Ronald Olivenstein

Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.

RATIONALE Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. OBJECTIVES To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. METHODS A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). MEASUREMENTS AND MAIN RESULTS The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). CONCLUSIONS BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

IL-9 and its receptor in allergic and nonallergic lung disease: Increased expression in asthma

BACKGROUND Bronchial asthma is a chronic inflammatory disease associated with genetic components. Recently IL-9 has been reported as a candidate gene for asthma and to be associated with bronchial hyperresponsiveness and elevated levels of total serum IgE. OBJECTIVE To investigate the contribution of IL-9 to the pathogenesis of asthma, we examined the expression of IL-9 and its receptor (IL-9R) in bronchial tissue from subjects with atopic asthma (n = 10), chronic bronchitis (n = 11), and sarcoidosis (n = 9) and from atopic (n = 7) and nonatopic (n = 10) healthy control subjects. METHODS Bronchial biopsy specimens were examined for the presence of IL-9 and IL-9R protein and messenger RNA (mRNA) by immunocytochemistry and in situ hybridization, respectively. To phenotype the cells expressing IL-9 in asthmatic tissue, combined in situ hybridization and immunocytochemistry was also performed. RESULTS There was a highly significant difference (P <.001) in the expression of IL-9 mRNA in asthmatic airways (20.6 +/- 4.0 cells/mm of basement membrane) compared with chronic bronchitis (5.6 +/- 4.4), sarcoidosis (2.5 +/- 1.8), atopic control subjects (7.7 +/- 2.2), and healthy control subjects (2.7 +/- 2.3). The number of IL-9 immunoreactive cells was also greater in asthmatic patients compared with the other groups (P <.05). Although the level of IL-9R mRNA expression did not differ in any of the groups (P >.05), IL-9R immunoreactivity was significantly higher in asthmatic compared with control subjects. Furthermore, IL-9 mRNA expression levels were also significantly correlated with FEV(1) (P <.05) and the airway responsiveness to methacholine producing a 20% fall in FEV(1) (P <. 01). The cells expressing IL-9 mRNA in asthmatic tissue were CD3(+) lymphocytes (68%), major basic protein(+) eosinophils (16%), and elastase(+) neutrophils (8%). CONCLUSION The results of this study demonstrate the potential of IL-9 to be a marker for atopic asthma and furthermore suggest an important role for this cytokine in the pathophysiologic mechanisms of this disease.

Gene expression of the GATA-3 transcription factor is increased in atopic asthma

BACKGROUND High expression of IL-5 by T cells in the airways of asthmatic individuals is believed to play a fundamental role in the eosinophilia associated with this disease. Recently, the transcription factor GATA-3 was shown to be critical for IL-5 gene expression in TH2 cells in vitro. OBJECTIVE Our aim was to examine the expression of GATA-3 mRNA and its colocalization within the airways of asthmatic and nonasthmatic individuals. METHODS We investigated the association between GATA-3 gene expression, airway inflammatory cells, and IL-5 gene expression in bronchoalveolar lavage fluid and bronchial biopsy specimens from atopic asthmatic subjects (n = 10) and normal control subjects (n = 10). RESULTS We report that GATA-3 mRNA expression is significantly increased in the airways of asthmatic subjects compared with those of normal control subjects (P <.001). Numbers of cells expressing GATA-3 transcripts correlated significantly with reduced airway caliber (P <.05) and airways hyperresponsiveness (P <.05) in asthmatic subjects. Colocalization studies showed that the majority (approximately 60% to 90%) of GATA-3 mRNA+ cells in asthmatic airways were CD3(+) T cells, with smaller contributions from major basic protein+ eosinophils and tryptase+ mast cells. The density of GATA-3 mRNA+ cells correlated significantly with the numbers of cells expressing IL-5 mRNA (P <.001, r = 0.879 for bronchoalveolar lavage fluid; P <. 05, r = 0.721 for biopsy specimens). Furthermore, double in situ hybridization demonstrated that approximately 76% of GATA-3 mRNA+ cells coexpressed IL-5 mRNA and that 91% of IL-5 mRNA+ cells coexpressed GATA-3 mRNA. CONCLUSION The results of this study provide the first evidence of increased GATA-3 gene expression in association with IL-5 mRNA+ cells in asthmatic airways. These findings support a causal association between augmented GATA-3 expression and dysregulated IL-5 expression in atopic asthma.

Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction

BACKGROUND The patterns of airway remodeling and the biomarkers that distinguish different subtypes of severe asthma are unknown. OBJECTIVES We sought to characterize subjects with severe asthma with and without chronic persistent airflow obstruction with respect to airway wall remodeling (histopathologic and radiologic) and specific sputum biomarkers. METHODS Subjects with severe asthma with chronic persistent (n = 16) or intermittent (n = 18) obstruction were studied. Endobronchial biopsy specimens were analyzed for airway smooth muscle area, epithelial detachment, basement membrane thickness, and submucosal fibrosis. Levels of eosinophil cationic protein, myeloperoxidase, matrix metalloproteinase 9, tissue inhibitor of matrix metalloproteinase 1 (ELISA), and 27 cytokines (multiplex assay) and differential cell counts were measured in induced sputum. Airway thickness was measured by means of high-resolution computed tomographic scanning. RESULTS Chronic persistent obstruction was associated with earlier age of onset, longer disease duration, more inflammatory cells in the sputum, and greater smooth muscle area (15.65% +/- 2.69% [n = 10] vs 8.96% +/- 1.99% [n = 14], P = .0325). No differences between groups were found for any of the biomarker molecules measured in sputum individually. However, principal component analysis revealed that the dominant variables in the chronic persistent obstruction group were IL-12, IL-13, and IFN-gamma, whereas IL-9, IL-17, monocyte chemotactic protein 1, and RANTES were dominant in the other group. Airway imaging revealed no differences between groups. CONCLUSION Subjects with severe asthma with chronic persistent obstruction have increased airway smooth muscle with ongoing T(H)1 and T(H)2 inflammatory responses. Neither airway measurements on high-resolution computed tomographic scans nor sputum analysis seem able to identify such patients.

Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial

Background: Airway inflammation in chronic obstructive pulmonary disease (COPD) is characterised by infiltration of CD8+ T cells and CD68+ macrophages and an increased number of neutrophils, whereas few studies have described the presence of eosinophils. Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear, recent studies suggest that combination therapy could be beneficial. A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate (SFC) and fluticasone propionate (FP) alone on inflammatory cells in the airways of patients with COPD. Methods: Patients were treated in a randomised, double blind, parallel group, placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily (SFC, n = 19, 19 men, mean age 62 years), 500 µg FP twice daily (n = 20, 15 men, mean age 64 years) or placebo (n = 21, 17 men, mean age 66 years) for 3 months. At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8+ T lymphocytes, CD68+ macrophages, neutrophils and eosinophils were measured. Results: CD8+ cells were significantly reduced by SFC compared with placebo (difference −98.05 cells/mm2; 95% CI −143.14 to −52.9; p<0.001). Such a marked effect was not seen with FP alone (−44.67 cells/mm2; 95% CI −90.92 to 1.57; p = 0.06). CD68+ macrophages were also reduced by SFC compared with placebo (difference −31.68 cells/mm2; 95% CI −61.07 to −2.29; p = 0.03) but not by FP. SFC did not significantly change neutrophils and eosinophils compared with placebo. Conclusions: SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone.

Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma

BACKGROUND Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. OBJECTIVE We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. METHODS BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.govNCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. RESULTS One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV₁ values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. CONCLUSIONS These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting β₂-agonists.

Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial

BackgroundBronchial thermoplasty (BT) is a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle. Treated patients have been followed out to 5 years to evaluate long-term safety of this procedure.MethodsPatients enrolled in the Asthma Intervention Research Trial were on inhaled corticosteroids ≥200 μg beclomethasone or equivalent + long-acting-beta2-agonists and demonstrated worsening of asthma on long-acting-β2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4 year safety study. Adverse events (AEs) and spirometry data were used to assess long-term safety out to 5 years post-BT.Results45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years respectively. The rate of respiratory adverse events (AEs/subject) was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively,). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in Years 2, 3, 4, and 5 compared to Year 1. The FVC and FEV1 values showed no deterioration over the 5 year period in the BT group. Similar results were obtained for the Control group.ConclusionsThe absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FVC and FEV1) over a 5-year period post-BT in this group of patients with moderate to severe asthma support the long-term safety of the procedure out to 5 years.

Prevalence of obstructive sleep apnea–hypopnea in severe versus moderate asthma

BACKGROUND Previous studies have suggested a link between obstructive sleep apnea and poor asthma control, which may be mediated through airway inflammation, obesity, and other mechanisms. OBJECTIVE To test the hypothesis that the prevalence and severity of sleep apnea is greater among patients with severe compared with moderate asthma and controls without asthma. METHODS Complete overnight home polysomnography was performed in 26 patients with severe asthma consecutively recruited to a difficult asthma program, 26 patients with moderate asthma, and 26 controls without asthma of similar age and body mass index. Flow rates and Juniper asthma control and quality of life questionnaires were also obtained. RESULTS Obstructive sleep apnea-hypopnea, defined by an Apnea-Hypopnea Index > or = 15 events/h of sleep scored using Chicago criteria, was present in 23 of 26 (88%) patients with severe asthma, 15 of 26 (58%) patients with moderate asthma, and 8 of 26 (31%) controls without asthma (chi(2): P < .001). Using the more restrictive scoring criteria applied in the Wisconsin cohort study, Apnea-Hypopnea Index > or = 5/h was present in 50% (severe), 23% (moderate), and 12% (control) of subjects (P = .007). Mean nocturnal arterial oxygen saturation was significantly lower in patients with severe asthma versus controls, and apnea-hypopnea severity measures were significantly worse for both asthmatic groups compared with controls. Among subjects with asthma, no significant correlations were identified between the severity of sleep-disordered breathing and asthma severity or control measures (FEV(1), Juniper scores). CONCLUSIONS Obstructive sleep apnea-hypopnea was significantly more prevalent among patients with severe compared with moderate asthma, and more prevalent for both asthma groups than controls without asthma. These observations suggest potential pathophysiologic interactions between obstructive sleep apnea-hypopnea and asthma severity and control.

Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma

BACKGROUND The origin of the excess airway smooth muscle in asthma and when in the course of the disease it is acquired are uncertain. OBJECTIVES We examined the relative sensitivities of 2 markers of proliferation, proliferating cell nuclear antigen (PCNA) and Ki 67, in airway smooth muscle in vivo and in vitro. We then studied whether muscle remodeling is a dynamic process in asthma by quantifying proliferation rate and area. Finally we examined heparin-binding epidermal growth factor as a biomarker of remodeling. METHODS We obtained bronchoscopic biopsies from subjects with moderate or severe asthma and healthy controls (n = 9/group). For in vitro studies, airway smooth muscle cells were cultured from tracheas of transplant donors. The proliferation rate was quantified from PCNA and Ki 67, co-localized to smooth muscle-specific alpha-actin cells in vivo. Muscle area was assessed morphometrically. We examined the expression of heparin-binding epidermal growth factor on tissues by in situ hybridization and by immunohistochemistry and in cells in culture by RT-PCR. RESULTS Proliferating cell nuclear antigen and Ki 67 were highly correlated, but PCNA was a significantly more sensitive marker both in vivo and in vitro. Muscle area was 3.4-fold greater and the fraction of PCNA(+) nuclei in muscle was 5-fold greater in severe asthma than in healthy subjects. Heparin-binding epidermal growth factor was upregulated in proliferating muscle cells in culture and in airway smooth muscle in severe asthmatic tissues. CONCLUSION Proliferating cell nuclear antigen is a highly sensitive marker of proliferation and heparin-binding epidermal growth factor is a potential biomarker during active remodeling of ASM in severe asthma.

The expression of stem cell factor and c‐kit receptor in human asthmatic airways

Background Asthmatic airways are characterized by infiltration with a variety of inflammatory cells such as mast cells and eosinophils. Stem cell factor (SCF) is an important activating and chemotactic factor for both mast cells and eosinophils. In addition, it is a critical growth and differentiation factor for mast cells.