Association of Gas Diffusing Capacity of the Lung for Carbon Monoxide with Cardiovascular Morbidity and Survival in a Disadvantaged Clinical Population.

PURPOSE: Low diffusing capacity of the lung for carbon monoxide (DLCO) and spirometry values are associated with increased mortality risk. However, associations between mortality risk and cardiovascular disease with the transfer coefficient of the lung for carbon monoxide (KCO) and alveolar volume (VA) are unknown. This cohort study: (i) evaluated whether DLCO, KCO, and VA abnormalities are independently associated with cardiovascular morbidity and/or elevated mortality risk and, (ii) compared these associations with those using spirometry values. METHODS: Gas-diffusing capacity and spirometry data of 1165 adults seen at specialist respiratory outreach clinics over an 8-year period (241 with cardiovascular disease; 108 deceased) were analysed using multivariable Cox and logistic regression. RESULTS: DLCO, KCO, and VA values below the lower limit of normal (< - 1.64 Z-scores) were associated with elevated cardiovascular disease prevalence [respective odds ratios of 1.83 (95% CI 1.31-2.55), 1.56 (95% CI 1.08-2.25), 2.20 (95% CI 1.60-3.01)] and increased all-cause mortality risk [respective hazard ratios of 2.99 (95% CI 1.83-4.90), 2.14 (95% CI 1.38-3.32), 2.75 (95% CI 1.18-2.58)], after adjustment for factors including age, personal smoking, and respiratory disease. Compared to similar levels of spirometry abnormality, DLCO, KCO, and VA were associated with similar or greater mortality risk, and similar cardiovascular disease prevalence. Analysis of only those patients with clinical normal spirometry values (n = 544) showed these associations persisted for DLCO. CONCLUSION: Low DLCO, KCO, and VA measurements are associated with cardiovascular disease prevalence. As risk factors of all-cause mortality, they are more sensitive than spirometry even among patients with no diagnosed respiratory disease.

Associations between lung function and future cardiovascular morbidity and overall mortality in a predominantly First Nations population: a cohort study.

BACKGROUND: Spirometric lung function impairment is an independent predictor of respiratory and cardiovascular disease, and mortality across a broad range of socioeconomic backgrounds and environmental settings. No contemporary studies have explored these relationships in a predominantly regional/remote First Nations population, whose health outcomes are worse than for non-First Nations populations, and First Nations people living in urban centres. METHODS: This was a retrospective cohort study of 1,734 adults (1,113 First Nations) referred to specialist respiratory outreach clinics in the state of Queensland, Australia from February 2012 to March 2020. Regression modelling was used to test associations between lung function and mortality and cardiovascular disease. FINDINGS: At the time of analysis (August 2020), 189 patients had died: 88 (47%) from respiratory causes and 38 (20%) from cardiovascular causes. When compared to patients with forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) Z-scores of >0 to -1, patients with Z-scores <-1 were at elevated mortality risk (HR=3•2, 95%CI 1•4-7•4; HR=2•6, 95%CI 1•3-5•1), and elevated cardiovascular disease risk (OR=1•5, 95%CI 1•1-2•2; OR=1•6, 95%CI 1•2-2•3). FEV1/FVC% Z-scores <-1 were associated with increased overall mortality (HR=1•6, 95%CI 1•1-2•3), but not cardiovascular disease (OR=1•1, 95%CI 0•8-1•4). These associations were not affected by First Nations status. INTERPRETATION: Reduced lung function even within the clinically normal range is associated with increased mortality, and cardiovascular disease in First Nations Australians. These findings highlight the importance of lung function optimisation and inform the need for future investment to improve outcomes in First Nations populations. FUNDING: None.

Determinants and Follow-up of Lung Function Data from a Predominantly First Nations Cohort of Adults Referred to Specialist Respiratory Outreach Clinics in Regional and Remote Queensland.

PURPOSE: Northern Territory (NT)-based clinical service data suggest substantial lung function impairment amongst First Nations adults as young as 18-40 years. Our objectives were to describe the burden of disease and lung function of adults living in regional-remote Queensland, identify determinants of lung function, and evaluate the impact of a specialist respiratory outreach service on lung function. METHODS: Retrospective 8-year cohort study (February 2012-March 2020) of 1113 First Nations Australian adults (and 648 non-First Nations adults) referred to respiratory outreach clinics in regional-remote Queensland. RESULTS: In the combined cohort, the forced expiratory volume in 1 s (FEV1) was clinically abnormal for 54% of First Nations patients (51% of non-First Nations patients), forced vital capacity (FVC) for 46% (36%), FEV1/FVC% for 30% (36%), and gas diffusing capacity (DLCO) for 44% (37%). A respiratory diagnosis was assigned by a respiratory physician in 78% of First Nations (76% non-First Nations) patients. Smoking, household smoke exposure, underweight BMI, and respiratory disease were associated with reduced lung function. In the 40% of patients (709/1765) followed up, FEV1 and FVC significantly improved (mean change: zFEV1 = 0.15 [95% CI 0.10-0.20]; zFVC = 0.25 [0.20, 0.31]), and FEV1/FVC% significantly reduced (mean = - 0.10 [95%CI - 0.07 to - 0.03]), with no significant change in DLCO. Patients with COPD had lower FEV1 improvement, whilst underweight and obese patients had lower FVC improvement. CONCLUSION: Regional-remote First Nations adult Queenslanders have higher lung function than previously reported, with no lung function decline observed at follow-up visit, including for those with respiratory disease.

Volatile organic compound breath testing detects in-situ squamous cell carcinoma of bronchial and laryngeal regions and shows distinct profiles of each tumour.

Volatile organic compound (VOC) breath testing of lung and head and neck squamous cell carcinoma (SCC) has been widely studied, however little is known regarding VOC profiles of in-situ SCC. A prospective study of VOC in patients with histologically proven SCC, either in-situ or advanced, and controls. Breath samples were analysed using the E-nose Cyranose ®320 and by gas chromatography/mass spectroscopy. Predictive models were developed using bootstrap forest using all 32 sensors. Data from 55 participants was analysed: 42 SCC cases comprising 20 bronchial (10 in-situ, 10 advanced) and 22 laryngeal (12 in-situ, 10 advanced), and 13 controls. There were 32 (76%) male SCC cases with mean age 63.6 (SD = 9.5) compared with 11 (85%) male controls with mean age 61.9 (SD = 10.1). Predictive models for in situ cases had good sensitivity and specificity compared to controls (overall, 95% and 69%; laryngeal, 100% and 85%; bronchial, 77% and 80%). When distinguishing in-situ and advanced tumours, sensitivity and specificity 82% and 75% respectively. For different tumour types (bronchial versus advanced laryngeal) sensitivity and specificity were 100% and 80% respectively. VOCs isolated from in-situ cancers included some previously demonstrated in advanced cancers and some novel VOCs. In-situ bronchial and laryngeal cancer can be detected by VOC analysis. Distinction from normal controls and between the two tumour types could allow screening in high risk groups for these curable lesions.

Diagnosis and treatment of early lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer death in Australia. Recently there have been unparalleled advances in the screening and management of lung cancer. OBJECTIVE: The aim of this article is to discuss diagnosis and management of lung cancer, including advances that are likely to translate into future practice. DISCUSSION: Screening with low-dose computed tomography scans has proven to be effective for detecting early curable disease, reducing mortality by ≥20% in randomised controlled trials. Implementation trials are underway within Australia and overseas, and a Commonwealth Inquiry is ongoing. Breath and blood biomarkers are less invasive alternatives that show potential but remain under investigation. Early diagnosis of lung cancer is key to improving survival - this includes familiarity with nodule screening recommendations and facilitating access to early tissue diagnosis via transthoracic needle aspiration or bronchoscopy. Treatment decisions can then be guided by staging with scans, molecular testing and multidisciplinary team consideration in the frame of patient factors/preferences. The therapeutic armamentarium is boosted by an increasing range of effective therapies including modern surgical and radiation techniques, and systemic treatments including targeted therapies and immunotherapy.

Biomarkers of progression of chronic obstructive pulmonary disease (COPD).

Disease progression of chronic obstructive pulmonary disease (COPD) is variable, with some patients having a relatively stable course, while others suffer relentless progression leading to severe breathlessness, frequent acute exacerbations of COPD (AECOPD), respiratory failure and death. Radiological markers such as CT emphysema index, bronchiectasis and coronary artery calcification (CAC) have been linked with increased mortality in COPD patients. Molecular changes in lung tissue reflect alterations in lung pathology that occur with disease progression; however, lung tissue is not routinely accessible. Cell counts (including neutrophils) and mediators in induced sputum have been associated with lung function and risk of exacerbations. Examples of peripheral blood biological markers (biomarkers) include those associated with lung function (reduced CC-16), emphysema severity (increased adiponectin, reduced sRAGE), exacerbations and mortality [increased CRP, fibrinogen, leukocyte count, IL-6, IL-8, and tumor necrosis factor α (TNF-α)] including increased YKL-40 with mortality. Emerging approaches to discovering markers of gene-environment interaction include exhaled breath analysis [volatile organic compounds (VOCs), exhaled breath condensate], cellular and systemic responses to exposure to air pollution, alterations in the lung microbiome, and biomarkers of lung ageing such as telomere length shortening and reduced levels of sirtuins. Overcoming methodological challenges in sampling and quality control will enable more robust yet easily accessible biomarkers to be developed and qualified, in order to optimise personalised medicine in patients with COPD.

Indigenous Respiratory Outreach Care: the first 18 months of a specialist respiratory outreach service to rural and remote Indigenous communities in Queensland, Australia.

OBJECTIVE: Respiratory diseases are a leading cause of morbidity and mortality in Indigenous Australians. However, there are limited approaches to specialist respiratory care in rural and remote communities that are culturally appropriate. A specialist Indigenous Respiratory Outreach Care (IROC) program, developed to address this gap, is described. METHODS: The aim of the present study was to implement, pilot and evaluate multidisciplinary specialist respiratory outreach medical teams in rural and remote Indigenous communities in Queensland, Australia. Sites were identified based on a perception of unmet need, burden of respiratory disease and/or capacity to use the clinical service and capacity building for support offered. RESULTS: IROC commenced in March 2011 and, to date, has been implemented in 13 communities servicing a population of approximately 43000 Indigenous people. Clinical service delivery has been possible through community engagement and capacity building initiatives directed by community protocols. CONCLUSION: IROC is a culturally sensitive and sustainable model for adult and paediatric specialist outreach respiratory services that may be transferrable to Indigenous communities across Queensland and Australia.

Exhaled breath analysis for lung cancer.

Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection.

Personalizing and targeting therapy for COPD: the role of molecular and clinical biomarkers.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by persistent airflow limitation. It is the third leading cause of death worldwide, and there are currently no curative strategies for this disease. Many factors contribute to COPD susceptibility, progression and exacerbations. These include cigarette smoking, environmental and occupational pollutants, respiratory infections and comorbidities. As the clinical phenotypes of COPD are so variable, it has been difficult to devise an individualized treatment plan for patients with this complex chronic disease. This review will highlight how potential clinical, inflammatory, genomic and epigenomic biomarkers for COPD could be used to personalize treatment, leading to improved disease management and prevention for our patients.

The Global Lung Initiative 2012 reference values reflect contemporary Australasian spirometry.

We aimed to ascertain the fit of the European Respiratory Society Global Lung Initiative 2012 reference ranges to contemporary Australasian spirometric data. Z-scores for spirometry from Caucasian subjects aged 4-80 years were calculated. The mean (SD) Z-scores were 0.23 (1.00) for forced expirtory volume in 1 s (FEV(1)), 0.23 (1.00) for forced vital capacity (FVC), -0.03 (0.87) for FEV(1)/FVC and 0.07 (0.95) for forced expiratory flows between 25% and 75% of FVC. These results support the use of the Global Lung Initiative 2012 reference ranges to interpret spirometry in Caucasian Australasians.

Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD).

BACKGROUND: Pulmonary hypertension (PH) is a complication of chronic obstructive pulmonary disease (COPD). This study examined genetic variations in mediators of vascular remodelling and their association with PH in patients with COPD. In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia. METHODS: In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia. RESULTS: 580 COPD patients were recruited, 341 patients had a transthoracic echocardiogram, with RVSP measurable in 278 patients (mean age 69 years, mean FEV1 50% predicted, mean RVSP 44 mmHg, median history of 50 pack-years). Of the 7 tested SNPs, the NOS3-VNTR polymorphism was significantly associated with RVSP in a dose-dependent fashion for the risk allele: mean RVSP for a/a and a/b genotypes were 52.0 and 46.6 mmHg respectively, compared to 43.2 mmHg for b/b genotypes (P = 0.032). No associations were found between RVSP and other polymorphisms. ACE II or ID genotypes were associated with a lower FEV1% predicted than the ACE DD genotype (P = 0.028). The NOS3-298 TT genotype was associated with lower KCO % predicted than the NOS3-298 GG or GT genotype (P = 0.031). CONCLUSIONS: The NOS3-VNTR polymorphism was associated with RVSP in patients with COPD, supporting its involvement in the pathogenesis of PH in COPD. ACE and NOS3 genotypes were associated with COPD disease severity, but not with the presence of PH. Further study of these genes could lead to the development of prognostic and screening tools for PH in COPD.

The all-age spirometry reference ranges reflect contemporary Australasian spirometry.

BACKGROUND AND OBJECTIVE: Advances in statistical modelling have allowed the creation of smoothly changing spirometry reference ranges that apply across a wide age range and better define the lower limit of normal. The objective of this study was to assess the agreement of the Stanojevic 2009 all-age reference ranges to contemporary lung function data to verify the appropriateness of this reference for clinical use in Australia and New Zealand. METHODS: Spirometry data from healthy Caucasians measured between 2000-2009 in Australia and New Zealand were collected. Z-scores were calculated for the standard spirometry outcomes based on the all-age reference ranges. RESULTS: Spirometry from 2066 subjects aged 4-80 years (55% male) from 14 centres were eligible. Statistically, the collated contemporary dataset differed from the all-age reference ranges, but these differences were relatively small and clinically irrelevant representing differences of approximately 3% predicted. Significant differences were also observed between some centres and equipment, potentially indicating varying influence of equipment or subject selection. CONCLUSIONS: Spirometry from contemporary Australasian healthy subjects fits the all-age reference ranges well. While the current study supports the use of the all-age reference ranges, the between-centre differences highlight the need for spirometry to be used in conjunction with other clinical findings.