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.

BLTR1 Is Decreased in Steroid Resistant Pro-Inflammatory CD28nullCD8+ T Lymphocytes in Patients with COPD-The Spillover Hypothesis Explained?

INTRODUCTION: Pro-inflammatory CD8+ T cells are increased in the lungs and also in the peripheral circulation of both smokers and chronic obstructive pulmonary disease (COPD) patients. The reason for this is unclear but has been described as a spillover from cells in the lungs that may cause the systemic inflammation noted in COPD. We have recently shown an increase in steroid-resistant CD28nullCD8+ senescent lymphocytes in the lungs and peripheral blood in COPD. Leukotreine B4 (LB4) receptor 1 (BLTR1) is involved in recruitment of CD8+ T cells to sites of inflammation, and we hypothesized that it may be involved in the migration of these senescent lymphocytes from the lungs in COPD. METHODS: Via flow cytometry and Western blot BLTR1, IFNγ, and TNFα expression were measured in peripheral blood, BAL, and large proximal and small distal airway CD28±, CD8± T, and NKT-like cells from COPD patients and healthy control subjects (±prednisolone) following in vitro stimulation. Chemotaxis of leucocyte subsets was determined (±LB4 ± prednisolone). RESULTS: There was an increase in BLTR1-CD28nullCD8+ lymphocytes in the lungs and blood in patients with COPD compared with controls. BLTR1-CD28nullCD8+ T and NKT-like cells produce more IFN/TNF than BLTR+ cells and fail to migrate to LTB4. Treatment with 1 µM prednisolone in vitro resulted in upregulation of BLTR1 expression in pro-inflammatory CD28nullCD8+ cells and migration to LB4. CONCLUSIONS: Loss of BLTR1 is associated with an increased inflammatory potential of CD28nullCD8+ T cells and may allow these pro-inflammatory steroid-resistant cells to migrate to peripheral blood. Treatment strategies that upregulate BLTR1 may reduce systemic inflammation and associated co-morbidity in patients with COPD.

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.

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.

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).

Association between grass, tree and weed pollen and asthma health outcomes in Adelaide, South Australia: a time series regression analysis.

OBJECTIVES: We aim to establish daily risk estimates of the relationships between grass, tree and weed pollen and asthma health outcomes. DESIGN: Time series regression analysis of exposure and health outcomes using interaction by month to determine risk estimates all year round. SETTING: Metropolitan Adelaide, South Australia. PARTICIPANTS: Health outcomes for asthma are based on 15 years of hospital admissions, 13 years emergency presentations and ambulance callouts. In adults (≥18 years), there were 10 381 hospitalisations, 26 098 emergency department (ED) presentations and 11 799 ambulance callouts and in children (0-17 years), 22 114, 39 813 and 3774, respectively. OUTCOME MEASURES: The cumulative effect of 7 day lags was calculated as the sum of the coefficients and reported as incidence rate ratio (IRR) related to an increase in 10 grains of pollen/m3. RESULTS: In relation to grass pollen, children and adults were disparate in their timing of health effects. Asthma outcomes in children were positively related to grass pollen in May, and for adults in October. Positive associations with weed pollen in children was seen from February to May across all health outcomes. For adults, weed pollen-related health outcomes were restricted to February. Adults were not affected by tree pollen, while children's asthma morbidity was associated with tree pollen in August and September. In children, IRRs ranged from 1.14 (95% CI 1.06 to 1.21) for ED presentations for tree pollen in August to 1.98 (95% CI 1.06 to 3.72) for weed pollen in February. In adults, IRRs ranged from 1.28 (95% CI 1.01 to 1.62) for weed pollen in February to 1.31 (95% CI 1.08 to 1.57) for grass pollen in October. CONCLUSION: Monthly risk assessment indicated that most pollen-related asthma health outcomes in children occur in the colder part of the year, while adults are affected in the warm season. The findings indicate a need for year-round pollen monitoring and related health campaigns to provide effective public health prevention.

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.

Pollen Exposure and Cardiopulmonary Health Impacts in Adelaide, South Australia.

(1) Background: Limited research has suggested that cardiopulmonary health outcomes should be considered in relation to pollen exposure. This study sets out to test the relationship between pollen types (grasses, trees, weeds) and cardiovascular, lower respiratory and COPD health outcomes using 15 years (2003-2017) of data gathered in Adelaide, South Australia; (2) Methods: A time-series analysis by months was conducted using cardiopulmonary data from hospital admissions, emergency presentations and ambulance callouts in relation to daily pollen concentrations in children (0-17) for lower respiratory outcomes and for adults (18+). Incidence rate ratios (IRR) were calculated over lags from 0 to 7 days; (3) Results: IRR increases in cardiovascular outcomes in March, May, and October were related to grass pollen, while increases in July, November, and December were related to tree pollen. IRRs ranged from IRR 1.05 (95% confidence interval (CI) 1.00-1.10) to 1.25 (95% CI 1.12-1.40). COPD increases related to grass pollen occurred only in May. Pollen-related increases were observed for lower respiratory outcomes in adults and in children; (4) Conclusion: Notable increases in pollen-related associations with cardiopulmonary outcomes were not restricted to any one season. Prevention measures for pollen-related health effects should be widened to consider cardiopulmonary outcomes.

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.

Respiratory surveillance for coal mine dust and artificial stone exposed workers in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand.

Coal mine lung dust disease (CMDLD) and artificial stone (AS) silicosis are preventable diseases which have occurred in serious outbreaks in Australia recently. This has prompted a TSANZ review of Australia's approach to respiratory periodic health surveillance. While regulating respirable dust exposure remains the foundation of primary and secondary prevention, identification of workers with early disease assists with control of further exposure, and with the aims of preserving lung function and decreasing respiratory morbidity in those affected. Prompt detection of an abnormality also allows for ongoing respiratory specialist clinical management. This review outlines a medical framework for improvements in respiratory surveillance to detect CMDLD and AS silicosis in Australia. This includes appropriate referral, improved data collection and interpretation, enhanced surveillance, the establishment of a nationwide Occupational Lung Disease Registry and an independent advisory group. These measures are designed to improve health outcomes for workers in the coal mining, AS and other dust-exposed and mining industries.

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.

Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes.

BACKGROUND: The class III NAD-dependent histone deacetylase (HDAC) sirtuin 1 (SIRT1) is an important regulator of senescence, aging, and inflammation. SIRT1de-acetylates chromatin histones, thereby silencing inflammatory gene transcription. We have reported increased steroid-resistant senescent pro-inflammatory CD28nullCD8+ T cells in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that SIRT1 is reduced in these cells in COPD, and that treatment with SIRT1 activators (resveratrol, curcumin) and agents preventing NAD depletion (theophylline) would upregulate SIRT1 and reduce pro-inflammatory cytokine expression in these steroid-resistant cells. METHODS: Blood was collected from n = 10 COPD and n = 10 aged-matched controls. Expression of CD28, SIRT1, and pro-inflammatory cytokines was determined in CD8+ and CD8- T and natural killer T (NKT)-like cells cultured in the presence of ±1 µM prednisolone, ±5 mg/L theophylline, ±1 µM curcumin, ±25 µM resveratrol, using flow cytometry and immunofluorescence. RESULTS: There was an increase in the percentage of CD28nullCD8+ T and NKT-like cells in COPD patients compared with controls. Decreased SIRT1 expression was identified in CD28nullCD8+T and NKT-like cells compared with CD28+ counterparts from both patients and controls (e.g. CD28null 11 ± 3% versus CD28+ 57 ± 9%). Loss of SIRT1 was associated with increased production of IFNγ and TNFα, steroid resistance, and disease severity. SIRT1 expression was upregulated in the presence of all drugs and was associated with a decrease in steroid resistance and IFNγ and TNFα production by CD28nullCD8+T and NKT-like cells. The presence of the SIRT1 inhibitor, EX-527 negated [by 92 ± 12% (median ± SEM)] the effect of the SIRT1 activator SRT720 on the percentage of CD8+ T cells producing IFNγ and TNFα. CONCLUSIONS: Steroid resistance in pro-inflammatory CD28nullCD8+ T and NKT-like cells is associated with decreased SIRT1 expression. Treatment with prednisolone, in combination with theophylline, curcumin or resveratrol increases SIRT1 expression, restores steroid sensitivity, and inhibits pro-inflammatory cytokine production from these cells and may reduce systemic inflammation in COPD. The reviews of this paper are available via the supplemental material section.