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Marsha A Ivey,1,2 Sheree M Smith,3,4 Geza Benke,1 Brett G Toelle,5,6 Michael L Hunter,7 Alan L James,8 Graeme P Maguire,9 Richard Wood-Baker,10 David P Johns,11 Guy B Marks,5,12 Michael J Abramson1 1School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia; 2School of Medicine, Faculty of Medical Sciences, The University of the West Indies, St Augustine, Trinidad and Tobago; 3School of Nursing and Midwifery, Campbelltown Campus, Western Sydney University, Penrith, NSW, 2751, Australia; 4Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; 5Respiratory and Environmental Epidemiology Group, Woolcock Institute of Medical Research, Sydney, NSW, 2037, Australia; 6Sydney Local Health District, Sydney, NSW, 2050, Australia; 7School of Population and Global Health, University of Western Australia, Perth, WA, 6009, Australia; 8Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital and Medical School, University of Western Australia, Perth, WA, 6009, Australia; 9Curtin Medical School, Curtin University, Perth, WA, 6102, Australia; 10School of Medicine, University of Tasmania, Hobart, TAS, 7000, Australia; 11Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia; 12School of Clinical Medicine, University of New South Wales, Sydney, NSW, 2052, AustraliaCorrespondence: Michael J Abramson, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia, Tel +61 3 9903 0573, Fax +61 3 9903 0556, Email michael.abramson@monash.eduPurpose: Tobacco smoking is the major risk factor for COPD, and it is common for other risk factors in never-smokers to be overlooked. We examined the prevalence of COPD among never-smokers in Australia and identified associated risk factors.Methods: We used data from the Australia Burden of Obstructive Lung Disease (BOLD) study, a cross-section of people aged ≥ 40 years from six sites. Participants completed interviews and post-bronchodilator spirometry. COPD was primarily defined as an FEV1/FVC ratio < 0.70 and secondarily as the ratio less than the lower limit of normal (LLN).Results: The prevalence of COPD in the 1656 never-smokers who completed the study was 10.5% (95% CI: 9.1– 12.1%) [ratio

Yijun Zhou,1 Maria R Ampon,2 Michael J Abramson,3 Alan L James,4 Graeme P Maguire,5 Richard Wood-Baker,6 David P Johns,6 Guy B Marks,1,7 Helen K Reddel,2,8,9 Brett G Toelle1,8,9 1The Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia; 2Australian Centre for Airways Disease Monitoring, The Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia; 3School of Public Health & Preventive Medicine, Monash University, Melbourne, VIC, Australia; 4Sir Charles Gairdner Hospital, Perth, WA, Australia; 5Curtin Medical School, Curtin University, Perth, WA, Australia; 6Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia; 7South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia; 8Faculty of Medicine, Health and Human Science, Macquarie University, Sydney, NSW, Australia; 9Sydney Local Health District, Sydney, NSW, AustraliaCorrespondence: Brett G Toelle, Woolcock Institute of Medical Research, 431 Glebe Point Road, Glebe, NSW, 2037, Australia, Email brett.toelle@woolcock.org.auPurpose: Population data on the burden of chronic obstructive pulmonary disease (COPD) are often based on patient-reported diagnoses of COPD, emphysema or chronic bronchitis, without spirometry. We aimed to investigate the relationship between health burden, quality of life and severity of airway obstruction in Australian adults aged ≥ 40 years.Methods: We used data from the BOLD Australia study, which included randomly selected adults aged ≥ 40 years from six study sites to reflect the sociodemographic and geographic diversity of the Australian population (n = 3522). Participants with post-bronchodilator airflow limitation (ratio of forced expiratory volume in 1 second FEV1 to forced vital capacity < 0.7) were grouped by GOLD spirometry grades 1– 4. Quality of life was assessed with Short Form 12 (SF-12) Health Survey Questionnaire. Health burden was assessed as lost time off work or social activities, and healthcare utilization.Results: Of the study sample, 2969 participants did not have airflow limitation, 294 (8.4%) were classified as GOLD Grade 1, 212 (6.0%) as GOLD 2 and 43 (1.2%) as GOLD 3– 4. Participants with higher GOLD grades had more respiratory symptoms, more comorbidities and greater burden than those with lower GOLD grades. The scores of mental and physical subscales of SF-12 were lower, indicating worse quality of life, from the no airflow limitation group to the GOLD 3– 4 group (P = 0.03 and P < 0.001, respectively).Conclusion: Greater airflow limitation is associated with greater burden and poor quality of life. Interventions to prevent, or reduce the level of, airflow limitation will reduce the symptom burden and improve quality of life for patients.Keywords: chronic obstructive pulmonary disease, airflow limitation, comorbidities, The Burden of Obstructive Lung Disease, quality of life

Kate Petrie,1 Brett G Toelle,2,3 Richard Wood-Baker,4 Graeme P Maguire,5 Alan L James,6,7 Michael Hunter,8,9 David P Johns,4 Guy B Marks,2,10 Johnson George,1,11 Michael J Abramson11 1Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia; 2Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia; 3Sydney Local Health District, Sydney, NSW, Australia; 4College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia; 5Western Clinical School, University of Melbourne, Melbourne, Australia and General Internal Medicine, Western Health, Melbourne, VIC, Australia; 6Sir Charles Gairdner Hospital, West Australian Sleep Disorders Research Institute, Department of Pulmonary Physiology and Sleep Medicine, Perth, WA, Australia; 7University of Western Australia, Medical School, Perth, WA, Australia; 8School of Population and Global Health, University of Western Australia, Perth, WA, Australia; 9Busselton Population Medical Research Institute, Busselton, WA, Australia; 10South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia; 11School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, AustraliaCorrespondence: Michael J AbramsonSchool of Public Health and Preventive Medicine, Monash University, Level 2, 553 St Kilda Road, Melbourne, VIC, 3004, AustraliaTel +61 3 9903 0573Fax +61 3 9903 0556Email michael.abramson@monash.eduPurpose: Spirometry is necessary to confirm COPD, but many patients are diagnosed based on clinical presentation and/or chest x-ray. There are also those who do not present to primary care for case finding and remain undiagnosed. We aimed to identify: (a) factors that are associated with undiagnosed COPD; and (b) factors that are associated with a potential misdiagnosis of COPD.Patients and Methods: This analysis used data from the Burden of Obstructive Lung Disease (BOLD), a cross-sectional study of community dwelling adults randomly selected from six study sites, chosen to provide a representative sample of the Australian population (n= 3357). Participants were grouped by COPD diagnostic criteria based on spirometry and self-reported diagnosis. Odds ratios for predictors of undiagnosed and misdiagnosed were estimated using logistic regression.Results: Of the BOLD Australia sample, 1.8% had confirmed COPD, of whom only half self-reported a diagnosis of COPD. A further 6.9% probably had COPD, but were undiagnosed. The priority target population for case finding of undiagnosed COPD was aged ≥ 60 years (particularly those ≥ 75 years), with wheezing, shortness of breath and a body mass index (BMI) < 25kg/m2. The priority target population for identifying and reviewing misdiagnosed COPD was aged < 60 years, female, with no wheezing and a BMI ≥ 25kg/m2.Conclusion: Challenges continue in accurately diagnosing COPD and greater efforts are needed to identify undiagnosed and misdiagnosed individuals to ensure an accurate diagnosis and the initiation of appropriate management in order to reduce the burden of COPD.Keywords: case finding, diagnosis, spirometry, epidemiology

David P Johns,1 Aruneema Das,1 Brett G Toelle,2,3 Michael J Abramson,4 Guy B Marks,2,5 Richard Wood-Baker,1 E Haydn Walters1,6 1Faculty of Health, NHMRC Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, 2Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, 3Sydney Local Health District, Sydney, New South Wales, 4Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, 5South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, 6Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia Background and objective: We have explored whether assessing the degree of concavity in the descending limb of the maximum expiratory flow–volume curve enhanced spirometric detection of early small airway disease. Methods: We used spirometry records from 890 individuals aged ≥40 years (mean 59 years), recruited for the Burden of Obstructive Lung Disease Australia study. Central and peripheral concavity indices were developed from forced expired flows at 50% and 75% of the forced vital capacity, respectively, using an ideal line joining peak flow to zero flow. Results: From the 268 subjects classified as normal never smokers, mean values for post-bronchodilator central concavity were 18.6% in males and 9.1% in females and those for peripheral concavity were 50.5% in males and 52.4% in females. There were moderately strong correlations between concavity and forced expired ratio (forced expiratory volume in 1 second/forced vital capacity) and mid-flow rate (forced expiratory flow between 25% and 75% of the FVC [FEF25%–75%]; r=-0.70 to -0.79). The additional number of individuals detected as abnormal using the concavity indices was substantial, especially compared with FEF25%–75%, where it was approximately doubled. Concavity was more specific for symptoms. Conclusion: The inclusion of these concavity measures in the routine reports of spirometry would add information on small airway obstruction at no extra cost, time, or effort. Keywords: early airway disease, airflow obstruction, COPD

The small size and large surface area of ultrafine particles (UFP) enhance their ability to deposit in the lung periphery and their reactivity. The Ultrafine Particles from Traffic Emissions and Children's Health (UPTECH) cross-sectional study was conducted in 8-11-year-old schoolchildren attending 25 primary (elementary) schools, randomly selected from the Brisbane Metropolitan Area, Queensland, Australia. Main study findings outlined indirect evidence of distal airway deposition (raised C reactive protein) but as yet, there is no direct evidence in the literature of effects of UFP exposure on peripheral airway function. We present further UPTECH study data from two sensitive peripheral airway function tests, Oscillometry and Multiple Breath Nitrogen Washout (MBNW), performed in 577 and 627 children (88% and 96% of UPTECH study cohort) respectively: mean(SD) age 10.1(0.9) years, 46% male, with 50% atopy and 14% current asthma. Bayesian generalised linear mixed effects regression models were used to estimate the effect of UFP particle number count (PNC) exposure on key oscillometry (airway resistance, (Rrs), and reactance, (Xrs)) and MBNW (lung clearance index, (LCI) and functional residual capacity, (FRC)) indices. We adjusted for age, sex, and height, and potential confounders including socio-economic disadvantage, PM 2.5 and NO 2 exposure. All models contained an interaction term between UFP PNC exposure and atopy, allowing estimation of the effect of exposure on non-atopic and atopic students. Increasing UFP PNC was associated with greater lung stiffness as evidenced by a decrease in Xrs [mean (95% credible interval) -1.63 (-3.36 to -0.05)%] per 1000#.cm -3 ]. It was also associated with greater lung stiffness (decrease in Xrs) in atopic subjects across all models [mean change ranging from -2.06 to -2.40% per 1000#.cm -3 ]. A paradoxical positive effect was observed for Rrs across all models [mean change ranging from -1.55 to -1.70% per 1000#.cm -3 ] (decreases in Rrs indicating an increase in airway calibre), which was present for both atopic and non-atopic subjects. No effects on MBNW indices were observed. In conclusion, a modest detrimental effect of UFP on peripheral airway function among atopic subjects, as assessed by respiratory system reactance, was observed extending the main UPTECH study findings which reported a positive association with a biomarker for systemic inflammation, C-reactive protein (CRP). Further studies are warranted to explore the pathophysiological mechanisms underlying increased respiratory stiffness, and whether it persists through to adolescence and adulthood., (Copyright © 2022. Published by Elsevier Inc.)

The prevalence of allergic diseases in Australian children is high, but few studies have assessed the potential role of outdoor air pollution in allergic sensitization. We investigated the association between outdoor air pollution and the prevalence of aeroallergen sensitization in a national cross-sectional study of Australian children aged 7-11 years. Children were recruited from 55 participating schools in 12 Australian cities during 2007-2008. Parents completed a detailed (70-item) questionnaire. Outdoor nitrogen dioxide (NO 2 ), as a proxy for exposure to traffic-related emissions, was estimated using measurements from regulatory monitors near each school and a national land-use regression (LUR) model. Three averaging periods were assessed, using information on duration of residence at the address, including lifetime, previous (lifetime, excluding the last year), and recent (the last year only). The LUR model was used as an additional source of recent exposure estimates at school and home addresses. Skin prick tests (SPTs) were performed to measure sensitization to eight common aeroallergens. Multilevel logistic regression estimated the association between NO 2 and sensitization (by individual allergens, indoor and outdoor allergens, and all allergens combined), after adjustment for individual- and area-level covariates. In total, 2226 children had a completed questionnaire and SPT. The prevalence of sensitization to any allergen was 44.4%. Sensitization to house dust mites (HDMs) was the most common (36.1%), while sensitization to Aspergillus was the least common (3.4%). Measured mean (±s.d.) NO 2 exposure was between 9 (±2.9) ppb and 9.5 (±3.2) ppb, depending on the averaging period. An IQR (4 ppb) increase in measured previous NO 2 exposure was associated with greater odds of sensitization to HDMs (OR: 1.21, 95% CI: 1.01-1.43, P = 0.035). We found evidence of an association between relatively low outdoor NO 2 concentrations and sensitization to HDMs, but not other aeroallergens, in Australian children aged 7-11 years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A critical element of the risk assessment of exposure to airborne ambient ultrafine particles (UFP) is the quantification of respiratory tract deposition (RTD) of the particles, which is intrinsically challenging, particularly at the population scale. In this study, we used a recently proposed method to experimentally determine the RTD of urban UFP in a large group of children exposed to these particles in a school setting in Brisbane, Australia. Children are one of the most susceptible population groups; However, little is known about the deposition of UFP from urban traffic in their airways. In order to advance the knowledge in this field, the objectives of this study were: to determine the deposition of ambient urbane UFP in large number children, to catergorize the source of inhaled UFPs and hence to assess the contribution of air pollution sources to the deposition. RTD was measured in children aged 8-11 at primary schools using a flow-through chamber bag system. First, the inhaled and exhaled air was separated; then the particle number size distribution and particle number concentration were measured. The sources of inhaled UFP were categorized according to their particle number size distribution by a K means cluster technique. A total of 128 children from five schools performed the RTD measurement. The mean total deposition fraction of urban UFP in all children was 0.59 ± 0.10. Inhaled UFP were categorized into two groups: traffic and urban background, with the GMD of corresponding particle number size distribution of 20 nm and 40 nm, respectively. The total deposition fraction (mean ± SD) of UFP from these two groups was 0.68 ± 0.09 for traffic and 0.55 ± 0.08 for urban background respectively. This is the first study in which RTD was measured in a large group of children inhaling real urban UFP. First, we proved that this novel method can indeed be applied easily and quickly to a large group of people. Second, we quantified the RTD of children, thus providing an important input to the risk assessment for exposure to UFP., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Most studies of long-term air pollution exposure and children's respiratory health have been performed in urban locations with moderate pollution levels. We assessed the effect of outdoor nitrogen dioxide (NO 2 ), as a proxy for urban air pollution, on current asthma and lung function in Australia, a low-pollution setting. We undertook a national population-based cross-sectional study of children aged 7-11 years living in 12 Australian cities. We collected information on asthma symptoms from parents via questionnaire and measured children's lung function (forced expiratory volume in 1 s [FEV 1 ], forced vital capacity [FVC]) and fractional exhaled nitric oxide [Fe NO ]). We estimated recent NO 2 exposure (last 12 months) using monitors near each child's school, and used a satellite-based land-use regression (LUR) model to estimate NO 2 at each child's school and home. Our analysis comprised 2630 children, among whom the prevalence of current asthma was 14.9%. Mean (±SD) NO 2 exposure was 8.8 ppb (±3.2) and 8.8 ppb (±2.3) for monitor- and LUR-based estimates, respectively. Mean percent predicted post-bronchodilator FEV 1 and FVC were 101.7% (±10.5) and 98.8% (±10.5), respectively. The geometric mean Fe NO concentration was 9.4 ppb (±7.1). An IQR increase in NO 2 (4.0 ppb) was significantly associated with increased odds of having current asthma; odds ratios (ORs) were 1.24 (95% CI: 1.08, 1.43) and 1.54 (95% CI: 1.26, 1.87) for monitor- and LUR-based estimates, respectively. Increased NO 2 exposure was significantly associated with decreased percent predicted FEV 1 (-1.35 percentage points [95% CI: -2.21, -0.49]) and FVC (-1.19 percentage points [95% CI: -2.04, -0.35], and an increase in Fe NO of 71% (95% CI: 38%, 112%). Exposure to outdoor NO 2 was associated with adverse respiratory health effects in this population-based sample of Australian children. The relatively low NO 2 levels at which these effects were observed highlight the potential benefits of continuous exposure reduction., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Evidence for an association between traffic-related air pollution and allergic disease is inconsistent, possibly because the adverse effects may be limited to susceptible subgroups and these have not been identified. This study examined children in the Childhood Asthma Prevention Study (CAPS), potentially susceptible to air pollution effects because of a family history of asthma., Methods: We examined cross-sectional associations at age eight years between road density within 75 m and 50 m of home address weighted by road type (traffic density), as a proxy for traffic-related air pollution, on the following allergic and respiratory outcomes: skin prick tests (SPTs), total and specific serum IgE, pre- and post-bronchodilator lung function, airway hyperresponsiveness, exhaled NO, and reported asthma and rhinitis., Results: Weighted road density was positively associated with allergic sensitisation and allergic rhinitis. Adjusted relative risk (RR) for house dust mite (HDM) positive SPT was 1.25 (95% CI: 1.06-1.48), for detectable house dust mite-specific IgE was 1.19 (95% CI: 1.01-1.41) and for allergic rhinitis was 1.30 (95% CI: 1.03-1.63) per 100 m local road or 33.3 m motorway within 50 m of home. Associations were also seen with small decrements of peak and mid-expiratory flows and increased risk of asthma, current wheeze and rhinitis in atopic children., Conclusion: Associations between road density and allergic disease were found in a potentially susceptible subgroup of children at high risk of developing atopy and asthma.

Objective: The construction of a new road tunnel in Sydney, Australia, and concomitant reduction in traffic on a major road presented the opportunity to study the effects of this traffic intervention on respiratory health., Methods: We made measurements in a cohort of residents in the year before the tunnel opened (2006) and in each of two years afterwards (2007-2008). Cohort members resided in one of four exposure zones, including a control zone. Each year, a respiratory questionnaire was administered (n = 2,978) and a panel sub-cohort (n = 380) performed spirometry once and recorded peak expiratory flow and symptoms twice daily for nine weeks., Results: There was no consistent evidence of improvement in respiratory health in residents living along the bypassed main road, despite a reduction in traffic from 90,000 to 45,000 vpd. Residents living near tunnel feeder roads reported more upper respiratory symptoms in the survey but not in the panel sub-cohort. Residents living around the tunnel ventilation stack reported more upper and lower respiratory symptoms and had lower spirometric volumes after the tunnel opened. Air pollutant levels measured near the stack did not increase over the study period., Conclusion: The finding of adverse health effects among residents living around the stack is unexpected and difficult to explain, but might be due to unmeasured pollutants or risk factors or an unrecognized pollutant source nearby. The lack of improvement in respiratory health among people living along the bypassed main road probably reflects a minimal change in exposure due to distance of residence from the road.

Over 30 genomic regions show linkage to asthma traits. Six asthma genes have been cloned, but the putative loci in many linked regions have not been identified. To search for asthma susceptibility loci, we performed genomewide univariate linkage analyses of seven asthma traits, using 202 Australian families ascertained through a twin proband. House-dust mite sensitivity (Dpter) exceeded the empirical threshold for significant linkage at 102 cM on chromosome 20q13, near marker D20S173 (empirical pointwise P = .00001 and genomewide P = .005, both uncorrected for multiple-trait testing). Atopy, bronchial hyperresponsiveness (BHR), and forced expiratory volume in 1 s (FEV1) were also linked to this region. In addition, 16 regions were linked to at least one trait at the suggestive level, including 12q24, which has consistently shown linkage to asthma traits in other studies. Some regions were expected to be false-positives arising from multiple-trait testing. To address this, we developed a new approach to estimate genomewide significance that accounts for multiple-trait testing and for correlation between traits and that does not require a Bonferroni correction. With this approach, Dpter remained significantly linked to 20q13 (empirical genomewide P = .042), and airway obstruction remained linked to 12q24 at the suggestive level. Finally, we extended this method to show that the linkage of Dpter, atopy, BHR, FEV1, asthma, and airway obstruction to chromosome 20q13 is unlikely to be due to chance and may result from a quantitative trait locus in this region that affects several of these traits.