Mannitol challenge testing for asthma in a community cohort of young adults.

BACKGROUND AND OBJECTIVE: Mannitol challenge testing is an established tool for clinical asthma diagnosis, and can be performed outside of specialized respiratory laboratories. Despite applicability in both clinical and non-clinical populations, with different pre-test asthma probabilities, differences in diagnostic properties have not been well explored. This study aimed to quantify the diagnostic utility of mannitol challenge testing for asthma in a community cohort and a symptomatic wheezing subset of this cohort. METHODS: During the 22-year follow-up of the Western Australian Pregnancy (Raine) Cohort, 772 participants (384 males) completed mannitol challenge and skin prick testing and respiratory health questionnaires, of whom 148 reporting wheeze in the past 12 months were included in a wheezing subset. RESULTS: Responsiveness to mannitol had low sensitivity (19%) and high specificity (97%) to identify current asthma in the complete cohort, with positive and negative predictive values (PPV and NPV) of 45% and 92%, respectively. Within the wheezing subset, sensitivity (19%) and specificity (94%) remained similar, but PPV increased to 79%, and NPV decreased to 52%. CONCLUSION: Our findings support previously reported high specificity and good PPV for mannitol challenge testing in symptomatic wheezing populations, and highlight the need for caution when interpreting mannitol test results in non-clinical populations.

Rationale, design and methods for the 22 year follow-up of the Western Australian Pregnancy Cohort (Raine) Study.

BACKGROUND: Young adulthood is a critical life period for health and health behaviours. Related measurements collected before and after birth, and during childhood and adolescence can provide a life-course analysis of important factors that contribute to health and behaviour in young adulthood. The Western Australian Pregnancy Cohort (Raine) Study has collected a large number of such measurements during the fetal, perinatal, infancy, childhood and adolescence periods and plans to relate them to common health issues and behaviours in young adults, including spinal pain, asthma, sleep disorders, physical activity and sedentary behaviour and, work absenteeism and presenteeism. The aim of this paper is to describe the rationale, design and methods of the 22 year follow-up of the Raine Study cohort. METHODS/DESIGN: The Raine Study is a prospective cohort study. Participants still active in the cohort (n = 2,086) were contacted around the time of their 22nd birthday and invited to participate in the 22 year follow-up. Each was asked to complete a questionnaire, attend a research facility for physical assessment and an overnight sleep study, wear activity monitors for a week, and to maintain a sleep and activity diary over this week. The questionnaire was broad and included questions related to sociodemographics, medical history, quality of life, psychological factors, lifestyle factors, spinal pain, respiratory, sleep, activity and work factors. Physical assessments included anthropometry, blood pressure, back muscle endurance, tissue sensitivity, lung function, airway reactivity, allergic status, 3D facial photographs, cognitive function, and overnight polysomnography. DISCUSSION: Describing the prevalence of these health issues and behaviours in young adulthood will enable better recognition of the issues and planning of health care resources. Providing a detailed description of the phenotype of these issues will provide valuable information to help educate health professionals of the needs of young adults. Understanding the life-course risk factors of health issues and behaviours in young adulthood will have important health planning implications, supporting the development of targeted interventions to improve current health status and reduce the onset and development of further ill-health across adulthood.

The Prevalence of Bronchodilator Responsiveness "Asthma" Among Adult Indigenous Australians Referred for Lung Function Testing in the Top End Northern Territory of Australia.

Background: Among Indigenous Australians, studies examining the clinical significance of airway bronchodilator responsiveness (BDR) are limited. In this retrospective study, we examined the nature of underlying lung disease in adult Indigenous patients with BDR referred for lung function testing (LFT) in the Top End Health Service region of the Northern Territory of Australia. Methods: Presence or absence of BDR as per usual (FVC or FEV1 change pre to post ≥12% and ≥0.2L) and updated (2021 ">10% predicted) ATS/ERS criteria among Indigenous and non-Indigenous Australians was determined. The radiological findings in the Indigenous study participants with and without BDR were next assessed for the presence of underlying chronic airway/lung disease. Results: We found that 123/742 (17%) Indigenous and 578/4579 (13%) non-Indigenous patients had a significant BDR. Indigenous patients with BDR were younger (mean difference 7 years), with a greater proportion of females (52 vs 32%), underweight (15 vs 4%) and current smokers (52 vs 25%). Indigenous patients with BDR displayed lower LFT values, and a higher proportion exhibited FVC BDR compared to non-Indigenous (34 vs 20%). Almost half (46%) of Indigenous patients with BDR had evidence of COPD and/or bronchiectasis on radiology. Adjusting for the presence of radiologic or spirometric evidence of COPD, the presence of BDR was similar between Indigenous and non-Indigenous patients (5-8 vs 7-11%), irrespective of which BDR criteria was used. Conclusion: BDR was higher overall among Indigenous in comparison to non-Indigenous patients; however, a significant proportion of Indigenous patients demonstrating BDR had evidence of underlying COPD/bronchiectasis. This study highlights that although presence of BDR among Indigenous people may indicate asthma, it may also be observed among patients with COPD/bronchiectasis or could represent asthma/COPD/bronchiectasis overlap. Hence, a combination of clinical history, LFT and radiology should be considered for precise diagnosis of lung disease in this population.

Characterisation of lung function trajectories and associated early-life predictors in an Australian birth cohort study.

Background: There is growing evidence that lung function in early-life predicts later lung function. Adverse events over the lifespan might influence an individual's lung function trajectory, resulting in poor respiratory health. The aim of this study is to identify early-life risk factors and their impact on lung function trajectories to prevent long-term lung impairments. Methods: Our study included participants from the Raine Study, a prospective pregnancy cohort, with at least two spirometry measurements. Lung function trajectories from the 6- to 22-year follow-ups were characterised using finite mixture modelling. Multinomial logistic regression analyses were used to evaluate the association between early-life predictors and lung function trajectories. Main results: A total of 1512 participants (768 males, 744 females), representing 53% of the whole cohort, were included in this analysis. Four lung function trajectories of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC (z-scores) were identified. FEV1 and FVC trajectories were categorised as: "very low", "low", "average" and "above average", respectively. Based on their shape, lung function trajectories of FEV1/FVC were categorised as "very low", "low-average", "average-low" and "average". Asthma and maternal smoking were identified as risk factors for low lung function trajectories in this cohort, as well as early-life exposure to PM2.5Absorbance. Conclusions: Early-life risk factors may influence lung function trajectories over time. Nonetheless, identifying children with a high risk of having low lung function trajectories should be prioritised to prevent deficits in later life.

Implications of using the GLI-2012, GOLD and Australian COPD-X recommendations in assessing the severity of airflow limitation on spirometry among an Indigenous population with COPD: an Indigenous Australians perspective study.

BACKGROUND: Assessment of airflow limitation (AFL) is crucial in the clinical evaluation of patients with chronic obstructive pulmonary disease (COPD). However, in the absence of normative reference values among adult Australian Indigenous population, the implications of utilising the Global Lung Function Initiative (GLI-2012), Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the Australian concise COPD-X recommended severity classifications is not known. Moreover, spirometry values (forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)) are observed to be 20%-30% lower in an apparently healthy Indigenous population in comparison to Caucasian counterparts. METHODS: Adult Indigenous patients diagnosed to have COPD on spirometry (postbronchodilator (BD) FEV1/FVC <0.7 ((GOLD, (COPD-X)) and ≤lower limit of normal (others/mixed reference equations) for GLI-2012) were assessed for AFL severity classifications on Post-BD FEV1 values (mild, moderate, severe, very severe) as per the recommended classifications. RESULTS: From a total of 742 unique patient records of Indigenous Australians, 253 were identified to have COPD via GOLD/COPD-X criteria (n=238) or GLI-2012 criteria (n=238) with significant agreeance between criteria (96%, κ=0.901). Of these, the majority were classified as having moderate or severe/very-severe AFL with significant variability across classification criteria (COPD-X (40%-43%), GOLD (33%-65%), GLI-2012 (18%-75%)). The FVC and FEV1 values also varied significantly between classification criterion (COPD-X/GOLD/GLI-2012) within the same AFL category, with COPD-X 'moderate' AFL almost matching 'severe' AFL categorisation by GOLD or GLI-2012. CONCLUSIONS: Health professionals caring for Indigenous patients with COPD should be aware of the clinical implications and consequences of utilising various recommended AFL classifications in the absence of validated spirometry reference norms among adult Indigenous patients.

Lung function parameters among Australian Aboriginal 'apparently healthy' adults: an Australian Caucasian and Global Lung Function Initiative (GLI-2012) various ethnic norms comparative study.

Background: There is sparse literature evidence evaluating the applicability of the GLI-2012 spirometric norms for Australian Aboriginal adults.Methods: Lung function parameters (LFPs) were compared between Australian Aboriginal and Australian Caucasians, and the fit of Australian Aboriginals LFPs with various ethnic GLI equations was tested.Results: Of 1350 and 5634 Pulmonary function tests (PFTs) in Australian Aboriginal and Australian Caucasian adults, 153 and 208 PFTs matched for anthropometrics and normal chest radiology, respectively. Absolute FVC and FEV1 values were 20% lower in Australian Aboriginals compared to Australian Caucasians. Differences remained significant after accounting for age, sex, height, weight and smoking status in multivariate regression (FVC -0.84 L (-0.98, -0.71), FEV1 - 0.72 L (-0.84, -0.59), but with nearly preserved FEV1/FVC. GLI-2012 transformation resulted in z-scores significantly below zero for each of FVC, FEV1 and FEV1/FVC with z-scores ranging from -4.52 (-4.87, -4.16) for North East Asian FVC transformation for males, to -0.34 (-0.73, 0.05) for Black FVC transformation for females.Conclusions: Australian Aboriginal adults had 20% lower values for FVC and FEV1 but nearly preserved absolute FEV1/FVC in comparison to Australian Caucasians. The GLI-2012 spirometric norms do not appear to fit for Australian Aboriginal adults regardless of which ethnicity options selected, including 'others/mixed'.

Comparison of diffusing capacity of carbon monoxide (DLCO) and total lung capacity (TLC) between Indigenous Australians and Australian Caucasian adults.

BACKGROUND AND OBJECTIVE: Currently there is paucity of evidence in the literature in relation to normative values for diffusing capacity of carbon monoxide (DLCO) and total lung capacity (TLC) among Indigenous Australians. Hence, in this study we assessed the DLCO and TLC parameters among Indigenous Australians in comparison to Australian Caucasian counterparts. METHODS: DLCO and TLC values were assessed and compared between Indigenous Australians and Australian Caucasians matched for age, sex and body mass index, with normal chest radiology. RESULTS: Of the 1350 and 5634 pulmonary function tests assessed in Indigenous Australian and Australian Caucasian adults respectively, a total of 129 Indigenous Australians and 197 Australian Caucasians met the inclusion criteria. Absolute DLCO and TLC values for Indigenous Australians were a mean 4.3 ml/min/mmHg (95% CI 2.86, 5.74) and 1.03 L (95% CI 0.78, 1.27) lower than Australian Caucasians (p<0.01). Percentage predicted values were 15.38 (95% CI 11.59, 19.17) and 16.63 (95% CI 13.59, 19.68) points lower for DLCO and TLC, respectively. Lower limit of normal (LLN) values did not significantly differ between groups, however a significantly greater proportion of Indigenous Australians recorded values below the LLN in comparison to Australian Caucasians for DLCO (64 vs. 25%, p<0.01) and TLC (66 vs. 21%, p<0.01). Significant differences for the interaction of sex on DLCO and TLC were noted in Australian Caucasians, with reduced or absent sex differentiation among Indigenous Australians. CONCLUSIONS: There are significant differences in DLCO and TLC parameters between Indigenous Australian compared to Australian Caucasians. Appropriate DLCO and TLC norms need to be established for Indigenous Australians.

Persistent activation of interlinked type 2 airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic asthmatics.

Atopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced type 2-associated inflammation. However, the vast majority of atopics do not develop asthma despite ongoing aeroallergen exposure, suggesting additional mechanisms operate in conjunction with type 2 immunity to drive asthma pathogenesis. We employed RNA-Seq profiling of sputum-derived cells to identify gene networks operative at baseline in house dust mite-sensitized (HDMS) subjects with/without wheezing history that are characteristic of the ongoing asthmatic state. The expression of type 2 effectors (IL-5, IL-13) was equivalent in both cohorts of subjects. However, in HDMS-wheezers they were associated with upregulation of two coexpression modules comprising multiple type 2- and epithelial-associated genes. The first module was interlinked by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3 and mucociliary clearance genes. Our findings provide new insight into the molecular mechanisms operative at baseline in the airway mucosa in atopic asthmatics undergoing natural aeroallergen exposure, and suggest that susceptibility to asthma amongst these subjects involves complex interactions between type 2- and epithelial-associated gene networks, which are not operative in equivalently sensitized/exposed atopic non-asthmatics.