact [email protected] reviewedPublisher PD