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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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]
© 2019 Asian Pacific Society of Respirology Background and objective: Severe asthma is responsible for a disproportionate burden of illness and healthcare costs spent on asthma. T... [more]
© 2019 Asian Pacific Society of Respirology 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 |
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.', Eur Respir J, (2020)
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2020 |
Wark PAB, 'Contemporary Concise Review 2019: Asthma.', Respirology, 25 651-656 (2020) [C1]
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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]
© 2019 Background: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or effi... [more]
© 2019 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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2020 |
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.', J Allergy Clin Immunol Pract, (2020)
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2020 |
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, (2020)
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2020 |
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.', Intern Med J, (2020)
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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.', Endocr Metab Immune Disord Drug Targets, 20 1590-1596 (2020)
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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]
© 2020 Elsevier Ltd Background: Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecif... [more]
© 2020 Elsevier Ltd 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 |
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)
© 2020, The Author(s). Chronic obstructive pulmonary disease (COPD) is the third commonest cause of death globally, and manifests as a progressive inflammatory lung disease with n... [more]
© 2020, The Author(s). Chronic obstructive pulmonary disease (COPD) is the third commonest cause of death globally, and manifests as a progressive inflammatory lung disease with no curative treatment. The lung microbiome contributes to COPD progression, but the function of the gut microbiome remains unclear. Here we examine the faecal microbiome and metabolome of COPD patients and healthy controls, finding 146 bacterial species differing between the two groups. Several species, including Streptococcus sp000187445, Streptococcus vestibularis and multiple members of the family Lachnospiraceae, also correlate with reduced lung function. Untargeted metabolomics identifies a COPD signature comprising 46% lipid, 20% xenobiotic and 20% amino acid related metabolites. Furthermore, we describe a disease-associated network connecting Streptococcus parasanguinis_B with COPD-associated metabolites, including N-acetylglutamate and its analogue N-carbamoylglutamate. While correlative, our results suggest that the faecal microbiome and metabolome of COPD patients are distinct from those of healthy individuals, and may thus aid in the search for biomarkers for COPD.
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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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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 and New Zealand Journal of Obstetrics and Gynaecology, 60 840-851 (2020)
© 2020 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zeal... [more]
© 2020 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists To date, 18 living recommendations for the clinical care of pregnant and postpartum women with COVID-19 have been issued by the National COVID-19 Clinical Evidence Taskforce. This includes recommendations on mode of birth, delayed umbilical cord clamping, skin-to-skin contact, breastfeeding, rooming-in, antenatal corticosteroids, angiotensin-converting enzyme inhibitors, disease-modifying treatments (including dexamethasone, remdesivir and hydroxychloroquine), venous thromboembolism prophylaxis and advanced respiratory support interventions (prone positioning and extracorporeal membrane oxygenation). Through continuous evidence surveillance, these living recommendations are updated in near real-time to ensure clinicians in Australia have reliable, evidence-based guidelines for clinical decision-making. Please visit https://covid19evidence.net.au/ for the latest recommendation updates.
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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]
Copyright © 2020 by the American Thoracic Society. In asthma, goblet cell numbers are increased within the airway epithelium, perpetuating the production of mucus that is more dif... [more]
Copyright © 2020 by the American Thoracic Society. 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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2020 |
Loo S-L, Wark PAB, Esneau C, Nichol KS, Hsu AC-Y, Bartlett NW, 'Human coronaviruses 229E and OC43 replicate and induce distinct antiviral responses in differentiated primary human bronchial epithelial cells.', Am J Physiol Lung Cell Mol Physiol, 319 L926-L931 (2020)
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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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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)
© 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology Pulmonary nocardiosis is an ... [more]
© 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology Pulmonary nocardiosis is an uncommon pulmonary infection that is more likely found in immunocompromised patients with underlying chronic lung disease. The presentation of pulmonary nocardiosis is widely variable and shares features with other types of pulmonary infections. Nocardia is also not as easily isolated on standard culture mediums and hence more difficult to identify. We describe the case of a patient with a severe necrotising pneumonia who was chronically immunosuppressed with steroids and has alpha-1 antitrypsin deficiency.
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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]
© 2020 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd. Background: Both the six gene signature (6GS: CPA3, DNASE1L3, CLC, IL1B, ALPL, and... [more]
© 2020 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd. 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 |
Jin-Ying Wong, 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 (Lond), 15 2955-2970 (2020)
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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)
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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)
© Copyright © 2020 Veerati, Troy, Reid, Li, Nichol, Kaur, Maltby, Wark, Knight, Bosco, Grainge and Bartlett. Respiratory viral infections, particularly those caused by rhinovirus,... [more]
© Copyright © 2020 Veerati, Troy, Reid, Li, Nichol, Kaur, Maltby, Wark, Knight, Bosco, Grainge and Bartlett. Respiratory viral infections, particularly those caused by rhinovirus, exacerbate chronic respiratory inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the primary site of rhinovirus replication and responsible of initiating the host immune response to infection. Numerous studies have reported that the anti-viral innate immune response (including type I and type III interferon) in asthma is less effective or deficient leading to the conclusion that epithelial innate immunity is a key determinant of disease severity during a rhinovirus induced exacerbation. However, deficient rhinovirus-induced epithelial interferon production in asthma has not always been observed. We hypothesized that disparate in vitro airway epithelial infection models using high multiplicity of infection (MOI) and lacking genome-wide, time course analyses have obscured the role of epithelial innate anti-viral immunity in asthma and COPD. To address this, we developed a low MOI rhinovirus model of differentiated primary epithelial cells obtained from healthy, asthma and COPD donors. Using genome-wide gene expression following infection, we demonstrated that gene expression patterns are similar across patient groups, but that the kinetics of induction are delayed in cells obtained from asthma and COPD donors. Rhinovirus-induced innate immune responses were defined by interferons (type-I, II, and III), interferon response factors (IRF1, IRF3, and IRF7), TLR signaling and NF-¿B and STAT1 activation. Induced gene expression was evident at 24 h and peaked at 48 h post-infection in cells from healthy subjects. In contrast, in cells from donors with asthma or COPD induction was maximal at or beyond 72¿96 h post-infection. Thus, we propose that propensity for viral exacerbations of asthma and COPD relate to delayed (rather than deficient) expression of epithelial cell innate anti-viral immune genes which in turns leads to a delayed and ultimately more inflammatory host immune response.
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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]
© 2020 Baines et al. Background: The 6 gene expression signature (6GS) predicts in¿ammatory phenotype, exacerbation risk, and corticosteroid responsiveness in asthma. In COPD, pat... [more]
© 2020 Baines et al. 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 |
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, (2020)
© 2020, © 2020 Taylor & Francis Group, LLC. The present study aimed to formulate celastrol into liquid crystalline nanoparticles (LCNPs) through ultrasonication to enhance i... [more]
© 2020, © 2020 Taylor & Francis Group, LLC. The present study aimed to formulate celastrol into liquid crystalline nanoparticles (LCNPs) through ultrasonication to enhance its therapeutic efficacy in the treatment of asthma. The physiochemical characteristics, in-vitro release studies were determined along with molecular simulations. Celastrol-loaded LCNPs showed the mean particle size of 194.1 ± 9.78 nm and high entrapment efficiency of 99.1 ± 0.02%. TEM revealed cubical-like structure of the nanoparticles and in-vitro release study demonstrated sustained drug release. They also demonstrated significant activity in reducing IL-1ß production, when evaluated using immortalized human bronchial epithelial cell lines (BCi-NS1.1), that may help alleviate the symptoms of asthma.
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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.', Eur Respir J, 55 (2020)
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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 sensitisation', The journal of allergy and clinical immunology. In practice, (2020)
Copyright © 2020. Published by Elsevier Inc. BACKGROUND: Severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) are important complicati... [more]
Copyright © 2020. Published by Elsevier Inc. BACKGROUND: Severe asthma with fungal sensitisation (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 severe allergic asthma patients comparing those with and without evidence of fungal sensitisation using data recorded in the Australian Xolair registry. METHODS: Data from 205 patients who received omalizumab and recorded in the Australian Xolair Registry was analysed to determine change in Asthma Control Questionnaire (ACQ-5) score, exacerbation frequency, and oral corticosteroid (OCS) dosage over a 24 month period of omalizumab treatment. Patients were grouped into cohorts based on fungal sensitisation 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 severe asthma and fungal sensitisation (n=62), including those with ABPA (ASAFS), were as likely to demonstrate significant improvements to omalizumab in ACQ-5, exacerbations and reduced regular OCS dose over 24-months as those with severe asthma without sensitisation to fungi (n=156). After adjusting for age, sex, BMI, smoking history and baseline FEV1% the effects still remained. A subgroup analysis of 11 ABPA patients similarly demonstrated a significant improvement on omalizumab. CONCLUSION: 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 due to the small sample. .
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2020 |
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, (2020)
© 2020 Elsevier Ltd Clinical registries that monitor and review outcomes for patients with cystic fibrosis have existed internationally for many decades. However, their purpose co... [more]
© 2020 Elsevier Ltd 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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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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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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2020 |
Saladié M, Caparrós-Martín 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.', Front Microbiol, 11 572504 (2020)
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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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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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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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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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2020 |
Eapen MS, Lu W, Hackett T-L, 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.', Am J Physiol Lung Cell Mol Physiol, (2020)
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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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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 Immunol, 13 877-891 (2020)
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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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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]
Copyright © 2019 by the American Thoracic Society. Acute asthma remains an important medical emergency, the most frequent cause of acute admissions in children and a major source ... [more]
Copyright © 2019 by the American Thoracic Society. 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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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]
© 2019 Australian and New Zealand Society for Immunology Inc. The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptor... [more]
© 2019 Australian and New Zealand Society for Immunology Inc. 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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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]
©2018 Society for Leukocyte Biology Pulmonary inflammation in chronic obstructive pulmonary disease (COPD) is characterized by both innate and adaptive immune responses; however,... [more]
©2018 Society for Leukocyte Biology 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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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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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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2019 |
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 (2019) [C1]
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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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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)
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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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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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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]
© 2018 Asian Pacific Society of Respirology Background and objective: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases inclu... [more]
© 2018 Asian Pacific Society of Respirology 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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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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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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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]
© 2019 Lokwani et al. Purpose: To characterize neutrophils in obstructive airway disease by measuring their surface adhesion molecules and oxidative burst along with characterizin... [more]
© 2019 Lokwani et al. 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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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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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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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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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]
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. Background In 2017, Australia experienced record in... [more]
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. 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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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]
© 2018 The Authors In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is a... [more]
© 2018 The Authors 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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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]
© the American Physiological Society. Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. Th... [more]
© the American Physiological Society. 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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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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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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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]
© 2019, Society for Mucosal Immunology. Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, ... [more]
© 2019, Society for Mucosal Immunology. 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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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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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]
© 2017 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... [more]
© 2017 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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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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2018 |
Hiles SA, Harvey ES, McDonald VM, Peters M, Bardin P, Reynolds PN, Upham JW, 'Working while unwell: Workplace impairment in people with severe asthma', CLINICAL AND EXPERIMENTAL ALLERGY, 48 650-662 (2018)
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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]
© 2018 Elsevier B.V. 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 hav... [more]
© 2018 Elsevier B.V. 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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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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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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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]
© 2018 by Thieme Medical Publishers, Inc. Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus ... [more]
© 2018 by Thieme Medical Publishers, Inc. 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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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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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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2018 |
King GG, James A, Harkness L, Wark PAB, 'Pathophysiology of severe asthma: We ve only just started', Respirology, 23 262-271 (2018) [C1]
© 2018 Asian Pacific Society of Respirology Severe asthma is defined by the high treatment requirements to partly or fully control the clinical manifestations of disease. It remai... [more]
© 2018 Asian Pacific Society of Respirology 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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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]
© 2018 Newlands Press. Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immu... [more]
© 2018 Newlands Press. 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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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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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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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]
© 2016 Asian Pacific Society of Respirology Asthma is a chronic respiratory disease characterized by respiratory symptoms, airway inflammation, airway obstruction and airway hyper... [more]
© 2016 Asian Pacific Society of Respirology 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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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]
© 2017 Elsevier Ltd Background Purified a1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe a1 antitrypsin deficiency in a randomised controlled tr... [more]
© 2017 Elsevier Ltd 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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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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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]
© 2016 Elsevier Inc. 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 ex... [more]
© 2016 Elsevier Inc. 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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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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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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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]
© 2017 by the American Thoracic Society. Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pat... [more]
© 2017 by the American Thoracic Society. 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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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]
© 2017 Negewo et al. Background: COPD patients are often prescribed multiple medications for their respiratory disease and comorbidities. This can lead to complex medication regim... [more]
© 2017 Negewo et al. 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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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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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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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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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]
© 2016 Informa UK Limited, trading as Taylor & Francis Group. ABSTRACT: Viral exacerbations continue to represent the major burden in terms of morbidity, mortality and healt... [more]
© 2016 Informa UK Limited, trading as Taylor & Francis Group. 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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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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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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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]
© 2016 Cousins et al. 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 patient... [more]
© 2016 Cousins et al. 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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2016 |
Wark P, Frith P, 'Asthma, COPD and when they coexist', Medicine Today, 17 16-24 (2016) [C1] |
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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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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]
© 2016 John Wiley & Sons Ltd Background: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omali... [more]
© 2016 John Wiley & Sons Ltd 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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2016 |
Loo S-L, Wark PAB, 'Recent advances in understanding and managing asthma.', F1000Res, 5 (2016) [C1]
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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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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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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]
© 2016 Negewo et al. Introduction: Sputum eosinophilia occurs in approximately one-third of stable chronic obstructive pulmonary disease (COPD) patients and can predict exacerbati... [more]
© 2016 Negewo et al. 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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2016 |
Wark P, Hsu A, Starkey M, Hansbro P, 'Micro-RNA-125a/b target A20 and MAVS to promote inflammatory and impair antiviral responses in chronic obstructive pulmonary disease', EUROPEAN RESPIRATORY JOURNAL, 48 (2016)
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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]
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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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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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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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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]
© 2014 Elsevier Ireland Ltd. Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still... [more]
© 2014 Elsevier Ireland Ltd. 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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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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2015 |
Wark P, Hilton J, 'Minimising the risk of acute asthma in children', Medicine Today, 16 35-44 (2015)
© MedicineToday 2015. A diagnosis of asthma is important before preventive treatment can be commenced in children after an acute asthma episode. Careful continuing assessment of t... [more]
© MedicineToday 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 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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2015 |
Pathinayake PS, Hsu A, wark PA, 'Innate Immunity and Immune Evasion by Enterovirus 71', Viruses, 7 (2015) [C1]
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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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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]
Copyright © 2015 by the American Thoracic Society. Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients ... [more]
Copyright © 2015 by the American Thoracic Society. 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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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)
© 2014 Elsevier España, S.L.U. and SEMICYUC. We must change how antibiotics are used and adopt proactive strategies, similar to those used to save endangered species. Preservation... [more]
© 2014 Elsevier España, S.L.U. and SEMICYUC. 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)
© 2015 Elsevier Ltd. Background: Person-to-person transmission is a potential pathway of Pseudomonas aeruginosa acquisition in cystic fibrosis. Reports of cross-infection of share... [more]
© 2015 Elsevier Ltd. 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]
© 2015 Elsevier Ltd. We provide estimates of the influenza vaccine protection against hospitalisation with laboratory-confirmed influenza in the 2014 Australian season where the A... [more]
© 2015 Elsevier Ltd. 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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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]
© 2015 Tolosa et al. Background Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1.We hypothesise... [more]
© 2015 Tolosa et al. 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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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.METHODS AND OUTCOMES: We conducted a systematic review, aiming to answer the following clinical question: What are the effects of treatments for acute bronchitis in people without chronic respiratory disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2015 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).RESULTS: At this update, searching of electronic databases retrieved 420 studies. After deduplication and removal of conference abstracts, 306 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 245 studies and the further review of 61 full publications. Of the 61 full articles evaluated, three updated systematic reviews and three RCTs were added at this update. We performed a GRADE evaluation for 12 PICO combinations.CONCLUSIONS: In this systematic review we categorised the efficacy for six intervention-comparison combinations, based on information about the effectiveness and safety of the following interventions: antibiotics, antihistamines, antitussives, beta2 agonists (inhaled), and expectorants/mucolytics.
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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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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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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)
This work is copyright. You may download, display, print and reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organis... [more]
This work is copyright. You may download, display, print and reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that 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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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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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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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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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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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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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)
This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonweal... [more]
This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Commonwealth Copyright Administration, Attorney General's Department, Robert Garran Offices, National Circuit, Barton ACT 2600 or 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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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2010 |
Wark PA, 'Viral and bacterial interactions in pneumonia', Expert Review of Respiratory Medicine, 4 221-228 (2010) [C1]
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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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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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2009 |
Wark PA, McDonald VM, 'Nebulised hypertonic saline for cystic fibrosis', Cochrane Database of Systematic Reviews, - CD001506 (2009) [C1]
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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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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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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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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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2008 |
Wark PA, 'Guest editorial', Paediatric Respiratory Reviews, 9 233-235 (2008) [C3]
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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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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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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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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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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.METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute bronchitis in people without chronic respiratory disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).RESULTS: We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (amoxicillin [with or without clavulanic acid], cephalosporins, or macrolides), antihistamines, antitussives, beta(2) agonists (inhaled or oral), cephalosporins, expectorants, and analgesics.
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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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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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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)
© 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Background: Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fum... [more]
© 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 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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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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Saedisomeolia A, Wood LG, Garg ML, Gibson PG, Wark PAB, 'Anti-inflammatory effects of long-chain n-3 PUFA in rhinovirus-infected cultured airway epithelial cells', British Journal of Nutrition, 101 533-540
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Wark P, Pathinyake P, Kaiko G, Nichol K, Ali A, Chen L, et al., 'ACE2 Expression is elevated in Airway Epithelial Cells from aged and male donors but reduced in asthma
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