A 6-year experience of Zephyr endobronchial valves for severe emphysema in an Australian single-centre cohort.

BACKGROUND: Endobronchial valve (EBV) insertion for lung volume reduction is a management option for patients with severe emphysema. One-way valves cause lobar deflation and improve lung function, exercise capacity and quality of life. AIMS: To retrospectively analyse and compare the outcomes of the first 57 patients treated with EBVs between 2015 and 2021 at the Royal Adelaide Hospital to international standards. METHODS: Clinical outcomes of forced expiratory volume in 1 s (FEV1), residual volume (RV), treated lobe volume reduction (TLVR) and 6-min walk distance (6MWD) at 3, 6 and 12 months after valve insertion were reviewed against established minimally clinically important differences (MCIDs). Complications and subjective breathlessness measured by Borg scores were also reviewed. RESULTS: Fifty-seven patients were included. At 12 months, 77.2% achieved TLVR. FEV1 improved by 170 mL (95% confidence interval (CI): 100-250, P < 0.001), 80 mL (95% CI: 10-150, P = 0.019) and 40 mL (95% CI: -60 to 130, P 0.66) at 3, 6 and 12 months respectively. RV improved by -610 mL (95% CI: -330 to -900, P < 0.0001) at 3 months, -640 mL (95% CI: -360 to -920, P < 0.0001) at 6 months and -360 mL (95% CI: -60 to -680, P = 0.017) at 12 months. 6MWD improved by 57.34 m (95% CI: 36.23-78.45, P < 0.0001) and 44.93 m (95% CI: 7.19-82.67, P = 0.02) at 3 and 6 months. Borg score improved by -0.53 (95% CI: 0.11 to -1.2, P = 0.11) and -0.49 (95% CI: 0.17 to -1.15, P = 0.16) at 3 and 6 months. Complication rates aligned with international standards with mucous/infection (26.3%) and pneumothorax (17.5%) as the most common. Subgroup analysis signalled improved outcomes in patients with heterogeneous emphysema. CONCLUSION: Our study represents the first publicly funded Australian analysis of EBVs. The results align with international prospective trials demonstrating improved lung function and exercise capacity. Australians with severe emphysema and gas trapping should be referred to a multidisciplinary centre for consideration of EBVs.

The 'ABC' of respiratory disorders among adult Indigenous people: asthma, bronchiectasis and COPD among Aboriginal Australians - a systematic review.

BACKGROUND: Aboriginal Australians are reported to have higher presence of chronic respiratory diseases. However, comprehensive evidence surrounding this is sparse. Hence, a systematic review was undertaken to appraise the current state of knowledge on respiratory health in the adult Aboriginal Australians, in particular among the three most common respiratory disorders: asthma, bronchiectasis and chronic obstructive pulmonary disease (COPD). METHODS: A systematic review of primary literature published between January 2012 and October 2022, using the databases PubMed and Scopus, was conducted. Studies were included if they reported adult Aboriginal Australian prevalence's or outcomes related to asthma, bronchiectasis or COPD, and excluded if adult data were not reported separately, if Aboriginal Australian data were not reported separately or if respiratory disorders were combined into a single group. Risk of bias was assessed by both Joanne Briggs Institute checklists and Hoys' bias assessment. Summary data pertaining to prevalence, lung function, symptoms, sputum cultures and mortality for each of asthma, bronchiectasis and COPD were extracted from the included studies. RESULTS: Thirty-seven studies were included, involving approximately 33 364 participants (71% female). Eighteen studies reported on asthma, 21 on bronchiectasis and 30 on COPD. The majority of studies (94%) involved patients from hospitals or respiratory clinics and were retrospective in nature. Across studies, the estimated prevalence of asthma was 15.4%, bronchiectasis was 9.4% and COPD was 13.7%, although there was significant geographical variation. Only a minority of studies reported on clinical manifestations (n=7) or symptoms (n=4), and studies reporting on lung function parameters (n=17) showed significant impairment, in particular among those with concurrent bronchiectasis and COPD. Airway exacerbation frequency and hospital admission rates including mortality are high. DISCUSSION: Although risk of bias globally was assessed as low, and study quality as high, there was limited diversity of studies with most reporting on referred populations, and the majority originating from two centres in the Northern Territory. The states with the greatest Aboriginal Australian population (Victoria and New South Wales) reported the lowest number of studies and patients. This limits the generalisability of results to the wider Aboriginal Australian population due to significant environmental, cultural and socioeconomic variation across the population. Regardless, Aboriginal Australians appear to display a high prevalence, alongside quite advanced and complex chronic respiratory diseases. There is however significant heterogeneity of prevalence, risk factors and outcomes geographically and by patient population. Further collaborative efforts are required to address specific diagnostic and management pathways in order to close the health gap secondary to respiratory disorders in this population.

First Asia-Pacific experience of trans-bronchial core biopsy with a Franseen needle.

Background: Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is the standard for evaluating mediastinal and hilar lesions. EBUS-TBNA is limited by small volume of material obtained for immunohistochemistry (IHC) and ancillary studies important for oncological therapies. The Franseen AcquireTM needle is designed for EBUS-transbronchial needle core biopsy (TBNB) allowing larger core sizes with evidence in gastroenterology literature but little in pulmonology. This study reports the first Asia-Pacific experience of EBUS-TBNB and adequacy of samples for diagnosis and ancillary studies. Methods: A retrospective cohort study of EBUS-TBNB at the Royal Adelaide Hospital was conducted between December 2019 and May 2021. Diagnostic rate, adequacy for ancillary studies and complications were evaluated. Samples were flushed into formalin for histological processing with no rapid on-site cytological evaluation (ROSE). For suspected lymphoma, samples were flushed into HANKS for flow cytometry. Cases performed with the Olympus VizishotTM during the same 18-month were similarly analysed. Results: One hundred and eighty-nine patients were sampled with the AcquireTM needle. Diagnostic rate was 174/189 (92.1%). Where reported [146/189 (77.2%)], average core aggregate sample size was 13.4 mm × 10.7 mm × 1.7 mm. For non-small cell lung cancer (NSCLC) cases, 45/49 (91.8%) had adequate tissue for programmed cell death-ligand 1 (PD-L1). 32/35 (91.4%) adenocarcinoma cases had sufficient tissue for ancillary studies. There was one false negative malignant lymph node at the first AcquireTM procedure. There were no major complications. One hundred and one patients were sampled with the VizishotTM needle. Diagnostic rate was 86/101 (85.1%) with only 25/101 (24.8%) having reported tissue cores (P<0.0001 of VizishotTM) with the remaining samples processed via cell block. Conclusions: AcquireTM EBUS-TBNB diagnostic rate is comparable to historical data with >90% of cases having sufficient core material for ancillary studies. There appears to be a role for the AcquireTM alongside the standard of care for the work up of lymphadenopathy and particularly for lung cancer.

Radial Endobronchial Ultrasound-guided Transbronchial Cryobiopsy versus Forceps Biopsy for the Diagnosis of Solitary Pulmonary Nodules: A Prospective Randomised Trial.

Background: Improvements in pulmonary diagnostic imaging and the development of lung cancer screening are increasing the prevalence of Solitary pulmonary nodules (SPNs). Fluoroscopically guided radial endobronchial ultrasound (EBUS) with transbronchial forceps biopsy (TB-FB) has been the conventional diagnostic method. Transbronchial cryobiopsy (TB-CB) is an alternative biopsy method. We sought to compare transbronchial cryobiopsy to transbronchial forceps biopsy for the diagnosis of SPNs. Methods: A prospective, single-centre, randomised controlled trial was conducted at the Royal Adelaide Hospital (RAH). Patients with SPNs were randomised to either 5 transbronchial forceps biopsies or one transbronchial cryobiopsy. Complete blinding of investigators and participants was not possible, as transbronchial cryobiopsy required general anaesthesia. The primary outcome was diagnostic yield with secondary outcomes of specimen size, diagnostic yield for subsets challenging to access with forceps and safety. Results: The overall diagnostic yield for the 28 enrolled subjects was 76.8%(22/28). The diagnostic yield was 91.7% (11/12 patients) for transbronchial cryobiopsy and 68.8% (11/16 patients) for forceps biopsy (p=0.14). Median biopsy sizes were consistently larger for the cryobiopsy arm at 7.0mm compared to 2.5mm(p<0.0001). An eccentric EBUS image signalling the probe was adjacent to the nodule occurred in 4/28 cases, and TB-CB confirmed a diagnosis in 3/3 randomised to this arm. There were no major complications with either technique. Conclusion: Transbronchial cryobiopsy under the guidance of fluoroscopy and radial EBUS facilitates larger biopsy specimens without a significant increase in major complications. Further research is required to confirm the effect on diagnostic yield; however, our study supports a role for TB-CB in the diagnosis of SPNs and small, nodule-adjacent biopsies. Clinical Trial Registration Number: Reference number of R20160213(HREC/16/RAH/37).

Organotypic sinonasal airway culture systems are predictive of the mucociliary phenotype produced by bronchial airway epithelial cells.

Differentiated air-liquid interface models are the current standard to assess the mucociliary phenotype using clinically-derived samples in a controlled environment. However, obtaining basal progenitor airway epithelial cells (AEC) from the lungs is invasive and resource-intensive. Hence, we applied a tissue engineering approach to generate organotypic sinonasal AEC (nAEC) epithelia to determine whether they are predictive of bronchial AEC (bAEC) models. Basal progenitor AEC were isolated from healthy participants using a cytological brushing method and differentiated into epithelia on transwells until the mucociliary phenotype was observed. Tissue architecture was assessed using H&E and alcian blue/Verhoeff-Van Gieson staining, immunofluorescence (for cilia via acetylated α-tubulin labelling) and scanning electron microscopy. Differentiation and the formation of tight-junctions were monitored over the culture period (day 1-32) by quantifying trans-epithelial electrical resistance. End point (day 32) tight junction protein expression was assessed using Western blot analysis of ZO-1, Occludin-1 and Claudin-1. Reverse transcription qPCR-array was used to assess immunomodulatory and autophagy-specific transcript profiles. All outcome measures were assessed using R-statistical software. Mucociliary architecture was comparable for nAEC and bAEC-derived cultures, e.g. cell density P = 0.55, epithelial height P = 0.88 and cilia abundance P = 0.41. Trans-epithelial electrical resistance measures were distinct from day 1-14, converged over days 16-32, and were statistically similar over the entire culture period (global P < 0.001). This agreed with end-point (day 32) measures of tight junction protein abundance which were non-significant for each analyte (P > 0.05). Transcript analysis for inflammatory markers demonstrated significant variation between nAEC and bAEC epithelial cultures, and favoured increased abundance in the nAEC model (e.g. TGFß and IL-1ß; P < 0.05). Conversely, the abundance of autophagy-related transcripts were comparable and the range of outcome measures for either model exhibited a considerably more confined uncertainty distribution than those observed for the inflammatory markers. Organotypic air-liquid interface models of nAEC are predictive of outcomes related to barrier function, mucociliary architecture and autophagy gene activity in corresponding bAEC models. However, inflammatory markers exhibited wide variation which may be explained by the sentinel immunological surveillance role of the sinonasal epithelium.

COPD is associated with increased pro-inflammatory CD28null CD8 T and NKT-like cells in the small airways.

We previously showed increased steroid-resistant CD28null CD8+ senescent lymphocyte subsets in the peripheral blood from patients with chronic obstructive pulmonary disease (COPD). These cells expressed decreased levels of the glucocorticoid receptor (GCR), suggesting their contribution to the steroid-resistant property of these cells. COPD is a disease of the small airways (SA). We, therefore, hypothesized that there would be a further increase in these steroid-resistant lymphocytes in the lung, particularly in the SA. We further hypothesized that the pro-inflammatory/cytotoxic potential of these cells could be negated using prednisolone with low-dose cyclosporin A. Blood, bronchoalveolar lavage, large proximal, and small distal airway brushings were collected from 11 patients with COPD and 10 healthy aged-matched controls. The cytotoxic mediator granzyme b, pro-inflammatory cytokines IFNγ/TNFα, and GCR were determined in lymphocytes subsets before and after their exposure to 1µM prednisolone and/or 2.5 ng/mL cyclosporin A. Particularly in the SA, COPD subjects showed an increased percentage of CD28null CD8 T-cells and NKT-like cells, with increased expression of granzyme b, IFNγ and TNFα and a loss of GCR, compared with controls. Significant negative correlations between SA GCR expression and IFNγ/TNFα production by T and NKT-like cells (eg, T-cell IFNγ R = -0.834, P = 0.031) and with FEV1 (R = -0.890) were shown. Cyclosporine A and prednisolone synergistically increased GCR expression and inhibited pro-inflammatory cytokine production by CD28null CD8- T and NKT-like cells. COPD is associated with increased pro-inflammatory CD28null CD8+ T and NKT-like cells in the SA. Treatments that increase GCR in these lymphocyte subsets may improve the efficacy of clinical treatment.

Inhibition of LC3-associated phagocytosis in COPD and in response to cigarette smoke.

INTRODUCTION/RATIONALE: In chronic obstructive pulmonary disease (COPD), defective macrophage phagocytic clearance of cells undergoing apoptosis by efferocytosis may lead to secondary necrosis of the uncleared cells and contribute to airway inflammation. The precise mechanisms for this phenomenon remain unknown. LC3-associated phagocytosis (LAP) is indispensable for effective efferocytosis. We hypothesized that cigarette smoke inhibits the regulators of LAP pathway, potentially contributing to the chronic airways inflammation associated with COPD. METHODS: Bronchoalveolar (BAL)-derived alveolar macrophages, lung tissue macrophages obtained from lung resection surgery, and monocyte-derived macrophages (MDM) were prepared from COPD patients and control participants. Lung/airway samples from mice chronically exposed to cigarette smoke were also investigated. Differentiated THP-1 cells were exposed to cigarette smoke extract (CSE). The LAP pathway including Rubicon, as an essential regulator of LAP, efferocytosis and inflammation was examined using western blot, ELISA, flow cytometry, and/or immunofluorescence. RESULTS: Rubicon was significantly depleted in COPD alveolar macrophages compared with non-COPD control macrophages. Rubicon protein in alveolar macrophages of cigarette smoke-exposed mice and cigarette smoke-exposed MDM and THP-1 was decreased with a concomitant impairment of efferocytosis. We also noted increased expression of LC3 which is critical for LAP pathway in COPD and THP-1 macrophages. Furthermore, THP-1 macrophages exposed to cigarette smoke extract exhibited higher levels of other key components of LAP pathway including Atg5 and TIM-4. There was a strong positive correlation between Rubicon protein expression and efferocytosis. CONCLUSION: LAP is a requisite for effective efferocytosis and an appropriate inflammatory response, which is impaired by Rubicon deficiency. Our findings suggest dysregulated LAP due to reduced Rubicon as a result of CSE exposure. This phenomenon could lead to a failure of macrophages to effectively process phagosomes containing apoptotic cells during efferocytosis. Restoring Rubicon protein expression has unrecognized therapeutic potential in the context of disease-related modifications caused by exposure to cigarette smoke.

AIM2 nuclear exit and inflammasome activation in chronic obstructive pulmonary disease and response to cigarette smoke.

INTRODUCTION: The role inflammasomes play in chronic obstructive pulmonary disease (COPD) is unclear. We hypothesised that the AIM2 inflammasome is activated in the airways of COPD patients, and in response to cigarette smoke. METHODS: Lung tissue, bronchoscopy-derived alveolar macrophages and bronchial epithelial cells from COPD patients and healthy donors; lungs from cigarette smoke-exposed mice; and cigarette smoke extract-stimulated alveolar macrophages from healthy controls and HBEC30KT cell line were investigated. AIM2 inflammasome activation was assessed by multi-fluorescence quantitative confocal microscopy of speck foci positive for AIM2, inflammasome component ASC and cleaved IL-1ß. Subcellular AIM2 localization was assessed by confocal microscopy, and immunoblot of fractionated cell lysates. Nuclear localization was supported by in-silico analysis of nuclear localization predicted scores of peptide sequences. Nuclear and cytoplasmic AIM2 was demonstrated by immunoblot in both cellular fractions from HBEC30KT cells. RESULTS: Increased cytoplasmic AIM2 speck foci, colocalized with cleaved IL-1ß, were demonstrated in COPD lungs (n = 9) vs. control (n = 5), showing significant positive correlations with GOLD stages. AIM2 nuclear-to-cytoplasmic redistribution was demonstrated in bronchiolar epithelium in cigarette-exposed mice and in HBEC30KT cells post 24 h stimulation with 5% cigarette smoke extract. Alveolar macrophages from 8 healthy non-smokers responded to cigarette smoke extract with an > 8-fold increase (p < 0.05) of cytoplasmic AIM2 and > 6-fold increase (p < 0.01) of colocalized cleaved IL-1ß speck foci, which were also localized with ASC. CONCLUSION: The AIM2 inflammasome is activated in the airway of COPD patients, and in response to cigarette smoke exposure, associated with a nuclear to cytoplasmic shift in the distribution of AIM2.

Use of Ventilation-Perfusion Single-Photon Emission Computed Tomography to Select the Target Lobe for Endobronchial Valve Lung Volume Reduction.

BACKGROUND: Quantitative planar ventilation-perfusion (VQ) has a complementary role in target lobe selection for endobronchial valve lung volume reduction (EBV-LVR), especially in homogenous disease. We investigated a novel method of lung lobar quantitation using VQ single-photon emission computed tomography (SPECT) with computed tomography (CT) to generate a parameter called the ventilation-perfusion differential index (VQDI). AIM: The aim of this study was to validate VQDI as a parameter for target lobe selection in EBV-LVR against the gold standard test of quantitative computed tomography (qCT). METHODS: This study was a prospective, multi-centre, single-blinded, observational study of EBV-LVR patients. Baseline and 3-month post intervention VQ SPECT and qCT were performed. The target lobe was chosen using qCT and planar VQ report (CTTL) whilst blinded to VQDI. Post EBV-LVR, our nuclear physician, blinded to CTTL, selected a target lobe using deidentified VQDI (VQDITL). Inter-rater agreement between CTTL and VQDITL was calculated by Kappa statistic. Treatment outcomes were analysed with a linear mixed-effects model. RESULTS: There was a high concordance between CTTL and VQDITL in 16 patients (89%, Kappa statistic = 0.85). Post EBV-LVR, our subjects showed significant changes in FEV1 (mean difference [MD] +150 mL, p < 0.001), target lobe volume reduction (MD -973 mL, p < 0.001), residual volume (MD -800 mL, p < 0.001), and St. George's Respiratory Questionnaire score (MD -11, p = 0.001). Improvements in 6-minute walk distances did not reach statistical significance. CONCLUSION: In this study of treatment responders, EBV-LVR target lobe selection using VQDI concurs with qCT and thus supports its value for this purpose. It complements qCT and may potentially be of synergistic value especially in homogenous emphysema.

Human T-cell leukaemia virus type 1 associated pulmonary disease: clinical and pathological features of an under-recognised complication of HTLV-1 infection.

The lung is one of several organs that can be affected by HTLV-1 mediated inflammation. Pulmonary inflammation associated with HTLV-1 infection involves the interstitium, airways and alveoli, resulting in several clinical entities including interstitial pneumonias, bronchiolitis and alveolitis, depending on which structures are most affected. Augmentation of the inflammatory effects of HTLV-1 infected lymphocytes by recruitment of other inflammatory cells in a positive feedback loop is likely to underlie the pathogenesis of HTLV-1 associated pulmonary disease, as has been proposed for HTLV-1 associated myelopathy. In contrast to the conclusions of early case series, HTLV-1 associated pulmonary disease can be associated with significant parenchymal damage, which may progress to bronchiectasis where this involves the airways. Based on our current understanding of HTLV-1 associated pulmonary disease, diagnostic criteria are proposed.

Pulmonary Disease Is Associated With Human T-Cell Leukemia Virus Type 1c Infection: A Cross-sectional Survey in Remote Aboriginal Communities.

BACKGROUND: The human T-cell leukemia virus type 1 (HTLV-1) subtype c is endemic to central Australia. We report the first large-scale, community-based, health survey of HTLV-1 and its disease associations in this setting. METHODS: Aboriginal community residents aged >2 years in 7 remote communities were invited to do a health survey that included a questionnaire, spirometry, and clinical examination by a physician blinded to HTLV-1 status, clinical records, and spirometry results. Blood was drawn for HTLV-1 serology and proviral load (PVL). Pulmonary disease was assessed clinically and spirometrically and, where records were available, radiologically after the clinical assessment. Associations between specific diseases and HTLV-1 status were determined using logistic regression, adjusting for available confounders. RESULTS: Overall, 579 residents (164 children aged 3-17 years; 415 adults) were examined (37.7% of the estimated resident population). HTLV-1 prevalences for children and adults were 6.1% and 39.3%, respectively. No associations were found between HTLV-1 and any assessed clinical condition among children. Chronic pulmonary disease and gait abnormalities were more common among adults with HTLV-1 infection. Adjusted odds ratios among participants with PVL ≥1000 per 105 peripheral blood leukocytes were 7.08 (95% confidence interval [CI], 2.67-18.74; P < .001), 9.81 (95% CI, 3.52-27.35; P < .001), and 14.4 (95% CI, 4.99-41.69; P < .001) for clinically defined chronic pulmonary disease, moderate-severe expiratory airflow limitation, and radiologically determined bronchiectasis/bronchiolitis, respectively, and 5.21 (95% CI, 1.50-18.07; P = .009) for gait abnormalities. CONCLUSIONS: In the first study of HTLV-1 disease associations based on community recruitment and blinded assessment, HTLV-1 infection was strongly associated with pulmonary disease and gait abnormalities.

A challenging diagnosis of malignant mesothelioma with osteosarcomatous differentiation metastasizing to bone.

Malignant pleural mesothelioma (MPM) is an insidious primary neoplasm of the pleura that can be challenging to diagnose and is commonly considered to be only locally invasive. We present the case of a 74-year-old male who presented with clinical features of MPM but from whom pleural fluid and biopsies initially suggested benign pathology. He later developed diffuse bony metastases and re-examination of pleural biopsies using modern immunohistochemistry and molecular testing revealed a diagnosis of sarcomatoid and desmoplastic MPM with heterologous osteosarcomatous differentiation. This case not only demonstrates the rare potential of skeletal metastasis of MPM, but also highlights the importance of recognizing the utility of modern diagnostic tests and their potential to prevent the need for unnecessary invasive procedures. To our knowledge this is the first description of this rare histological sub-type presenting with skeletal metastases.

HTLV-1c associated bronchiolitis in an Aboriginal man from central Australia.

We describe the first case of HTLV associated bronchiolitis to be associated with HTLV-1c subtype infection. An Aboriginal man with HTLV-1 infection was repeatedly admitted to Alice Springs Hospital, central Australia, with hypercapnic respiratory failure from the age of 28 years. High resolution CT chest findings were consistent with bronchiolitis and large numbers of lymphocytes were found in bronchoalveolar lavage fluid (BALF). After extensive investigations failed to find a cause, he was tested for HTLV-1 and found to have a high HTLV-1c proviral load (6.8 %) in peripheral blood leukocytes and in BALF (4.7 %). The administration of systemic corticosteroids resulted in a rapid clinical response; however, he did not continue treatment after discharge and died due to respiratory failure in the community.

Predictors of non-cystic fibrosis bronchiectasis in Indigenous adult residents of central Australia: results of a case-control study.

The human T-cell leukaemia virus type 1 (HTLV-1) is associated with pulmonary inflammation. Indigenous Australians in central Australia have a very high prevalence of HTLV-1 infection and we hypothesised that this might contribute to high rates of bronchiectasis in this population. 80 Indigenous adults with confirmed bronchiectasis, each matched by age, sex and language to two controls without bronchiectasis, were recruited. Case notes and chest imaging were reviewed, HTLV-1 serology and the number of peripheral blood leukocytes (PBLs) infected with HTLV-1 (pro-viral load (PVL)) were determined, and radiological abnormality scores were calculated. Participants were followed for a mean±sd of 1.14±0.86 years and causes of death were determined. Median (interquartile range) HTLV-1 PVL for cases was 8-fold higher than controls (cases 213.8 (19.7-3776.3) copies per 105 PBLs versus controls 26.6 (0.9-361) copies per 105 PBLs; p=0.002). Radiological abnormality scores were higher for cases with HTLV-1 PVL ≥1000 copies per 105 PBLs and no cause of bronchiectasis other than HTLV-1 infection. Major predictors of bronchiectasis were prior severe lower respiratory tract infection (adjusted OR (aOR) 17.83, 95% CI 4.51-70.49; p<0.001) and an HTLV-1 PVL ≥1000 copies per 105 PBLs (aOR 12.41, 95% CI 3.84-40.15; p<0.001). Bronchiectasis (aOR 4.27, 95% CI 2.04-8.94; p<0.001) and HTLV-1 PVL ≥1000 copies per 105 PBLs (aOR 3.69, 95% CI 1.11-12.27; p=0.033) predicted death. High HTLV-1 PVLs are associated with bronchiectasis and with more extensive radiological abnormalities, which may result from HTLV-1-mediated airway inflammation.

Radial Endobronchial Ultrasound Greyscale Texture Analysis Using Whole-Lesion Analysis Can Characterise Benign and Malignant Lesions without Region-of-Interest Selection Bias.

BACKGROUND: Radial-probe endobronchial ultrasound (RP-EBUS) is predominantly used clinically for the localisation of peripheral pulmonary lesions prior to biopsy. However, the RP-EBUS image itself contains information that can characterise the aetiology of lesions. OBJECTIVES: The aim of this study was to show the utility of RP-EBUS image analysis using unconstrained regions of interest (ROIs) that utilise more image information and eliminate ROI selection bias. METHODS: We developed custom software to analyse RP-EBUS images digitally captured during clinical procedures. Unconstrained ROIs were mapped onto lesions. We computed first-order greyscale image statistics of minimum, maximum, mean, standard deviation and range of pixel intensities, and entropy. We also computed second-order greyscale texture features of contrast, correlation, energy and homogeneity. The results of image analysis were compared to gold-standard tissue diagnosis. Features from expert- and non-expert-defined ROIs were also compared. RESULTS: Eighty-five images were analysed (38 benign and 47 malignant). Five greyscale features were significantly different between benign and malignant lesions. Benign lesions had higher mean (p < 0.01) and maximal (p < 0.001) intensity, greater range (p < 0.001) of pixel intensities and greater entropy (p < 0.01). The highest positive predictive values were associated with maximal (87.8%) and range of pixel (83.8%) intensities. There were no significant differences between expert- and non-expert-defined ROIs. CONCLUSION: RP-EBUS image analysis using unconstrained ROIs eliminates ROI selection bias and can characterise benign and malignant lesions with an accuracy of up to 85%.

Airway epithelial cells exposed to wildfire smoke extract exhibit dysregulated autophagy and barrier dysfunction consistent with COPD.

BACKGROUND: Individuals with respiratory disease are being increasingly exposed to wildfire smoke as populations encroach further into forested regions and climate change continues to bring higher temperatures with lower rainfall. Frequent exposures have significant potential to accelerate conditions such as chronic obstructive pulmonary disease (COPD) which is characterised by an exaggerated inflammatory response to environmental stimuli. Here we employ models of human airway epithelium exposed to wildfire smoke-extract (WFSE) to examine modulation in airway epithelial cell (AEC) survival, fragility and barrier function. METHODS: Submerged cultures of small airway epithelial cells (SAEC) and differentiated air-liquid interface (ALI) cultures of primary bronchial AEC (bAEC) were treated for 1-24 h with 1-10% WFSE generated from plant species found in the Australian bushland. Autophagy (LC3-II and Sequestosome), apoptosis (Poly-(ADP)-Ribose Polymerase (PARP) cleavage) and tight junction proteins were measured using western blot. Barrier function was assessed via permeability of fluorescein tracers and measuring trans-epithelial electrical resistance. The production of IL-6 was assessed using ELISA. RESULTS: Primary epithelial models exposed to WFSE exhibited a significant blockade in autophagy as evidenced by an increase in LC3-II coupled with a concomitant elevation in Sequestosome abundance. These exposures also induced significant PARP cleavage indicative of apoptotic changes. ALI cultures of bAEC treated with 5% WFSE demonstrated barrier dysfunction with significant increases in paracellular molecular permeability and ionic conductance, and a reduction in the abundance of the tight junction proteins ZO-1 and Claudin-1. These cultures also exhibited increased IL-6 secretion consistent with the aberrant and pro-inflammatory repair response observed in the COPD airways. Further, blocks in autophagy and barrier disruption were significantly elevated in response to WFSE in comparison to similar exposures with cigarette smoke-extract. CONCLUSION: WFSE inhibits autophagic flux and induces barrier dysfunction in the airway epithelium. As autophagy is a central regulator of cellular repair, viability, and inflammation, targeting the block in autophagic flux may ameliorate the consequences of wildfire smoke-exposure for individuals with pre-existing respiratory conditions.

Accuracy of rapid on-site evaluation of endobronchial ultrasound guided transbronchial needle aspirates by respiratory registrars in training and medical scientists compared to specialist pathologists-an initial pilot study.

BACKGROUND: Rapid on-site evaluation (ROSE) of endobronchial ultrasound guided transbronchial needle aspirates (EBUS-TBNA) increases diagnostic accuracy but in many institutions requires a specialist pathologist. This study aimed to determine if medical scientists or respiratory registrars could adequately perform ROSE to determine sufficiency of EBUS samples. METHODS: ROSE was performed on the first two EBUS-TBNA passes per patient by a pathologist, a medical scientist and two respiratory registrars. The medical scientists involved had all previously performed ROSE on over 50 procedures. The two respiratory registrars received cytology education from a pathologist in four separate hour-long training sessions. Each ROSE reviewer recorded whether each sample was sufficient or insufficient. Pathologist interpretation was taken as gold standard. Specific diagnosis was not required. Final diagnosis and the total number of passes were also recorded. This study recruited 25 patients (50 passes) for statistical evaluation. RESULTS: Assessment by specialist pathologists deemed 16/50 (32%) to be sufficient and 34/50 (68%) insufficient respectively. Medical scientists were 90% concordant with the pathologist (K =0.774; 95% CI, 0.587-0.961). The two respiratory registrars were 78% (K =0.568; 95% CI, 0.338-0.798) and 72% (K =0.448; 95% CI, 0.222-0.674) concordant, respectively. The mean number of passes per patient was 4.9 (range, 3-7). A diagnosis was established in 21/25 (82%) patients from the first EBUS-TBNA procedures with the remaining four patients requiring a further procedure or monitoring with serial CT scans to establish the diagnosis. Malignancy was found in 14/25 (56%) patients and a benign process in 11/25 (44%) patients. CONCLUSIONS: Medical scientist review of ROSE samples is not significantly different to a specialist pathologist and is an acceptable alternative. Respiratory registrars are not a realistic alternative for ROSE without more intensive training, which may be difficult to facilitate in addition to existing respiratory training commitments.

Persistent air leak successfully treated with endobronchial valves and digital drainage system.

A 62-year old man with severe chronic obstructive pulmonary disease developed a persistent air leak from an iatrogenic pneumothorax following Computed Tomography-guided core biopsy of a pulmonary nodule. The pneumothorax was treated with an 8.5F intercostal catheter, which was then replaced by a 28F thoracostomy tube after development of significant subcutaneous emphysema and a tension pneumothorax. The air leak showed no improvement until endobronchial valve (EBV) insertion guided by objective flow data from a digital drainage system (DDS). The air leak subsequently reduced with -20 cmH2O suction from the DDS, and the thoracostomy tube was removed once the objective measured flow rate had sufficiently diminished. The combination of EBV insertion and suction from the DDS successfully treated the persistent air leak, with timing of thoracostomy tube removal guided by DDS flow data.