Which reference equation should we use for interpreting spirometry values for First Nations Australians? A cross-sectional study.

OBJECTIVES: To evaluate the suitability of the Global Lung Function Initiative (GLI)-2012 other/mixed and GLI-2022 global reference equations for evaluating the respiratory capacity of First Nations Australians. DESIGN, SETTING: Cross-sectional study; analysis of spirometry data collected by three prospective studies in Queensland, the Northern Territory, and Western Australia between March 2015 and December 2022. PARTICIPANTS: Opportunistically recruited First Nations participants in the Indigenous Respiratory Reference Values study (Queensland, Northern Territory; age, 3-25 years; 18 March 2015 - 24 November 2017), the Healthy Indigenous Lung Function Testing in Adults study (Queensland, Northern Territory; 18 years or older; 14 August 2019 - 15 December 2022) and the Many Healthy Lungs study (Western Australia; five years or older; 10 October 2018 - 7 November 2021). MAIN OUTCOME MEASURES: Goodness of fit to spirometry data for each GLI reference equation, based on mean Z-score and its standard deviation, and proportions of participants with respiratory parameter values within 1.64 Z-scores of the mean value. RESULTS: Acceptable and repeatable forced expiratory volume in the first second (FEV1) values were available for 2700 First Nations participants in the three trials; 1467 were classified as healthy and included in our analysis (1062 children, 405 adults). Their median age was 12 years (interquartile range, 9-19 years; range, 3-91 years), 768 (52%) were female, and 1013 were tested in rural or remote areas (69%). Acceptable and repeatable forced vital capacity (FVC) values were available for 1294 of the healthy participants (88%). The GLI-2012 other/mixed and GLI-2022 global equations provided good fits to the spirometry data; the race-neutral GLI-2022 global equation better accounted for the influence of ageing on FEV1 and FVC, and of height on FVC. Using the GLI-2012 other/mixed reference equation and after adjusting for age, sex, and height, mean FEV1 (estimated difference, -0.34; 95% confidence interval [CI], -0.46 to -0.22) and FVC Z-scores (estimated difference, -0.45; 95% CI, -0.59 to -0.32) were lower for rural or remote than for urban participants, but their mean FEV1/FVC Z-score was higher (estimated difference, 0.14; 95% CI, 0.03-0.25). CONCLUSION: The normal spirometry values of healthy First Nations Australians may be substantially higher than previously reported. Until more spirometry data are available for people in urban areas, the race-neutral GLI-2022 global or the GLI-2012 other/mixed reference equations can be used when assessing the respiratory function of First Nations Australians.

A core outcome set for bronchiectasis in children and adolescents for use in clinical research: an international consensus study.

Improving the treatment of non-cystic fibrosis bronchiectasis in children and adolescents requires high-quality research with outcomes that meet study objectives and are meaningful for patients and their parents and caregivers. In the absence of systematic reviews or agreement on the health outcomes that should be measured in paediatric bronchiectasis, we established an international, multidisciplinary panel of experts to develop a core outcome set (COS) that incorporates patient and parent perspectives. We undertook a systematic review from which a list of 21 outcomes was constructed; these outcomes were used to inform the development of separate surveys for ranking by parents and patients and by health-care professionals. 562 participants (201 parents and patients from 17 countries, 361 health-care professionals from 58 countries) completed the surveys. Following two consensus meetings, agreement was reached on a ten-item COS with five outcomes that were deemed to be essential: quality of life, symptoms, exacerbation frequency, non-scheduled health-care visits, and hospitalisations. Use of this international consensus-based COS will ensure that studies have consistent, patient-focused outcomes, facilitating research worldwide and, in turn, the development of evidence-based guidelines for improved clinical care and outcomes. Further research is needed to develop validated, accessible measurement instruments for several of the outcomes in this COS.

The effect of early childhood respiratory infections and pneumonia on lifelong lung function: a systematic review.

Early childhood respiratory infections, including pneumonia, are an important global public health issue, with more than 40 million annual cases resulting in approximately 650 000 deaths. A growing number of published studies have examined the effects of early childhood lower respiratory tract infections (LRTIs) or pneumonia on lung function, particularly as part of large early-life exposure studies. To our knowledge, there is no published systematic review of these data. We searched PubMed, Embase, and Web of Science for studies published between database inception and May 12, 2022. Case-control, cohort, and cross-sectional studies were included if they reported forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC) values of participants older than 5 years. Article titles and abstracts were screened in Rayyan before retrieval, assessment, and data extraction of the full text. Primary outcome measures were differences in mean FEV1 or FVC values between exposed groups (ie, children aged ≤5 years with LRTIs) and non-exposed groups. This study is registered with PROSPERO, CRD42021265295. Database searches yielded 3070 articles, and 14 studies were included in this systematic review, providing a total of 23 276 participants, including 9969 children and 13 307 adults. Eight of 14 articles reported significant reductions in FEV1 values, and six of 12 studies reported reductions in FVC values in children and adults with a history of early childhood LRTIs or pneumonia, compared with unexposed controls (p<0·05). Most studies reporting reductions in lung function described deficits consistent with a restrictive spirometry pattern. Only two of 14 studies reported data from low-income and middle-income countries or disadvantaged populations in middle-income and high-income countries, and there were scarce data available on the effect of LRTI severity and recurrence on lung function. LRTIs in early childhood could be associated with a restrictive spirometry pattern in later childhood and adulthood. Data are needed from low-income and middle-income nations, and from disadvantaged populations in middle-income and high-income countries in which early childhood respiratory infection burden is disproportionately high. Data are also needed on the effect of LRTI severity and recurrence on future lung function.

Developing Fractional Exhaled Nitric Oxide Predicted and Upper Limit of Normal Values for a Disadvantaged Population.

BACKGROUND: Fractional exhaled nitric oxide (Feno), used as a biomarker, is influenced by several factors including ethnicity. Normative data are essential for interpretation, and currently single cutoff values are used in children and adults. RESEARCH QUESTION: Accounting for factors that influence Feno, (1) what are appropriate predicted and upper limit of normal (ULN) Feno values in an underserved population (First Nations Australians), (2) how do these values compare with age-based interpretive guidelines, and (3) what factors influence Feno and what is the size of the effect? STUDY DESIGN AND METHODS: Feno data of First Nations Australians (age < 16 years, n = 862; age ≥ 16 years, n = 348) were obtained. Medical history using participant questionnaires and medical records were used to define healthy participants. Flexible regression using spline functions, as used by the Global Lung Function Initiative, were used to generate predicted and ULN values. RESULTS: Look-up tables for predicted and ULN values using age (4-76 years) and height (100-200 cm) were generated and are supplied with a calculator for clinician use. In healthy First Nations children (age < 18 years), ULN values ranged between 25 and 60 parts per billion (ppb) when considering only biologically plausible age and height combinations. For healthy adults, ULN values ranged between 39 and 88 ppb. Neither the current Feno interpretation guidelines, nor the currently recommended cutoff of 50 ppb for First Nations children 16 years of age or younger were appropriate for use in this cohort. Our modelling revealed that predicted and ULN values of healthy participants varied nonlinearly with age and height. INTERPRETATION: Because single pediatric, adult, or all-age Feno cutoff values used by current interpretive guidelines to define abnormality fail to account for factors that modify Feno values, we propose predicted and ULN values for First Nations Australians 4 to 76 years of age. Creating age- and height-adjusted predicted and ULN values could be considered for other ethnicities.

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.

Quality standards for managing children and adolescents with bronchiectasis: an international consensus.

The global burden of bronchiectasis in children and adolescents is being recognised increasingly. However, marked inequity exists between, and within, settings and countries for resources and standards of care afforded to children and adolescents with bronchiectasis compared with those with other chronic lung diseases. The European Respiratory Society (ERS) clinical practice guideline for the management of bronchiectasis in children and adolescents was published recently. Here we present an international consensus of quality standards of care for children and adolescents with bronchiectasis based upon this guideline. The panel used a standardised approach that included a Delphi process with 201 respondents from the parents and patients' survey, and 299 physicians (across 54 countries) who care for children and adolescents with bronchiectasis. The seven quality standards of care statements developed by the panel address the current absence of quality standards for clinical care related to paediatric bronchiectasis. These internationally derived, clinician-, parent- and patient-informed, consensus-based quality standards statements can be used by parents and patients to access and advocate for quality care for their children and themselves, respectively. They can also be used by healthcare professionals to advocate for their patients, and by health services as a monitoring tool, to help optimise health outcomes.

Early Childhood Pneumonia Is Associated with Reduced Lung Function and Asthma in First Nations Australian Children and Young Adults.

BACKGROUND: Some but not all previous studies report that pneumonia in children aged less than five years is associated with lower lung function and elevated risk of respiratory disease. To date, none have explored these associations in at-risk populations such as First Nations Australians, whose incidence of early childhood pneumonia is among the highest reported in the world. METHODS: This cross-sectional study included 1276 First Nations Australian children/young adults aged 5-25 years recruited from regional/remote Queensland and Northern Territory communities and schools. Associations between pneumonia and both spirometry values and asthma were investigated using linear and logistic regression. RESULTS: Early childhood pneumonia was associated with lower FEV1 and FVC Z-scores, but not FEV1/FVC% Z-scores, when occurring before age three (FEV1 ß = -0.42, [95%CI -0.79, -0.04]; FVC ß = -0.62, [95%CI -1.14, -0.09]), and between three and five years (ß = -0.50, [95%CI -0.88, -0.12]; ß = -0.63, [95%CI -1.17, -0.10]), compared to those who never had pneumonia. Similarly, pneumonia occurring when aged before age three years (OR = 3.68, 95%CI 1.96-6.93) and three to five years (OR = 4.81, 95%CI 1.46-15.8) was associated with increased risk of asthma in later childhood. CONCLUSIONS: Early childhood pneumonia is associated with lung function deficits and increased asthma risk in later childhood/early adulthood in First Nations Australians. The disproportionate impact of pneumonia on at-risk children must be addressed as a priority.

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.

How do Cormic Index profiles contribute to differences in spirometry values between White and First Nations Australian children?

BACKGROUND: Spirometry values of First Nations Australian children are lower than White children. One explanation relates to differences in the sitting-height/standing-height ratio (Cormic Index), as this accounts for up to half the observed differences in spirometry values between White children and other ethnicities. We investigated whether the Cormic Index of First Nations children differs from White children and if this explains the lower spirometry values of First Nations children. METHODS: First Nations children (n = 619) aged 8-16 years were recruited from nine Queensland communities. Their spirometry and Cormic Index data were compared to that of White children (n = 907) aged 8-16 years from the NHANES III dataset. RESULTS: FEV1 and FVC of First Nations children was 8% lower for children aged 8-11.9 years and 9%-10% lower for children aged 12-16 years. The Cormic Index was statistically lower in the First Nations 8-11.9 years group (median = 0.515, interquartile range [IQR]: 0.506-0.525) compared with White children (0.519, IQR: 0.511-0.527), and this difference was greater in the 12-16 years group (0.505, IQR: 0.492-0.516; 0.520, IQR: 0.510-0.529). Adjusting for age, sex, and standing height, lower Cormic Index of First Nations children accounts for 14% (95% confidence interval [CI]: 7%-21%) of FEV1 and 15% (95% CI: 8%-21%) of FVC differences in the younger group, and 26% (95% CI: 16%-37%) of FEV1 and 31% (95% CI: 19%-42%) of FVC differences in the older group. CONCLUSION: Ethnic differences in Cormic Index partly account for why healthy First Nations Australian children have lower spirometry values than White children. As childhood spirometry values impact adult health, other contributing factors require attention.

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.

Pediatric Patients of Outreach Specialist Queensland Clinics Have Lung Function Improvement Comparable to That of Tertiary Pediatric Patients.

BACKGROUND: Inequitable access to quality health care contributes to the known poorer outcomes of people living in regional/remote areas (compared with urban-based), especially for First Nations people. Integration of specialist outreach services within primary care is one strategy that can reduce the inequity when modeled to the needs and available resources of target communities. RESEARCH QUESTION: To evaluate whether respiratory outreach clinics in regional and remote Queensland are as effective as tertiary respiratory services at improving the lung function of children. STUDY DESIGN AND METHODS: From existing databases, we obtained spirometry data of children (aged 3-18 years) seen at Indigenous-focused outreach clinics in regional and remote Queensland and Brisbane-based pediatric tertiary hospitals over the same contemporary period (October 2010 to July 2019). We compared the change in spirometry z scores (Δz) at follow-up for both groups of children. RESULTS: Lung function significantly improved in both groups: Tertiary hospital (n = 2,249; ΔzFEV1 = 0.22, 95% CI, 0.17 to 0.27; ΔzFVC = 0.23, 95% CI, 0.18 to 0.28); outreach (n = 252; ΔzFEV1 = 0.35, 95% CI, 0.22 to 0.48; ΔzFVC = 0.36, 95% CI, 0.23 to 0.50). No significant intergroup differences were found in ΔzFEV1 (0.13; 95%CI, -0.02 to 0.28; P = .10) or ΔzFVC (0.14; 95% CI, -0.02 to 0.29; P = .08) improvement from baseline. In both groups, the proportion of children with zFEV1 > 0 at follow-up (hospital = 31.7%; outreach = 46.8%) significantly increased (hospital P = .001; outreach P = .009) from baseline (hospital = 27.2%; outreach = 35.3%). Numbers of children with zFEV1 > 0 significantly increased for asthma and bronchiectasis outreach subgroups, and for children with asthma in the hospital-based group. INTERPRETATION: Comparable significant lung function improvement of children was seen in Indigenous-focused outreach remote/regional clinics and paediatric tertiary hospitals. This suggests that effective clinical care is achievable within the outreach setting.

Culturally Appropriate Outreach Specialist Respiratory Medical Care Improves the Lung Function of Children in Regional and Remote Queensland.

BACKGROUND AND OBJECTIVES: Indigenous Respiratory Outreach Care (IROC) is a culturally appropriate specialist respiratory service established to deliver multidisciplinary respiratory care to regional and remote Queensland communities. Our objective was to evaluate the impact of an outreach specialist respiratory service on the spirometry of children attending IROC clinics, particularly Indigenous children with asthma and bronchiectasis. METHODS: Retrospective single-arm cohort study of 189 children who performed spirometry at twelve sites across regional and remote Queensland between October 2010 and December 2017. Each child's baseline spirometry was compared to their best spirometry at follow-up visit occurring within (1) 12 months of their most recent visit with at least 12 months of specialist care and; (2) each year of their first 3 years of care. RESULTS: Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) z-scores improved significantly across the whole group from baseline to follow-up (change in z-scores (Δz) of FEV1 = 0.38, 95% CI 0.22, 0.53; ΔzFVC = 0.36, 95% CI 0.21, 0.51). In subgroup analyses, lung function significantly improved in Indigenous children (n = 141, ΔzFEV1 = 0.37, 95% CI 0.17, 0.57; ΔzFVC = 0.36, 95% CI 0.17, 0.55) including those with asthma (n = 117, ΔzFEV1 = 0.41, 95% CI 0.19, 0.64; ΔzFVC = 0.46, 95% CI 0.24, 0.68) and bronchiectasis (n = 38, ΔzFEV1 = 0.33, 95% CI 0.07, 0.59; ΔzFVC = 0.26, 95% CI - 0.03, 0.53). Significant improvements in FEV1 and FVC were observed within the first and second year of follow-up for Indigenous children, but not for non-Indigenous children. CONCLUSION: The IROC model of care in regional and remote settings leads to significant lung function improvement in Indigenous children with asthma and bronchiectasis.