Model analysis of multiple breath nitrogen washout data: robustness to variations in breathing pattern.

We recently developed a model-based method for analyzing multiple breath nitrogen washout data that does not require identification of Phase-III. In the present study, we assessed the effect of irregular breathing patterns on the intra-subject variabilities of the model parameters. Nitrogen fraction at the mouth was measured in 18 healthy and 20 asthmatic subjects during triplicate performances of multiple breath nitrogen washout, during controlled (target tidal volume 1 L at 8-12 breaths per minute) and free (unrestricted) breathing. The parameters Scond, Sacin and functional residual capacity (FRC) were obtained by conventional analysis of the slope of Phase-III. Fitting the model to the washout data provided functional residual capacity (FRCM), dead space volume (VD), the coefficient of variation of regional specific ventilation ([Formula: see text]), and the model equivalent of Sacin (Sacin-M). Intra-participant coefficients of variation for the model parameters for both health and asthma were FRCM < 5.2%, VD < 5.4%, [Formula: see text] < 9.0%, and Sacin-M < 45.6% for controlled breathing, and FRCM < 4.6%, VD < 5.3%, [Formula: see text] < 13.2%, and Sacin-M < 103.2% for free breathing. The coefficients of variation limits for conventional parameters were FRC < 6.1%, with Scond < 73.6% and Sacin < 49.2% for controlled breathing and Scond < 35.0% and Sacin < 74.4% for free breathing. The model-fitting approach to multiple breath nitrogen washout analysis provides a measure of regional ventilation heterogeneity in [Formula: see text] that is less affected by irregularities in the breathing pattern than its corresponding Phase-III slope analysis parameter Scond.

Thoracic Society of Australia and New Zealand Position Statement on Acute Oxygen Use in Adults: 'Swimming between the flags'.

Oxygen is a life-saving therapy but, when given inappropriately, may also be hazardous. Therefore, in the acute medical setting, oxygen should only be given as treatment for hypoxaemia and requires appropriate prescription, monitoring and review. This update to the Thoracic Society of Australia and New Zealand (TSANZ) guidance on acute oxygen therapy is a brief and practical resource for all healthcare workers involved with administering oxygen therapy to adults in the acute medical setting. It does not apply to intubated or paediatric patients. Recommendations are made in the following six clinical areas: assessment of hypoxaemia (including use of arterial blood gases); prescription of oxygen; peripheral oxygen saturation targets; delivery, including non-invasive ventilation and humidified high-flow nasal cannulae; the significance of high oxygen requirements; and acute hypercapnic respiratory failure. There are three sections which provide (1) a brief summary, (2) recommendations in detail with practice points and (3) a detailed explanation of the reasoning and evidence behind the recommendations. It is anticipated that these recommendations will be disseminated widely in structured programmes across Australia and New Zealand.

Interventional bronchoscopy for chronic obstructive pulmonary disease: more than a pipe dream.

Endoscopic lung volume reduction (ELVR) is recognised in both national and international expert guidelines as one of the few additive treatments to benefit patients with advanced chronic obstructive pulmonary disease (COPD) who are otherwise receiving optimal medical and supportive care. Despite these recommendations and a growing evidence base, these procedures are not widely offered across Australia and New Zealand, and general practitioner and physician awareness of this therapy can be improved. ELVR aims to mitigate the impact of hyperinflation and gas trapping on dyspnoea and exercise intolerance in COPD. Effective ELVR is of proven benefit in improving symptoms, quality of life, lung function and survival. Several endoscopic techniques to achieve ELVR have been developed, with endobronchial valve placement to collapse a single lobe being the most widely studied and commonly practised. This review describes the physiological rationale underpinning lung volume reduction, highlights the challenges of patient selection, and provides an overview of the evidence for current and investigational endoscopic interventions for COPD.

Longitudinal monitoring of asthma in the clinic using respiratory oscillometry.

BACKGROUND AND OBJECTIVE: Asthma guidelines emphasize the importance of assessing lung function and symptoms. The forced oscillation technique (FOT) and its longitudinal relationship with spirometry and symptoms are unresolved. We examined concordance between longitudinal spirometry, FOT and symptom control, and determined FOT limits of agreement in stable asthma. METHODS: Over a 3-year period, adults with asthma attending a tertiary clinic completed the asthma control test (ACT), fraction of exhaled nitric oxide (FeNO), FOT and spirometry. Analysis included between-visit concordance for significant change using Cohen's kappa (κ) and stable asthma FOT limits of agreement. RESULTS: Data (n = 186) from 855 visits (mean ± SD 4.6 ± 3.0 visits), 114 ± 95 days apart, were analysed. Between-visit concordance was moderate between reactance at 5 Hz (X5) and forced expiratory volume in 1 s (FEV1 ) (κ = 0.34, p = 0.001), and weak between ACT and FEV1 (κ = 0.18, p = 0.001). Change in FeNO did not correlate with lung function or ACT (κ < 0.05, p > 0.1). Stable asthma between visits (n = 75; 132 visits) had reduced lung function variability, but comparable concordance to the entire cohort. Limits of agreement for FEV1 (0.42 L), resistance at 5 Hz (2.06 cm H2 O s L-1 ) and X5 (2.75 cm H2 O s L-1 ) in stable asthma were at least twofold greater than published values in health. CONCLUSION: In adults with asthma, there is moderate concordance between longitudinal change in FOT and spirometry. Both tests relate poorly to changes in asthma control, highlighting the need for multi-modal assessment in asthma rather than symptoms alone. The derivation of longitudinal FOT limits of agreement will assist in its clinical interpretation.

Effects of adopting the Global Lung Function Initiative 2017 reference equations on the interpretation of carbon monoxide transfer factor.

The recently published Global Lung Function Initiative (GLI) carbon monoxide transfer factor (T LCO) reference equations provide an opportunity to adopt a current, all-age, widely applicable reference set. The aim of this study was to document the effect of changing to GLI from commonly utilised reference equations on the interpretation of T LCO results.33 863 T LCO results (48% female, 88% Caucasian, n=930 aged <18 years) from clinical pulmonary function laboratories within three Australian teaching hospitals were analysed. The lower limit of normal (LLN) and proportion of patients with a T LCO below this value were calculated using GLI and other commonly used reference equations.The average T LCO LLN for GLI was similar or lower than the other equations, with the largest difference seen for Crapo equations (median: -1.25, IQR: -1.64, -0.86 mmol·min-1·kPa-1). These differences resulted in altered rates of reduced T LCO for GLI particularly for adults (+1.9% versus Miller to -27.6% versus Crapo), more so than for children (-0.8% versus Kim to -14.2% versus Cotes). For adults, the highest raw agreement for GLI was with Miller equations (94.7%), while for children it was with Kim equations (98.1%). Results were reclassified from abnormal to normal more frequently for younger adults, and for adult females, particularly when moving from Roca to GLI equations (30% of females versus 16% of males).The adoption of GLI T LCO reference equations in adults will result in altered interpretation depending on the equations previously used and to a greater extent in adult females. The effect on interpretation in children is less significant.

Day-to-day variability of forced oscillatory mechanics for early detection of acute exacerbations in COPD.

BACKGROUND: Telemonitoring trials for early detection of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have provided mixed results. Day-to-day variations in lung function measured by the forced oscillation technique (FOT) may yield greater insight. We evaluated the clinical utility of home telemonitoring of variability in FOT measures in terms of 1) the relationship with symptoms and quality of life (QoL); and 2) the timing of variability of FOT measures and symptom changes prior to AECOPD. METHODS: Daily FOT parameters at 5 Hz (resistance (R) and reactance (X); Resmon Pro Diary, Restech Srl, Milan, Italy), daily symptoms (COPD Assessment Test (CAT)) and 4-weekly QoL data (St George's Respiratory Questionnaire (SGRQ)) were recorded over 8-9 months from chronic obstructive pulmonary disease (COPD) patients. Variability of R and X was calculated as the standard deviation (sd) over 7-day running windows and we also examined the effect of varying window size. The relationship of FOT versus CAT and SGRQ was assessed using linear mixed modelling, daily changes in FOT variability and CAT prior to AECOPD using one-way repeated measures ANOVA. RESULTS: Fifteen participants with a mean±sd age of 69±10 years and a % predicted forced expiratory volume in 1 s (FEV1) of 39±10% had a median (interquartile range (IQR)) adherence of 95.4% (79.0-98.8%). Variability of the inspiratory component of X (indicated by the standard deviation of inspiratory reactance (SDXinsp)) related to CAT and weakly to SGRQ (fixed effect estimates 1.57, 95% CI 0.65-2.49 (p=0.001) and 4.41, 95% CI -0.06 to 8.89 (p=0.05), respectively). SDXinsp changed significantly on the same day as CAT (1 day before AECOPD, both p=0.02) and earlier when using shorter running windows (3 days before AECOPD, p=0.01; accuracy=0.72 for 5-day windows). CONCLUSIONS: SDXinsp from FOT telemonitoring reflects COPD symptoms and may be a sensitive biomarker for early detection of AECOPD.

Mepolizumab effectiveness and identification of super-responders in severe asthma.

Severe asthma is a high-burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are applicable in a broader population.The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia.Patients (n=309) with severe eosinophilic asthma (median age 60 years, 58% female) commenced mepolizumab. They had poor symptom control (median Asthma Control Questionnaire (ACQ)-5 score of 3.4), frequent exacerbations (median three courses of oral corticosteroids (OCS) in the previous 12 months), and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590 cells·µL-1 Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%.Mepolizumab treatment reduced exacerbations requiring OCS compared with the previous year (annualised rate ratio 0.34 (95% CI 0.29-0.41); p<0.001) and hospitalisations (rate ratio 0.46 (95% CI 0.33-0.63); p<0.001). Treatment improved symptom control (median ACQ-5 reduced by 2.0 at 6 months), quality of life and lung function. Higher blood eosinophil levels (p=0.003) and later age of asthma onset (p=0.028) predicted a better ACQ-5 response to mepolizumab, whilst being male (p=0.031) or having body mass index ≥30 (p=0.043) predicted a lesser response. Super-responders (upper 25% of ACQ-5 responders, n=61, 24%) had a higher T2 disease burden and fewer comorbidities at baseline.Mepolizumab therapy effectively reduces the significant and long-standing disease burden faced by patients with severe eosinophilic asthma in a real-world setting.

The need for physiological phenotyping to develop new drugs for airways disease.

Asthma and COPD make up the majority of obstructive airways diseases (OADs), which affects ∼11 % of the population. The main drugs used to treat OADs have not changed in the past five decades, with advancements mainly comprising variations on existing treatments. The recent biologics are beneficial to only specific subsets of patients. Part of this may lie in our inability to adequately characterise the tremendous heterogeneity in every aspect of OAD. The field is currently moving towards the concept of personalised medicine, based on a focus on treatable traits that are objective, measurable and modifiable. We propose extending this concept via the use of emerging clinical tools for comprehensive physiological phenotyping. We describe, based on published data, the evidence for the use of functional imaging, gas washout techniques and oscillometry, as well as potential future applications, to more comprehensively assess and predict treatment response in OADs. In this way, we hope to demonstrate how physiological phenotyping tools will improve the way in which drugs are prescribed, but most importantly, will facilitate development of new drugs for OADs.

Cumulative dispensing of high oral corticosteroid doses for treating asthma in Australia.

OBJECTIVE: To estimate the level of dispensing of oral corticosteroids (OCS) for managing asthma in Australia, with a particular focus on the cumulative dispensing of doses associated with long term toxicity (≥ 1000 mg prednisolone-equivalent). DESIGN: Retrospective cohort study; analysis of 10% random sample of Pharmaceutical Benefits Scheme (PBS) dispensing data. PARTICIPANTS, SETTING: People aged 12 years or more treated for asthma during 2014-2018, according to dispensing of controller inhaled corticosteroids (ICS). MAIN OUTCOME MEASURES: Number of people dispensed OCS for managing asthma during 2014-2018; proportion who were cumulatively dispensed at least 1000 mg prednisolone-equivalent. The secondary outcome was the number of people dispensed at least 1000 mg prednisolone-equivalent during 2018, stratified by inhaler controller dose and use. RESULTS: 124 011 people had been dispensed at least two prescriptions of ICS during 2014-2018 and met the study definition for asthma, of whom 64 112 (51.7%) had also been dispensed OCS, including 34 580 (27.9% of the asthma group) cumulatively dispensed 1000 mg prednisolone-equivalent or more. Of 138 073 people dispensed OCS at this level, 68 077 (49%) were patients with airway diseases. Dispensing of diabetes and osteoporosis medications was more common for people cumulatively dispensed 1000 mg prednisolone-equivalent or more. During 2018, 4633 people with asthma using high dose ICS controllers were dispensed 1000 mg prednisolone-equivalent or more, for 2316 of whom (50%) controller use was inadequate. CONCLUSIONS: Cumulative exposure to OCS in Australia reaches levels associated with toxicity in one-quarter of patients with asthma using ICS. Cumulative dispensing of potentially toxic OCS amounts often accompanies inadequate inhaler controller dispensing. Better approaches are needed to improve adherence to controller therapy, improve outcomes for people with asthma, and to minimise the use and toxicity of OCS.

Reduced lung elastic recoil and fixed airflow obstruction in asthma.

BACKGROUND AND OBJECTIVE: Fixed airflow obstruction (FAO) in asthma occurs despite optimal inhaled treatment and no smoking history, and remains a significant problem, particularly with increasing age and duration of asthma. Increased lung compliance and loss of lung elastic recoil has been observed in older people with asthma, but their link to FAO has not been established. We determined the relationship between abnormal lung elasticity and airflow obstruction in asthma. METHODS: Non-smoking asthmatic subjects aged >40 years, treated with 2 months of high-dose inhaled corticosteroid/long-acting beta-agonist (ICS/LABA), had FAO measured by spirometry, and respiratory system resistance at 5 Hz (Rrs5 ) and respiratory system reactance at 5 Hz (Xrs5 ) measured by forced oscillation technique. Lung compliance (K) and elastic recoil (B/A) were calculated from pressure-volume curves measured by an oesophageal balloon. Linear correlations between K and B/A, and forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC), Rrs5 and Xrs5 were assessed. RESULTS: Eighteen subjects (11 males; mean ± SD age: 64 ± 8 years, asthma duration: 39 ± 22 years) had moderate FAO measured by spirometry ((mean ± SD z-score) post-bronchodilator FEV1 : -2.2 ± 0.5, FVC: -0.7 ± 1.0, FEV1 /FVC: -2.6 ± 0.7) and by increased Rrs5 (median (IQR) z-score) 2.7 (1.9 to 3.2) and decreased Xrs5 : -4.1(-2.4 to -7.3). Lung compliance (K) was increased in 9 of 18 subjects and lung elastic recoil (B/A) reduced in 5 of 18 subjects. FEV1 /FVC correlated negatively with K (rs = -0.60, P = 0.008) and Rrs5 correlated negatively with B/A (rs = -0.52, P = 0.026), independent of age. Xrs5 did not correlate with lung elasticity indices. CONCLUSION: Increased lung compliance and loss of elastic recoil relate to airflow obstruction in older non-smoking asthmatic subjects, independent of ageing. Thus, structural lung tissue changes may contribute to persistent, steroid-resistant airflow obstruction. CLINICAL TRIAL REGISTRATION: ACTRN126150000985583 at anzctr.org.au (UTN: U1111-1156-2795).

Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1ß treatment: a novel role for CCL20 in chronic mucus hypersecretion.

Chronic mucus hypersecretion (CMH) contributes to the morbidity and mortality of asthma, and remains uncontrolled by current therapies in the subset of patients with severe, steroid-resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as interleukin (IL)-1ß, provides a potential mechanism that influences CMH. This study investigated mechanisms underlying CMH by comparing IL-1ß-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production in vitroIL-1ß-treated ASMCs from asthmatic patients and healthy donors were profiled using microarray analysis and ELISA. Air-liquid interface (ALI)-cultured CALU-3 and primary airway epithelial cells were treated with identified candidates and mucus production assessed.The IL-1ß-induced CCL20 expression and protein release was increased in ASMCs from moderate compared with mild asthmatic patients and healthy controls. IL-1ß induced lower MIR146A expression in asthma-derived ASMCs compared with controls. Decreased MIR146A expression was validated in vivo in bronchial biopsies from 16 asthmatic patients versus 39 healthy donors. miR-146a-5p overexpression abrogated CCL20 release in ASMCs. CCL20 treatment of ALI-cultured CALU-3 and primary airway epithelial cells induced mucus production, while CCL20 levels in sputum were associated with increased levels of CMH in asthmatic patients.Elevated CCL20 production by ASMCs, possibly resulting from dysregulated expression of the anti-inflammatory miR-146a-5p, may contribute to enhanced mucus production in asthma.

Peripheral airway dysfunction and relationship with symptoms in smokers with preserved spirometry.

BACKGROUND AND OBJECTIVE: Smokers develop respiratory symptoms and peripheral airway dysfunction even when spirometry is preserved. Multiple breath nitrogen washout (MBNW) and impulse oscillometry system (IOS) are potentially useful measures of peripheral airway function but they have not been compared in such subjects. We hypothesized that MBNW and IOS are jointly abnormal in smokers with normal spirometry and that these abnormalities relate to respiratory symptoms. METHODS: Eighty smokers with normal spirometry completed a symptom questionnaire, had ventilation heterogeneity in diffusion (Sacin) and convection-dependent (Scond) airways and trapped gas volume at functional residual capacity as a percentage of vital capacity (%VtrFRC/VC) measured by MBNW. Respiratory resistance and reactance at 5 and 20 Hz were measured using IOS. RESULTS: Respiratory symptoms were reported in 55 (68%) subjects. Forty (50%) subjects had at least one abnormal MBNW parameter, predominantly in Sacin. Forty-one (51%) subjects had at least one abnormal IOS parameter, predominantly in resistance. Sixty-one (76%) subjects had an abnormality in either MBNW or IOS. Chronic bronchitis symptoms were associated with an increased Scond, while wheeze was associated with lower spirometry and an increased resistance. Abnormalities in MBNW and IOS parameters were unrelated to each other. CONCLUSIONS: Respiratory symptoms and peripheral airway dysfunction are common in smokers with normal spirometry. Symptoms of chronic bronchitis related to conductive airway abnormalities, while wheeze was related to spirometry and IOS. The clinical significance of abnormalities in peripheral airway function in smokers remains undetermined.

Bronchodilator Responses in Respiratory Impedance, Hyperinflation and Gas Trapping in COPD.

Hyperinflation, gas trapping and their responses to long-acting bronchodilator are clinically important in COPD. The forced oscillation technique (FOT) measures of respiratory system resistance and reactance are sensitive markers of bronchodilator response in COPD. The relationships between changes in resistance and reactance, and changes in hyperinflation and gas trapping, following long-acting bronchodilator (LA-BD) have not been studied. 15 subjects with mild-moderate COPD underwent FOT, spirometry then body plethysmography, before and 2 hours after a single 150 microg dose of the LA-BD indacaterol. Hyperinflation was quantified as the inspiratory capacity to total lung capacity ratio (IC/TLC), and gas trapping as residual volume to TLC ratio (RV/TLC). At baseline, FOT parameters were moderately correlated with IC/TLC (|r| 0.53-0.73, p < 0.05). At 2 hours post-LA-BD, there were moderate correlations between change in FOT and change in RV/TLC (|r| 0.60-0.82, p < 0.05). Baseline FOT parameters also correlated with the subsequent post-LA-BD change in both IC/TLC (|r| 0.54-0.62, p < 0.05) and RV/TLC (|r| 0.57-0.76, p < 0.05). FOT impedance reflects hyperinflation and gas trapping in COPD, and the potential for long-acting bronchodilator responsiveness. These results provide us with further insight into the physiological mechanisms of action of long-acting bronchodilator treatment, and may be clinically useful for predicting treatment responses.

Bronchodilator responsiveness of peripheral airways in smokers with normal spirometry.

BACKGROUND AND OBJECTIVE: Cigarette smoke exposure increases airway smooth muscle (ASM) contractility. Abnormalities in peripheral airway function in smokers with normal spirometry could be due to the effects of ASM tone. We aimed to determine the contribution of ASM tone to peripheral airway function in smokers with normal spirometry from the response to bronchodilator (BD). METHODS: Ventilation heterogeneity in peripheral conductive (Scond) and acinar (Sacin) airways were measured in 50 asymptomatic smokers and 20 never-smokers using multiple breath nitrogen washout, before and 20 min after inhalation of 200 µg salbutamol and 80 µg ipratropium bromide. Z-scores were calculated to define abnormality in Sacin and Scond. RESULTS: Nineteen smokers had abnormal Sacin, and 12 had abnormal Scond; 7 had abnormalities in both. After BD, Sacin improved in smokers with normal Sacin (6.5 ± 15.9%, P = 0.02), smokers with abnormal Sacin (9.2 ± 16.9%, P = 0.03) and in control subjects (11.7 ± 18.2%, P = 0.01), with no differences in improvements between groups. Sacin remained abnormal in 15/19 smokers and their post-BD values correlated with smoking exposure (r = 0.53, P = 0.02). After BD, Scond improved in smokers with abnormal Scond (28.3 ± 15.9%, P = 0.002) and normalized in 9/12 subjects, but not in those with normal Scond (0.25 ± 32.7%, P = 0.44) or control subjects (-1.7 ± 21.2%, P = 0.64). CONCLUSION: In smokers with normal spirometry, abnormal conductive airway function could be attributed to increased bronchomotor tone. In contrast, bronchomotor tone in acinar airways is unaffected by smoking and functional abnormality. There may be different causal mechanisms underlying acinar and conductive airway abnormalities in smokers with normal spirometry.

Association between peripheral airway function and neutrophilic inflammation in asthma.

BACKGROUND AND OBJECTIVE: Small airway dysfunction is associated with asthma severity and control, but its association with airway inflammation is unknown. The aim was to determine the association between sputum inflammatory cells and the site of small airway dysfunction, measured by multiple breath nitrogen washout in convection-dependent (Scond) and more peripheral diffusion-dependent (Sacin) airways. METHODS: Fifty-three (20-67 years) subjects with asthma on inhaled corticosteroid (ICS) treatment were characterized by spirometry, Scond, Sacin and induced sputum differential counts. %Predicted values for Scond and Sacin were calculated from published reference equations to adjust for the effects of age. Univariate correlations were assessed using the Spearman test. Multivariate linear regressions were performed to account for potential confounders, including age, gender, disease duration, body mass index and ICS dose. RESULTS: Sacin (%predicted) correlated significantly with neutrophil% (rs = 0.33, P = 0.02), ICS dose (rs = -0.28, P = 0.04) and age (rs = 0.27, P = 0.05). In multivariate analysis, Sacin related only to neutrophil% (adjusted R(2) = 0.18, P = 0.001). Scond (%predicted) correlated significantly only with eosinophil% (rs = 0.39, P = 0.004). There was a trend for a negative relationship with ICS dose (rs = -0.26, P = 0.06). In multivariate analysis, Scond related to eosinophil% and ICS dose independently (adjusted R(2) = 0.12, P = 0.02). CONCLUSIONS: Acinar and conductive airway dysfunction is associated with different inflammatory profiles in asthmatic airways, independently of the effects of age and disease duration. The association between acinar airway dysfunction and neutrophilic airway inflammation may have implications for asthma treatment.