2024 |
Marchant JM, Chang AB, Kennedy E, King D, Perret JL, Schultz A, et al., 'Cough in Children and Adults: Diagnosis, Assessment and Management (CICADA). Summary of an updated position statement on chronic cough in Australia', Medical Journal of Australia, 220 35-45 (2024) [C1]
Introduction: Cough is the most common symptom leading to medical consultation. Chronic cough results in significant health care costs, impairs quality of life, and may indicate t... [more]
Introduction: Cough is the most common symptom leading to medical consultation. Chronic cough results in significant health care costs, impairs quality of life, and may indicate the presence of a serious underlying condition. Here, we present a summary of an updated position statement on cough management in the clinical consultation. Main recommendations: Assessment of children and adults requires a focused history of chronic cough to identify any red flag cough pointers that may indicate an underlying disease. Further assessment with examination should include a chest x-ray and spirometry (when age > 6 years). Separate paediatric and adult diagnostic management algorithms should be followed. Management of the underlying condition(s) should follow specific disease guidelines, as well as address adverse environmental exposures and patient/carer concerns. First Nations adults and children should be considered a high risk group. The full statement from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia for managing chronic cough is available at https://lungfoundation.com.au/resources/cicada-full-position-statement. Changes in management as a result of this statement: Algorithms for assessment and diagnosis of adult and paediatric chronic cough are recommended. High quality evidence supports the use of child-specific chronic cough management algorithms to improve clinical outcomes, but none exist in adults. Red flags that indicate serious underlying conditions requiring investigation or referral should be identified. Early and effective treatment of chronic wet/productive cough in children is critical. Culturally specific strategies for facilitating the management of chronic cough in First Nations populations should be adopted. If the chronic cough does not resolve or is unexplained, the patient should be referred to a respiratory specialist or cough clinic.
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2024 |
Budden KF, Shukla SD, Bowerman KL, Vaughan A, Gellatly SL, Wood DLA, et al., 'Faecal microbial transfer and complex carbohydrates mediate protection against COPD.', Gut, (2024) [C1]
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2024 |
Thomas D, McDonald VM, Stevens S, Harvey ES, Baraket M, Bardin P, et al., 'Biologics (mepolizumab and omalizumab) induced remission in severe asthma patients.', Allergy, 79 384-392 (2024) [C1]
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2023 |
Kritikos V, Harvey ES, Stevens S, Katelaris CH, Langton D, Rimmer J, et al., 'Comorbidities Modify the Phenotype but Not the Treatment Effectiveness to Mepolizumab in Severe Eosinophilic Asthma.', J Allergy Clin Immunol Pract, 11 885-895.e13 (2023) [C1]
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Nova |
2023 |
Wark P, McDonald VM, Smith S, 'Nebulised hypertonic saline for cystic fibrosis.', Cochrane Database Syst Rev, 6 CD001506 (2023) [C1]
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Nova |
2023 |
Vanders RL, Gomez HM, Hsu AC, Daly K, Wark PAB, Horvat JC, Hansbro PM, 'Inflammatory and antiviral responses to influenza A virus infection are dysregulated in pregnant mice with allergic airway disease.', Am J Physiol Lung Cell Mol Physiol, 325 L385-L398 (2023) [C1]
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Nova |
2023 |
Girkin JLN, Bryant NE, Loo S-L, Hsu A, Kanwal A, Williams TC, et al., 'Upper Respiratory Tract OC43 Infection Model for Investigating Airway Immune-Modifying Therapies.', Am J Respir Cell Mol Biol, 69 614-622 (2023) [C1]
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2023 |
Veerati PC, Reid AT, Nichol KS, Wark PAB, Knight DA, Bartlett NW, Grainge CL, 'Mechanical forces suppress antiviral innate immune responses from asthmatic airway epithelial cells following rhinovirus infection.', Am J Physiol Lung Cell Mol Physiol, 325 L206-L214 (2023) [C1]
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2023 |
Ramsahai JM, Simpson JL, Cook A, Gibson PG, McDonald V, Grainge C, et al., 'Randomised controlled trial for the titration of oral corticosteroids using markers of inflammation in severe asthma.', Thorax, 78 868-874 (2023) [C1]
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2023 |
Tunney MM, Wark P, 'Long-term therapy with elexacaftor/tezacaftor/ivacaftor (ETI) in cystic fibrosis: improved clinical outcomes but infection and inflammation persist', EUROPEAN RESPIRATORY JOURNAL, 62 (2023)
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2023 |
Dey S, Lu W, Haug G, Chia C, Larby J, Weber HC, et al., 'Airway inflammatory changes in the lungs of patients with asthma-COPD overlap (ACO): a bronchoscopy endobronchial biopsy study', Respiratory Research, 24 (2023) [C1]
Background: Although asthma and chronic obstructive pulmonary disease (COPD) are two distinct chronic airway inflammatory diseases, they often co-exist in a patient¿and the condit... [more]
Background: Although asthma and chronic obstructive pulmonary disease (COPD) are two distinct chronic airway inflammatory diseases, they often co-exist in a patient¿and the condition is¿referred to as asthma-COPD overlap (ACO). Lack of evidence regarding the inflammatory cells in ACO airways has led to their poor prognosis and treatment. The objective of this endobronchial biopsy (EBB) study was to enumerate inflammatory cellular changes in the airway wall of ACO compared with asthma, COPD current smokers (CS) and ex-smokers (ES), normal lung function smokers (NLFS), and non-smoker controls (HC). Methods: EBB tissues from 74 patients were immunohistochemically stained for macrophages, mast cells, eosinophils, neutrophils, CD8+ T-cells and CD4+ T-cells. The microscopic images of stained tissues were evaluated in the epithelium, reticular basement membrane (RBM) cells/mm RBM length, and lamina propria (LP) cells/mm2 up to a depth of¿120 µM using the image analysis software Image-Pro Plus 7.0. The observer was blinded to the images and disease diagnosis. Statistical analysis was performed using GraphPad Prism v9. Results: The tissue macrophages in ACO were substantially higher in the epithelium and RBM than¿in HC (P < 0.001 for both), COPD-ES (P < 0.001 for both), and -CS (P < 0.05 and < 0.0001, respectively). The ACO LP macrophages were significantly higher¿in number than COPD-CS (P < 0.05). The mast cell¿numbers in ACO were lower than in¿NLFS (P < 0.05) in the epithelium, lower than COPD (P < 0.05) and NLFS (P < 0.001) in RBM; and lower than HC (P < 0.05) in LP. We noted lower eosinophils in ACO LP than HC (P < 0.05) and the lowest neutrophils in both ACO and asthma. Furthermore, CD8+ T-cell¿numbers increased in the ACO RBM than HC (P < 0.05), COPD-ES (P < 0.05), and NLFS (P < 0.01); however, they were similar in¿number in epithelium and LP across groups. CD4+ T-cells remained lower in number¿across all regions and groups. Conclusion: These results suggest that the ACO airway tissue inflammatory cellular profile differed from the contributing diseases of asthma and COPD with a predominance of macrophages.
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2023 |
Wark PAB, Hew M, Xu Y, Ghisla C, Nguyen T-M, Erdemli B, et al., 'Regional variation in prevalence of difficult-to-treat asthma and oral corticosteroid use for patients in Australia: heat map analysis', JOURNAL OF ASTHMA, 60 727-736 (2023) [C1]
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Nova |
2023 |
Pathinayake PS, Awatade NT, Wark PAB, 'Type 2 Immunity and Its Impact on COVID-19 Infection in the Airways', VIRUSES-BASEL, 15 (2023) [C1]
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Nova |
2023 |
Dwyer TJ, Elkins MR, Dentice R, Forbes S, Cooper P, Jaffe A, et al., 'Saline at lower tonicity in cystic fibrosis (SALTI-CF) trial comparing 0.9% versus 3% versus 6% nebulised saline.', Eur Respir J, 62 (2023) [C1]
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2023 |
Tomaszewski EL, Atkinson MJ, Janson C, Karlsson N, Make B, Price D, et al., 'Chronic Airways Assessment Test: psychometric properties in patients with asthma and/or COPD', Respiratory Research, 24 (2023) [C1]
Background: No short patient-reported outcome (PRO) instruments assess overall health status across different obstructive lung diseases. Thus, the wording of the introduction to t... [more]
Background: No short patient-reported outcome (PRO) instruments assess overall health status across different obstructive lung diseases. Thus, the wording of the introduction to the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) was modified to permit use in asthma and/or COPD. This tool is called the Chronic Airways Assessment Test (CAAT). Methods: The psychometric properties of the CAAT were evaluated using baseline data from the NOVELTY study (NCT02760329) in patients with physician-assigned asthma, asthma + COPD or COPD. Analyses included exploratory/confirmatory factor analyses, differential item functioning and analysis of construct validity. Responses to the CAAT and CAT were compared in patients with asthma + COPD and those with COPD. Results: CAAT items were internally consistent (Cronbach¿s alpha: > 0.7) within each diagnostic group (n = 510). Models for structural and measurement invariance were strong. Tests of differential item functioning showed small differences between asthma and COPD in individual items, but these were not consistent in direction and had minimal overall impact on the total score. The CAAT and CAT were highly consistent when assessed in all NOVELTY patients who completed both (N = 277, Pearson¿s correlation coefficient: 0.90). Like the CAT itself, CAAT scores correlated moderately (0.4¿0.7) to strongly (> 0.7) with other PRO measures and weakly (< 0.4) with spirometry measures. Conclusions: CAAT scores appear to reflect the same health impairment across asthma and COPD, making the CAAT an appropriate PRO instrument for patients with asthma and/or COPD. Its brevity makes it suitable for use in clinical studies and routine clinical practice. Trial registration: NCT02760329.
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2023 |
Dedrick RM, Smith BE, Cristinziano M, Freeman KG, Jacobs-Sera D, Belessis Y, et al., 'Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.', Clin Infect Dis, 76 103-112 (2023) [C1]
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Nova |
2023 |
Awatade NT, Reid AT, Nichol KS, Budden KF, Veerati PC, Pathinayake PS, et al., 'Comparison of commercially available differentiation media on cell morphology, function, and anti-viral responses in conditionally reprogrammed human bronchial epithelial cells.', Scientific reports, 13 11200 (2023) [C1]
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2023 |
Liu Y, Sánchez-Ovando S, Carolan L, Dowson L, Khvorov A, Jessica Hadiprodjo A, et al., 'Superior immunogenicity of mRNA over adenoviral vectored COVID-19 vaccines reflects B cell dynamics independent of anti-vector immunity: Implications for future pandemic vaccines', Vaccine, 41 7192-7200 (2023) [C1]
Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. The aim of this study was to v... [more]
Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. The aim of this study was to validate whether immunogenicity differs for adenoviral vectored (AdV) versus mRNA vaccines against SARS-CoV-2, and to investigate how anti-vector immunity and B cell dynamics modulate immunogenicity. We enrolled SARS-CoV-2 infection-naïve health care workers who had received two doses of either AdV AZD1222 (n = 184) or mRNA BNT162b2 vaccine (n = 274) between April and October 2021. Blood was collected at least once, 10¿48 days after vaccine dose 2 for antibody and B cell analyses. Median ages were 42 and 39 years, for AdV and mRNA vaccinees, respectively. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p < 0.001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine, which reflected greater B cell expansion and targeting of the RBD rather than an attenuating effect of anti-vector antibodies. ClinicalTrials.gov Identifier: NCT05110911.
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2023 |
Liu G, Haw TJ, Starkey MR, Philp AM, Pavlidis S, Nalkurthi C, et al., 'TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase.', Nat Commun, 14 7349 (2023) [C1]
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2023 |
Malik B, Bartlett NW, Upham JW, Nichol KS, Harrington J, Wark PAB, 'Severe asthma ILC2s demonstrate enhanced proliferation that is modified by biologics.', Respirology, 28 758-766 (2023) [C1]
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2023 |
Schultz A, McLeod C, Berry S, Marsh J, McKenzie A, Messer M, et al., 'BEAT CF pulmonary exacerbations core protocol for evaluating the management of pulmonary exacerbations in people with cystic fibrosis', Trials, 24 (2023)
Background: 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 recur... [more]
Background: 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. Here, we present the protocol for the BEAT CF PEx cohort, a prospective, multi-site, perpetual, platform enrolling adults and children with CF. The BEAT CF PEx cohort will be used to evaluate the comparative effectiveness of interventions for the treatment of PEx requiring intensive therapy (PERITs), with a primary focus on short-term improvements in lung function. This will be achieved through the conduct of cohort-nested studies, including adaptive clinical trials, within the BEAT CF PEx cohort. This protocol will outline key features of the BEAT CF PEx cohort, including the design, implementation, data collection and management, governance and analysis, and dissemination of results. Methods: This platform will be conducted across multiple sites, commencing with CF treatment centers in Australia. People of all ages with a clinical diagnosis of CF will be eligible to participate, except those who have previously received a lung transplant. Data including demographic and clinical information, treatment details, and outcomes (including safety, microbiology, and patient-reported outcome measures including quality of life scores) will be systematically collected and securely stored via a digital centralized trial management system (CTMS). The primary endpoint is the absolute change in the percentage predicted forced expiratory volume in 1¿s (ppFEV1) from the commencement of intensive therapy to 7 to 10 days afterwards. Discussion: The BEAT CF PEx cohort will report clinical, treatment, and outcome data for PEx among people with CF and is intended to serve as a core (master) protocol for future nested, interventional trials evaluating treatment(s) for these episodes. The protocols for nested sub-studies are beyond the scope of this document and will be reported separately. Trial registration: ANZCTR BEAT CF Platform ¿ ACTRN12621000638831. Registration date: Sept. 26, 2022.
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2023 |
Faiz A, Mahbub RM, Boedijono FS, Tomassen MI, Kooistra W, Timens W, et al., 'IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels.', Am J Respir Crit Care Med, 208 1075-1087 (2023) [C1]
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2023 |
He LX, Deng K, Wang J, Zhang X, Wang L, Zhang HP, et al., 'Clinical Subtypes of Neutrophilic Asthma: A Cluster Analysis From Australasian Severe Asthma Network', Journal of Allergy and Clinical Immunology: In Practice, (2023) [C1]
Background: Clinical heterogeneity may exist within asthma subtypes defined by inflammatory markers. However, the heterogeneity of neutrophilic asthma (NA) remains largely unexplo... [more]
Background: Clinical heterogeneity may exist within asthma subtypes defined by inflammatory markers. However, the heterogeneity of neutrophilic asthma (NA) remains largely unexplored. Objective: To explore potential clusters and the stability of NA. Methods: Participants with NA from the Australasian Severe Asthma Network underwent a multidimensional assessment. They were then asked to participate in a 12-month longitudinal cohort study. We explored potential clusters using a hierarchical cluster analysis and validated the differential future risk of asthma exacerbations in the identified clusters. A decision tree analysis was developed to predict cluster assignments. Finally, the stability of prespecified clusters was examined within 1 month. Results: Three clusters were identified in 149 patients with NA. Cluster 1 (n = 99; 66.4%) was characterized by female-predominant nonsmokers with well-controlled NA, cluster 2 (n = 16; 10.7%) by individuals with comorbid anxiety/depressive symptoms with poorly controlled NA, and cluster 3 by older male smokers with late-onset NA. Cluster 2 had a greater proportion of participants with severe exacerbations (P =.005), hospitalization (P =.010), and unscheduled visits (P =.013) and a higher number of emergency room visits (P =.039) than that of the other two clusters. The decision tree assigned 92.6% of participants correctly. Most participants (87.5%; n = 7) in cluster 2 had a stable NA phenotype, whereas participants of clusters 1 and 3 had variable phenotypes. Conclusions: We identified three clinical clusters of NA, in which cluster 2 represents an uncontrolled and stable NA subtype with an elevated risk of exacerbations. These findings have clinical implications for the management of NA.
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2023 |
Wilde LJ, Percy C, Clark C, Ward G, Wark PA, Sewell L, 'Views and experiences of healthcare practitioners supporting people with COPD who have used activity monitors: More than just steps ', Respiratory Medicine, 218 (2023) [C1]
Introduction: Activity monitors (apps and wearables) are increasingly used by the general population, including people with Chronic Obstructive Pulmonary Disease (COPD). There is ... [more]
Introduction: Activity monitors (apps and wearables) are increasingly used by the general population, including people with Chronic Obstructive Pulmonary Disease (COPD). There is potential for activity monitors to support increases in physical activity for people with COPD and healthcare practitioners (HCPs) are likely to be key in supporting their use, but little is currently known about HCPs' views or experiences. This qualitative research aimed to explore HCPs¿ views and experiences of supporting people with COPD who have used activity monitors. Methods: Seventeen semi-structured telephone or online interviews were conducted with HCPs between September 2020 and May 2021. HCPs included two nurses, an occupational therapist, a physician, and 13 physiotherapists. Participants were recruited via social media advertisements. They all had experience of supporting people with COPD who had used activity monitors. Interviews were analysed using reflexive thematic analysis. Findings: Four themes were developed highlighting the challenges and benefits of HCPs supporting patients with using activity monitors and utilising patient-collected activity data; 1) Skills and experience are needed to increase accessibility and engagement, 2) Objectively monitored physical activity can support exercise prescription, 3) Applications of activity monitors vary across different settings, and 4) Support is needed for future use of activity monitors. Discussion: HCPs recognised the potential for activity monitors to impact patients¿ ability to self-manage their COPD. However, there is a lack of guidance and information to support integration within practice. Future research is needed to co-develop information and guidelines for people with COPD and HCPs.
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2023 |
Hughes R, Rapsomaniki E, Bansal AT, Vestbo J, Price D, Agustí A, et al., 'Cluster Analyses From the Real-World NOVELTY Study: Six Clusters Across the Asthma-COPD Spectrum', Journal of Allergy and Clinical Immunology: In Practice, 11 2803-2811 (2023) [C1]
Background: Asthma and chronic obstructive pulmonary disease (COPD) are complex diseases, the definitions of which overlap. Objective: To investigate clustering of clinical/physio... [more]
Background: Asthma and chronic obstructive pulmonary disease (COPD) are complex diseases, the definitions of which overlap. Objective: To investigate clustering of clinical/physiological features and readily available biomarkers in patients with physician-assigned diagnoses of asthma and/or COPD in the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329). Methods: Two approaches were taken to variable selection using baseline data: approach A was data-driven, hypothesis-free and used the Pearson dissimilarity matrix; approach B used an unsupervised Random Forest guided by clinical input. Cluster analyses were conducted across 100 random resamples using partitioning around medoids, followed by consensus clustering. Results: Approach A included 3796 individuals (mean age, 59.5 years; 54% female); approach B included 2934 patients (mean age, 60.7 years; 53% female). Each identified 6 mathematically stable clusters, which had overlapping characteristics. Overall, 67% to 75% of patients with asthma were in 3 clusters, and approximately 90% of patients with COPD were in 3 clusters. Although traditional features such as allergies and current/ex-smoking (respectively) were higher in these clusters, there were differences between clusters and approaches in features such as sex, ethnicity, breathlessness, frequent productive cough, and blood cell counts. The strongest predictors of the approach A cluster membership were age, weight, childhood onset, prebronchodilator FEV1, duration of dust/fume exposure, and number of daily medications. Conclusions: Cluster analyses in patients from NOVELTY with asthma and/or COPD yielded identifiable clusters, with several discriminatory features that differed from conventional diagnostic characteristics. The overlap between clusters suggests that they do not reflect discrete underlying mechanisms and points to the need for identification of molecular endotypes and potential treatment targets across asthma and/or COPD.
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2023 |
Hough RF, Wark PA, 'Obesity and COVID-19 Disease: To Inflame or Not', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 207 503-504 (2023)
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2023 |
Gilbert B, Kaiko G, Smith S, Wark P, 'A systematic review of the colorectal microbiome in adult cystic fibrosis patients.', Colorectal Dis, 25 843-852 (2023) [C1]
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2023 |
Wang H, Yip KH, Keam SP, Vlahos R, Nichol K, Wark P, et al., 'Dual inhibition of airway inflammation and fibrosis by common ß cytokine receptor blockade.', J Allergy Clin Immunol, (2023) [C1]
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2023 |
Salvato I, Ricciardi L, Dal Col J, Nigro A, Giurato G, Memoli D, et al., 'Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation', Frontiers in Immunology, 14 (2023) [C1]
Introduction: The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, tw... [more]
Introduction: The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss. Results: RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3¿-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets¿ steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFa/IL1ß/IFN¿/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression. Discussion: Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells.
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2023 |
Awatade NT, Wark PAB, Chan ASL, Mamun SMAA, Mohd Esa NY, Matsunaga K, et al., 'The Complex Association between COPD and COVID-19.', J Clin Med, 12 (2023) [C1]
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Nova |
2022 |
Williams TC, Loo S-L, Nichol KS, Reid AT, Veerati PC, Esneau C, et al., 'IL-25 blockade augments antiviral immunity during respiratory virus infection', COMMUNICATIONS BIOLOGY, 5 (2022) [C1]
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Nova |
2022 |
Dey S, Eapen MS, Chia C, Gaikwad AV, Wark PAB, Sohal SS, 'Pathogenesis, clinical features of asthma COPD overlap, and therapeutic modalities.', Am J Physiol Lung Cell Mol Physiol, 322 L64-L83 (2022) [C1]
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2022 |
Agustí A, Rapsomaniki E, Beasley R, Hughes R, Müllerová H, Papi A, et al., 'Treatable traits in the NOVELTY study', Respirology, 27 929-940 (2022) [C1]
Background and objective: Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent and complex diseases that require personalized management. Although a strategy ... [more]
Background and objective: Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent and complex diseases that require personalized management. Although a strategy based on treatable traits (TTs) has been proposed, the prevalence and relationship of TTs to the diagnostic label and disease severity established by the attending physician in a real-world setting are unknown. We assessed how the presence/absence of specific TTs relate to the diagnosis and severity of ¿asthma¿, ¿COPD¿ or ¿asthma + COPD¿. Methods: The authors selected 30 frequently occurring TTs from the NOVELTY study cohort (NOVEL observational longiTudinal studY; NCT02760329), a large (n¿=¿11,226), global study that systematically collects data in a real-world setting, both in primary care clinics and specialized centres, for patients with ¿asthma¿ (n¿=¿5932, 52.8%), ¿COPD¿ (n¿=¿3898, 34.7%) or both (¿asthma + COPD¿; n¿=¿1396, 12.4%). Results: The results indicate that (1) the prevalence of the 30 TTs evaluated varied widely, with a mean ± SD of 4.6 ± 2.6, 5.4 ± 2.6 and 6.4 ± 2.8 TTs/patient in those with ¿asthma¿, ¿COPD¿ and ¿asthma + COPD¿, respectively (p¿< 0.0001); (2) there were no large global geographical variations, but the prevalence of TTs was different in primary versus specialized clinics; (3) several TTs were specific to the diagnosis and severity of disease, but many were not; and (4) both the presence and absence of TTs formed a pattern that is recognized by clinicians to establish a diagnosis and grade its severity. Conclusion: These results provide the largest and most granular characterization of TTs in patients with airway diseases in a real-world setting to date.
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2022 |
Donovan C, Kim RY, Galvao I, Jarnicki AG, Brown AC, Jones-Freeman B, et al., 'Aim2 suppresses cigarette smoke-induced neutrophil recruitment, neutrophil caspase-1 activation and anti-Ly6G-mediated neutrophil depletion', IMMUNOLOGY AND CELL BIOLOGY, 100 235-249 (2022) [C1]
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2022 |
Liu G, Jarnicki AG, Paudel KR, Lu W, Wadhwa R, Philp AM, et al., 'Adverse roles of mast cell chymase-1 in chronic obstructive pulmonary disease.', European Respiratory Journal, 60 2101431-2101431 (2022) [C1]
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2022 |
Pathinayake PS, Waters DW, Nichol KS, Brown AC, Reid AT, Hsu AC-Y, et al., 'Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma', THORAX, 77 443-451 (2022) [C1]
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2022 |
Holland LR, Hilton J, Cookson K, Heinsch M, Gilligan C, Wark P, 'Understanding motivation for Australian adolescents and young adults with cystic fibrosis: Modifiable factors to support self-management.', Health Soc Care Community, 30 e2712-e2723 (2022) [C1]
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2022 |
Dey S, Lu W, Weber HC, Young S, Larby J, Chia C, et al., 'Differential airway remodeling changes were observed in patients with asthma COPD overlap compared to patients with asthma and COPD alone', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 323 L473-L483 (2022) [C1]
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2022 |
Johansen MD, Mahbub RM, Idrees S, Nguyen DH, Miemczyk S, Pathinayake P, et al., 'Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined with Single-Cell RNA Sequencing', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 206 712-729 (2022) [C1]
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2022 |
Chan LLY, Anderson DE, Cheng HS, Ivan FX, Chen S, Kang AEZ, et al., 'The establishment of COPD organoids to study host-pathogen interaction reveals enhanced viral fitness of SARS-CoV-2 in bronchi', NATURE COMMUNICATIONS, 13 (2022) [C1]
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2022 |
Budden KF, Gellatly SL, Vaughan A, Amorim N, Horvat JC, Hansbro NG, et al., 'Probiotic Bifidobacterium longum subsp. longum Protects against Cigarette Smoke-Induced Inflammation in Mice.', Int J Mol Sci, 24 (2022) [C1]
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2022 |
Wark PAB, 'We need to understand why viral infections lead to acute asthma', EUROPEAN RESPIRATORY JOURNAL, 60 (2022)
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2022 |
Ruseckaite R, Salimi F, Earnest A, Bell SC, Douglas T, Frayman K, et al., 'Survival of people with cystic fibrosis in Australia', Scientific Reports, 12 (2022) [C1]
Survival statistics, estimated using data from national cystic fibrosis (CF) registries, inform the CF community and monitor disease progression. This study aimed to estimate surv... [more]
Survival statistics, estimated using data from national cystic fibrosis (CF) registries, inform the CF community and monitor disease progression. This study aimed to estimate survival among people with CF in Australia and to identify factors associated with survival. This population-based cohort study used prospectively collected data from 23 Australian CF centres participating in the Australian CF Data Registry (ACFDR) from 2005¿2020. Period survival analysis was used to calculate median age of survival estimates for each 5-year window from 2005¿2009 until 2016¿2020. The overall median survival was estimated using the Kaplan¿Meier method. Between 2005¿2020 the ACFDR followed 4,601 people with CF, noting 516 (11.2%) deaths including 195 following lung transplantation. Out of the total sample, more than half (52.5%) were male and 395 (8.6%) had undergone lung transplantation. Two thirds of people with CF (66.1%) were diagnosed before six weeks of age or by newborn/prenatal screening. The overall median age of survival was estimated as 54.0¿years (95% CI: 51.0¿57.04). Estimated median survival increased from 48.9¿years (95% CI: 44.7¿53.5) for people with CF born in 2005¿2009, to 56.3¿years (95% CI: 51.2¿60.4) for those born in 2016¿2020. Factors independently associated with reduced survival include receiving a lung transplant, having low FEV1pp and BMI. Median survival estimates are increasing in CF in Australia. This likely reflects multiple factors, including newborn screening, improvement in diagnosis, refinements in CF management and centre-based multidisciplinary care.
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2022 |
Tickner C, Holland L, Wark P, Hilton J, Morrison C, Kay-Lambkin F, Heinsch M, 'Mental health care needs in cystic fibrosis: A scoping review.', Social work in health care, 1-15 (2022) [C1]
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2022 |
Sutharsan S, McKone EF, Downey DG, Duckers J, MacGregor G, Tullis E, et al., 'Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial', The Lancet Respiratory Medicine, 10 267-277 (2022) [C1]
Background: Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally s... [more]
Background: Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation. Methods: We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40¿90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972. Findings: Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (-1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV1 increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (-0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference -42·8 mmol/L [¿46·2 to -39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plu...
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2022 |
Veerati PC, Nichol KS, Read JM, Bartlett NW, Wark PAB, Knight DA, et al., 'Conditionally reprogrammed asthmatic bronchial epithelial cells express lower
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2022 |
Li L, Mac Aogáin M, Xu T, Jaggi TK, Chan LLY, Qu J, et al., 'Neisseria species as pathobionts in bronchiectasis', Cell Host and Microbe, 30 1311-1327.e8 (2022) [C1]
Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generatio... [more]
Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis samples and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group.
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2022 |
Golam SM, Janson C, Beasley R, FitzGerald JM, Harrison T, Chipps B, et al., 'The burden of mild asthma: Clinical burden and healthcare resource utilisation in the NOVELTY study', Respiratory Medicine, 200 (2022) [C1]
Background: Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to des... [more]
Background: Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma. Methods: Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits. Results: Overall, 2004 patients with mild asthma were included; 22.8% experienced =1 exacerbation in the previous 12 months, of whom 72.3% experienced =1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 [standard deviation ± 17.9]). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score <20), increasing to 55.6% for those with =2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring =1 emergency department visit and 1.1% requiring =1 hospital admission. Conclusions: In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU.
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2022 |
Carr SB, McClenaghan E, Elbert A, Faro A, Cosgriff R, Abdrakhmanov O, et al., 'Factors associated with clinical progression to severe COVID-19 in people with cystic fibrosis: A global observational study', Journal of Cystic Fibrosis, 21 e221-e231 (2022) [C1]
Background: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe o... [more]
Background: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe outcomes. Methods Data from 22 countries prior to 13th December 2020 and the introduction of vaccines were included. It was de-identified and included patient demographics, clinical characteristics, treatments, outcomes and sequalae following SARS-CoV-2 infection. Multivariable logistic regression was used to investigate factors associated with clinical progression to severe COVID-19, using the primary outcome of hospitalisation with supplemental oxygen. Results: SARS-CoV-2 was reported in 1555 people with CF, 1452 were included in the analysis. One third were aged <18 years, and 9.4% were solid-organ transplant recipients. 74.5% were symptomatic and 22% were admitted to hospital. In the non-transplanted cohort, 39.5% of patients with ppFEV1<40% were hospitalised with oxygen verses 3.2% with ppFEV >70%: a 17-fold increase in odds. Worse outcomes were independently associated with older age, non-white race, underweight body mass index, and CF-related diabetes. Prescription of highly effective CFTR modulator therapies was associated with a significantly reduced odds of being hospitalised with oxygen (AOR 0.43 95%CI 0.31-0.60 p<0.001). Transplanted patients were hospitalised with supplemental oxygen therapy (21.9%) more often than non-transplanted (8.8%) and was independently associated with the primary outcome (Adjusted OR 2.45 95%CI 1.27-4.71 p=0.007). Conclusions: This is the first study to show that there is a protective effect from the use of CFTR modulator therapy and that people with CF from an ethnic minority are at more risk of severe infection with SARS-CoV-2.
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2022 |
Thota RN, Wynne K, Pradeepan S, Wark PAB, Garg ML, 'Association of Islet Amyloid Polypeptide to C-Peptide Ratio with Cystic Fibrosis-Related Diabetes: A Prospective Cross-sectional Study', Pancreas, 51 1029-1036 (2022) [C1]
Objectives Early detection of cystic fibrosis (CF) related diabetes (CFRD) improves health outcomes and reduces CF-related mortality. The study aims to evaluate the ratio of islet... [more]
Objectives Early detection of cystic fibrosis (CF) related diabetes (CFRD) improves health outcomes and reduces CF-related mortality. The study aims to evaluate the ratio of islet amyloid polypeptide (IAPP) to C-peptide in CF patients with diabetes and without diabetes. Methods Cross-sectional analysis was carried out in a prospective cohort of 33 participants (CF [n=16] and CFRD [n=18]). We examined the association of plasma IAPP:C-peptide ratio with clinical information, including glycated hemoglobin, and lung function markers. Results The median (interquartile range) IAPP:C-peptide ratio was significantly (P=0.004) higher in people with CFRD (4.8 [4.5]) compared with participants without CFRD (12.1 [19.7]). The ratio of IAPP to C-peptide significantly accounted for a 38% variation in the diabetes status in patients with CF (r2=0.399, P < 0.001). Islet amyloid polypeptide is strongly correlated with serum ferritin levels (r=0.683, P=0.005) and forced expiratory volume in CFRD, but not in nondiabetic participants with CF. Conclusions Islet amyloid polypeptide:C-peptide ratio could be a potential marker of CFRD in adults with CF. Further research requires validation of this marker in longitudinal cohort studies to confirm the capability of IAPP:C-peptide to predict CFRD.
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2022 |
Cheng AC, Dwyer DE, Holmes M, Irving L, Simpson G, Senenayake S, et al., 'Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2019: the Influenza Complications Alert Network (FluCAN).', Communicable diseases intelligence (2018), 46 (2022) [C1]
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2022 |
Begum H, Dwyer DE, Holmes M, Irving L, Simpson G, Senenayake S, et al., 'Surveillance for severe influenza and COVID-19 in patients admitted to sentinel Australian hospitals in 2020: the Influenza Complications Alert Network (FluCAN)', Communicable diseases intelligence (2018), 46 (2022) [C1]
Introduction: Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respirat... [more]
Introduction: Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. Methods: The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Influenza and COVID-19 cases were defined as patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. Results: There were 448 patients with COVID-19 admitted between 16 March and 31 December 2020, and only 20 patients with influenza admitted between 1 April and 30 November 2020, to one of 22 FluCAN hospitals. Of the COVID-19 cases, 173 (39%) were > 65 years of age, 36 (8%) were children (< 16 years), 6 (1%) were Aboriginal and Torres Strait Islander peoples, 4 (1%) were pregnant and 289 (65%) had chronic comorbidities. COVID-19 hospital admissions peaked between weeks 13 and 15 (first wave) nationally, and again between weeks 31 and 35 (Victoria), with most admissions represented by those above 40 years of age. Discussion: There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.
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2022 |
Hosseini B, Berthon BS, Jensen ME, McLoughlin RF, Wark PAB, Nichol K, et al., 'The Effects of Increasing Fruit and Vegetable Intake in Children with Asthma on the Modulation of Innate Immune Responses', Nutrients, 14 3087-3087 (2022) [C1]
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2022 |
Tu X, Kim RY, Brown AC, de Jong E, Jones-Freeman B, Ali MK, et al., 'Airway and parenchymal transcriptomics in a novel model of asthma and COPD overlap', Journal of Allergy and Clinical Immunology, 150 817-829.e6 (2022) [C1]
Background: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases, and some patients have overlapping disease features, termed asthma-COP... [more]
Background: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases, and some patients have overlapping disease features, termed asthma-COPD overlap (ACO). Patients characterized with ACO have increased disease severity; however, the mechanisms driving this have not been widely studied. Objectives: This study sought to characterize the phenotypic and transcriptomic features of experimental ACO in mice induced by chronic house dust mite antigen and cigarette smoke exposure. Methods: Female BALB/c mice were chronically exposed to house dust mite antigen for 11 weeks to induce experimental asthma, cigarette smoke for 8 weeks to induce experimental COPD, or both concurrently to induce experimental ACO. Lung inflammation, structural changes, and lung function were assessed. RNA-sequencing was performed on separated airway and parenchyma lung tissues to assess transcriptional changes. Validation of a novel upstream driver SPI1 in experimental ACO was assessed using the pharmacological SPI1 inhibitor, DB2313. Results: Experimental ACO recapitulated features of both asthma and COPD, with mixed pulmonary eosinophilic/neutrophilic inflammation, small airway collagen deposition, and increased airway hyperresponsiveness. Transcriptomic analysis identified common and distinct dysregulated gene clusters in airway and parenchyma samples in experimental asthma, COPD, and ACO. Upstream driver analysis revealed increased expression of the transcription factor Spi1. Pharmacological inhibition of SPI1 using DB2313, reduced airway remodeling and airway hyperresponsiveness in experimental ACO. Conclusions: A new experimental model of ACO featuring chronic dual exposures to house dust mite and cigarette smoke mimics key disease features observed in patients with ACO and revealed novel disease mechanisms, including upregulation of SPI1, that are amenable to therapy.
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2022 |
Fricker M, Qin L, Sánchez-Ovando S, Simpson JL, Baines KJ, Riveros C, et al., 'An altered sputum macrophage transcriptome contributes to the neutrophilic asthma endotype.', Allergy, 77 1204-1215 (2022) [C1]
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2022 |
Sánchez-Ovando S, Pavlidis S, Kermani NZ, Baines KJ, Barker D, Gibson PG, et al., 'Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts.', Respirology (Carlton, Vic.), 27 730-738 (2022) [C1]
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2021 |
Thomas D, Harvey ES, McDonald VM, Stevens S, Upham JW, Katelaris CH, et al., 'Mepolizumab and Oral Corticosteroid Stewardship: Data from the Australian Mepolizumab Registry', Journal of Allergy and Clinical Immunology: In Practice, 9 2715-2724.e5 (2021) [C1]
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2021 |
Girkin J, Loo S-L, Esneau C, Maltby S, Mercuri F, Chua B, et al., 'TLR2-mediated innate immune priming boosts lung anti-viral immunity', EUROPEAN RESPIRATORY JOURNAL, 58 (2021) [C1]
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2021 |
Williams TC, Jackson DJ, Maltby S, Walton RP, Ching Y-M, Glanville N, et al., 'Rhinovirus-induced CCL17 and CCL22 in Asthma Exacerbations and Differential Regulation by STAT6', AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 64 344-356 (2021) [C1]
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2021 |
Tu X, Donovan C, Kim RY, Wark PAB, Horyat JC, Hansbro PM, 'Asthma-COPD overlap: current understanding and the utility of experimental models', EUROPEAN RESPIRATORY REVIEW, 30 (2021) [C1]
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2021 |
Berthon BS, McLoughlin RF, Jensen ME, Hosseini B, Williams EJ, Baines KJ, et al., 'The effects of increasing fruit and vegetable intake in children with asthma: A randomized controlled trial', CLINICAL AND EXPERIMENTAL ALLERGY, 51 1144-1156 (2021) [C1]
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2021 |
Hosseini B, Berthon BS, Starkey MR, Collison A, McLoughlin RF, Williams EJ, et al., 'Children With Asthma Have Impaired Innate Immunity and Increased Numbers of Type 2 Innate Lymphoid Cells Compared With Healthy Controls', FRONTIERS IN IMMUNOLOGY, 12 (2021) [C1]
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2021 |
Bokern MP, Robijn AL, Jensen ME, Barker D, Callaway L, Clifton V, et al., 'Factors Associated with Asthma Exacerbations During Pregnancy', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, 9 4343-+ (2021) [C1]
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2021 |
Skerrett-Byrne DA, Bromfield EG, Murray HC, Jamaluddin MFB, Jarnicki AG, Fricker M, et al., 'Time-resolved proteomic profiling of cigarette smoke-induced experimental chronic obstructive pulmonary disease', Respirology, 26 960-973 (2021) [C1]
Background and objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with n... [more]
Background and objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with none able to reverse disease or stop its progression. We explored the major molecular changes in COPD pathogenesis. Methods: We employed quantitative label-based proteomics to map the changes in the lung tissue proteome of cigarette smoke-induced experimental COPD that is induced over 8 weeks and progresses over 12 weeks. Results: Quantification of 7324 proteins enabled the tracking of changes to the proteome. Alterations in protein expression profiles occurred in the induction phase, with 18 and 16 protein changes at 4- and 6-week time points, compared to age-matched controls, respectively. Strikingly, 269 proteins had altered expression after 8 weeks when the hallmark pathological features of human COPD emerge, but this dropped to 27 changes at 12 weeks with disease progression. Differentially expressed proteins were validated using other mouse and human COPD bronchial biopsy samples. Major changes in RNA biosynthesis (heterogeneous nuclear ribonucleoproteins C1/C2 [HNRNPC] and RNA-binding protein Musashi homologue 2 [MSI2]) and modulators of inflammatory responses (S100A1) were notable. Mitochondrial dysfunction and changes in oxidative stress proteins also occurred. Conclusion: We provide a detailed proteomic profile, identifying proteins associated with the pathogenesis and disease progression of COPD establishing a platform to develop effective new treatment strategies.
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2021 |
Winter NA, Gibson PG, Fricker M, Simpson JL, Wark PA, McDonald VM, 'Hemopexin: A novel anti-inflammatory marker for distinguishing COPD from Asthma', Allergy, Asthma and Immunology Research, 13 450-467 (2021) [C1]
Purpose: Systemic inflammatory biomarkers can improve diagnosis and assessment of chronic obstructive pulmonary disease (COPD) and asthma. We aimed to validate an airway disease b... [more]
Purpose: Systemic inflammatory biomarkers can improve diagnosis and assessment of chronic obstructive pulmonary disease (COPD) and asthma. We aimed to validate an airway disease biomarker panel of 4 systemic inflammatory biomarkers, a2-macroglobulin, ceruloplasmin, haptoglobin and hemopexin, to establish their relationship to airway disease diagnosis and inflammatory phenotypes and to identify an optimized biomarker panel for disease differentiation. Methods: Participants with COPD or asthma were classified by inflammatory phenotypes. Immunoassay methods were used to measure levels of validation biomarkers in the sera of participants with disease and non-respiratory disease controls. Markers were analyzed individually and in combination for disease differentiation and compared to established biomarkers (C-reactive protein, interleukin-6, and white blood cell/blood eosinophil count). Results: The study population comprised of 141 COPD, 127 severe asthma, 54 mild-moderate asthma and 71 control participants. Significant differences in ceruloplasmin, haptoglobin and hemopexin levels between disease groups and between systemic inflammatory phenotypes were observed. However, no differences were found between airway inflammatory phenotypes. Hemopexin was the best performing individual biomarker and could diagnose COPD versus control participants (area under the curve [AUC], 98.3%; 95% confidence interval [CI], 96.7%-99.9%) and differentiate COPD from asthmatic participants (AUC, 97.0%; 95% CI, 95.4%-98.6%), outperforming established biomarkers. A biomarker panel, including hemopexin, haptoglobin and other established biomarkers, could diagnose asthma versus control participants (AUC, 87.5%; 95% CI, 82.8%-92.2%). Conclusions: Hemopexin can be a novel biomarker with superior diagnostic ability in differentiating COPD and asthma. We propose an anti-inflammatory axis between the airways and systemic circulation, in which hemopexin is a protective component in airway disease.
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2021 |
Robijn AL, Barker D, Gibson PG, Giles WB, Clifton VL, Mattes J, et al., 'Factors Associated with Nonadherence to Inhaled Corticosteroids for Asthma During Pregnancy', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, 9 1242-+ (2021) [C1]
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2021 |
Chong WC, Shastri MD, Peterson GM, Patel RP, Pathinayake PS, Dua K, et al., 'The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders', Clinical and Translational Immunology, 10 (2021) [C1]
Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, pa... [more]
Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders.
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2021 |
Pathinayake PS, Hsu AC-Y, Wark PAB, 'PAT in the ER for Transmembrane Protein Folding (vol 46, pg 1007, 2020)', TRENDS IN BIOCHEMICAL SCIENCES, 46 344-344 (2021)
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2021 |
Maltby S, McDonald VM, Upham JW, Bowler SD, Chung LP, Denton EJ, et al., 'Severe asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings', INTERNAL MEDICINE JOURNAL, 51 169-180 (2021) [C1]
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2021 |
Wark PAB, Pathinayake PS, Kaiko G, Nichol K, Ali A, Chen L, et al., 'ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma', Respirology, 26 442-451 (2021) [C1]
Background and objective: 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 protea... [more]
Background and objective: 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. Methods: 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. Results: Increased gene expression of ACE2 was associated with older age (P = 0.03) and male sex (P = 0.03), but not with pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma patients (P = 0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in patients with asthma (P = 0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface, was increased (P = 0.02). ACE2 protein expression was also reduced in endobronchial biopsies from asthma patients. Conclusion: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID-19 complications.
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2021 |
Eapen MS, Lu W, Hackett TL, Singhera GK, Thompson IE, McAlinden KD, et al., 'Dysregulation of endocytic machinery and ACE2 in small airways of smokers and COPD patients can augment their susceptibility to SARS-CoV-2 (COVID-19) infections', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 320 L158-L163 (2021) [C1]
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2021 |
Upham JW, Le Lievre C, Jackson DJ, Masoli M, Wechsler ME, Price DB, et al., 'Defining a Severe Asthma Super-Responder: Findings from a Delphi Process', Journal of Allergy and Clinical Immunology: In Practice, 9 3997-4004 (2021) [C1]
Background: Clinicians are increasingly recognizing severe asthma patients in whom biologics and other add-on therapies lead to dramatic improvement. Currently, there is no agreed... [more]
Background: Clinicians are increasingly recognizing severe asthma patients in whom biologics and other add-on therapies lead to dramatic improvement. Currently, there is no agreed-upon super-responder (SR) definition. Objective: To survey severe asthma experts using a modified Delphi process, to develop an international consensus-based definition of a severe asthma SR. Methods: The Delphi panel was composed of 81 participants (94% specialist pulmonologists or allergists) from 24 countries and consisted of three iterative online voting rounds. Consensus on individual items, whether acceptance or rejection, required at least 70% agreement by panel members. Results: Consensus was achieved that the SR definition should be based on improvement across three or more domains assessed over 12 months. Major SR criteria included exacerbation elimination, a large improvement in asthma control (two or more times the minimal clinically important difference), and cessation of maintenance of oral steroids (or weaning to adrenal insufficiency). Minor SR criteria were composed of a 75% exacerbation reduction, having well-controlled asthma, and 500 mL or greater improvement in FEV1. The SR definition requires improvement in at least two major criteria. In the future, the SR definition should be expanded to incorporate quality of life measures, although current tools can be difficult to implement in a clinical setting and further research is needed. Conclusions: This international consensus-based definition of severe asthma SRs is an important prerequisite for better understanding SR prevalence, predictive factors, and the mechanisms involved. Further research is needed to understand the patient's perspective and to measure quality of life more precisely in SRs.
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2021 |
Ahern S, Dean J, Liman J, Ruseckaite R, Burke N, Gollan M, et al., 'Redesign of the Australian Cystic Fibrosis Data Registry: A multidisciplinary collaboration', Paediatric Respiratory Reviews, 37 37-43 (2021) [C1]
Clinical registries that monitor and review outcomes for patients with cystic fibrosis have existed internationally for many decades. However, their purpose continues to evolve an... [more]
Clinical registries that monitor and review outcomes for patients with cystic fibrosis have existed internationally for many decades. However, their purpose continues to evolve and now includes the capability to support clinical effectiveness research, clinical trials and Phase IV studies, and international data comparisons and projects. To achieve this, registries must regularly update the information that they collect and ensure design that is adaptable and flexible to changing needs. The Australian Cystic Fibrosis Data Registry commenced in 1998, and in 2018¿19 undertook a transformation to enable it to meet the needs of multiple stakeholders into the future. This included a comprehensive, multidisciplinary review of the registry's data elements, and a redesign and rebuild of the registry's database. The data element review comprised the processes of alignment, comparison, selection, consolidation, revision and definition of finalised data elements. The database redesign included attention to each of the registry functions of data collection, storage and management, and reporting. The revision of a national data collection system is a time-intensive process, and requires significant clinical and other expert engagement. The resulting database, while being continually refined, is now fit for purpose to support Australian clinicians and patients with CF to receive best practice care.
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2021 |
Kim RY, Sunkara KP, Bracke KR, Jarnicki AG, Donovan C, Hsu AC, et al., 'microRNA-21-mediated SATB1/S100A9/NF-kappa B axis promotes chronic obstructive pulmonary disease pathogenesis', SCIENCE TRANSLATIONAL MEDICINE, 13 (2021) [C1]
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Nova |
2021 |
Wark PAB, Pathinayake PS, Eapen MS, Sohal SS, 'Asthma, COPD and SARS-CoV-2 infection (COVID-19): potential mechanistic insights', EUROPEAN RESPIRATORY JOURNAL, 58 (2021)
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2021 |
Kim RY, Oliver BG, Wark PAB, Hansbro PM, Donovan C, 'COPD exacerbations: targeting IL-33 as a new therapy', LANCET RESPIRATORY MEDICINE, 9 1213-1214 (2021)
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2021 |
Wark PAB, MacIntyre CR, Bell S, Oliver B, Marks GB, 'We are not doing enough to prevent the spread of COVID-19 and other respiratory viruses in Australian hospitals', MEDICAL JOURNAL OF AUSTRALIA, 215 152-+ (2021)
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2021 |
Cook A, Harrington J, Simpson JL, Wark P, 'Mepolizumab asthma treatment failure due to refractory airway eosinophilia, which responded to benralizumab', RESPIROLOGY CASE REPORTS, 9 (2021)
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2021 |
Zounemat Kermani N, Saqi M, Agapow P, Pavlidis S, Kuo C, Tan KS, et al., 'Type 2-low asthma phenotypes by integration of sputum transcriptomics and serum proteomics', ALLERGY, 76 380-383 (2021)
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2021 |
Fawcett LK, Wakefield CE, Sivam S, Middleton PG, Wark P, Widger J, et al., 'Avatar acceptability: views from the Australian Cystic Fibrosis community on the use of personalised organoid technology to guide treatment decisions.', ERJ open research, 7 448-2020 (2021) [C1]
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Nova |
2021 |
Lu Z, Van Eeckhoutte HP, Liu G, Nair PM, Jones B, Gillis CM, et al., 'Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 204 667-681 (2021) [C1]
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2021 |
Pacitti D, Scotton CJ, Kumar V, Khan H, Wark PAB, Torregrossa R, et al., 'Gasping for sulfide: A critical appraisal of hydrogen sulfide in lung disease and accelerated aging', Antioxidants and Redox Signaling, 35 551-579 (2021) [C1]
Hydrogen sulfide (H2S) is a gaseous signaling molecule involved in a plethora of physiological and pathological processes. It is primarily synthesized by cystathionine-b-synthase,... [more]
Hydrogen sulfide (H2S) is a gaseous signaling molecule involved in a plethora of physiological and pathological processes. It is primarily synthesized by cystathionine-b-synthase, cystathionine-c-lyase, and 3-mercaptopyruvate sulfurtransferase as a metabolite of the transsulfuration pathway. H2S has been shown to exert beneficial roles in lung disease acting as an anti-inflammatory and antiviral and to ameliorate cell metabolism and protect from oxidative stress. H2S interacts with transcription factors, ion channels, and a multitude of proteins via post-translational modifications through S-persulfidation (¿¿sulfhydration¿¿). Perturbation of endogenous H2S synthesis and/or levels have been implicated in the development of accelerated lung aging and diseases, including asthma, chronic obstructive pulmonary disease, and fibrosis. Furthermore, evidence indicates that persulfidation is decreased with aging. Here, we review the use of H2S as a biomarker of lung pathologies and discuss the potential of using H2S-generating molecules and synthesis inhibitors to treat respiratory diseases. Furthermore, we provide a critical appraisal of methods of detection used to quantify H2S concentration in biological samples and discuss the challenges of characterizing physiological and pathological levels. Considerations and caveats of using H2S delivery molecules, the choice of generating molecules, and concentrations are also reviewed. Antioxid. Redox Signal. 35, 551¿579.
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2021 |
Fricker M, McDonald VM, Winter NA, Baines KJ, Wark PAB, Simpson JL, Gibson PG, 'Molecular markers of type 2 airway inflammation are similar between eosinophilic severe asthma and eosinophilic COPD', ALLERGY, 76 2079-2089 (2021) [C1]
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2021 |
Sanchez-Ovando S, Simpson JL, Barker D, Baines KJ, Wark PAB, 'Transcriptomics of biopsies identifies novel genes and pathways linked to neutrophilic inflammation in severe asthma', CLINICAL AND EXPERIMENTAL ALLERGY, 51 1279-1294 (2021) [C1]
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2020 |
Baines KJ, Fricker M, McDonald VM, Simpson JL, Wood LG, Wark PAB, et al., 'Sputum transcriptomics implicates increased p38 signalling activity in severe asthma', Respirology, 25 709-718 (2020) [C1]
Background and objective: Severe asthma is responsible for a disproportionate burden of illness and healthcare costs spent on asthma. This study analyses sputum transcriptomics to... [more]
Background and objective: Severe asthma is responsible for a disproportionate burden of illness and healthcare costs spent on asthma. This study analyses sputum transcriptomics to investigate the mechanisms and novel treatment targets of severe asthma. Methods: Induced sputum samples were collected in a cross-sectional study from participants with severe asthma (n = 12, defined as per GINA criteria), non-severe uncontrolled (n = 21) and controlled asthma (n = 21) and healthy controls (n = 15). Sputum RNA was extracted and transcriptomic profiles were generated (Illumina HumanRef-8 V2) and analysed (GeneSpring). Sputum protein lysates were analysed for p38 activation in a validation study (n = 24 asthma, n = 8 healthy) by western blotting. Results: There were 2166 genes differentially expressed between the four groups. In severe asthma, the expression of 1875, 1308 and 563 genes was altered compared to healthy controls, controlled and uncontrolled asthma, respectively. Of the 1875 genes significantly different to healthy controls, 123 were >2-fold change from which four networks were identified. Thirty genes (>2-fold change) were significantly different in severe asthma compared to both controlled asthma and healthy controls. There was enrichment of genes in the p38 signalling pathway that were associated with severe asthma. Phosphorylation of p38 was increased in a subset of severe asthma samples, correlating with neutrophilic airway inflammation. Conclusion: Severe asthma is associated with substantial differences in sputum gene expression that underlie unique cellular mechanisms. The p38 signalling pathway may be important in the pathogenesis of severe asthma, and future investigations into p38 inhibition are warranted as a ¿non-Th2¿ therapeutic option.
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2020 |
Wark P, Hussaini S, Holder C, Powell H, Gibson P, Oldmeadow C, 'Omalizumab Is an Effective Intervention in Severe Asthma with Fungal Sensitization', Journal of Allergy and Clinical Immunology: In Practice, 8 3428-3433.e1 (2020) [C1]
Background: Severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) are important complications of severe asthma. The evidence for treati... [more]
Background: Severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) are important complications of severe asthma. The evidence for treating them with omalizumab is limited. Objective: To determine the effectiveness of treatment with omalizumab in patients with severe allergic asthma comparing those with and without evidence of fungal sensitization using data recorded in the Australian Xolair Registry. Methods: Data from 205 patients who received omalizumab and recorded in the Australian Xolair Registry were analyzed to determine change in the Juniper 5-item Asthma Control Questionnaire (ACQ-5) score, exacerbation frequency, and oral corticosteroid dose over a 24-month period of omalizumab treatment. Patients were grouped into cohorts on the basis of fungal sensitization, and an analysis of improvement in outcomes between baseline and 24 months was conducted within each group. A further subgroup analysis of patients with ABPA was also conducted. Results: Patients with SAFS (n = 62), including those with ABPA (ASAFS), were as likely to demonstrate significant improvements in ACQ-5 score and exacerbations and reduced regular oral corticosteroid dose over 24 months as those with severe asthma without sensitization to fungi (n = 156). After adjusting for age, sex, body mass index, smoking history, and baseline FEV1%, the effects still remained. A subgroup analysis of 11 patients with ABPA similarly demonstrated a significant improvement on omalizumab. Conclusions: Omalizumab is an effective therapy in ASAFS, leading to sustained improvements in symptoms and exacerbations for 24 months. The benefit for ABPA is less clear because of the small sample size.
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Nova |
2020 |
Tong K, Barker D, France M, Burr L, Greville H, Visser S, et al., 'Lumacaftor/ivacaftor reduces exacerbations in adults homozygous for Phe508del mutation with severe lung disease', Journal of Cystic Fibrosis, 19 415-420 (2020) [C1]
Background: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy da... [more]
Background: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 < 40 would reduce the rate of pulmonary exacerbations. Methods: This was a case control study performed on patients > 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events. Results: Data was collected from 7 Australian CF centres on 105 patients; 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI; 0.306 ¿ 0.676), p < 0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common; chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%. Conclusions: Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent, and resulted in a very high discontinuation rate.
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Nova |
2020 |
Saladie M, Caparros-Martin JA, Agudelo-Romero P, Wark PAB, Stick SM, O'Gara F, 'Microbiomic Analysis on Low Abundant Respiratory Biomass Samples; Improved Recovery of Microbial DNA From Bronchoalveolar Lavage Fluid', FRONTIERS IN MICROBIOLOGY, 11 (2020) [C1]
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Nova |
2020 |
Pavord ID, Holliday M, Reddel HK, Braithwaite I, Ebmeier S, Hancox RJ, et al., 'Predictive value of blood eosinophils and exhaled nitric oxide in adults with mild asthma: a prespecified subgroup analysis of an open-label, parallel-group, randomised controlled trial', The Lancet Respiratory Medicine, 8 671-680 (2020) [C1]
Background: Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysi... [more]
Background: Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysis of a previously published open-label clinical trial, we aimed to assess associations between blood eosinophil counts and FeNO with outcomes and response to asthma treatment. Methods: In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only ß agonist reliever inhalers were enrolled at one of 16 clinical trials units in New Zealand, the UK, Italy, or Australia. Eligible participants were randomly assigned (1:1:1, stratified by country), to receive inhalers to take as-needed salbutamol (two inhalations of 100 µg in a pressurised metered dose inhaler), maintenance budesonide (200 µg twice per day by inhaler) plus as-needed salbutamol (two inhalations of 100 µg), or as-needed budesonide¿formoterol (one inhalation of 200 µg budesonide and 6µg formoterol by inhaler). The primary outcome was the annual rates of asthma exacerbations per patient, and in this prespecified subgroup analysis, we assessed whether annual exacerbation rates in each treatment group were significantly different depending on levels of blood eosinophil count, FeNO, or a composite score of both. Analyses were done for patients with available biomarker measurements The study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000999538. Findings: 675 participants were enrolled between March 17, 2016, and Aug 29, 2017, of whom 656 had results for blood eosinophil analysis and 668 had results for FeNO. Of the patients who received as-needed salbutamol, the proportion of patients having a severe exacerbation increased progressively with increasing blood eosinophil count (two [4%] of 49 participants with <0·15 × 109/L, six [6%] of 93 with 0·15 to <0·3 × 109/L, and 15 [19%] of 77 with =0·3 × 109/L; p=0·014). There were no significant interactions between blood eosinophil count or FeNO level and the effect of as-needed budesonide¿formoterol compared with as-needed salbutamol for either exacerbations or severe exacerbations. However, there were significant interactions between blood eosinophil count subgroups and the effect of maintenance budesonide plus as-needed salbutamol compared with as-needed salbutamol, both for exacerbations (p=0·0006) and severe exacerbations (p=0·0007). Maintenance budesonide plus as-needed salbutamol was more effective than as-needed salbutamol in patients with blood eosinophil counts of 0·3 × 109/L or more, both for exacerbations (rate ratio 0·13 [95% CI 0·05¿0·33]) and severe exacerbations (risk odds ratio 0·11 [0·03¿0·45]). This difference was not seen for blood eosinophil counts of less than 0·15 × 109/L (1·15 [0·51¿1·28] for exacerbations and 5·72 [0·97¿33·60] for severe exacerbations). There was no consistent interaction between treatment response and FeNO or the composite score. Interpretation: In patients with mild asthma, the effects of as-needed budesonide¿formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts than in patients with low counts. Funding: AstraZeneca, Health Research Council of New Zealand.
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2020 |
Pathinayake PS, Hsu AC-Y, Wark PAB, 'PAT in the ER for Transmembrane Protein Folding', TRENDS IN BIOCHEMICAL SCIENCES, 45 1007-1008 (2020)
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2020 |
Shukla SD, Walters EH, Simpson JL, Keely S, Wark PAB, O'Toole RF, Hansbro PM, 'Hypoxia-inducible factor and bacterial infections in chronic obstructive pulmonary disease', RESPIROLOGY, 25 53-63 (2020) [C1]
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Nova |
2020 |
Kicic A, de Jong E, Ling K-M, Nichol K, Anderson D, Wark PAB, et al., 'Assessing the unified airway hypothesis in children via transcriptional profiling of the airway epithelium', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 145 1562-1573 (2020) [C1]
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Nova |
2020 |
Vogel JP, Tendal B, Giles M, Whitehead C, Burton W, Chakraborty S, et al., 'Clinical care of pregnant and postpartum women with COVID-19: Living recommendations from the National COVID-19 Clinical Evidence Taskforce', AUSTRALIAN & NEW ZEALAND JOURNAL OF OBSTETRICS & GYNAECOLOGY, 60 840-851 (2020)
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2020 |
Reid AT, Nichol KS, Veerati PC, Moheimani F, Kicic A, Stick SM, et al., 'Blocking notch3 signaling abolishes MUC5AC production in airway epithelial cells from individuals with asthma', American Journal of Respiratory Cell and Molecular Biology, 62 513-523 (2020) [C1]
In asthma, goblet cell numbers are increased within the airway epithelium, perpetuating the production of mucus that is more difficult to clear and results in airway mucus pluggin... [more]
In asthma, goblet cell numbers are increased within the airway epithelium, perpetuating the production of mucus that is more difficult to clear and results in airway mucus plugging. Notch1, Notch2, or Notch3, or a combination of these has been shown to influence the differentiation of airway epithelial cells. How the expression of specific Notch isoforms differs in fully differentiated adult asthmatic epithelium and whether Notch influences mucin production after differentiation is currently unknown. We aimed to quantify different Notch isoforms in the airway epithelium of individuals with severe asthma and to examine the impact of Notch signaling on mucin MUC5AC. Human lung sections and primary bronchial epithelial cells from individuals with and without asthma were used in this study. Primary bronchial epithelial cells were differentiated at the air-liquid interface for 28 days. Notch isoform expression was analyzed by Taqman quantitative PCR. Immunohistochemistry was used to localize and quantify Notch isoforms in human airway sections. Notch signaling was inhibited in vitro using dibenzazepine or Notch3-specific siRNA, followed by analysis of MUC5AC. NOTCH3 was highly expressed in asthmatic airway epithelium compared with nonasthmatic epithelium. Dibenzazepine significantly reduced MUC5AC production in air-liquid interface cultures of primary bronchial epithelial cells concomitantly with suppression of NOTCH3 intracellular domain protein. Specific knockdown using NOTCH3 siRNA recapitulated the dibenzazepine-induced reduction in MUC5AC. We demonstrate that NOTCH3 is a regulator of MUC5AC production. Increased NOTCH3 signaling in the asthmatic airway epithelium may therefore be an underlying driver of excess MUC5AC production.
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Nova |
2020 |
Ramsahai JM, King E, Niven R, Tavernier G, Wark PAB, Simpson JL, 'Serum prednisolone levels as a marker of oral corticosteroid adherence in severe asthma', BMC Pulmonary Medicine, 20 1-8 (2020) [C1]
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Nova |
2020 |
Jin-Ying WYW, Yin Ng Z, Mehta M, Shukla SD, Panneerselvam J, Madheswaran T, et al., 'Curcumin-loaded niosomes downregulate mRNA expression of pro-inflammatory markers involved in asthma: An in vitro study', Nanomedicine, 15 2955-2970 (2020) [C1]
Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent ... [more]
Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent various physicochemical characterization experiments, an in vitro release study, molecular simulations and was evaluated for in vitro anti-inflammatory activity. Results: Results showed that Nio-Curc had a mean particle size of 284.93 ± 14.27 nm, zeta potential of -46.93 and encapsulation efficacy of 99.62%, which demonstrates optimized physicochemical characteristics. Curcumin release in vitro could be sustained for up to 24 h. Additionally, Nio-Curc effectively reduced mRNA transcript expression of pro-inflammatory markers; IL-6, IL-8, IL-1ß and TNF-a in immortalized human airway basal cell line (BCi-NS1.1). Conclusion: In this study, we have demonstrated that Nio-Curc mitigated the mRNA expression of pro-inflammatory markers in an in vitro study, which could be applied to treatment of asthma with further studies.
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2020 |
Sánchez-Ovando S, Baines KJ, Barker D, Wark PA, Simpson JL, 'Six gene and TH2 signature expression in endobronchial biopsies of participants with asthma', Immunity, Inflammation and Disease, 8 40-49 (2020) [C1]
Background: Both the six gene signature (6GS: CPA3, DNASE1L3, CLC, IL1B, ALPL, and CXCR2) and T-helper 2 signature (TH2S: CLCA1, SERPINB2, and POSTN) are proposed as biomarkers in... [more]
Background: Both the six gene signature (6GS: CPA3, DNASE1L3, CLC, IL1B, ALPL, and CXCR2) and T-helper 2 signature (TH2S: CLCA1, SERPINB2, and POSTN) are proposed as biomarkers in the identification of inflammatory phenotypes of asthma in induced sputum and epithelial brushings, respectively. The aim of this study was to explore patterns of gene expression of known signatures, 6GS and TH2S in endobronchial biopsies. Methods: This was an exploratory cross-sectional study of gene expression in endobronchial biopsies of 55 adults with asthma and 9 healthy controls (HC). The expression of the 6GS and TH2S was determined by quantitative polymerase chain reaction. Correlations with clinical and cellular characteristics were performed, and receiver operating characteristic was utilized to assess signatures' ability to predict asthma from HC and inflammatory phenotypes. Results: Gene expression of DNASE1L3 (P =.045) was upregulated in asthma compared with HC, and IL1B (P =.017) was upregulated in neutrophilic asthma compared with non-neutrophilic asthma. In asthma, the expression of CPA3 was negatively associated with ICS daily dose (r = -.339; P =.011), IL1B expression was positively associated with bronchial lavage fluid (BLF) total cell count (r =.340; P =.013) and both CLC and POSTN expression were associated with lymphocytes percentage in BLF (r = -.355, P =.009; r = -.300, P =.025, respectively). Both 6GS (area under curve [AUC] = 86.3%; P =.017) and TH2S (AUC = 72.7%; P =.037) could significantly predict asthma from HC. In addition, 6GS can identify neutrophilic (AUC = 93.2%; P =.005) and TH2S identifies eosinophilic (AUC = 62.7%; P =.033) asthma. Conclusions and Clinical Relevance: There was increased expression of DNASE1L3 in asthma and IL1B in neutrophilic asthma. These results show similar upregulated patterns of expression in two genes of the 6GS in endobronchial biopsies, previously identified in sputum. The upregulation of DNASE1L3 and IL1B suggests that common mechanisms may be at play throughout the airway.
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2020 |
Loo SL, Wark PAB, Esneau C, Nichol KS, Hsu ACY, Bartlett NW, 'Human coronaviruses 229E and OC43 replicate and induce distinct antiviral responses in differentiated primary human bronchial epithelial cells', American Journal of Physiology - Lung Cellular and Molecular Physiology, 319 L926-L931 (2020) [C1]
The recurrent emergence of novel, pathogenic coronaviruses (CoVs) severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; 2002), Middle East respiratory syndrome (MERS)-CoV (... [more]
The recurrent emergence of novel, pathogenic coronaviruses (CoVs) severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; 2002), Middle East respiratory syndrome (MERS)-CoV (2012), and most recently SARS-CoV-2 (2019) has highlighted the need for physiologically informative airway epithelial cell infection models for studying immunity to CoVs and development of antiviral therapies. To address this, we developed an in vitro infection model for two human coronaviruses; alphacoronavirus 229E-CoV (229E) and betacoronavirus OC43-CoV (OC43) in differentiated primary human bronchial epithelial cells (pBECs). Primary BECs from healthy subjects were grown at air-liquid interface (ALI) and infected with 229E or OC43, and replication kinetics and time-course expression of innate immune mediators were assessed. OC43 and 229E-CoVs replicated in differentiated pBECs but displayed distinct replication kinetics: 229E replicated rapidly with viral load peaking at 24 h postinfection, while OC43 replication was slower peaking at 96 h after infection. This was associated with diverse antiviral response profiles defined by increased expression of type I/III interferons and interferon-stimulated genes (ISGs) by 229E compared with no innate immune activation with OC43 infection. Understanding the host-virus interaction for previously established coronaviruses will give insight into pathogenic mechanisms underpinning SARS-CoV-2-induced respiratory disease and other future coronaviruses that may arise from zoonotic sources.
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2020 |
Yong DOC, Saker SR, Chellappan DK, Madheswaran T, Panneerselvam J, Choudhury H, et al., 'Molecular and immunological mechanisms underlying the various pharmacological properties of the potent bioflavonoid, rutin', Endocrine, Metabolic and Immune Disorders - Drug Targets, 20 1590-1596 (2020) [C1]
The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent ... [more]
The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and anti-diabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
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2020 |
Baines KJ, Negewo NA, Gibson PG, Fu JJ, Simpson JL, Wark PAB, et al., 'A Sputum 6 Gene Expression Signature Predicts Inflammatory Phenotypes and Future Exacerbations of COPD', International Journal of COPD, 15 1577-1590 (2020) [C1]
Background: The 6 gene expression signature (6GS) predicts in¿ammatory phenotype, exacerbation risk, and corticosteroid responsiveness in asthma. In COPD, patterns of airway in¿am... [more]
Background: The 6 gene expression signature (6GS) predicts in¿ammatory phenotype, exacerbation risk, and corticosteroid responsiveness in asthma. In COPD, patterns of airway in¿ammation are similar, suggesting the 6GS may be useful. This study determines the diagnostic and prognostic ability of 6GS in predicting in¿ammatory phenotypes and exacerbation risk in COPD. Methods: We performed 2 studies: a cross-sectional phenotype prediction study in stable COPD (total N=132; n=34 eosinophilic (E)-COPD, n=42 neutrophilic (N)-COPD, n=39 paucigranulocytic (PG)-COPD, n=17 mixed-granulocytic (MG)-COPD) that assessed 6GS ability to discriminate phenotypes (eosinophilia=3%; neutrophilia=61%); and a prospective cohort study (total n=54, n=8 E-COPD; n=18 N-COPD; n=20 PG-COPD; n=8 MG-COPD, n=21 exacerbation prone (=2/year)) that investigated phenotype and exacerbation prediction utility. 6GS was measured by qPCR and evaluated using multiple logistic regression and area under the curve (AUC). Short-term reproducibility (intra-class correlation) and phenotyping method agreement (¿ statistic) were assessed. Results: In the phenotype prediction study, 6GS could accurately identify and discriminate patients with E-COPD from N-COPD (AUC=96.4%; p<0.0001), PG-COPD (AUC=88.2%; p<0.0001) or MG-COPD (AUC=86.2%; p=0.0001), as well as N-COPD from PG-COPD (AUC=83.6%; p<0.0001) or MG-COPD (AUC=87.4%; p<0.0001) and was reproducible. In the prospective cohort study, 6GS had substantial agreement for neutrophilic in¿ammation (82%, ¿=0.63,p<0.001)and moderate agreement foreosinophilici n¿ammation(78%, ¿=0.42,p<0.001). 6GS could signi¿cantly discriminate exacerbationprone patients (AUC=77.2%; p=0.034). Higher IL1B levels were associated with poorer lung function and increased COPD severity. Conclusion: 6GS can signi¿cantly and reproducibly discriminate COPD in¿ammatory phenotypes and predict exacerbation prone patients and may become a useful molecular diagnostic tool assisting COPD management..
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2020 |
McDonald VM, Clark VL, Cordova-Rivera L, Wark PAB, Baines KJ, Gibson PG, 'Targeting treatable traits in severe asthma: a randomised controlled trial', EUROPEAN RESPIRATORY JOURNAL, 55 (2020) [C1]
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Nova |
2020 |
Chan Y, Ng SW, Chellappan DK, Madheswaran T, Zeeshan F, Kumar P, et al., 'Celastrol-loaded liquid crystalline nanoparticles as an anti-inflammatory intervention for the treatment of asthma', INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS, 70 754-763 (2020) [C1]
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Nova |
2020 |
Ali MK, Kim RY, Brown AC, Mayall JR, Karim R, Pinkerton JW, et al., 'Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma', EUROPEAN RESPIRATORY JOURNAL, 55 (2020) [C1]
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Nova |
2020 |
Veerati PC, Troy NM, Reid AT, Li NF, Nichol KS, Kaur P, et al., 'Airway Epithelial Cell Immunity Is Delayed During Rhinovirus Infection in Asthma and COPD', FRONTIERS IN IMMUNOLOGY, 11 (2020) [C1]
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Nova |
2020 |
Bowerman KL, Rehman SF, Vaughan A, Lachner N, Budden KF, Kim RY, et al., 'Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease', NATURE COMMUNICATIONS, 11 (2020) [C1]
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Nova |
2020 |
Ramsahai JM, Simpson JL, Heaney L, Gallagher N, Wark PAB, 'A survey of specialist opinions on biomarker use in severe asthma in Australia: scepticism but hope?', ERJ open research, 6 (2020) [C1]
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Nova |
2020 |
Cousins JL, Wark PAB, Hiles SA, McDonald VM, 'Understanding clinicians perceived barriers and facilitators to optimal use of acute oxygen therapy in adults', International Journal of COPD, 15 2275-2287 (2020) [C1]
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Nova |
2020 |
Dummer J, Dobler CC, Holmes M, Chambers D, Yang IA, Parkin L, et al., 'Diagnosis and treatment of lung disease associated with alpha one-antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*', Respirology, 25 321-335 (2020) [C1]
AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema rem... [more]
AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD-related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD-related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non-pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.
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Nova |
2020 |
Chan DECY, Hamed D, Lennon D, Wark P, 'Severe Nocardia pneumonia in an immunocompromised patient with alpha-1 antitrypsin deficiency', RESPIROLOGY CASE REPORTS, 8 (2020)
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2020 |
Johansen MD, Irving A, Montagutelli X, Tate MD, Rudloff I, Nold MF, et al., 'Animal and translational models of SARS-CoV-2 infection and COVID-19', Mucosal Immunology, 13 877-891 (2020) [C1]
COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The m... [more]
COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.
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Nova |
2020 |
Tew XN, Lau NJX, Chellappan DK, Madheswaran T, Zeeshan F, Tambuwala MM, et al., 'Immunological axis of berberine in managing inflammation underlying chronic respiratory inflammatory diseases', CHEMICO-BIOLOGICAL INTERACTIONS, 317 (2020) [C1]
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Nova |
2020 |
Chin LH, Hon CM, Chellappan DK, Chellian J, Madheswaran T, Zeeshan F, et al., 'Molecular mechanisms of action of naringenin in chronic airway diseases', European Journal of Pharmacology, 879 (2020) [C1]
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Nova |
2020 |
Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al., 'Mepolizumab effectiveness and identification of super-responders in severe asthma', EUROPEAN RESPIRATORY JOURNAL, 55 (2020) [C1]
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Nova |
2020 |
Maltby S, Gibson PG, Reddel HK, Smith L, Wark PAB, King GG, et al., 'Severe Asthma Toolkit: an online resource for multidisciplinary health professionals-needs assessment, development process and user analytics with survey feedback', BMJ OPEN, 10 (2020) [C1]
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Nova |
2020 |
Wark PAB, 'Contemporary Concise Review 2019: Asthma', RESPIROLOGY, 25 651-656 (2020) [C1]
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Nova |
2020 |
Cousins JL, Wood-Baker R, Wark PAB, Yang IA, Gibson PG, Hutchinson A, et al., 'Management of acute COPD exacerbations in Australia: do we follow the guidelines?', ERJ OPEN RESEARCH, 6 (2020) [C1]
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Nova |
2020 |
Wijker NE, Vidmar S, Grimwood K, Sly PD, Byrnes CA, Carlin JB, et al., 'Early markers of cystic fibrosis structural lung disease: Follow-up of the ACFBAL cohort', European Respiratory Journal, 55 (2020) [C1]
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Nova |
2020 |
Wark PAB, 'Asthma and the Dysregulated Immune Response to Rhinovirus', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 202 157-159 (2020)
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2019 |
Ramsahai JM, Hansbro PM, Wark PAB, 'Mechanisms and management of asthma exacerbations', American Journal of Respiratory and Critical Care Medicine, 199 423-432 (2019) [C1]
Acute asthma remains an important medical emergency, the most frequent cause of acute admissions in children and a major source of morbidity for adults with asthma. In all ages wi... [more]
Acute asthma remains an important medical emergency, the most frequent cause of acute admissions in children and a major source of morbidity for adults with asthma. In all ages with asthma, the presence of exacerbations is an important defining characteristic of asthma severity. In this review, we assess the epidemiology of acute asthma, the triggers of acute exacerbations, and the mechanisms that underlie these exacerbations. We also assess current treatments that prevent exacerbations, with an emphasis on the role of type 2 airway inflammation in the context of acute exacerbations and the novel treatments that effectively target this. Finally we review current mana ement strate ies of the exacerbations themselves
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Nova |
2019 |
Hayman TJ, Hsu AC, Kolesnik TB, Dagley LF, Willemsen J, Tate MD, et al., 'RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses', Immunology and Cell Biology, 97 840-852 (2019) [C1]
The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascade... [more]
The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid¿inducible gene-I (RIG-I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN-stimulated genes. Ubiquitination of RIG-I by the E3 ligases tripartite motif-containing 25 (TRIM25) and Riplet is thought to be requisite for RIG-I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG-I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG-I agonists. This is in contrast to deletion of either Rig-i or Riplet, which completely abrogated RIG-I-dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG-I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in¿vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG-I signaling in viral infections and will inform future studies in the field.
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Nova |
2019 |
Donovan C, Starkey MR, Kim RY, Rana BMJ, Barlow JL, Jones B, et al., 'Roles for T/B lymphocytes and ILC2s in experimental chronic obstructive pulmonary disease', Journal of Leukocyte Biology, 105 143-150 (2019) [C1]
Pulmonary inflammation in chronic obstructive pulmonary disease (COPD) is characterized by both innate and adaptive immune responses; however, their specific roles in the pathogen... [more]
Pulmonary inflammation in chronic obstructive pulmonary disease (COPD) is characterized by both innate and adaptive immune responses; however, their specific roles in the pathogenesis of COPD are unclear. Therefore, we investigated the roles of T and B lymphocytes and group 2 innate lymphoid cells (ILC2s) in airway inflammation and remodelling, and lung function in an experimental model of COPD using mice that specifically lack these cells (Rag1 -/- and Rora fl/fl Il7r Cre [ILC2-deficient] mice). Wild-type (WT) C57BL/6 mice, Rag1 -/- , and Rora fl/fl Il7r Cre mice were exposed to cigarette smoke (CS; 12 cigarettes twice a day, 5 days a week) for up to 12¿weeks, and airway inflammation, airway remodelling (collagen deposition and alveolar enlargement), and lung function were assessed. WT, Rag1 -/- , and ILC2-deficient mice exposed to CS had similar levels of airway inflammation and impaired lung function. CS exposure increased small airway collagen deposition in WT mice. Rag1 -/- normal air- and CS-exposed mice had significantly increased collagen deposition compared to similarly exposed WT mice, which was associated with increases in IL-33, IL-13, and ILC2 numbers. CS-exposed Rora fl/fl Il7r Cre mice were protected from emphysema, but had increased IL-33/IL-13 expression and collagen deposition compared to WT CS-exposed mice. T/B lymphocytes and ILC2s play roles in airway collagen deposition/fibrosis, but not inflammation, in experimental COPD.
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Nova |
2019 |
Lokwani R, Wark PAB, Baines KJ, Barker D, Simpson JL, 'Hypersegmented airway neutrophils and its association with reduced lung function in adults with obstructive airway disease: An exploratory study', BMJ Open, 9 (2019) [C1]
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Nova |
2019 |
Wang H, FitzPatrick M, Wilson NJ, Anthony D, Reading PC, Satzke C, et al., 'CSF3R/CD114 mediates infection-dependent transition to severe asthma', Journal of Allergy and Clinical Immunology, 143 785-788.e6 (2019) [C1]
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Nova |
2019 |
Hu MJ, Schulze KE, Ghildyal R, Henstridge DC, Kolanowski JL, New EJ, et al., 'Respiratory syncytial virus co-opts host mitochondrial function to favour infectious virus production', eLife, 8 1-30 (2019) [C1]
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Nova |
2019 |
Cheng AC, Holmes M, Dwyer DE, Senanayake S, Cooley L, Irving LB, et al., 'Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2018: the Influenza Complications Alert Network (FluCAN)', COMMUNICABLE DISEASES INTELLIGENCE, 43 (2019)
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2019 |
Cheng AC, Holmes M, Dwyer DE, Senanayake S, Cooley L, Irving LB, et al., 'Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2017: the Influenza Complications Alert Network (FluCAN)', Communicable diseases intelligence (2018), 43 (2019) [C1]
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Nova |
2019 |
Wark PAB, Cookson K, Thiruchelvam T, Brannan J, Dorahy DJ, 'Lumacaftor/ Ivacaftor improves exercise tolerance in patients with Cystic Fibrosis and severe airflow obstruction', BMC Pulmonary Medicine, 19 1-8 (2019) [C1]
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Nova |
2019 |
McDonald VM, Fingleton J, Agusti A, Hiles SA, Clark VL, Holland AE, et al., 'Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under International Workshop report.', The European respiratory journal, 53 (2019) [C1]
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Nova |
2019 |
McDonald VM, Hiles SA, Godbout K, Harvey ES, Marks GB, Hew M, et al., 'Treatable traits can be identified in a severe asthma registry and predict future exacerbations', Respirology, 24 37-47 (2019) [C1]
Background and objective: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whet... [more]
Background and objective: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. Methods: The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. Results: In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. Conclusion: Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.
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Nova |
2019 |
Yong DOC, Saker SR, Wadhwa R, Chellappan DK, Madheswaran T, Panneerselvam J, et al., 'Preparation, characterization and in-vitro efficacy of quercetin loaded liquid crystalline nanoparticles for the treatment of asthma', JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY, 54 (2019) [C1]
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Nova |
2019 |
Wark PAB, 'Why are people with asthma more susceptible to influenza?', The European respiratory journal, 54 1-3 (2019) [C1]
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Nova |
2019 |
Lokwani R, Wark PAB, Baines KJ, Fricker M, Barker D, Simpson JL, 'Blood neutrophils in copd but not asthma exhibit a primed phenotype with downregulated cd62l expression', International Journal of COPD, 14 2517-2525 (2019) [C1]
Purpose: To characterize neutrophils in obstructive airway disease by measuring their surface adhesion molecules and oxidative burst along with characterizing them into different ... [more]
Purpose: To characterize neutrophils in obstructive airway disease by measuring their surface adhesion molecules and oxidative burst along with characterizing them into different subsets as per their adhesion molecule expression. Patients and methods: Peripheral blood from adults with COPD (n=17), asthma (n=20), and healthy participants (n=19) was examined for expression of CD16, CD62L, CD11b, CD11c, and CD54, and analyzed by flow cytometry. For oxidative burst and CD62L shedding analysis, CD16 and CD62L stained leukocytes were loaded with Dihydrorhodamine-123 (DHR-123) and stimulated with N-Formylmethionine-leucyl-phenylalanine (fMLF). Neutrophil subsets were characterized based on CD16 and CD62L expression. Marker surface expression was recorded on CD16+ neutrophils as median fluorescence intensity (MFI). Results: Neutrophil surface expression of CD62L was significantly reduced in COPD (median (IQR) MFI: 1156 (904, 1365)) compared with asthma (1865 (1157, 2408)) and healthy controls (2079 (1054, 2960)); p=0.028. COPD neutrophils also demonstrated a significant reduction in CD62L expression with and without fMLF stimulation. Asthma participants had a significantly increased proportion and number of CD62Lbright/CD16dim neutrophils (median: 5.4% and 0.14 × 109/L, respectively), in comparison with healthy (3.54% and 0.12 × 109/L, respectively); p<0.017. Conclusion: Reduced CD62L expression suggests blood neutrophils have undergone priming in COPD but not in asthma, which may be the result of systemic inflammation. The increased shedding of CD62L receptor by COPD blood neutrophils suggests a high sensitivity for activation.
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Nova |
2019 |
Liu G, Cooley MA, Jarnicki AG, Borghuis T, Nair PM, Tjin G, et al., 'Fibulin-1c regulates transforming growth factor-beta activation in pulmonary tissue fibrosis', JCI INSIGHT, 4 (2019) [C1]
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Nova |
2019 |
Nair PM, Starkey MR, Haw TJ, Liu G, Collison AM, Mattes J, et al., 'Enhancing tristetraprolin activity reduces the severity of cigarette smoke-induced experimental chronic obstructive pulmonary disease', CLINICAL & TRANSLATIONAL IMMUNOLOGY, 8 (2019) [C1]
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Nova |
2019 |
Cheng AC, Holmes M, Dwyer DE, Senanayake S, Cooley L, Irving LB, et al., 'Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2017: the Influenza Complications Alert Network (FluCAN)', Communicable diseases intelligence (2018), 43 (2019) [C1]
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Nova |
2019 |
Blyth CC, Macartney KK, McRae J, Clark JE, Marshall HS, Buttery J, et al., 'Influenza Epidemiology, Vaccine Coverage and Vaccine Effectiveness in Children Admitted to Sentinel Australian Hospitals in 2017: Results from the PAEDS-FluCAN Collaboration', Clinical Infectious Diseases, 68 940-948 (2019) [C1]
Background In 2017, Australia experienced record influenza notifications. Two surveillance programs combined to summarize the epidemiology of hospitalized influenza in children an... [more]
Background In 2017, Australia experienced record influenza notifications. Two surveillance programs combined to summarize the epidemiology of hospitalized influenza in children and report on vaccine effectiveness (VE) in the context of a limited nationally funded vaccination program. Methods Subjects were prospectively recruited (April-October 2017). Case patients were children aged =16 years admitted to 11 hospitals with an acute respiratory illness and laboratory-confirmed influenza. Controls were hospitalized with acute respiratory illness and tested negative for influenza. VE estimates were calculated using the test-negative design. Results A total of 1268 children were hospitalized with influenza: 31.5% were <2 years old, 8.3% were indigenous, and 45.1% had comorbid conditions predisposing to severe influenza. Influenza B was detected in 34.1% with influenza A/H1N1 and A/H3N2 detected in 47.2% and 52.8% of subtyped influenza A specimens. The median length of stay was 3 days (interquartile range, 1-5), 14.5% were admitted to the intensive care unit, and 15.9% received oseltamivir. Four in-hospital deaths occurred (0.3%): one was considered influenza associated. Only 17.1% of test-negative-controls were vaccinated. The VE of inactivated quadrivalent influenza vaccine for preventing hospitalized influenza was estimated at 30.3% (95% confidence interval, 2.6%-50.2%). Conclusions Significant influenza-associated morbidity was observed in 2017 in Australia. Most hospitalized children had no comorbid conditions. Vaccine coverage and antiviral use was inadequate. Influenza vaccine was protective in 2017, yet VE was lower than previous seasons. Multiple Australian states have introduced funded preschool vaccination programs in 2018. Additional efforts to promote vaccination and monitor effectiveness are required.
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Nova |
2019 |
Ng SW, Chan Y, Chellappan DK, Madheswaran T, Zeeshan F, Chan YL, et al., 'Molecular modulators of celastrol as the keystones for its diverse pharmacological activities', Biomedicine and Pharmacotherapy, 109 1785-1792 (2019) [C1]
In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their ... [more]
In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
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Nova |
2019 |
Singanayagam A, Loo SL, Calderazzo M, Finney LJ, Torralbo MBT, Bakhsoliani E, et al., 'Antiviral immunity is impaired in COPD patients with frequent exacerbations', American Journal of Physiology - Lung Cellular and Molecular Physiology, 317 L893-L903 (2019) [C1]
Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. The aim of this study was to determine t... [more]
Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virusassociated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (=2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the antiviral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cellintrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro rhinovirus (RV) infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 wk following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention and treatment of frequent exacerbations.
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Nova |
2019 |
Starkey MR, Plank MW, Casolari P, Papi A, Pavlidis S, Guo Y, et al., 'IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis', EUROPEAN RESPIRATORY JOURNAL, 54 (2019) [C1]
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Nova |
2019 |
Duplancic C, Crough T, Bell SC, Thomson R, Wainwright C, Clements A, et al., 'Multi-centre ethics and research governance review can impede non-interventional clinical research', INTERNAL MEDICINE JOURNAL, 49 722-728 (2019)
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2019 |
Robijn AL, Jensen ME, Gibson PG, Powell H, Giles WB, Clifton VL, et al., 'Trends in asthma self-management skills and inhaled corticosteroid use during pregnancy and postpartum from 2004 to 2017.', The Journal of asthma : official journal of the Association for the Care of Asthma, 56 594-602 (2019) [C1]
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Nova |
2019 |
Liu G, Mateer SW, Hsu A, Goggins BJ, Tay H, Mathe A, et al., 'Platelet activating factor receptor regulates colitis-induced pulmonary inflammation through the NLRP3 inflammasome', Mucosal Immunology, 12 862-873 (2019) [C1]
Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patient... [more]
Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patients. In animal models of colitis, pulmonary inflammation is driven by neutrophilic infiltrations, primarily in response to the systemic bacteraemia and increased bacterial load in the lungs. Platelet activating factor receptor (PAFR) plays a critical role in regulating pulmonary responses to infection in conditions, such as chronic obstructive pulmonary disease and asthma. We investigated the role of PAFR in pulmonary EIMs of IBD, using dextran sulfate sodium (DSS) and anti-CD40 murine models of colitis. Both models induced neutrophilic inflammation, with increased TNF and IL-1ß levels, bacterial load and PAFR protein expression in mouse lungs. Antagonism of PAFR decreased lung neutrophilia, TNF, and IL-1ß in an NLRP3 inflammasome-dependent manner. Lipopolysaccharide from phosphorylcholine (ChoP)-positive bacteria induced NLRP3 and caspase-1 proteins in human alveolar epithelial cells, however antagonism of PAFR prevented NLRP3 activation by ChoP. Amoxicillin reduced bacterial populations in the lungs and reduced NLRP3 inflammasome protein levels, but did not reduce PAFR. These data suggest a role for PAFR in microbial pattern recognition and NLRP3 inflammasome signaling in the lung.
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Nova |
2019 |
Vanders RL, Hsu A, Gibson PG, Murphy VE, Wark PAB, 'Nasal epithelial cells to assess in vitro immune responses to respiratory virus infection in pregnant women with asthma', RESPIRATORY RESEARCH, 20 (2019) [C1]
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Nova |
2018 |
Reid AT, Veerati PC, Gosens R, Bartlett NW, Wark PA, Grainge CL, et al., 'Persistent induction of goblet cell differentiation in the airways: Therapeutic approaches', Pharmacology and Therapeutics, 185 155-169 (2018) [C1]
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, ... [more]
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.
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Nova |
2018 |
Cousins J, Wood-Baker R, Wark P, Yang I, Hutchinson A, Sajkov D, et al., 'MANAGEMENT OF ACUTE COPD EXACERBATIONS: DO WE FOLLOW THE GUIDELINES?', RESPIROLOGY, 23 72-72 (2018)
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2018 |
Ramsahai JM, Simpson J, Wark P, 'Eosinophilia as a treatable trait in three patients with asthma and copd', Respirology Case Reports, 6 (2018) [C1]
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Nova |
2018 |
Hiles SA, Harvey ES, McDonald VM, Peters M, Bardin P, Reynolds PN, et al., 'Working while unwell: Workplace impairment in people with severe asthma', CLINICAL AND EXPERIMENTAL ALLERGY, 48 650-662 (2018) [C1]
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Nova |
2018 |
Ng ZY, Wong JY, Panneerselvam J, Madheswaran T, Kumar P, Pillay V, et al., 'Assessing the potential of liposomes loaded with curcumin as a therapeutic intervention in asthma', Colloids and Surfaces B: Biointerfaces, 172 51-59 (2018) [C1]
Curcumin a component of turmeric, which is derived from Curcuma longa is used as a colouring agent and as a dietary spice for centuries. Extensive studies have been done on the an... [more]
Curcumin a component of turmeric, which is derived from Curcuma longa is used as a colouring agent and as a dietary spice for centuries. Extensive studies have been done on the anti-inflammatory activity of curcumin along with its molecular mechanism involving different signalling pathways. However, the physicochemical and biological properties such as poor solubility and rapid metabolism of curcumin have led to low bioavailability and hence limits its application. Current therapies for asthma such as bronchodilators and inhaled corticosteroids (ICS) are aimed at controlling disease symptoms and prevent asthma exacerbation. However, this approach requires lifetime therapy and is associated with a constellation of side effects. This creates a clear unmet medical need and there is an urgent demand for new and more-effective treatments. The present study is aimed to formulate liposomes containing curcumin and evaluate for its anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation on BCi-NS1.1 cell line. Curcumin and salbutamol liposomes were formulated using lipid hydration method. The prepared liposomes were characterized in terms of particle size, zeta potential, encapsulation efficiency and in-vitro release profile. The liposomes were tested on BCI-NS1.1 cell line to evaluate its anti-inflammatory properties. The various pro-inflammatory markers studied were Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-1ß (IL-1ß) and Tumour Necrosis Factor-a (TNF-a). Additionally, molecular mechanics simulations were used to elucidate the positioning, energy minimization, and aqueous dispersion of the liposomal architecture involving lecithin and curcumin. The prepared curcumin formulation showed an average size and zeta potential of 271.3 ± 3.06 nm and -61.0 mV, respectively. The drug encapsulation efficiency of liposomal curcumin is 81.1%. Both curcumin-loaded liposomes formulation (1 µg/mL, 5 µg/mL) resulted in significant (p < 0.05) reduction in the level of pro-inflammatory marker expression such as IL-6, IL-8, IL-1ß and TNF-a compared to positive control group. Liposomal curcumin with the dose of 1 µg/mL reduced the inflammatory markers more effectively compared to that of 5 µg/mL. Liposomal curcumin could be a promising intervention for asthma therapy showing their efficacy in suppressing the important pro-inflammatory markers involved in the pathogenesis of asthma.
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Nova |
2018 |
Pradeepan S, Wark P, 'Pseudomonas pharyngitis in a cystic fibrosis patient', RESPIROLOGY CASE REPORTS, 6 (2018)
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2018 |
Singanayagam A, Glanville N, Girkin JL, Ching YM, Marcellini A, Porter JD, et al., 'Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations', NATURE COMMUNICATIONS, 9 (2018) [C1]
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Nova |
2018 |
Kaiko GE, Wark PAB, 'Developments in cystic fibrosis personalised epithelial assays: Science and patient perspectives', JOURNAL OF CYSTIC FIBROSIS, 17 289-291 (2018)
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2018 |
Tan DBA, Teo T-H, Setiawan AM, Ong NE, Zimmermann M, Hsu AC-Y, et al., 'Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade', CLINICAL IMMUNOLOGY, 188 64-66 (2018)
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2018 |
Ramsahai JM, Wark PAB, 'Appropriate use of oral corticosteroids for severe asthma', MEDICAL JOURNAL OF AUSTRALIA, 209 S18-S21 (2018) [C1]
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Nova |
2018 |
Wark P, Mcdonald VM, 'Nebulised hypertonic saline for cystic fibrosis', Cochrane Database of Systematic Reviews, 2018 (2018)
Background: Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive infl... [more]
Background: Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review. Objectives: To investigate efficacy and tolerability of treatment with nebulised hypertonic saline on people with CF compared to placebo and or other treatments that enhance mucociliary clearance. Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases. Date of most recent searches: 08 August 2018. Selection criteria: Randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). Data collection and analysis: Two authors independently reviewed all identified trials and data, and assessed trial quality. The quality of the evidence was assessed using GRADE. Main results: A total of 17 trials (966 participants, aged 4 months to 63 years) were included; 19 trials were excluded, three trials are ongoing and 16 are awaiting classification. We judged 14 of the 17 included trials to have a high risk of bias due to participants ability to discern the taste of the solutions. Hypertonic saline 3% to 7% versus placebo At four weeks, we found very low-quality evidence from three placebo-controlled trials (n = 225) that hypertonic saline (3% to 7%, 10 mL twice-daily) increased the mean change from baseline of the forced expiratory volume at one second (FEV1) (% predicted) by 3.44% (95% confidence interval (CI) 0.67 to 6.21), but there was no difference between groups in lung clearance index in one small trial (n = 10). By 48 weeks the effect was slightly smaller in one trial (n = 134), 2.31% (95% CI -2.72 to 7.34) (low-quality evidence). No deaths occurred in the trials. Two trials reporting data on exacerbations were not combined as the age difference between the participants in the trials was too great. One trial (162 adults) found 0.5 fewer exacerbations requiring antibiotics per person in the hypertonic saline group; the second trial (243 children, average age of two years) found no difference between groups (low-quality evidence). There was insufficient evidence reported across the trials to determine the rate of different adverse events such as cough, chest tightness, tonsillitis and vomiting (very low-quality evidence). Four trials (n = 80) found very low-quality evidence that sputum clearance was better with hypertonic saline. A further trial was performed in adults with an acute exacerbation of lung disease (n = 132). The effects of hypertonic saline on short-term lung function, 5.10% higher (14.67% lower to 24.87% higher) and the time to the subsequent exacerbation post-discharge, hazard ratio 0.86 (95% CI 0.57 to 1.30) are uncertain (low-quality evidence). No deaths were reported. Cough and wheeze were reported but no serious adverse events (very low-quality evidence). Hypertonic saline versus mucus mobilising treatments Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two (61 participants) provided data for inclusion in the review. There was insufficient evidence from one three-week trial (14 participants) to determine the effects of hypertonic saline on FEV1 % predicted, mean difference (MD) 1.60% (95% CI -7.96 to 11.16) (very low-quality evidence). In the second trial, rhDNase led to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease, MD 8.00% (95% CI 2.00 to 14.00) (low-quality evidence). One cross-over trial...
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2018 |
Wark P, McDonald VM, 'Nebulised hypertonic saline for cystic fibrosis', COCHRANE DATABASE OF SYSTEMATIC REVIEWS, (2018)
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2018 |
Wark PAB, Ramsahai JM, Pathinayake P, Malik B, Bartlett NW, 'Respiratory Viruses and Asthma', Seminars in Respiratory and Critical Care Medicine, 39 45-55 (2018) [C1]
Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus infection and asthma has long been recogni... [more]
Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus infection and asthma has long been recognized, though remains incompletely understood. In this article, we will address key issues around this relationship. These will include the crucial role virus infection plays in early life, as a potential risk factor for the development of asthma and lung disease. We will assess the impact that virus infection has on those with established asthma as a trigger for acute disease and how this may influence asthma throughout life. Finally, we will explore the complex interaction that occurs between the airway and the immune responses that make those with asthma so susceptible to the effects of virus infection.
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Nova |
2018 |
Pathinayake PS, Hsu AC-Y, Waters DW, Hansbro PM, Wood LG, Wark PAB, 'Understanding the Unfolded Protein Response in the Pathogenesis of Asthma', FRONTIERS IN IMMUNOLOGY, 9 (2018) [C1]
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Nova |
2018 |
Moheimani F, Koops J, Williams T, Reid AT, Hansbro PM, Wark PA, Knight DA, 'Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics', Respiratory Research, 19 (2018) [C1]
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Nova |
2018 |
King GG, James A, Harkness L, Wark PAB, 'Pathophysiology of severe asthma: We ve only just started', Respirology, 23 262-271 (2018) [C1]
Severe asthma is defined by the high treatment requirements to partly or fully control the clinical manifestations of disease. It remains a problem worldwide with a large burden f... [more]
Severe asthma is defined by the high treatment requirements to partly or fully control the clinical manifestations of disease. It remains a problem worldwide with a large burden for individuals and health services. The key to improving targeted treatments, reducing disease burden and improving patient outcomes is a better understanding of the pathophysiology and mechanisms of severe disease. The heterogeneity, complexity and difficulties in undertaking clinical studies in severe asthma remain challenges to achieving better understanding and better outcomes. In this review, we focus on the structural, mechanical and inflammatory abnormalities that are relevant in severe asthma.
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Nova |
2018 |
Chellappan DK, Ng ZY, Wong JY, Hsu A, Wark P, Hansbro N, et al., 'Immunological axis of curcumin-loaded vesicular drug delivery systems', Future Medicinal Chemistry, 10 839-844 (2018) [C1]
Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Suc... [more]
Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Such systems use particles at a nanoscale range, bringing about their intended use through a range of complex mechanisms. Apart from delivering drug substances into target tissues, these vesicular systems also effectively overcome problems like insolubility and unequal drug distribution. Several mechanisms are explored lately by different workers, and interest over vesicular curcumin has been renewed in the past decade. This commentary discusses several immunological targets in which curcumin is employed in a vesicular form.
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Nova |
2018 |
Hosseini B, Berthon BS, Saedisomeolia A, Starkey MR, Collison A, Wark PAB, Wood LG, 'Effects of fruit and vegetable consumption on inflammatory biomarkers and immune cell populations: a systematic literature review and meta-analysis.', The American journal of clinical nutrition, 108 136-155 (2018) [C1]
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Nova |
2017 |
Conickx G, Mestdagh P, Cobos FA, Verhamme FM, Maes T, Vanaudenaerde BM, et al., 'MicroRNA profiling reveals a role for MicroRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, 195 43-56 (2017) [C1]
Rationale: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. Objectives: To identify dysregulated miRNAs in lung tissue of patients wi... [more]
Rationale: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. Objectives: To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD). Methods: We performed miRNA and mRNA profiling using high throughput stem-loop reverse-transcriptase quantitative polymerase chain reaction and mRNA microarray, respectively, on lung tissue of 30 patients (screening cohort) encompassing 8 never-smokers, 10 smokers without airflow limitation, and 12 smokers with COPD. Differential expression of miRNA-218-5p (miR-218-5p) was validated by reverse-transcriptase quantitative polymerase chain reaction in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells. Localization of miR-218-5p was assessed by in situ hybridization. In vitro and in vivo perturbation of miR-218-5p combined with RNA sequencing and gene set enrichment analysis was used to elucidate its functional role in COPD pathogenesis. Measurements and Main Results: Several miRNAs were differentially expressed among the different patient groups. Interestingly, miR-218-5p was significantly down-regulated in smokers without airflow limitation and in patients with COPD compared with never-smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice, and in human bronchial epithelial cells. Importantly, expression of miR-218-5p strongly correlated with airway obstruction. Furthermore, cellular localization of miR-218-5p in human and murine lung revealed highest expression of miR-218-5p in the bronchial airway epithelium. Perturbation experiments with a miR-218-5p mimic or inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD. Conclusions: We highlight a role for miR-218-5p in the pathogenesis of COPD.
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Nova |
2017 |
McDonald VM, Maltby S, Reddel HK, King GG, Wark PAB, Smith L, et al., 'Severe asthma: Current management, targeted therapies and future directions A roundtable report', Respirology, 22 53-60 (2017) [C1]
Asthma is a chronic respiratory disease characterized by respiratory symptoms, airway inflammation, airway obstruction and airway hyper-responsiveness. Asthma is common and direct... [more]
Asthma is a chronic respiratory disease characterized by respiratory symptoms, airway inflammation, airway obstruction and airway hyper-responsiveness. Asthma is common and directly affects 10% of Australians, 1¿5% of adults in Asia and 300 million people worldwide. It is a heterogeneous disorder with many clinical, molecular, biological and pathophysiological phenotypes. Current management strategies successfully treat the majority of patients with asthma who have access to them. However, there is a subset of an estimated 5¿10% of patients with asthma who have severe disease and are disproportionately impacted by symptoms, exacerbations and overall illness burden. The care required for this relatively small proportion of patients is also significant and has a major impact on the healthcare system. A number of new therapies that hold promise for severe asthma are currently in clinical trials or are entering the Australian and international market. However, recognition of severe asthma in clinical practice is variable, and there is little consensus on the best models of care or how to integrate emerging and often costly therapies into current practice. In this article, we report on roundtable discussions held with severe asthma experts from around Australia, and make recommendations about approaches for better patient diagnosis and assessment. We assess current models of care for patient management and discuss how approaches may be optimized to improve patient outcomes. Finally, we propose mechanisms to assess new therapies and how to best integrate these approaches into future treatment.
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Nova |
2017 |
McElvaney NG, Burdon J, Holmes M, Glanville A, Wark PAB, Thompson PJ, et al., 'Long-term efficacy and safety of a1 proteinase inhibitor treatment for emphysema caused by severe a1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE)', The Lancet Respiratory Medicine, 5 51-60 (2017) [C1]
Background Purified a1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe a1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), whi... [more]
Background Purified a1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe a1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. Methods Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. Findings Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48. Interpretation RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment. Funding CSL Behring.
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Nova |
2017 |
Hosseini B, Berthon BS, Wark P, Wood LG, 'Effects of Fruit and Vegetable Consumption on Risk of Asthma, Wheezing and Immune Responses: A Systematic Review and Meta-Analysis', NUTRIENTS, 9 (2017) [C1]
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Nova |
2017 |
Murray LA, Grainge C, Wark PA, Knight DA, 'Use of biologics to treat acute exacerbations and manage disease in asthma, COPD and IPF', Pharmacology and Therapeutics, 169 1-12 (2017) [C1]
A common feature of chronic respiratory disease is the progressive decline in lung function. The decline can be indolent, or it can be accelerated by acute exacerbations, whereby ... [more]
A common feature of chronic respiratory disease is the progressive decline in lung function. The decline can be indolent, or it can be accelerated by acute exacerbations, whereby the patient experiences a pronounced worsening of disease symptoms. Moreover, acute exacerbations may also be a marker of insufficient disease management. The underlying cause of an acute exacerbation can be due to insults such as pathogens or environmental pollutants, or the cause can be unknown. For each acute exacerbation, the patient may require medical intervention such as rescue medication, or in more severe cases, hospitalization and ventilation and have an increased risk of death. Biologics, such as monoclonal antibodies, are being developed for chronic respiratory diseases including asthma, COPD and IPF. This therapeutic approach is particularly well suited for chronic use based on the route and frequency of delivery and importantly, the potential for disease modification. In recent clinical trials, the frequency of acute exacerbation has often been included as an endpoint, to help determine whether the investigational agent is impacting disease. Therefore the significance of acute exacerbations in driving disease, and their potential as a marker of disease activity and progression, has recently received much attention. There is also now a need to standardize the definition of an acute exacerbation in specific disease settings, particularly as this endpoint is increasingly used in clinical trials to also assess therapeutic efficacy. Moreover, specifically targeting exacerbations may offer a new therapeutic approach for several chronic respiratory diseases.
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Nova |
2017 |
Ferreira D, Davies A, Thiruchelvam T, Wark P, 'Acute myocardial infarction in disseminated mucormycosis infection', EUROPEAN HEART JOURNAL, 38 838-838 (2017)
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2017 |
Huff RD, Hsu ACY, Nichol KS, Jones B, Knight DA, Wark PAB, et al., 'Regulation of xanthine dehydrogensase gene expression and uric acid production in human airway epithelial cells', PLoS ONE, 12 1-17 (2017) [C1]
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Nova |
2017 |
Liu G, Cooley MA, Nair PM, Donovan C, Hsu AC, Jarnicki AG, et al., 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c', JOURNAL OF PATHOLOGY, 243 510-523 (2017) [C1]
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Nova |
2017 |
Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, et al., 'Role for NLRP3 inflammasome-mediated, IL-1ß-dependent responses in severe, steroid-resistant asthma', American Journal of Respiratory and Critical Care Medicine, 196 283-297 (2017) [C1]
Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identifica... [more]
Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1ß responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma. Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1ß in severe, steroid-resistant asthma. Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1ß responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1ß responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1ß antibody. Roles for IL-1ß-induced neutrophilic inflammation were examined using IL-1ß and anti-Ly6G. Measurements and Main Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1ß responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1ß expression. Treatment with anti-IL-1ß, Ac- YVAD-cho, and MCC950 suppressed IL-1ß responses and the important steroid-resistant features of disease in mice, whereas IL-1ß administration recapitulated these features. Neutrophil depletion suppressed IL-1ß-induced steroid-resistant airway hyperresponsiveness. Conclusions: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
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Nova |
2017 |
Negewo NA, Gibson PG, Wark PAB, Simpson JL, McDonald VM, 'Treatment burden, clinical outcomes, and comorbidities in COPD: An examination of the utility of medication regimen complexity index in COPD', International Journal of COPD, 12 2929-2942 (2017) [C1]
Background: COPD patients are often prescribed multiple medications for their respiratory disease and comorbidities. This can lead to complex medication regimens resulting in poor... [more]
Background: COPD patients are often prescribed multiple medications for their respiratory disease and comorbidities. This can lead to complex medication regimens resulting in poor adherence, medication errors, and drug-drug interactions. The relationship between clinical outcomes and medication burden beyond medication count in COPD is largely unknown. Objectives: The aim of this study was to explore the relationships of medication burden in COPD with clinical outcomes, comorbidities, and multidimensional indices. Methods: In a cross-sectional study, COPD patients (n=222) were assessed for demographic information, comorbidities, medication use, and clinical outcomes. Complexity of medication regimens was quantified using the validated medication regimen complexity index (MRCI). Results: Participants (58.6% males) had a mean (SD) age of 69.1 (8.3) years with a postbronchodilator forced expiratory volume in 1 second % predicted of 56.5 (20.4) and a median of five comorbidities. The median (q1, q3) total MRCI score was 24 (18.5, 31). COPD-specific medication regimens were more complex than those of non-COPD medications (median MRCI: 14.5 versus 9, respectively; P<0.0001). Complex dosage formulations contributed the most to higher MRCI scores of COPD-specific medications while dosing frequency primarily drove the complexity associated with non-COPD medications. Participants in Global Initiative for Chronic Obstructive Lung Disease quadrant D had the highest median MRCI score for COPD medications (15.5) compared to those in quadrants A (13.5; P=0.0001) and B (12.5; P<0.0001). Increased complexity of COPD-specific treatments showed significant but weak correlations with lower lung function and 6-minute walk distance, higher St George¿s Respiratory Questionnaire and COPD assessment test scores, and higher number of prior year COPD exacerbations and hospitalizations. Comorbid cardiovascular, gastrointestinal, or metabolic diseases individually contributed to higher total MRCI scores and/or medication counts for all medications. Charlson Comorbidity Index and COPD-specific comorbidity test showed the highest degree of correlation with total MRCI score (¿=0.289 and ¿=0.326; P<0.0001, respectively). Conclusion: In COPD patients, complex medication regimens are associated with disease severity and specific class of comorbidities.
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Nova |
2017 |
Cheng AC, Holmes M, Dwyer DE, Irving L, Korman T, Senenayake S, et al., 'Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2016: the Influenza Complications Alert Network (FluCAN).', Communicable Diseases Intelligence Quarterly Report, 41 E337-E347 (2017) [C1]
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Nova |
2017 |
Kedzierski L, Tate MD, Hsu AC, Kolesnik TB, Linossi EM, Dagley L, et al., 'Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling', eLife, 6 1-27 (2017) [C1]
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Nova |
2017 |
Hsu AC-Y, Dua K, Starkey MR, Haw T-J, Nair PM, Nichol K, et al., 'MicroRNA-125a and -b inhibit A20 and MAVS to promote inflammation and impair antiviral response in COPD', JCI INSIGHT, 2 (2017) [C1]
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Nova |
2016 |
Tay H, Wark PAB, Bartlett NW, 'Advances in the treatment of virus-induced asthma', Expert Review of Respiratory Medicine, 10 629-641 (2016) [C1]
ABSTRACT: Viral exacerbations continue to represent the major burden in terms of morbidity, mortality and health care costs associated with asthma. Those at greatest risk for acut... [more]
ABSTRACT: Viral exacerbations continue to represent the major burden in terms of morbidity, mortality and health care costs associated with asthma. Those at greatest risk for acute asthma are those with more severe airways disease and poor asthma control. It is this group with established asthma in whom acute exacerbations triggered by virus infections remain a serious cause of increased morbidity. A range of novel therapies are emerging to treat asthma and in particular target this group with poor disease control, and in most cases their efficacy is now being judged by their ability to reduce the frequency of acute exacerbations. Critical for the development of new treatment approaches is an improved understanding of virus-host interaction in the context of the asthmatic airway. This requires research into the virology of the disease in physiological models in conjunction with detailed phenotypic characterisation of asthma patients to identify targets amenable to therapeutic intervention.
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Nova |
2016 |
Dentice RL, Elkins MR, Middleton PG, Bishop JR, Wark PAB, Dorahy DJ, et al., 'A randomised trial of hypertonic saline during hospitalisation for exacerbation of cystic fibrosis', Thorax, 71 141-147 (2016) [C1]
Background: The mucoactive effects of hypertonic saline should promote exacerbation resolution in people with cystic fibrosis (CF). Objectives: To determine the effects of hyperto... [more]
Background: The mucoactive effects of hypertonic saline should promote exacerbation resolution in people with cystic fibrosis (CF). Objectives: To determine the effects of hypertonic saline inhalation during hospitalisation for exacerbation of CF on length of stay, lung function, symptoms, oxygenation, exercise tolerance, quality of life, bacterial load and time to next hospitalisation. Methods: 132 adults with an exacerbation of CF were randomised to inhale three nebulised doses a day of either 4 mL 7% saline or a taste-masked control of 0.12% saline, throughout the hospital admission. The primary outcome measure was length of hospital stay. Results: All participants tolerated their allocated saline solution. There was no significant difference in length of stay, which was 12 days in the hypertonic saline group and 13 days in controls, with a mean between-group difference (MD) of 1 day (95% CI 0 to 2). The likelihood of regaining pre-exacerbation FEV1 by discharge was significantly higher in the hypertonic saline group (75% vs 57%), and the number needed to treat was 6 (95% CI 3 to 65). On a 0-100 scale, the hypertonic saline group had significantly greater reduction in symptom severity than the control group at discharge in sleep (MD=13, 95% CI 4 to 23), congestion (MD=10, 95% CI 3 to 18) and dyspnoea (MD=8, 95% CI 1 to 16). No significant difference in time to next hospitalisation for a pulmonary exacerbation was detected between groups (HR=0.86 (CI 0.57 to 1.30), p=0.13). Other outcomes did not significantly differ. Conclusions: Addition of hypertonic saline to the management of a CF exacerbation did not reduce the length of hospital stay. Hypertonic saline speeds the resolution of exacerbation symptoms and allows patients to leave hospital with greater symptom resolution.
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Nova |
2016 |
Haw TJ, Starkey MR, Nair PM, Pavlidis S, Liu G, Nguyen DH, et al., 'A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease', Mucosal Immunology, 9 859-872 (2016) [C1]
Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective ... [more]
Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-Type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL + CD11b + monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.
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Nova |
2016 |
Grainge CL, Maltby S, Gibson PG, Wark PAB, McDonald VM, 'Targeted therapeutics for severe refractory asthma: monoclonal antibodies', EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 9 927-941 (2016) [C1]
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Nova |
2016 |
Gibson PG, Reddel H, McDonald VM, Marks G, Jenkins C, Gillman A, et al., 'Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry', Internal Medicine Journal, 46 1054-1062 (2016) [C1]
Background: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway; however, effectiveness data in a population with significant comorbiditie... [more]
Background: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway; however, effectiveness data in a population with significant comorbidities are limited. Aims: To describe severe allergic asthma, omalizumab treatment outcomes and predictors of response among the Australian Xolair Registry participants. Methods: A web-based post-marketing surveillance registry was established to characterise the use, effectiveness and adverse effects of omalizumab (Xolair) for severe allergic asthma. Results: Participants (n = 192) (mean age 51 years, 118 female) with severe allergic asthma from 21 clinics in Australia were assessed, and 180 received omalizumab therapy. They had poor asthma control (Asthma Control Questionnaire, ACQ-5, mean score 3.56) and significant quality of life impairment (Asthma-related Quality of Life Questionnaire score 3.57), and 52% were using daily oral corticosteroid (OCS). Overall, 95% had one or more comorbidities (rhinitis 48%, obesity 45%, cardiovascular disease 23%). The omalizumab responder rate, assessed by an improvement of at least 0.5 in ACQ-5, was high at 83%. OCS use was significantly reduced. The response in participants with comorbid obesity and cardiovascular disease was similar to those without these conditions. Baseline ACQ-5 = 2.0 (P = 0.002) and older age (P = 0.05) predicted the magnitude of change in ACQ-5 in response to omalizumab. Drug-related adverse events included anaphylactoid reactions (n = 4), headache (n = 2) and chest pains (n = 1). Conclusion: Australian patients with severe allergic asthma report a high disease burden and have extensive comorbidity. Symptomatic response to omalizumab was high despite significant comorbid disease. Omalizumab is an effective targeted therapy for severe allergic asthma with comorbidity in a real-life setting.
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Nova |
2016 |
Cousins JL, Wark PAB, McDonald VM, 'Acute oxygen therapy: A review of prescribing and delivery practices', International Journal of COPD, 11 1067-1075 (2016) [C1]
Oxygen is a commonly used drug in the clinical setting and like other drugs its use must be considered carefully. This is particularly true for those patients who are at risk of t... [more]
Oxygen is a commonly used drug in the clinical setting and like other drugs its use must be considered carefully. This is particularly true for those patients who are at risk of type II respiratory failure in whom the risk of hypercapnia is well established. In recent times, several international bodies have advocated for the prescription of oxygen therapy in an attempt to reduce this risk in vulnerable patient groups. Despite this guidance, published data have demonstrated that there has been poor uptake of these recommendations. Multiple interventions have been tested to improve concordance, and while some of these interventions show promise, the sustainability of these interventions are less convincing. In this review, we summarize data that have been published on the prevalence of oxygen prescription and the accurate and appropriate administration of this drug therapy. We also identify strategies that have shown promise in facilitating changes to oxygen prescription and delivery practice. There is a clear need to investigate the barriers, facilitators, and attitudes of clinicians in relation to the prescription of oxygen therapy in acute care. Interventions based on these findings then need to be designed and tested to facilitate the application of evidence-based guidelines to support sustained changes in practice, and ultimately improve patient care.
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Nova |
2016 |
Wark P, Frith P, 'Asthma, COPD and when they coexist', Medicine Today, 17 16-24 (2016) [C1]
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Nova |
2016 |
Cheng AC, Holmes M, Dwyer DE, Irving LB, Korman TM, Senenayake S, et al., 'Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2015: the Influenza Complications Alert Network.', Commun Dis Intell Q Rep, 40 E521-E526 (2016) [C1]
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Nova |
2016 |
Gibson P, Reddel H, Jenkins C, Marks G, Upham J, Gillman A, et al., 'EFFECTIVENESS AND RESPONSE PREDICTORS OF OMALIZUMAB IN A SEVERE ALLERGIC ASTHMA POPULATION WITH A HIGH PREVALENCE OF COMORBIDITIES: THE AUSTRALIAN XOLAIR REGISTRY', RESPIROLOGY, 21 93-93 (2016)
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2016 |
Hew M, Gillman A, Sutherland M, Wark P, Bowden J, Guo M, et al., 'Real-life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria', Clinical and Experimental Allergy, 46 1407-1415 (2016) [C1]
Background: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ran... [more]
Background: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30¿1500 IU/mL) and bodyweight (30¿150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government-subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR). Objectives: To determine whether AXR participants above the recommended dosing ranges benefit from omalizumab and to compare their response to within-range participants. Methods: Data were stratified according to dose range status (above-range or within-range). Further sub-analyses were conducted according to the reason for being above the dosing range (IgE only vs. IgE and weight). Results: Data for 179 participants were analysed. About 55 (31%) were above recommended dosing criteria; other characteristics were similar to within-range participants. Above-range participants had higher baseline IgE [812 (IQR 632, 1747) IU/mL vs. 209 (IQR 134, 306) IU/mL] and received higher doses of omalizumab [750 (IQR 650, 750) mg] compared to within-range participants [450 (IQR, 300, 600) mg]. At 6 months, improvements in Juniper 5-item Asthma Control Questionnaire (ACQ-5, 3.61 down to 2.01 for above-range, 3.47 down to 1.93 for within-range, P < 0.0001 for both) and Asthma Quality of Life Questionnaire (AQLQ mean score (3.22 up to 4.41 for above-range, 3.71 up to 4.88 for within-range, P < 0.0001) were observed in both groups. Forced expiratory volume in one second (FEV1) improved among above-range participants. There was no difference in response between above-range and within-range participants. Above-range participants due to either IgE alone or IgE and weight had similar improvements in ACQ-5, AQLQ and FEV1. Conclusions and Clinical Relevance: Patients with severe allergic asthma above recommended dosing criteria for omalizumab have significantly improved symptom control, quality of life and lung function to a similar degree to within-range participants, achieved without dose escalation above 750 mg.
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Nova |
2016 |
Loo S-L, Wark PAB, 'Recent advances in understanding and managing asthma.', F1000Res, 5 (2016) [C1]
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Nova |
2016 |
Sin DD, Miravitlles M, Mannino DM, Soriano JB, Price D, Celli BR, et al., 'What is asthma?COPD overlap syndrome? Towards a consensus definition from a round table discussion', European Respiratory Journal, 48 664-673 (2016) [C1]
Patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) have been largely excluded from pivotal therapeutic trials and, as a result, its treatment remai... [more]
Patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) have been largely excluded from pivotal therapeutic trials and, as a result, its treatment remains poorly defined and lacking firm evidence. To date, there is no universally accepted definition of ACOS, which has made it difficult to understand its epidemiology or pathophysiology. Despite many uncertainties, there is emerging agreement that some of the key features of ACOS include persistent airflow limitation in symptomatic individuals 40 years of age and older, a well-documented history of asthma in childhood or early adulthood and a significant exposure history to cigarette or biomass smoke. In this perspective, we propose a case definition of ACOS that incorporates these key features in a parsimonious algorithm that may enable clinicians to better diagnose patients with ACOS and most importantly enable researchers to design therapeutic and clinical studies to elucidate its epidemiology and pathophysiology and to ascertain its optimal management strategies.
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Nova |
2016 |
Hsu ACY, Parsons K, Moheimani F, Knight DA, Hansbro PM, Fujita T, Wark PA, 'Impaired antiviral stress granule and IFN-ß enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium', American Journal of Respiratory Cell and Molecular Biology, 55 117-127 (2016) [C1]
Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infection... [more]
Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infections that result in exacerbations with exaggerated symptoms with increased mortality. The mechanisms underpinning this increased susceptibility to infection in COPD are unclear. In this study, we show that primary bronchial epithelial cells (pBECs) from subjects with COPD have impaired induction of type I IFN (IFN-ß) and lead to heightened viral replication after influenza viral infection. COPD pBECs have reduced protein levels of protein kinase (PK) R and decreased formation of PKR-mediated antiviral stress granules, which are critical in initiating type I IFNinductions. In addition, reduced protein expression of p300 resulted in decreased activation of IFN regulatory factor 3 and subsequent formation of IFN-ß enhanceosome in COPD pBECs. The decreased p300 induction was the result of enhanced levels of microRNA (miR)-132. Ectopic expression of PKR or miR-132 antagomiR alone failed to restore IFN-ß induction, whereas cotreatment increased antiviral stress granule formation, induction of p300, and IFN-ß in COPD pBECs. This study reveals that decreased induction of both PKR and p300 proteins contribute to impaired induction of IFN-ß in COPD pBECs upon influenza infection.
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Nova |
2016 |
Negewo NA, McDonald VM, Baines KJ, Wark PAB, Simpson JL, Jones PW, Gibson PG, 'Peripheral blood eosinophils: A surrogate marker for airway eosinophilia in stable COPD', International Journal of COPD, 11 1495-1504 (2016) [C1]
Introduction: Sputum eosinophilia occurs in approximately one-third of stable chronic obstructive pulmonary disease (COPD) patients and can predict exacerbation risk and response ... [more]
Introduction: Sputum eosinophilia occurs in approximately one-third of stable chronic obstructive pulmonary disease (COPD) patients and can predict exacerbation risk and response to corticosteroid treatments. Sputum induction, however, requires expertise, may not always be successful, and does not provide point-of-care results. Easily applicable diagnostic markers that can predict sputum eosinophilia in stable COPD patients have the potential to progress COPD management. This study investigated the correlation and predictive relationship between peripheral blood and sputum eosinophils. It also examined the repeatability of blood eosinophil counts. Methods: Stable COPD patients (n=141) were classified as eosinophilic or noneosinophilic based on their sputum cell counts (=3%), and a cross-sectional analysis was conducted comparing their demographics, clinical characteristics, and blood cell counts. Receiver operating characteristic curve analysis was used to assess the predictive ability of blood eosinophils for sputum eosinophilia. Intraclass correlation coefficient was used to examine the repeatability of blood eosinophil counts. Results: Blood eosinophil counts were significantly higher in patients with sputum eosinophilia (n=45) compared to those without (0.3×109/L vs 0.15×109/L; P<0.0001). Blood eosinophils correlated with both the percentage (¿=0.535; P<0.0001) and number of sputum eosinophils (¿=0.473; P<0.0001). Absolute blood eosinophil count was predictive of sputum eosinophilia (area under the curve =0.76, 95% confidence interval [CI] =0.67¿0.84; P<0.0001). At a threshold of =0.3×109/L (specificity =76%, sensitivity =60%, and positive likelihood ratio =2.5), peripheral blood eosinophil counts enabled identification of the presence or absence of sputum eosinophilia in 71% of the cases. A threshold of =0.4×109/L had similar classifying ability but better specificity (91.7%) and higher positive likelihood ratio (3.7). In contrast, =0.2×109/L offered a better sensitivity (91.1%) for ruling out sputum eosinophilia. There was a good agreement between two measurements of blood eosinophil count over a median of 28 days (intraclass correlation coefficient =0.8; 95% CI =0.66¿0.88; P<0.0001). Conclusion: Peripheral blood eosinophil counts can help identify the presence or absence of sputum eosinophilia in stable COPD patients with a reasonable degree of accuracy.
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Nova |
2016 |
Gang L, Hsu A, Cooley MA, Jarnicki AG, Nair PM, Haw TJ, et al., 'Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases', Journal of Clinical Investigation Insight, 1 (2016) [C1]
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Nova |
2016 |
Wark PAB, Hew M, Maltby S, McDonald VM, Gibson PG, 'Diagnosis and investigation in the severe asthma clinic.', Expert Rev Respir Med, 10 491-503 (2016) [C1]
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Nova |
2016 |
Moheimani F, Hsu AC-Y, Reid AT, Williams T, Kicic A, Stick SM, et al., 'The genetic and epigenetic landscapes of the epithelium in asthma', RESPIRATORY RESEARCH, 17 (2016) [C1]
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Nova |
2015 |
Wark PAB, McDonald VM, Gibson PG, 'Adjusting prednisone using blood eosinophils reduces exacerbations and improves asthma control in difficult patients with asthma.', Respirology, 20 1282-1284 (2015) [C1]
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2015 |
Vanders RL, Murphy VE, Gibson PG, Hansbro PM, Wark PAB, 'CD8 T cells and dendritic cells: Key players in the attenuated maternal immune response to influenza infection', Journal of Reproductive Immunology, 107 1-9 (2015) [C1]
Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still being capable of inducing an... [more]
Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still being capable of inducing an immune response against invading pathogens. To achieve this, numerous changes must occur in the activity and function of maternal immune cells throughout the course of pregnancy. Respiratory viruses take advantage of these changes, altering the sensitive balance of maternal immunity, leaving the mother with increased susceptibility to viral infections and increased disease severity. Influenza virus is one of the most common respiratory virus infections during pregnancy, leading to an increased risk of ICU hospitalisations, pneumonia, acute respiratory distress syndrome and even death. Whilst much research has been performed to understand the changes that must take place in maternal immunity during pregnancy, considerable work is still needed to fully comprehend this tremendous feat. To date, few studies have focused on the alterations that occur in maternal immunity during respiratory virus infections. This review highlights the role of dendritic cells (DCs) and CD8 T cells during pregnancy, and the changes that occur in these antiviral cells following influenza virus infections.
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Nova |
2015 |
Kumar RK, Shadie AM, Bucknall MP, Rutlidge H, Garthwaite L, Herbert C, et al., 'Differential injurious effects of ambient and traffic-derived particulate matter on airway epithelial cells', RESPIROLOGY, 20 73-79 (2015) [C1]
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Nova |
2015 |
Wark P, Hilton J, 'Minimising the risk of acute asthma in children', Medicine Today, 16 35-44 (2015)
A diagnosis of asthma is important before preventive treatment can be commenced in children after an acute asthma episode. Careful continuing assessment of the severity of the chi... [more]
A diagnosis of asthma is important before preventive treatment can be commenced in children after an acute asthma episode. Careful continuing assessment of the severity of the child's condition is needed to determine the risk of future episodes.
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2015 |
Cheng AC, Holmes M, Senenayake S, Dwyer DE, Hewagama S, Korman T, et al., 'Influenza epidemiology in adults admitted to sentinel Australian hospitals in 2014: the Influenza Complications Alert Network (FluCAN).', Communicable diseases intelligence quarterly report, 39 E355-E360 (2015) [C1]
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Nova |
2015 |
Pathinayake PS, Hsu A, wark PA, 'Innate Immunity and Immune Evasion by Enterovirus 71', Viruses, 7 (2015) [C1]
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Nova |
2015 |
Hatchwell L, Collison A, Girkin J, Parsons K, Li J, Zhang J, et al., 'Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia', Thorax, (2015) [C1]
© 2015 BMJ Publishing Group Ltd & British Thoracic Society.Background Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), w... [more]
© 2015 BMJ Publishing Group Ltd & British Thoracic Society.Background Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), which is sensed by Toll-like receptors (TLR) such as TLR7. Some asthmatics have impaired interferon (IFN) responses to RV, but the underlying mechanisms of this clinically relevant observation are poorly understood. Objectives To investigate the importance of intact TLR7 signalling in vivo during RV exacerbation using mouse models of house dust mite (HDM)-induced allergic airways disease exacerbated by a superimposed RV infection. Methods Wild-type and TLR7-deficient (Tlr7<sup>-/-</sup>) BALB/c mice were intranasally sensitised and challenged with HDM prior to infection with RV1B. In some experiments, mice were administered recombinant IFN or adoptively transferred with plasmacytoid dendritic cells (pDC). Results Allergic Tlr7<sup>-/-</sup> mice displayed impaired IFN release upon RV1B infection, increased virus replication and exaggerated eosinophilic inflammation and airways hyper reactivity. Treatment with exogenous IFN or adoptive transfer of TLR7-competent pDCs blocked these exaggerated inflammatory responses and boosted IFN? release in the absence of host TLR7 signalling. TLR7 expression in the lungs was suppressed by allergic inflammation and by interleukin (IL)-5-induced eosinophilia in the absence of allergy. Subjects with moderate-to-severe asthma and eosinophilic but not neutrophilic airways inflammation, despite inhaled steroids, showed reduced TLR7 and IFN?2/3 expression in endobronchial biopsies. Furthermore, TLR7 expression inversely correlated with percentage of sputum eosinophils. Conclusions This implicates IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression and antiviral responses, which provides a molecular mechanism underpinning the effect of eosinophil-targeting treatments for the prevention of asthma exacerbations.
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Nova |
2015 |
Hsu ACY, Starkey MR, Hanish I, Parsons K, Haw TJ, Howland LJ, et al., 'Targeting PI3K-p110a suppresses influenza virus infection in chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, 191 1012-1023 (2015) [C1]
Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which ... [more]
Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations. Objectives: To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting. Methods: We used a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD, and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors. Measurements and Main Results: COPDpBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity, reduced retinoic acid-inducible gene-I, and IFN/cytokine and chemokine responses. Increased PI3K-p110a levels and activity inCOPDpBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110a inhibitors, or exogenous IFN-b restored protective antiviral responses, suppressed infection, and improved lung function. Conclusions: The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110a activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.
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Nova |
2015 |
Carlet J, Aaron L, Abassi MS, Abbo L, Aboderin O, Abraham E, et al., 'World alliance against antibiotic resistance: The WAAAR declaration against antibiotic resistance', Medicina Intensiva, 39 34-39 (2015)
We must change how antibiotics are used and adopt proactive strategies, similar to those used to save endangered species. Preservation of the efficacy of antibiotics and to stabil... [more]
We must change how antibiotics are used and adopt proactive strategies, similar to those used to save endangered species. Preservation of the efficacy of antibiotics and to stabilization of antibiotic-susceptible bacterial ecosystems should be global goals.
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2015 |
Kidd TJ, Magalhães RJS, Paynter S, Bell SC, Grimwood K, Armstrong DS, et al., 'The social network of cystic fibrosis centre care and shared Pseudomonas aeruginosa strain infection: A cross-sectional analysis', The Lancet Respiratory Medicine, 3 640-650 (2015)
Background: Person-to-person transmission is a potential pathway of Pseudomonas aeruginosa acquisition in cystic fibrosis. Reports of cross-infection of shared cystic-fibrosis-spe... [more]
Background: Person-to-person transmission is a potential pathway of Pseudomonas aeruginosa acquisition in cystic fibrosis. Reports of cross-infection of shared cystic-fibrosis-specific P aeruginosa strains across large geographical distances are concerning. Therefore, we aimed to assess the extent to which patient movement between cystic fibrosis centres contributes to dissemination. Methods: We did a cross-sectional study to assess movement of patients with cystic fibrosis who were infected with P aeruginosa between Sept 3, 2007, and June 16, 2010, at 18 Australian cystic fibrosis centres. We applied social network analysis to patient movement data from P aeruginosa-infected patients to assess the role of patient mobility in P aeruginosa genotype prevalence. We generated networks linking treatment centres based on the movement of patients attending adult and paediatric cystic fibrosis centres, and compared these with the movement of patients infected with all P aeruginosa strains, unique strains, and predominant Australian shared strains (AUST-01 and AUST-02). We summarised connectivity using degree centrality, in-degree centrality, out-degree centrality, and k-core estimates. Infection control and surveillance practices were also assessed by use of a questionnaire. Findings: 983 patients (mean age 25 years [SD 10]; 551 [56%] male) provided 2887 P aeruginosa isolates for ERIC-PCR genotyping, which yielded 531 distinct genotypes: 493 unique strains in 373 patients and 38 shared strains in 610 patients. AUST-01 infections were associated with higher in-degree centrality (p=0·004) and k-core (p=0·005) estimates and AUST-02 infections with higher degree centrality (p=0·002), out-degree centrality (p=0·002), and k-core (p=0·007) estimates for the previous health-care facilities; associations for the present cystic fibrosis centre were not significant. These findings were significant for adult patients (AUST-01 in-degree centrality p=0·004 and k-core p=0·005; AUST-02 degree centrality p=0·004, out-degree centrality p=0·003, and k-core p=0·007), but not for paediatric patients. By contrast, infections with unique strains were associated with a lower k-core estimate for the present cystic fibrosis centre overall (p<0·0001); this finding was significant in adults (p<0·0001), but not in paediatric patients. Interpretation: Our results show that the connectivity of cystic fibrosis centres, as measured by the movement of patients, seems to be an important risk factor for the acquisition of shared P aeruginosa strain infections. These results show the importance of prioritising infection control interventions (eg, prospective molecular surveillance for shared P aeruginosa strains, strict universal infection control precautions, and hospital design and ventilation) to limit P aeruginosa cross-infection between patients with cystic fibrosis. Funding: Australian National Health and Medical Research Council; Children's Health Foundation Queensland; Office of Health and Medical Research, Queensland Health; European Respiratory Society-European Union; Australian Cystic Fibrosis Research Trust; Prince Charles Hospital Foundation; and Rotary Australia.
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2015 |
Cheng AC, Kotsimbos T, Kelly PM, Wark P, Hunter C, Hewagama S, et al., 'Influenza vaccine effectiveness against hospitalisation with influenza in adults in Australia in 2014', Vaccine, 33 7352-7356 (2015) [C1]
We provide estimates of the influenza vaccine protection against hospitalisation with laboratory-confirmed influenza in the 2014 Australian season where the A/H1N1/pdm09 strain pr... [more]
We provide estimates of the influenza vaccine protection against hospitalisation with laboratory-confirmed influenza in the 2014 Australian season where the A/H1N1/pdm09 strain predominated. This was performed using a case-test negative study design as part of a national sentinel surveillance system in Australia. Vaccine effectiveness was estimated as (1-OR). ×. 100% where the odds ratio of vaccination in cases vs test negative participants was estimated from a conditional logistic regression. Between April and November, 1692 adult patients were admitted with laboratory-confirmed influenza. Vaccine effectiveness was estimated from 1283 patients with influenza and 1116 test negative patients where vaccination status was ascertained. Vaccination was associated with a reduction in the risk of hospitalisation with influenza of 51.5% (95% CI: 41.6%, 59.7%) in all patients, and a reduction of 50.7% (95% CI: 40.1%, 59.3%) in the target population for vaccination. We estimate that the influenza vaccine was moderately protective against hospitalisation with laboratory-confirmed influenza during the 2014 influenza season in Australia.
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Nova |
2015 |
Tolosa JM, Parsons KS, Hansbro PM, Smith R, Wark PB, 'The placental protein syncytin-1 impairs antiviral responses and exaggerates inflammatory responses to influenza', PLoS ONE, 10 (2015) [C1]
Background Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1.We hypothesised that exposure of pe... [more]
Background Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1.We hypothesised that exposure of peripheral monocytes (PBMCs) to syncytin-1 would impair responses to H1N1pdm09 influenza. Methods and Findings Recombinant syncytin-1 was produced. PBMCs from non-pregnant women (n=10) were exposed to H1N1pdm09 in the presence and absence of syncytin-1 and compared to responses of PBMCs from pregnant women (n=12). PBMCs were characterised using flow cytometry, release of interferon (IFN)-a, IFN-¿, IFN-¿, IL-10, IL-2, IL-6 and IL-1ß were measured by cytometric bead array or ELISA. Exposure of PBMCs to H1N1pdm09 resulted in the release of IFN-a, (14,787 pg/mL, 95% CI 7311-22,264 pg/mL) IFN-¿ (1486 pg/mL, 95% CI 756-2216 pg/mL) and IFN-¿ (852 pg/mL, 95% CI 193-1511 pg/mL) after 48 hours. This was significantly impaired in pregnant women (IFN-a; p<0.0001 and IFN-¿; p<0.001). Furthermore, in the presence of syncytin-1, PBMCs demonstrated marked reductions in IFN-a and IFN-¿, while enhanced release of IL-10 as well as IL-6 and IL-1ß. Conclusions Our data indicates that a placental derived protein, syncytin-1 may be responsible for the heightened vulnerability of pregnant women to influenza.
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Nova |
2015 |
Wark P, 'Bronchitis (acute)', BMJ clinical evidence, 2015 (2015)
INTRODUCTION: Acute bronchitis affects more than 40 in 1000 adults per year in the UK. The causes are usually considered to be infective, but only around half of people have ident... [more]
INTRODUCTION: Acute bronchitis affects more than 40 in 1000 adults per year in the UK. The causes are usually considered to be infective, but only around half of people have identifiable pathogens. The role of smoking or of environmental tobacco smoke inhalation in predisposing to acute bronchitis is unclear. One third of people may have longer-term symptoms or recurrence.
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2015 |
Baines KJ, Wright TK, Simpson JL, McDonald VM, Wood LG, Parsons KS, et al., 'Airway beta-Defensin-1 Protein Is Elevated in COPD and Severe Asthma', MEDIATORS OF INFLAMMATION, 2015 (2015) [C1]
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Nova |
2014 |
Djukanovic R, Harrison T, Johnston SL, Gabbay F, Wark P, Thomson NC, et al., 'The Effect of Inhaled IFN-beta on Worsening of Asthma Symptoms Caused by Viral Infections A Randomized Trial', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 190 145-154 (2014) [C1]
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Nova |
2014 |
Cheng AC, Dwyer DE, Holmes M, Irving LB, Brown SGA, Waterer GW, et al., 'Influenza epidemiology, vaccine coverage and vaccine effectiveness in sentinel Australian hospitals in 2013: the Influenza Complications Alert Network', Communicable diseases intelligence quarterly report, 38 E143-E149 (2014)
The National Influenza Program aims to reduce serious morbidity and mortality from influenza by providing public funding for vaccination to at-risk groups. The Influenza Complicat... [more]
The National Influenza Program aims to reduce serious morbidity and mortality from influenza by providing public funding for vaccination to at-risk groups. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at 14 sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with confirmed influenza, estimates vaccine coverage and influenza vaccine protection against hospitalisation with influenza during the 2013 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals, with influenza confirmed by nucleic acid testing. Controls were patients who had acute respiratory illnesses who were test-negative for influenza. Vaccine effectiveness was estimated as 1 minus the odds ratio of vaccination in case patients compared with control patients, after adjusting for known confounders. During the period 5 April to 31 October 2012, 631 patients were admitted with confirmed influenza at the 14 FluCAN sentinel hospitals. Of these, 31% were more than 65 years of age, 9.5% were Indigenous Australians, 4.3% were pregnant and 77% had chronic co-morbidities. Influenza B was detected in 30% of patients. Vaccination coverage was estimated at 81% in patients more than 65 years of age but only 49% in patients aged less than 65 years with chronic comorbidities. Vaccination effectiveness against hospitalisation with influenza was estimated at 50% (95% confidence interval: 33%, 63%, P<0.001). We detected a significant number of hospital admissions with confirmed influenza in a national observational study. Vaccine coverage was incomplete in at-risk groups, particularly non-elderly patients with medical comorbidities. Our results suggest that the seasonal influenza vaccine was moderately protective against hospitalisation with influenza in the 2013 season.
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2014 |
Wark PAB, Murphy V, Mattes J, 'The interaction between mother and fetus and the development of allergic asthma', Expert Review of Respiratory Medicine, 8 57-66 (2014) [C1]
The rising prevalence of asthma and atopic disease in industrialized countries in the last 50 years has raised important questions about how and why the disease develops in suscep... [more]
The rising prevalence of asthma and atopic disease in industrialized countries in the last 50 years has raised important questions about how and why the disease develops in susceptible populations. Most asthma begins in childhood in association with allergic sensitization and the development of a TH2 phenotype. It is recognized that asthma arises in the context of a complex interaction between genetic factors and the evolving immune system of the infant and the environment to which it is exposed, which now includes its in utero exposure. Early life exposures that lead to allergen sensitization and airway damage, especially in the form of viral respiratory tract infections, may lead to disease induction that commence the process that leads in some to asthma. Asthma models and early life observations suggest that repeated exposure to allergens and viral infection perpetuate a state of chronic airway inflammation leading to a maladaptive innate immune response that fails to resolve, characterized by chronic airway inflammation, airway remodeling and airway hyperresponsiveness. This article will concentrate on the development of asthma in the context of early life and maternal influences, including the effect of asthma on both the fetus and the mother. © 2014 Informa UK Ltd.
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Nova |
2014 |
Parsons KS, Hsu AC, Wark PAB, 'TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection', Clinical and Experimental Allergy, 44 91-101 (2014) [C1]
Summary: Background: Rhinoviruses (RV) are the most common acute triggers of asthma, and airway epithelial cells are the primary site of infection. Asthmatic bronchial epithelial ... [more]
Summary: Background: Rhinoviruses (RV) are the most common acute triggers of asthma, and airway epithelial cells are the primary site of infection. Asthmatic bronchial epithelial cells (BECs) have been found to have impaired innate immune responses to RV. RV entry and replication is recognized by pathogen recognition receptors (PRRs), specifically toll-like receptor (TLR)3 and the RNA helicases; retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Objective: Our aim was to assess the relative importance of these PRRs in primary bronchial epithelial cells (pBEC) from healthy controls and asthmatics following RV infection and determine whether deficient innate immune responses in asthmatic pBECs were due to abnormal signalling via these PRRs. Methods: The expression patterns and roles of TLR3 and MDA5 were investigated using siRNA knock-down, with subsequent RV1B infection in pBECs from each patient group. We also used BX795, a specific inhibitor of TBK1 and IKKi. Results: Asthmatic pBECs had significantly reduced release of IL-6, CXCL-8 and IFN-¿ in response to RV1B infection compared with healthy pBECs. In healthy pBECs, siMDA5, siTLR3 and BX795 all reduced release of IL-6, CXCL-10 and IFN-¿ to infection. In contrast, in asthmatic pBECs where responses were already reduced, there was no further reduction in IL-6 and IFN-¿, although there was in CXCL-10. Conclusion and Clinical Relevance: Impaired antiviral responses in asthmatic pBECs are not due to deficient expression of PRRs; MDA5 and TLR3, but an inability to later activate types I and III interferon immune responses to RV infection, potentially increasing susceptibility to the effects of RV infection. © 2013 John Wiley & Sons Ltd.
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Nova |
2013 |
Murphy VE, Powell H, Wark PAB, Gibson PG, 'A Prospective Study of Respiratory Viral Infection in Pregnant Women With and Without Asthma', CHEST, 144 420-427 (2013) [C1]
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Nova |
2013 |
Hansbro P, Beckett E, Stevens R, Jarnicki A, Wark P, Foster P, 'A short-term model of COPD identifies a role for mast cell tryptase', EUROPEAN RESPIRATORY JOURNAL, 42 (2013) [C3]
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2013 |
Vanders RL, Gibson PG, Murphy VE, Wark PAB, 'Plasmacytoid Dendritic Cells and CD8 T Cells From PregnantWomen Show Altered Phenotype and Function Following H1N1/09 Infection', JOURNAL OF INFECTIOUS DISEASES, 208 1062-1070 (2013) [C1]
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Nova |
2013 |
Beckett EL, Stevens RL, Jarnicki AG, Kim RY, Hanish I, Hansbro NG, et al., 'A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis', The Journal of Allergy and Clinical Immunology, 131 752-762 (2013) [C1]
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Nova |
2013 |
Kidd TJ, Ramsay KA, Hu H, Marks GB, Wainwright CE, Bye PT, et al., 'Shared Pseudomonas aeruginosa genotypes are common in Australian cystic fibrosis centres', European Respiratory Journal, 41 1091-1100 (2013) [C1]
Recent molecular-typing studies suggest cross-infection as one of the potential acquisition pathways for Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In Australia... [more]
Recent molecular-typing studies suggest cross-infection as one of the potential acquisition pathways for Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In Australia, there is only limited evidence of unrelated patients sharing indistinguishable P. aeruginosa strains. We therefore examined the point-prevalence, distribution, diversity and clinical impact of P. aeruginosa strains in Australian CF patients nationally. 983 patients attending 18 Australian CF centres provided 2887 sputum P. aeruginosa isolates for genotyping by enterobacterial repetitive intergenic consensus-PCR assays with confirmation by multilocus sequence typing. Demographic and clinical details were recorded for each participant. Overall, 610 (62%) patients harboured at least one of 38 shared genotypes. Most shared strains were in small patient clusters from a limited number of centres. However, the two predominant genotypes, AUST-01 and AUST-02, were widely dispersed, being detected in 220 (22%) and 173 (18%) patients attending 17 and 16 centres, respectively. AUST-01 was associated with significantly greater treatment requirements than unique P. aeruginosa strains. Multiple clusters of shared P. aeruginosa strains are common in Australian CF centres. At least one of the predominant and widespread genotypes is associated with increased healthcare utilisation. Longitudinal studies are now needed to determine the infection control implications of these findings. Copyright ©ERS 2013.
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2013 |
Collison AM, Hatchwell LM, Verrills NM, Wark PA, Pereira De Siqueira AL, Tooze MK, et al., 'The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity', Nature Medicine, 19 232-237 (2013) [C1]
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Nova |
2013 |
Frith P, Thompson P, Wark P, Lindstrom S, Bateman E, 'BENEFITS OF DUAL BRONCHODILATION WITH QVA149 ONCE DAILY VERSUS PLACEBO, INDACATEROL, NVA237 AND TIOTROPIUM IN PATIENTS WITH COPD: THE SHINE STUDY', RESPIROLOGY, 18 20-20 (2013)
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2013 |
Cheng AC, Brown S, Waterer G, Holmes M, Senenayake S, Friedman ND, et al., 'Influenza epidemiology, vaccine coverage and vaccine effectiveness in sentinel Australian hospitals in 2012: the Influenza Complications Alert Network (FluCAN)', Communicable diseases intelligence quarterly report, 37 E246-E252 (2013)
Influenza is mostly a mild, self-limiting infection and severe infection requiring hospitalisation is uncommon. Immunisation aims to reduce serious morbidity and mortality. The In... [more]
Influenza is mostly a mild, self-limiting infection and severe infection requiring hospitalisation is uncommon. Immunisation aims to reduce serious morbidity and mortality. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at 15 sites across all states and territories in Australia. This study reports on the epidemiology of hospitalisation with confirmed influenza, estimate vaccine coverage and influenza vaccine protection against hospitalisation with influenza during the 2012 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals with influenza confirmed by nucleic acid detection. Controls were patients who had acute respiratory illnesses who were test-negative for influenza. Vaccine effectiveness was estimated as 1¿minus the odds ratio of vaccination in case patients compared with control patients, after adjusting for known confounders. During the period 9 April to 31 October 2012, 1,231 patients were admitted with confirmed influenza at the 15 FluCAN sentinel hospitals. Of these, 47% were more than 65 years of age, 8% were Indigenous Australians, 3% were pregnant and 76% had chronic co-morbidities. Influenza A was detected in 83% of patients. Vaccination coverage was calculated from the vaccination status of 1,216 test negative controls and was estimated at 77% in patients 65 years or over and 61% in patients with chronic comorbidities. Vaccination effectiveness was estimated at 41% (95% CI: 28%, 51%, P<0.001). Vaccine coverage was incomplete in at-risk groups, particularly non-elderly patients with medical comorbidities. The study results suggest that the seasonal influenza vaccine was moderately protective against hospitalisation with influenza during the 2012 season.
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2013 |
Vanders RL, Gibson PG, Wark PAB, Murphy VE, 'Alterations in inflammatory, antiviral and regulatory cytokine responses in peripheral blood mononuclear cells from pregnant women with asthma', RESPIROLOGY, 18 827-833 (2013) [C1]
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Nova |
2013 |
Wark PAB, Tooze M, Powell H, Parsons K, 'Viral and bacterial infection in acute asthma and chronic obstructive pulmonary disease increases the risk of readmission', RESPIROLOGY, 18 996-1002 (2013) [C1]
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Nova |
2013 |
Baines KJ, Hsu AC-Y, Tooze M, Gunawardhana LP, Gibson PG, Wark PAB, 'Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD', RESPIRATORY RESEARCH, 14 (2013) [C1]
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Nova |
2013 |
Cheng AC, Holmes M, Irving LB, Brown SGA, Waterer GW, Korman TM, et al., 'Influenza Vaccine Effectiveness against Hospitalisation with Confirmed Influenza in the 2010-11 Seasons: A Test-negative Observational Study', PLOS ONE, 8 (2013) [C1]
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Nova |
2012 |
Sukkar MB, Ullah MA, Gan WJ, Wark PA, Chung KF, Hughes JM, et al., 'RAGE: a new frontier in chronic airways disease', British Journal of Pharmacology, 167 1161-1176 (2012) [C1]
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Nova |
2012 |
Hurt AC, Hardie K, Wilson NJ, Deng YM, Osbourn M, Leang SK, et al., 'Characteristics of a widespread community cluster of H275Y Oseltamivir-Resistant A (H1N1)pdm09 influenza in Australia', Journal of Infectious Diseases, 206 148-157 (2012) [C1]
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Nova |
2012 |
Vanders RL, Wark PA, Murphy VE, Gibson PG, 'Pregnant women have attenuated innate interferon responses to 2009 pandemic influenza a virus subtype H1N1', Journal of Infectious Diseases, 206 646-653 (2012) [C1]
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Nova |
2012 |
Bozinovski S, Uddin M, Vlahos R, Thompson M, McQualter JL, Merritt A-S, et al., 'Serum amyloid A opposes lipoxin A(4) to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease', Proceedings of the National Academy of Sciences of the United States of America, 109 935-940 (2012) [C1]
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Nova |
2012 |
Vanders RL, Gibson PG, Murphy VE, Wark PAB, 'Impaired type I and III interferon response to rhinovirus infection during pregnancy and asthma', Thorax, 67 209-214 (2012) [C1]
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Nova |
2012 |
Sukkar MB, Wood LG, Tooze MK, Simpson JL, McDonald VM, Gibson PG, Wark PA, 'Soluble RAGE is deficient in neutrophilic asthma and COPD', European Respiratory Journal, 39 721-729 (2012) [C1]
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Nova |
2012 |
Wark PA, Tooze M, Cheese L, Whitehead BF, Gibson PG, Wark K, McDonald VM, 'Viral infections trigger exacerbations of cystic fibrosis in adults and children', European Respiratory Journal, 40 510-512 (2012) [C1]
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Nova |
2012 |
Ryan NM, Vertigan AE, Ferguson JK, Wark PA, Gibson PG, 'Clinical and physiological features of postinfectious chronic cough associated with H1N1 infection', Respiratory Medicine, 106 138-144 (2012) [C1]
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Nova |
2012 |
Wark PA, 'Airway inflammation in asthma, a single measurement is not enough', Respirology, 17 393-394 (2012) [C3]
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2012 |
Hsu A, See HV, Hansbro PM, Wark PA, 'Innate immunity to influenza in chronic airways diseases', Respirology, 17 1166-1175 (2012) [C1]
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Nova |
2012 |
Pretto JJ, McDonald VM, Wark PA, Hensley MJ, 'Multicentre audit of inpatient management of acute exacerbations of chronic obstructive pulmonary disease: Comparison with clinical guidelines', Internal Medicine Journal, 42 380-387 (2012) [C1]
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2012 |
Vlahos R, Wark PAB, Anderson GP, Bozinovski S, 'Glucocorticosteroids Differentially Regulate MMP-9 and Neutrophil Elastase in COPD', PLOS ONE, 7 (2012) [C1]
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2012 |
Hsu A, Parsons KS, Barr I, Lowther S, Middleton D, Hansbro PM, Wark PA, 'Critical role of constitutive type I interferon response in bronchial epithelial cell to influenza infection', PLoS One, 7 (2012) [C1]
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Nova |
2011 |
Wark PA, 'Tiotropium reduced exacerbations more than salmeterol in moderate-to-very severe COPD', Annals of Internal Medicine, 155 3 (2011) [C3]
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2011 |
Cheng AC, Kotsimbos T, Kelly HA, Irving LB, Bowler SD, Brown SGA, et al., 'Effectiveness of H1N1/09 monovalent and trivalent influenza vaccines against hospitalization with laboratory-confirmed H1N1/09 influenza in Australia: A test-negative case control study', Vaccine, 29 7320-7325 (2011) [C1]
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Nova |
2011 |
Wood LG, Simpson JL, Wark PA, Powell H, Gibson PG, 'Characterization of innate immune signalling receptors in virus-induced acute asthma', Clinical and Experimental Allergy, 41 640-648 (2011) [C1]
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Nova |
2011 |
Katelaris CH, Linneberg A, Magnan A, Thomas WR, Wardlaw AJ, Wark PA, 'Developments in the field of allergy in 2010 through the eyes of Clinical and Experimental Allergy', Clinical and Experimental Allergy, 41 1690-1710 (2011) [C3]
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2011 |
Hsu A, Barr I, Hansbro PM, Wark PA, 'Human influenza is more effective than Avian influenza at antiviral suppression in airway cells', American Journal of Respiratory Cell and Molecular Biology, 44 906-913 (2011) [C1]
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Nova |
2010 |
Wood LG, Wark PA, Garg ML, 'Antioxidant and anti-inflammatory effects of resveratrol in airway disease', Antioxidants & Redox Signaling, 13 1535-1548 (2010) [C1]
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Nova |
2010 |
Wark PA, 'Viral and bacterial interactions in pneumonia', Expert Review of Respiratory Medicine, 4 221-228 (2010) [C1]
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Nova |
2010 |
Ivison SM, Himmel ME, Hardenberg G, Wark PAJ, Kifayet A, Levings MK, Steiner TS, 'TLR5 Is Not Required for Flagellin-mediated Exacerbation of DSS Colitis', INFLAMMATORY BOWEL DISEASES, 16 401-409 (2010)
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2010 |
Reddel HK, Gibson PG, Peters MJ, Wark PA, Sand IB, Hoyos CM, Jenkins CR, 'Down-titration from high-dose combination therapy in asthma: Removal of long-acting b2-agonist', Respiratory Medicine, 104 1110-1120 (2010) [C1]
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Nova |
2010 |
Osei-Kumah A, Wark PA, Smith R, Clifton VL, 'Asthma during pregnancy alters immune cell profile and airway epithelial chemokine release', Inflammation Research, 59 349-358 (2010) [C1]
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Nova |
2009 |
Wark PA, McDonald VM, 'Nebulised hypertonic saline for cystic fibrosis', Cochrane Database of Systematic Reviews, - CD001506 (2009) [C1]
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Nova |
2009 |
Saedi Some Olia A, Wood LG, Garg ML, Gibson PG, Wark PA, 'Anti-inflammatory effects of long-chain n-3 PUFA in rhinovirus-infected cultured airway epithelial cells', British Journal of Nutrition, 101 533-540 (2009) [C1]
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Nova |
2009 |
Ramirez-Farias C, Slezak K, Fuller Z, Duncan A, Holtrop G, Louis P, 'Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii.', The British journal of nutrition, 101 541-550 (2009)
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2009 |
Kidd TJ, Ramsay KA, Hu H, Bye PTP, Elkins MR, Grimwood K, et al., 'Low Rates of Pseudomonas aeruginosa Misidentification in Isolates from Cystic Fibrosis Patients', JOURNAL OF CLINICAL MICROBIOLOGY, 47 1503-1509 (2009)
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2009 |
Saedi Some Olia A, Wood LG, Garg ML, Gibson PG, Wark PA, 'Lycopene enrichment of cultured airway epithelial cells decreases the inflammation induced by rhinovirus infection and lipopolysaccharide', Journal of Nutritional Biochemistry, 20 577-585 (2009) [C1]
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Nova |
2009 |
Wark PA, Grissell TV, Davies BL, See HV, Gibson PG, 'Diversity in the bronchial epithelial cell response to infection with different rhinovirus strains', Respirology, 14 180-186 (2009) [C1]
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Nova |
2008 |
Saedi Some Olia A, Wood LG, Garg ML, Gibson PG, Wark PA, 'Supplementation of long chain N-3 polyunsaturated fatty acids increases the utilization of lycopene in cultured airway epithelial cells', Journal of Food Lipids, 15 421-432 (2008) [C1]
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Nova |
2008 |
Wark PA, 'Guest editorial', Paediatric Respiratory Reviews, 9 233-235 (2008) [C3]
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Nova |
2008 |
See HV, Wark PA, 'Innate immune response to viral infection of the lungs', Paediatric Respiratory Reviews, 9 243-250 (2008) [C1]
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Nova |
2008 |
Simpson JL, Wark PA, 'The role of exhaled nitric oxide and exhaled breath condensates in evaluating airway inflammation in asthma', Expert Opinion on Medical Diagnostics, 2 607-620 (2008) [C1]
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Nova |
2008 |
Saedisomeolia A, Wood LG, Garg ML, Gibson PG, Wark PAB, 'Anti-inflammatory effects of long-chain
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2008 |
Oliver BGG, Lim S, Wark PA, Laza-Stanca V, King N, Black JL, et al., 'Rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages', Thorax, 63 519-525 (2008) [C1]
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Nova |
2008 |
Hansbro NG, Horvat JC, Wark PA, Hansbro PM, 'Understanding the mechanisms of viral induced asthma: New therapeutic directions', Pharmacology & Therapeutics, 117 313-353 (2008) [C1]
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Nova |
2008 |
Wark P, 'Bronchitis (acute)', BMJ clinical evidence, 2008 (2008)
INTRODUCTION: Acute bronchitis, with transient inflammation of the trachea and major bronchi, affects over 40/1000 adults a year in the UK. The causes are usually considered to be... [more]
INTRODUCTION: Acute bronchitis, with transient inflammation of the trachea and major bronchi, affects over 40/1000 adults a year in the UK. The causes are usually considered to be infective, but only around half of people have identifiable pathogens. The role of smoking or of environmental tobacco smoke inhalation in predisposing to acute bronchitis is unclear. A third of people may have longer-term symptoms or recurrence.
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2007 |
Weckmann M, Collison A, Simpson JL, Kopp MV, Wark PA, Smyth MJ, et al., 'Critical link between TRAIL and CCL20 for the activation of T(H)2 cells and the expression of allergic airway disease', Nature Medicine, 13 1308-1315 (2007) [C1]
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2007 |
Wark PA, Bucchieri F, Johnston SL, Gibson PG, Hamilton L, Mimica J, et al., 'IFN-gamma-induced protein 10 is a novel biomarker of rhinovirus-induced asthma exacerbations', Journal of Allergy and Clinical Immunology, 120 586-593 (2007) [C1]
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2006 |
Wark PA, Gibson PG, 'Asthma exacerbations 3: Pathogenesis', Thorax, 61 909-915 (2006) [C1]
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Nova |
2006 |
Wark PA, 'Safety concerns with salmeterool', Australian Prescriber, 29 118-119 (2006) [C3] |
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2006 |
Wark P, 'Bronchitis (acute).', Clinical evidence, 1996-2005 (2006)
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2006 |
Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett N, et al., 'Role of eficient type III interferon-lambda production in asthma exacerbations', Nature Medicine, 12 1023-1026 (2006) [C1]
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2005 |
Wark PAB, McDonald V, Jones AP, 'Nebulised hypertonic saline for cystic fibrosis', COCHRANE DATABASE OF SYSTEMATIC REVIEWS, (2005)
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2005 |
Wood LG, Garg ML, Simpson JL, Mori TA, Croft KD, Wark PA, Gibson PG, 'Induced sputum 8-isoprostane concentrations in inflammatory airway diseases', American Journal of Respiratory and Critical Care Medicine, 171 426-430 (2005) [C1]
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Nova |
2005 |
Wark P, 'Bronchitis (acute).', Clinical evidence, 1844-1852 (2005) |
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2005 |
Wark PA, Johnston S, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, et al., 'Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus', Journal of Experimental Medicine, 201 937-947 (2005) [C1]
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2004 |
Wark P, Gibson PG, Wilson A, 'Azoles for allergic bronchopulmonary aspergillosis associated with asthma', COCHRANE DATABASE OF SYSTEMATIC REVIEWS, (2004)
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2004 |
Wark PA, 'Bronchitis (acute)', AMERICAN FAMILY PHYSICIAN, 70 557-558 (2004) |
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2004 |
Walter E, Gibbins N, Vandersteen A, Kinton L, Wark P, Jonas M, 'Hyperkalaemic ascending paralysis', JOURNAL OF THE ROYAL SOCIETY OF MEDICINE, 97 330-331 (2004)
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2004 |
Wark PA, 'Pathogenesis of allergic bronchopulmonary aspergillosis and an evidence-based review of azoles in treatment', Respiratory Medicine, 98 915-923 (2004) [C1]
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2004 |
Wark P, 'Bronchitis (acute).', Clinical evidence, 1923-1932 (2004) |
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2004 |
Wark P, Gibson PG, Wilson A, 'Azoles for allergic bronchopulmonary aspergillosis associated with asthma', Cochrane Database of Systematic Reviews, 2017 (2004)
Background: Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fumigatus that complicates patients with asthma and cystic fibrosis. The mainstay... [more]
Background: Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fumigatus that complicates patients with asthma and cystic fibrosis. The mainstay of treatment for allergic bronchopulmonary aspergillosis remains oral corticosteroids, though this does not completely prevent exacerbations and may not prevent the decline in lung function. Objectives: The purpose of this review was to determine the efficacy of azoles in the treatment of allergic bronchopulmonary aspergillosis. Search methods: We searched the Cochrane Airways Group Asthma trials register, CENTRAL, MEDLINE and EMBASE. Searches are current as of May 2008. Selection criteria: All controlled trials that assessed the effect of azole antifungal agents compared to placebo or other standard therapy for allergic bronchopulmonary aspergillosis were reviewed. Patients with cystic fibrosis were not included. Data collection and analysis: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. Main results: Twelve trials were identified, but only three were prospective, randomised and controlled. A total of 94 participants were included. One demonstrated a reduction in immunological markers of disease activity and symptom scores using ketoconazole 400 mg daily for 12 months. There was no significant improvement in lung function. The other two examined the use of itraconazole for 16 weeks. In one there was a reduction in sputum eosinophils by 35% compared to 19% with placebo (p < 0.01). In the same trial, the number of exacerbations requiring oral corticosteroids was 0.4 per patient with itraconazole compared with 1.3 per patient with placebo (p < 0.03). Meta-analysis of data from both trials showed that itraconazole treated patients were more likely to have decline in serum IgE over 25% or more (Peto OR 3.30; 95% confidence intervals 1.30 to 8.15). Authors' conclusions: Itraconazole modifies the immunologic activation associated with allergic bronchopulmonary aspergillosis and improves clinical outcome, at least over the period of 16 weeks. Adrenal suppression with inhaled corticosteroids and itraconazole is a potential concern.
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2004 |
Wark PA, 'Bronchitis (acute)', Clinical Evidence, 12 (2004) [C3]
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2003 |
Simpson JL, Moric I, Wark PA, Johnston S, Gibson PG, 'Use of induced sputum for the diagnosis of influenza and infections in asthma: a comparison of diagnostic techniques', Journal of Clinical Virology, 339-346 (2003) [C1]
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2003 |
Wark P, 'Drug treatment for chronic obstructive pulmonary disease', IDRUGS, 6 874-879 (2003) |
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2003 |
Wark P, 'Acute bronchitis.', Clinical evidence, 1716-1723 (2003)
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2003 |
Wark PA, McDonald V, 'Nebulised hypertonic saline for cystic fibrosis.', Cochrane database of systematic reviews (Online), (2003)
BACKGROUND: The lung disease in cystic fibrosis is characterised by impaired mucociliary clearance. Hypertonic saline (HS) has been shown to enhance mucociliary clearance in-vitro... [more]
BACKGROUND: The lung disease in cystic fibrosis is characterised by impaired mucociliary clearance. Hypertonic saline (HS) has been shown to enhance mucociliary clearance in-vitro and this may act to lessen the destructive inflammatory process in the airways. OBJECTIVES: To investigate the effects of treatment with nebulised hypertonic saline on people with CF compared to placebo and or other treatments that enhance mucociliary clearance. SEARCH STRATEGY: 'We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search of the Group's register: October 2001. SELECTION CRITERIA: All controlled trials (any language) assessing the effect of hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with cystic fibrosis of any age or severity. DATA COLLECTION AND ANALYSIS: All identified trials were independently reviewed by both reviewers & all data collected. Trial quality was assessed along with allocation concealment. MAIN RESULTS: Fourteen controlled trials were identified. Nine trials met the inclusion criteria; these involved 235 participants with an age range of 6 to 46 years. Two short-term trials of immediate effect on mucociliary clearance demonstrated that HS increased isotope clearance compared to control. Lung function as measured by improvement in Forced Expiratory Volume at one second (FEV1 l/min) was observed in four trials. When 3% to 7% saline was used in a volume of 10mls twice a day, in comparison to placebo, HS led to a significant increase in FEV1, WMD 12.20 (95%CI 4.30 to 20.10). In comparison to deoxyribonuclease (DNase) two trials used a similar concentration and volume of HS. Over a three week period the groups showed a similar increase in FEV1, WMD -1.60 (95%CI -11.16 to 7.96). However after 12 weeks treatment in participants with moderate to severe lung disease compared to DNase, HS 5mls twice a day showed less benefit to FEV1, WMD -13.00 (95%CI -22.46 to -3.54). No serious adverse events were noted. REVIEWER'S CONCLUSIONS: Nebulised hypertonic saline improves mucociliary clearance in short term clinical trials and appears to increase lung function compared to control. In comparison to DNase it may be less effective at improving lung function, after three months. At this stage there is insufficient evidence to support the use of hypertonic saline as routine treatment for people with cystic fibrosis.
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2003 |
Wark PA, Gibson PG, Wilson AJ, 'Azoles for allergic bronchopulmonary aspergillosis associated with asthma.', Cochrane database of systematic reviews (Online), (2003)
BACKGROUND: Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fumigatus that complicates patients with asthma and cystic fibrosis. The mainstay... [more]
BACKGROUND: Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fumigatus that complicates patients with asthma and cystic fibrosis. The mainstay of treatment for allergic bronchopulmonary aspergillosis remains oral corticosteroids, though this does not completely prevent exacerbations and may not prevent the decline in lung function. OBJECTIVES: The purpose of this review was to determine the efficacy of azoles in the treatment of allergic bronchopulmonary aspergillosis. SEARCH STRATEGY: We searched the Cochrane Airways Group Asthma trials register using the terms: (allergic bronchopulmonary aspergillosis OR aspergillosis OR allergic pulmonary aspergillosis OR allergic fungal and disease OR allergic mycotic and disease) AND (azole OR triazole OR itraconazole OR ketoconazole). Date of last search January 2003. SELECTION CRITERIA: All controlled trials that assessed the effect of azole antifungal agents compared to placebo or other standard therapy for allergic bronchopulmonary aspergillosis were reviewed. Patients with cystic fibrosis were not included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Twelve trials were identified, but only three were prospective, randomised and controlled. A total of 94 participants were included. One demonstrated a reduction in immunological markers of disease activity and symptom scores using ketoconazole 400 mg daily for 12 months. There was no significant improvement in lung function. The other two examined the use of itraconazole for 16 weeks. In one there was a reduction in sputum eosinophils by 35% compared to 19% with placebo (p < 0.01). In the same trial, the number of exacerbations requiring oral corticosteroids was 0.4 per patient with itraconazole compared with 1.3 per patient with placebo (p < 0.03). Meta-analysis of data from both trials showed that itraconazole treated patients were more likely to have decline in serum IgE over 25% or more (Peto OR 3.30; 95% confidence intervals 1.30 to 8.15). REVIEWER'S CONCLUSIONS: Itraconazole modifies the immunologic activation associated with allergic bronchopulmonary aspergillosis and improves clinical outcome, at least over the period of 16 weeks. Adrenal suppression with inhaled corticosteroids and itraconazole is a potential concern.
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2003 |
Wark PA, Hensley MJ, Saltos N, Boyle MJ, Toneguzzi R, Simpson JL, et al., 'Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: A randomized controlled trial', The Journal of Allergy and Clinical Immunology, 111 952-957 (2003) [C1]
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2003 |
Gibson PG, Wark PA, Simpson JL, Meldrum CJ, Meldrum S, Saltos N, Boyle MJ, 'Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis', European Respiratory Journal, 21 582-588 (2003) [C1]
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2003 |
Wark PAB, Gibson PG, 'Clinical Usefulness of Inflammatory Markers in Asthma', American Journal of Respiratory & Critical Care Medicine, 2 11-19 (2003) [C1]
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2002 |
Wark PA, Johnston S, Simpson JL, Hensley MJ, Gibson PG, 'Chlamydia pneumoniae immunoglobulin A reactivation and airway inflammation in acute asthma', The European Respiratory Journal, 20 834-840 (2002) [C1]
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2002 |
Wark PA, Johnston S, Moric I, Simpson JL, Hensley MJ, Gibson PG, 'Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma', The European Respiratory Journal, 19 68-75 (2002) [C1]
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2002 |
Gibson PG, Grootendor D, Henry R, Pin I, Rytila P, Wark P, et al., 'Sputum induction in children', European Respiratory Journal, 37 44s-46s (2002) [C3]
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2002 |
Wark PA, Simpson JL, Hensley MJ, Gibson PG, 'Airway inflammation in thunderstorm asthma', Clinical and Experimental Allergy, 32 1750-1756 (2002) [C1]
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2002 |
Wark PAB, 'DX-890 Dyax', IDrugs, 5 586-589 (2002)
Dyax (formerly Protein Engineering Corp) and Debiopharm are developing DX-890, an inhibitor of human ncutrophil elastase (HNE),for the potential treatment of pulmonary diseases su... [more]
Dyax (formerly Protein Engineering Corp) and Debiopharm are developing DX-890, an inhibitor of human ncutrophil elastase (HNE),for the potential treatment of pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). In December 1999, Debiopharm initiated phase I trials with an aerosol formulation of DX-890; studies were completed by October 2000. By August 2000, DX-890 was in phase II evaluation for the potential treatment of CF, and in May 2002, Dyax planned to initiate a further study, in children with CF, within the year. By June 2002, phase II trials in CF were ongoing in France and Spain, with results expected soon after this date. In September 2000, JP Morgan predicted a 2005 launch for this drug, with estimated sales in that year of US $23 million rising to US $63 million in 2007. © PharmaPress Ltd.
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2002 |
Simpson JL, Gibson PG, Wark PA, 'Optimization of sputum-processing methods for the measurement of interleukin-5: Effects of protease inhibition', Respirology, 7 111-116 (2002) [C1]
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2002 |
British Thoracic Society Standards of Care Committee, 'Non-invasive ventilation in acute respiratory failure.', Thorax, 57 192-211 (2002)
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2001 |
Wark PA, Simpson J, Hensley MJ, Gibson PG, 'Safety of sputum induction with isotonic saline in adults with acute severe asthma', Clinical and Experimental Allergy, 31 1745-1753 (2001) [C1]
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2001 |
Gibson PG, Simpson J, Chalmers AC, Toneguzzi R, Wark PA, Wilson AJ, Hensley MJ, 'Airway Eosinophilia is associated with Wheeze but is uncommon in Children with Persistent Cough and Frequent Chest Colds', American Journal of Respiratory and Critical Care Medicine, 164 977-981 (2001) [C1]
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Nova |
2001 |
Wark PA, 'Sputum lactate dehydrogenase, a marker of cell necrosis, is elevated in acute asthma', Respirology, 6 (2001)
Rationale: The role of neutrophils in airway inflammation in acute asthma is unclear. Lactate dehydrogenase (LDH) is a marker of cell necrosis. The aim of this study was to determ... [more]
Rationale: The role of neutrophils in airway inflammation in acute asthma is unclear. Lactate dehydrogenase (LDH) is a marker of cell necrosis. The aim of this study was to determine if levels of LDH were elevated in acute asthma and to determine how this related to airway inflammation and the clinical severity of acute asthma. Methods: Subjects with acute asthma had spirometry and sputum induction. Infection was determined using sputum PCR for common respiratory viruses. Sputum supernatant LDH activity was measured using the enzymatic rate method with isoenzyme pattern determined by gel electrophoresis. Results: We recruited 37 subjects with acute severe asthma: 12 had infection with respiratory syncytial virus (RSV), 9 with influenza, 6 picornaviruses, 10 non-infective exacerbations. There were 8 healthy controls. Sputum LDH was highest in those with RSV (653.1 lU/mL), influenza infection (549.5 lU/raL) and picornaviruses (501.2 lU/mL) compared to those with no infection (182 lU/mL), while all those with acute asthma were higher than the controls (25 lU/mL, p 0.01). LDH-5 was the main isoenzyme present suggesting neutrophil lysis with elevated LDH-5. Sputum LDH was associated with elevated sputum neutrophils (r = 0.8), a lower FEV| (r = -0.5), more severe acute symptoms (r = 0.6) and a longer length of hospital stay (r = 0.4). Conclusion: Sputum LDH is elevated in acute asthma with viral infection. Cell necrosis in acute asthma may potentiate neutrophilic airway inflammation and more severe clinical disease.
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2001 |
Wark P, Wilson AJ, Gibson PG, 'Azoles for allergic bronchopulmonary aspergillosis', Praxis, 90 1780 (2001)
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2001 |
Wark PA, Gibson PG, Johnston S, 'Exacerbations of asthma: addressing the triggers and treatments', Monaldi Archives for Chest Disease, 56 429-435 (2001) [C1]
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2001 |
Wark PA, Gibson PG, 'Allergic bronchopulmonary aspergillosis: New concepts of pathogenesis and treatment', Respirology, 6 1-7 (2001) [C2]
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2000 |
Wark PA, Saltos N, Simpson J, Slater S, Hensley MJ, Gibson PG, 'Induced sputum easinophils and neutrophils and bronchiectasis severity in allergic bronchopulmonary aspergillosis', European Respiratory Journal, 16 1095-1101 (2000) [C1]
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2000 |
Wark PA, Gibson PG, Fakes K, 'Induced sputum eosinophils in the assessment of asthma and chronic cough*', Respirology, 5 51-57 (2000) [C1]
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2000 |
Wark PA, Wilson A, Gibson PG, 'Azoles for allergic bronchopulmonary aspergillosis', The Cochrane Library, 1-9 (2000) [C1]
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2000 |
Wark PA, McDonald V, 'Nebulised hypertonic saline for cystic fibrosis.', Cochrane database of systematic reviews (Online : Update Software), (2000)
BACKGROUND: The lung disease in cystic fibrosis is characterised by impaired mucociliary clearance, recurrent bronchial infection and airway inflammation. Hypertonic saline has be... [more]
BACKGROUND: The lung disease in cystic fibrosis is characterised by impaired mucociliary clearance, recurrent bronchial infection and airway inflammation. Hypertonic saline has been shown to enhance mucociliary clearance in-vitro and this may act to lessen the destructive inflammatory process in the airways. OBJECTIVES: To determine if nebulised hypertonic saline treatment improved lung function, exercise tolerance, quality of life and decreased the incidence of exacerbations of respiratory infections in patients with cystic fibrosis. SEARCH STRATEGY: Studies were identified from the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register. Titles and abstracts were reviewed to identify all controlled trials. Review articles and bibliographies identified from this process were surveyed for additional citations & RCTs. Identification of unpublished work was obtained from abstract books from the three major Cystic Fibrosis conferences (International Cystic Fibrosis Conference, The European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference). Trial authors were contacted for additional information when only abstracts were available to review. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All controlled trials that assessed the effect of hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in subjects with cystic fibrosis of any age or severity were reviewed. Studies in languages other than English were included. DATA COLLECTION AND ANALYSIS: All identified trials were independently reviewed by both reviewers & all data collected. Trial quality was scored by the Cochrane assessment of allocation concealment & the Jadad scale of methodological quality. MAIN RESULTS: Twelve controlled trials of hypertonic saline were identified. Seven trials met the inclusion criteria; these involved 143 subjects with an age range of 6 to 46 years. Of these, six were published studies and one in abstract form. The durations of the trials were limited to immediate effects on mucociliary clearance to a maximum of three weeks. In two studies, involving thirty five subjects, a score for the feeling of cleared chest was made using visual analogue scales. This analysis showed a weighted mean difference of -0.98 (95% confidence Interval -1.6, -0.34), favouring hypertonic saline over isotonic saline. In two trials with 22 subjects hypertonic saline improved mucociliary clearance as measured by isotope clearance from the lungs in 90 minutes demonstrating a weighted mean difference of -11.3 (95% confidence Interval -18.6, -4.0), and as area under the clearance time curve; weighted mean difference of -212 (95%CI -272, -152), also favouring hypertonic saline over isotonic saline. Lung function as measured by improvement in FEV1 was observed in one study of 27 subjects. The percentage increase in FEV1 at two weeks increased by a mean 15.0% with hypertonic saline and 2.8% with isotonic saline (p=0.004). Adverse events were adequately described in only one trial and none were serious. REVIEWER'S CONCLUSIONS: Nebulised hypertonic saline improves mucociliary clearance immediately after administration which may have a longer term beneficial effect in cystic fibrosis. The maximum time data were recorded for was only three weeks. Most of the patients had mild to moderate lung disease and the effect on severe lung disease remains unclear. Further studies of hypertonic saline should be carried out to determine the effect on pulmonary function tests, quality of life, frequency of exacerbations of respiratory disease and efficacy comparisons with nebulised deoxyribonuclease, with larger numbers and for longer duration. At this stage there is insufficient evidence to support the use of hypertonic saline in routine treatment for patients with cystic fibrosis.
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1999 |
Wark P, Simpson J, Fakes K, Burgess H, Timmins N, Hensley M, Gibson PG, 'Airway inflammation in allergic bronchopulmonary aspergillosis', Respirology, 4 (1999)
Allergic bronchopulmonary aspergillosis (ABPA) is a serious complication of asthma. In uncomplicated asthma airway inflammation(ai) is characterised by sputum eosinophilia without... [more]
Allergic bronchopulmonary aspergillosis (ABPA) is a serious complication of asthma. In uncomplicated asthma airway inflammation(ai) is characterised by sputum eosinophilia without an increase in the total cell count (TCC). In bronchiectasis the intensity of ai increased and there is a neutrophil infiltrate. Airway inflammation in ABPA is not well defined. This study tested the hypothesis that ai in ABPA would be of increased intensity with a mixed eosinophil/neutrophil pattern. Methods: In subjects with asthma, ABPA was assessed by 5 criteria; 1. positive allergy skin test to Aspergillus Fumigatus (Af); 2. raised specific serum IgE to Af; 3. positive precipitating antibodies to Af; 4. total IgE > 10001U/ml and 5. bronchiectasis (CT scan). Subjects were classified as definite ABPA (n=13) with criteria 1, 2, 3 and either 4 or 5; or as probable ABPA (n=18) with 1 and 2 and either 3, 4 or 5 (n=13). These groups were combined for analysis. Af sensitised subjects (n=19 with positive skin testing alone), were compared to a matched group with asthma (negative to Af on skin test) (n=15) and healthy controls (n=8). Spirometry, saline challenge and sputum induction were performed, with results reported as medians and interquartile ranges. Results: Patients with ABPA had an increased TCC (4.6, 0.9-29.6) compared to: Af sensitised (3.6, 1.4-7.4), asthma (1.5, 0.8-3.2), and controls (1.35, 1.3-1.4) (p<0.05). Those with ABPA had increased sputum eosinophils (3.8, 0.3-16.3), compared to: Af sensitised (1.4, 0.1-6), asthma (1.6, 0.01-3), and controls (0.3, 0.3-0.31 ) (p=0.001). Those with ABPA had increased levels of eosinophil cationic protein(ng/ml) (5471, 311-42485) compared to: Af sensitised (1432, 338-6902), asthma (244, 78-857), and controls (110, 99-121 ) (p<0.001). Neutrophil counts were similar in all groups. Myeloperoxidase was similar in ABPA (232, 66-454) and asthma (177, 57-318) (p=0.3) but greater than in healthy controls (76, 76-89) Conclusion: Airway inflammation in ABPA is of increased intensity compared to that of chronic asthma. Unlike bronchiectasis, the cellular infiltrate is predominantly eosinophilic. The eosinophils demonstrate increased activation.
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1999 |
Wark P, McDonald V, 'The effectiveness of nebulised hypertonic saline on lung function, exercise tolerance and quality of life in cystic fibrosis', Respirology, 4 (1999)
Thick tenacious secretions that are difficult to expectorate and recurrent infection that leads to progressive end stage fibrotic disease typify lung disease in cystic fibrosis (C... [more]
Thick tenacious secretions that are difficult to expectorate and recurrent infection that leads to progressive end stage fibrotic disease typify lung disease in cystic fibrosis (CF). Mucolytic treatment can improve expectoration of sputum and lung function in CF. Our aim was to examine the efficacy of hypertonic saline (HS) in CF as an alternative or supplementary treatment. Methods: A meta-analysis of controlled trials was done. A search was carried out via the Cochrane Cystic Fibrosis Group specialist trials register. The titles and abstracts were reviewed to identify all potential controlled trials, articles were surveyed for additional citations. Identification of unpublished work was obtained from abstract books from (The International CF Conference, The European CF Conference and the North American CF Conference). All controlled trials that assessed the efficacy of Hypertonic Saline in subjects with cystic fibrosis were reviewed. The reviewers independently reviewed all trials. Data was analysed and compared using Revman. Results: A total of ten controlled trials were identified. Adequate data was available for analysis from seven of the studies, n = 166, age range (7-36years). Two studies showed that hypertonic saline (HS) improved lung function at two weeks by increasing the percentage change in FEV1. This showed a weighted mean difference (WMD) of +12.2 (95%CI +13.860, +10.540), favouring HS over isotonic saline (IS). An immediate effect on mucociliary clearance as measured by radioisotope was assessed in two trials. Analysis of isotope clearance at 90 mins found a WMD of +11.28 (95%CI +18.562, +3.998), favouring HS over IS. Measuring clearance as area under the curve showed a WMD of +212.059 (95%CI +271.641, +152.477), favouring HS over IS. Nebulised hypertonic saline appears to have a beneficial effect in cystic fibrosis, improving muco-ciliary clearance immediately after administration and lung function after two weeks of administration in combination with chest physiotherapy. Comparative data was not available to assess outcomes such as improvement in objective exercise testing, effect on symptom scores, quality of life measures or long term efficacy.
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1998 |
Wark P, Goldberg H, Ferson M, McKenzie D, Lau E, Rivas K, 'Mycobacterial lymphadenitis in eastern Sydney', AUSTRALIAN AND NEW ZEALAND JOURNAL OF MEDICINE, 28 453-458 (1998)
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1846 |
Swett JA, 'Bronchitis', The Boston Medical and Surgical Journal, 34 249-253 (1846)
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