Stephen Stick
Head, P4 Respiratory Health for Kids
MB BChir PhD MRCP FRACP
Areas for research expertise: Research Interests; Paediatric respiratory disease; Cystic fibrosis; Respiratory epithelium; Lung structure-function relation; Health service delivery models
Dr Stick is a career clinician and clinical researcher and holds a National Health and Medical Research (NHMRC) Practitioner Fellowship. Dr Stick is a member of the Royal Australasian College of Physicians Research and Education Subcommittee, the NHMRC Scholarships Committee and the NHMRC Grant Review Panel. He is also a member of the American Thoracic Society (ATS), Pediatric Program Committee, Joint ATS/European Respiratory Society (ERS) Task Force on Infant Lung Function and USCF Foundation Data Safety Monitoring Committee.
In 2007, Dr Stick was appointed Clinical Lead of the Health Department of Western Australia, Respiratory Health Network, responsible for the translation of evidenced based models of care into state-wide health policy. Since 2005, he has been the Principal Investigator for the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF). AREST CF has developed a unique early surveillance program that has focussed attention on early manifestations of CF lung disease and has contributed to a paradigm shift from an approach based on amelioration of respiratory disease to one focussed on prevention of bronchiectasis, the major cause of morbidity/mortality in CF.
In July 2010, a collaboration between centres in Perth and Melbourne to investigate early childhood lung disease that Dr Stick lead was designated as a NHMRC Centre of Research Excellence. Dr Stick is also principal investigator for the 1st intervention trial to prevent bronchiectasis in newborns diagnosed with cystic fibrosis (COMBAT CF).
Projects
COCOON: Virus transmission, immunity, and family wellbeing during COVID-19
Containing Coronavirus Disease 19 (ConCorD-19)
SYNERGY CF: Getting the best start to life - preventing early cystic fibrosis lung disease by solving the host-inflammation infection conundrum
SHIP CT: A Phase 3 randomised, double-blind, controlled trial of inhaled 7% hypertonic saline versus 0.9% isotonic saline for 48 weeks in patients with Cystic Fibrosis at 3-6 years of age in parallel with the North American SHIP clinical trial.
SHIP-CT, led by Professor Stephen Stick, Director of the Wal-yan Respiratory Research Centre at The Kids, is a unique study in preschool-aged children (from 3-6 years of age) with CF using images of the lung from chest CT scans as the main outcome measure.
DEFEND CF: Biomarkers to define the treatment end-point for pulmonary exacerbations in cystic fibrosis
AREST CF Early Surveillance Program
October 2020
BANK CF: The Respiratory Centre BIOBANK
COMBAT CF: A phase 3 multi-centre randomized placebo-controlled study of azithromycin in the primary prevention of radiologically-defined bronchiectasis in infants with cystic fibrosis.
A phase 3 multi-centre randomized placebo-controlled study of azithromycin in the primary prevention of radiologically-defined bronchiectasis in infants with cystic fibrosis
WA Epithelial Research Program for Childhood Respiratory Diseases
Vulnerable from the first breath - epithelial dysfunction and respiratory outcomes in children
Epithelial Drivers of Neutrophil Plasticity in Early Cystic Fibrosis Lung Disease
Developing a novel therapeutic pipeline for antibiotic resistant bacterial lung infection in children: investigating and assessing the potential phage therapy
Defective cell migration as a mechanism of dysregulated asthmatic airway repair
Children’s regenerative and genetic medicine program
The next generation of impact in cystic fibrosis
Lung damage in children with CF occurs much earlier than previously thought, and proving this is related to the decline that occurs later will create new paradigms for prevention and treatment.
Biomarkers to define the treatment end-point for pulmonary exacerbations in cystic fibrosis
PREDICT CF: Assessing the role of lung clearance index in predicting disease progression in children with cystic fibrosis
Objective measures of bronchial hyper-responsiveness for asthma diagnosis in young children: Mannitol and exercise challenge testing
Newborn Nasal Sampling Evaluation (NOSE) Study
ARIEL study
July 2020
BEAT-CF: Bayesian Evidence-Adaptive Tool to optimise management of Cystic Fibrosis
Cystic Fibrosis Early Surveillance Program
Researchers are able to track the progress of lung disease through a comprehensive longitudinal set of biological samples, images and data archives.
Published research
Exploring the Complexity of the Human Respiratory Virome through an In Silico Analysis of Shotgun Metagenomic Data Retrieved from Public Repositories
Respiratory viruses significantly impact global morbidity and mortality, causing more disease in humans than any other infectious agent. Beyond pathogens, various viruses and bacteria colonize the respiratory tract without causing disease, potentially influencing respiratory diseases’ pathogenesis.
Azithromycin reduces bronchial wall thickening in infants with cystic fibrosis
COMBAT-CF showed that children aged 0-3 years treated with azithromycin did clinically better than placebo but there was no effect on CT-scores. We reanalysed CTs using an automatic bronchus-artery (BA) analysis.
A phase I clinical trial assessing the safety, tolerability, and pharmacokinetics of inhaled ethanol in humans as a potential treatment for respiratory tract infections
Current treatments for respiratory infections are severely limited. Ethanol's unique properties including antimicrobial, immunomodulatory, and surfactant-like activity make it a promising candidate treatment for respiratory infections if it can be delivered safely to the airway by inhalation. Here, we explore the safety, tolerability, and pharmacokinetics of inhaled ethanol in a phase I clinical trial.
An Analysis of the Gut Microbiota and Related Metabolites following PCSK9 Inhibition in Statin-Treated Patients with Elevated Levels of Lipoprotein(a)
Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, often associated with high blood levels of LDL cholesterol (LDL-c). Medications like statins and PCSK9 inhibitors, are used to manage LDL-c levels and reduce ASCVD risk. Recent findings connect the gut microbiota and its metabolites to ASCVD development.
Stability Considerations for Bacteriophages in Liquid Formulations Designed for Nebulization
Pulmonary bacterial infections present a significant health risk to those with chronic respiratory diseases including cystic fibrosis and chronic-obstructive pulmonary disease. With the emergence of antimicrobial resistance, novel therapeutics are desperately needed to combat the emergence of resistant superbugs.
Interferon β-1a ring prophylaxis to reduce household transmission of SARS-CoV-2: a cluster randomised clinical trial
Accumulating evidence indicates that an early, robust type 1 interferon (IFN) response to SARS-CoV-2 is important in determining COVID-19 outcomes, with an inadequate IFN response associated with disease severity. Our objective was to examine the prophylactic potential of IFN administration to limit viral transmission.
Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease
Myeloperoxidase is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid, hypobromous acid, and hypothiocyanous acid, respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell exposure to its oxidants.
Ca-EDTA restores the activity of ceftazidime-avibactam or aztreonam against carbapenemase-producing Klebsiella pneumoniae infections
Developing an effective therapy to overcome carbapenemase-positive Klebsiella pneumoniae (CPKp) is an important therapeutic challenge that must be addressed urgently. Here, we explored a Ca-EDTA combination with aztreonam or ceftazidime-avibactam in vitro and in vivo against diverse CPKp clinical isolates.
Prevalence of tracheobronchomalacia is higher than previously reported in children with cystic fibrosis
Tracheobronchomalacia (TBM) is estimated to be present in 1 in 2100 children. Previous reports suggest the prevalence is higher in children with cystic fibrosis (CF). This has clinical implications with potential to influence airway clearance and lung health.
Detection of bile acids in bronchoalveolar lavage fluid defines the inflammatory and microbial landscape of the lower airways in infants with cystic fibrosis
Cystic Fibrosis (CF) is a genetic condition characterized by neutrophilic inflammation and recurrent infection of the airways. How these processes are initiated and perpetuated in CF remains largely unknown. We have demonstrated a link between the intestinal microbiota-related metabolites bile acids and inflammation in the bronchoalveolar lavage fluid from children with stable CF lung disease.
Defining the pediatric response to SARS-CoV-2 variants
The global population has been severely affected by the coronavirus disease 2019 (COVID-19) pandemic, however, with older age identified as a risk factor, children have been underprioritized. This article discusses the factors contributing to the less severe response observed in children following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including, differing viral entry receptor expression and immune responses.
Pulmonary bacteriophage and cystic fibrosis airway mucus: friends or foes?
For those born with cystic fibrosis (CF), hyper-concentrated mucus with a dysfunctional structure significantly impacts CF airways, providing a perfect environment for bacterial colonization and subsequent chronic infection. Early treatment with antibiotics limits the prevalence of bacterial pathogens but permanently alters the CF airway microenvironment, resulting in antibiotic resistance and other long-term consequences.
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
SHIP-CT showed that 48-week treatment with inhaled 7% hypertonic saline (HS) reduced airway abnormalities on chest CT using the manual PRAGMA-CF method relative to isotonic saline (IS) in children aged 3-6 years with cystic fibrosis (CF). An algorithm was developed and validated to automatically measure bronchus and artery (BA) dimensions of BA-pairs on chest CT. Aim of the study was to assess the effect of HS on bronchial wall thickening and bronchial widening using the BA-analysis.
The effect of CFTR modulators on structural lung disease in cystic fibrosis
Newly developed quantitative chest computed tomography (CT) outcomes designed specifically to assess structural abnormalities related to cystic fibrosis (CF) lung disease are now available. CFTR modulators potentially can reduce some structural lung abnormalities. We aimed to investigate the effect of CFTR modulators on structural lung disease progression using different quantitative CT analysis methods specific for people with CF (PwCF).
BEAT CF pulmonary exacerbations core protocol for evaluating the management of pulmonary exacerbations in people with cystic fibrosis
Cystic fibrosis (CF) is a rare, inherited, life-limiting condition predominantly affecting the lungs, for which there is no cure. The disease is characterized by recurrent pulmonary exacerbations (PEx), which are thought to drive progressive lung damage. Management of these episodes is complex and generally involves multiple interventions targeting different aspects of disease. The emergence of innovative trials and use of Bayesian statistical methods has created renewed opportunities for studying heterogeneous populations in rare diseases.
The effect of azithromycin on structural lung disease in infants with cystic fibrosis (COMBAT CF): a phase 3, randomised, double-blind, placebo-controlled clinical trial
Structural lung disease and neutrophil-dominated airway inflammation is present from 3 months of age in children diagnosed with cystic fibrosis after newborn screening. We hypothesised that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans.
Pseudomonas aeruginosa modulates neutrophil granule exocytosis in an in vitro model of airway infection
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.
Complete Genome Sequences of Four Pseudomonas aeruginosa Bacteriophages: Kara-mokiny 8, Kara-mokiny 13, Kara-mokiny 16, and Boorn-mokiny 1
Pseudomonas aeruginosa is an opportunistic pathogen. Here, we report the isolation of four bacteriophages from wastewater. All four bacteriophages belong to the Myoviridae family.
Complete Genomes of Three Pseudomonas aeruginosa Bacteriophages, Kara-mokiny 1, Kara-mokiny 2, and Kara-mokiny 3
Here, we present the complete genome sequence of Pseudomonas aeruginosa phages Kara-mokiny 1, Kara-mokiny 2, and Kara-mokiny 3. These phages have lytic capabilities against P. aeruginosa and belong to the myovirus morphotype. The genomes of Kara-mokiny 1 and Kara-mokiny 2 are 67,075 bp while that of Kara-mokiny 3 is 66,019 bp long.
Genome Sequences of Two Lytic Staphylococcus aureus Bacteriophages Isolated from Wastewater
Two lytic double-stranded DNA (dsDNA) bacteriophages, belonging to the family Herelleviridae, were isolated from wastewater in Western Australia. Biyabeda-mokiny 2 appears to belong to the genus Kayvirus, and Koomba-kaat 1 to Silviavirus.
Genome Sequence of a Lytic Staphylococcus aureus Bacteriophage Isolated from Breast Milk
We identified a double-stranded DNA (dsDNA) bacteriophage appearing to belong to Herelleviridae, genus Kayvirus. The bacteriophage, Biyabeda-mokiny 1, was isolated from breast milk using a clinical isolate of Staphylococcus aureus.
Standardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study): protocol for an open-label, single-arm trial
There has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy.
Bacteriophage: A new therapeutic player to combat neutrophilic inflammation in chronic airway diseases
Persistent respiratory bacterial infections are a clinical burden in several chronic inflammatory airway diseases and are often associated with neutrophil infiltration into the lungs. Following recruitment, dysregulated neutrophil effector functions such as increased granule release and formation of neutrophil extracellular traps (NETs) result in damage to airway tissue, contributing to the progression of lung disease.
Macrophage PD-1 associates with neutrophilia and reduced bacterial killing in early cystic fibrosis airway disease
Macrophages are the major resident immune cells in human airways coordinating responses to infection and injury. In cystic fibrosis, neutrophils are recruited to the airways shortly after birth, and actively exocytose damaging enzymes prior to chronic infection, suggesting a potential defect in macrophage immunomodulatory function.
AI-Driven Cell Tracking to Enable High-Throughput Drug Screening Targeting Airway Epithelial Repair for Children with Asthma
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.
Association between early respiratory viral infections and structural lung disease in infants with cystic fibrosis
Infants with cystic fibrosis (CF) develop structural lung disease early in life, and viral infections are associated with progressive lung disease. We hypothesized that the presence of respiratory viruses would be associated with structural lung disease on computed tomography (CT) of the chest in infants with CF.
Mucus and mucus flake composition and abundance reflect inflammatory and infection status in cystic fibrosis
Mucus hyperconcentration in cystic fibrosis (CF) lung disease is marked by increases in both mucin and DNA concentration. Additionally, it has been shown that half of the mucins present in bronchial alveolar lavage fluid from preschool-aged CF patients are present in as non-swellable mucus flakes.
Investigating the Implications of CFTR Exon Skipping Using a Cftr Exon 9 Deleted Mouse Model
Severity and disease progression in people with Cystic Fibrosis is typically dependent on their genotype. One potential therapeutic strategy for people with specific mutations is exon skipping with antisense oligonucleotides. CFTR exon 9 is an in-frame exon and hence the exclusion of this exon would excise only 31 amino acids but not alter the reading frame of the remaining mRNA.
The effect of inhaled hypertonic saline on lung structure in children aged 3-6 years with cystic fibrosis (SHIP-CT): a multicentre, randomised, double-blind, controlled trial
In the Saline Hypertonic in Preschoolers (SHIP) study, inhaled 7% hypertonic saline improved the lung clearance index in children aged 3-6 years with cystic fibrosis, but it remained unclear whether improvement is also seen in structural lung disease. We aimed to assess the effect of inhaled hypertonic saline on chest CT imaging in children aged 3-6 years with cystic fibrosis.
Primary Nasal Epithelial Cells as a Surrogate Cell Culture Model for Type-II Alveolar Cells to Study ABCA-3 Deficiency
ATP Binding Cassette Subfamily A Member 3 (ABCA-3) is a lipid transporter protein highly expressed in type-II alveolar (AT-II) cells. Mutations in ABCA3 can result in severe respiratory disease in infants and children. To study ABCA-3 deficiency in vitro, primary AT-II cells would be the cell culture of choice although sample accessibility is limited. Our aim was to investigate the suitability of primary nasal epithelial cells, as a surrogate culture model for AT-II cells, to study ABCA-3 deficiency.
Role of Tris-CaEDTA as an adjuvant with nebulised tobramycin in cystic fibrosis patients with Pseudomonas aeruginosa lung infections: A randomised controlled trial
We tested if disrupting iron utilisation by P. aeruginosa by adding the Tris-buffered chelating agent CaEDTA to nebulised tobramycin would enhance bacterial clearance and improve lung function in CF patients.
Comparison of home ambulatory type 2 polysomnography with a portable monitoring device and in-laboratory type 1 polysomnography for the diagnosis of obstructive sleep apnea in children
To compare type 2 polysomnography (T2PSG) to the gold standard type 1 in-laboratory polysomnography (T1PSG) for diagnosing obstructive sleep apnea (OSA) in children; validate home T2PSG in children with suspected OSA.
Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze
The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined.
Development and validation of a miniaturized bacteriophage host range screening assay against antibiotic resistant Pseudomonas aeruginosa
Antimicrobial resistance is a current global health crisis, and the increasing emergence of multidrug resistant infections has led to the resurgent interest in bacteriophages as an alternative treatment.
A screening tool to identify risk for bronchiectasis progression in children with cystic fibrosis
The marked heterogeneity in cystic fibrosis (CF) disease complicates the selection of those most likely to benefit from existing or emergent treatments. We aimed to predict the progression of bronchiectasis in preschool children with CF.
Phage therapy for multi-drug resistant respiratory tract infections
The emergence of multi-drug resistant (MDR) bacteria is recognised today as one of the greatest challenges to public health. As traditional antimicrobials are becoming ineffective and research into new antibiotics is diminishing, a number of alternative treatments for MDR bacteria have been receiving greater attention. Bacteriophage therapies are being revisited and present a promising opportunity to reduce the burden of bacterial infection in this post-antibiotic era.
Cystic fibrosis clinical isolates of aspergillus fumigatus induce similar muco-inflammatory responses in primary airway epithelial cells
Aspergillus is increasingly associated with lung inflammation and mucus plugging in early cystic fibrosis disease during which conidia burden is low and strains appear to be highly diverse. It is unknown whether clinical Aspergillus strains vary in their capacity to induce epithelial inflammation and mucus production.
A cluster randomized trial of interferon ss-1a for the reduction of transmission of SARS-Cov-2: protocol for the Containing Coronavirus Disease 19 trial (ConCorD-19)
SARS-CoV-2 infection rapidly spreads in populations due to the high rates of community transmission. Interrupting the shedding of SARS-CoV-2 may reduce the incidence of Coronavirus Disease 19 (COVID-19).
Previous Influenza Infection Exacerbates Allergen Specific Response and Impairs Airway Barrier Integrity in Pre-Sensitized Mice
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.
Lung inflammation and simulated airway resistance in infants with cystic fibrosis
Cystic fibrosis (CF) is characterized by small airway disease; but central airways may also be affected. We hypothesized that airway resistance estimated from computational fluid dynamic (CFD) methodology in infants with CF was higher than controls and that early airway inflammation in infants with CF is associated with airway resistance.
Systems biology and bile acid signalling in microbiome-host interactions in the cystic fibrosis lung
The study of the respiratory microbiota has revealed that the lungs of healthy and diseased individuals 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.
Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis
Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life.
Minimal structural lung disease in early life represents significant pathology
In this cohort, as compared with the AREST CF cohort, the authors highlight the limited correlation between infection and inflammation with lung function and structural impairment, and that this was mainly explained by the mild changes identified in lung function and on chest CT scan.
Overcoming Challenges to Make Bacteriophage Therapy Standard Clinical Treatment Practice for Cystic Fibrosis
Individuals with cystic fibrosis (CF) are given antimicrobials as prophylaxis against bacterial lung infection, which contributes to the growing emergence of multidrug resistant (MDR) pathogens isolated. Pathogens such as Pseudomonas aeruginosa that are commonly isolated from individuals with CF are armed with an arsenal of protective and virulence mechanisms, complicating eradication and treatment strategies.
Pseudomonas aeruginosa Resistance to Bacteriophages and Its Prevention by Strategic Therapeutic Cocktail Formulation
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 individuals 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.
Changes in airway inflammation with pseudomonas eradication in early cystic fibrosis
Neutrophil elastase is a significant risk factor for structural lung disease in cystic fibrosis, and Pseudomonas aeruginosa airway infection is linked with neutrophilic inflammation and substantial respiratory morbidity. We aimed to evaluate how neutrophil elastase (NE) activity changes after P. aeruginosa eradication and influences early disease outcomes. We assessed participants in the AREST CF cohort between 2000 and 2018 who had P. aeruginosa cultured from their routine annual bronchoalveolar lavage (BAL) fluid and who underwent eradication treatment and a post eradication BAL. Factors associated with persistent P. aeruginosa infection, persistent neutrophilic inflammation following eradication and worse structural lung disease one year post-eradication were evaluated.
ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma
COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter AEC. We determined what factors are associated with ACE2 expression particularly in patients with asthma and COPD. We obtained lower AEC from 145 people from two independent cohorts, aged 2-89 years, Newcastle (n = 115) and Perth (n = 30), Australia. The Newcastle cohort was enriched with people with asthma (n = 37) and COPD (n = 38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry was assessed by qPCR, and protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AEC.
BAL Inflammatory Markers Can Predict Pulmonary Exacerbations in Children With Cystic Fibrosis
Pulmonary exacerbations in cystic fibrosis are characterized by airway inflammation and may cause irreversible lung damage. Early identification of such exacerbations may facilitate early initiation of treatment, thereby potentially reducing long-term morbidity. Research question: Is it possible to predict pulmonary exacerbations in children with cystic fibrosis, using inflammatory markers obtained from BAL fluid?
Bile Acid Signal Molecules Associate Temporally with Respiratory Inflammation and Microbiome Signatures in Clinically Stable Cystic Fibrosis Patients
Cystic fibrosis (CF) is a congenital disorder resulting in a multisystemic impairment in ion homeostasis. The subsequent alteration of electrochemical gradients severely compromises the function of the airway epithelia.
Early disease surveillance in young children with cystic fibrosis: A qualitative analysis of parent experiences
Sensitive measures of early lung disease are being integrated into therapeutic trials and clinical practice in cystic fibrosis (CF). The impact of early disease surveillance (EDS) using these novel and often intensive techniques on young children and their families is not well researched.
Microbiomic Analysis on Low Abundant Respiratory Biomass Samples; Improved Recovery of Microbial DNA From Bronchoalveolar Lavage Fluid
In recent years the study of the commensal microbiota is driving a remarkable paradigm shift in our understanding of human physiology. However, intrinsic technical difficulties associated with investigating the Microbiomics of some body niches are hampering the development of new knowledge. This is particularly the case when investigating the functional role played by the human microbiota in modulating the physiology of key organ systems. A major hurdle in investigating specific Microbiome communities is linked to low bacterial density and susceptibility to bias caused by environmental contamination.
Azithromycin Partially Mitigates Dysregulated Repair of Lung Allograft Small Airway Epithelium
Chronic airway injury and dysregulated repair programs are evident in airway epithelium obtained from patients with bronchiolitis obliterans syndrome
Assessing the unified airway hypothesis in children via transcriptional profiling of the airway epithelium
Upper and lower airways are conserved in their transcriptional composition, and variations associated with disease are present in both nasal and tracheal epithelium
Epithelial Mesenchymal Transition in Respiratory Disease: Fact or Fiction
In this translational review, the mechanisms, roles, and impact of epithelial-mesenchymal transition in chronic lung diseases are discussed
Structural determinants of long term functional outcomes in young children with cystic fibrosis
Chest CT identifies children at an early age who have adverse long-term outcomes
The detection of bile acids in the lungs of paediatric cystic fibrosis patients is associated with altered inflammatory patterns
Our work has identified a clinically relevant host-derived factor that may participate in shaping early events in the aetiology of CF respiratory disease
Assessment of early lung disease in young children with CF: A comparison between pressure-controlled and free-breathing chest computed tomography
Our data suggest that FRC PC-CTs are less sensitive than TLC PC-CTs and that FB-CTs have similar sensitivity to PC-CTs in detecting lung disease
Rhinovirus Infection Is Associated With Airway Epithelial Cell Necrosis and Inflammation via Interleukin-1 in Young Children With Cystic Fibrosis
This study found rhinovirus infection drives necrotic cell death in cystic fibrosis airway epithelial cells
Blocking Notch3 Signaling Abolishes MUC5AC Production in Airway Epithelial Cells from Asthmatics
We demonstrate that NOTCH3 is a regulator of MUC5AC production
Azithromycin reduces airway inflammation induced by human rhinovirus in lung allograft recipients
Our data illustrate that rhinovirus infection is capable of infecting upper and lower airway epithelial cells, driving cell death and inflammation
Early respiratory viral infections in infants with cystic fibrosis
Early viral infections were associated with greater neutrophilic inflammation and bacterial pathogens
Oxidative stress and abnormal bioactive lipids in early cystic fibrosis lung disease
Several lipid biomarkers of early cystic fibrosis lung disease were identified, which point toward potential disease monitoring and therapeutic approaches
Changing Prevalence of Lower Airway Infections in Young Children with Cystic Fibrosis
Aspergillus species and P. aeruginosa are commonly present in the lower airways from infancy
The cumulative effect of inflammation and infection on structural lung disease in early cystic fibrosis
Pulmonary inflammation in surveillance bronchoalveolar lavage has a cumulative effect on structural lung disease extent, more so than infection
Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis
These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease
Elastase Exocytosis by Airway Neutrophils Associates with Early Lung Damage in Cystic Fibrosis Children
Protease elastase exocytosis by airway neutrophils occurs in all cystic fibrosis children, and its cellular measure correlates with early lung damage
Use of a primary epithelial cell screening tool to investigate phage therapy in cystic fibrosis
This study demonstrates the feasibility of utilizing pre-clinical in vitro culture models to screen therapeutic candidates
Elucidating the interaction of CF airway epithelial cells and rhinovirus: Using the host-pathogen relationship to identify future therapeutic strategies
A better understanding of the innate immune responses by CF airway epithelial cells is needed to identify why viral infections are more severe in CF
Predicting disease progression in cystic fibrosis
Comprehensive scores incorporating clinical, lung function, imaging and laboratory data will become essential in the future for predicting disease progression and for use in clinical trials
Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis
Our data associates IL-1α with early structural lung damage in CF and suggests this pathway as a novel anti-inflammatory target
CrossTalk opposing view: Mucosal acidification does not drive early progressive lung disease in cystic fibrosis
Whether airway mucosal acidification drives early progressive lung disease is controversial
The association between Staphylococcus aureus and subsequent bronchiectasis in children with cystic fibrosis
De novo S. aureus acquisition at age 3 is associated with later bronchiectasis and FEF25-75 in children with CF
Effects of human rhinovirus on epithelial barrier integrity and function in children with asthma
This study demonstrates novel intrinsic differences in tight junctions gene and protein expression between airway epithelial cells of children with and without asthma
Persistent induction of goblet cell differentiation in the airways: Therapeutic approaches
Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation
Visualisation of Multiple Tight Junctional Complexes in Human Airway Epithelial Cells
Apically located tight junctions in airway epithelium perform a fundamental role in controlling macromolecule migration through paracellular spaces.
Accumulation mode particles and LPS exposure induce TLR-4 dependent and independent inflammatory responses in the lung
We aimed to delineate the effects of LPS and AMP on airway inflammation, and potential contribution to airway disease by measuring airway inflammatory responses
Persistent activation of interlinked type 2 airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic asthmatics
Our findings provide new insight into the molecular mechanisms operative at baseline in the airway mucosa in atopic asthmatic with natural aeroallergen exposure
Assessment of p.Phe508del-CFTR functional restoration in pediatric primary cystic fibrosis airway epithelial cells
This study assessed an alternative approach, using a small scale halide assay that can be adapted for a personalized high throughput setting to analyze CFTR function of pAEC.
Conditionally reprogrammed primary airway epithelial cells maintain morphology, lineage and disease specific functional characteristics
Here, we show that conditionally reprogrammed airway epithelial cells (CRAECs) can be established from both healthy and diseased phenotypes.
Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis
Background: We assessed the effect of posture on ventilation distribution and the impact on associations with structural lung disease.
Airway surface liquid pH is not acidic in children with cystic fibrosis
Modulation of ASL pH has been proposed as a therapy for CF. However, evidence that ASL pH is reduced in CF is limited and conflicting.
Quantitative assessment of airway dimensions in young children with cystic fibrosis lung disease using chest computed tomography
To evaluate lung disease progression using AA dimensions on chest CT over 2-years in young CF patients longitudinally and compare to disease controls.
The AREST CF experience in biobanking - More than just tissues, tubes and time.
Research to further improve outcomes for people with CF is dependent upon well characterised, archived and accessible clinical specimens.
Multiple-breath washout outcomes are sensitive to inflammation and infection in children with cystic fibrosis
The lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection
Air trapping in early cystic fibrosis lung disease-Does CT tell the full story?
Mosaic attenuation on expiratory chest computed tomography (CT) is common in early life cystic fibrosis (CF) and often referred to as "air trapping"
Vitamin D supplementation of initially vitamin D-deficient mice diminishes lung inflammation with limited effects on pulmonary epithelial integrity
In disease settings, vitamin D may be important for maintaining optimal lung epithelial integrity and suppressing inflammation, but less is known of its effects prior to disease onset.
Early lung disease in infants and preschool children with cystic fibrosis: What have we learned and what should we do about it?
This review summarizes what we have learned about early lung disease in children with CF and discusses the implications for clinical practice and research
Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma
In this study, we aimed to use microRNAs-which are critical regulators of signaling cascades-to identify so far uncharacterized asthma pathogenesis pathways
Induced sputum to detect lung pathogens in young children with cystic fibrosis
we aimed to determine the sensitivity and specificity of induced sputum with and without airway clearance techniques to detect lower airway pathogens in kids.
Hypoxia and sterile inflammation in cystic fibrosis airways: Mechanisms and potential therapies
In this review, we consider recent evidence regarding hypoxia and sterile inflammation in cystic fibrosis airways
Respiratory function and symptoms in young preterm children in the contemporary era
Preterm children have worse lung function than healthy controls
Impaired airway epithelial cell responses from children with asthma to rhinoviral infection
Human rhinovirus infection delays repair and inhibits apoptotic processes in epithelial cells from non-asthmatic and asthmatic children
Effect of human rhinovirus infection on airway epithelium tight junction protein disassembly and transepithelial permeability
HRV-1B infection directly alters human airway epithelial TJ expression leading to increased epithelial permeability potentially via antiviral response of IL-15
Reduced transforming growth factor β1 (TGF-β1) in the repair of airway epithelial cells of children with asthma
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.
Of pigs, mice, and men: Understanding early triggers of cystic fibrosis lung disease
Understanding early triggers of Cystic Fibrosis Lung Disease
The genetic and epigenetic landscapes of the epithelium in asthma
Genetic factors in airway epithelial cells that are functionally associated with asthma pathogenesis
Dissecting the regulation of bile-induced biofilm formation in staphylococcus aureus
Wall teichoic acid may be important for protecting S. aureus against exposure to bile
Bile signalling promotes chronic respiratory infections and antibiotic tolerance
Bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease
Alpha-1 antitrypsin mitigates the inhibition of airway epithelial cell repair by neutrophil elastase
Free NE activity is deleterious for epithelial homeostasis and support the hypothesis that proteases in the airway contribute to CF structural lung disease
Airway epithelial repair in health and disease: Orchestrator or simply a player?
This review attempts to highlight migration-specific and cell-extracellular matrix (ECM) aspects of repair used by epithelial cells
Lung Clearance Index and Structural Lung Disease on Computed Tomography in Early Cystic Fibrosis
Lung clearance index may be a useful surveillance tool to monitor structural lung disease in preschool and school-age children with cystic fibrosis
Impact of lung disease on respiratory impedance in young children with cystic fibrosis
The present study investigated whether lung function measured by forced oscillation technique would be impaired in the presence of infection,...
Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection
This study aimed to determine how pulmonary inflammation & infection impacts on ventilation distribution throughout early life in people with cystic fibrosis.
Disruption of β-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair.
The airway epithelium of both children and adults with asthma is relatively undifferentiated characterized by a significantly increased proportion of...
Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis
The aim of this study was to assess if MMP activation positively correlates with neutrophil elastase activity, disease severity and bronchiectasis in young...
Productive infection of human embryonic stem cell-derived nkx2.1+ respiratory progenitors with human rhinovirus.
Our experiments provide proof of principle for the use of PSC-derived respiratory epithelial cells in the study of cell-virus interactions.
Respiratory tract exacerbations revisited: Ventilation, inflammation, perfusion, and structure (VIPS) monitoring to redefine treatment
For cystic fibrosis (CF) patients older than 6 years there are convincing data that suggest respiratory tract exacerbations (RTE) play an important role in...
Early pulmonary inflammation and lung damage in children with cystic fibrosis
Airway inflammation and infection are present from early in life, often before children are symptomatic.
PRAGMA-CF. A Quantitative Structural Lung Disease Computed Tomography Outcome in Young Children with Cystic Fibrosis
Chest computed tomography (CT) is the gold standard for demonstrating cystic fibrosis (CF) airway disease. However, there are no standardized outcome...
Biomarkers in paediatric Cystic Fibrosis lung disease
Biomarkers in cystic fibrosis are used for the measurement of cystic fibrosis transmembrane regulator function in order to diagnose cystic fibrosis,...
Feasibility of parental collected nasal swabs for virus detection in young children with cystic fibrosis
No evidence to demonstrate relationships with symptoms and viruses, prolonged symptoms, prolonged shedding or patterns of virus infections in CF
Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis
We hypothesized that the presence of these markers of cystic fibrosis lung disease in the first 2 years of life would be associated with reduced lung...
House dust mite induced lung inflammation does not alter circulating vitamin D levels
We hypothesized that allergic inflammation decreases the level of circulating 25(OH)D and tested this using a mice model of house dust mite (HDM) induced...
Determinants of culture success in an airway epithelium sampling program of young children with cystic fibrosis
Determinants of culture success through retrospective analysis of a program of routinely brushing children with Cystic Fibrosis airway disease
Early cystic fibrosis lung disease
This paper is about lung disease in patients with cyctic Fibrosis and prevention strategies to slow the onset of lung disease.
Multi-modality monitoring of cystic fibrosis lung disease: the role of chest computed tomography
Stratification of monitoring protocols based on the risk profile of the patient can help us in the future to better care for people with Cystic Fibrosis.
Parental experiences of early pulmonary surveillance for children with cystic fibrosis: A research proposal for improved family psychosocial outcomes
The proposed study intends to explore parental experiences, including coping, related to their child's involvement in the early surveillance program.
Transcription factor p63 regulates key genes and wound repair in human airway epithelial Basal cells
The airway epithelium in asthma displays altered repair and incomplete barrier formation.
The safety and feasibility of the inhaled mannitol challenge test in young children
Mannitol challenge tests are used clinically to diagnose asthma and, in particular, exercise-induced broncoconstriction (EIB) in adults and children above 6...
Assessment of early bronchiectasis in young children with cystic fibrosis is dependent on lung volume
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...
Chest computed tomography: a validated surrogate endpoint of cystic fibrosis lung disease?
Clinical trials for the treatment of cystic fibrosis (CF) lung disease are important to test and optimise new therapeutic interventions.
Expiratory flow limitation and breathing strategies in overweight adolescents during submaximal exercise
Young people who are overweight/obese are more likely to display expFL during submaximal exercise compared with children of healthy weight.
Distribution of Early Structural Lung Changes due to Cystic Fibrosis Detected with Chest Computed Tomography
To examine the distribution of early structural lung changes in clinically stable infants and young children with cystic fibrosis using chest computed...
Novel end points for clinical trials in young children with cystic fibrosis
Cystic fibrosis (CF) lung disease commences early in the disease progression and is the most common cause of mortality.
Risk factors for bronchiectasis in children with cystic fibrosis
We sought to determine risk factors for the onset of bronchiectasis, using data collected by the Australian Respiratory Early Surveillance Team for Cystic...
Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin
Dysregulated repair following epithelial injury is a key forerunner of disease in many organs, and the acquisition of a mesenchymal phenotype by the injured...
Characterization of maximal respiratory pressures in healthy children
Measurements of maximal voluntary inspiratory (Pi max) and expiratory (Pe max) pressures are used in the management of respiratory muscle disease...
DNA Methylation Profiles of Airway Epithelial Cells and PBMCs from Healthy, Atopic and Asthmatic Children
Allergic inflammation is commonly observed in a number of conditions that are associated with atopy including asthma, eczema and rhinitis.
Suppression of adrenomedullin contributes to vascular leakage and altered epithelial repair during asthma
The anti-inflammatory peptide, adrenomedullin (AM), and its cognate receptor are expressed in lung tissue, but its pathophysiological significance in airway...
Progression of early structural lung disease in young children with cystic fibrosis assessed using CT
Cross-sectional studies implicate neutrophilic inflammation and pulmonary infection as risk factors for early structural lung disease in infants and young...
Clinical investigation of respiratory system admittance in preschool children
We compared the ability of Ars, to standard oscillatory outcomes, to determine respiratory disease and differentiate responses to inhaled bronchial challenges.
Hypoglycemia does not change the threshold for arousal from sleep in adolescents with type 1 diabetes
In adolescents with type 1 diabetes, hypoglycemia does not impair arousal from slow-wave sleep induced by an external auditory stimulus.
Air Trapping on Chest CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis
In school-aged children with cystic fibrosis (CF) structural lung damage assessed using chest CT is associated with abnormal ventilation distribution.
Defective function at the epithelial junction: A novel therapeutic frontier in asthma?
The airway epithelium forms a highly regulated physical barrier that normally prevents invasion of inhaled pathogens and allergens from the airway lumen.
Infection, inflammation,and lung function decline in infants with cystic fibrosis
Better understanding of evolution of lung function in infants with cystic fibrosis...
Exciting new clinical trials in cystic fibrosis: Infants need not apply
The recent announcement of the negative results of the TIGER- 2 phase 3 study of denufosol tetrasodium
The airway epithelium is a direct source of matrix degrading enzymes in bronchiolitis obliterans syndrome
Long-term survival after lung transplantation is hindered by the development of bronchiolitis obliterans syndrome (BOS).
Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis
Improved nutrition is the major proven benefit of newborn screening programmes for cystic fibrosis (CF) and is associated with better clinical outcomes.
Bronchial brushings for investigating airway inflammation and remodelling
Asthma is the commonest medical cause for hospital admission for children in Australia, affects more than 300 million people worldwide, and is incurable...
Innate inflammatory responses of pediatric cystic fibrosis airway epithelial cells: Effects of nonviral and viral stimulation
There is controversy regarding whether cystic fibrosis (CF) airway epithelial cells (AECs) are intrinsically proinflammatory.
Randomised controlled trials in cystic fibrosis: What, when and how?
The major morbidity and mortality from cystic fibrosis (CF) comes from progressive lung disease with bronchiectasis leading to respiratory failure
Expression of bronchodilator response using forced oscillation technique measurements: absolute versus relative
Expression of bronchodilator response using forced oscillation technique measurements: absolute versus relative
Lung function testing in preschool-aged children with cystic fibrosis in the clinical setting
This study investigated the nature and prevalence of atypical pain responses in Rett syndrome and their relationships with specific MECP2 mutations.
Decreased fibronectin production significantly contributes to dysregulated repair of asthmatic epithelium
In human asthma, and experimental allergic airways disease in mice, antigen-presenting cells and CD4(+) effector cells at the airway mucosa orchestrate, and CD4
Successful establishment of primary small airway cell cultures in human lung transplantation
The study of small airway diseases such as post-transplant bronchiolitis obliterans syndrome (BOS) is hampered by the difficulty in assessing peripheral airway