Publications by authors named "Paul D Robinson"

93 Publications

Update in management of paediatric primary spontaneous pneumothorax.

Paediatr Respir Rev 2021 Aug 10. Epub 2021 Aug 10.

Department of Respiratory Medicine, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia. Electronic address:

Paediatric spontaneous pneumothorax (PSP) management continues to lack paediatric-specific guideline recommendations. There have been increasing reports of paediatric retrospective case studies supplemented by important well designed RCT (predominantly) adult studies. Taken together, these suggest that conservative management may have an increasing role to play in the management of PSP and that aspiration may have limited utility as a first line intervention. Our local experience, as part of a multicentre retrospective analysis and subsequent audit of management since, corroborates recent published data: it highlights an increasing trend towards conservative management in spontaneous pneumothorax with similar rates of recurrence, compared to intervention, and low use of aspiration with similarly low success rates. We have therefore updated our local practice guidelines and share these with readers. Specifically, we have removed aspiration in the management of primary spontaneous pneumothorax and reserved intervention for children who are clinically unstable or show evidence of increasing air leak irrespective of pneumothorax size. Whilst the success of this change in clinical practice will need to be reviewed in the next 5-10 years, the overall low incidence of the condition, demands a multicentre, and probably multinational, collaborative approach to allow the best chance of obtaining definitive evidence to guide clinical paediatric management.
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http://dx.doi.org/10.1016/j.prrv.2021.08.001DOI Listing
August 2021

Cord blood group 2 innate lymphoid cells are associated with lung function at 6 weeks of age.

Clin Transl Immunology 2021 21;10(7):e1296. Epub 2021 Jul 21.

Priority Research Centre GrowUpWell® - Hunter Medical Research Institute The University of Newcastle Newcastle NSW Australia.

Objective: Offspring born to mothers with asthma in pregnancy are known to have lower lung function which tracks with age. Human group 2 innate lymphoid cells (ILC2) accumulate in foetal lungs, at 10-fold higher levels compared to adult lungs. However, there are no data on foetal ILC2 numbers and the association with respiratory health outcomes such as lung function in early life. We aimed to investigate cord blood immune cell populations from babies born to mothers with asthma in pregnancy.

Methods: Cord blood from babies born to asthmatic mothers was collected, and cells were stained in whole cord blood. Analyses were done using traditional gating approaches and computational methodologies (t-distributed stochastic neighbour embedding and PhenoGraph algorithms). At 6 weeks of age, the time to peak tidal expiratory flow as a percentage of total expiratory flow time (tPTEF/tE%) was determined as well as Lung Clearance Index (LCI), during quiet natural sleep.

Results: Of 110 eligible infants (March 2017 to November 2019), 91 were successfully immunophenotyped (82.7%). Lung function was attempted in 61 infants (67.0%), and 43 of those infants (70.5% of attempted) had technically acceptable tPTEF/tE% measurements. Thirty-four infants (55.7% of attempted) had acceptable LCI measurements. Foetal ILC2 numbers with increased expression of chemoattractant receptor-homologous molecule (CRTh2), characterised by two distinct analysis methodologies, were associated with poorer infant lung function at 6 weeks of age."

Conclusion: Foetal immune responses may be a surrogate variable for or directly influence lung function outcomes in early life.
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http://dx.doi.org/10.1002/cti2.1296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292948PMC
July 2021

Exposure to Stress and Air Pollution from Bushfires during Pregnancy: Could Epigenetic Changes Explain Effects on the Offspring?

Int J Environ Res Public Health 2021 07 13;18(14). Epub 2021 Jul 13.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW 2308, Australia.

Due to climate change, bushfires are becoming a more frequent and more severe phenomenon which contributes to poor health effects associated with air pollution. In pregnancy, environmental exposures can have lifelong consequences for the fetus, but little is known about these consequences in the context of bushfire smoke exposure. In this review we summarise the current knowledge in this area, and propose a potential mechanism linking bushfire smoke exposure in utero to poor perinatal and respiratory outcomes in the offspring. Bushfire smoke exposure is associated with poor pregnancy outcomes including reduced birth weight and an increased risk of prematurity. Some publications have outlined the adverse health effects on young children, particularly in relation to emergency department presentations and hospital admissions for respiratory problems, but there are no studies in children who were exposed to bushfire smoke in utero. Prenatal stress is likely to occur as a result of catastrophic bushfire events, and stress is known to be associated with poor perinatal and respiratory outcomes. Changes to DNA methylation are potential epigenetic mechanisms linking both smoke particulate exposure and prenatal stress to poor childhood respiratory health outcomes. More research is needed in large pregnancy cohorts exposed to bushfire events to explore this further, and to design appropriate mitigation interventions, in this area of global public health importance.
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http://dx.doi.org/10.3390/ijerph18147465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305161PMC
July 2021

A Short extension to multiple breath washout provides additional signal of distal airway disease in people with CF: A pilot study.

J Cyst Fibros 2021 Jul 15. Epub 2021 Jul 15.

Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, Manresa Rd, London, United Kingdom; European Cystic Fibrosis Society Lung Clearance Index Core Facility, London, United Kingdom.

Background: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI).

Methods: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCI). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores.

Results: HC/ CF group differences were larger with LCI than LCI (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI. Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCI 2.5% LCI). PEx signal was significantly greater for LCI both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCI correlated with mucus plugging.

Conclusions: UVLU captured within the LCI varies between individuals; the lack of relationship with LCI demonstrates that new, additional information is being captured. LCI repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status.
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http://dx.doi.org/10.1016/j.jcf.2021.06.013DOI Listing
July 2021

Update in Pediatrics 2020.

Am J Respir Crit Care Med 2021 08;204(3):274-284

Department of Respiratory Medicine, Children's Hospital at Westmead, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1164/rccm.202103-0605UPDOI Listing
August 2021

Improved agreement between N and SF multiple-breath washout in healthy infants and toddlers with improved EXHALYZER D sensor performance.

J Appl Physiol (1985) 2021 07 27;131(1):107-118. Epub 2021 May 27.

Danish Paediatric Pulmonary Service, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Recent studies indicate limited utility of nitrogen multiple-breath washout (NMBW) in infancy and advocate for using sulfur hexafluoride (SF) MBW in this age-group. Modern NMBW systems, such as EXHALYZER D (ECO MEDICS AG, Duernten, Switzerland), use O and CO sensors to calculate N concentrations (in principle, N% = 100 - CO% - O%). High O and CO concentrations have now been shown to significantly suppress signal output from the other sensor, raising apparent N concentrations. We examined whether improved EXHALYZER D N signal, accomplished after thorough examination of this CO and O interaction on gas sensors and its correction, leads to better agreement between NMBW and SFMBW in healthy infants and toddlers. Within the same session, 52 healthy children aged 1-36 mo [mean = 1.30 (SD = 0.72) yr] completed SFMBW and NMBW recordings (EXHALYZER D, SPIROWARE version 3.2.1) during supine quiet sleep. SF and N SPIROWARE files were reanalyzed offline with in-house software using identical algorithms as in SPIROWARE with or without application of the new correction factors for NMBW provided by ECO MEDICS AG. Applying the improved N signal significantly reduced mean [95% confidence interval (CI)] differences between NMBW and SFMBW recorded functional residual capacity (FRC) and lung clearance index (LCI): for FRC, from 26.1 (21.0, 31.2) mL, < 0.0001, to 1.18 (-2.3, 4.5) mL, = 0.5, and for LCI, from 1.86 (1.68, 2.02), < 0.001, to 0.44 (0.33, 0.55), < 0.001. Correction of N signal for CO and O interactions on gas sensors resulted in markedly closer agreement between NMBW and SFMBW outcomes in healthy infants and toddlers. Modern nitrogen multiple-breath washout (NMBW) systems such as EXHALYZER D use O and CO sensors to calculate N concentrations. New corrections for interactions between high O and CO concentrations on the gas sensors now provide accurate N signals. The correct N signal led to much improved agreement between NMBW and sulfur hexafluoride (SF) MBW functional residual capacity (FRC) and lung clearance index (LCI) in 52 sleeping healthy infants and toddlers, suggesting a role for NMBW in this age-group.
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http://dx.doi.org/10.1152/japplphysiol.00129.2021DOI Listing
July 2021

Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis.

Thorax 2021 Apr 29. Epub 2021 Apr 29.

Department of Respiratory Medicine, Children's Hospital at Westmead, Westmead, New South Wales, Australia

Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of 'normal' (FEV≥90% predicted) and 'mild lung disease' (FEV 70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled 'Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis', was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216085DOI Listing
April 2021

Further considerations on normative data for multiple breath washout outcomes.

Eur Respir J 2021 04 22;57(4). Epub 2021 Apr 22.

Dept of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia.

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http://dx.doi.org/10.1183/13993003.04536-2020DOI Listing
April 2021

Tobramycin and Colistin display anti-inflammatory properties in CuFi-1 cystic fibrosis cell line.

Eur J Pharmacol 2021 Jul 20;902:174098. Epub 2021 Apr 20.

Respiratory Technology, The Woolcock Institute of Medical Research, Glebe, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. Electronic address:

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and H NMR. HRMS showed pairing of Ibuprofen and Tobramycin, further confirmed by H NMR whilst no pairing was observed for either Ibuprofen:Colistin or Ibuprofen:Tadim combinations. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa showed that neither paired nor non-paired Ibuprofen:antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was next determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of Ibuprofen:Tobramycin combination was observed between the two concentrations due to changes in the structural conformation of the paired Ibuprofen:Tobramycin complex at High concentration, confirmed by H NMR. In contrast, the non-pairing of the Ibuprofen:Colistin and Ibuprofen:Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics.
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http://dx.doi.org/10.1016/j.ejphar.2021.174098DOI Listing
July 2021

Reply: Fixed breathing protocols in multiple-breath-washout testing: truly an option in children?

Eur Respir J 2021 03 4;57(3). Epub 2021 Mar 4.

Respiratory Division, University Hospital UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

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http://dx.doi.org/10.1183/13993003.00189-2021DOI Listing
March 2021

Maternal asthma is associated with reduced lung function in male infants in a combined analysis of the BLT and BILD cohorts.

Thorax 2021 Feb 25. Epub 2021 Feb 25.

Priority Research Centre GrowUpWell, University of Newcastle, Callaghan, New South Wales, Australia

Rationale: Asthma in pregnancy is associated with respiratory diseases in the offspring.

Objective: To investigate if maternal asthma is associated with lung function in early life.

Methods: Data on lung function measured at 5-6 weeks of age were combined from two large birth cohorts: the Bern Infant Lung Development (BILD) and the Australian Breathing for Life Trial (BLT) birth cohorts conducted at three study sites (Bern, Switzerland; Newcastle and Sydney, Australia). The main outcome variable was time to reach peak tidal expiratory flow as a percentage of total expiratory time(tPTEF:tE%). Bayesian linear hierarchical regression analyses controlling for study site as random effect were performed to estimate the effect of maternal asthma on the main outcome, adjusting for sex, birth order, breast feeding, weight gain and gestational age. In separate adjusted Bayesian models an interaction between maternal asthma and sex was investigated by including an interaction term.

Measurements And Main Results: All 406 BLT infants were born to mothers with asthma in pregnancy, while 193 of the 213 (91%) BILD infants were born to mothers without asthma. A significant interaction between maternal asthma and male sex was negatively associated with tPTEF:tE% (intercept 37.5; estimate: -3.5; 95% credible interval -6.8 to -0.1). Comparing the model posterior probabilities provided decisive evidence in favour of an interaction between maternal asthma and male sex (Bayes factor 33.5).

Conclusions: Maternal asthma is associated with lower lung function in male babies, which may have lifelong implications on their lung function trajectories and future risk of wheezing and asthma.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215526DOI Listing
February 2021

Controlled free breathing for multiple breath nitrogen washout in healthy adults.

ERJ Open Res 2021 Jan 25;7(1). Epub 2021 Jan 25.

Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW, Australia.

Multiple breath nitrogen washout (MBNW) quantifies ventilation heterogeneity. Two distinct protocols are currently used for MBNW testing: "controlled breathing", with targeted tidal volume ( ) and respiratory rate (RR); and "free breathing", with no constraints on breathing pattern. Indices derived from the two protocols (functional residual capacity (FRC), lung clearance index (LCI), , ) have not been directly compared in adults. We aimed to determine whether MBNW indices are comparable between protocols, to identify factors underlying any between-protocol differences and to determine the between-session variabilities of each protocol. We performed MBNW testing by both protocols in 27 healthy adult volunteers, applying the currently proposed correction for to and derived from free breathing. To establish between-session variability, we repeated testing in 15 volunteers within 3 months. While FRC was comparable between controlled free breathing (3.17 (0.98) 3.18 (0.94) L, p=0.88), indices of ventilation heterogeneity derived from the two protocols were not, with poor correlation for (r=0.18, p=0.36) and significant bias for (0.057 (0.021) L 0.085 (0.038) L, p=0.0004). Between-protocol differences in were related to differences in the breathing pattern, (p=0.004) and RR (p=0.01), rather than FRC. FRC and LCI showed good between-session repeatability, but and from free breathing showed poor repeatability with wide limits of agreement. These findings have implications for the ongoing clinical implementation of MBNW, as they demonstrate that and from free breathing, despite correction, are not equivalent to the controlled breathing protocol. The poor between-session repeatability of during free breathing may limit its clinical utility.
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http://dx.doi.org/10.1183/23120541.00435-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836463PMC
January 2021

Rhinovirus bronchiolitis, maternal asthma, and the development of asthma and lung function impairments.

Pediatr Pulmonol 2021 02 24;56(2):362-370. Epub 2020 Nov 24.

University of Newcastle, Callaghan, New South Wales, Australia.

Background: Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing subsequent asthma. Maternal asthma might also increase this risk. The aim of this study was to investigate the combined effects of hospitalization for RV positive bronchiolitis in infancy and a history of maternal asthma on the development of asthma at preschool age.

Methods: This is a prospective cohort study of 139 preschool-aged children, with a history of hospital admission for bronchiolitis in infancy, followed-up to ascertain asthma and asthma-like symptoms, skin prick allergy test positivity, and lung function measured pre- and post-bronchodilator using impulse oscillometry.

Results: Children with a past hospitalization for RV positive bronchiolitis (42.4% of all) and a history of maternal asthma (36.7% of all) had the greatest prevalence and risk ratio (RR) for doctor-diagnosed asthma (prevalence 81.8% and RR 2.10, 95% confidence interval [CI] 1.37-3.19, p = .001), use of inhaled corticosteroids (68.2% and RR 2.17, 95% CI 1.19-3.99, p = .001) and short-acting β-agonists in the last 12 months (95.2% and RR 1.49, 95% CI 1.17-1.89, p = .001), as compared to those with RV negative bronchiolitis and no maternal asthma history. More children in this group had an abnormal airway resistance (33.3% and adjusted risk ratio [aRR] 3.11, 95% CI 1.03-9.47, p = .045) and reactance (27.8% and aRR 2.11, 95% CI 1.06-4.26, p = .035) at 5 Hz, as compared to those with RV negative bronchiolitis and no maternal asthma history.

Conclusion: Hospitalization for RV positive bronchiolitis in early life combined with a history of maternal asthma identifies a subgroup of children with a high asthma burden while participants with only one of the two risk factors had intermediate risk for asthma.
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http://dx.doi.org/10.1002/ppul.25165DOI Listing
February 2021

Mitigating increased variability of multiple breath washout indices due to tidal breathing.

Eur Respir J 2021 02 17;57(2). Epub 2021 Feb 17.

Respiratory Division, University Hospital UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

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http://dx.doi.org/10.1183/13993003.02765-2020DOI Listing
February 2021

End-expiratory lung volume remains stable during N MBW in healthy sleeping infants.

Physiol Rep 2020 08;8(16):e14477

Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, NSW, Australia.

We have previously shown that functional residual capacity (FRC) and lung clearance index were significantly greater in sleeping healthy infants when measured by N (nitrogen) washout using 100% O (oxygen) versus 4% SF (sulfur hexafluoride) washout using air. Following 100% O exposure, tidal volumes decreased by over 30%, while end-expiratory lung volume (EELV, i.e., FRC) rose markedly based on ultrasonic flow meter assessments. In the present study to investigate the mechanism behind the observed changes, N MBW was performed in 10 separate healthy full-term spontaneously sleeping infants, mean (range) 26 (18-31) weeks, with simultaneous EELV monitoring (respiratory inductance plethysmography, RIP) and oxygen uptake (V´O ) assessment during prephase air breathing, during N washout by exposure to 100% O , and subsequently during air breathing. While flow meter signals suggested a rise in ELLV by mean (SD) 26 (9) ml over the washout period, RIP signals demonstrated no EELV change. V'O /FRC ratio during air breathing was mean (SD) 0.43 (0.08)/min, approximately seven times higher than that calculated from adult data. We propose that our previously reported flow meter-based overestimation of EELV was in fact a physiological artifact caused by rapid and marked movement of O across the alveolar capillary membrane into the blood and tissue during 100% O exposure, without concomitant transfer of N to the same degree in the opposite direction. This may be driven by the high observed O consumption and resulting cardiac output encountered in infancy. Furthermore, the low resting lung volume in infancy may make this error in lung volume determination by N washout relatively large.
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http://dx.doi.org/10.14814/phy2.14477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448799PMC
August 2020

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

Pharmacol Res 2020 09 19;159:105029. Epub 2020 Jun 19.

Airway Physiology and Imaging Group and Woolcock Emphysema Centre, The Woolcock Institute of Medical Research, The University of Sydney, Glebe NSW 2037, Australia; Faculty of Medicine and Health Sciences, The University of Sydney, NSW 2006, Australia.

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.
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http://dx.doi.org/10.1016/j.phrs.2020.105029DOI Listing
September 2020

Clinical and lung function outcomes in a cohort of children with severe asthma.

BMC Pulm Med 2020 Mar 18;20(1):66. Epub 2020 Mar 18.

Priority Research Centre GrowUpWell, Hunter Medical Research Institute, University of Newcastle, Lookout Road, New Lambton, 2305, Australia.

Background: Uncontrolled severe asthma in children is burdensome and challenging to manage. This study aims to describe outcomes in children with uncontrolled severe asthma managed in a nurse-led severe asthma clinic (SAC).

Methods: This retrospective analysis uses data collected from children referred by a paediatric respiratory specialist to a nurse-led SAC for uncontrolled severe asthma between 2014 and 2019. The pre-clinical assessments included a home visit to assess modifiable factors that could be addressed to improve control. A comprehensive lung function analysis was conducted at each visit. Interventions were personalised and included biologic agents. Statistical analysis was performed using nonparametric, two-tailed Mann-Whitney U-test, the parametric Student's t-test, or analysis of variance (ANOVA) as appropriate.

Results: Twenty-three children with a median age of 12 years were seen once, and 16 were followed up. Compared to a non-asthmatic (NA) and asthmatic (A) age-matched cohort, children with severe asthma (SA) had a lower FEV1, and FVC% predicted before and after bronchodilator inhalation, and a higher mean Lung Clearance Index [LCI] (10.5 [SA] versus 7.3 [NA] versus 7.6 [A], p = 0.003). Almost 80% of children with SA had an abnormal LCI, and 48% had a reduced FEV1% at the first SAC visit. Asthma control and FEV1% predicted significantly improved at a follow-up visit, while LCI remained abnormal in the majority of children (83%).

Conclusion: Over time, many children with severe asthma showed improved clinical outcomes and lung function while lung ventilation inhomogeneities persisted. Future appropriately controlled studies are required to determine if a nurse-led multidisciplinary SAC is associated with better outcomes.
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http://dx.doi.org/10.1186/s12890-020-1101-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081619PMC
March 2020

Integrating the multiple breath washout test into international multicentre trials.

J Cyst Fibros 2020 07 24;19(4):602-607. Epub 2019 Nov 24.

Translational Medicine, Hospital for Sick Children, Toronto, Canada; University of Toronto, Toronto, Canada. Electronic address:

Background: The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials.

Methods: Here we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial.

Results: Three regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data. One hundred and thirty-two naïve operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing.  Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%).

Conclusion: With this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome.
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http://dx.doi.org/10.1016/j.jcf.2019.11.006DOI Listing
July 2020

Effect of change of body position in spontaneous sleeping healthy infants on SF-based multiple breath washout.

Eur Respir J 2019 12 4;54(6). Epub 2019 Dec 4.

Dept of Pediatrics, Central Hospital, Skövde, Sweden.

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http://dx.doi.org/10.1183/13993003.00259-2019DOI Listing
December 2019

Long-term morbidity of respiratory viral infections during chemotherapy in children with leukaemia.

Pediatr Pulmonol 2019 11 8;54(11):1821-1829. Epub 2019 Aug 8.

Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia.

Background: Respiratory viruses are a common cause of infection in immunosuppressed children undergoing cancer therapy. Pulmonary sequelae have been documented following respiratory viral infections (RVIs) in hematopoietic stem cell transplant (HSCT) recipients; however potential late effects in children undergoing nonmyeloablative chemotherapy have not been investigated.

Aim: To evaluate the long-term pulmonary morbidity of respiratory viral infections during chemotherapy in children with acute lymphoblastic leukemia (ALL).

Methods: Childhood ALL survivors, aged 7 to 18 years, greater than 6 months posttreatment were recruited. Exclusion criteria included HSCT or proven bacterial/fungal respiratory infection during treatment. Subjects were classified into "viral" or "control" groups according to retrospective medical records that documented the presence of laboratory-proven RVIs during chemotherapy. Symptom questionnaires (Liverpool, ISAAC) and lung function testing (spirometry, plethysmography, diffusing capacity, forced oscillation technique to ATS/ERS standards) were then performed cross-sectionally at the time of recruitment.

Results: Fifty-four patients (31 viral, 23 control) were recruited: median (range) age 11.2 (7.2-18.1) years, and at 4.9 (0.5-13) years posttherapy. Abnormalities were detected in 17 (31%) individuals (8 viral, 9 control), with the most common being DLCO impairment (3 viral, 4 control) and reduced respiratory reactance at 5 Hz (5 viral, 6 control). Children with RVIs during chemotherapy reported more current respiratory symptoms, particularly wheeze (odds ratio [OR], 3.0; 95% confidence interval [CI]: 0.9-10.0; P = .09) and cough (OR, 2.7; 95% CI: 0.8-9.5; P = .11). No differences in lung function tests were observed between the two groups.

Conclusions: Our study found children with RVIs during chemotherapy developed more long-term respiratory symptoms than controls; however, differences did not reach statistical significance. No differences in static lung function were found between the two groups. Overall, pulmonary abnormalities and/or significant ongoing respiratory symptoms were detected in nearly a third of ALL survivors treated without HSCT. Larger, prospective studies are warranted to evaluate the etiology and clinical significance of these findings.
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http://dx.doi.org/10.1002/ppul.24456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167615PMC
November 2019

Does asplenia make some immunisations obligatory?

J Paediatr Child Health 2019 May;55(5):499-501

Children's Hospital at Westmead, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/jpc.14418DOI Listing
May 2019

Disease caused by non-tuberculous mycobacteria in children with cystic fibrosis.

Paediatr Respir Rev 2019 Feb 19;29:42-52. Epub 2018 May 19.

Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.

Non-tuberculous mycobacterial (NTM) (especially M. abscessus complex) infections pose a considerable challenge in the management of lung disease in patients with cystic fibrosis (CF). The apparent increase in prevalence is likely multifactorial. Emergent evidence of patient-to-patient transmission and isolation of highly resistant strains is a concern for all CF centers around the world. Treatment is often long and burdensome with multiple agents. Treatment side effects are frequent and can cause significant morbidity. Although consensus guidelines provide some direction, many units are faced with the challenges of: finding drug combinations for highly resistant strains; dealing with interruptions of treatment; discussing additional facilitating procedures in the form of gastrostomy and long-term vascular access devices; as well as supporting families emotionally and psychologically through the process.
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http://dx.doi.org/10.1016/j.prrv.2018.05.001DOI Listing
February 2019

Contribution of peripheral airway function to changes in FEV/FVC and RV/TLC with aging.

J Appl Physiol (1985) 2018 11 23;125(5):1378-1383. Epub 2018 Aug 23.

The Woolcock Institute of Medical Research, The University of Sydney, Glebe, NSW, Australia.

Multiple breath nitrogen washout (MBNW) indices provide insight into ventilation heterogeneity globally [lung clearance index (LCI)] and within acinar (S) and conducting (S) airways. Normal aging leads to an accelerated deterioration of S in older adults, but little is known about the contribution of peripheral airway function to changes in pulmonary function indices reflecting expiratory airflow [forced expiratory volume in one second (FEV)/forced vital capacity (FVC)] and gas trapping [residual volume (RV)/total lung capacity (TLC)] with aging. We aimed to examine associations between MBNW and FEV/FVC as well as RV/TLC in healthy adults, and to determine if these relationships differ in older (≥50 yr) versus younger subjects (<50 yr). Seventy-nine healthy adult volunteers aged 23-89 yr with no cardiac or respiratory disease and a smoking history of <5 pack-years underwent spirometry, plethysmography, and MBNW. After adjustment for sex, height, and body mass index, the following relationships were present across the entire cohort: S was inversely related to FEV/FVC (R = 0.22, P < 0.001); S and S were positively related to RV/TLC (R = 0.53, P < 0.001); on separate analyses, the relationship between S and FEV/FVC was strongest in the older group (R = 0.20, P = 0.003) but markedly weaker in the younger group (R = 0.09, P = 0.04); and S and S were related to RV/TLC in older (R = 0.20, P = 0.003) but not younger subgroups. No relationships were observed between LCI and FEV/FVC or RV/TLC. Changes in FEV/FVC and RV/TLC are at least in part due to changes in peripheral airway function with aging. Further studies of the relationships between MBNW and standard pulmonary function indices may prove useful for their combined application and interpretation in obstructive airways disease. NEW & NOTEWORTHY This study explores associations between multiple breath nitrogen washout (MBNW) and standard pulmonary function indices reflecting expiratory airflow [forced expiratory volume in one second (FEV)/forced vital capacity (FVC)] and gas trapping [residual volume (RV)/total lung capacity (TLC)] in healthy adults across a wide range of ages. We have demonstrated statistically significant relationships between MBNW and FEV/FVC as well as RV/TLC. These findings provide novel evidence of the contribution of peripheral airway function to changes in standard pulmonary function indices with aging.
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http://dx.doi.org/10.1152/japplphysiol.00114.2018DOI Listing
November 2018

Ventilation inhomogeneity and NO and CO diffusing capacity in ex-premature school children.

Respir Med 2018 07 6;140:94-100. Epub 2018 Jun 6.

Danish Pediatric Pulmonary Service, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Electronic address:

Aim: Ex-premature school children show mild-to-moderate airway obstruction and decreased CO diffusing capacity. Multiple breath nitrogen washout (N2MBW) and NO diffusing capacity (DLNO) measurements may provide new insight into long-term pulmonary and vascular impairment in bronchopulmonary dysplasia (BPD).

Methods: We examined a randomly selected group of 70 ex-premature children (gestational age <28 weeks or birth weight <1500 g; 42 with and 28 without BPD) and 38 term-born healthy controls of 8-13 years of age. Subjects performed N2MBW (lung clearance index, LCI; Sacin, and Scond), DLNO (membrane related diffusing capacity, Dm and pulmonary capillary volume, Vc), Fractional exhaled NO, CO diffusing capacity, conventional spirometry (FEV1, FVC, FEF25-75) and plethysmography (RV, TLC). Respiratory symptoms were assessed by questionnaire.

Results: Compared to healthy controls, the BPD group had higher z-scores for lung clearance index (P = 0.003), Sacin (P = 0.005), lower CO diffusing capacity (P = 0.025), DLNO (P = 0.022), DLNO/VA z-scores (P = 0.025) and a significant larger proportion had respiratory complaints. Amongst ex-premature children, the BPD group did not differ from the non-BPD group except for a decreased Dm (P = 0.023). Ex-premature with BPD showed predominantly airway obstruction (FEV1/FVC; P < 0.0001), signs of hyperinflation (RV/TLC-ratio; P = 0.028), and 25% had a positive bronchodilator response (>12% in FEV1).

Conclusion: Ex-premature school children exhibited relatively mild but significant long-term respiratory symptoms and pulmonary peripheral impairment judged by N2MBW and DLNO measurements along with well-known airway obstruction. Larger longitudinal studies are needed to assess the clinical use of these advanced methods of assessing ventilation inhomogeneity and DLNO.
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http://dx.doi.org/10.1016/j.rmed.2018.06.006DOI Listing
July 2018

Highly efficient all-optical beam modulation utilizing thermo-optic effects.

Opt Express 2018 Apr;26(8):9502-9514

Suspensions of plasmonic nanoparticles can diffract optical beams due to the combination of thermal lensing and self-phase modulation. Here, we demonstrate extremely efficient optical continuous wave (CW) beam switching across the visible range in optimized suspensions of 5-nm Au and Ag nanoparticles in non-polar solvents, such as hexane and decane. On-axis modulation of greater than 30 dB is achieved at incident beam intensities as low as 100 W/cm with response times under 200 μs, at initial solution transparency above 70%. No evidence of laser-induced degradation is observed for the highest intensities used. Numerical modeling of experimental data reveals thermo-optic coefficients of up to -1.3 × 10 /K, which, to our knowledge, is the highest observed to date in such nanoparticle suspensions.
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http://dx.doi.org/10.1364/OE.26.009502DOI Listing
April 2018

Osteoarthritis and arthroplasty of the hip and knee.

Br J Hosp Med (Lond) 2018 Apr;79(4):C54-C59

Consultant, Department of Trauma and Orthopaedics, Salisbury District Hospital, Salisbury.

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http://dx.doi.org/10.12968/hmed.2018.79.4.C54DOI Listing
April 2018

Spontaneous Pneumothorax in a Young Child With Pulmonary Tuberculosis.

Pediatr Infect Dis J 2018 12;37(12):e343-e345

Department of Respiratory Medicine, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

We report a 2-year-old, previously healthy boy, who presented with chronic pneumonia. He was diagnosed with culture-confirmed pulmonary tuberculosis. Complications included spontaneous pneumothorax presumed to be secondary to cavity formation and complete subsegmental airway obstruction that did not resolve with prolonged oral corticosteroid treatment.
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http://dx.doi.org/10.1097/INF.0000000000002018DOI Listing
December 2018

Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma.

J Allergy Clin Immunol 2018 12 8;142(6):1765-1772.e4. Epub 2018 Mar 8.

Priority Research Centre GrowUpWell, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia; School of Medicine and Public Health, University of Newcastle, Newcastle, Australia; Department of Paediatric Respiratory and Sleep Medicine, John Hunter Children's Hospital, Newcastle, Australia. Electronic address:

Background: The single-center double-blind, randomized controlled Managing Asthma in Pregnancy (MAP) trial in Newcastle, Australia, compared a treatment algorithm using the fraction of exhaled nitric oxide (FENO) in combination with asthma symptoms (FENO group) against a treatment algorithm using clinical symptoms only (clinical group) in pregnant asthmatic women (Australian New Zealand Clinical Trials Registry, no. 12607000561482). The primary outcome was a 50% reduction in asthma exacerbations during pregnancy in the FENO group. However, the effect of FENO-guided management on the development of asthma in the offspring is unknown.

Objective: We sought to investigate the effect of FENO-guided asthma management during pregnancy on asthma incidence in childhood.

Methods: A total of 179 mothers consented to participate in the Growing into Asthma (GIA) double-blind follow-up study with the primary aim to determine the effect of FENO-guided asthma management on childhood asthma incidence.

Results: A total of 140 children (78%) were followed up at 4 to 6 years of age. FENO-guided as compared to symptoms-only approach significantly reduced doctor-diagnosed asthma (25.9% vs 43.2%; odds ratio [OR], 0.46, 95% CI, 0.22-0.96; P = .04). Furthermore, frequent wheeze (OR, 0.27; 95% CI, 0.09-0.87; P = .03), use of short-acting β-agonists (OR, 0.49; 95% CI, 0.25-0.97; P = .04), and emergency department visits for asthma (OR, 0.17; 95% CI, 0.04-0.76; P = .02) in the past 12 months were less common in children born to mothers from the FENO group. Doctor-diagnosed asthma was associated with common risk alleles for early onset asthma at gene locus 17q21 (P = .01 for rs8069176; P = .03 for rs8076131), and higher airways resistance (P = .02) and FENO levels (P = .03). A causal mediation analysis suggested natural indirect effects of FENO-guided asthma management on childhood asthma through "any use" and "time to first change in dose" of inhaled corticosteroids during the MAP trial (OR: 0.83; 95% CI: 0.59-0.99, and OR: 0.90; 95% CI: 0.70-1.03, respectively).

Conclusions: FENO-guided asthma management during pregnancy prevented doctor-diagnosed asthma in the offspring at preschool age, in part mediated through changes in use and dosing of inhaled corticosteroids during the MAP trial.
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http://dx.doi.org/10.1016/j.jaci.2018.02.039DOI Listing
December 2018

Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement.

Am J Respir Crit Care Med 2018 03;197(5):e1-e19

Background: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention.

Methods: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed.

Results: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work.

Conclusions: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.
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http://dx.doi.org/10.1164/rccm.201801-0074STDOI Listing
March 2018
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