Cryobiopsy for Identification of Usual Interstitial Pneumonia and Other Interstitial Lung Disease Features. Further Lessons from COLDICE, a Prospective Multicenter Clinical Trial.

Rationale: Transbronchial lung cryobiopsy (TBLC) is an emerging technique for interstitial lung disease diagnosis. Good histopathologic agreement between TBLC and surgical lung biopsy (SLB) was demonstrated in the COLDICE (Cryobiopsy versus Open Lung Biopsy in the Diagnosis of Interstitial Lung Disease Alliance) study; however, diagnostic confidence was frequently lower for TBLC than SLB. Objectives: To characterize specific features of TBLC predictive of usual interstitial pneumonia (UIP) in corresponding SLB and to identify clinical indices predictive of biopsy concordance. Methods: The COLDICE study was a prospective, multicenter study investigating diagnostic agreement between TBLC and SLB. The participants underwent both procedures with blinded pathologist analysis of specimens, applying international guideline criteria. The TBLC features predictive of UIP in the paired SLB and predictive features of overall concordance were analyzed. Measurements and Main Results: A total of 65 patients (66.1 ± 9.3 yr; FVC, 84.7 ± 14.2%; DlCO, 63.4 ± 13.8%) participated in the COLDICE study. UIP was identified in 33/65 (50.8%) SLB, and 81.5% were concordant with corresponding TBLC (κ, 0.61; 95% confidence interval [CI], 0.38-0.77). The UIP guideline criteria of "predominantly subpleural or paraseptal fibrosis" was infrequently reported in TBLC (8/33, 24.2%), whereas "patchy fibrosis," "fibroblast foci," and the "absence of alternative diagnostic features" were frequently observed in TBLC. The combination of these three features strongly predicted UIP in paired SLB (odds ratio [OR], 23.4; 95% CI, 6.36-86.1; P < 0.0001). Increased numbers of TBLC samples predicted histopathologic concordance with SLB (OR, 1.8; 95% CI, 1.08-3.01; P = 0.03). The predictors of discordance included older age, family history, and radiologic asymmetry. Conclusions: Subpleural and/or paraseptal fibrosis were not essential for diagnosing UIP in TBLC, provided that other guideline criteria features were present. The diagnostic accuracy of TBLC was strengthened when increased numbers of samples were taken. Clinical trial registered with www.anzctr.org.au (ACTRN12615000718549).

Pleuroscopic cryoprobe biopsies of the pleura: a feasibility and safety study.

BACKGROUND AND OBJECTIVE: Flexi-rigid pleuroscopy is a useful tool in the work-up of pleural effusions, but pleural biopsy using flexible forceps can be difficult in some patients. This study evaluated the feasibility, safety and diagnostic value of using a flexible cryoprobe to obtain parietal pleural biopsies during pleuroscopy. METHODS: This was a single-centre retrospective study. In patients undergoing diagnostic pleuroscopy, pleural biopsy using flexible forceps, followed by a flexible cryoprobe introduced through the pleuroscope, were performed. A pathologist independently reviewed all biopsies. Any complications, particularly bleeding, were recorded. All patients were followed up for ≥ 6 months (median 12 months (range 7-26)). RESULTS: Twenty-two patients (21 males; median age 72 years; 14 right-sided effusions) were included. All underwent flexible forceps biopsies (FFB) and cryoprobe biopsies (CB) of pleura. FFB and CB established a definitive diagnosis in 20/22 (90%). CB successfully obtained pleural tissue suitable for histopathological analysis in all patients. CB was larger than FFB (median, 25-75 IQR of 10, 7-15.8mm vs 4, 3-8mm), and had better preserved cellular architecture and tissue integrity. Crush artefacts were less common with CB (2/22) compared with FFB (21/22). No significant bleeding was reported. CONCLUSIONS: CB during flexi-rigid pleuroscopy is feasible, safe and effective. Its routine use during flexi-rigid pleuroscopy requires further evaluation.

Medical thoracoscopy: rigid thoracoscopy or flexi-rigid pleuroscopy?

PURPOSE OF REVIEW: In managing pleural diseases, medical thoracoscopy is often performed as a diagnostic and/or therapeutic procedure, particularly in undiagnosed pleural effusions. Flexi-rigid pleuroscopes are now widely available as an alternative to conventional rigid thoracoscopes. There is an ongoing debate on which is the better instrument. This review analyses the current literature that compared rigid and flexi-rigid approaches, and outlines the medical advances that may influence the future role of thoracoscopy. RECENT FINDINGS: Both rigid and flexi-rigid thoracoscopies are well tolerated. Although biopsies are smaller with flexi-rigid biopsy forceps, two small randomized trials reported similar diagnostic yield using either instrument. No studies have specifically examined patient comfort or the outcome of talc poudrage using the two devices. New techniques (e.g. insulated-tip knife and cryobiopsy) have been used as adjuncts with flexi-rigid pleuroscopy to overcome the difficulties in sampling thickened pleura. SUMMARY: The rigid and flex-rigid instruments have different merits and limitations. Both approaches provide comparable diagnostic yields in the overall patient population undergoing diagnostic thoracoscopy, though their performances specifically in patients with fibrotic pleural thickening have not been examined. Operators using the flexi-rigid approach should have alternative strategies for sampling thickened pleura. Advances in cytopathology and imaging-guided biopsy will likely reduce the need of medical thoracoscopy in the future.

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 ß2-agonists.

Role of endobronchial ultrasound in diagnosis and molecular assessment of metastatic melanoma.

BACKGROUND AND OBJECTIVE: Vemurafenib is a new inhibitor of the mutated BRAF oncogene. In the presence of mutated BRAF in metastatic melanoma, treatment with vemurafenib leads to a reduction in mortality and in tumour progression when compared with chemotherapy. This study describes nine cases in which endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA) was used to assess mediastinal and hilar lymph nodes for the presence of metastatic melanoma and demonstrates the ability to detect mutations in BRAF on the tissue obtained. METHODS: A retrospective review was performed of all patients who had a history of melanoma and underwent EBUS TBNA to investigate hilar or mediastinal lymphadenopathy for the presence of metastatic melanoma. RESULTS: In seven of the nine cases, metastatic melanoma was confirmed on cytology. The two negative cases were proven to be true negatives by follow up or by demonstrating an alternate diagnosis. In five cases, analysis for BRAF mutation was performed. Four cases were positive for mutation and one demonstrated wild-type BRAF. CONCLUSIONS: Tissue samples obtained from EBUS TBNA are adequate to diagnose metastatic melanoma in hilar and mediastinal lymph nodes and to detect the presence or absence of mutations in the BRAF gene. Our findings suggest that close collaboration between bronchoscopists and pathologists will be needed to implement BRAF testing in routine practice in the era of targeted therapy.

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).

Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a novel technique for sampling lung tissue for interstitial lung disease diagnosis. The aim of this study was to establish the diagnostic accuracy of TBLC compared with surgical lung biopsy (SLB), in the context of increasing use of TBLC in clinical practice as a less invasive biopsy technique. METHODS: COLDICE was a prospective, multicentre, diagnostic accuracy study investigating diagnostic agreement between TBLC and SLB, across nine Australian tertiary hospitals. Patients with interstitial lung disease aged between 18 and 80 years were eligible for inclusion if they required histopathological evaluation to aid diagnosis, after detailed baseline evaluation. After screening at a centralised multidisciplinary discussion (MDD), patients with interstitial lung disease referred for lung biopsy underwent sequential TBLC and SLB under one anaesthetic. Each tissue sample was assigned a number between 1 and 130, allocated in a computer-generated random sequence. Encoded biopsy samples were then analysed by masked pathologists. At subsequent MDD, de-identified cases were discussed twice with either TBLC or SLB along with clinical and radiological data, in random non-consecutive order. Co-primary endpoints were agreement of histopathological features in TBLC and SLB for patterns of definite or probable usual interstitial pneumonia, indeterminate for usual interstitial pneumonia, and alternative diagnosis; and for agreement of consensus clinical diagnosis using TBLC and SLB at MDD. Concordance and κ values were calculated for each primary endpoint. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12615000718549. FINDINGS: Between March 15, 2016, and April 15, 2019, we enrolled 65 patients (31 [48%] men, 34 [52%] women; mean age 66·1 years [SD 9·3]; forced vital capacity 83·7% [SD 14·2]; diffusing capacity for carbon monoxide 63·4% [SD 12·8]). TBLC (7·1 mm, SD 1·9) and SLB (46·5 mm, 14·9) samples were each taken from two separate ipsilateral lobes. Histopathological agreement between TBLC and SLB was 70·8% (weighted κ 0·70, 95% CI 0·55-0·86); diagnostic agreement at MDD was 76·9% (κ 0·62, 0·47-0·78). For TBLC with high or definite diagnostic confidence at MDD (39 [60%] of 65 cases), 37 (95%) were concordant with SLB diagnoses. In the 26 (40%) of 65 cases with low-confidence or unclassifiable TBLC diagnoses, SLB reclassified six (23%) to alternative high-confidence or definite MDD diagnoses. Mild-moderate airway bleeding occurred in 14 (22%) patients due to TBLC. The 90-day mortality was 2% (one of 65 patients), following acute exacerbation of idiopathic pulmonary fibrosis. INTERPRETATION: High levels of agreement between TBLC and SLB for both histopathological interpretation and MDD diagnoses were shown. The TBLC MDD diagnoses made with high confidence were particularly reliable, showing excellent concordance with SLB MDD diagnoses. These data support the clinical utility of TBLC in interstitial lung disease diagnostic algorithms. Further studies investigating the safety profile of TBLC are needed. FUNDING: University of Sydney, Hunter Medical Research Institute, Erbe Elektromedizin, Medtronic, Cook Medical, Rymed, Karl-Storz, Zeiss, and Olympus.

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.

Exercise training for people following curative intent treatment for non-small cell lung cancer: a randomized controlled trial.

OBJECTIVE: In people following curative intent treatment for non-small cell lung cancer, to investigate the effects of supervised exercise training on exercise capacity, physical activity and sedentary behavior, peripheral muscle force, health-related quality of life, fatigue, feelings of anxiety and depression, and lung function. METHOD: This pilot randomized controlled trial included participants 6-10 weeks after lobectomy for non-small cell lung cancer or, for those who required adjuvant chemotherapy, 4-8 weeks after their last cycle. Participants were randomized to either 8 weeks of supervised exercise training (exercise group) or 8 weeks of usual care (control group). Prior to and following the intervention period, both groups completed measurements of exercise capacity, physical activity and sedentary behavior, quadriceps and handgrip force, HRQoL, fatigue, feelings of anxiety and depression, and lung function. Intention-to-treat analysis was undertaken. RESULTS: Seventeen participants (mean age 67, SD=9 years; 12 females) were included. Nine and eight participants were randomized to the exercise and control groups, respectively. Four participants (44%) adhered to exercise training. Compared with any change seen in the control group, those in the exercise group demonstrated greater gains in the peak rate of oxygen consumption (mean difference, 95% confidence interval for between-group difference: 0.19 [0.04-0.33]Lmin-1) and 6-minute walk distance (52 [12-93]m). No other between-group differences were demonstrated. CONCLUSIONS: In people following curative intent treatment for non-small cell lung cancer, 8 weeks of supervised exercise training improved exercise capacity, measured by both laboratory- and field-based exercise tests. These results suggest that this clinical population may benefit from attending exercise training programs.

Multiple endobronchial polyps.

Multiple endobronchial polyps are a rare finding. We describe a case of multiple benign endobronchial polyps in a 60-year-old woman who presented with a chronic cough and occasional hemoptysis. Chest computed tomography revealed bilateral basal cylindrical bronchiectasis, with filling defects in both main bronchi. Bronchoscopy revealed the presence of polyps in the distal trachea, both main bronchi, and in the lobar and segmental bronchi of all lobes of both lungs, with lesions from 2 to 10 mm in diameter. Larger lesions were treated with argon plasma coagulation. Histopathology was consistent with benign fibroepithelial polyps. Culture from bronchial washings isolated Pseudomonas aeruginosa, and the patient was treated with ciprofloxacin followed by a prolonged course of azithromycin. Symptoms improved, and repeat bronchoscopy at 3 and 6 months revealed complete resolution of all polyps.

Posture influences patient cough rate, sedative requirement and comfort during bronchoscopy: An observational cohort study.

OBJECTIVES: To investigate differences between semi-recumbent and supine postures in terms of cough rate, oxygen desaturation, sedative use, and patient comfort during the initial phase of bronchoscopy. METHODS: Consecutive bronchoscopy patients (n = 69) participated in this observational cohort study. Posture was determined by the bronchoscopist's usual practice. Patient demographics, spirometry, pulse, and SpO2 were recorded. The initial phase was defined as the time from bronchoscopy insertion to visualisation of both distal main bronchi. Cough rate, peak pulse, nadir SpO2, oxygen supplementation, and sedative use during the initial phase were recorded. A post-procedure questionnaire was administered to the patient and the attending nurse. RESULTS: 36 patients had bronchoscopy in the semi-recumbent posture, 33 in the supine posture. 3 of 5 bronchoscopists performed in both postures. There were no differences in baseline parameters between the groups. The semi-recumbent posture resulted in significantly less cough (mean (SD) 3.6 (2.3) vs. 6.1 (4.5) coughs/min, p = 0.007) and less fentanyl use (70 (29) vs. 88 (28) mcg, p = 0.011) in the initial phase. There were no significant differences in the nadir SpO2, fall in SpO2, oxygen supplementation, or increase in pulse rate between the groups. On 100 mm visual analogue scale, nurse perception of patient discomfort was lower in the semi-recumbent position (23 (21) vs. 39 (28) mm, p = 0.01), and there was a trend towards less patient perceived cough in the semi-recumbent group (28 (25) vs. 40 (28) mm, p = 0.06). CONCLUSIONS: Bronchoscopy performed in the semi-recumbent posture results in less cough and sedative requirement, and may improve patient comfort.

Feasibility of Applying Real-time Optical Imaging During Bronchoscopic Interventions for Central Airway Obstruction.

BACKGROUND: Interventional bronchoscopists manage central airway obstruction (CAO) through dilation, tumor ablation, and/or stent insertion. Anatomical optical coherence tomography (aOCT), a validated light-based imaging technique, has the unique capacity of providing bronchoscopists with intraprocedural central airway measurements. This study aims to describe the potential role of real-time aOCT in guiding interventions during CAO procedures. METHODS: Prospective case series were recruited from patients referred for bronchoscopic management of symptomatic CAO. Preprocedure chest computed tomography (CT) scans were analyzed for relevant airway dimensions, such as stenosis caliber and length, and aided procedure planning. During bronchoscopy, an aOCT fiberoptic probe was inserted through the working channel of the bronchoscope to image the airway stenosis. From these aOCT images, stenosis dimensions were measured and compared with the preprocedure CT measurements. Preprocedure and postprocedure spirometry, Medical Research Council dyspnea score, and Eastern Cooperative Oncology Group performance status were collected to assess intervention efficacy. RESULTS: Fourteen patients were studied. CT and aOCT-based measurements of airway caliber and length correlated closely (r=0.87, P<0.001). Bland-Altman analysis showed strong agreement between measurements (mean difference 0.4±8.6 mm). The real-time nature of aOCT imaging provided the advantage of more up-to-date measurements where a delay occurred between CT and bronchoscopy or where the quality of the CT image was suboptimal. After bronchoscopy, the predicted forced expiratory flow in 1 second increased from 67±26% to 78±19% (P=0.04). Eastern Cooperative Oncology Group and dyspnea scores improved in 83% and 75% of the patients, respectively. CONCLUSIONS: aOCT provides real-time measurements of obstructing central airway lesions that can assist therapeutic interventions such as selection of endobronchial stents and airway dilatation procedures.

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.

Pulmonary alveolar proteinosis associated with psoriasis and complicated by mycobacterial infection: successful treatment with granulocyte-macrophage colony stimulating factor after a partial response to whole lung lavage.

Pulmonary alveolar proteinosis (PAP) is a rare lung disease. Although whole lung lavage is considered the most effective treatment, not every patient shows a complete response. The case ofa young man with PAP in association with psoriasis who underwent frequent whole lung lavage but only achieved remission following treatment with granulocyte-macrophage colony stimulating factor (GM-CSF) is reported. His lung problem was complicated by atypical mycobacterial infection,which resolved with treatment. The role of GM-CSF is discussed.