ORCID Profile
0000-0002-5386-8482
Current Organisations
Perth Children's Hospital
,
Telethon Kids Institute
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Paediatrics | Public Health and Health Services | Epidemiology | Respiratory Diseases
ANZSRC Socio-Economic Objective (SEO)
Respiratory system and diseases (incl. asthma) | Air quality | Child health |
Related Links
Publications
Clinical trials in infants with cystic fibrosis detected following newborn screening
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.PRRV.2008.05.004
Abstract: Despite the wide implementation of newborn screening for cystic fibrosis there have been few clinical trials aimed at reducing the burden of lung disease in screened infants. Emerging tools such as infant lung function and low-dose computed tomography (CT) provide early indicators of lung disease and could be effective outcome measures in randomized controlled trials (RCTs) of interventions that aim to delay or prevent the onset of bronchiectasis. The most recent data suggest that strategies to reduce neutrophilic inflammation and prevent infection are good candidates for RCTs. However, cooperation between centres is needed if they are to be large enough to detect differences due to the intervention that otherwise may be masked by subtle differences in management practices between centres, and to detect rare but significant adverse effects.
Respiratory function in healthy young children using forced oscillations
Publisher: BMJ
Date: 06-2007
Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis
Publisher: European Respiratory Society (ERS)
Date: 17-09-2202
DOI: 10.1183/09031936.00043108
Abstract: When do infants and young children with cystic fibrosis acquire infection with Pseudomonas aeruginosa? Can this be eradicated when first detected? Children <6 yrs of age participated in an annual bronchoalveolar lavage (BAL)-based microbiological surveillance programme in Perth, Australia. When P. aeruginosa was detected, an eradication programme using combination treatment with i.v., oral and nebulised antibiotics was undertaken. Repeat BAL was performed 3 months following treatment, to assess eradication success. P. aeruginosa was detected in 33 (28.4%) children median (range) age at detection was 30.5 (3.3-71.4) months. P. aeruginosa was mucoid at detection in six (18.2%) out of 33 patients and associated with respiratory symptoms in 16 (48.5%) out of 33 children. In total, 26 children underwent eradication therapy, with P. aeruginosa eradicated in 20 (77%) out of 26 following one eradication cycle and in three (total 88%) additional children following a second cycle. Eradication was associated with a significant decrease in neutrophil elastase and interleukin-1beta in BAL fluid 12 months post eradication. Eradication of Pseudomonas aeruginosa infection is achievable in young children with cystic fibrosis for up to 5 yrs using combination i.v., oral and nebulised antibiotic therapy and is associated with reduced pulmonary inflammation 12 months post eradication.
Finite element modelling and analysis of composites toecaps
Publisher: IOP Publishing
Date: 08-2009
Innate inflammatory responses of pediatric cystic fibrosis airway epithelial cells: Effects of nonviral and viral stimulation
Publisher: American Thoracic Society
Date: 06-2011
Improved detection of obstructive events in childhood sleep apnoea with the use of the nasal cannula and the differentiated sum signal
Publisher: Wiley
Date: 12-2005
DOI: 10.1111/J.1365-2869.2005.00474.X
Abstract: The efficacy of the nasobuccal thermistor (NT) was compared with the nasal pressure cannula (NC) and the calibrated, time-differentiated respiratory inductance plethysmography sum signal (DS) in the detection of obstructive events in children during polysomnography (PSG). The overnight PSG of 20 consecutive referrals were selected for analysis. Obstructive events were scored in each study three times by one operator using a blinded procedure whereby either the NT, the NC or the DS was visible. The standard PSG channels were also visible. SPSS software was used for statistical analysis. Twenty patients aged 5 weeks to 16 years were studied. Agreement in obstructive apnoea-hypopnoea index (OAHI) was highest between the NT and NC, and the NC and DS. The NC signal was significantly more likely to be uninterpretable than the NT (P = 0.02) and this did not correlate with age. Event detection by the NT was significantly improved by the addition of either the NC (P = 0.01) or the DS (P = 0.001), while the NC stood alone unless the DS was added (P = 0.02). There was no significant difference in OAHI by the NC versus the DS. The NC detected significantly more OA than the NT or the DS (P = 0.04), while the DS trended towards detecting more OH. There was no significant difference in OAHI between any combination pair. The nasal cannula and differentiated sum signal perform better as measures of paediatric airflow than the NT. To optimize the detection of obstructive events in children we recommend using at least one, if not both these methods in paediatric sleep laboratories.
Flow-independent nitric oxide parameters in infants with and without recurrent wheeze
Publisher: European Respiratory Society (ERS)
Date: 09-2008
Reference Values for Acoustic Rhinometry in Children from 4 to 13 Years Old
Publisher: SAGE Publications
Date: 05-2008
Abstract: Despite a growing number of studies using acoustic rhinometry (AR) in children, no reference material exists that incorporates the entire age and height interval of preschool children up to puberty for a range of rhinometric variables. The aim of this study is to provide a reference range for nasal volumes and minimum cross-sectional areas (MCAs) in healthy nondecongested children aged 4-13 years old. Two hundred fifty-six primary school children (mean, 7.95 years range, 3.8-13.1 years 123 boys/133 girls) were measured by AR. Variables were MCA (first, second, and absolute minimum) and nasal volumes from 0 to 4 cm (Vol0-4), 0 to 5 cm (Vol0-5), 1 to 4 cm (Vol1-4), and 2 to 5 cm (Vol2-5) into the nasal cavity. Height and weight were measured and atopic status was determined by skin-prick test. Age and current and past respiratory health were recorded from a questionnaire. In multiple linear regression models height was the main predictor for all AR variables although weight also was a significant predictor of MCAs. There was no association between any AR variables with sex, atopy, or hay fever but children with current wheeze (within last 12 months) and asthma had decreased nasal patency. This article presents the most extensive current reference material for AR in nondecongested prepubescent healthy children. The presented reference material will facilitate the interpretation and evaluation of future and present epidemiologic studies based on AR in children.
The International Pharmacists-as-Immunizers Partnership (IPIP)—Advancing Research on Pharmacist-Administered Immunizations Worldwide
Publisher: MDPI AG
Date: 04-06-2019
Abstract: This article describes the formation of the International Pharmacists-as-Immunizers Partnership (IPIP), an international network of pharmacy practice researchers with an interest in pharmacist-administered immunizations. Using funds obtained from a university-sponsored grant, a two-day meeting was held at the University of Waterloo in Canada to discuss published and in-progress research on the topic, identify gaps and priorities for future research, and share implementation strategies used in different jurisdictions. Twelve researchers from five countries attended this initial meeting, identified from both personal networks and from authorship lists from published research. Small- and large-group discussions addressed a number of themes, including: clinical, economic and educational outcomes of the service the perspectives of pharmacists, patients, and other health professionals operational and policy factors influencing uptake safety and the immunizing pharmacist’s role in disaster preparedness. Feedback on our first meeting and outcomes achieved were evaluated on the basis of participant feedback. Key components of the meeting that were considered successful and important lessons learned are summarized, so that other like-minded researchers with a shared pharmacy practice research interest could consider leveraging funding opportunities to establish other international pharmacy practice research networks.
Role of high-resolution computed tomography in the detection of early cystic fibrosis lung disease
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.PRRV.2008.05.009
Abstract: High-resolution computed tomography (HRCT) has been demonstrated to be sensitive at detecting early lung disease in cystic fibrosis (CF), often before it is apparent clinically. There is emerging evidence that structural changes in the lung occur earlier in life than previously appreciated. Despite this, the role of HRCT in young children with CF has yet to be defined, principally because the repeated exposure of children to X-ray doses several multiples that of a standard chest X-ray raises the concern of the long-term risks of ionizing radiation. With the challenges of acquiring HRCT images in young children in mind, we review scanning protocols and settings specific to young children, and review the best available evidence that describes early structural lung disease in young children with CF. The role of CT scoring and quantitative measures of CF lung disease are reviewed. The challenge for the future is to develop techniques that provide clinically useful information at the lowest possible radiation risk.
Novel end points for clinical trials in young children with cystic fibrosis
Publisher: Informa UK Limited
Date: 06-2013
DOI: 10.1586/ERS.13.25
Air trapping in early cystic fibrosis lung disease—Does CT tell the full story?
Publisher: Wiley
Date: 06-07-2017
DOI: 10.1002/PPUL.23754
Abstract: Mosaic attenuation on expiratory chest computed tomography (CT) is common in early life cystic fibrosis (CF) and often referred to as "air trapping". It is presumed to be localized hyperinflation due to small airway obstruction. In order to test this assumption, we compared air trapping extent to lung volumes measured on CT in young children with CF. Children aged below 7 years undergoing inspiratory/expiratory CT were recruited from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis cohort. Automated lung segmentation was used to determine functional residual capacity (FRC), total lung capacity (TLC), and their ratio (FRC/TLC). Structural lung disease (%Disease) and air trapping (%TrappedAir) extent were assessed using PRAGMA-CF. Lung clearance index (LCI), an index of ventilation heterogeneity, was measured. Linear mixed model analysis was used to determine associations. Seventy-three scans from 55 patients were obtained. %TrappedAir was associated with %Disease (0.19 [0.07, 0.31] P = 0.003) and LCI (0.22 [0.04, 0.39] P = 0.016), but not FRC/TLC (0.00 [-0.02, 0.02] P = 0.931). CT mosaic attenuation is associated with CF lung disease, however it is not always accompanied by physiologic hyperinflation. Other pathologies may contribute to mosaic attenuation. A better understanding of these factors could guide future therapies.
Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis
Publisher: American Thoracic Society
Date: 04-2019
Measuring Exhaled Breath Condensates in Infants
Publisher: Wiley
Date: 02-2006
DOI: 10.1002/PPUL.20362
Abstract: There is growing interest in investigating compounds of exhaled breath condensates (EBC) as potential noninvasive markers of airways disease processes. Some of these markers have the potential to provide information on the early stages of disease. In this paper, we present a method for collecting EBC during both oral and nasal breathing in infants. Fifty-four infants (mean age, 13.3 months range, 1-30 months) undergoing infant lung-function testing were recruited for this study. Breath condensates were collected during sedated sleep, using a custom-made collection device. Collections were made for 10 min during normal tidal breathing. Nasal measurements were attempted in all children by placing a face-mask over the nose and mouth and keeping the mouth closed. In 14 infants, oral measurements were made by placing a face-mask over the mouth only and occluding the nose. Condensates were collected successfully in all but one child. The collected volume ranged from 50-550 microl (mean +/- SD, 281.8 +/- 145.8 microl). The volume of EBC collected was correlated to age, length, weight, and minute ventilation. Significantly more EBC was collected during oral compared to nasal breathing (354.3 vs. 277.5 microl, P=0.03). There were no significant changes in heart rate, respiratory rate, or oxygen saturation during collection. The collection of EBC in young children and infants is feasible and safe, and the method used here allows the successful collection of reasonable amounts of exhaled condensate.
Snoring in primary school children and domestic environment: A Perth school based study
Publisher: Springer Science and Business Media LLC
Date: 04-11-2004
Optimal design of sandwich panels made of wood veneer hollow cores
Publisher: Elsevier BV
Date: 28-02-2011
House dust mite induced lung inflammation does not alter circulating vitamin D levels
Publisher: Public Library of Science (PLoS)
Date: 12-11-2014
DNA methylation profiles of airway epithelial cells and PBMCs from healthy, atopic and asthmatic children.
Publisher: Public Library of Science (PLoS)
Date: 06-09-2012
Value of serology in predicting Pseudomonas aeruginosa infection in young children with cystic fibrosis
Publisher: BMJ
Date: 10-2010
Abstract: Early detection of Pseudomonas aeruginosa is essential for successful eradication. The accuracy of serum antibodies against specific and multiple P aeruginosa antigens at predicting lower airway infection in young children with cystic fibrosis (CF) was investigated. A commercial P aeruginosa multiple antigen (MAg) ELISA and an in-house exotoxin A (ExoA) ELISA were compared in two populations: a discovery population of 76 children (0.1-7.1 years) undergoing annual bronchoalveolar lavage (BAL)-based microbiological surveillance and a test population of 55 children (0.1-5.6 years) participating in the Australasian CF Bronchoalveolar Lavage Trial. In the discovery population, P aeruginosa was cultured from BAL fluid (≥10(5) colony-forming units (cfu)/ml) in 15/76 (19.7%) children (median age 1.88 years). Positive MAg and ExoA serological results were found in 38 (50.0%) and 30 (39.5%) children, respectively. Positive (PPV) and negative (NPV) predictive values for serology at diagnosing P aeruginosa infection (≥10(5) cfu/ml) were 0.14 and 0.99 respectively (MAg assay) and 0.11 and 0.98 (ExoA assay). In the test population, P aeruginosa was cultured from BAL fluid (≥10(5) cfu/ml) in 16/55 (29.1%) children (median age 1.86 years) and from oropharyngeal swabs in 32/36 (88.9%). Positive MAg and ExoA serology was detected in 19 (34.5%) and 33 (60.0%) children, respectively. The PPV and NPV of serology were 0.26 and 0.94 respectively (MAg assay) and 0.19 and 0.98 (ExoA assay) and were marginally higher for oropharyngeal cultures. Measuring serum antibody responses against P aeruginosa is of limited value for detecting early P aeruginosa infection in young children with CF.
Lung Disease at Diagnosis in Infants with Cystic Fibrosis Detected by Newborn Screening
Publisher: American Thoracic Society
Date: 15-07-2009
The hypoxia challenge test does not accurately predict hypoxia in flight in ex-preterm neonates
Publisher: Elsevier BV
Date: 05-2008
Abstract: Air travel may pose risks to ex-preterm neonates due to the low oxygen environment encountered during flights. We aimed to study the utility of the preflight hypoxia challenge test (HCT) to detect in-flight hypoxia in such infants. Ex-preterm (gestation < or = 35 completed weeks) infants ready for air transfer from the intensive/special care nursery to regional hospitals were studied. A pretransfer HCT was performed by exposing infants to 14% oxygen for 20 min. Failure was defined as a sustained fall in pulse oxygen saturation (Spo(2)) < or = 85%. A nurse blinded to the test result monitored the in-flight oxygen saturations in each infant. If Spo(2) fell to < or = 85%, oxygen was administered. Forty-six infants with median gestation of 32.2 weeks (range, 24 to 35.6 weeks) and birth weight of 1,667 g (range, 655 to 2,815 g) were recruited. No infants were receiving supplemental oxygen at the time of transfer. The HCT was performed at a median corrected age of 35.8 weeks (range, 33.1 to 43 weeks). Thirty-five infants (76%) passed the test, and the remainder failed. During the flight, 16 infants met the criteria for in-flight oxygen, but 12 of these infants (75%) had passed the preflight HCT. Of the 11 infants who failed the HCT, only 4 infants (36%) required in-flight oxygen. The HCT incorrectly predicted in-flight responses in 42% (19 of 46 infants). A significant percentage of ex-preterm neonates require in-flight oxygen supplementation. The HCT is not accurate for identifying which infants are at risk for in-flight hypoxia.
Spatial variability of particulates in homes: Implications for infant exposure
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.SCITOTENV.2007.01.060
Abstract: Personal monitoring of particulate matter (PM) exposure in infants is difficult. Indirect, microenvironment modelling methods are more practical. Infants spend most of their time indoors at home and the aim of this study was to investigate spatial variations in PM concentrations within homes. Three size fractions of PM - particles with an aerodynamic diameter of less than 10 microm (PM(10)), less than 2.5 microm (PM(2.5)) and total suspended particulates (TSP) - were monitored in the homes of 77 infants (0-2 years) using a multi-stage virtual impactor. In all homes PM was monitored simultaneously in the main living room at heights of 1.4 m and 0.2 m from the floor. In 26 of these homes monitoring was also conducted simultaneously in the infant's bedroom. Further, PM(10) was measured simultaneously in the living room, bedroom and child's cot in 14 homes using a real-time photometer. All homes in the study were non-smoking households. On average, there were no significant differences between concentrations of any of the different PM size fractions measured at the two heights (living room) and between living room and bedroom concentrations. However, there were only moderate correlations in concentrations between the different microenvironments and in some homes there was considerable variation between s ling sites. From the real-time measurements there seemed to be good agreement between concentrations measured in different rooms and in the cot and short-term peak concentrations at one s ling site were often mirrored at other sites. These results suggest that, although large variations in PM concentrations between rooms within homes can occur, a single monitoring station can provide a reasonable estimate of indoor concentrations.
Epithelial Mesenchymal Transition in Respiratory Disease
Publisher: Elsevier BV
Date: 06-2020
Azithromycin reduces airway inflammation induced by human rhinovirus in lung allograft recipients.
Publisher: Wiley
Date: 15-04-2019
DOI: 10.1111/RESP.13550
Abstract: Human rhinovirus (RV) is a common upper and lower respiratory pathogen in lung allograft recipients causing respiratory tract exacerbation and contributing towards allograft dysfunction and long-term lung decline. In this study, we tested the hypothesis that RV could infect both the small and large airways, resulting in significant inflammation. Matched large and small airway epithelial cells (AEC) were obtained from five lung allograft recipients. Primary cultures were established, and monolayers were infected with RV1b over time with varying viral titre. Cell viability, receptor expression, viral copy number, apoptotic induction and inflammatory cytokine production were also assessed at each region. Finally, the effect of azithromycin on viral replication, induction of apoptosis and inflammation was investigated. RV infection caused significant cytotoxicity in both large AEC (LAEC) and small AEC (SAEC), and induced a similar apoptotic response in both regions. There was a significant increase in receptor expression in the LAEC only post viral infection. Viral replication was elevated in both LAEC and SAEC, but was not significantly different. Prophylactic treatment of azithromycin reduced viral replication and d ened the production of inflammatory cytokines post-infection. Our data illustrate that RV infection is capable of infecting upper and lower AEC, driving cell death and inflammation. Prophylactic treatment with azithromycin was found to mitigate some of the detrimental responses. Findings provide further support for the prophylactic prescription of azithromycin to minimize the impact of RV infection.
Impact of lung disease on respiratory impedance in young children with cystic fibrosis
Publisher: European Respiratory Society (ERS)
Date: 24-09-2015
DOI: 10.1183/13993003.00156-2015
Abstract: This study aimed to evaluate the ability of the forced oscillation technique (FOT) to detect underlying lung disease in preschool children with cystic fibrosis (CF) diagnosed following newborn screening. 184 children (aged 3–6 years) with CF underwent lung function testing on 422 occasions using the FOT to assess respiratory resistance and reactance at the time of their annual bronchoalveolar lavage collection and chest computed tomography scan. We examined associations between FOT outcomes and the presence and progression of respiratory inflammation, infection and structural lung disease. Children with CF who had pronounced respiratory disease, including free neutrophil elastase activity, infection with pro-inflammatory pathogens and structural lung abnormalities had similar FOT outcomes to those children without detectable lung disease. In addition, the progression of lung disease over 1 year was not associated with worsening FOT outcomes. We conclude that the forced oscillation technique is relatively insensitive to detect underlying lung disease in preschool children with CF. However, FOT may still be of value in improving our understanding of the physiological changes associated with early CF lung disease.
Predicting disease progression in cystic fibrosis
Publisher: Informa UK Limited
Date: 13-09-2018
DOI: 10.1080/17476348.2018.1519400
Abstract: Progressive lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Methods of correctly predicting the future progression of lung disease in patients with CF are essential for directing aggressive treatment to prevent loss of lung function and end stage respiratory failure. Areas covered: This review addresses predictors of respiratory disease progression in patients with CF. We searched Web of Science and Medline, with no restriction on publication date, with the search terms 'cystic fibrosis' and 'disease progression', 'lung function decline', 'prognosis', 'prediction redictive', 'prediction rognostic scores', 'risk factors', 'outcome measures/endpoints/disease surrogate', 'longitudinal/long term', 'statistical model', and 'survival'. Expert commentary: Forced expiratory volume in 1 sec (FEV
Automatic bronchus and artery analysis on chest computed tomography to evaluate the effect of inhaled hypertonic saline in children aged 3-6 years with cystic fibrosis in a randomized clinical trial
Publisher: Elsevier BV
Date: 05-2023
Exhaled nitric oxide is not reduced in infants with cystic fibrosis
Publisher: European Respiratory Society (ERS)
Date: 02-2006
DOI: 10.1183/09031936.06.00071005
Abstract: Fractional exhaled nitric oxide (F(eNO)) has been reported to be reduced in cystic fibrosis (CF) patients. However, data from young children are conflicting and it is not clear whether this is a primary feature of the disease or a secondary response. The present study compared F(eNO) between CF and healthy infants using a validated single-breath technique. A total of 23 healthy infants (11 females mean age 40.1 weeks) and 18 infants with CF (nine females 64.9 weeks) underwent tests of lung function and F(eNO). Bronchoalveolar lavage (BAL) was collected from all CF infants 2-5 days after lung function testing. There was no significant difference in F(eNO) between the CF and healthy infants (geometric mean: 23.1 parts per billion (ppb) and 17.0 ppb, respectively). There was an inverse relationship between age and F(eNO) in the CF patients, but not in the healthy group. Within the CF group, there was no association between F(eNO) and any marker of airway inflammation measured in the BAL. Exhaled nitric oxide is not reduced in cystic fibrosis infants, but does decrease with age. The current data indicate that F(eNO) is not a good marker of airway inflammation in cystic fibrosis.
β2 -adrenoceptor polymorphisms and asthma phenotypes: Interactions with passive smoking
Publisher: European Respiratory Society (ERS)
Date: 14-03-2007
DOI: 10.1183/09031936.00123206
Abstract: The aim of the present study was to assess the effects of possible interactions between beta(2)-adrenoceptor gene polymorphisms and passive smoking on forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC) and exhaled nitric oxide (eNO) in children aged 11 yrs. A cross-sectional analysis of the longitudinal cohort was conducted for associations between beta(2)-adrenoceptor gene polymorphisms and lung function and eNO with regard to passive smoking. Among children exposed to tobacco smoke, those with Arg16 (at least one Arg allele) exhibited lower adjusted mean FEV(1) (2.19 versus 2.38 L) and FVC (2.43 versus 2.64 L) than Gly16 homozygotes. Those with Gln27 (at least one Gln allele) also exhibited a lower adjusted mean FEV(1) relative to Glu27 homozygotes (2.24 versus 2.39 L). Among children with no exposure to smoking, those with Arg16 or Gln27 showed lower adjusted geometric mean eNO levels compared with Gly16 homozygotes (15.4 versus 30.9 ppb) and Glu27 homozygotes (18.0 versus 49.7 ppb). In conclusion, passive smoking had a significant effect on associations between beta(2)-adrenoceptor gene polymorphisms and asthma-related phenotypes, enhancing the relationship between Arg16 and lung function and removing the relationship between Arg16 or Gln27 and exhaled nitric oxide levels.
Multi-modality monitoring of cystic fibrosis lung disease: The role of chest computed tomography
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.PRRV.2013.05.003
Abstract: Cystic fibrosis [CF] lung disease is characterized by progressive bronchiectasis and small airways disease. To monitor CF lung disease traditionally spirometry has been the most important modality. In addition to spirometry chest radiography was used to monitor progression of structural lung abnormalities. However, the importance of chest radiography in disease management has been limited due to its poor sensitivity and specificity to detect disease progression. Over the last decade chest CT has become the gold standard for monitoring the severity and progression of bronchiectasis. Small airways disease can be monitored using spirometry, multiple breath washout techniques, and chest CT. In modern CF-care a multi-modality approach is needed to monitor CF lung disease and to personalize treatment for the needs of the patient. When state-of-the-art low dose bi-annual chest CT protocols are used radiation risk is considered to be low. In between chest CT imaging, physiologic measures are important to obtain for monitoring. Stratification of monitoring protocols based on the risk profile of the patient can help us in the future to better care for people with CF.
Chest computed tomography: A validated surrogate endpoint of cystic fibrosis lung disease?
Publisher: European Respiratory Society (ERS)
Date: 20-12-2013
DOI: 10.1183/09031936.00051512
Abstract: Clinical trials for the treatment of cystic fibrosis (CF) lung disease are important to test and optimise new therapeutic interventions. To evaluate the effect of these interventions, sensitive and accurate outcome measures are needed. The most commonly used endpoints are spirometric variables such as the forced expiratory volume in 1 s and respiratory tract exacerbations. Unfortunately, these endpoints are relatively insensitive for monitoring progression of CF lung disease, and thus require a large number of patients when used in clinical studies. In addition, these endpoints are not suitable to study CF lung disease in young children. Chest computed tomography (CT) holds great promise for use as a sensitive surrogate endpoint in CF. A large body of evidence has been produced to validate the use of chest CT as a primary endpoint to study CF lung disease. However, before chest CT can be used in clinical trials, it has to be recognised as a validated surrogate endpoint by regulatory agencies. The aim of this review is to summarise what is currently known about the use of chest CT as surrogate endpoint in clinical trials in CF.
Airway tapering: an objective image biomarker for bronchiectasis
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1007/S00330-019-06606-W
Abstract: To estimate airway tapering in control subjects and to assess the usability of tapering as a bronchiectasis biomarker in paediatric populations. Airway tapering values were semi-automatically quantified in 156 children with control CTs collected in the Normal Chest CT Study Group. Airway tapering as a biomarker for bronchiectasis was assessed on spirometer-guided inspiratory CTs from 12 patients with bronchiectasis and 12 age- and sex-matched controls. Semi-automatic image analysis software was used to quantify intra-branch tapering (reduction in airway diameter along the branch), inter-branch tapering (reduction in airway diameter before and after bifurcation) and airway-artery ratios on chest CTs. Biomarkers were further stratified in small, medium and large airways based on three equal groups of the accompanying vessel size. Control subjects showed intra-branch tapering of 1% and inter-branch tapering of 24–39%. Subjects with bronchiectasis showed significantly reduced intra-branch of 0.8% and inter-branch tapering of 19–32% and increased airway–artery ratios compared with controls ( p 0.01). Tapering measurements were significantly different between diseased and controls across all airway sizes. Difference in airway–artery ratio was only significant in small airways. Paediatric normal values for airway tapering were established in control subjects. Tapering showed to be a promising biomarker for bronchiectasis as subjects with bronchiectasis show significantly less airway tapering across all airway sizes compared with controls. Detecting less tapering in larger airways could potentially lead to earlier diagnosis of bronchiectasis. Additionally, compared with the conventional airway–artery ratio, this novel biomarker has the advantage that it does not require pairing with pulmonary arteries. • Tapering is a promising objective image biomarker for bronchiectasis that can be extracted semi-automatically and has good correlation with validated visual scoring methods. • Less airway tapering was observed in patients with bronchiectasis and can be observed sensitively throughout the bronchial tree, even in the more central airways. • Tapering values seemed to be less influenced by variety in scanning protocols and lung volume making it a more robust biomarker for bronchiectasis detection.
Blocking Notch3 Signaling Abolishes MUC5AC Production in Airway Epithelial Cells from Asthmatics.
Publisher: American Thoracic Society
Date: 06-2202
The effects of in-utero tobacco-toxin exposure on the respiratory system in children
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2006
Induced sputum to detect lung pathogens in young children with cystic fibrosis
Publisher: Wiley
Date: 30-11-0002
DOI: 10.1002/PPUL.23636
Abstract: Induced sputum s ling holds promise as a method for obtaining s les representative of the lower airways in young children. Collection of induced sputum s les in young children differs from older children and adults' as pharyngeal suctioning is often required. Our aim was to determine the sensitivity and specificity of induced sputum with and without airway clearance techniques to detect lower airway pathogens in children less than age 7 with cystic fibrosis. Microbiological culture results were compared between 61 paired induced sputum and bronchoalveolar lavage fluid s les from young children with cystic fibrosis. The first cohort received no airway clearance and the second cohort received airway clearance. Induced sputum was s led within 7 days of bronchoscopy. Median age (range) of participants was 3.3 years (0.9-6.7). Sensitivity and specificity (95%CI) of induced sputum was 36.8% (16.3, 61.6), and 69% (52.9, 82.4), respectively (N = 61). In subgroup analysis, induced sputum with (N = 31) and without airway clearance (N = 30) demonstrated sensitivity of 50% (15.7, 84.3) and 27.3% (6.0, 61.0), respectively, and specificity of 60.9% (38.5, 80.3), and 78.9% (54.4, 93.9), respectively. Induced sputum is not highly sensitive or specific as routine surveillance for detection of lower airway pathogens in young children with cystic fibrosis. Pediatr Pulmonol. 2017 :182-189. © 2016 Wiley Periodicals, Inc.
The airway epithelium is a direct source of matrix degrading enzymes in bronchiolitis obliterans syndrome.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.HEALUN.2011.06.007
Abstract: Long-term survival after lung transplantation is hindered by the development of bronchiolitis obliterans syndrome (BOS), and recent evidence suggests that dysregulated epithelial repair may underlie its development. Because matrix metalloproteinase (MMP) -2 and MMP-9 secretion is integral to repair, we hypothesized that airway epithelial cells from patients with BOS would over-express these matrix-degrading enzymes. Cells obtained from bronchial and bronchiolar brushings from patients with and without BOS (without acute rejection or infection) were analyzed via quantitative polymerase chain reaction and immunocytochemistry for MMP-2, and MMP-9 gene and protein expression. The expression of tissue inhibitor of metalloproteinase (TIMP)2 and TIMP1 was also assessed. MMP activity in bronchoalveolar lavage was determined via gelatin zymography. MMP-2 and MMP-9 production was significantly higher in bronchoalveolar lavage (3.85- and 11.59-fold, p < 0.001) and airway epithelium (MMP-2 bronchial: 6.33-fold, bronchiolar: 3.57-fold, both p < 0.001 MMP-9 bronchial: 32.55-fold, p < 0.001 bronchiolar: 8.60-fold, p = 0.01) in patients with BOS, but expression in patients without BOS was not different from healthy controls. TIMP expression was similar in patients with and without BOS. Immunostaining confirmed that the airway epithelium was a direct source of MMP-2 and MMP-9 expression in patients with BOS. In patients with BOS, the airway epithelium over-expresses MMPs, even in the absence of acute rejection or infection. Dysregulated epithelial repair may be a key feature of BOS.
Bile signalling promotes chronic respiratory infections and antibiotic tolerance
Publisher: Springer Science and Business Media LLC
Date: 19-07-2016
DOI: 10.1038/SREP29768
Abstract: Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa , while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum s les demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease.
Investigating self-efficacy, disease knowledge and adherence to treatment in adolescents with cystic fibrosis.
Publisher: Wiley
Date: 10-02-2017
DOI: 10.1111/JPC.13458
Abstract: Patient adherence is integral to the effectiveness of prescribed treatment, and is associated with beneficial disease outcomes, yet in adolescents with cystic fibrosis, adherence is often sub-optimal. Multiple factors may contribute to treatment adherence, including disease knowledge and self-efficacy. In adolescents with cystic fibrosis: (i) to compare the disease knowledge of adolescents and their parents before transition to adult care (ii) to determine the relationship between disease knowledge (adolescent, parent) and adherence and (iii) to evaluate self-efficacy and its association with disease knowledge and adherence. Adolescents with cystic fibrosis and their parents were recruited from a tertiary children's hospital. Disease knowledge and self-efficacy was assessed using the Knowledge of Disease Management-CF and General Self-Efficacy Scales respectively. Using pharmacy records, medication possession ratio was calculated to measure treatment adherence in the preceding year. Thirty-nine adolescent (aged 12-17 (median 14) years) and parent pairs were recruited. Adherence to hypertonic saline, but not other medications, was significantly associated with disease knowledge in adolescents (r Disease knowledge is sub-optimal in adolescents with cystic fibrosis, even in the 2 years immediately before transition to adult care. Given that adherence with some treatments has been associated with disease knowledge our results suggest the need for educational interventions in adolescents with cystic fibrosis to optimise self-management and health outcomes.
Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-04-2019
DOI: 10.1126/SCITRANSLMED.AAV3488
Abstract: Increased airway mucus, occurs before infection or structural lung disease in early cystic fibrosis and promotes inflammation.
Systems Biology and Bile Acid Signalling in Microbiome-Host Interactions in the Cystic Fibrosis Lung
Publisher: MDPI AG
Date: 24-06-2021
DOI: 10.3390/ANTIBIOTICS10070766
Abstract: The study of the respiratory microbiota has revealed that the lungs of healthy and diseased in iduals harbour distinct microbial communities. Imbalances in these communities can contribute to the pathogenesis of lung disease. How these imbalances occur and establish is largely unknown. This review is focused on the genetically inherited condition of Cystic Fibrosis (CF). Understanding the microbial and host-related factors that govern the establishment of chronic CF lung inflammation and pathogen colonisation is essential. Specifically, dissecting the interplay in the inflammation–pathogen–host axis. Bile acids are important host derived and microbially modified signal molecules that have been detected in CF lungs. These bile acids are associated with inflammation and restructuring of the lung microbiota linked to chronicity. This community remodelling involves a switch in the lung microbiota from a high bio ersity/low pathogen state to a low bio ersity athogen-dominated state. Bile acids are particularly associated with the dominance of Proteobacterial pathogens. The ability of bile acids to impact directly on both the lung microbiota and the host response offers a unifying principle underpinning the pathogenesis of CF. The modulating role of bile acids in lung microbiota dysbiosis and inflammation could offer new potential targets for designing innovative therapeutic approaches for respiratory disease.
The safety and feasibility of the inhaled mannitol challenge test in young children
Publisher: European Respiratory Society (ERS)
Date: 29-08-2013
Indoor environmental quality in a 'low allergen' school and three standard primary schools in Western Australia
Publisher: Hindawi Limited
Date: 02-2006
DOI: 10.1111/J.1600-0668.2005.00405.X
Abstract: To investigate indoor environmental quality in classrooms, assessments were undertaken in a 'low allergen' school and three standard primary schools in Western Australia. Dust allergens, air pollutants and physical parameters were monitored in the four schools at four times (summer school term, autumn holiday, winter school term and winter holiday) in 2002. The levels of particulate matter (PM(10)) and volatile organic compounds were similar between the four primary schools. Although slightly decreased levels of dust-mite and cat allergens were observed in the 'low allergen' school, the reductions were not statistically significant and the allergen levels in all schools were much lower than the recommended sensitizing thresholds. However, significantly lower levels of relative humidity and formaldehyde level during summer-term were recorded in the 'low allergen' school. In conclusion, the evidence here suggests that the 'low allergen' school did not significantly improve the indoor environmental quality in classrooms. Practical Implications School is an important environment for children in terms of exposure to pollutants and allergens. By assessing the levels of key pollutants and allergens in a low allergen school and three standard primary schools in Western Australia, this study provides useful information for implementation of healthy building design that can improve the indoor environment in schools.
Lung Function in Infants with Cystic Fibrosis Diagnosed by Newborn Screening
Publisher: American Thoracic Society
Date: 15-12-2008
International consensus on (ICON) pediatric asthma
Publisher: Wiley
Date: 15-06-2012
Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis
Publisher: BMJ
Date: 12-03-2011
Abstract: Improved nutrition is the major proven benefit of newborn screening programmes for cystic fibrosis (CF) and is associated with better clinical outcomes. It was hypothesised that early pulmonary inflammation and infection in infants with CF is associated with worse nutrition. Weight, height and pulmonary inflammation and infection in bronchoalveolar lavage (BAL) were assessed shortly after diagnosis in infants with CF and again at 1, 2 and 3 years of age. Body mass index (BMI) was expressed as z-scores. Inflammatory cells and cytokines (interleukin 1β (IL-1β), IL-6, IL-8 and tumour necrosis factor α (TNFα)), free neutrophil elastase activity and myeloperoxidase were measured in BAL. Mixed effects modelling was used to assess longitudinal associations between pulmonary inflammation, pulmonary infection (Staphylococcus aureus and Pseudomonas aeruginosa) and BMI z-score after adjusting for potential confounding factors. Forty-two infants were studied (16 (38%) male 39 (93%) pancreatic insufficient) 36 were diagnosed by newborn screening (at median age 4 weeks) and six by early clinical diagnosis (meconium ileus). Thirty-one (74%) received antistaphylococcal antibiotics. More than two-thirds were asymptomatic at each assessment. Mean BMI z-scores were -1.5 at diagnosis and 0.5, -0.2 and -0.1 at 1, 2 and 3 years, respectively. Neutrophil elastase and infection with S aureus were associated with lower BMI, whereas age (p=0.01) and antistaphylococcal antibiotics (p=0.013) were associated with increased BMI. On average, each log(10) increase in free neutrophil elastase activity was associated with a 0.43 (95% CI 0.06 to 0.79) reduction in BMI z-score. Early nutritional status is associated with the underlying pulmonary pathophysiology in CF, and better understanding of these relationships is required. Studies are required to assess whether interventions can decrease pulmonary inflammation and improve nutrition. Early surveillance will enable such targeted interventions with the aim of improving these important clinical outcomes.
The clinical significance of oropharyngeal cultures in young children with cystic fibrosis
Publisher: European Respiratory Society (ERS)
Date: 20-04-2018
DOI: 10.1183/13993003.00238-2018
Abstract: In children with cystic fibrosis (CF) the associations between oropharyngeal swabs (OPSs) for detection of Pseudomonas and lung disease have not been evaluated. OPS and bronchoalveolar lavage (BAL) s les were obtained annually in children with CF from 2005 to 2017. OPS test characteristics were calculated using BAL as “gold standard”. Results were related to lung inflammation (BAL neutrophil elastase and interleukin-8), structural lung disease (chest computed tomography PRAGMA-CF (Perth–Rotterdam Annotated Grid Morphometric Analysis for CF) scores), respiratory exacerbations and future detection of Pseudomonas on BAL. From 181 patients, 690 paired OPS–BAL cultures were obtained. Prevalence of Pseudomonas in BAL was 7.4%. OPS sensitivity was 23.0% and specificity was 91.4%, reducing the post-test probability for a positive BAL following a negative OPS to 6.3%. Pseudomonas on OPS was not associated with lung inflammation or respiratory exacerbations, but was weakly associated with current PRAGMA-CF %Disease score (p=0.043). Pseudomonas on BAL was associated with positive neutrophil elastase (OR 4.17, 95% CI 2.04–8.53 p .001), increased interleukin-8 (p .001), increased all baseline PRAGMA computed tomography scores (p .001), progression of PRAGMA computed tomography scores (p .05) and increased risk of respiratory exacerbations (incidence rate ratio 2.11, 95% CI 1.15–3.87 p=0.017). In children with CF OPSs only marginally change the probability of detecting lower airway Pseudomonas and are not associated with lung disease indices nor exacerbations risk.
Determinants of culture success in an airway epithelium sampling program of young children with cystic fibrosis.
Publisher: Informa UK Limited
Date: 05-09-2014
DOI: 10.3109/01902148.2014.946631
Abstract: The bronchial brushing technique presents an opportunity to establish a gold standard in vitro model of Cystic Fibrosis (CF) airway disease. However, unique obstacles exist when establishing CF airway epithelial cells (pAECCF). We aimed to identify determinants of culture success through retrospective analysis of a program of routinely brushing children with CF. Anaesthetised children (CF and non-CF) had airway s les taken which were immediately processed for cell culture. Airway data for the CF cohort was obtained from clinical records and the AREST CF database. Of 260 brushings processed for culture, 114 (43.8%) pAECCF successfully cultured to passage one (P1) and 63 (24.2% of total) progressed to passage two (P2). However, >80% of non-CF specimens (pAECnon-CF) cultured to P2 from similar cell numbers. Within the CF cohort, specimens successfully cultured to P2 had a higher initial cell count and lower proportion of severe CF mutation phenotype than those that did not proliferate beyond initial seeding. Elevated airway IL-8 concentration was also negatively associated with culture establishment. Contamination by opportunistic pathogens was observed in 81 (31.2% of total) cultures and brushings from children with lower respiratory tract infections were more likely to co-culture contaminating flora. Lower passage rates of pAECCF cultures uniquely contrasts with pAECnon-CF despite similar cell numbers. An equivalent establishment rate of CF nasal epithelium reported elsewhere, significant associations to CFTR mutation phenotype, elevated airway IL-8 and opportunistic pathogens all suggest this is likely related to the CF disease milieu.
Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze.
Publisher: American Society for Clinical Investigation
Date: 09-04-2020
Early cystic fibrosis lung disease
Publisher: European Respiratory Society
Date: 06-2014
Interferon β-1a ring prophylaxis to reduce household transmission of SARS-CoV-2: a cluster randomised clinical trial
Publisher: Elsevier BV
Date: 08-2023
Defective function at the epithelial junction: A novel therapeutic frontier in asthma?
Publisher: Elsevier BV
Date: 09-2011
Application of a shortened inhaled adenosine-5′-monophosphate challenge in young children using the forced oscillation technique
Publisher: Elsevier BV
Date: 07-2009
Abstract: Adenosine-5'-monophosphate (AMP) is an indirect challenge agent thought to reflect allergic airway inflammation. The forced oscillation technique (FOT) is ideal for use in young children and is suitable for inhaled challenge studies in patients who are in this age group. We assessed the agreement between a shortened and a standard AMP challenge and the repeatability of the shortened AMP challenge using FOT as a primary outcome variable. Eighteen children completed a shortened and a standard AMP challenge, and 20 children completed repeated shortened AMP challenges. The children inhaled nebulized AMP tidally for 2 min, following which the presence of wheeze and pulse oximetric saturation (Spo(2)) was recorded prior to FOT measurement. Testing continued until the maximum dose was reached or until wheeze, a decrease in Spo(2) to < 90%, or an increase in respiratory resistance at 8 Hz of 2.0 hPa/s/L or 30% was noted. Concordance was assessed as a binary response, and agreement in provocation concentrations (PCs) causing a response was assessed with intraclass correlations. There was a high degree of concordance between the shortened and standard AMP protocols (94%) and repeated shortened AMP protocols (100%). The mean log(10) PCs displayed a high degree of agreement for both AMP protocols, with intraclass correlation coefficients of 0.94 (95% confidence interval, 0.85 to 0.98) and 0.94 (95% confidence interval, 0.82 to 0.98), respectively. We demonstrated that a shortened AMP challenge that can be applied to young children is comparable to the standard AMP challenge and is highly repeatable. Further studies in young children to assess the clinical role of a shortened AMP challenge using FOT are required.
Previous Influenza Infection Exacerbates Allergen Specific Response and Impairs Airway Barrier Integrity in Pre-Sensitized Mice
Publisher: MDPI AG
Date: 16-08-2021
DOI: 10.3390/IJMS22168790
Abstract: In this study we assessed the effects of antigen exposure in mice pre-sensitized with allergen following viral infection on changes in lung function, cellular responses and tight junction expression. Female BALB/c mice were sensitized to ovalbumin and infected with influenza A before receiving a second ovalbumin sensitization and challenge with saline, ovalbumin (OVA) or house dust mite (HDM). Fifteen days post-infection, bronchoalveolar inflammation, serum antibodies, responsiveness to methacholine and barrier integrity were assessed. There was no effect of infection alone on bronchoalveolar lavage cellular inflammation 15 days post-infection however, OVA or HDM challenge resulted in increased bronchoalveolar inflammation dominated by eosinophils/neutrophils or neutrophils, respectively. Previously infected mice had higher serum OVA-specific IgE compared with uninfected mice. Mice previously infected, sensitized and challenged with OVA were most responsive to methacholine with respect to airway resistance, while HDM challenge caused significant increases in both tissue d ing and tissue elastance regardless of previous infection status. Previous influenza infection was associated with decreased claudin-1 expression in all groups and decreased occludin expression in OVA or HDM-challenged mice. This study demonstrates the importance of the respiratory epithelium in pre-sensitized in iduals, where influenza-infection-induced barrier disruption resulted in increased systemic OVA sensitization and downstream effects on lung function.
Early pulmonary inflammation and lung damage in children with cystic fibrosis
Publisher: Wiley
Date: 30-03-2015
DOI: 10.1111/RESP.12521
Abstract: In iduals with cystic fibrosis (CF) suffer progressive airway inflammation, infection and lung damage. Airway inflammation and infection are present from early in life, often before children are symptomatic. CF gene mutations cause changes in the CF transmembrane regulator protein that result in an aberrant airway microenvironment including airway surface liquid (ASL) dehydration, reduced ASL acidity, altered airway mucin and a dysregulated inflammatory response. This review discusses how an altered microenvironment drives CF lung disease before overt airway infection, the response of the CF airway to early infection, and methods to prevent inflammation and early lung disease.
Home Ventilation and Respiratory Support
Publisher: Elsevier
Date: 2008
Respiratory tract exacerbations revisited: Ventilation, inflammation, perfusion, and structure (VIPS) monitoring to redefine treatment
Publisher: Wiley
Date: 03-09-2015
DOI: 10.1002/PPUL.23266
Abstract: For cystic fibrosis (CF) patients older than 6 years there are convincing data that suggest respiratory tract exacerbations (RTE) play an important role in the progressive loss of functional lung tissue. There is a poor understanding of the pathobiology of RTE and whether specific treatment of RTE reduces lung damage in the long term. In addition, there are limited tools available to measure the various components of CF lung disease and responses to therapy. Therefore, in order to better understand the impact of RTE on CF lung disease we need to develop sensitive measures to characterize RTE and responses to treatment and improve our understanding of structure-function changes during treatment of RTE. In this paper we review our current knowledge of the impact of RTE on the progression of lung disease and identify strategies to improve our understanding of the pathobiology of RTE. By improving our knowledge regarding RTE in CF we will be better positioned to develop approaches to treatment that are in idualized and that can prevent permanent structural damage. We suggest the development of a ventilation, perfusion, inflammation and structure (VIPS)-MRI suite that supplies the clinician with data on ventilation, inflammation, perfusion, and structure in one MRI session. VIPS-MRI could be an important step to better understand the factors that contribute to and limit treatment efficacy of RTE.
Suppression of adrenomedullin contributes to vascular leakage and altered epithelial repair during asthma.
Publisher: Wiley
Date: 12-06-2012
DOI: 10.1111/J.1398-9995.2012.02851.X
Abstract: The anti-inflammatory peptide, adrenomedullin (AM), and its cognate receptor are expressed in lung tissue, but its pathophysiological significance in airway inflammation is unknown. This study investigated whether allergen-induced airway inflammation involves an impaired local AM response. Airway AM expression was measured in acute and chronically sensitized mice following allergen inhalation and in airway epithelial cells of asthmatic and nonasthmatic patients. The effects of AM on experimental allergen-induced airway inflammation and of AM on lung epithelial repair in vitro were investigated. Adrenomedullin mRNA levels were significantly (P < 0.05) reduced in acute ovalbumin (OVA)-sensitized mice after OVA challenge, by over 60% at 24 h and for up to 6 days. Similarly, reduced AM expression was observed in two models of chronic allergen-induced inflammation, OVA- and house dust mite-sensitized mice. The reduced AM expression was restricted to airway epithelial and endothelial cells, while AM expression in alveolar macrophages was unaltered. Intranasal AM completely attenuated the OVA-induced airway hyperresponsiveness and mucosal plasma leakage but had no effect on inflammatory cells or cytokines. The effects of inhaled AM were reversed by pre-inhalation of the putative AM receptor antagonist, AM ((22-52)) . AM mRNA levels were significantly (P < 0.05) lower in human asthmatic airway epithelial s les than in nonasthmatic controls. In vitro, AM dose-dependently (10(-11) -10(-7) M) accelerated experimental wound healing in human and mouse lung epithelial cell monolayers and stimulated epithelial cell migration. Adrenomedullin suppression in T(H) 2-related inflammation is of pathophysiological significance and represents loss of a factor that maintains tissue integrity during inflammation.
Comparison of techniques for obtaining lower airway epithelial cells from children
Publisher: European Respiratory Society (ERS)
Date: 09-2008
DOI: 10.1183/09031936.00162507
Abstract: Airway epithelial cells (AECs) are important in asthma as they are the first cells to encounter pathogens/allergens. In children, AECs can be obtained using a "blind" nonbronchoscopic technique through an endotracheal tube. However, due to the increasing use of laryngeal masks the number of children in whom this technique is applicable has become limited. Recently, the present authors began to use a portable "bronchoscope-directed" technique to s le AECs. The current study compares both techniques in both asthmatic and nonasthmatic children. A total of 81 children undergoing elective surgery, were grouped according to atopic status and respiratory symptoms. Cellular yield of blind and bronchoscope-directed brushings were compared and immunocytochemistry performed. AECs were cultured and cytokine analysis of culture supernatant undertaken. Both techniques were equally well-tolerated, with the only adverse effect being a cough in 10% of the subjects. The mean+/-SD cell yield was higher in bronchoscope-directed than blind brushings (5.1+/-2.4 versus 3.1+/-1.4x10(6) cells). Immunocytochemistry confirmed an epithelial cell lineage. Culture supernatant cytokine concentrations were similar regardless of s ling technique with patterns preserved between asthmatic and healthy nonatopic phenotypes. Compared with blind brushing portable bronchoscope-directed brushing is well-tolerated, yields significantly more cells and is a potentially quick and useful technique for obtaining airway epithelial cells for research into childhood respiratory disease, specifically asthma.
Decreased Epinephrine Responses to Hypoglycemia during Sleep
Publisher: Massachusetts Medical Society
Date: 04-06-1998
DOI: 10.1056/NEJM199806043382303
Abstract: The analysis of the congruence between the demand- and supply-side of populism is key to understand the relationship between citizens and populist parties, and to what extent this is mainly a "pull" or "push" phenomenon. Although the study of populism has experienced an unprecedented growth across social sciences during the last decade, research directly addressing this connection remains scarce. Moreover, most existing tools used to measure populism have not been created paying much consideration to their compatibility with those applied in the other side of this demand-supply ide. This article critically revisits the influential Comparative Study of Electoral Systems (CSES) Module 5 dataset to illustrate shortcomings regarding current efforts to measure the demand- and supply-sides of populism. We show that according to CSES data the, often presumed, correspondence between "populist" attitudes and likelihood of voting for "populist parties" is only partial and country specific. But more importantly, we identify three main potential sources of such mismatch linked to instrumental issues: (i) problems with the choice, design and operationalization of attitudinal survey items (ii) problems in the assessment of parties' populism and (iii) instrument biases that make them more effective with some varieties of populism than with others. These methodological limitations are hindering our ability to settle longstanding theoretical debates concerning the correspondence between the demand- and supply-side, the relative centrality of attributes, and varieties of populism. Therefore, we invite scholars working in this field to update existing measurement tools, or develop new ones, considering the multidimensionality of this latent construct, the ersity of movements, and the need to apply consistent criteria and operationalization techniques when assessing degrees of populism in citizens and parties.
Effects of human rhinovirus on epithelial barrier integrity and function in children with asthma.
Publisher: Wiley
Date: 20-02-2018
DOI: 10.1111/CEA.13097
Abstract: Bronchial epithelial tight junctions (TJ) have been extensively assessed in healthy airway epithelium. However, no studies have yet assessed the effect of human rhinovirus (HRV) infection on the expression and resultant barrier function in epithelial tight junctions (TJ) in childhood asthma. To investigate the impact of HRV infection on airway epithelial TJ expression and barrier function in airway epithelial cells (AECs) of children with and without asthma. Furthermore, to test the hypothesis that barrier integrity and function is compromised to a greater extent by HRV in AECs from asthmatic children. Primary AECs were obtained from children with and without asthma, differentiated into air-liquid interface (ALI) cultures and infected with rhinovirus. Expression of claudin-1, occludin and zonula occluden-1 (ZO-1) was assessed via qPCR, immunocytochemistry (ICC), in-cell western (ICW) and confocal microscopy. Barrier function was assessed by transepithelial electrical resistance (TER R Basal TJ gene expression of claudin-1 and occludin was significantly upregulated in asthmatic children compared to non-asthmatics however, no difference was seen with ZO-1. Interestingly, claudin-1, occludin and ZO-1 protein expression was significantly reduced in AEC of asthmatic children compared to non-asthmatic controls suggesting possible post-transcriptional inherent differences. HRV infection resulted in a transient dissociation of TJ and airway barrier integrity in non-asthmatic children. Although similar dissociation of TJ was observed in asthmatic children, a significant and sustained reduction in TJ expression concurrent with both a significant decrease in TER and an increase in permeability in asthmatic children was observed. This study demonstrates novel intrinsic differences in TJ gene and protein expression between AEC of children with and without asthma. Furthermore, it correlates directly the relationship between HRV infection and the resultant dissociation of epithelial TJ that causes a continued altered barrier function in children with asthma.
Assessment of bronchodilator responsiveness in preschool children using forced oscillations
Publisher: BMJ
Date: 09-2007
Airway surface liquid pH is not acidic in children with cystic fibrosis
Publisher: Springer Science and Business Media LLC
Date: 08-2017
DOI: 10.1038/S41467-017-00532-5
Abstract: Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). However, evidence that ASL pH is reduced in CF is limited and conflicting. The technical challenges associated with measuring ASL pH in vivo have precluded accurate measurements in humans. In order to address this deficiency, ASL pH was measured in vivo in children using a novel luminescent technology integrated with fibre-optic probes. Here we show that ASL pH in children with CF is similar to that of children without CF. Findings were supported by highly controlled direct pH measurements in primary human airway epithelial cell culture models, which also suggest that the potential ASL pH gradient produced by defective apical ion transport is balanced out by paracellular shunting of acid/base. Thus, reduced baseline ASL pH is unlikely to be an important pathobiological factor in early CF lung disease.
Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection
Publisher: European Respiratory Society (ERS)
Date: 17-09-2015
DOI: 10.1183/13993003.00622-2015
Abstract: Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF. Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2 years of life. Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150–0.648 p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p .05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484–1.612 p .001). Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF.
High prevalence and incidence of HIV, sexually transmissible infections and penile foreskin cutting among sexual health clinic attendees in Papua New Guinea.
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/SH13197
Abstract: Background Papua New Guinea (PNG) has one of the highest prevalences of HIV and sexually transmissible infections (STIs) in the Asia-Pacific region, and one of the highest burdens of maternal syphilis and cervical cancer globally. Despite this disease burden, only limited clinical research in sexual and reproductive health has been conducted in PNG. Methods: A longitudinal clinical cohort study was conducted at two sexual health clinics. Participants completed a behavioural interview, clinical assessment and genital examination at baseline, and at 12, 24 and 50 weeks, including specimen collection for STI diagnostics. Results: In total, 154 people attended a screening visit. Reattendance at 12, 24 and 50-weeks was 87%, 78% and 80% respectively. At baseline, HIV prevalence was 3.3% chlamydia (Chlamydia trachomatis), 29.2% gonorrhoea (Neisseria gonorrhoeae), 22.1% Trichomonas vaginalis 15.6% herpes simplex type-2 (HSV-2), 46.1% active syphilis, 11.7%. Multiple infections were common particularly among women. The incidence of chlamydia was 27 per 100 person-years (PY) gonorrhoea, 15 out of 100 PY T. vaginalis, 29 out of 100 PY HSV-2, 12 out of 100 PY syphilis, 8 out of 100 PY. No incident HIV cases were recorded. At baseline, 39% of men in Mt Hagen and 65% in Port Moresby had a penile foreskin cut, with a dorsal slit being the most common. Two men underwent penile cutting during the follow-up period. Conclusions: The prevalence and incidence of STIs, HIV and penile cutting were high among sexual health clinic attendees. High retention figures suggest that this population may be suitable for future interventions research and clinical trials.
Clinical investigation of respiratory system admittance in preschool children
Publisher: Wiley
Date: 09-08-2012
DOI: 10.1002/PPUL.21515
Abstract: The upper airway shunt attenuates measurements of respiratory system impedance (Zrs), with greater impact in young children. Changes in respiratory system admittance, Ars (or Zrs(-1)), are theoretically independent of the shunt. This study compared the ability of Ars, to standard oscillatory outcomes, to determine respiratory disease and differentiate responses to inhaled bronchial challenges in the clinical setting. The forced oscillation technique (FOT) was used to establish reference equations for Ars in healthy preschool children, compare the change in Ars to standard oscillatory outcomes during bronchial challenge with inhaled adenosine-5'-monophosphate (AMP) and to inhaled bronchodilator in healthy children and those with respiratory disease. Children with respiratory disease had lower baseline Ars than healthy children (P < 0.05). However, there was no improved ability for Ars to differentiate between bronchodilator responses in healthy and disease populations. In contrast, the response to inhaled AMP occurred at a lower concentration, [25 (3.12-400) mg ml(-1) median (10th-90th centile)], as measured by Ars when compared to respiratory system resistance [225 (6.25-400) mg ml(-1) P = 0.016]. This study supports the use of Ars during inhaled challenges, but not in response to bronchodilation.
Association of domestic exposure to volatile organic compounds with asthma in young children
Publisher: BMJ
Date: 09-2004
Interactions Between Airway Epithelial Cells and Dendritic Cells: Implications for the Regulation of Airway Inflammation
Publisher: Bentham Science Publishers Ltd.
Date: 05-2006
DOI: 10.2174/138945006776818647
Abstract: Airway epithelial cells (AEC) and dendritic cells (DC) are situated in close proximity within the airway epithelium, and are the first cells to encounter inhaled pathogens, allergens and environmental pollutants. AEC and DC interact through the release of cytokines and other soluble mediators and through direct cell-cell contact, and these interactions are likely to play an important role in maintaining immune homeostasis. Increasing evidence indicates that both AEC and DC from asthmatic in iduals exhibit distinct functional properties, compared with AEC and DC from healthy in iduals. Both animal models, and novel co-culture models for directly studying human AEC/DC interactions are providing new insight into the cross-talk between these two important cells types, as a foundation for the development of new drug targets for use in asthma, cystic fibrosis and chronic obstructive pulmonary disease.
The potential of antisense oligonucleotide therapies for inherited childhood lung diseases
Publisher: Springer Science and Business Media LLC
Date: 06-02-2018
Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath
Publisher: BMJ
Date: 09-2004
The association between Staphylococcus aureus and subsequent bronchiectasis in children with cystic fibrosis
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JCF.2017.12.002
Abstract: Staphylococcus aureus (S. aureus) may be related to more rapid progression of cystic fibrosis (CF) lung disease. In the AREST CF cohort study, children diagnosed with CF undergo annual bronchoscopies with bronchoalveolar lavage and ultra-low-dose, chest computed tomography (CT) up to 6-years-old. Spirometry was assessed 3-monthly from the age of 4years. Associations between de novo S. aureus acquisition before school age and CT and lung function at ages 5-7years were investigated. Models were adjusted for multiple markers of disease severity at baseline. De novo S. aureus acquisition at 3-years-old (n/N=12/122) was associated with increased bronchiectasis score at age 5-6years. This association decreased but remained significant after adjustment for confounders. S. aureus at 3 was associated with significantly reduced FEF De novo S. aureus acquisition at age 3 is associated with later bronchiectasis and FEF
Definition of cutoff values for the hypoxia test used for preflight testing in young children with neonatal chronic lung disease
Publisher: Elsevier BV
Date: 04-2008
Abstract: The hypoxia test can be performed to identify potential hypoxia that might occur in an at-risk in idual during air travel. In 2004, the British Thoracic Society increased the hypoxia test cutoff guideline from 85 to 90% in young children. The aim of this study was to investigate how well the cutoff values of 85% and 90% discriminated between healthy children and those with neonatal chronic lung disease (nCLD). We performed a prospective, interventional study in young children with nCLD who no longer required supplemental oxygen and healthy control subjects. A hypoxia test (involving the administration of 14% oxygen for 20 min) was performed in all children, and the nadir in pulse oximetric saturation (Spo(2)) recorded. Hypoxia test results were obtained in 34 healthy children and 35 children with a history of nCLD. Baseline Spo(2) in room air was unable to predict which children would "fail" the hypoxia test. In those children < 2 years of age, applying a cutoff value of 90% resulted in 12 of 24 healthy children and 14 of 23 nCLD children failing the hypoxia test (p = 0.56), whereas a cutoff value of 85% was more discriminating, with only 1 of 24 healthy children and 6 of 23 nCLD children failing the hypoxia test (p = 0.048). In the present study, using a hypoxia test limit of 90% did not discriminate between healthy children and those with nCLD. A cutoff value of 85% may be more appropriate in this patient group. The clinical relevance of fitness to fly testing in young children remains to be determined.
Disruption of β-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.BIOCEL.2015.08.014
Abstract: The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor β-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the β-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the β-catenin 300 axis is associated with cell differentiation. We hypothesized that disrupting the β-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFβ1 in the presence or absence of the selective small molecule ICG-001 to inhibit β-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, β-catenin, fibronectin and ITGβ1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFβ1 induced EMT, characterized by reduced E-cadherin expression with increased expression of α-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFβ1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFβ1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGβ1 and fibronectin expression. These data support our hypothesis that modulating the β-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.
Management of tuberculosis in children
Publisher: Wiley
Date: 12-2000
DOI: 10.1046/J.1440-1754.2000.00565.X
Abstract: This paper provides specific guidelines on the management of tuberculosis infection and disease, covering general principles, recommended drug regimens and discuss the evidence to support these. It also covers use of corticosteroids, intermittent therapy, directly observed therapy and an approach to the management of a patient with drug-resistant tuberculosis.
Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis
Publisher: American Thoracic Society
Date: 15-11-2014
Persistent induction of goblet cell differentiation in the airways: Therapeutic approaches
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.PHARMTHERA.2017.12.009
Abstract: Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, therapeutic strategies to reduce mucus accumulation have focused primarily on altering the properties of the mucus itself, or have aimed to limit the production of mucus-stimulating cytokines. Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation and highlights both pre-existing and novel therapeutic strategies to combat this pathology.
Measurement of exhaled nitric oxide in children, 2001: E. Baraldi and J.C. de Jongste on behalf of the Task Force
Publisher: European Respiratory Society (ERS)
Date: 07-2002
DOI: 10.1183/09031936.02.00293102
Abstract: Measurement of fractional exhaled nitric oxide in exhaled air is an exciting innovative technique that gives new insights in to the pathophysiology of lung disease and asthma in particular, with many potential clinical applications. Careful standardisation of measurement techniques will facilitate the use of this new measurement in paediatric respiratory medicine: this Task Force was set up for this purpose. Methodologies, for use in all age groups, are already available and there are abundant questions relating to interpretation and application of fractional exhaled nitric oxide waiting to be addressed. Noninvasiveness and instantaneous results potentially make it a suitable monitoring instrument for use in children. Exhaled nitric oxide measurement has definitely found its way into clinical research in paediatric respiratory medicine. Evidence for clinically-useful applications is accumulating, and the merits of this new technique must now be demonstrated in larger studies, using standardised methodology in an appropriate setting.
Respiratory: Editorial
Publisher: Wiley
Date: 02-05-2002
Oxidative stress and abnormal bioactive lipids in early cystic fibrosis lung disease
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JCF.2019.04.011
Abstract: Clinical data indicate that airway inflammation in children with cystic fibrosis (CF) arises early, is associated with structural lung damage, and predicts progression. In bronchoalveolar lavage fluid (BALF) from CFTR mutant mice, several aspects of lipid metabolism are abnormal that contributes to lung disease. We aimed to determine whether lipid pathway dysregulation is also observed in BALF from children with CF, to identify biomarkers of early lung disease and potential therapeutic targets. A comprehensive panel of lipids that included Sphingolipids, oxylipins, isoprostanes and lysolipids, all bioactive lipid species known to be involved in inflammation and tissue remodeling, were measured in BALF from children with CF (1-6 years, N = 33) and age-matched non-CF patients with unexplained inflammatory disease (N = 16) by HPLC-MS/MS. Lipid data were correlated with chest CT scores and BALF inflammation biomarkers. The ratio of long chain to very long chain ceramide species (LCC/VLCC) and lysolipid levels were enhanced in CF compared to non-CF patients, despite comparable neutrophil counts and bacterial load. In CF patients both LCC/VLCC and lysolipid levels correlated with inflammation and chest CT scores. The ceramide precursors Sphingosine, Sphinganine, Sphingomyelin, correlated with inflammation, whilst the oxidative stress marker isoprostane correlated with inflammation and chest CT scores. No correlation between lipids and current bacterial infection in CF (N = 5) was observed. Several lipid biomarkers of early CF lung disease were identified, which point toward potential disease monitoring and therapeutic approaches that can be used to complement CFTR modulators.
Variability of nitric oxide metabolites in exhaled breath condensate
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.RMED.2005.03.033
Abstract: The collection of exhaled breath condensate (EBC) is simple and non-invasive, however, there are few data on the methodological aspects affecting concentrations of compounds in EBC. The aim of this study was to investigate methodological issues for measuring nitric oxide metabolites (NO(x)) in EBC. Twenty-five healthy adults (12 females, age range 23-55 years) and 22 children (11 females, age range 7-6 years) were recruited for studies investigating inter- and intra-day repeatability, repeatability with controlled expiratory flows and temperature, flow dependence, and analytical variability of EBC NO(x). Both intra- and inter-day repeatability was poor with a coefficient of repeatability of 103.4% of the mean difference between intra-day (15 min) measures and 118.6% of inter-day (24 h) differences. Repeatability was not improved when expiratory flow and temperature of the collection device were controlled. However, some of the variability (approximately 50%) may be accounted for by variability in the analytical technique (analytical variability) and this may result from difficulties in controlling for contamination. NO(x) levels were not affected by different expiratory flows in either adults or children but there was still significant variation within in iduals. Levels of NO(x) in EBC seem to be highly variable and this needs to be considered if EBC NO(x) is to be used in clinical studies.
The first 2 years of life: Implications of recent findings
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2009
Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin
Publisher: Public Library of Science (PLoS)
Date: 21-12-2012
Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis
Publisher: European Respiratory Society (ERS)
Date: 11-11-2016
DOI: 10.1183/13993003.00524-2016
Abstract: Neutrophilic airway inflammation plays a role in early structural lung disease in cystic fibrosis, but the mechanisms underlying this pathway are incompletely understood. Metabolites associated with neutrophilic inflammation were identified by discovery metabolomics on bronchoalveolar lavage fluid supernatant from 20 preschool children (2.9±1.3 years) with cystic fibrosis. Targeted mass-spectrometric detection of relevant metabolites was then applied to 34 children (3.5±1.5 years) enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) who underwent chest computed tomography and bronchoalveolar lavage from two separate lobes during 42 visits. Relationships between metabolites and localised structural lung disease were assessed using multivariate analyses. Discovery metabolomics identified 93 metabolites associated with neutrophilic inflammation, including pathways involved in metabolism of adenyl purines, amino acids and small peptides, cellular energy and lipids. In targeted mass spectrometry, products of adenosine metabolism, protein catabolism and oxidative stress were associated with structural lung disease and predicted future bronchiectasis, and activities of enzymes associated with adenosine metabolism were elevated in the s les with early disease. Metabolomics analyses revealed metabolites and pathways altered with neutrophilic inflammation and destructive lung disease. These pathways can serve as biomarkers and potential therapeutic targets for early cystic fibrosis lung disease.
Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JCF.2017.01.013
Abstract: We assessed the effect of posture on ventilation distribution and the impact on associations with structural lung disease. Multiple breath washout (MBW) was performed in seated and supine postures in 25 healthy children and 21 children with CF. Children with CF also underwent a chest CT scan. Functional residual capacity (FRC), lung clearance index (LCI) and moment ratios were calculated from the MBW test. CT scans were evaluated for CF-related structural lung disease. FRC was lower in the supine than in the seated posture, whereas LCI was higher in the supine than in the seated posture. In children with CF, associations between LCI and the extent of structural lung disease were stronger when performed in the supine posture. Body posture influences lung volumes and ventilation distribution in both healthy children and children with CF. MBW testing in the supine posture strengthened associations with structural lung damage.
Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma
Publisher: Springer Science and Business Media LLC
Date: 06-04-2017
DOI: 10.1038/SREP46026
Abstract: Asthma is highly prevalent, but current therapies cannot influence the chronic course of the disease. It is thus important to understand underlying early molecular events. In this study, we aimed to use microRNAs (miRNAs) - which are critical regulators of signaling cascades - to identify so far uncharacterized asthma pathogenesis pathways. Therefore, deregulation of miRNAs was assessed in whole lungs from mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI). In silico predicted target genes were confirmed in reporter assays and in house-dust-mite (HDM) induced AAI and primary human bronchial epithelial cells (NHBE) cultured at the air-liquid interface. We identified and validated the transcription factor cAMP-responsive element binding protein (Creb1) and its transcriptional co-activators (Crtc1-3) as targets of miR-17, miR-144, and miR-21. Sec14-like 3 (Sec14l3) - a putative target of Creb1 - was down-regulated in both asthma models and in NHBE cells upon IL13 treatment, while it’s expression correlated with ciliated cell development and decreased along with increasing goblet cell metaplasia. Finally, we propose that Creb1/Crtc1-3 and Sec14l3 could be important for early responses of the bronchial epithelium to Th2-stimuli. This study shows that miRNA profiles can be used to identify novel targets that would be overlooked in mRNA based strategies.
Cells of Epithelial Lineage Are Present in Blood, Engraft the Bronchial Epithelium, and Are Increased in Human Lung Transplantation
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.HEALUN.2009.03.013
Abstract: There is a growing expectation that cell-based therapies will prove effective for a wide range of conditions including lung diseases such as cystic fibrosis. The promise of these therapies will depend largely on effective delivery and engraftment. In this study, in the setting of human lung transplantation, we sought to determine whether exogenous epithelial cells are able to engraft the transplanted organ and if cells of a similar phenotype could be detected in peripheral blood. Cells obtained from bronchial brushings and peripheral blood were analyzed via dual fluorescent in situ hybridization/fluorescent immunohistochemistry (FISH/IHC), short tandem repeat polymerase chain reaction (STR-PCR) and flow cytometry. In 2 of 3 gender-mismatched patients we observed limited (5.9% to 6.8% by STR-PCR and 3.5% to 4% by FISH/IHC) engraftment of the bronchial epithelium by exogenous epithelial cells. Engrafting cells were CD34(-) CD15(-) CD68(-) c-Kit(-), but expressed CXCR4 on the cell surface. Cells with a similar phenotype were also identified in peripheral blood. In 8 patients, at 2 to 66 months post-transplant, 0.57 +/- 0.17% of CD14(-) peripheral blood mononuclear cells were of epithelial lineage. Almost all were CD45(+) and most expressed CXCR4 on the cell membrane. Cells of epithelial lineage were also identified in peripheral blood in healthy in iduals but in much lower numbers (0.08 +/- 0.01%, p < 0.05). Cells of epithelial lineage are detectable in peripheral blood and are able to engraft the bronchial epithelium in humans. Cell numbers are increased in lung transplantation.
Decreased fibronectin production significantly contributes to dysregulated repair of asthmatic epithelium
Publisher: American Thoracic Society
Date: 05-2010
Characteristics of a silk fibre reinforced biodegradable plastic
Publisher: Elsevier BV
Date: 03-2011
Assessment of p.Phe508del-CFTR functional restoration in pediatric primary cystic fibrosis airway epithelial cells
Publisher: Public Library of Science (PLoS)
Date: 23-01-2018
Does aberrant activation of the epithelial-mesenchymal trophic unit play a key role in asthma or is it an unimportant sideshow?
Publisher: Elsevier BV
Date: 06-2004
Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) birth cohort: study protocol
Publisher: Cold Spring Harbor Laboratory
Date: 03-05-2023
DOI: 10.1101/2023.04.29.23289314
Abstract: Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, in utero exposures, and respiratory exposures in the first year of life. The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to five years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to six weeks, one, three, and five years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and in utero exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal s ling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses. Ethical approval has been obtained from Ramsey Health Care HREC WA-SA (#1908). Results will be disseminated through open-access peer-reviewed manuscripts, conference presentations, and through different media channels to consumers, ORIGINS families, and the wider community.
Bronchiectasis in Infants and Preschool Children Diagnosed with Cystic Fibrosis after Newborn Screening
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.JPEDS.2009.05.005
Abstract: To determine the prevalence of bronchiectasis in young children with cystic fibrosis (CF) diagnosed after newborn screening (NBS) and the relationship of bronchiectasis to pulmonary inflammation and infection. Children were diagnosed with CF after NBS. Computed tomography and bronchoalveolar lavage were performed with anesthesia (n = 96). Scans were analyzed for the presence and extent of abnormalities. The prevalence of bronchiectasis was 22% and increased with age (P = .001). Factors associated with bronchiectasis included absolute neutrophil count (P = .03), neutrophil elastase concentration (P = .001), and Pseudomonas aeruginosa infection (P = .03). Pulmonary abnormalities are common in infants and young children with CF and relate to neutrophilic inflammation and infection with P. aeruginosa. Current models of care for infants with CF fail to prevent respiratory sequelae. Bronchiectasis is a clinically relevant endpoint that could be used for intervention trials that commence soon after CF is diagnosed after NBS.
Vitamin D supplementation of initially vitamin D-deficient mice diminishes lung inflammation with limited effects on pulmonary epithelial integrity
Publisher: Wiley
Date: 08-2017
DOI: 10.14814/PHY2.13371
Rebuttal from Stephen M. Stick and André Schultz
Publisher: Wiley
Date: 17-07-2018
DOI: 10.1113/JP276145
Risk factors for bronchiectasis in children with cystic fibrosis
Publisher: Massachusetts Medical Society
Date: 23-05-2013
Dissecting the regulation of bile-induced biofilm formation in Staphylococcus aureus
Publisher: Microbiology Society
Date: 08-2016
DOI: 10.1099/MIC.0.000317
Abstract: Aspiration of bile into the cystic fibrosis (CF) lung has emerged as a prognostic factor for reduced microbial lung bio ersity and the establishment of often fatal, chronic pathogen infections. Staphylococcus aureus is one of the earliest pathogens detected in the lungs of children with CF, and once established as a chronic infection, strategies for its eradication become limited. Several lung pathogens are stimulated to produce biofilms in vitro in the presence of bile. In this study, we further investigated the effects of bile on S. aureus biofilm formation. Most clinical S. aureus strains and the laboratory strain RN4220 were stimulated to form biofilms with sub-inhibitory concentrations of bovine bile. Additionally, we observed bile-induced sensitivity to aminoglycosides, which we exploited in a bursa aurealis transposon screen to isolate mutants reduced in aminoglycoside sensitivity and augmented in bile-induced biofilm formation. We identified five mutants that exhibited hypersensitivity to bile with respect to bile-induced biofilm formation, three of which carried transposon insertions within gene clusters involved in wall teichoic acid (WTA) biosynthesis or transport. Strain TM4 carried an insertion between the ergently oriented tagH and tagG genes, which encode the putative WTA membrane translocation apparatus. Ectopic expression of tagG in TM4 restored a wild-type bile-induced biofilm response, suggesting that reduced translocation of WTA in TM4 induced sensitivity to bile and enhanced the bile-induced biofilm formation response. We propose that WTA may be important for protecting S. aureus against exposure to bile and that bile-induced biofilm formation may be an evolved response to protect cells from bile-induced cell lysis.
Pseudomonas aeruginosa Resistance to Bacteriophages and Its Prevention by Strategic Therapeutic Cocktail Formulation
Publisher: MDPI AG
Date: 02-02-2021
DOI: 10.3390/ANTIBIOTICS10020145
Abstract: Antimicrobial resistance poses a significant threat to modern healthcare as it limits treatment options for bacterial infections, particularly impacting those with chronic conditions such as cystic fibrosis (CF). Viscous mucus accumulation in the lungs of in iduals genetically predisposed to CF leads to recurrent bacterial infections, necessitating prolonged antimicrobial chemotherapy. Pseudomonas aeruginosa infections are the predominant driver of CF lung disease, and airway isolates are frequently resistant to multiple antimicrobials. Bacteriophages, or phages, are viruses that specifically infect bacteria and are a promising alternative to antimicrobials for CF P. aeruginosa infections. However, the narrow host range of P. aeruginosa-targeting phages and the rapid evolution of phage resistance could limit the clinical efficacy of phage therapy. A promising approach to overcome these issues is the strategic development of mixtures of phages (cocktails). The aim is to combine phages with broad host ranges and target multiple distinct bacterial receptors to prevent the evolution of phage resistance. However, further research is required to identify and characterize phage resistance mechanisms in CF-derived P. aeruginosa, which differ from their non-CF counterparts. In this review, we consider the mechanisms of P. aeruginosa phage resistance and how these could be overcome by an effective future phage therapy formulation.
Hypoglycemia does not change the threshold for arousal from sleep in adolescents with type 1 diabetes
Publisher: Mary Ann Liebert Inc
Date: 02-2012
Abstract: Nocturnal hypoglycemia is a significant problem for children and adolescents with type 1 diabetes. The counterregulatory hormone response to hypoglycemia is blunted in both patients with type 1 diabetes and healthy subjects during sleep. It is not known whether the threshold for arousal from sleep is also modified by hypoglycemia. To address this question we compared the acoustic arousal threshold from sleep during hypoglycemia and euglycemia in adolescents with type 1 diabetes. Adolescents with type 1 diabetes were studied on two occasions: under hypoglycemic and euglycemic conditions. During the hypoglycemia night, subjects underwent a hyperinsulinemic hypoglycemic cl with nadir glucose level of 2.8 mmol/L. Hypoglycemia was initiated during stage 2 sleep and maintained during slow-wave sleep. During the euglycemia night, blood glucose was maintained at 5.5 mmol/L using the same cl technique. The acoustic arousal threshold was determined during the first cycle of slow-wave sleep. Seven subjects (mean±SE, 14.2±0.8 years old, mean glycosylated hemoglobin 8.1±0.3%, duration of diagnosis 2.5±0.5 years) completed both study nights. Arousal was only noted during acoustic testing and did not occur during hypoglycemia alone. The acoustic arousal threshold during slow-wave sleep was similar under both conditions: 79±8 dB during euglycemia and 71±6 dB (P=0.353) during hypoglycemia. In adolescents with type 1 diabetes, hypoglycemia does not impair arousal from slow-wave sleep induced by an external auditory stimulus.
Impaired airway epithelial cell responses from children with asthma to rhinoviral infection.
Publisher: Wiley
Date: 07-2016
DOI: 10.1111/CEA.12767
Abstract: The airway epithelium forms an effective immune and physical barrier that is essential for protecting the lung from potentially harmful inhaled stimuli including viruses. Human rhinovirus (HRV) infection is a known trigger of asthma exacerbations, although the mechanism by which this occurs is not fully understood. To explore the relationship between apoptotic, innate immune and inflammatory responses to HRV infection in airway epithelial cells (AECs) obtained from children with asthma and non-asthmatic controls. In addition, to test the hypothesis that aberrant repair of epithelium from asthmatics is further dysregulated by HRV infection. Airway epithelial brushings were obtained from 39 asthmatic and 36 non-asthmatic children. Primary cultures were established and exposed to HRV1b and HRV14. Virus receptor number, virus replication and progeny release were determined. Epithelial cell apoptosis, IFN-β production, inflammatory cytokine release and epithelial wound repair and proliferation were also measured. Virus proliferation and release was greater in airway epithelial cells from asthmatics but this was not related to the number of virus receptors. In epithelial cells from asthmatic children, virus infection d ened apoptosis, reduced IFN-β production and increased inflammatory cytokine production. HRV1b infection also inhibited wound repair capacity of epithelial cells isolated from non-asthmatic children and exaggerated the defective repair response seen in epithelial cells from asthmatics. Addition of IFN-β restored apoptosis, suppressed virus replication and improved repair of airway epithelial cells from asthmatics but did not reduce inflammatory cytokine production. Collectively, HRV infection delays repair and inhibits apoptotic processes in epithelial cells from non-asthmatic and asthmatic children. The delayed repair is further exaggerated in cells from asthmatic children and is only partially reversed by exogenous IFN-β.
Assessment of Early Bronchiectasis in Young Children With Cystic Fibrosis Is Dependent on Lung Volume
Publisher: Elsevier BV
Date: 10-2013
Abstract: The aim of this study was to determine whether assessment of early CT scan-detected bronchiectasis in young children with cystic fibrosis (CF) depends on lung volume. This study, approved by the hospital ethics committee, included 40 young children with CF from a newborn screened population contributing paired volume-controlled inspiratory and expiratory volumetric chest CT scans acquired under general anesthesia while clinically stable. Bronchiectasis was assessed with a semiquantitative CT scan score in inspiration and expiration, and the sensitivity of the expiratory CT scan to detect bronchiectasis was compared with the inspiratory CT scan by sensitivity and intraclass correlation coefficient analysis and Bland-Altman plots. Matched inspiratory and expiratory airway-vessel measurements were obtained in a subset of 10 children, and the relationship between lung volume and airway:vessel ratio after adjusting for age and vessel size was examined with the use of a linear regression model with generalized estimating equations. The number of visible airways in inspiration and expiration was compared in all 40 children by Wilcoxon signed rank test. Expiratory scans had poor sensitivity (0.46) to detect bronchiectasis, underestimating disease extent (P .001). Airway:vessel ratios were consistently higher in inspiration, independent of age and vessel size (P .001), with significantly more airways visible in inspiration than in expiration, independent of age (median, 71 vs 28, respectively P .001). In young children with CF, radiologic assessment of early bronchiectasis with chest CT scan depends on lung volume thus, expiratory scans may not be appropriate for evaluating bronchiectasis in this population. Lung volume during CT image acquisition should be standardized to evaluate airway dimensions in young children.
Accumulation mode particles and LPS exposure induce TLR-4 dependent and independent inflammatory responses in the lung
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
The airway epithelium as immune modulator: The LARC ascending
Publisher: American Thoracic Society
Date: 06-2003
DOI: 10.1165/RCMB.F271
Chest MRI in patients with cystic fibrosis: a radiation-free method Response
Publisher: BMJ
Date: 16-10-2013
Comparison of single-breath and tidal breathing exhaled nitric oxide levels in infants
Publisher: European Respiratory Society (ERS)
Date: 03-2004
DOI: 10.1183/09031936.04.00084604
Abstract: The aim of this study was to compare two different methods, tidal breathing (TB) and single-breath (SB), for measuring fractional exhaled nitric oxide (FENO) in infants. FENO was measured in 71 infants with either recurrent wheeze (n=32), recurrent cough (n=16) or no symptoms (healthy, n=23) using both methods. For TB measurements five breaths were collected into a gas s ling bag (off-line reservoir s ling). The SB method was modified from the raised volume rapid thoraco-abdominal technique. Agreement between the two methods was investigated and both methods were used to compare FENO in infants with and without symptoms. Flow dependence of SB FENO was demonstrated using two expiratory flows (11 and 40 mL x s(-1)). There was a moderate correlation (r=0.60) but poor agreement between levels using the TB and SB methods. A significant difference in FENO between healthy children and children with wheeze was found using the SB but not the TB method. Due to lower expiratory flow and reduced nasal nitric oxide contamination the single-breath technique may be more sensitive than the tidal breathing method for detecting differences in exhaled nitric oxide between infants with and without respiratory symptoms.
Effect of human rhinovirus infection on airway epithelium tight junction protein disassembly and transepithelial permeability.
Publisher: Informa UK Limited
Date: 08-08-2016
DOI: 10.1080/01902148.2016.1235237
Abstract: No studies have assessed the effects of human rhinovirus (HRV) infection on epithelial tight junctions (TJs) and resultant barrier function. To correlate viral infection with TJ disassembly, epithelial barrier integrity, and function. Human airway epithelial cells were infected with HRV minor serotype 1B (HRV-1B) at various 50% tissue culture infectivity doses (TCID HRV-1B infection affected viability that was both time and TCID HRV-1B infection directly alters human airway epithelial TJ expression leading to increased epithelial permeability potentially via an antiviral response of IL-15.
Changing Prevalence of Lower Airway Infections in Young Children with Cystic Fibrosis
Publisher: American Thoracic Society
Date: 09-2019
Home oxygen therapy after preterm birth in Western Australia
Publisher: Wiley
Date: 09-2004
DOI: 10.1111/J.1440-1754.2004.00455.X
Abstract: Objectives: To review our management of infants discharged home receiving supplemental oxygen. Stable preterm infants receive low flow O 2 by nasal cannulae aiming for SaO 2 of ≥ 95%. Oxygen‐dependent infants must pass an air test (ability to maintain SaO 2 80% during 4 h disconnection from oxygen) before discharge home with supplemental oxygen. A sleep study is performed before nocturnal O 2 is ceased. Methods: Infants less than 33 weeks gestational age (GA) who were admitted January 1999−June 2001 and discharged home with supplemental oxygen were identified through the databases and medical records of the King Edward Memorial/Princess Margaret Hospitals. The data collected were compared with an audit performed a decade earlier. Results: Ninety‐three infants were discharged home with supplemental oxygen between 1999 and 2001 (10% neonatal intensive care unit admissions less than 33 weeks GA median GA 26 weeks (interquartile range 25−28). All infants had an air test before discharge: 63% failed the first air test and 30% at least two air tests. The median delay between the first air test and discharge was 2 weeks. The median postmenstrual age at discharge was 40 weeks gestation (interquartile range 38−41). Ninety infants had a sleep study before nocturnal oxygen was ceased and nine failed the first sleep study. Hospital readmission rate was 60%. More preterm infants (less than 33 weeks) were discharged with supplemental oxygen in 1999−2001 (10%, n = 96 in 1999−2001) than in 1987−1992 (2.5%, n = 53) and this was associated with an earlier discharge (40 vs 44 weeks postmenstrual age), lower oxygen requirements at discharge (60 vs 125 mL/min), earlier discontinuation of daytime and nocturnal oxygen (1 vs 4 months postmenstrual age and 2.5 vs 6 months postmenstrual age) and no increase in readmission rate (64% vs 60%). The incidence of bronchopulmonary dysplasia for these infants has remained stable at 20%. Conclusion: Our home oxygen programme, based on an air test predischarge and a sleep study prediscontinuation of nocturnal oxygen, facilitates early discharge home. Our data suggest that over the last decade, bronchopulmonary dysplasia is associated with less impairment in lung function. Further evidence from randomized clinical trials is required to determine optimal target range for oxygen saturation in preterm infants.
Diagnosis of cystic fibrosis after newborn screening: The Australasian experience - Twenty years and five million babies later: A consensus statement from the Australasian Paediatric Respiratory Group
Publisher: Wiley
Date: 05-2005
DOI: 10.1002/PPUL.20191
Abstract: Newborn screening for cystic fibrosis has been used in Australia and New Zealand for over 20 years. In that time, considerable experience has been developed regarding the early diagnosis of cystic fibrosis after newborn screening. To date, there has not been a consensus on the process of screening and clinical evaluation leading to the diagnosis of cystic fibrosis in infants, many of whom are not symptomatic at time of notification of the screening result. The aim of this paper is to provide some consensus on the important issues of a cystic fibrosis diagnosis arising from newborn screening, based on the experience gained in Australia and New Zealand over the last 20 years.
The cumulative effect of inflammation and infection on structural lung disease in early cystic fibrosis.
Publisher: European Respiratory Society (ERS)
Date: 25-04-2019
DOI: 10.1183/13993003.01771-2018
Abstract: Pulmonary inflammation and infection are important clinical and prognostic markers of lung disease in cystic fibrosis (CF). However, whether in young children they are transient findings or have cumulative, long-term impacts on respiratory health is largely unknown. We aimed to determine whether their repeated detection has a deleterious effect on structural lung disease. All patients aged years with annual computed tomography (CT) and bronchoalveolar lavage (BAL) were included. Structural lung disease on CT (%Disease) was determined using the PRAGMA-CF (Perth–Rotterdam Annotated Grid Morphometric Analysis for CF) method. The number of times free neutrophil elastase (NE) and infection were detected in BAL were counted, to determine cumulative BAL history. Linear mixed model analysis, accounting for repeat visits and adjusted for age, was used to determine associations. 265 children (683 scans) were included for analysis, with BAL history comprising 1161 visits. %Disease was significantly associated with the number of prior NE (0.31, 95% CI 0.09–0.54 p=0.007) but not infection (0.23, 95% CI −0.01–0.47 p=0.060) detections. Reference equations were determined. Pulmonary inflammation in surveillance BAL has a cumulative effect on structural lung disease extent, more so than infection. This provides a strong rationale for therapies aimed at reducing inflammation in young children.
Association of Antibiotics, Airway Microbiome, and Inflammation in Infants with Cystic Fibrosis
Publisher: American Thoracic Society
Date: 10-2017
Lung clearance index and structural lung disease on computed tomography in early cystic fibrosis
Publisher: American Thoracic Society
Date: 2016
Use of a Primary Epithelial Cell Screening Tool to Investigate Phage Therapy in Cystic Fibrosis
Publisher: Frontiers Media SA
Date: 28-11-2018
Transcription factor p63 regulates key genes and wound repair in human airway epithelial Basal cells
Publisher: American Thoracic Society
Date: 12-2013
Early‐onset atopy is associated with enhanced lymphocyte cytokine responses in 11‐year‐old children
Publisher: Wiley
Date: 03-2007
DOI: 10.1111/J.1365-2222.2007.02668.X
Abstract: Early age at onset of atopy is associated with more severe asthma and increased airway responsiveness (AR) the underlying mechanism is unclear but may involve T cell responses. To test the hypothesis that enhanced T cell responses may be associated with early-onset atopy. In a longitudinal study, atopy was determined in infancy and at 6 and 11 years of age. In iduals were categorized as persistent infant-onset atopy (PIOA), early childhood-onset atopy (ECOA) and later childhood-onset atopy (LCOA). At 11 years of age, peripheral blood T cell cytokine responses, AR, exhaled nitric oxide (FE(NO)) and forced expiratory volume in 1 s were determined. The age at onset of atopy was determined for 60 children, of whom 15 had PIOA, 24 had ECOA and 21 had LCOA. An additional 76 children who were never atopic were also included. T cell responses to house dust mite, including interleukin-5, -9, -10 and tumour necrosis factor alpha, were higher among children with PIA and ECOA, and lower in children with LCOA, P<0.05. In contrast, those children with LCOA or who were not atopic had the highest IL-10 response to PHA (P=0.014). Children with PIOA and ECOA, but not LCOA, had higher AR and FE(NO) compared with non-atopic children (P<0.05). The group with PIOA were more likely among the atopic children to be admitted to hospital for asthma (P<0.05) and also had lower %FEV(1) compared with non-atopic children (P=0.023). Early age at sensitization is associated with enhanced T cell cytokine responses and indices of adverse asthma outcome. T cell cytokine responses might be programmed at the time of initial atopic sensitization.
Pre-flight testing of preterm infants with neonatal lung disease: a retrospective review
Publisher: BMJ
Date: 04-2006
Household hygiene practices in relation to dampness at home and current wheezing and rhino-conjunctivitis among school age children
Publisher: Wiley
Date: 18-10-2005
DOI: 10.1111/J.1399-3038.2005.00325.X
Abstract: Good household hygiene practices may improve indoor air quality in the domestic environment. Conversely, a 'hygiene hypothesis' is challenging the importance of hygiene and sanitation at home. This study aims to investigate the relationship between household hygiene practices and d ness at home and current wheezing, asthma and other allergic conditions among Australian children. Nine hundred and ninety-six children from four primary schools in Perth, Western Australia, were recruited for a domestic environmental and health survey during March and April of 2002. The results showed that high cleanliness scores were negatively associated with moulds at home before and after adjustment for age of dwelling (p < 0.001). High ventilation scores were inversely related with d patches, condensation and moulds at home (p < 0.05). However, households with high cleanliness scores appeared to have significantly higher prevalence of current wheezing (p < 0.05) and current rhino-conjunctivitis (p < 0.05) in children. The association remained even after controlling for confounders such as age and gender of children, asthma history of parents, passive smoking and d ness at home.
Inducible NO synthase expression is low in airway epithelium from young children with cystic fibrosis
Publisher: BMJ
Date: 06-2006
Distribution of Early Structural Lung Changes due to Cystic Fibrosis Detected with Chest Computed Tomography
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.JPEDS.2012.12.042
Abstract: To examine the distribution of early structural lung changes in clinically stable infants and young children with cystic fibrosis using chest computed tomography (CT). This cross-sectional study included 62 children aged 1-6 years with volume-controlled volumetric chest CT scans performed under general anesthesia as part of an early surveillance program. Each lobe was scored for presence and extent of bronchiectasis, mucus plugging, and air trapping using a semiquantitative score. The topographic distribution of structural abnormalities was evaluated by comparing the presence and extent of abnormalities in different lung regions and examining relationships between components. Although bronchiectasis was most common in the right upper lobe, overall changes in lung structure were not more common or more extensive in the upper lobes. Rather, bronchiectasis was more common in the right lung (right lung 0.95, left lung 0.68, P = .003), and mucus plugging (upper 0.41, middle 0.41, lower 0.72, P = .028) and air trapping (upper 0.79, middle 0.48, lower 0.96, P < .001) were more common in the lower lobes. The extents of bronchiectasis (P < .001) and air trapping (P = .011) were greater in the right lung. Scans with bronchiectasis were also more likely to have coexisting mucus plugging (P = .008) and air trapping (P < .001). Early structural lung disease is heterogeneously distributed in the lung. Quantitative scoring tools for studies using chest CT as an end point, and mechanistic studies that seek to better understand the pathogenesis of early cystic fibrosis lung disease, should take account of this differential topographic expression of disease early in life.
CrossTalk opposing view: mucosal acidification does not drive early progressive lung disease in cystic fibrosis
Publisher: Wiley
Date: 17-07-2018
DOI: 10.1113/JP275426
Repeatability of peak oxygen uptake in children who are healthy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1097/01.PEP.0000154340.43505.91
Abstract: This study was designed to determine test-retest repeatability of variables during a maximal cardiopulmonary exercise test (CPET) in children, and to report repeatability coefficients using limits of agreement analysis. This method of analysis is recommended for valid interpretation of outcome measures used in clinical or research interventions, and has not been reported in previous studies of peak oxygen uptake (VO2peak) in children. Two exercise tests were performed three to seven days apart in nine healthy children aged eight to 11 years, using a treadmill protocol. Limits of agreement analyses were performed, with bias (mean difference test 2 - test 1) and coefficients of repeatability (2 standard deviations [SD] of difference) calculated for VO2peak, peak heart rate (HRpeak) and peak minute ventilation (VEpeak). No significant differences were found between test and retest scores for any variable. VO2peak data demonstrated a bias of 1.4 ml kg/min with repeatability coefficient of 4.4 ml kg/min. The range described by 95% limits of agreement for VO2peak was -3 to + 5 ml kg/min. Bias and 95% limits of agreement for VEpeak and HRpeak were similarly described. The 95% limits of agreement for VO2peak imply that on repeated testing, a reduction of 3 or increase of 5.8 ml kg/min is likely to be clinically significant. This study provides reference values for repeatability of key variables during CPET in healthy children that should be considered when interpreting results from repeated testing.
Assessing fitness to fly in young infants and children [2]
Publisher: BMJ
Date: 03-2007
NOS1 polymorphism is associated with atopy but not exhaled nitric oxide levels in healthy children
Publisher: Wiley
Date: 08-2003
DOI: 10.1034/J.1399-3038.2003.00065.X
Abstract: Exhaled nitric oxide (FENO) is raised in atopy. The mechanism for this is unclear. The aim of this study was to investigate whether the number of AAT repeats in intron 20 of the NOS1 gene, recently associated with variations in FENO in adults with asthma and cystic fibrosis, was associated with the raised FENO in healthy atopic children. Eighty-seven healthy children (44 girls, 42 atopic, age range 6-18 years) underwent measurements of FENO, spirometry, airway responsiveness and skin prick testing. Genotyping was carried out to determine the number of AAT repeats. There was no association between the number of AAT repeats and FENO in either the whole s le of healthy children (n = 87) or in the subs le of healthy atopics (n = 42). However, a greater number of atopic children had two high repeat alleles compared with non-atopic children (33.3% vs. 13.6%, respectively, p = 0.03). This suggests that variations in the NOS1 gene may contribute to atopy without this relationship being reflected by FENO.
Parental smoking increases exhaled nitric oxide in young children
Publisher: European Respiratory Society (ERS)
Date: 10-2006
DOI: 10.1183/09031936.06.00007206
Abstract: The present study investigated the association between reported parental smoking and exhaled nitric oxide fraction (F(eNO)) in young children. In total, 78 children (24 females, mean age 51.3 weeks) were recruited. Fourteen lived with one smoking parent and eight with two smoking parents. F(eNO) was measured using the modified single-breath technique. Mean+/-sd F(eNO) levels were 33.0+/-18.9, 38.3+/-15.0 and 48.3+/-14.7 ppb for children with no, one and two smoking parents, respectively. There was a significant linear trend across the groups and, after controlling for other relevant factors, a significant difference between the groups. In the present study, exposure to environmental tobacco smoke was associated with increased exhaled nitric oxide fraction in young children. Furthermore, there was evidence of a dose-response relationship between childhood exhaled nitric oxide fraction and the number of smoking parents.
Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis.
Publisher: European Respiratory Society (ERS)
Date: 30-04-2015
DOI: 10.1183/09031936.00212114
Abstract: Neutrophil elastase is the most significant predictor of bronchiectasis in early-life cystic fibrosis however, the causal link between neutrophil elastase and airway damage is not well understood. Matrix metalloproteinases (MMPs) play a crucial role in extracellular matrix modelling and are activated by neutrophil elastase. The aim of this study was to assess if MMP activation positively correlates with neutrophil elastase activity, disease severity and bronchiectasis in young children with cystic fibrosis. Total MMP-1, MMP-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 levels were measured in bronchoalveolar lavage fluid collected from young children with cystic fibrosis during annual clinical assessment. Active ro-enzyme ratio of MMP-9 was determined by gelatin zymography. Annual chest computed tomography imaging was scored for bronchiectasis. A higher MMP-9/TIMP-1 ratio was associated with free neutrophil elastase activity. In contrast, MMP-2/TIMP-2 ratio decreased and MMP-1 and MMP-7 were not detected in the majority of s les. Ratio of active ro-enzyme MMP-9 was also higher in the presence of free neutrophil elastase activity, but not infection. Across the study cohort, both MMP-9/TIMP-1 and active MMP-9 were associated with progression of bronchiectasis. Both MMP-9/TIMP-1 and active MMP-9 increased with free neutrophil elastase and were associated with bronchiectasis, further demonstrating that free neutrophil elastase activity should be considered an important precursor to cystic fibrosis structural disease.
The impact of chest computed tomography and chest radiography on clinical management of cystic fibrosis lung disease
Publisher: Elsevier BV
Date: 07-2020
DOI: 10.1016/J.JCF.2019.08.005
Abstract: Recent standards of care mention chest radiography (CR) but not chest computed tomography (CT) in routine annual follow-up of children with cystic fibrosis (CF). To minimise radiation risk, CT or CR should only be performed if they impact clinical decision making. We investigated whether in addition to a wide range of commonly used clinical parameters, chest CT and/or CR in routine follow-up of CF patients influence clinical decisions. 36 web based clinical vignettes (i.e. case simulations) were designed using clinical data from patients aged 8-18 years, randomly selected from two CF centres in The Netherlands. In a randomized cross-over design, clinicians assessed eight vignettes and suggested therapeutic/diagnostic management on two occasions, with a ten-week interval. Radiological information (CT or CR) was included at only one of the two assessments, in random order. Any differences in management could be attributed to information from CT or CR, and were compared by McNemar analysis. 44 European and Australian clinicians completed a total of 143 CT vignette pairs and 167 CR vignette pairs. CT was associated with a significant increase in antifungal treatment (Risk Ratio (RR) 2.8 (1.3-6.0, p = .02)), bronchoscopies (RR 1.6 (1.1-2.5, p = .04)), mycobacterial cultures (RR 1.3 (1.0-1.5, p = .02)), and 'need for hospitalization' (i.e. intravenous antibiotics and/or bronchoscopy) (RR 1.4 (1.0-1.9, p = .03)). CR led to a significant increase in inhaled antibiotics only (RR 1.3 (1.0-1.6, p = .04)). CT but not CR, at routine biennial follow-up was associated with several changes in treatment and/or diagnostic testing, including the need for hospitalization.
Respiratory function and symptoms in young preterm children in the contemporary era
Publisher: Wiley
Date: 26-05-2016
DOI: 10.1002/PPUL.23487
Abstract: To determine the relationships between respiratory symptoms, lung function, and neonatal events in young preterm children. Preterm children (<32 w gestation), classified as bronchopulmonary dysplasia (BPD) or non-BPD, and healthy term controls were studied. Lung function was measured by forced oscillation technique (respiratory resistance [Rrs] and reactance [Xrs]) and spirometry. Respiratory symptom questionnaires were administered. One hundred and fifty children (74 BPD, 44 non-BPD, 32 controls) 4-8 years were studied. Lung function (median Z-score [10,90th centile]) was significantly impaired in preterm children compared to controls for FVC (0.00 [-1.18, 1.76], 0.69 [-0.17,1.86]), FEV Preterm children have worse lung function than healthy controls. Only respiratory reactance differentiated between preterm children with and without BPD and was influenced by days of O
Ever eczema and itchy rash in relation to domestic environments in primary school children
Publisher: SAGE Publications
Date: 12-2006
Abstract: Domestic risk factors as well as pollutant and allergen exposure in the home environment may contribute to the increasing prevalence of allergic conditions. This study aimed to investigate domestic environmental factors associated with ever eczema and itchy rash in children. A total of 996 children aged 4-12 years were recruited from four primary schools in Perth and surveyed between March and April of 2002. A subgroup of 88 children aged 4-6 years were further selected for assessment of exposure to pollutants and allergens. For both ever eczema and itchy rash, parents’ history of eczema was a strong risk factor. Use of a portable fan for summer cooling was also a significant risk factor, with adjusted odds ratios of 1.38 (95% Cl 1.01-1.88) for ever eczema and 1.53 (95% Cl 1.05-2.24) for itchy rash. Age of dwellings was negatively associated with the prevalence of ever eczema (P=0.001). Passive smoking, gas cooking and condensation inside the house were associated with a significant increase in risk of ever itchy rash as, in the sub-study, was exposure to particulate matter (PM 10 ) (P=0.046). The findings confirmed several environmental risk factors responsible for ever eczema and itchy rash, and suggested that domestic particle sources may be linked with the occurrence of ever itchy rash among primary school children.
Randomised controlled trials in cystic fibrosis: What, when and how?
Publisher: European Respiratory Society (ERS)
Date: 30-04-2011
CD14 C-159T and early infection with Pseudomonas aeruginosa in children with cystic fibrosis
Publisher: Springer Science and Business Media LLC
Date: 23-06-2005
Domestic exposure to formaldehyde significantly increases the risk of asthma in young children
Publisher: European Respiratory Society (ERS)
Date: 08-2002
DOI: 10.1183/09031936.02.00245002
Abstract: Concern has arisen in recent years about indoor air pollution as a risk factor for asthma. Formaldehyde exposure was examined in relation to asthma among young children (between 6 months and 3 yrs old) in a population-based control study carried out in Perth, Western Australia, between 1997-1999. An association between exposure to formaldehyde and asthma in young children has been suggested. Cases (n=88), whose parents were recruited at Princess Margaret Hospital Accident and Emergency Dept (Perth, Western Australia), were children discharged with asthma as the primary diagnosis. Controls (n=104), who were children in the same age group without asthma diagnosed by a doctor, were identified from birth records through the Health Dept of Western Australia (Perth, Western Australia). Health outcomes for the children were studied using a respiratory questionnaire and skin-prick tests. Formaldehyde, average temperature and relative humidity were measured on two occasions, winter (July-September 1998) and summer (December 1998-March 1999) in the child's bedroom and in the living room. The study found seasonal differences in formaldehyde levels in the children's bedrooms and living rooms with significantly greater formaldehyde exposure during the summer period for case and control subjects. The generalised estimating equation model showed that children exposed to formaldehyde levels of > or = 60 microg x m(-3) are at increased risk of having asthma. The results suggest that domestic exposure to formaldehyde increases the risk of childhood asthma.
Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children
Publisher: Public Library of Science (PLoS)
Date: 18-01-2018
Airway epithelial repair in health and disease: Orchestrator or simply a player?
Publisher: Wiley
Date: 25-01-2016
DOI: 10.1111/RESP.12731
Abstract: Epithelial cells represent the most important surface of contact in the body and form the first line of defence of the body to external environment. Consequently, epithelia have numerous roles in order to maintain a homeostatic defence barrier. Although the epithelium has been extensively studied over several decades, it remains the focus of new research, indicating a lack of understanding that continues to exist around these cells in specific disease settings. Importantly, evidence is emerging that airway epithelial cells in particular have varied complex functions rather than simple passive roles. One area of current interest is its role following injury. In particular, the epithelial-specific cellular mechanisms regulating their migration during wound repair remain poorly understood and remain an area that requires much needed investigation. A better understanding of the physiological, cellular and molecular wound repair mechanisms could assist in elucidating pathological processes that contribute to airway epithelial pathology. This review attempts to highlight migration-specific and cell-extracellular matrix (ECM) aspects of repair used by epithelial cells under normal and disease settings, in the context of human airways.
AI-Driven Cell Tracking to Enable High-Throughput Drug Screening Targeting Airway Epithelial Repair for Children with Asthma
Publisher: MDPI AG
Date: 17-05-2022
DOI: 10.3390/JPM12050809
Abstract: The airway epithelium of children with asthma is characterized by aberrant repair that may be therapeutically modifiable. The development of epithelial-targeting therapeutics that enhance airway repair could provide a novel treatment avenue for childhood asthma. Drug discovery efforts utilizing high-throughput live cell imaging of patient-derived airway epithelial culture-based wound repair assays can be used to identify compounds that modulate airway repair in childhood asthma. Manual cell tracking has been used to determine cell trajectories and wound closure rates, but is time consuming, subject to bias, and infeasible for high-throughput experiments. We therefore developed software, EPIC, that automatically tracks low-resolution low-framerate cells using artificial intelligence, analyzes high-throughput drug screening experiments and produces multiple wound repair metrics and publication-ready figures. Additionally, unlike available cell trackers that perform cell segmentation, EPIC tracks cells using bounding boxes and thus has simpler and faster training data generation requirements for researchers working with other cell types. EPIC outperformed publicly available software in our wound repair datasets by achieving human-level cell tracking accuracy in a fraction of the time. We also showed that EPIC is not limited to airway epithelial repair for children with asthma but can be applied in other cellular contexts by outperforming the same software in the Cell Tracking with Mitosis Detection Challenge (CTMC) dataset. The CTMC is the only established cell tracking benchmark dataset that is designed for cell trackers utilizing bounding boxes. We expect our open-source and easy-to-use software to enable high-throughput drug screening targeting airway epithelial repair for children with asthma.
Exhaled nitric oxide and asthma: Complex interactions between atopy, airway responsiveness, and symptoms in a community population of children
Publisher: BMJ
Date: 12-2003
DOI: 10.1136/THORAX.58.12.1048
Abstract: Exhaled nitric oxide (FE(NO)) is raised in asthmatic children, but there are inconsistencies in the relationship between FE(NO) and characteristics of asthma, including atopy, increased airway responsiveness (AR), and airway inflammation. The aim of this study was to investigate the relationship between FE(NO) and asthma, atopy, and increased AR in children. One hundred and fifty five children (79 boys) of mean age 11.5 years underwent an assessment that included FE(NO) measurements, spirometric tests, inhaled histamine challenge, and a skin prick test. Blood was collected for eosinophil count. Current and past asthma like symptoms were determined by questionnaire. In multiple linear regression analyses FE(NO) was associated with atopy (p<0.001), level of AR (p = 0.005), blood eosinophil count (p = 0.007), and height (p = 0.002) but not with physician diagnosed asthma (p = 0.1) or reported wheeze in the last 12 months (p = 0.5). Separate regression models were conducted for atopic and non-atopic children and associations between FE(NO) and AR, blood eosinophils and height were only evident in atopic children. Exhaled NO was raised in children with a combination of atopy and increased AR independent of symptoms. Raised FE(NO) seems to be associated with an underlying mechanism linking atopy and AR but not necessarily respiratory symptoms.
Lung function testing in preschool-aged children with cystic fibrosis in the clinical setting
Publisher: Wiley
Date: 2010
DOI: 10.1002/PPUL.21192
Abstract: In cystic fibrosis (CF) lung function testing is a means of monitoring progression of lung disease. The preschool years have often been referred to as the "silent years" due to the previous lack suitable measures of lung function testing in this age group. This review outlines the various techniques of lung function testing in preschool children with CF in the clinical setting. This includes measures requiring tidal breathing including the forced oscillation technique, the interrupter technique, plethysmography, and multiple breath washout, as well as spirometry that requires respiratory maneuvers. We describe the feasibility and variability of different lung function methods used in preschoolers and report measurements made during tidal breathing have greater feasibility, although greater variability compared to spirometry. We also report associations with lung function and markers of CF lung disease. In the preschool age group measurements made during tidal breathing may be more appropriate in the clinic setting than those that require a higher degree of cooperation and specific respiratory maneuvers.maneuvers.
The contribution of airway development to paediatric and adult lung disease
Publisher: BMJ
Date: 07-2000
Abstract: In summary, factors that affect airway growth early in development appear to cause physiological effects that can be persistent. Reduced airway function early in life does not necessarily result in persistent symptoms, but the long term effects and impact on the development of chronic airflow limitation in adults are yet to be determined. Generally, long term sequelae seem to be related to the severity of the initial insult, but the development of persistent increased bronchial responsiveness is an independent risk factor for symptoms and abnormal lung function in later life. In addition, there appear to be separate genetic factors that influence atopy, airway development, and bronchial responsiveness.
Pseudomonas aeruginosa modulates neutrophil granule exocytosis in an in vitro model of airway infection
Publisher: Wiley
Date: 11-04-2022
DOI: 10.1111/IMCB.12547
Abstract: A population of neutrophils recruited into cystic fibrosis (CF) airways is associated with proteolytic lung damage, exhibiting high expression of primary granule exocytosis marker CD63 and reduced phagocytic receptor CD16. Causative factors for this population are unknown, limiting intervention. Here we present a laboratory model to characterize responses of differentiated airway epithelium and neutrophils following respiratory infection. Pediatric primary airway epithelial cells were cultured at the air–liquid interface, challenged in idually or in combination with rhinovirus (RV) and Pseudomonas aeruginosa , then apically washed with medical saline to s le epithelial infection milieus. Cytokine multiplex analysis revealed epithelial antiviral signals, including IP‐10 and RANTES, increased with exclusive RV infection but were diminished if P. aeruginosa was also present. Proinflammatory signals interleukin‐1α and β were dominant in P. aeruginosa infection milieus. Infection washes were also applied to a published model of neutrophil transmigration into the airways. Neutrophils migrating into bacterial and viral–bacterial co‐infection milieus exhibited the in vivo CF phenotype of increased CD63 expression and reduced CD16 expression, while neutrophils migrating into milieus of RV‐infected or uninfected cultures did not. In idually, bacterial products lipopolysaccharide and N ‐formylmethionyl‐leucyl‐phenylalanine and isolated cytokine signals only partially activated this phenotype, suggesting that additional soluble factors in the infection microenvironment trigger primary granule release. Findings identify P. aeruginosa as a trigger of acute airway inflammation and neutrophil primary granule exocytosis, underscoring potential roles of airway microbes in prompting this neutrophil subset. Further studies are required to characterize microbes implicated in primary granule release, and identify potential therapeutic targets.
The use of non-bronchoscopic brushings to study the paediatric airway
Publisher: Springer Science and Business Media LLC
Date: 08-06-2005
Abstract: The use of cytology brushes for the purpose of obtaining respiratory cells from adults for clinical and research purposes is well established. However, the safety and utility of non-bronchoscopic brushings to study the paediatric airway has not been assessed. The purpose of this study was to assess the practicality of using non-bronchoscopic brushing to s le epithelial cells from children for investigation of epithelial function in health and disease using a wide range of molecular and cellular techniques. Non-bronchoscopic brushing was investigated in a non-selected cohort of healthy, and mildly asthmatic children presenting for surgery unrelated to respiratory conditions, at the major children's hospital in Perth. Safety and side-effects of the procedure were assessed. Cell number, phenotype and viability were measured for all s les. The potential of these cells for use in long-term cell culture, immunohistochemistry, western blotting, quantitative PCR and gene arraying was examined. Non-bronchoscopic brushing was well tolerated in all children. The only significant side effect following the procedure was cough: nursing staff reported cough in 20% of patients parents reported cough in 40% of patients. Cells s led were of sufficient quantity and quality to allow cell culture in 93% of s les. Similarly, protein and RNA extracted from the cells was suitable for investigation of both gene and protein expression using micro-array and real-time PCR. Non-bronchoscopic brushing in children is safe and easy to perform, and is not associated with any complications. Using this technique, adequate numbers of epithelial cells can be retrieved to allow cell culture, western blotting, real time PCR, and microarray analysis. The purpose of this study is to demonstrate the utility of non-bronchoscopic airway brushing to obtain and study epithelial cells and to encourage others so that we can accelerate our knowledge regarding the role of the epithelium in childhood respiratory disease.
Characterization of Side Population Cells from Human Airway Epithelium
Publisher: Oxford University Press (OUP)
Date: 24-07-2008
DOI: 10.1634/STEMCELLS.2008-0171
Abstract: The airway epithelium is the first line of contact with the inhaled external environment and is continuously exposed to and injured by pollutants, allergens, and viruses. However, little is known about epithelial repair and in particular the identity and role of tissue resident stem rogenitor cells that may contribute to epithelial regeneration. The aims of the present study were to identify, isolate, and characterize side population (SP) cells in human tracheobronchial epithelium. Epithelial cells were obtained from seven nontransplantable healthy lungs and four asthmatic lungs by pronase digestion. SP cells were identified by verapamil-sensitive efflux of the DNA-binding dye Hoechst 33342. Using flow cytometry, CD45− SP, CD45+ SP, and non-SP cells were isolated and sorted. CD45− SP cells made up 0.12% ± 0.01% of the total epithelial cell population in normal airway but 4.1% ± 0.06% of the epithelium in asthmatic airways. All CD45− SP cells showed positive staining for epithelial-specific markers cytokeratin-5, E-cadherin, ZO-1, and p63. CD45− SP cells exhibited stable telomere length and increased colony-forming and proliferative potential, undergoing population expansion for at least 16 consecutive passages. In contrast with non-SP cells, fewer than 100 CD45− SP cells were able to generate a multilayered and differentiated epithelium in air-liquid interface culture. SP cells are present in human tracheobronchial epithelium, exhibit both short- and long-term proliferative potential, and are capable of generation of differentiated epithelium in vitro. The number of SP cells is significantly greater in asthmatic airways, providing evidence of dysregulated resident SP cells in the asthmatic epithelium. Disclosure of potential conflicts of interest is found at the end of this article.
Early intervention studies in infants and preschool children with cystic fibrosis: Are we ready?
Publisher: European Respiratory Society (ERS)
Date: 21-03-2013
DOI: 10.1183/09031936.00108212
Abstract: Cystic fibrosis (CF) lung disease starts early in life and progresses even in the absence of clinical symptoms. Therefore, sensitive outcome measures to quantify and track these early abnormalities in infants and young children are needed both for clinical care and interventional trials. Currently, the efficacy of most therapeutic interventions in CF has not been tested in children under the age of 6 years and drug development programmes have focused on assessing safety rather than efficacy in this age group. This article summarises the current status for outcome measures that can be utilised in clinical trials in infants and children with CF. Two methodologies are specifically highlighted in this review chest computed tomography to assess structural damage of the lung and multiple breath washout as a technique to quantify ventilation inhomogeneity. While not all questions regarding the utility of these outcome measures in infants and young children have been resolved, significant advances have been made and it now appears feasible to design and conduct adequately powered efficacy studies in this age group. This could be a crucial step to further improve outcomes in CF patients as initiating effective treatment early is considered essential to prevent permanent lung damage.
Determining the time to maximal bronchodilator response in asthmatic children
Publisher: Informa UK Limited
Date: 2009
DOI: 10.1080/02770900802460555
Abstract: The interval between bronchodilator administration and post-bronchodilator lung function testing is critical for accurate interpretation of the bronchodilator response. The time course of this response in children is not well documented. We aimed to document the time taken to achieve maximal lung function following salbutamol inhalation. Eighteen asthmatic children between 7 and 18 years of age with a history of bronchodilator responsiveness were recruited. Spirometry was performed before and at 0, 10, 15, 20, 40, 60, and 90 minutes after salbutamol inhalation 600 microg (Ventolin GlaxoSmithKline) via a spacer (Volumatic GlaxoSmithKline). Spirometric indices significantly increased after salbutamol inhalation (p < 0.001). The group median time to maximal response in forced expiratory volume in 1 second (FEV(1)) was 17.5 (10-60: 10th-90th centiles) minutes after salbutamol. The magnitude of group response in FEV(1) was significantly higher at 15 and 20 minutes than at 0 and 10 minutes post-salbutamol inhalation (repeat measures analysis of variance [ANOVA] on ranks p < 0.05). We conclude that a minimal interval of 20 minutes, before re-testing spirometry, is required to document the maximal response to bronchodilators in the majority of asthmatic children.
Aspergillus infections and progression of structural lung disease in children with cystic fibrosis
Publisher: American Thoracic Society
Date: 15-03-2020
Sialic acid-to-urea ratio as a measure of airway surface hydration
Publisher: American Physiological Society
Date: 03-2017
DOI: 10.1152/AJPLUNG.00398.2016
Abstract: Although airway mucus dehydration is key to pathophysiology of cystic fibrosis (CF) and other airways diseases, measuring mucus hydration is challenging. We explored a robust method to estimate mucus hydration using sialic acid as a marker for mucin content. Terminal sialic acid residues from mucins were cleaved by acid hydrolysis from airway s les, and concentrations of sialic acid, urea, and other biomarkers were analyzed by mass spectrometry. In mucins purified from human airway epithelial (HAE), sialic acid concentrations after acid hydrolysis correlated with mucin concentrations ( r 2 = 0.92). Sialic acid-to-urea ratios measured from filters applied to the apical surface of cultured HAE correlated to percent solids and were elevated in s les from CF HAEs relative to controls (2.2 ± 1.1 vs. 0.93 ± 1.8, P 0.01). Sialic acid-to-urea ratios were elevated in bronchoalveolar lavage fluid (BALF) from β-epithelial sodium channel (ENaC) transgenic mice, known to have reduced mucus hydration, and mice sensitized to house dust mite allergen. In a translational application, elevated sialic acid-to-urea ratios were measured in BALF from young children with CF who had airway infection relative to those who did not (5.5 ± 3.7 vs. 1.9 ± 1.4, P 0.02) and could be assessed simultaneously with established biomarkers of inflammation. The sialic acid-to-urea ratio performed similarly to percent solids, the gold standard measure of mucus hydration. The method proved robust and has potential to serve as flexible techniques to assess mucin hydration, particularly in s les like BALF in which established methods such as percent solids cannot be utilized.
Quantitative assessment of airway dimensions in young children with cystic fibrosis lung disease using chest computed tomography
Publisher: Wiley
Date: 07-09-2017
DOI: 10.1002/PPUL.23787
Abstract: To evaluate lung disease progression using airway and artery (AA) dimensions on chest CT over 2-year interval in young CF patients longitudinally and compare to disease controls cross-sectionally. Retrospective analysis of pressure controlled end-inspiratory CTs, 12 routine baseline (CT CF, median age CT AA-ratio differences were present in young CF patients relative to disease controls. A
Infection, Inflammation, and Lung Function Decline in Infants with Cystic Fibrosis
Publisher: American Thoracic Society
Date: 07-2011
The genetic and epigenetic landscapes of the epithelium in asthma
Publisher: Springer Science and Business Media LLC
Date: 22-09-2016
The allergic sensitization in infants with atopic eczema from different countries
Publisher: Wiley
Date: 21-01-2009
DOI: 10.1111/J.1398-9995.2008.01779.X
Abstract: No study has compared allergic sensitization patterns in infants with atopic eczema from different countries. The aim of this study was to investigate the patterns of allergic sensitization in a cohort of infants with atopic eczema participating in a multicentre, international study. Two thousand one hundred and eighty-four infants (mean age 17.6 months) with atopic eczema from allergic families were screened in 94 centres in 12 countries to participate in a randomized trial for the early prevention of asthma. Clinical history, Severity Scoring of Atopic Dermatitis Index, measurements for total serum IgE and specific IgE antibodies to eight food and inhalant allergens were entered into a database before randomization to treatment. A history of type of feeding in the first weeks of life and exposure to animals was recorded. A total of 52.9% of the infants had raised total IgE, and 55.5% were sensitized to at least one allergen. There was a wide difference in the total IgE values and in the sensitization rates to foods and aeroallergens among infants from different countries. The highest prevalence rates of allergen-sensitized infants were found in Australia (83%), the UK (79%) and Italy (76%). Infants from Belgium and Poland consistently had the lowest sensitization rates. In each country, a characteristic pattern of sensitization was found for aeroallergens (house dust mite > cat > grass pollen > Alternaria), but not for food allergens. In infants with atopic eczema, there is a wide variation in the pattern of allergic sensitization between countries, and data from one country are not necessarily generalizable to other countries.
Respiratory impedance in children with cystic fibrosis using forced oscillations in clinic
Publisher: European Respiratory Society (ERS)
Date: 11-2007
DOI: 10.1183/09031936.00003407
Abstract: Measurement of lung function is an important component of clinical management in cystic fibrosis (CF), but has been difficult in young children. The present study aimed to characterise the utility of the forced oscillation technique for measurement of lung function in preschool-aged children with CF in a routine clinical setting. Lung function was assessed in 56 young children (aged 2-7 yrs) with CF. Respiratory system resistance (R(rs)) and reactance (X(rs)) at 6, 8 and 10 Hz were measured and expressed as Z-scores. Children were classified as asymptomatic or symptomatic based on an administered respiratory questionnaire and physical examination at the time of testing. Between-test repeatability was assessed in 25 children. Measurement of lung function using the forced oscillation technique was feasible in the CF clinic. The children with CF, as a group, had Z-scores for R(rs) at 6 Hz (R(rs,6)) R(rs,8), R(rs,10), X(rs) at 6 Hz (X(rs,6)) and X(rs,8) that were significantly different from zero. Children with current symptoms showed significantly decreased X(rs) and increased R(rs,6) compared with asymptomatic children. Measurement of lung function using the forced oscillation technique is feasible in young children with cystic fibrosis in a clinical setting. The technique has the potential to improve knowledge concerning early cystic fibrosis lung disease.
Measuring exhaled nitric oxide levels in adults: The importance of atopy and airway responsiveness
Publisher: Elsevier BV
Date: 11-2004
Abstract: Raised exhaled nitric oxide (Feno) levels have been associated with asthma. However, we have found that in children, Feno was increased in atopic children with increased airway responsiveness (AR), and this was independent of a diagnosis of asthma. The current study was designed to test the hypothesis that in adults there is no association between Feno and asthma after controlling for atopy and AR. One hundred fifteen adults (77 women mean age, 41 years) underwent an assessment that included Feno measurements, spirometry, skin-prick testing, blood eosinophil count, and inhaled histamine challenge (results are expressed as a dose-response slope [DRS]). When only atopic in iduals were considered (n = 73), Feno was positively associated with the DRS (p = 0.003), male gender (0.02), and negatively associated with current smoking (p = 0.09). Only male gender (p = 0.03) was associated with Feno among nonatopic in iduals (n = 36). In multivariate analysis, there was no association between Feno and current asthma, current wheeze, or asthma ever. We conclude that in adult subjects, elevated Feno measurements are associated with a phenotype characterized by atopy and increased AR regardless of the presence of asthma or asthma-like symptoms.
Conditionally reprogrammed primary airway epithelial cells maintain morphology, lineage and disease specific functional characteristics
Publisher: Springer Science and Business Media LLC
Date: 21-12-2017
DOI: 10.1038/S41598-017-17952-4
Abstract: Current limitations to primary cell expansion led us to test whether airway epithelial cells derived from healthy children and those with asthma and cystic fibrosis (CF), co-cultured with an irradiated fibroblast feeder cell in F-medium containing 10 µM ROCK inhibitor could maintain their lineage during expansion and whether this is influenced by underlying disease status. Here, we show that conditionally reprogrammed airway epithelial cells (CRAECs) can be established from both healthy and diseased phenotypes. CRAECs can be expanded, cryopreserved and maintain phenotypes over at least 5 passages. Population doublings of CRAEC cultures were significantly greater than standard cultures, but maintained their lineage characteristics. CRAECs from all phenotypes were also capable of fully differentiating at air-liquid interface (ALI) and maintained disease specific characteristics including defective CFTR channel function cultures and the inability to repair wounds. Our findings indicate that CRAECs derived from children maintain lineage, phenotypic and importantly disease-specific functional characteristics over a specified passage range.
Expression of bronchodilator response using forced oscillation technique measurements: absolute versus relative
Publisher: European Respiratory Society (ERS)
Date: 30-06-2010
Early atopic disease and early childhood immunization – is there a link?
Publisher: Wiley
Date: 10-10-2008
DOI: 10.1111/J.1398-9995.2008.01696.X
Abstract: There are frequent concerns about early immunizations among the parents of children at heightened risk for atopy. The study assessed the effect of vaccine immunization before the first birthday on eczema severity and allergic sensitization in the second year of life. A total of 2184 infants, aged 1-2 years, with established atopic dermatitis and a family history of allergy, from 97 study centres in 10 European countries, South Africa and Australia were included. Exposure to vaccines (diphtheria, tetanus, pertussis, polio, Haemophilus influenzae Type B, hepatitis B, mumps, measles, rubella, varicella, BCG, meningococci and pneumococci) and immunization dates were recorded from immunization cards. Immunoglobulin E (IgE) was determined by RAST and eczema severity was assessed by scoring atopic dermatitis (SCORAD). Immunization against any target was not associated with an increased risk of allergic sensitization to food or inhalant allergens. Varicella immunization (only 0.7% immunized) was inversely associated with total IgE > 30 kU/l (OR 0.27 95% CI 0.08-0.87) and eczema severity (OR 0.34 95% CI 0.12-0.93). Pertussis immunization (only 1.7% nonimmunized) was inversely associated with eczema severity (OR 0.30 95% CI 0.10-0.89). Cumulative received vaccine doses were inversely associated with eczema severity (P = 0.0107). The immunization coverage of infants before and after the onset of atopic dermatitis was similar. In children at heightened risk for atopy, common childhood immunization in the first year is not associated with an increased risk of more severe eczema or allergic sensitization. Parents of atopic children should be encouraged to fully immunize their children.
Shear Strength Optimization of Reinforced Honeycomb Core Materials
Publisher: Informa UK Limited
Date: 19-10-2010
Progression of early structural lung disease in young children with cystic fibrosis assessed using CT
Publisher: BMJ
Date: 26-12-2012
DOI: 10.1136/THORAXJNL-2011-200912
Abstract: Cross-sectional studies implicate neutrophilic inflammation and pulmonary infection as risk factors for early structural lung disease in infants and young children with cystic fibrosis (CF). However, the longitudinal progression in a newborn screened population has not been investigated. To determine whether early CF structural lung disease persists and progresses over 1 year and to identify factors associated with radiological persistence and progression. 143 children aged 0.2-6.5 years with CF from a newborn screened population contributed 444 limited slice annual chest CT scans for analysis that were scored for bronchiectasis and air trapping and analysed as paired scans 1 year apart. Logistic and linear regression models, using generalised estimating equations to account for multiple measures, determined associations between persistence and progression over 1 year and age, sex, severe cystic fibrosis transmembrane regulator (CFTR) genotype, pancreatic sufficiency, current respiratory symptoms, and neutrophilic inflammation and infection measured by bronchoalveolar lavage. Once detected, bronchiectasis persisted in 98/133 paired scans (74%) and air trapping in 178/220 (81%). The extent of bronchiectasis increased in 139/227 (63%) of paired scans and air trapping in 121/264 (47%). Radiological progression of bronchiectasis and air trapping was associated with severe CFTR genotype, worsening neutrophilic inflammation and pulmonary infection. CT-detected structural lung disease identified in infants and young children with CF persists and progresses over 1 year in most cases, with deteriorating structural lung disease associated with worsening inflammation and pulmonary infection. Early intervention is required to prevent or arrest the progression of structural lung disease in young children with CF.
Home oxygen for children with acute bronchiolitis.
Publisher: BMJ
Date: 16-10-2008
Abstract: A prospective randomised controlled pilot study was performed comparing home oxygen therapy with traditional inpatient hospitalisation for children with acute bronchiolitis. Children aged 3-24 months with acute bronchiolitis, still requiring oxygen supplementation 24 h after admission to hospital, were randomly assigned to receive oxygen supplementation at home with support from "hospital in the home" (HiTH) or to continue oxygen supplementation in hospital. 44 children (26 male, mean age 9.2 months) were recruited (HiTH n = 22) between 1 August and 30 November 2007. Only one child from each group was readmitted to hospital and there were no serious complications. Children in the HiTH group spent almost 2 days less in a hospital bed than those managed as traditional inpatients: HiTH 55.2 h (interquartile range (IQR) 40.3-88.9) versus in hospital 96.9 h (IQR 71.2-147.2) p = 0.001. Home oxygen therapy appears to be a feasible alternative to traditional hospital oxygen therapy in selected children with acute bronchiolitis.
Of pigs, mice, and men: Understanding early triggers of cystic fibrosis lung disease
Publisher: American Thoracic Society
Date: 10-2016
Exciting New Clinical Trials in Cystic Fibrosis
Publisher: American Thoracic Society
Date: 15-06-2011
Respiratory infection rates differ between geographically distant paediatric cystic fibrosis cohorts
Publisher: European Respiratory Society (ERS)
Date: 07-2016
DOI: 10.1183/23120541.00014-2016
Abstract: Respiratory infections are a major cause of pulmonary decline in children with cystic fibrosis (CF). We compared the prevalence of infection in early life at geographically distant CF treatment centres participating in the same surveillance programme in Australia. Lower airway microbiology, inflammation and structural lung disease at annual review were evaluated for 260 children 0–8 years old with CF at 1032 visits to CF treatment centres in Melbourne or Perth. Melbourne patients were more likely to be culture-positive for common respiratory pathogens at all age groups (odds ratio (OR) 1.85, 95% CI 1.33–2.58). Subjects years old in Melbourne were also more likely to have neutrophil elastase present (OR 3.11, 95% CI 1.62–5.95). Bronchiectasis (OR 2.02, 95% CI 1.21–3.38) and air trapping (OR 2.53, 95% CI 1.42–4.51) in subjects 2–5 years old was more common in Melbourne subjects. The severity of structural lung disease was also worse in Melbourne patients years old. Patients at both centres had a similar rate of hospitalisations and prescribed antibiotics. No procedural differences were identified that could explain the disparity between pathogen prevalence. Geographical differences in early acquisition of infection may contribute to variability in outcomes between CF centres.
Exhaled nitric oxide is reduced in infants with rhinorrhea
Publisher: Wiley
Date: 02-2005
DOI: 10.1002/PPUL.20149
Abstract: In infants, the effect of colds and other respiratory tract infections (RTI) on exhaled nitric oxide (FE(NO)) is not clear. In this study, we measured FE(NO) in 24 infants (14 boys) who presented with rhinorrhea, with or without cough but not wheeze. Twelve of these infants had a history of recurrent wheeze. Levels were compared with a group of 23 healthy infants (13 boys). Further, 8 infants (5 with a history of recurrent wheeze) with rhinorrhea were tested after symptoms had resolved. Infants with rhinorrhea had significantly lower FE(NO) than the healthy infants (11.9 vs. 23.8 ppb, respectively, P < 0.0007). Levels increased from 7.5 ppb to 34.1 ppb in the 8 infants tested with and without symptoms (P = 0.0002). Infants with rhinorrhea have reduced FE(NO), irrespective of their respiratory history.
BILE ACIDS IN LOWER AIRWAYS AS A NOVEL INDICATOR OF AIRWAY MICROBIOTA CHANGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2023
DOI: 10.1101/2023.06.04.23290702
Abstract: Chronic obstructive pulmonary disease (COPD) is a complex disorder with a high degree of interin idual variability. Gastrointestinal dysfunction is common in COPD patients and has been proposed to influence the clinical progression of the disease. Using the presence of bile acid(s) (BA) in bronchoalveolar lavage fluid (BAL) as a marker of gastric aspiration, we evaluated the relationships between BAs, clinical outcomes, and bacterial lung colonisation. We used BAL specimens from a cohort of COPD patients and healthy controls. Bile acids were profiled and quantified in BAL supernatants using mass spectrometry. Microbial DNA was extracted from BAL cell pellets and quantified using qPCR. We profiled the BAL microbiota using an licon sequencing approach targeting the V3-V4 region of the 16S rRNA gene. Detection of BAs in BAL was more likely at earliest clinical stages of COPD and was independent of the degree of airway obstruction. BAL specimens with BAs demonstrated higher bacterial biomass and lower ersity. Likewise, the odds of recovering bacterial cultures from BAL were higher if BAs were also detected. Detection of BAs in BAL was not associated with either inflammatory markers or clinical outcomes. We also observed different bacterial community types in BAL, which were associated with different clinical groups, levels of inflammatory markers, and the degree of airway obstruction. Detection of BAs in BAL was associated with different parameters of airway ecology. Further studies are needed to evaluate whether BAs in BAL can be used to stratify patients and for predicting disease progression trajectories.
Hypoxia and sterile inflammation in cystic fibrosis airways: Mechanisms and potential therapies
Publisher: European Respiratory Society (ERS)
Date: 23-12-2017
DOI: 10.1183/13993003.00903-2016
Abstract: Cystic fibrosis is one of the most common autosomal recessive genetic diseases in Caucasian populations. Diagnosis via newborn screening and targeted nutritional and antibiotic therapy have improved outcomes, however respiratory failure remains the key cause of morbidity and mortality. Progressive respiratory disease in cystic fibrosis is characterised by chronic neutrophilic airway inflammation associated with structural airway damage leading to bronchiectasis and decreased lung function. Mucus obstruction is a characteristic early abnormality in the cystic fibrosis airway, associated with neutrophilic inflammation often in the absence of detectable infection. Recent studies have suggested a link between hypoxic cell death and sterile neutrophilic inflammation in cystic fibrosis and other diseases via the IL-1 signalling pathway. In this review, we consider recent evidence regarding the cellular responses to respiratory hypoxia as a potential driver of sterile neutrophilic inflammation in the lung, current knowledge on hypoxia as a pathogenic mechanism in cystic fibrosis and the potential for current and future therapies to alleviate hypoxia-driven sterile inflammation.
Cystic Fibrosis Clinical Isolates of Aspergillus fumigatus Induce Similar Muco-inflammatory Responses in Primary Airway Epithelial Cells.
Publisher: MDPI AG
Date: 13-08-2021
DOI: 10.3390/PATHOGENS10081020
Abstract: Aspergillus is increasingly associated with lung inflammation and mucus plugging in early cystic fibrosis (CF) disease during which conidia burden is low and strains appear to be highly erse. It is unknown whether clinical Aspergillus strains vary in their capacity to induce epithelial inflammation and mucus production. We tested the hypothesis that in idual colonising strains of Aspergillus fumigatus would induce different responses. Ten paediatric CF Aspergillus isolates were compared along with two systemically invasive clinical isolates and an ATCC reference strain. Isolates were first characterised by ITS gene sequencing and screened for antifungal susceptibility. Three clusters (A−C) of Aspergillus isolates were identified by ITS. Antifungal susceptibility was variable, particularly for itraconazole. Submerged CF and non-CF monolayers as well as differentiated primary airway epithelial cell cultures were incubated with conidia for 24 h to allow germination. None of the clinical isolates were found to significantly differ from one another in either IL-6 or IL-8 release or gene expression of secretory mucins. Clinical Aspergillus isolates appear to be largely homogenous in their mucostimulatory and immunostimulatory capacities and, therefore, only the antifungal resistance characteristics are likely to be clinically important.
Characterization of Maximal Respiratory Pressures in Healthy Children
Publisher: S. Karger AG
Date: 2012
DOI: 10.1159/000342298
Abstract: b i Background: /i /b Measurements of maximal voluntary inspiratory (P smlcap i /smlcap sub max /sub ) and expiratory (P smlcap e /smlcap sub max /sub ) pressures are used in the management of respiratory muscle disease. There is little data on the appropriate reference range, success rates, or repeatability of P smlcap i /smlcap sub max /sub and P smlcap e /smlcap sub max /sub in children or on methodological factors affecting test outcomes. b i Objectives: /i /b To determine P smlcap i /smlcap sub max /sub and P smlcap e /smlcap sub max /sub in healthy children and examine which published reference equations are best suited to a contemporary population. Secondary objectives were to assess within-test repeatability and the influence of lung volumes on P smlcap i /smlcap sub max /sub and P smlcap e /smlcap sub max /sub . b i Methods: /i /b Healthy children were prospectively recruited from the community on a volunteer basis and underwent spirometry, static lung volumes, and P smlcap i /smlcap sub max /sub and P smlcap e /smlcap sub max /sub testing. b i Results: /i /b Acceptable and repeatable (to within 20%) P smlcap i /smlcap sub max /sub and P smlcap e /smlcap sub max /sub were obtained in 156 children, with 105 (67%) children performing both P smlcap i /smlcap sub max /sub and P smlcap e /smlcap sub max /sub measurements to within 10% repeatability. The reference equations of Wilson et al. [Thorax 1984 :535–538] best matched our healthy Caucasian children. There was an inverse relationship between P smlcap i /smlcap sub max /sub and the percent of total lung capacity (TLC) at which the measurement was obtained (beta coefficient –0.96 95% CI –1.52 to –0.39 p = 0.001), whereas at lung volumes of % TLC P smlcap e /smlcap sub max /sub was independent of lung volume (p = 0.26). b i Conclusion: /i /b We demonstrated that the Wilson et al. [Thorax 1984 :535–538] reference ranges are most suited for contemporary Caucasian Australasian children. However, robust multiethnic reference equations for maximal respiratory pressures are required. This study suggests that 10% within-test repeatability criteria are feasible in clinical practice, and that the use of lung volume measurements will improve the quality of maximal respiratory pressure measurements.
Feasibility of parental collected nasal swabs for virus detection in young children with cystic fibrosis
Publisher: Elsevier BV
Date: 12-2014
Successful establishment of primary small airway cell cultures in human lung transplantation
Publisher: Springer Science and Business Media LLC
Date: 26-10-2009
Abstract: The study of small airway diseases such as post-transplant bronchiolitis obliterans syndrome (BOS) is h ered by the difficulty in assessing peripheral airway function either physiologically or directly. Our aims were to develop robust methods for s ling small airway epithelial cells (SAEC) and to establish submerged SAEC cultures for downstream experimentation. SAEC were obtained at 62 post-transplant bronchoscopies in 26 patients using radiologically guided bronchial brushings. Submerged cell cultures were established and SAEC lineage was confirmed using expression of clara cell secretory protein (CCSP). The cell yield for SAEC (0.956 ± 0.063 × 10 6 ) was lower than for large airway cells (1.306 ± 0.077 × 10 6 ) but did not significantly impact on the culture establishment rate (79.0 ± 5.2% vs. 83.8 ± 4.7% p = 0.49). The presence of BOS significantly compromised culture success (independent of cell yield) for SAEC (odds ratio (95%CI) 0.067 (0.01-0.40)) but not LAEC (0.3 (0.05-1.9)). Established cultures were successfully passaged and expanded. Primary SAEC can be successfully obtained from human lung transplant recipients and maintained in culture for downstream experimentation. This technique will facilitate the development of primary in vitro models for BOS and other diseases with a small airway component such as asthma, cystic fibrosis and COPD.
Correlation of forced oscillation technique in preschool children with cystic fibrosis with pulmonary inflammation
Publisher: BMJ
Date: 02-2005
Early Lung Disease in Infants and Preschool Children with Cystic Fibrosis. What Have We Learned and What Should We Do about It?
Publisher: American Thoracic Society
Date: 15-06-2017
The effect of age on oxygen desaturation during histamine inhalation challenge in normal infants
Publisher: Wiley
Date: 09-1993
Abstract: Arterial oxygen saturation (SaO2) is usually measured during inhalation challenges in infants as desaturation has been demonstrated with provoked bronchoconstriction. We wished to examine whether measurement of SaO2 would provide a simple noninvasive indicator of respiratory function (RF) changes occurring during inhalation challenge in infants. Histamine inhalation challenges were performed longitudinally in 22 normal healthy infants at 4 and 26 weeks of age. RF was measured by calculating maximum forced expiratory flow at functional residual capacity (VmaxFRC) using the rapid thoracic compression technique. Airway responsiveness was assessed using histamine the provoking concentration (PC) was that which caused a fall in VmaxFRC of at least 40% from baseline. The provocative concentration for an exact fall of 40% in VmaxFRC (PC40) from baseline was derived by linear interpolation. SaO2 was continuously monitored by pulse oximetry. One month old infants had higher SaO2 levels throughout the inhalation challenge in comparison to their SaO2 levels at 6 months of age. Significant falls in SaO2 were observed at the PC at both ages. However, at the age of 26 weeks the infants had greater median falls in SaO2 [PC, 4.5% (95%CI: 3.0, 7.0)] compared to the response at age 4 weeks [3.0% (95%CI: 1.0, 4.0) (P < 0.01)]. Median falls in VmaxFRC at the PC were not different between the ages. These results indicate an age-dependent discordance between airway and SaO2 response in healthy infants during histamine-induced bronchoconstriction.
No more dogma
Publisher: American Thoracic Society
Date: 15-01-2009
Lung function and bronchial challenges in infants: Repeatability of histamine and comparison with methacholine challenges
Publisher: Wiley
Date: 09-1993
Abstract: Limited information exists regarding the repeatability of lung function and bronchial challenge tests using the rapid thoracic compression technique (RTC) in infants. To determine the repeatability of lung function and histamine challenge test results using the RTC technique and to compare the results obtained for bronchial challenges using histamine (H) and methacholine (M). Twelve infants [7 healthy, 5 with cystic fibrosis (CF) had pairs of H challenges 1 week apart. Eleven infants (7 healthy, 4 CF) had one H and one M challenge a week apart. The provocative concentration of H or M to cause a 40% fall in maximum flow at functional residual capacity (PC40) was determined using the RTC technique. Twenty-three comparisons were possible between maximal expiratory flow at functional residual capacity (VmaxFRC) measurements made 1 week apart. The mean difference between pairs of VmaxFRC measurements was 6.4% of baseline, and the coefficient of repeatability was 31.1% of baseline. The mean difference between PC40(H) measurements was 0.163 doubling concentrations, with a coefficient of repeatability of 1.66 doubling concentrations. The mean difference between PC40(H) and PC40(M) was 0.75 doubling concentrations, with 95% of PC40(H) between -0.18 to 1.69 doubling concentrations of the PC40(M). Although the repeatability of VmaxFRC using the RTC technique is less than for voluntary forced expiratory flow parameters in older children, similar results were obtained for infants as observed in older subjects for repeatability of H challenges and agreement between measures of bronchial responsiveness using H or M.
Air Trapping on Chest CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis Diagnosed following Newborn Screening
Publisher: Public Library of Science (PLoS)
Date: 19-08-2011
Identification of Epithelial Phospholipase A2 Receptor 1 as a Potential Target in Asthma
Publisher: American Thoracic Society
Date: 12-2016
Azithromycin Partially Mitigates Dysregulated Repair of Lung Allograft Small Airway Epithelium.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2020
Lower Airway Infection in Preschool Children with Cystic Fibrosis: An International Comparison Reply
Publisher: American Thoracic Society
Date: 15-03-2020
Transcriptomic analyses reveal regional signatures in lung allograft recipients
Publisher: Cold Spring Harbor Laboratory
Date: 03-04-2023
DOI: 10.1101/2023.04.03.23288063
Abstract: Long term outcomes of allograft recipients are compromised by the development of chronic lung allograft dysfunction (CLAD) promoting bronchiolitis obliterans syndrome (BOS). We established baseline transcriptomic profiles of both the large and small airway epithelial cells (referred as LAEC and SAEC, respectively) to identify regional differences irrespective of initiating disease. We obtained matched primary LAEC and SAEC from lung allograft recipients (n=4, 42.5 ± 4.2 years) and established primary cultures. Bulk RNA sequencing was performed to determine differentially expressed genes. We observed differences in the transcriptional program between LAEC and SAEC Transcription factors (TF) were ranked within the top ten differentially regulated genes. The most abundant TF families included C2H2-ZF, homeobox and bHLH. Upstream regulator analyses identified homeobox genes being significantly in LAEC. Protein-protein interaction network analysis emphasised the role of TFs ( ISL1, MSX1, HOXA1, GATA6, ZNF423 ) in airway modulation. Additionally, functional enrichment analysis revealed the activation of chemotaxis, metalloendipeptidase/metallopeptidase activity and pro-inflammatory signatures (IL17 signalling and RAGE), in LAEC, while SAEC were characterised by elevated expression of surfactant metabolism related genes. Moreover, alveolar and club cells-related genes were expressed in SAEC, suggesting a lower airway-specific signature. Our analysis shows robust transcriptional differences between LAEC and SAEC. We suggest a potential role for homeobox TF family as well as the activation of the immune system in the biology of LAEC. Conversely, we observed an alveoli-like transcriptional signature in SAEC, including gas-exchange signals and surfactant metabolism pathways involved in lung homeostasis.
How free of tobacco smoke are 'smoke-free' homes?
Publisher: Hindawi Limited
Date: 06-2008
DOI: 10.1111/J.1600-0668.2008.00517.X
Abstract: The risks of exposure to environmental tobacco smoke (ETS) are well established and 'harm reduction' strategies such as smoking outside to protect infants and children from exposure to ETS have been advocated for some time. The aim of this study was to assess the validity of self-reported smoking levels in residential settings. The participants were families (n = 92) randomly selected from lower socioeconomic areas of Perth, Western Australia. Each household was monitored for vapor phase nicotine and particulates with an aerodynamic diameter of < or = 10 microm (PM(10)). Of the 42% (39) households who reported that someone smoked cigarettes at home, only four (4%) said that smoking occurred inside the house. There was a 'moderate' agreement between parental-reported tobacco smoking and levels of nicotine (kappa = 0.55, P < 0.01). There were significant differences in the median levels of air nicotine (P < 0.01) and PM(10) (P < 0.05) between households in which smoking was reported as only occurring outside, and the smoke-free households. The study outcome suggests that a strategy based on the separation of children and smoking activity is inadequate to protect the former from ETS at home, and that health professionals should give parents unambiguous advice to give up smoking in order to make their homes a completely smoke-free environment.
Inflammatory markers should be the basis of monitoring asthma. The case for the pro's
Publisher: Elsevier BV
Date: 2006
PRAGMA-CF. A Quantitative Structural Lung Disease Computed Tomography Outcome in Young Children with Cystic Fibrosis
Publisher: American Thoracic Society
Date: 15-05-2015
Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants
Publisher: Elsevier BV
Date: 10-1996
DOI: 10.1016/S0140-6736(96)04446-7
Abstract: Infants of mothers who smoke have reduced respiratory function and are more likely to develop wheezing. Little evidence is available on the effect of in-utero cigarette-smoke exposure as opposed to postnatal exposure to environmental tobacco smoke. We used a previously validated non-invasive method to measure the time to peak tidal expiratory flow (tPTEF) as a proportion of expiratory time (tE) in newborn infants soon after birth to examine the effects of a family history of asthma and in-utero cigarette-smoke exposure on the infants' respiratory function. We collected respiratory-function data from 500 healthy infants of mothers taking part in the Western Australia Pregnancy Cohort Study. During behaviourally defined quiet sleep, measurements were obtained a median of 58 h (range 26-159) after the infants were born. We used uncalibrated inductance plethysmography. The uncalibrated volume signal was differentiated to flow and used to calculate respiratory rate, total inspiratory time, tE, and tPTEF. Mothers answered questionnaires on demographic, medical, and pregnancy characteristics, including smoking history. Serum cotinine measurements were available to validate self-reported smoking history in a subset of mothers (238). Data suitable for analysis were obtained from 461 infants. In multivariate regression analysis, lower values of tPTEF/tE were independently associated with respiratory rate (beta coefficient per 10 breaths/min 0.018 [SE 0.005], p < 0.01), age (beta coefficient per 10 h -0.008 [0.003], p 10 cigarettes daily beta coefficient -0.049 [0.022], p < 0.05), maternal hypertension during pregnancy (-0.037 [0.015], p < 0.02), and a family history of asthma (-0.028[0.014], p < 0.05). In-utero smoke exposure, a family history of asthma, and maternal hypertension during pregnancy are associated with reduced respiratory function after birth. We speculate that these factors adversely affect lung development in utero.
Inhaled fluticasone dipropionate decreases levels of nitric oxide in recurrenty wheezy infants
Publisher: Wiley
Date: 16-06-2004
DOI: 10.1002/PPUL.20055
Abstract: We examined the effect of inhaled fluticasone diproprionate (FDP) on symptoms, lung function (FEV(0.5)), and exhaled nitric oxide (Fe(NO)) in infants with recurrent wheeze and raised Fe(NO). Thirty-one infants aged 6-19 months (mean, 12.7 months 12 girls) completed the study. All infants had a history of recurrent wheeze and a parental history of atopy. All children had raised Fe(NO), as determined by an offline tidal breathing technique prior to randomization. Lung function and Fe(NO) were assessed before and after 4 weeks of treatment with FDP or placebo. The parents recorded daily symptoms during the treatment period. Sixteen infants received FDP and 15 the placebo for 4 weeks. At completion of the study, infants treated with FDP had a significant reduction in Fe(NO) (35.0 ppb to 16.5 ppb) compared to those that received placebo (35.2 ppb to 30.2 ppb) (P = 0.05). Small increases in FEV(0.5) were observed in both groups, but these changes were not different between groups (P = 0.8). Symptom scores were not significantly different in either group following the intervention. We showed that a moderate dose of inhaled FDP reduces levels of Fe(NO), a potential marker of airway inflammation, even in the absence of significant changes in lung function and symptoms.
Selection of housekeeping genes for real-time PCR in atopic human bronchial epithelial cells
Publisher: European Respiratory Society (ERS)
Date: 09-2008
DOI: 10.1183/09031936.00129107
Abstract: The stability of housekeeping genes (HKGs) is critical when performing real-time quantitative PCR. To date, the stability of common HKGs has not been systematically compared in human airway epithelial cells (AEC) in normal and atopic subjects. Expression levels of 12 HKGs were measured in AECs from a cohort of 30 healthy atopic nonasthmatic or atopic asthmatic children. Gene expression stability was determined using three different Visual Basic for Applications applets (geNorm, NormFinder and BestKeeper). All 12 HKGs were expressed in AECs. However, the hypoxanthine ribosyltransferase and TATA-binding protein genes were excluded from further analysis due to low expression levels. The cyclophilin A gene was ranked the most stable by all three methods. The expression levels of the beta-actin and glyceraldehyde-3-phosphate dehydrogenase genes were significantly different between the three groups of patients, with atopic asthmatics showing the highest expression levels for both genes. The results suggest that the cyclophilin A gene is the most suitable housekeeping gene analysed for expression studies utilising uncultured bronchial airway epithelial cells from healthy and asthmatic children, and highlight the importance of validating housekeeping genes for each experimental model.
Bronchiectasis in an asymptomatic infant with cystic fibrosis diagnosed following newborn screening
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.JCF.2009.04.009
Abstract: Many countries have introduced newborn screening for cystic fibrosis to facilitate diagnosis prior to the development of lung disease. Although most infants with cystic fibrosis are asymptomatic from a respiratory point of view at diagnosis, structural lung disease has been detected by computed tomography. We present a case of an asymptomatic infant with cystic fibrosis diagnosed following newborn screening who had endobronchial infection with Pseudomonas aeruginosa and radiological evidence of bronchiectasis at 3 months of age.
Biomarkers in Paediatric Cystic Fibrosis Lung Disease
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.PRRV.2015.05.004
Abstract: Biomarkers in cystic fibrosis are used i. for the measurement of cystic fibrosis transmembrane regulator function in order to diagnose cystic fibrosis, and ii. to assess aspects of lung disease severity (e.g. inflammation, infection). Effective biomarkers can aid disease monitoring and contribute to the development of new therapies. The tests of cystic fibrosis transmembrane regulator function each have unique strengths and weaknesses, and biomarkers of inflammation, infection and tissue destruction have the potential to enhance the management of cystic fibrosis through the early detection of disease processes. The development of biomarkers of cystic fibrosis lung disease, in particular airway inflammation and infection, is influenced by the challenges of obtaining relevant s les from infants and children for whom early detection and treatment of disease might have the greatest long term benefits.
Confirmation of the association between high levels of immunoglobulin E food sensitization and eczema in infancy: an international study
Publisher: Wiley
Date: 19-11-2007
DOI: 10.1111/J.1365-2222.2007.02861.X
Abstract: Studies of Australian infants have reported that more than 80% of those with moderate atopic eczema (AE) have high levels of IgE food sensitization (IgE-FS) that are commonly associated with IgE food allergy. To explore the relationship between high levels of IgE-FS and AE in a large cohort of young children with eczema participating in a multi-centre, international study. Two thousand one hundred and eighty-four subjects (mean age 17.6 months, range 11.8-25.4 1246 males) with active eczema from atopic families from 94 centres in 12 countries were studied. Clinical history, Scoring Atopic Dermatitis index as a measure of eczema severity and CAP-FEIA measurements for total IgE and IgE antibody levels to cow milk, egg and peanut were entered into a database. If CAP-FEIA levels exceeded previously reported age-specific cut-off levels for 95% positive predictive values (PPVs) for food allergy, subjects were defined as having high-risk IgE-FS (HR-IgE-FS). Serum was available from 2048 patients 55.5% were atopic. The frequency of HR-IgE-FS to milk, egg and/or peanut was the greatest in patients whose eczema developed in the first 3 months of life and the least in those whose eczema developed after 12 months (P<0.0001). In a regression analysis to allow for potential confounding factors, children with HR-IgE-FS had the most severe eczema and the youngest age of onset (P<0.001) 64% of infants with severe eczema of onset-age <3 months had HR-IgE-FS. Early-onset severe eczema in infancy was associated with HR-IgE-FS. Clinical implications Food allergies should be routinely assessed in infants with moderate or severe eczema. Capsule summary In eczematous infants, the earlier the age of onset, and the greater the severity of eczema, the greater the frequency of associated high levels of IgE-FS.
The AREST CF experience in biobanking - More than just tissues, tubes and time
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.JCF.2017.08.003
Abstract: Research to further improve outcomes for people with CF is dependent upon well characterised, archived and accessible clinical specimens. The recent article by Beekman et al. published in Journal of Cystic Fibrosis summarised a scientific meeting at the 13th ECFS Basic Science Conference. This meeting discussed how well-annotated, clinical biobanks for CF could be established in Europe to meet the needs of therapeutic development. The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has conducted biobanking of CF research and clinical specimens since the late 1990s and is custodian of the most comprehensive paediatric CF biobank in the world that focuses on the first years of life. This short communication will describe the approach undertaken by AREST CF in establishing a clinical specimen biobank.
Visualisation of Multiple Tight Junctional Complexes in Human Airway Epithelial Cells.
Publisher: Springer Science and Business Media LLC
Date: 02-2018
Productive infection of human embryonic stem cell-derived NKX2.1+ respiratory progenitors with human rhinovirus
Publisher: Oxford University Press (OUP)
Date: 14-04-2015
Abstract: This report provides proof-of-principle experiments demonstrating, for the first time, that human respiratory progenitor cells derived from stem cells in the laboratory can be productively infected with human rhinovirus, the predominant cause of the common cold.
Multiple-breath washout outcomes are sensitive to inflammation and infection in children with cystic fibrosis
Publisher: American Thoracic Society
Date: 09-2017
Forced oscillations in the clinical setting in young children with neonatal lung disease
Publisher: European Respiratory Society (ERS)
Date: 05-03-2008
DOI: 10.1183/09031936.00058107
Abstract: The extent of respiratory dysfunction is not well characterised in children with neonatal chronic lung disease (nCLD) too young to perform spirometry. Forced oscillations are easily performed by healthy young children however, they may be more difficult for those with nCLD. The present study aimed to describe the feasibility of using the forced oscillation technique in children with nCLD in a routine clinical setting and to investigate the influence of neonatal factors on subsequent lung function. Respiratory function tests were attempted in 64 patients with nCLD aged 3.2-6.6 yrs. Respiratory resistance and reactance at 6, 8 and 10 Hz were expressed as z-scores derived from a healthy reference population. The within-test variation and between-test repeatability were also assessed. Technically, satisfactory data were obtained from 77% of children. On grouped data, z-scores for all oscillatory indices were different from zero and related to hospital oxygen administration in the neonatal period. In conclusion, the forced oscillation technique was feasible in preschool children with neonatal chronic lung disease in the clinical outpatient setting. These children had lung function significantly worse than that predicted from healthy children. Respiratory function assessed using forced oscillations appeared to reflect the severity of lung disease during the neonatal period.
Exposure to airborne mould in school environments and nasal patency in children
Publisher: SAGE Publications
Date: 10-05-2013
Abstract: Mould in schools has been associated with increased upper airway obstruction in adults. In this study, we investigated the relationship between school indoor mould spore exposure and nasal patency in children. Airborne mould s les were collected in 32 classrooms from 4 primary schools during both summer and winter using a single-stage Anderson s ler. Nasal patency was measured in 275 children in summer and 200 children in winter using acoustic rhinometry. Various mould species were isolated but the most common species found inside the classrooms were Alternaria, Aspergillus niger, Cladosporium spp. and Penicillium spp. In the univariate analyses, significant negative correlations were found between exposure to various mould species, particularly Alternaria, and rhinometric measures in the children. In multivariate analyses, exposure to Alternaria was associated with both decreased mean nasal cross-sectional area ( p = 0.001) and decreased nasal volume ( p = 0.026). Decreased nasal patency was also associated with exposure to A. niger ( p = 0.034) and Penicillium ( p = 0.043) in the classrooms. The findings of this study suggest that exposure to airborne mould, particularly Alternaria, in school environments may affect the upper airways of children.
Elucidating the Interaction of CF Airway Epithelial Cells and Rhinovirus: Using the Host-Pathogen Relationship to Identify Future Therapeutic Strategies.
Publisher: Frontiers Media SA
Date: 07-11-2018
Dysregulated repair in asthmatic paediatric airway epithelial cells: The role of plasminogen activator inhibitor-1
Publisher: Wiley
Date: 19-11-2008
DOI: 10.1111/J.1365-2222.2008.03093.X
Abstract: Asthma is associated with structural changes to airways such as extracellular matrix deposition and epithelial damage. Evidence suggests that asthmatic airway epithelial repair is abnormal and that elevated plasminogen activator inhibitor-1 levels observed in asthma may be involved in the epithelial repair process and in excessive matrix accumulation. To assess the ability of asthmatic airway epithelial cells (AECs) to repair mechanically induced wounds and to investigate the role that plasminogen activator inhibitor-1 plays in the repair process. AECs were isolated from atopic asthmatic and healthy non-atopic children by bronchial brushing, subcultured and wound repair experiments were performed. Plasminogen activator inhibitor-1 gene expression was assessed using real-time PCR while protein activity was measured in cell lysates as well as plasma. The role of plasminogen activator inhibitor-1 in epithelial proliferation and wound repair was investigated using siRNA. Cells from asthmatic children have a significantly longer repair time in comparison with cells from otherwise healthy donors. Plasminogen activator inhibitor-1 mRNA expression was up-regulated 68-fold in freshly isolated asthmatic cells compared with normal cells, and protein levels were also significantly elevated in the asthmatic cell lysates, but plasma levels were similar in both groups. Plasminogen activator inhibitor-1 cells expression increased in both cohorts during culture. Gene silencing substantially reduced the rate of proliferation in asthmatic and healthy cells. Mechanical wounding of epithelial monolayers induced plasminogen activator inhibitor-1 expression in asthmatic and non-asthmatic cohorts, while gene silencing delayed wound repair of healthy cell, with minimal effect on those from asthmatics. Asthmatic AECs are inherently dysfunctional in their ability to repair wounds plasminogen activator inhibitor-1 mRNA and protein activity are constitutively up-regulated in asthmatic epithelium and play functional roles in both proliferation and repair of healthy cells. In asthmatic cells, elevated plasminogen activator inhibitors-1 levels fail to stimulate epithelial repair.
Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach
Publisher: European Respiratory Society (ERS)
Date: 14-05-2008
DOI: 10.1183/09031936.00002108
Abstract: There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.
Induction of Epithelial–Mesenchymal Transition in Primary Airway Epithelial Cells from Patients with Asthma by Transforming Growth Factor-β1
Publisher: American Thoracic Society
Date: 15-07-2009
Expiratory flow limitation and breathing strategies in overweight adolescents during submaximal exercise
Publisher: Springer Science and Business Media LLC
Date: 31-07-2013
DOI: 10.1038/IJO.2013.137
Abstract: To investigate whether ventilatory factors limit exercise in overweight and obese children during a 6-min step test and to compare ventilatory responses during this test with those of healthy weight children. Cross-sectional, prospective comparative study. Twenty-six overweight/obese subjects and 25 healthy weight subjects with no known respiratory illness. Various fatness and fat distribution parameters (using air displacement plethysmography and anthropometry), pulmonary function tests, breath-by-breath gas analysis during exercise, perceived exertion. Young people who are overweight or obese are more likely to experience expiratory flow limitation (expFL) during submaximal exercise compared with their healthy weight peers [OR 7.2 (1.4, 37.3), P=0.019]. Subjects who had lower lung volumes at rest were even more likely to experience exercise-induced expFLs [OR 8.35 (1.4-49.3)]. Both groups displayed similar breathing strategies during submaximal exercise. Young people who are overweight/obese are more likely to display expFL during submaximal exercise compared with children of healthy weight . Use of compensatory breathing strategies appeared to enable overweight children to avoid the experience of breathlessness at this intensity of exercise.
Reduced transforming growth factor β1 (TGF-β1) in the repair of airway epithelial cells of children with asthma.
Publisher: Wiley
Date: 24-05-2016
DOI: 10.1111/RESP.12810
Abstract: Evidence into the role of TGF-β1 in airway epithelial repair in asthma is still controversial. This study tested the hypothesis that the reduced TGF-β1 levels previously observed in paediatric asthmatic airway epithelial cells directly contribute to the dysregulated repair seen in these cells. Primary airway epithelial cells (pAEC) from children with asthma (n = 16) and non-asthmatic subjects (n = 20) were isolated, and subcultured for investigation of TGF-β1 gene and protein via quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Expression of other associated genes such as integrins αvβ6, αvβ8 and MT1-MMP were also tested. Small interfering RNA (siRNA) was employed to assess the role of TGF-β1 during wound repair. TGF-β1 gene and protein expression were significantly downregulated in asthmatic pAEC over the course of repair, compared with cells from non-asthmatic children. Messenger RNA (mRNA) expression of TGF-β1 was also directly implicated in non-asthmatic and asthmatic pAEC proliferation over their quiescent counterparts. Small interfering RNA-mediated knockdown of TGF-β1 compromised repair in non-asthmatic pAEC and exacerbated the dysregulated repair seen in asthmatic pAEC. Expression of major TGF-β1 activators of epithelial cells, integrin αvβ6 and αvβ8 was also measured and there was no difference in αvβ6 gene expression between the two cohorts. Although integrin αvβ8 gene expression was significantly higher in asthmatic pAEC, the expression of MT1-MMP (MMP14) which facilitates the αvβ8 mediated TGF-β1 activation was significantly downregulated. Our data has highlighted the importance of TGF-β1 in pAEC wound repair in vitro. The significantly lower levels seen in asthmatic pAEC subsequently contributes to the dysregulated repair observed in these cells.
Early respiratory viral infections in infants with cystic fibrosis.
Publisher: Elsevier BV
Date: 11-2019
Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.JCF.2018.05.006
Abstract: Little is known about the role of interleukin (IL)-1 in the pathogenesis of cystic fibrosis (CF) lung disease. This study investigated the relationship between IL-1 signalling, neutrophilic inflammation and structural lung changes in children with CF. Bronchoalveolar lavage fluid (BALf) from 102 children with CF were used to determine IL-1α, IL-1β, IL-8 levels and neutrophil elastase (NE) activity, which were then correlated to structural lung changes observed on chest computed tomography (CT) scans. IL-1α and IL-1β were detectable in BAL in absence of infection, increased in the presence of bacterial infection and correlated with IL-8 (p < 0.0001), neutrophils (p < 0.0001) and NE activity (p < 0.01 and p < 0.001). IL-1α had the strongest association with structural lung disease (p < 0.01) in the absence of infection (uninfected: p < 0.01 vs. infected: p = 0.122). Our data associates IL-1α with early structural lung damage in CF and suggests this pathway as a novel anti-inflammatory target.
Bronchial brushings for investigating airway inflammation and remodelling.
Publisher: Wiley
Date: 28-06-2011
DOI: 10.1111/J.1440-1843.2011.02001.X
Abstract: Asthma is the commonest medical cause for hospital admission for children in Australia, affects more than 300 million people worldwide, and is incurable, severe in large number and refractory to treatment in many. However, there have been no new significant treatments despite intense research and billions of dollars. The advancement in our understanding in this disease has been limited due to its heterogeneity, genetic complexity and has severely been h ered particularly in children by the difficulty in obtaining relevant target organ tissue. This review attempts to provide an overview of the currently used and recently developed/adapted techniques used to obtain lung tissue with specific reference to the airway epithelium.
Measuring Exhaled Nitric Oxide in Infants during Tidal Breathing: Methodological Issues
Publisher: Wiley
Date: 2004
DOI: 10.1002/PPUL.10382
Abstract: Exhaled nitric oxide (FENO) may provide a tool for identifying infants at risk of developing allergic disease in childhood. In infants there is no standardized collection technique however, the easiest method is to measure FENO during tidal breathing. In this study we investigated various methodological issues for tidal breathing (TB) FENO in infants. These included the effect of ambient NO, oral or nasal breathing, sedation, and tidal expiratory flow. Furthermore, we compared TB FENO in 88 infants with and without wheeze. Ambient NO greater than 5 ppb significantly affected FENO. There was no significant difference between NO levels measured during either oral or nasal breathing however, there was a significant difference between levels collected from infants before and after sedation (P < 0.001). Tidal breathing FENO decreased with increasing tidal flows (P < 0.001) and increased with age (P = 0.002). There was no significant difference in mixed expired NO between healthy and wheezy children, but children with doctor-diagnosed eczema had significantly raised levels (P = 0.014). There seem to be important methodological limitations for measuring FENO in infants during TB.
Intrinsic biochemical and functional differences in bronchial epithelial cells of children with asthma
Publisher: American Thoracic Society
Date: 15-11-2006
The value of FeNO measurement in asthma management: the motion against. FeNO to help manage childhood asthma - reality bites
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.PRRV.2007.12.004
Abstract: Since exhaled nitric oxide (FeNO) was first demonstrated to be raised in asthmatic patients in the early 1990s, there has been a strong interest in its potential role in the diagnosis and management of asthma. This culminated in 2003 when the US Food and Drug Administration cleared the NIOX nitric oxide analyser for clinical application in patients with asthma. The interest in FeNO is based on the assumptions that FeNO is a marker of asthma and asthma control, and that it reflects eosinophilic airway inflammation. However, the literature remains unconvincing and inconclusive. Furthermore, studies which have management algorithms that include FeNO as a guide to asthma treatment have failed to observe any improvement in asthma control compared with the use of standard asthma guidelines. At present, the cost of including FeNO in management guidelines far outweighs any potential benefits.
The efficacy and safety of fluticasone propionate in very young children with persistent asthma symptoms
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.RMED.2005.04.008
Abstract: We aimed to evaluate the efficacy and safety of fluticasone propionate (FP) in children aged 12-47 months with recurrent ersistent asthma symptoms. One hundred and sixty children (12-47 months) were randomised into this multicentre, double-blind, placebo-controlled, parallel-group study, and treated with either FP (100 microg bd) or placebo (2 puffs bd), both administered by metered-dose-inhaler and Babyhaler for 12 weeks. The primary endpoint was percentage of symptom-free 24h periods. Over weeks 1-12, FP-treated patients had significantly more percentage symptom-free 24-h periods compared with placebo (odds ratio 0.53 95% CI 0.29-0.95 P = 0.035). Relative to baseline, where all patients were symptomatic for at least 21/28 days of the run-in, the improvement equated to one additional symptom-free 24 h period per week. FP patients also had a significantly higher percentage of 24 h periods with no wheeze or cough, the odds ratio for treatment difference corresponding to two additional wheeze-free and one additional cough-free periods per week. FP was well-tolerated, with similar reported adverse events in both groups. Urinary cortisol-creatinine ratio was slightly decreased among FP patients after 12 weeks, but with no clinical correlates. FP is effective for the treatment of chronic persistent asthma symptoms in very young children.
Alpha-1 Antitrypsin Mitigates the Inhibition of Airway Epithelial Cell Repair by Neutrophil Elastase.
Publisher: American Thoracic Society
Date: 03-2016
Related Organisations
University Of Cambridge
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
Linkage Projects - Grant ID: LP0562421
Start Date: 12-2005
End Date: 12-2010
Amount: $385,839.00
Funder: Australian Research Council
View Funded Activity