Pallav L. Shah

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).

Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis

Background: Endobronchial ultrasound (EBUS) with transbronchial needle aspiration (TBNA) is becoming widely used for mediastinal lymph node staging in patients with known or suspected lung cancer. While a substantial number of case series have evaluated test performance of this investigation, the small sample sizes limited the ability to accurately evaluate the precision of EBUS-TBNA as a staging modality. A systematic review was performed of published studies evaluating EBUS-TBNA for mediastinal lymph node staging to ascertain the pooled sensitivity and specificity of this investigation. Methods: A literature search was constructed and performed by a professional medical librarian to identify the literature from 1960 to February 2008. Pooled specificity and sensitivity was estimated from the extracted data with an exact binomial rendition of the bivariate mixed-effects regression model. Results: Of 365 publications, 25 were identified in which EBUS-TBNA was specifically focused on mediastinal node staging. Of these, only 10 had data suitable for extraction and analysis. The overall test performance was excellent with an area under the summary receiver operating characteristics curve of 0.99 (95% CI 0.96 to 1.00); similarly, EBUS-TBNA had excellent pooled specificity of 1.00 (95% CI 0.92 to 1.00) and good pooled sensitivity of 0.88 (95% CI 0.79 to 0.94). Conclusions: EBUS-TBNA has excellent overall test performance and specificity for mediastinal lymph node staging in patients with lung cancer. The results compare favourably with published results for computed tomography and positron emission tomography.

Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis

Pulmonary alveolar proteinosis was first described by Rosen et al in 1958.1 It is an unusual diffuse lung disease characterised by the accumulation of large amounts of a phospholipoproteinaceous material in the alveoli. It has a variable clinical presentation and course. Most cases are primary but occasionally the condition is secondary to other conditions or inhalation of chemicals. Whole lung lavage remains the most effective treatment and the overall prognosis is good. Surfactant homeostasis is abnormal and animal experiments suggest that this may relate, in some instances at least, to defects in GM-CSF signalling. There are at least two congenital forms of the disease and several different animal models suggesting that pulmonary alveolar proteinosis is unlikely to be a single disease entity and more likely to represent a clinical syndrome. Pulmonary alveolar proteinosis is a rare lung disease and accurate estimates of incidence are not available. Current estimates suggest an incidence of one in two million people. The series reported in the literature suggest a male preponderance (male:female ratio 3:1).1-11 Peak onset is in the third or fourth decade of life with over 80% of reported cases occurring in this age group.1-9 However, there are reports of the disease occurring in neonates,12 children,13-15 and the elderly.11 ### CLINICAL PRESENTATION Dyspnoea is the most common presenting symptom. It usually occurs on moderate exertion but in a few patients occurs at rest.1-11 Cough is the other common symptom. These symptoms are often trivial and some patients do not present until they develop a supervening infection. This may explain the acute onset of symptoms and fever observed in some patients. A low grade fever may also occur as a consequence of pulmonary alveolar proteinosis in the absence of secondary infection.6 Physical examination is often normal and inspiratory crackles …

Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD

Background: The pathophysiology of chronic obstructive pulmonary disease (COPD) features pulmonary inflammation with a predominant alveolar macrophage involvement. Bronchoalveolar macrophages from patients with COPD release increased amounts of inflammatory cytokines in vitro, an effect that is not inhibited by the glucocorticosteroid dexamethasone. Resveratrol (3,5,4′-trihydroxystilbene) is a component of red wine extract that has anti-inflammatory and antioxidant properties. A study was undertaken to determine whether or not resveratrol would inhibit cytokine release in vitro by alveolar macrophages from patients with COPD. Methods: Alveolar macrophages were isolated from bronchoalveolar lavage (BAL) fluid from cigarette smokers and from patients with COPD (n=15 per group). The macrophages were stimulated with either interleukin (IL)-1β or cigarette smoke media (CSM) to release IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF). The effect of resveratrol was examined on both basal and stimulated cytokine release. Results: Resveratrol inhibited basal release of IL-8 in smokers and patients with COPD by 94% and 88% respectively, and inhibited GM-CSF release by 79% and 76% respectively. Resveratrol also inhibited stimulated cytokine release. Resveratrol reduced IL-1β stimulated IL-8 and GM-CSF release in both smokers and COPD patients to below basal levels. In addition, resveratrol inhibited CSM stimulated IL-8 release by 61% and 51% respectively in smokers and COPD patients, and inhibited GM-CSF release by 49% for both subject groups. Conclusions: Resveratrol inhibits inflammatory cytokine release from alveolar macrophages in COPD. Resveratrol or similar compounds may be effective pharmacotherapy for macrophage pathophysiology in COPD.

Refining the Diagnosis and EGFR Status of Non-small Cell Lung Carcinoma in Biopsy and Cytologic Material, Using a Panel of Mucin Staining, TTF-1, Cytokeratin 5/6, and P63, and EGFR Mutation Analysis

Introduction: The dichotomization of non-small cell carcinoma (NSCLC) subtype into squamous (SQCC) and adenocarcinoma (ADC) has become important in recent years and is increasingly required with regard to management. The aim of this study was to determine the utility of a panel of commercially available antibodies in refining the diagnosis on small biopsies and also to determine whether cytologic material is suitable for somatic EGFR genotyping in a prospectively analyzed series of patients undergoing investigation for suspected lung cancer. Methods: Thirty-two consecutive cases of NSCLC were first tested using a panel comprising cytokeratin 5/6, P63, thyroid transcription factor-1, 34&bgr;E12, and a D-PAS stain for mucin, to determine their value in refining diagnosis of NSCLC. After this test phase, two further pathologists independently reviewed the cases using a refined panel that excluded 34&bgr;E12 because of its low specificity for SQCC, and refinement of diagnosis and concordance were assessed. Ten cases of ADC, including eight derived from cytologic samples, were sent for EGFR mutation analysis. Results: There was refinement of diagnosis in 65% of cases of NSCLC to either SQCC or ADC in the test phase. This included 10 of 13 cases where cell pellets had been prepared from transbronchial needle aspirates. Validation by two further pathologists with varying expertise in lung pathology confirmed increased refinement and concordance of diagnosis. All samples were adequate for analysis, and they all showed a wild-type EGFR genotype. Conclusion: A panel comprising cytokeratin 5/6, P63, thyroid transcription factor-1, and a D-PAS stain for mucin increases diagnostic accuracy and agreement between pathologists when faced with refining a diagnosis of NSCLC to SQCC or ADC. These small samples, even cell pellets derived from transbronchial needle aspirates, seem to be adequate for EGFR mutation analysis.

Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial

BACKGROUND Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema. METHODS We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of ≥0·65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that airway bypass was superior to sham control (success threshold, 0·965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612. FINDINGS All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0·749, below the Bayesian success threshold of 0·965). The 6-month composite primary safety endpoint was 14·4% (30 of 208) for airway bypass versus 11·2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1·00 [Bayesian success threshold >0·95]). INTERPRETATION Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema. FUNDING Broncus Technologies.

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.

Cryobiopsy increases the diagnostic yield of endobronchial biopsy: a multicentre trial

Forceps, brushes or needles are currently the standard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies. The new biopsy technique of cryobiopsy appears to provide better diagnostic samples. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling. A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospective, randomised, single-blinded multicentre study. Patients were randomised to either sampling using forceps or the cryoprobe. After obtaining biopsy samples, a blinded histological evaluation was performed. According to the definitive clinical diagnosis, the diagnostic yield for malignancy was evaluated by a Chi-squared test. A total of 593 patients were randomised, of whom 563 had a final diagnosis of cancer. 281 patients were randomised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe. A definitive diagnosis was achieved in 85.1% of patients randomised to conventional forceps biopsy and 95.0% of patients who underwent cryobiopsy (p<0.001). Importantly, there was no difference in the incidence of significant bleeding. Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy.

Increased nitrotyrosine in exhaled breath condensate in cystic fibrosis

Exhaled nitric oxide (ENO), a marker of inflammation in airway diseases is decreased in cystic fibrosis (CF) patients, perhaps because nitric oxide (NO) is metabolized to oxidative end-products. A stable product, 3-nitrotyrosine, may indicate local formation of reactive nitrogen species. Whether NO metabolites in exhaled breath condensate may be increased in CF patients was investigated. The fractional concentration of ENO (Feno), nitrotyrosine and oxides of nitrogen in exhaled breath condensate from 36 stable CF patients were compared to 14 normal subjects using an enzyme immunoassay and fluorescence assay. Nitrotyrosine levels in breath condensate were increased significantly in stable CF patients, compared with normal subjects (25.3 +/- 1.5 versus 6.3 +/- 0.8 ng x mL(-1), p<0.0001). There was an inverse correlation between the levels of nitrotyrosine and the severity of lung disease. Feno levels were significantly lower in CF patients than in normal subjects (4.4 +/- 0.3 versus 5.6 +/- 0.4 (parts per billion), p<0.05). No correlation was found between nitrotyrosine and Feno levels in CF. There was no significant difference in the levels of nitrite and nitrate between CF patients and normals. The elevation in nitrotyrosine may reflect increased formation of reactive nitrogen species such as peroxynitrite or direct nitration by granulocyte peroxidases, indicating increased oxidative stress in airways of cystic fibrosis patients.

Endosonography vs Conventional Bronchoscopy for the Diagnosis of Sarcoidosis: The GRANULOMA Randomized Clinical Trial

IMPORTANCE Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis. Bronchoscopy with transbronchial lung biopsies, the current diagnostic standard, has moderate sensitivity in assessing granulomas. Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique. OBJECTIVE To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis. DESIGN, SETTING, AND PATIENTS Randomized clinical multicenter trial (14 centers in 6 countries) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis (stage I/II) in whom tissue confirmation of noncaseating granulomas was indicated. INTERVENTIONS Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography (esophageal or endobronchial ultrasonography) with aspiration of intrathoracic lymph nodes. All patients also underwent bronchoalveolar lavage. MAIN OUTCOMES AND MEASURES The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis. The diagnosis was based on final clinical judgment by the treating physician, according to all available information (including findings from initial bronchoscopy or endosonography). Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis. RESULTS A total of 149 patients were randomized to bronchoscopy and 155 to endosonography. Significantly more granulomas were detected at endosonography vs bronchoscopy (114 vs 72 patients; 74% vs 48%; P < .001). Diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73%-86%); for bronchoscopy, 53% (95% CI, 45%-61%) (P < .001). Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group; all patients recovered completely. Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54% (95% CI, 46%-62%) for flow cytometry and 24% (95% CI, 16%-34%) for cytospin analysis. CONCLUSION AND RELEVANCE Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation, the use of endosonographic nodal aspiration compared with bronchoscopic biopsy resulted in greater diagnostic yield. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00872612.