Martin J. Phillips

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).

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.

Segmental volume reduction using thermal vapour ablation in patients with severe emphysema: 6-month results of the multicentre, parallel-group, open-label, randomised controlled STEP-UP trial.

BACKGROUND Lung volume reduction of emphysematous lobes results in clinical improvement for patients with severe emphysema. However, some segments within a lobe are often substantially more diseased than others, thereby warranting a more targeted approach of the emphysematous parts of a lobe. We therefore did a study to assess whether or not selective sequential treatment of the more diseased upper lobe segments with bronchoscopic vapour ablation led to clinical improvement. METHODS For the multicentre, parallel-group, randomised, controlled, open-label Sequential Staged Treatment of Emphysema with Upper Lobe Predominance (STEP-UP) trial, adult patients aged 45-75 years with severe, upper lobe-predominant emphysema with a forced expiratory volume in 1 s (FEV1) between 20% and 45%, substantial hyperinflation, and post-rehabilitation 6-min walk test (6MWT) greater than 140 m were enrolled from 13 hospital sites in Europe (ten sites) and Australia (three sites). A computer-generated blocked randomisation scheme (block size three per site based on a random table from an independent biostatistician) stratified by site was used to randomly assign enrolled patients 2:1 to segmental vapour ablation (treatment group) or standard medical management (control group). Patients and investigators were not masked to group assignment. The primary efficacy endpoints were statistically significant changes in FEV1 and St Georges Respiratory Questionnaire (SGRQ-C) scores between trial groups at 6 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01719263. FINDINGS Between June 30, 2013, and Oct 1, 2014, 134 patients were screened and 70 were enrolled and randomly assigned: 46 to the treatment group and 24 to the control group. One patient in the treatment group did not receive treatment because of physician decision post-randomisation; this patient is excluded from all analyses. The mean relative improvement in FEV1 between the treatment group versus the control group was 14·7% (95% CI 7·8-21·5%; p<0·0001) and in SGRQ-C was -9·7 points (95% CI -15·7 to -3·7; p=0·0021). COPD exacerbation was the most common serious adverse event, occurring in 11 (24%) of 45 patients in the treatment group and one (4%) of 24 in the control group. One exacerbation resulted in a patient death 84 days after treatment; this was judged by the data and safety monitoring board to be possibly related to treatment. No pneumothorax occurred within 30 days of treatment. INTERPRETATION Compared with standard medical management, targeted thermal vapour ablation of more diseased segments and preservation of less diseased segments resulted in clinically meaningful and statistically significant improvements in lung function and quality of life at 6 months, with an acceptable safety profile. FUNDING Uptake Medical.

Using Optical Coherence Tomography To Improve Diagnostic and Therapeutic Bronchoscopy

Flexible bronchoscopy is a common procedure that is used in both diagnostic and therapeutic settings but does not readily permit measurement of central airway dimensions. Anatomic optical coherence tomography (a OCT), a modification of conventional optical coherence tomography (OCT), is a novel light-based imaging tool with the capacity to measure the diameter and lumen area of the central airways accurately during bronchoscopy. This study describes the first clinical use of aOCT imaging in the lower airways in three individuals with common endobronchial pathologies. During bronchoscopy, a specialized fiberoptic probe was passed through the biopsy channel of a standard flexible bronchoscope to the site of airway pathology. Airway dimensions were measured from the generated cross-sectional images in three subjects, one with subglottic tracheal stenosis (subject 1), one with malignant left main bronchus (LMB) obstruction (subject 2), and another with severe tracheomalacia (subject 3). Measured dimensions included internal airway diameter, cross-sectional area, and, in subject 1, stenosis length. Tracheal stenosis dimensions, measured using aOCT imaging, correlated with chest CT scan findings and guided the choice of airway stent (subject 1). The airway beyond a malignant obstruction of the LMB, and beyond bronchoscopic view, could be imaged using aOCT, and the distal extent of obstructing tumor identified (subject 2). The severity of newly diagnosed tracheomalacia was able to be quantified using aOCT imaging (subject 3). aOCT imaging during bronchoscopy allows accurate real-time airway measurements and may assist bronchoscopic assessment.

The effect of eicosapentaenoic acid consumption on human neutrophil chemiluminescence

The effect of eicosapentaenoic acid (EPA) on the inflammatory potential of neutrophils was investigated by supplementing the diets of 12 subjects with 2.16 g of EPA or 12 g of olive oil per day for 4 weeks in a double blind crossover study. Neutrophil function as assessed by luminol enhanced chemiluminescence responses to plateletactivating factor (PAF) and formyl-methionyl-leucyl-EPA but not after olive oil consumption in the subjects who consumed EPA first. In contrast, EPA had no significant effect on neutrophil chemiluminescence in the subjects who consumed olive oil first. Dietary supplementation with EPA inhibits neutrophil responses to inflammatory mediators such as PAF while other fatty acids appear to modify the effects of EPA.

Effects of different density gradient separation techniques on neutrophil function.

Investigation of the pathogenesis of inflammatory diseases has involved assessment of polymorphonuclear leukocyte (PMN) activity and a variety of techniques for separating PMNs from whole blood have been described. In this study the effects of Percoll gradient, Ficoll-Hypaque/Dextran sedimentation (FH/DS) and Mono-Poly Resolving Medium (M-PRM) on activation and function of PMNs were compared. All three separation techniques gave similar cell yield and purity. The mean (+/- SEM) percentage of cells demonstrating pseudopodia formation for Percoll, FH/DS and M-PRM were 39 +/- 9, 57 +/- 6 and 63 +/- 5, respectively, while superoxide release from resting cells was 1.9 +/- 0.9, 7.2 +/- 3.5 and 11 +/- 4.8 pmols per 10(6) cells min-1, respectively, indicating that activation of cells during separation may be less with Percoll compared to the other methods. The functional capacity of the cells to respond to a stimulus was similar for all methods as indicated by similar EC50 values for chemotaxis to zymosan-activated serum and similar superoxide production induced by tetradecanoyl phorbol acetate. All three separation techniques produce functionally active PMNs of high purity but the use of Percoll gradients may be preferable when a quick method of separation which causes minimum pre-activation of PMNs is required.

Applying anatomical optical coherence tomography to quantitative 3D imaging of the lower airway

Endoscopic treatment of lower airway pathologies requires accurate quantification of airway dimensions. We demonstrate the application of a real-time endoscopic optical coherence tomography system that can image lower airway anatomy and quantify airway lumen dimensions intra-operatively. Results demonstrate the ability to acquire 3D scans of airway anatomy and include comparison against a pre-operative X-ray CT. The paper also illustrates the capability of the system to assess the real-time dynamic changes within the airway that occur during respiration.

Oral Immunotherapy With Inactivated Nontypeable Haemophilus influenzae Reduces Severity of Acute Exacerbations in Severe COPD

BACKGROUND Acute exacerbations of COPD reflect in part an inappropriate host response to abnormal bacterial colonization. Orally administered inactivated nontypeable Haemophilus influenzae (NTHi) can drive a specific T-cell response that by promoting intrabronchial phagocytosis down-regulates bronchus inflammation. METHODS Subjects with recurrent exacerbations of COPD were studied in a randomized, multicenter, double-blind, placebo-controlled trial, to test efficacy of an NTHi oral immunotherapeutic (HI-164OV). This report describes the outcome in 38 subjects with severe COPD defined as having an FEV(1) < or = 50% of predicted normal. RESULTS Exacerbations defined as an increase in volume and purulence of sputum were reduced by 16% (not significant) in the active group. However, moderate-to-severe exacerbations (defined as requiring corticosteroid therapy) were reduced by 63% (P = .05). The proportion with any acute exacerbation was little changed with treatment, but the proportion with episodes requiring corticosteroid therapy was reduced by 56% (P = .07). The mean duration of episodes was reduced by 37% (P = .01) and prescribed courses of antibiotics were reduced by 56% (P = .03) following therapy. Exacerbations requiring admission into hospital were reduced by 90% (P = .04) in the active group. No specific adverse effect was detected. CONCLUSIONS Treatment of severe COPD with frequent exacerbations with HI-164OV was safe and effective, especially with respect to reduction in parameters of severity. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry, www.anzctr.org.au; identifier: ACTRN012606000074594.

Role of neutrophils in mediating human epithelial cell detachment from native basement membrane

Epithelial cell detachment from underlying basement membrane is a feature of diseases of many organs. In the lungs it is seen in disorders as diverse as bronchiectasis, allograft rejection, and asthma. The potential for different leukocytes to induce this change is not clear. In asthma both eosinophils and neutrophils are found in affected tissues, but the capacity of each of these types of cells to induce detachment of native epithelial cells from basement membrane requires clarification. Although eosinophils damage rather than detach human epithelial cells, the effects of neutrophils on epithelial cells naturally attached to basement membrane have not previously been described. Using the human amnion in vitro model, we tested the hypothesis that neutrophils have the capacity to detach intact human epithelial cells from basement membrane. The data indicate that increasing concentrations of neutrophils are able to detach epithelial cells from their underlying basement membrane. Detachment was increased when the neutrophils were activated in situ with tetradecanoyl phorbol acetate and after longer incubation periods. Platelet activating factor and opsonized zymosan showed similar boosting effects, whereas activated complement and formyl-methyl-leucyl-phenylalanine did not. Physical contact of the neutrophils with the epithelial cells was required to induce detachment. Detachment could be inhibited by glutathione and by soybean trypsin inhibitor, an inhibition pattern similar to cathepsin G and trypsin, but not collagenase, in this system. We conclude that neutrophils are capable of detaching human epithelial cells from basement membrane, which in part involves the release of chymotrypsin-like serine proteases, probably in conjunction with oxidants, and that this detachment can be inhibited.

Stenting therapy for stenosing airway diseases

Abstract Tracheobronchial stents have proved very valuable in the management of airway stenosis due to a variety of causes, both benign and malignant. These include benign strictures which are post‐traumatic (e.g. after intubation), post anastomotic (e.g. after lung transplantation), or post inflammatory (e.g. after inflammatory conditions such as tuberculosis or Wegeners granulomatosis); as well as narrowing due to malignant involvement of large airways. In addition, airway stents have been used to treat tracheobronchomalacia and oesophageal‐airway fistulae. The insertion of the stent may need to be combined with other procedures such as airway dilatation, laser photocoagulation, brachytherapy or a mixture of these treatment modalities. Stents have been fashioned out of silicone, wire mesh or a combination of these materials, but the perfect stent has yet to be devised. Common problems include displacement and obstruction with secretions or granulation tissue. Less commonly the stent may perforate the airway wall, sometimes into the accompanying blood vessel. Nonetheless, airway stents are valuable tools in the management of airway narrowing.