ORCID Profile
0000-0001-9517-8212
Current Organisations
University of St Andrews
,
QIMR Berghofer Medical Research Institute
,
University of Manchester
,
Royal College of Physicians
,
Royal Australasian College of Physicians
,
Queensland Health
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Physiological Society
Date: 05-2009
Publisher: Wiley
Date: 09-02-2012
Publisher: OMICS Publishing Group
Date: 11-2011
DOI: 10.2217/THY.11.77
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1016/S1053-2498(01)00319-9
Abstract: Recent publications have demonstrated potentially pathologic changes in bronchoalveolar lavage (BAL) from clinically stable lung transplant recipients (SLTRs), but there are few available data on alveolar macrophages (AMs). We formulated the hypothesis that changes in BAL AM and lymphocyte phenotypes would be apparent even in SLTRs.A cross-sectional study using a standardized 3 x 60 ml BAL, investigating lymphocyte and AM phenotypes in 19 SLTRs, 5 subjects with bronchiolitis obliterans syndrome (BOS) and 18 normal control volunteers. BAL lymphocyte and AM markers were assessed using flow cytometry. We confirmed a significant elevation of neutrophils in all lung transplant recipients with a more marked elevation in the BOS subjects. Flow-cytometric analysis showed increased numbers of natural killer (NK CD56/CD16-positive) cells, increased CD11b- and CD11c-positive CD3 lymphocytes, increased CD8-positive lymphocytes and increased HLA-DR expression in CD8 cells from the lung transplant recipients, when compared with normals (p <.005). In contrast, the expression of a number of AM surface markers, associated with a range of host defense functions against bacteria, fungi and viruses (CD11a, CD11b, CD11c, HLA-DR, CD14), was lower in both SLTRs and those with BOS (p <.05). These novel findings are consistent with complex lymphocyte and macrophage changes that may result from clinically silent infection, partially suppressed rejection, or both.
Publisher: Wiley
Date: 03-07-2007
DOI: 10.1111/J.1365-2222.2007.02762.X
Abstract: Back-titration of inhaled corticosteroid (ICS) dose in well-controlled asthma patients is emphasized in clinical guidelines, but there are few published data on the airway cell and cytokine changes in relation to ICS reduction. In our study, 20 mild-to-moderate persistent (inspite of low-moderate dose ICS treatment) asthmatic subjects prospectively rendered largely asymptomatic by high-dose ICS were assessed again by clinical, physiological, and airway inflammatory indices after 4-8 weeks of reduced ICS treatment. We aimed at assessing the underlying pathological changes in relation to clinical deterioration. Patients recorded daily symptom scores and peak expiratory flows (PEF). Spirometry and airways hyperreactivity (AHR) were measured and bronchoscopy was performed with assessment of airway biopsies (mast cells, eosinophils, neutrophils, and T lymphocytes), bronchoalveolar lavage (BAL) IL-5 and eotaxin levels and cellular profiles at the end of high-dose ICS therapy and again after ICS dose reduction. Baseline data were compared with symptomatic steroid-free asthmatics (n=42) and non-asthmatic controls (n=28). After ICS reduction, subjects experienced a variable but overall significant increase in symptoms and reductions in PEF and forced expiratory volume in 1 s. There were no corresponding changes in AHR or airways eosinophilia. The most relevant pathogenic changes were increased CD4(+)/CD8(+) T cell ratio, and decreased sICAM-1 and CD18 macrophage staining (potentially indicating ligand binding). However, there was no relationship between the spectrum of clinical deterioration and the changes in cellular profiles or BAL cytokines. These data suggest that clinical markers remain the most sensitive measures of early deterioration in asthma during back-titration of ICS, occurring at a time when AHR and conventional indices of asthmatic airway inflammation appear unchanged. These findings have major relevance to management and to how back-titration of ICS therapy is monitored.
Publisher: American Society for Microbiology
Date: 08-2013
DOI: 10.1128/IAI.00418-13
Abstract: Pseudomonas aeruginosa chronically infects the lungs of more than 80% of adult patients with cystic fibrosis (CF) and is a major contributor to the progression of disease pathology. P. aeruginosa requires iron for growth and has multiple iron uptake systems that have been studied in bacteria grown in laboratory culture. The purpose of this research was to determine which of these are active during infection in CF. RNA was extracted from 149 sputum s les obtained from 23 CF patients. Reverse transcription–quantitative real-time PCR (RT-qPCR) was used to measure the expression of P. aeruginosa genes encoding transport systems for the siderophores pyoverdine and pyochelin, for heme, and for ferrous ions. Expression of P. aeruginosa genes could be quantified in 89% of the sputum s les. Expression of genes associated with siderophore-mediated iron uptake was detected in most s les but was at low levels in some s les, indicating that other iron uptake mechanisms are active. Expression of genes encoding heme transport systems was also detected in most s les, indicating that heme uptake occurs during infection in CF. feoB expression was detected in all sputum s les, implying an important role for ferrous ion uptake by P. aeruginosa in CF. Our data show that multiple P. aeruginosa iron uptake mechanisms are active in chronic CF infection and that RT-qPCR of RNA extracted from sputum provides a powerful tool for investigating bacterial physiology during infection in CF.
Publisher: Springer Science and Business Media LLC
Date: 18-08-2010
Abstract: Whether acute pancreatitis can occur in pancreatically insufficient in iduals with cystic fibrosis remains a matter of debate. We describe a case of acute pancreatitis occurring in a 52-year-old Caucasian Australian man with moderately severe cystic fibrosis lung disease and pancreatic insufficiency. An inflammatory mass within the head of his pancreas was confirmed using computed tomography, magnetic resonance imaging and pancreatic biopsy, but serum amylase and lipase remained normal throughout the acute phase of his illness. His symptoms and the pancreatic mass resolved following the insertion of a biliary stent and the introduction of ursodeoxycholic acid. Our case report highlights the potential for acute pancreatitis to occur in patients with pancreatic insufficiency and cystic fibrosis. We further demonstrate that conventional biochemical markers that are normally assessed to confirm the diagnosis may not be of particular use. As patients with cystic fibrosis survive into their fourth and fifth decades of life, atypical presentations of acute pancreatitis may become more common.
Publisher: BMJ
Date: 05-2012
DOI: 10.1136/THORAXJNL-2011-200835
Abstract: Exposure to cigarette smoke (CS) is associated with increased risk of pneumococcal infection. The mechanism for this association is unknown. We recently reported that the particulate matter from urban air simulates platelet-activating factor receptor (PAFR)-dependent adhesion of pneumococci to airway cells. We therefore sought to determine whether CS stimulates pneumococcal adhesion to airway cells. Human alveolar (A549), bronchial (BEAS2-B), and primary bronchial epithelial cells (HBEpC) were exposed to CS extract (CSE), and adhesion of Streptococcus pneumoniae determined. The role of PAFR in mediating adhesion was determined using a blocker (CV-3988). PAFR transcript level was assessed by quantitative real-time PCR, and PAFR expression by flow cytometry. Lung PAFR transcript level was assessed in mice exposed to CS, and bronchial epithelial PAFR expression assessed in active-smokers by immunostaining. In A549 cells, CSE 1% increased pneumococcal adhesion (p<0.05 vs control), PAFR transcript level (p<0.01), and PAFR expression (p<0.01). Pneumococcal adhesion to A549 cells was attenuated by CV-3988 (p<0.001). CSE 1% stimulated pneumococcal adhesion to BEAS2-B cells and HBEpC (p<0.01 vs control). CSE 1% increased PAFR expression in BEAS2-B (p<0.01), and in HBEpC (p<0.05). Lung PAFR transcript level was increased in mice exposed to CS in vivo (p<0.05 vs room air). Active smokers (n=16) had an increased percentage of bronchial epithelium with PAFR-positive cells (p<0.05 vs never smokers, n=11). CSE stimulates PAFR-dependent pneumococcal adhesion to lower airway epithelial cells. We found evidence that CS increases bronchial PAFR in vivo.
Publisher: Springer Science and Business Media LLC
Date: 12-2008
Publisher: Informa UK Limited
Date: 08-2014
DOI: 10.2147/COPD.S67044
Publisher: Wiley
Date: 12-2005
DOI: 10.1111/J.1365-2222.2005.02365.X
Abstract: Asthma is accepted as a disease characterized by airway inflammation, with evidence that airway structural changes, or 'remodelling' occurs. There are few studies relating airway physiology, inflammation and remodelling, however. We have carried out a study of inter-relationships between airway inflammation, airway remodelling, reticular basement membrane (RBM) thickening, and bronchial hyper-reactivity (BHR), before and after high-dose inhaled corticosteroid (fluticasone propionate 750 microg b.d.), in a group of relatively mild but symptomatic, steroid naïve asthma patients. Double-blind, randomized, placebo-controlled, parallel group study of inhaled corticosteroid (ICS) in 35 asthmatics, with bronchoalveolar lavage (BAL) and airway endobronchial biopsy (EBB) for inflammatory cell profiles and EBB for airway remodelling carried out at baseline, 3 and 12 months. At baseline RBM thickening was related to BAL mast cells and EBB eosinophil counts. In turn baseline log EBB EG2 eosinophil count, log%BAL epithelial cells and log RBM thickness explained 55% of the variability in BHR. We provide new information that airway inflammation, remodelling, and BHR in asthma are inter-related and improved by ICS therapy. Our data potentially support the need for early and long-term intervention with ICS even in relatively mild asthmatics, and the need to further assess the potential merit of longitudinal BHR testing in management of some patients, as this may reflect both airway inflammation and remodelling.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.JCF.2013.03.008
Abstract: Intravenous antibiotics for pulmonary exacerbations (PEs) of cystic fibrosis (CF) usually target Pseudomonas aeruginosa. Insights into the CF lung microbiome have questioned this approach. We used RT-qPCR to determine whether intravenous antibiotics reduced P. aeruginosa numbers and whether this correlated with improved lung function. We also investigated antibiotic effects on other common respiratory pathogens in CF. Sputa were collected from patients when stable and again during a PE. Sputa were expectorated into a RNA preservation buffer for RNA extraction and preparation of cDNA. qPCR was used to enumerate viable P. aeruginosa as well as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Burkholderia cepacia complex and Aspergillus fumigatus. Fifteen CF patients were followed through 21 PEs. A complete set of serial sputum s les was unavailable for two patients (three separate PEs). P. aeruginosa numbers did not increase immediately prior to a PE, but numbers during intravenous antibiotic treatment were reduced ≥4-log in 6/18 and ≥1-log in 4/18 PEs. In 7/18 PEs, P. aeruginosa numbers changed very little with intravenous antibiotics and one patient demonstrated a ≥2-log increase in P. aeruginosa load. H. influenzae and S. pneumoniae were detected in ten and five PEs respectively, but with antibiotic treatment these bacteria rapidly became undetectable in 6/10 and 4/5 PEs, respectively. There was a negative correlation between P. aeruginosa numbers and FEV1 during stable phase (r(s)=0.75, p<0.05), and reductions in P. aeruginosa load with intravenous antibiotic treatment correlated with improved FEV1 (r(s)=0.52, p<0.05). Exacerbations are not due to increased P. aeruginosa numbers in CF adults. However, lung function improvements correlate with reduced P. aeruginosa burden suggesting that current antibiotic treatment strategies remain appropriate in most patients. Improved understanding of PE characterised by unchanged P. aeruginosa numbers and minimal lung function improvement following treatment may allow better targeted therapies.
Publisher: European Respiratory Society (ERS)
Date: 04-1998
DOI: 10.1183/09031936.98.11040937
Abstract: Conventional gravimetric (weight loss) calibration of jet nebulizers overestimates their aerosol output by up to 80% due to unaccounted evaporative loss. We examined two methods of measuring true aerosol output from jet nebulizers. A new adaptation of a widely available clinical assay for lithium (determined by flame photometry, LiCl method) was compared to an existing electrochemical method based on fluoride detection (NaF method). The agreement between the two methods and the repeatability of each method were examined. Ten Mefar jet nebulizers were studied using a Mefar MK3 inhalation dosimeter. There was no significant difference between the two methods (p=0.76) with mean aerosol output of the 10 nebulizers being 7.40 mg x s(-1) (SD 1.06 range 5.86-9.36 mg x s(-1)) for the NaF method and 7.27 mg x s(-1) (SD 0.82 range 5.52-8.26 mg x s(-1)) for the LiCl method. The LiCl method had a coefficient of repeatability of 13 mg x s(-1) compared with 3.7 mg x s(-1) for the NaF method. The LiCl method accurately measured true aerosol output and was considerably easier to use. It was also more repeatable, and hence more precise, than the NaF method. Because the LiCl method uses an assay that is routinely available from hospital biochemistry laboratories, it is easy to use and, thus, can readily be adopted by busy respiratory function departments.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2008
Publisher: Wiley
Date: 10-10-2013
DOI: 10.1002/RCR2.27
Publisher: European Respiratory Society (ERS)
Date: 08-2004
DOI: 10.1183/09031936.04.00104803
Abstract: Iron availability is critical to Pseudomonas aeruginosa. The current authors determined sputum iron, ferritin, microalbumin levels and total cell counts (TCC) in 19 adult patients with cystic fibrosis (CF) during an acute exacerbation and repeated analyses following a median of 12 days antibiotic treatment. The current authors also determined sputum interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha levels because of their putative role in intracellular iron homeostasis. Additional data were obtained from 17 stable CF patients, eight patients with stable chronic obstructive pulmonary disease (COPD) and six normal subjects. Overall, sputum iron, ferritin, microalbumin, IL-1beta and TNF-alpha concentrations and TCCs were significantly elevated in the CF patients compared to those with COPD and normal controls. Sputum ferritin levels were significantly elevated in acute versus stable CF patients and there was a trend for sputum TCC to be higher, but all other inflammatory indices were similar. In the CF patients, sputum iron was positively and strongly related to IL-1beta, TNF-alpha, ferritin and microalbumin levels, but negatively related to forced expiratory volume in one second % predicted. In those acute patients who clinically improved with antibiotics (n=14), there were significant decreases in sputum TCC, iron, ferritin and IL-1beta content, but not TNF-alpha or albumin levels. However, changes in sputum TNF-alpha in acute patients were still closely related to changes in iron, ferritin and albumin content, and changes in IL-1beta were related to changes in sputum ferritin content. Iron and iron-regulatory cytokines may play a role in cystic fibrosis lung disease and the increased iron content may even facilitate Pseudomonas aeruginosa infection.
Publisher: BMJ
Date: 24-01-2007
Publisher: Wiley
Date: 28-12-2015
DOI: 10.1111/RESP.12714
Abstract: In cystic fibrosis (CF), chronic Pseudomonas aeruginosa infection is associated with increased morbidity, antibiotic treatments and mortality. By linking Australian CF registry data with a national microbiological data set, we examined the association between where treatment was delivered, its intensity and P. aeruginosa antibiotic resistance. Sputa were collected from paediatric and adult CF patients attending 18 Australian CF centres. P. aeruginosa antibiotic susceptibilities determined by local laboratories were correlated with clinical characteristics, treatment intensity and infection with strains commonly shared among Australian CF patients. Between-centre differences in treatment and antibiotic resistance were also compared. Large variations in antibiotic usage, maintenance treatment practices and multi-antibiotic resistant P. aeruginosa (MARPA) prevalence exist between Australian CF centres, although the overall proportions of MARPA isolates were similar in paediatric and adult centres (31% vs 35%, P = 0.29). Among paediatric centres, MARPA correlated with intravenous antibiotic usage and the Australian state where treatment was delivered, while azithromycin, reduced lung function and treating state predicted intravenous antibiotic usage. In adult centres, body mass index (BMI) and treating state were associated with MARPA, while intravenous antibiotic use was predicted by gender, BMI, dornase-alpha, azithromycin, lung function and treating state. In adults, P. aeruginosa strains AUST-01 and AUST-02 independently predicted intravenous antibiotic usage. Increased treatment intensity in paediatric centres and the Australian state where treatment was received are both associated with greater risk of MARPA, but not worse clinical outcomes.
Publisher: American Physiological Society
Date: 07-2008
Publisher: European Respiratory Society (ERS)
Date: 09-08-2013
DOI: 10.1183/09031936.00060512
Abstract: 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, ersity 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.
Publisher: Frontiers Media SA
Date: 28-04-2016
DOI: 10.1080/09674845.2016.1157249
Abstract: To develop and determine the feasibility of using a liquid matrix adaptation of the Dictyostelium discoideum bacterial virulence assay by testing on well-characterised clinical and environmental isolates of Pseudomonas aeruginosa. Axenic AX2 D. discoideum were co-cultured with clinical and environmental isolates of P. aeruginosa in costar 24-well tissue culture plates for 24 h. A P. aeruginosa PAO1 positive control was tested in biological quintuplicate. Wells were then inspected using an inverted microscope and the degree of cytotoxic changes (sparse growth compared to control combined with rounding of cells and cytoplasmic shrinkage) on the D. discoideum cells was observed. A Klebsiella aerogenes negative control was included with each assay series. Sixty-five clinical and 20 environmental P. aeruginosa isolates were tested in the model. Cystic fibrosis respiratory isolates were found to be significantly (P < 0.05) less cytotoxic than P. aeruginosa from other sources. Limitations attached to the funding of this paper did not allow validation against previously employed models or animal models. A liquid matrix D. discoideum model for the analysis of P. aeruginosa virulence in a eukaryotic host is feasible, but further validation of the model is required before it may be employed in routine setting.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.JCF.2016.07.010
Abstract: Increased patient longevity and aggressive antibiotic treatment are thought to impact on the microbial composition of the airways of adults with cystic fibrosis (CF). In this study, we sought to determine if a temporal change in the airway microbiology of adults with CF has occurred over time. Longitudinal analysis of sputum microbiology results was undertaken on patients attending a large adult CF centre. Clinical status and health outcomes of transitioning patients were also assessed. A decrease in the prevalence of Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia cepacia complex and Aspergillus spp. (p=0.001, p<0.001, p=0.002 and p<0.001, respectively) occurred. Improvements in lung function among transitioning patients infected with P. aeruginosa were observed. Overtime, a decline in the prevalence of many CF airway pathogens has occurred. Significantly, an incremental improvement in lung function was reported for transitioning patients with current P. aeruginosa infections.
Publisher: Wiley
Date: 15-01-2023
DOI: 10.1111/RESP.14450
Abstract: Neutrophil elastase (NE), is an important host defence against lung pathogens. Maintaining a homeostatic balance between proteases such as NE and anti‐proteases such as secretory leukocyte protease inhibitor (SLPI), is important to prevent tissue damage. In the cystic fibrosis (CF) lung, elevated protease levels and impaired anti‐protease defences contribute to tissue destruction. We assessed lung function and sputum SLPI and NE levels from Pseudomonas aeruginosa infected and non‐infected CF patients (median age 20 years at recruitment) during different phases of clinical disease. Healthy, never smokers served as healthy controls (HC). Sputum total cell counts (TCC) and colony forming units of P. aeruginosa were also determined in each sputum s le. Compared to HC, sputum SLPI was significantly reduced and NE increased in all CF subjects whether infected with P. aeruginosa or not, but the presence of P. aeruginosa worsened these parameters. Females with chronic P. aeruginosa infection had significantly lower sputum SLPI levels than males ( p 0.001). Higher sputum SLPI levels were associated with a significantly reduced rate of longitudinal decline in FEV 1 % predicted ( p 0.05). Antibiotic treatment in P. aeruginosa ‐infected patients significantly decreased sputum TCC and increased SLPI levels, which positively correlated with improved lung function. Airway SLPI is deficient in CF, which appears more marked in P. aeruginosa ‐infected female patients. Importantly, a reduced anti‐protease to protease ratio is associated with accelerated lung function decline. Treatment of an exacerbation is accompanied by partial recovery of anti‐protease defences and significant improvement in lung function, an important clinical outcome.
Publisher: European Respiratory Society (ERS)
Date: 10-1997
DOI: 10.1183/09031936.97.10102436
Abstract: To analyze the epidemiological characteristics and changing trends of lumbar fractures in Xingtai Orthopedic Hospital in the past 10 years, and to improve the prevention and treatment of lumbar fractures. Using the hospital information system, data on patients with lumbar fractures in our hospital from 2009 to 2018 were collected regarding their age, gender, fracture time, injury mechanism, and the type of fracture. The epidemiological characteristics and trends of lumbar fractures for the period were summarized and analyzed. The age of male patients with a high incidence of lumbar fractures was 61 to 70 years, followed by 51 to 60 years. The age of female patients with the highest incidence rate was 61 to 70 years, followed by 51 to 60 years (19.22%). Lumbar fractures in group A were predominantly of men. The majority of lumbar fractures in group B were of women. In group A, the incidence rate was higher in young men (21-50 years) than in women and higher in women >51 years. Most of the affected in iduals were women. In group B, there were more middle-aged and young men (21-50 years) than women however, there were more women than men aged ≥51 years. Car accident injury was the main cause of fractures, but in group B women, low-energy injuries were the main cause of fractures. The periods of high incidence in groups A and B were 4 to 6 years and 7 to 9 years, respectively. The number of injuries in group A was the highest and burst fracture was the main fracture type. In group B, the number of fall injuries was the highest, followed by car accident injuries, and compression fracture was the main fracture type. The number of lumbar fractures in women caused by low-energy injuries showed an increasing trend. The type of compression fracture increased, which might be related to osteoporosis caused by the decrease in the estrogen level after menopause.
Publisher: Public Library of Science (PLoS)
Date: 24-03-2015
Publisher: American Thoracic Society
Date: 06-2006
Publisher: European Respiratory Society (ERS)
Date: 08-11-2012
DOI: 10.1183/09031936.00124012
Abstract: The aerobic Gram-negative bacterium Pseudomonas aeruginosa is an opportunistic pathogen responsible for life-threatening acute and chronic infections in humans. As part of chronic infection P. aeruginosa forms biofilms, which shield the encased bacteria from host immune clearance and provide an impermeable and protective barrier against currently available antimicrobial agents. P. aeruginosa has an absolute requirement for iron for infection success. By influencing cell-cell communication (quorum sensing) and virulence factor expression, iron is a powerful regulator of P. aeruginosa behaviour. Consequently, the imposed perturbation of iron acquisition systems has been proposed as a novel therapeutic approach to the treatment of P. aeruginosa biofilm infection. In this review, we explore the influence of iron availability on P. aeruginosa infection in the lungs of the people with the autosomal recessive condition cystic fibrosis as an archetypal model of chronic P. aeruginosa biofilm infection. Novel therapeutics aimed at disrupting P. aeruginosa are discussed, with an emphasis placed on identifying the barriers that need to be overcome in order to translate these promising in vitro agents into effective therapies in human pulmonary infections.
Publisher: American Society for Microbiology
Date: 11-2018
DOI: 10.1128/AAC.01789-18
Abstract: The lungs of in iduals with cystic fibrosis (CF) become chronically infected with Pseudomonas aeruginosa that is difficult to eradicate by antibiotic treatment. Two key P. aeruginosa antibiotic resistance mechanisms are the AmpC β-lactamase that degrades β-lactam antibiotics and MexXYOprM, a three-protein efflux pump that expels aminoglycoside antibiotics from the bacterial cells.
Publisher: Massachusetts Medical Society
Date: 17-05-2001
Publisher: European Respiratory Society (ERS)
Date: 19-03-2008
DOI: 10.1183/09031936.00152407
Abstract: The cystic fibrosis (CF) lung environment is poorly defined, but data suggest that bacteria may encounter reduced oxygen tensions and possibly an anaerobic environment. Pseudomonas aeruginosa produces the potent toxin cyanide under strictly microaerobic conditions. Evidence of bacterial cyanogenesis in the CF lung was investigated in the present study by measuring sputum cyanide concentrations. Sputum cyanide was measured in seven stable CF patients, as well as before and after intravenous antibiotic therapy during a hospital admission in a further eight patients experiencing acute exacerbations. All patients were chronically infected with P. aeruginosa. Comparative sputum data were obtained from nine CF patients with no documented P. aeruginosa infection and 10 healthy, nonsmoking normal controls. High levels of cyanide were detected in all the P. aeruginosa-infected stable CF patients (median (range) 0.56 (0.37-2.81) microg.mL(-1)), and in seven out of eight acute sputum s les (0.73 (0-1.43) microg.mL(-1)). In contrast, cyanide was not detectable in sputum from eight out of nine CF patients without P. aeruginosa infection or in any of the normal controls. Intravenous antibiotic treatment significantly reduced sputum cyanide levels (median 0.73 to median 0.0 microg.mL(-1)). The cyanide detected indicates that the cystic fibrosis lung provides a predominantly microaerobic environment for Pseudomonas aeruginosa. Cyanide is likely to be a potentially important virulence factor in Pseudomonas aeruginosa-infected cystic fibrosis patients.
Publisher: European Respiratory Society (ERS)
Date: 27-02-2009
DOI: 10.1183/09031936.00001208
Abstract: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension characterised by extensive fibrotic occlusion of pulmonary veins. PVOD has a similar insidious presentation to idiopathic pulmonary arterial hypertension but responds poorly to conventional therapies and has a worse prognosis. The current study reports the case of a Caucasian female with a long history of progressive dyspnoea ultimately diagnosed as focal granulomatous venulitis leading to a pulmonary veno-occlusive disease-like pathology. The present study highlights the challenges in diagnosing and treating this condition.
Publisher: Microbiology Society
Date: 03-2009
Publisher: Informa UK Limited
Date: 29-02-2016
DOI: 10.1586/17476348.2016.1151789
Abstract: Chronic obstructive pulmonary disease (COPD) is a chronic, inflammatory lung disease characterized by airflow limitation that is not fully reversible. The pathological changes in COPD lead to alveolar destruction (emphysema) and chronic airway inflammation, resulting in airflow obstruction and recurrent exacerbations. Inhaled corticosteroids (ICS) are anti-inflammatory agents that are widely used, especially in combination with long-acting beta-agonists, in patients with COPD. Here, we will summarize the benefits and risks of ICS use for COPD, and discuss approaches to more personalized medicine when selecting COPD patients to commence (or withdraw) ICS use. The conclusion arising is that further validation of clinical and biological markers should be undertaken in COPD, in order to in idualize ICS therapy to maximize efficacy for patients.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.PHARMTHERA.2008.01.007
Abstract: Angiogenesis is a prominent feature of the structural tissue remodelling that occurs in the chronic airway diseases of asthma, Bronchiolitis Obliterans Syndrome (BOS, post-lung transplantation), and in smoking-related Chronic Obstructive Pulmonary Disease (COPD). For each, we have explored the relationship between angiogenesis and underlying chronic inflammatory processes--are the hypervascular changes secondary to inflammation, or do they occur in parallel? What are the likely growth factors which stimulate the angiogenic process? We discuss the relationships that have been studied between angiogenesis and the physiological impairment of airflow obstruction. The pattern that emerges is complex and variable. In asthma, there is strong evidence to suggest that Vascular Endothelial Growth Factor (VEGF) and its receptor system is upregulated in the airway. Local production of VEGF has also been implicated as a major driver of angiogenesis in the airway component of COPD, though paradoxically emphysema seems to be due to lack of VEGF in the lung parenchyma. In BOS, the evidence suggests that VEGF is lacking in the airway: other mediators and especially C-X-C chemokines such as Interleukin (IL)-8, are likely to be more important in angiogenesis. The physiological consequences of angiogenesis are likely to be important in asthma (especially during acute episodes of deterioration), and probably also in COPD, although data is equivocal. In BOS, increased airway vascularity appears to occur early, but is not progressive. In terms of therapy, evidence for anti-angiogenic effectiveness is strongest for Inhaled Corticosteroid (ICS) and Long Acting Beta-Agonists (LABA) in asthma.
Publisher: American Physiological Society
Date: 11-2009
DOI: 10.1152/AJPLUNG.00132.2009
Abstract: Cystic fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations. It is a multiorgan system disease that affects the lungs, gastrointestinal tract, liver, and pancreas. The majority of morbidity and mortality in CF relates to chronic airway infection with a variety of bacterial species, commencing in very early infancy, which results in lung destruction and ultimately organ failure ( 41 , 43 ). This review focuses on iron homeostasis in the CF lung and its role in determining the success and chronicity of Pseudomonas aeruginosa infection. There have been previous excellent reviews regarding iron metabolism in the lower respiratory tract and mechanisms of P. aeruginosa iron acquisition, and we direct readers to these articles for further background reading ( 31 , 53 , 58 , 77 , 96 ). In this review, we have brought the “two sides of the coin” together to provide a holistic overview of the relationship between host and bacterial iron homeostasis and put this information into the context of current understanding on infection in the CF lung.
Publisher: BMJ
Date: 04-2002
Abstract: There are few data in asthma relating airway physiology, inflammation and remodelling and the relative effects of inhaled corticosteroid (ICS) treatment on these parameters. A study of the relationships between spirometric indices, airway inflammation, airway remodelling, and bronchial hyperreactivity (BHR) before and after treatment with high dose inhaled fluticasone propionate (FP 750 microg bd) was performed in a group of patients with relatively mild but symptomatic asthma. A double blind, randomised, placebo controlled, parallel group study of inhaled FP was performed in 35 asthmatic patients. Bronchoalveolar lavage (BAL) and airway biopsy studies were carried out at baseline and after 3 and 12 months of treatment. Twenty two normal healthy non-asthmatic subjects acted as controls. BAL fluid eosinophils, mast cells, and epithelial cells were significantly higher in asthmatic patients than in controls at baseline (p<0.01). Subepithelial reticular basement membrane (rbm) thickness was variable, but overall was increased in asthmatic patients compared with controls (p<0.01). Multiple regression analysis explained 40% of the variability in BHR, 21% related to rbm thickness, 11% to BAL epithelial cells, and 8% to BAL eosinophils. The longitudinal data corroborated the cross sectional model. Forced expiratory volume in 1 second improved after 3 months of treatment with FP with no further improvement at 12 months. PD(20) improved throughout the study. BAL inflammatory cells decreased following 3 months of treatment with no further improvement at 12 months (p<0.05 v placebo). Rbm thickness decreased in the FP group, but only after 12 months of treatment (mean change -1.9, 95% CI -3 to -0.7 microm p<0.01 v. baseline, p<0.05 v. placebo). A third of the improvement in BHR with FP was associated with early changes in inflammation, but the more progressive and larger improvement was associated with the later improvement in airway remodelling. Physiology, airway inflammation and remodelling in asthma are interrelated and improve with ICS. Changes are not temporally concordant, with prolonged treatment necessary for maximal benefit in remodelling and PD(20). Determining the appropriate dose of inhaled steroids only by reference to symptoms and lung function, as specified in current international guidelines, and even against indices of inflammation may be over simplistic. The results of this study support the need for early and long term intervention with ICS, even in patients with relatively mild asthma.
Publisher: Elsevier BV
Date: 08-2001
DOI: 10.1016/S1053-2498(01)00282-0
Abstract: Reactive oxygen species (ROS) may contribute to airway injury and the development of the bronchiolitis obliterans syndrome (BOS) following lung transplantation (LT). Chemically active iron released from ferritin stores and nitric oxide (NO)-derived radicals may add to the oxidative burden. We determined the concentrations of ferritin and the aqueous NO derivative nitrite (NO2(-)) within bronchoalveolar lavage fluid (BALF) of 14 stable LT recipients (ST) and 7 subjects with BOS and 21 normal controls. We also assessed the relationship between BALF ferritin and hemosiderin-laden macrophages (HLMs) using a hemosiderin score (HS) and determined BALF albumin concentration as a marker of microvascular leakage. BALF ferritin concentrations and HSs were significantly elevated in LT recipients overall compared with normal controls (p < 0.05). BALF NO2(-) levels were elevated in BOS subjects and STs compared with normal controls (p = 0.002 and p = 0.09, respectively), but there was no difference between transplant groups. BALF albumin concentrations were elevated in BOS patients compared with normal controls (p = 0.02) and ST (p = 0.05), but there was no difference between STs and controls. There was a significant relationship between BALF ferritin concentration and HS in LT recipients overall (r(s) = 0.7, p < 0.001). In BOS subjects, but not ST, BALF ferritin was significantly related to BALF albumin (r(s) = 0.8, p = 0.05) and there was a weak relationship with NO2(-) concentration (r(s) = 0.6, p = 0.1). BALF NO2(-) was strongly related to BALF % neutrophils in BOS subjects (r(s) = 0.9, p < 0.01), but there was no such relationship in STs. Our findings suggest that the allograft could be subject to significant iron-generated oxidative stress, which may be exacerbated by NO and neutrophil-derived ROS, particularly in BOS. Microvascular leakage may be a feature of established chronic rejection, which potentiates the iron overload and contributes to further airway damage and remodeling.
Publisher: Public Library of Science (PLoS)
Date: 22-05-2013
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JTEMB.2018.03.009
Abstract: We have recently shown that Pseudomonas aeruginosa, an opportunistic pathogen that chronically infects the lungs of patients with cystic fibrosis (CF) and other forms of lung disease, is extremely efficient in recruiting zinc from the environment and that this capability is required for its ability to cause acute lung infections in mice. To verify that P. aeruginosa faces zinc shortage when colonizing the lungs of human patients, we analyzed the expression of three genes that are highly induced under conditions of zinc deficiency (zrmA, dksA2 and rpmE2), in bacteria in the sputum of patients with inflammatory lung disease. All three genes were expressed in all the analyzed sputum s les to a level much higher than that of bacteria grown in zinc-containing laboratory medium, supporting the hypothesis that P. aeruginosa is under zinc starvation during lung infections. We also found that the expression of several virulence traits that play a central role in the ability of P. aeruginosa to colonize the lung is affected by disruption of the most important zinc importing systems. Virulence features dependent on zinc intake include swarming and swimming motility and the ability to form biofilms. Furthermore, alterations in zinc assimilation interfere with the synthesis of the siderophore pyoverdine, suggesting that zinc recruitment could modulate iron uptake and affect siderophore-mediated cell signaling. Our results reveal that zinc uptake is likely to play a key role in the ability of P. aeruginosa to cause chronic lung infections and strongly modulates critical virulence traits of the pathogen. Taking into account the recent discovery that zinc uptake in P. aeruginosa is promoted by the release of a small molecular weight molecule showing high affinity for zinc, our data suggest novel and effective possibilities to control lung infections by these bacteria.
Publisher: Elsevier
Date: 2004
Publisher: Springer Science and Business Media LLC
Date: 30-07-2010
Publisher: Springer Science and Business Media LLC
Date: 09-10-2015
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.HEALUN.2004.02.006
Abstract: Because bronchial hyperresponsiveness has been linked to the bronchiolitis obliterans syndrome (BOS), we determined PD(20) methacholine (PD(20(M))), PD(15) hypertonic saline (PD(15(HS))) and their dose-response slopes (DRS(M) and DRS(HS)) in 8 single and 18 double lung transplant recipients within 1 year of lung transplantation and examined the relationship to bronchoalveolar lavage cell profiles and subsequent development of BOS. Twenty-two patients (81%) had a positive methacholine and 6 (25%) a positive hypertonic saline challenge. A positive PD(15(HS)) was associated with an increased risk for BOS at 2 years (odds ratio 12.6, 95% confidence interval 1.3-123.5, p < 0.05), and time to BOS was significantly and negatively related to DRS(HS) (r = -0.5, p < 0.05) - that is, the greater the response, the shorter the time to BOS. Interestingly, DRS(HS) correlated positively with recipient:donor total lung capacity ratio (r = 0.5, p < 0.05), but there was no relationship between either challenge result and airway inflammation. Methacholine hyperresponsiveness is common after lung transplantation but is not prognostic, whereas response to hypertonic saline may reflect recipient:donor size matching and provide useful information regarding the potential for BOS development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2008
Publisher: Wiley
Date: 2006
DOI: 10.1002/PPUL.20420
Publisher: BMJ
Date: 03-2003
Publisher: European Respiratory Society (ERS)
Date: 17-07-2014
DOI: 10.1183/09031936.00203013
Abstract: Chronic airway infection in adults with cystic fibrosis (CF) is polymicrobial and the impact of intravenous antibiotics on the bacterial community composition is poorly understood. We employed culture-independent molecular techniques to explore the early effects of i.v. antibiotics on the CF airway microbiome. DNA was extracted from sputum s les collected from adult subjects with CF at three time-points (before starting treatment, and at day 3 and day 8–10 of i.v. antibiotics) during treatment of an infective pulmonary exacerbation. Microbial community profiles were derived through analysis of bacterial-derived 16S ribosomal RNA by pyrosequencing and changes over time were compared. 59 sputum s les were collected during 24 pulmonary exacerbations from 23 subjects. Between treatment onset and day 3 there was a significant reduction in the relative abundance of Pseudomonas and increased microbial ersity. By day 8–10, bacterial community composition was similar to pre-treatment. Changes in community composition did not predict improvements in lung function. The relative abundance of Pseudomonas falls rapidly in subjects with CF receiving i.v. antibiotic treatment for a pulmonary exacerbation and is accompanied by an increase in overall microbial ersity. However, this effect is not maintained beyond the first week of treatment.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.JCF.2012.11.004
Abstract: Few data exist on the functional activity of airway neutrophils in the milieu of the cystic fibrosis (CF) lung. We assessed reactive oxygen species (ROS) production by sputum neutrophils and the relationship to neutrophil viability. Identical assessments were made on peripheral blood neutrophils from CF patients. ROS production in sputum neutrophils was assessed in 31 CF patients at varying phases of clinical disease using flow cytometry. Twenty patients provided blood s les (including 16 who also provided a matched sputum s le). Neutrophil viability was determined using dual annexin V (apoptosis) and propidium iodide (necrosis) staining. Comparative peripheral blood data were obtained from 7 healthy controls. ROS production was reduced in sputum compared to blood neutrophils and they demonstrated a higher level of necrosis. Subpopulations of neutrophils with different ROS production capacity were apparent in peripheral blood. Lung function was positively associated with both the proportion of blood neutrophils demonstrating increased ROS production and the proportion of apoptotic sputum neutrophils. CF airway neutrophils display functional exhaustion. Healthier lungs in CF appear to be associated with subpopulations of blood neutrophils with increased oxidative burst capacity and evidence for increased neutrophil apoptosis within the airway.
Publisher: European Respiratory Society (ERS)
Date: 05-2017
Publisher: Wiley
Date: 21-10-2009
DOI: 10.1111/J.1365-2222.2009.03349.X
Abstract: Airway microcirculation is abnormal in asthma but the role of vascular changes in asthma deteriorations remains poorly defined. We prospectively assessed the vascular changes accompanying worsening of asthma control by using an inhaled corticosteroid (ICS) dose-reduction model. To evaluate airway vascularity, vascular permeability and expression of vascular endothelial growth factor (VEGF) in early asthma deterioration induced by ICS back-titration. Twenty mild-to-moderate persistent symptomatic asthmatics on low-to-moderate ICS were recruited and treated with 4 weeks of high-dose fluticasone propionate (1000 microg/day) to achieve symptom control. This was followed by dose reduction to half of the pre-study doses for 4-8 weeks until the symptoms began to return. Endobronchial biopsy and bronchoalveolar lavage (BAL) s les were obtained after both treatment periods. Vascularity as measured by the number and size of blood vessels, as well as VEGF expression did not change following ICS reduction. Even on high-dose ICS, perivascular albumin staining and BAL microalbumin levels in asthmatic subjects, as markers of permeability, were elevated when compared with normal subjects and both further increased significantly after ICS reduction. There was a significant association between changes in vascular leakiness and clinical deterioration. Increases in airway albumin correlated with previously reported increases in airway wall infiltration with T lymphocytes. Our results suggest that airway vascular leakage is a major pathophysiologic feature of early asthma deterioration, occurring before recrudescence of cellular inflammation.
Publisher: Wiley
Date: 26-06-2002
Publisher: BMJ
Date: 09-2002
Publisher: Elsevier BV
Date: 08-2015
Publisher: European Respiratory Society (ERS)
Date: 09-2007
DOI: 10.1183/09031936.00007306
Abstract: In the present review of airway remodelling and its response to therapies, clinical observations about airway physiological abnormalities, assumed to be caused by remodelling processes, are related to what is known about the components of structural changes from airway s ling and histopathological analysis. The review focuses on three important diseases: asthma, chronic obstructive pulmonary disease and bronchiolitis obliterans syndrome (BOS), which occurs commonly after lung transplantation as a manifestation of chronic rejection. The present authors chose to use BOS as an issue, because with routine bronchoscopic surveillance after lung transplantation there has been more opportunity to directly study airway pathology longitudinally than in more everyday conditions. In addition, the present authors have reviewed animal models of induced airway remodelling, where most information is available on the potential of therapeutic intervention. Finally, the limited information that can be gained from the literature on the effects of commonly used airway medications on remodelling components is reviewed. In conclusion, the present authors have detailed some of the gaps in knowledge surrounding the potential to improve or modulate remodelling processes in human disease. The areas where it is believed urgent research needs to be focused have also been highlighted.
Publisher: Informa UK Limited
Date: 09-2016
DOI: 10.2147/COPD.S113176
Publisher: Elsevier BV
Date: 05-2001
Abstract: We have previously shown that airway macrophages (AMs) from atopic nonasthmatic subjects, but not atopic asthmatic subjects, inhibit T-cell IL-5 production during an allergen-dependent interaction. However, the mechanisms responsible for the IL-5-modulating effect of the AMs are less clear. The aim of the present study was to define the roles of B7 and CD40 costimulatory signals delivered by AMs in regulating T-cell IL-5 responses in an allergen-stimulated coculture system. Peripheral blood CD4(+) T cells and AMs were cocultured under different conditions. Compared with those from well-matched atopic nonasthmatic subjects, AMs from atopic asthmatic subjects demonstrated a significantly lower expression of B7-1 and CD40, but not B7-2 and HLA-DR, after either fresh isolation or coculture with allergen-reactive CD4(+) T cells. Lower IL-12 production by the AMs from asthmatic subjects was also observed under the same conditions. Allergen-related T-cell IFN-gamma and IL-5 production was inhibited by the addition of either neutralizing B7-1 or B7-2 antibody to the cocultures in both atopic groups. In contrast, IL-5 production was significantly increased by the addition of blocking CD40 antibody, whereas IL-12 production by the AMs was inhibited. Anti-IL-12 mAb enhanced IL-5 production in the cocultures from atopic nonasthmatic subjects, whereas a dose-dependent suppressive effect of recombinant human IL-12 on IL-5 production was seen in atopic asthmatic subjects. In this coculture model system, lower IL-12 production by AMs and higher IL-5 production by CD4(+) T cells in atopic asthmatic subjects compared with that found in atopic nonasthmatic subjects are related to the lower expression of CD40 rather than B7-1 signals on the AMs from these patients.
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/AH10973
Abstract: Objectives. In Aboriginal and Torres Strait Islander peoples in Queensland, to (a) determine the disease burden of common chronic lung diseases and (b) identify areas of need with respect to lung health services. Methods. Literature reviews and analyses of hospitalisation and mortality data were used to describe disease epidemiology and available programs and services. Key stakeholder interviews and an online survey of health professionals were used to evaluate lung health services across the state and to identify services, needs and gaps. Results. Morbidity and mortality from respiratory diseases in the Indigenous population is substantially higher than the non-Indigenous population across all age groups and regions. There are inadequate clinical services and resources to address disease prevention, detection, intervention and management in an evidence-based and culturally acceptable fashion. There is a lack of culturally appropriate educational resources and management programs, insufficient access to appropriately engaged Indigenous health professionals, a lack of multi-disciplinary specialist outreach teams, fragmented information systems and inadequate coordination of care. Conclusions. Major initiatives are required at all levels of the healthcare system to adequately address service provision for Indigenous Queenslanders with lung diseases, including high quality research to investigate the causes for poor lung health, which are likely to be multifactorial. What is known about the topic? Chronic diseases, including lung disease contribute to, and influence outcomes of, the well-known health and socioeconomic disadvantage among Aboriginal and Torres Strait Islander Australians. Nationwide, the most common reason for hospitalisation of Indigenous Australians is for lung diseases (after renal dialysis). What does this paper add? There is currently no state- or nation-wide comprehensive review of chronic lung disease burden and the health services available to prevent, treat and manage lung disease. This review fills this gap in Queensland and has found that chronic lung disease burden is not homogenous. There are substantial gaps in, and barriers to, the provision of high quality, evidence based services and a paucity of well-designed research to inform policy and health service delivery. What are the implications for practitioners? Evidence-based strategies are needed at the primary, secondary and tertiary levels of the healthcare system. Fourteen recommendations relevant to practitioners and policy makers were formulated.
Publisher: European Respiratory Society
Date: 06-2014
Publisher: Springer Science and Business Media LLC
Date: 12-2011
Abstract: The reticular basement membrane (Rbm) in smokers and especially smokers with COPD is fragmented with "clefts" containing cells staining for the collagenase matrix-metalloproteinase-9 (MMP-9) and fibroblast protein, S100A4. These cells are also present in the basal epithelium. Such changes are likely hallmarks of epithelial mesenchymal transition (EMT). We aimed to confirm the epithelial origin of these Rbm cells, and to exclude potential confounding by infiltrating inflammatory cells. Endobronchial biopsy sections from 17 COPD current smokers, with documented Rbm splitting and cellularity were stained for neutrophil elastase (neutrophil marker), CD68 (macrophage/mature fibroblasts), CD4+/CD8+ T lymphocytes, CD19 (B-cells), CD11c (dendritic cells/inflammatory cells), and S100 (Langerhans cells). The number of cells in the Rbm and epithelium staining for these "inflammatory" cell markers were then compared to numbers staining for S100A4, "a documented EMT epitope". Slides were double stained for S100A4 and cytokeratin(s). In the basal epithelium significantly more cells stained for S100A4 compared to infiltrating macrophages, fibroblasts or immune cells: median, 26 (21.3 - 37.3) versus 0 (0 - 9.6) per mm, p 0.003. Markedly more S100A4 staining cells were also observed in the Rbm compared to infiltrating macrophages, neutrophils, fibroblasts or immune cells or any sub-type: 58 (37.3 - 92.6) versus 0 (0 - 4.8) cells/mm Rbm, p 0.003. Cells in the basal epithelium 26 (21.3 - 37.3) per mm) and Rbm (5.9 (2.3 - 13.8) per mm) frequently double stained for both cytokeratin and S100A4. These data provide additional support for active EMT in COPD airways.
Publisher: Springer Science and Business Media LLC
Date: 04-06-2011
DOI: 10.1007/S10534-011-9464-Z
Abstract: The lungs of patients with cystic fibrosis become chronically infected with the bacterium Pseudomonas aeruginosa, which heralds progressive lung damage and a decline in health. Iron is a crucial micronutrient for bacteria and its acquisition is a key factor in infection. P. aeruginosa can acquire this element by secreting pyoverdine and pyochelin, iron-chelating compounds (siderophores) that scavenge iron and deliver it to the bacteria. Siderophore-mediated iron uptake is generally considered a key factor in the ability of P. aeruginosa to cause infection. We have investigated the amounts of pyoverdine in 148 sputum s les from 36 cystic fibrosis patients (30 infected with P. aeruginosa and 6 as negative controls). Pyoverdine was present in 93 s les in concentrations between 0.30 and 51 μM (median 4.6 μM) and there was a strong association between the amount of pyoverdine and the number of P. aeruginosa present. However, pyoverdine was not present, or below the limits of detection (~0.3 μM), in 21 sputum s les that contained P. aeruginosa. Pyochelin was also absent, or below the limits of detection (~1 μM), in s les from P. aeruginosa-infected patients with little or no detectable pyoverdine. Our data show that pyoverdine is an important iron-scavenging molecule for P. aeruginosa in many cystic fibrosis patients, but other P. aeruginosa iron-uptake systems must be active in some patients to satisfy the bacterial need for iron.
Publisher: Wiley
Date: 11-09-2016
DOI: 10.1111/RESP.12882
Abstract: COPD is characterized by poorly reversible airflow obstruction usually due to cigarette smoking. Transforming growth factor (TGF)-β1 has been implicated in the pathogenesis of COPD, and in particular a process called epithelial mesenchymal transition (EMT), which may well be an intermediatory between smoking and both airway fibrosis and lung cancer. The downstream classical or 'canonical' TGF-β1 pathway is via the phosphorylated (p) Smad transcription factor system. We have investigated TGF-β1 expression and its 'pSmad fingerprint' in bronchoscopic airway biopsies from patients with COPD, and in smoking and non-smoking controls. A cross-sectional immunohistochemical study compared TGF-β1 and pSmad 2, 3 (excitatory) and 7 (inhibitory) expression in cells and blood vessels of three compartments of large airways: epithelium (especially the basal region), reticular basement membrane (Rbm) and underlying lamina propria (LP). TGF-β1 expression was generally higher in COPD subjects throughout the airway wall (P < 0.01), while pSmad 2/3 expression was associated with smoking especially in current smoking COPD (P < 0.05). Expression of inhibitory pSmad 7 was also prominently reduced in patients with COPD in contrast to smokers and controls (P < 0.01). In addition, pSmad, but not TGF-β1 expression, was related to airflow obstruction and a canonical EMT biomarker (S100 A4) expression. Activation of the Smad pathway in the airways is linked to EMT activity and loss of lung function. The disconnection between TGF-β1 and pSmad in terms of relationships to EMT activity and lung function suggests that factors other than or in addition to TGF-β1 are driving the process.
Publisher: Georg Thieme Verlag KG
Date: 31-03-2015
Abstract: Bronchiectasis is a pathological diagnosis describing dilatation of the airways and is characterized by chronic lung sepsis. Bronchiectasis has multiple etiologies, but is usually considered in terms of whether it is due to the genetic disorder cystic fibrosis (CF) or secondary to other causes (non-CF bronchiectasis, NCFB). Inhaled antibiotics are used in bronchiectasis to suppress bacterial pathogens and reduce long-term lung function decline. The majority of the literature on inhaled antibiotics comes from studies on CF where the dominant bacterial pathogen in the airway is usually Pseudomonas aeruginosa. Thus, most aerosolized antibiotic regimens target this bacterium, but the emergence of molecular diagnostic methods has questioned this approach and more tailored strategies may need to be considered in CF based on the community composition of the lung microbiome. Similarly, the lung microbiome in NCFB has been found to be a complex polymicrobial one and the current practice of employing the same inhaled antibiotic regimes as are used in CF may no longer be appropriate in many patients. In this article, the use of inhaled antibiotics in CF and NCFB is considered in the light of improved understanding of the lung microbiome and why more tailored therapy may be needed based on molecular identification of the microbial pathogens present. The evidence for the use of currently available inhaled antibiotics and advances in inhaled drug packaging and delivery devices are discussed. Finally, the urgent need for prospective randomized clinical trials in CF and NCFB is highlighted and areas for future research identified.
Publisher: Wiley
Date: 09-05-2003
DOI: 10.1046/J.1440-1843.2003.00449.X
Abstract: Microangiopathic haemolytic anaemia (MAHA) describes intravascular haemolysis due to mechanical destruction of red cells as a result of pathological changes in small blood vessels. It is well recognized as a complication of cyclosporin A therapy in solid organ transplantation but has been uncommonly reported in association with tacrolimus therapy and never before in the setting of lung transplantation. Discussed is a 54-year-old female recipient of a left single lung transplant who developed anaemia, thrombocytopenia and red blood cell fragmentation consistent with MAHA following lung volume reduction surgery (VRS) of the native right lung in the setting of high serum tacrolimus levels. Treatment with fresh frozen plasma and plasmapharesis plus supportive therapy with blood and platelet transfusions resulted in successful resolution of the haemolytic process. Cyclosporin A was substituted for tacrolimus and 18 months later there has been no evidence of recurrence. Tacrolimus therapy is a rare cause of MAHA in solid organ transplants but the diagnosis should be considered if there is an unexplained fall in haemoglobin and/or platelet count in the context of high serum tacrolimus levels.
Publisher: Wiley
Date: 11-2004
DOI: 10.1111/J.1440-1843.2004.00624.X
Abstract: In a longitudinal ex vivo placebo-controlled study, asthmatics already treated with inhaled corticosteroid received supplemental long-acting beta-agonist (LABA) or increased doses of their inhaled corticosteroid (ICS). Previously reports have shown significant reductions in biopsy eosinophil numbers after treatment with LABA. Following these findings, eosinophil chemokines eotaxin and IL-5 in the BAL fluid at baseline and after 3 months of study medication have now been measured, and these data with that from new cross-sectional controls have also been compared. It is hypothesised that changes in airway eosinophils would be related to eosinophil cytokines. BAL cytokines were measured by chemiluminescent enzyme-linked immunosorbent assay, while eosinophils were measured by immunohistochemistry or differential cell counting. For all measures, longitudinal data were compared to that from ICS-free asthmatics (n = 42) and non-asthmatic controls (n = 28). BAL eotaxin in asthmatics was elevated above non-asthmatic levels regardless of ICS levels. BAL IL-5 was elevated in ICS-free asthmatics, but not in asthmatics on low-dose ICS treatment. Longitudinally, BAL eotaxin was unchanged after 3 months. Unexpectedly, IL-5 increased after 3 months of additional LABA treatment but was not further affected by increasing the dose of ICS. Airway eotaxin seemed to be constitutively raised in asthmatics, whereas, IL-5 levels were more steroid-responsive. No relationship was observed between eosinophils and eosinophilic cytokines in the BAL. While the elevation of luminal IL-5 with LABA treatment cannot be accounted for, it may have contributed to luminal clearance of airway wall eosinophils. The lack of correlation between airways eosinophils and eosinophilic cytokines in the BAL is particularly important.
Publisher: Public Library of Science (PLoS)
Date: 29-06-2012
Publisher: American Society for Microbiology
Date: 05-2009
DOI: 10.1128/JCM.00014-09
Abstract: Pseudomonas aeruginosa is an important cause of pulmonary infection in cystic fibrosis (CF). Its correct identification ensures effective patient management and infection control strategies. However, little is known about how often CF sputum isolates are falsely identified as P. aeruginosa . We used P. aeruginosa -specific duplex real-time PCR assays to determine if 2,267 P. aeruginosa sputum isolates from 561 CF patients were correctly identified by 17 Australian clinical microbiology laboratories. Misidentified isolates underwent further phenotypic tests, lified rRNA gene restriction analysis, and partial 16S rRNA gene sequence analysis. Participating laboratories were surveyed on how they identified P. aeruginosa from CF sputum. Overall, 2,214 (97.7%) isolates from 531 (94.7%) CF patients were correctly identified as P. aeruginosa . Further testing with the API 20NE kit correctly identified only 34 (59%) of the misidentified isolates. Twelve (40%) patients had previously grown the misidentified species in their sputum. Achromobacter xylosoxidans ( n = 21), Stenotrophomonas maltophilia ( n = 15), and Inquilinus limosus ( n = 4) were the species most commonly misidentified as P. aeruginosa . Overall, there were very low rates of P. aeruginosa misidentification among isolates from a broad cross section of Australian CF patients. Additional improvements are possible by undertaking a culture history review, noting colonial morphology, and performing stringent oxidase, DNase, and colistin susceptibility testing for all presumptive P. aeruginosa isolates. Isolates exhibiting atypical phenotypic features should be evaluated further by additional phenotypic or genotypic identification techniques.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JCF.2013.12.001
Abstract: Bio-active trace metals have been identified in respiratory tract secretions of subjects with lung disease and may potentially influence bacterial virulence, inflammation and disease severity. We measured a erse range of metal ions in sputum s les from subjects with CF and non-CF bronchiectasis (NCFB) compared to healthy controls and examined their relationship to airway inflammation, disease severity and the presence of bacterial pathogens. We studied 45 subjects with CF, 8 with NCFB and 8 healthy controls. Metal concentrations were measured in sputum supernatant by inductively-coupled plasma mass spectrometry and correlated with sputum inflammatory cell counts, lactate dehydrogenase (LDH) and interleukin (IL)-8 concentrations, atmospheric particulate matter, lung function, clinical status and participant demographics. Sputum from subjects with CF and NCFB contained increased concentrations of magnesium, calcium, iron and zinc. Metal ion concentrations correlated positively with LDH levels. The concentrations of magnesium, iron and zinc positively correlated with IL-8. A sub-group of CF subjects with severe lung disease demonstrated increased sputum molybdenum concentrations. Elevated concentrations of sputum metal ions appear to be associated with cell/tissue necrosis and inflammation in subjects with CF and NCFB. Sputum molybdenum concentrations may be a biomarker of severe CF airway disease.
Publisher: Wiley
Date: 21-07-2010
DOI: 10.1111/J.1440-1843.2010.01808.X
Abstract: In COPD, the airways are chronically inflamed, and we have now observed fragmentation of the reticular basement membrane (Rbm). This appears to be a hallmark of the process known as epithelial mesenchymal transition (EMT), in which epithelial cells migrate through the Rbm and differentiate into fibroblasts. The aim of this study was to confirm the extent and relevance of Rbm fragmentation in smokers and patients with COPD, and to undertake a preliminary analysis of some classical markers of EMT. Endobronchial biopsies from current smokers (CS n = 17) and ex-smokers with COPD (ES n = 15), smokers with normal lung function (NS n = 16) and never-smoking control subjects (NC n = 15) were stained for the EMT markers, S100A4, vimentin, epidermal growth factor receptor and matrix metalloproteinase-9. Compared with NC, there was significant Rbm fragmentation in the CS, ES and NS groups, which was positively associated with smoking history in subjects with COPD. Staining for basal epithelial S100A4, epithelial epidermal growth factor receptor and matrix metalloproteinase-9 in cells within Rbm clefts, and for S100A4 in Rbm cells, was increased in the CS, NS and ES groups compared with the NC group. There was also increased Rbm cell S100A4 staining in the CS group compared with the ES and NS groups. Basal epithelial cell staining for S100A4 was inversely correlated with airflow limitation. Double staining for both S100A4 and vimentin further strengthened the likelihood that these changes represented active EMT. This is the first detailed description of fragmentation and cellularity of the Rbm in smokers, which were most marked in subjects with COPD. The data are consistent with active EMT in these subjects.
Publisher: Frontiers Media SA
Date: 11-06-2018
Publisher: Wiley
Date: 25-04-2013
DOI: 10.1111/RESP.12077
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.JCF.2018.08.013
Abstract: We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy. In this retrospective clinical study, 3 independent CF patient cohorts (US-American: 29, Australian: 12 and Irish: 19 cases) were enrolled carrying at least one Class III CFTR CF-causing mutation (p.Gly551Asp) and being treated with CFTR potentiator ivacaftor. Plasma HE4 was measured by immunoassay before treatment (baseline) and 1-6 months after commencement of ivacaftor, and were correlated with FEV After 1 month of therapy, HE4 levels were significantly lower than at baseline and remained decreased up to 6 months. A significant inverse correlation between absolute and delta values of HE4 and FEV This study shows that plasma HE4 levels inversely correlate with lung function improvement in CF patients receiving ivacaftor. Overall, this potential biomarker may be of value for routine clinical and laboratory follow-up of CFTR modulating therapy.
Publisher: Wiley
Date: 19-12-2006
DOI: 10.1111/J.1440-1843.2006.00962.X
Abstract: In cystic fibrosis (CF) very few studies have assessed sputum 8-iso-PGF2alpha levels during pulmonary exacerbations as a direct measure of airway oxidative stress. The role of other lipid-derived inflammatory mediators, such as the cysteinyl leukotrienes (cys-LTs) and prostaglandin (PG)-E2, during exacerbations is also poorly defined and the effect of conventional antibiotic therapy on these components of the inflammatory process is unclear. Sputum 8-iso-PGF2alpha, total cys-LT and PGE2 levels were measured in 17 CF patients experiencing a pulmonary exacerbation and repeated analysis were performed in 15 of these patients after antibiotic treatment. Eight stable CF and nine healthy subjects provided control data. Sputum 8-iso-PGF2alpha was significantly elevated in acute, but not stable CF patients versus healthy controls (P < 0.001). Similarly, sputum cys-LT and PGE2 levels were increased in acute compared with stable CF patients and healthy controls (P <or= 0.001). Although substantially lower than in acute patients, sputum cys-LT levels in stable patients were also significantly higher than in normal controls (P = 0.01). There were strong associations between cys-LT levels and sputum total cell counts, and blood neutrophils in acute patients (r2 = 0.53, P = 0.001 and r2 = 0.33, P < 0.05, respectively). Overall in the CF patients, FEV1% predicted was strongly and negatively correlated with sputum 8-iso-PGF2alpha (r2 = 0.34, P = 0.006), cys-LT (r2 = 0.40, P = 0.002) and PGE2 (r2 = 0.52, P < 0.001) levels. Antibiotic treatment reduced sputum total cell count (P = 0.03), but did not affect 8-iso-PGF2alpha, cys-LT or PGE2 levels. CF exacerbations are characterized by increased oxidative stress and sputum concentrations of bioactive lipid mediators. Treatment does not modulate these aspects of inflammation and more targeted therapy needs further study.
Publisher: Wiley
Date: 11-11-2013
DOI: 10.1002/MBO3.141
Publisher: Oxford University Press (OUP)
Date: 03-2009
Publisher: Springer Science and Business Media LLC
Date: 07-01-2009
DOI: 10.1007/S10534-008-9197-9
Abstract: The bacterium Pseudomonas aeruginosa is commonly isolated from the general environment and also infects the lungs of patients with cystic fibrosis (CF). Iron in mammals is not freely available to infecting pathogens although significant amounts of extracellular iron are available in the sputum that occurs in the lungs of CF patients. P. aeruginosa has a large number of systems to acquire this essential nutrient and many of these systems have been characterised in the laboratory. However, which iron acquisition systems are active in CF is not well understood. Here we review recent research that sheds light on how P. aeruginosa obtains iron in the lungs of CF patients.
Publisher: BMJ
Date: 07-2005
Publisher: Informa UK Limited
Date: 19-08-2013
DOI: 10.3109/17538157.2013.812646
Abstract: People with cystic fibrosis (CF) frequently experience isolation and are subjected to extensive complex treatment regimens which could be complemented by remote support. In the current research this is particularly relevant as the location, Tasmania, has the second highest incidence of CF in the world. This paper provides an overview of the evaluation of a pilot trial of an information system conceptualised and developed to assist people with CF, and their families, to enhance their skills and communication in relation to self-management for their condition. The pilot involved people with CF ranging in age from 19 months to 52 years and their families. The primary outcome was the perceived usability of the online-symptom diary from the user's perspective. To assess perceived usability qualitative semi-structured interviews were conducted pre- and post-pilot and analysed using thematic coding. Participants initially and primarily perceived myCF as a system that would help others and enable peer support. Connectivity and involvement were highlighted as complex issues that needed consideration. There was an overall encouraging response to the pilot and indications that the use of information communication technology to complement health care delivery and facilitate self-care skills may be particularly suited to the Australian context where geographical distances and isolation provide a relative barrier to specialist care for chronic complex conditions.
Publisher: Wiley
Date: 29-03-2011
DOI: 10.1111/J.1348-0421.2011.00314.X
Abstract: The characteristics of clinical and environmental isolates of Pseudomonas aeruginosa from both hospital and community settings were analyzed in a eukaryotic virulence model employing the AX2 and X22 mutants of Dictyostelium discoideum. Thirty-one strains, including two Australian epidemic strains, of P. aeruginosa were analyzed, five from environmental sources, six from clinical sources other than cystic fibrosis (CF) patients and nineteen from CF patients' respiratory secretions. The majority of CF isolates almost uniquely supported the growth of D. discoideum. CF isolates of P. aeruginosa were found to be less virulent than isolates from other sources. Varying degrees of inhibition of the developmental cycle of D. discoideum when growing on CF isolates were also noted. This is the first description of P. aeruginosa isolates from clinical and environmental sources supporting the growth of D. discoideum.
Publisher: Wiley
Date: 09-2008
DOI: 10.1111/J.1440-1843.2008.01383.X
Abstract: Clonal strains of Pseudomonas aeruginosa have been identified in large cystic fibrosis (CF) centres. Whether such strains are more virulent or whether cross-infection between patients explains their widespread prevalence is unknown. This study described the epidemiology of P. aeruginosa infection in CF patients in Tasmania, Australia, an area with a high CF birth incidence. Patients in Tasmania are geographically dispersed and when this study was conducted (2003) there was no central CF clinic, with patients receiving treatment in regional hospitals. P. aeruginosa isolates from CF adults aged 15 years and over in Tasmania were genotyped using random lified polymorphic DNA (RAPD)-PCR and clonal strains confirmed with pulsed field gel electrophoresis. Airway s les were obtained from 41 patients (82% of the adult CF population). P. aeruginosa was isolated from 34 patients and nine (26%) of these in iduals harboured P. aeruginosa strains with identical RAPD-PCR and pulsed field gel electrophoresis patterns (Australian Epidemic Strain III--AES III). AES III was isolated from patients in all regions of Tasmania and was distinct from the epidemic CF strains described on mainland Australia (AES I and II). The possible link between CF adults infected with AES III was attendance at family c s more than 12 years previously. Patients harbouring AES III had suffered significantly more exacerbations requiring hospitalisation during the 2 years prior to the study compared with patients infected with unique strains (P < 0.01). AES III displayed increased multi-antibiotic resistance compared with other strains (P < 0.001). Clonal strains of P. aeruginosa may arise even in isolated CF populations. The increased exacerbation rate in patients infected with AES III and its antibiotic resistance profile strongly suggest increased virulence.
Publisher: Wiley
Date: 27-12-2009
DOI: 10.1111/J.1440-1843.2009.01649.X
Abstract: Haemochromatosis (HFE) mutations increase the risk of bowel obstruction in cystic fibrosis (CF), but the impact on other disease manifestations is unknown. We determined the prevalence of HFE mutations (C282Y and H63D) in the Tasmanian CF population and assessed the relationship to systemic iron stores, Pseudomonas aeruginosa infection, lung disease severity and prevalence of diabetes. DNA was obtained from 82 in iduals (96% of the entire CF population) 19 (23.2%) were H63D heterozygotes, three (3.7%) were H63D homozygotes and two patients were compound C282Y/H63D (2.4%). Seven (8.5%) patients were heterozygous for the C282Y mutation. Overall, 31 (37.8%) patients carried a HFE mutation. CF patients possessing HFE mutations had significantly better iron stores than non-carriers (P < 0.05). The mean slopes of annual decline in FEV1 and FVC % predicted were significantly steeper in HFE carriers compared with non-carriers (P < 0.01). Patients with HFE mutations were more likely to have had childhood bowel obstruction (RR 2.44, 95% CI: 1.04-5.74, P < 0.05). Diabetes was more common in HFE carriers (RR 2.96, 95% CI: 0.99-8.8, P = 0.05), but this effect attenuated when corrected for age (RR 2.89, 95% CI: 0.91-9.21, P = 0.07). HFE gene mutations modify disease severity in CF, through probable effects on iron homeostasis.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.GENE.2018.10.002
Abstract: Genetic modifiers contribute to variable disease phenotype in cystic fibrosis (CF). We explored the association between mutations in the hemochromatosis (HFE) gene and disease severity in adults with CF. HFE genotyping was performed in 163 adults with CF attending a single centre. Results were correlated with lung disease severity, prevalence of CF-related diabetes (CFRD) and history of meconium ileus (MI) or distal intestinal obstruction syndrome (DIOS). Subjects with the C282Y substitution in the HFE protein (C282Y mutation) had a lower FEV In subjects with CF, the C282Y HFE substitution was associated with worse lung function, and increased rates of CFRD and gastrointestinal complications. The H63D HFE substitution also impacted on disease phenotype, but to a lesser extent. The results support a role for HFE gene mutations as modifiers of CF phenotype.
Publisher: Elsevier BV
Date: 08-1998
Publisher: European Respiratory Society (ERS)
Date: 08-1999
DOI: 10.1034/J.1399-3003.1999.14B31.X
Abstract: Multicentre studies of airway responsiveness (AR) are increasingly important tools in asthma epidemiology. Because comparisons of AR are made between centres it is essential that measurement techniques are accurate and standard. This study investigated the Mefar dosimeter which is currently used in the 35 centre European Community Respiratory Health Survey (ECRHS) with the next phase currently being planned. Significant differences were found in driving pressures and aerosol outputs between the three Mefar dosimeters in the laboratory. A linear relationship was also found between driving pressure and aerosol output (R2=0.96). These differences are important as they may lead to variations between centres of < or =35% in the drug dose delivered in AR measurement, which could potentially diminish the power of in idual study centres to accurately detect national differences in AR. Dosimeter driving pressure and nebulizer output should be standardized in future studies of airway responsiveness. With relatively simple quality control measures in place it is believed that the Mefar dosimeter can produce reliable between-centre longitudinal data with an increase in the accuracy of these important studies.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.JCF.2009.12.003
Abstract: Two recent studies have demonstrated the presence of biologically significant amounts of cyanide within the airways of cystic fibrosis (CF) patients infected with Pseudomonas aeruginosa. Whilst environmental strains of P. aeruginosa are known to synthesise cyanide, there has been a relative lack of investigation into bacterial cyanogenesis from a medical viewpoint, despite the role P. aeruginosa plays in many serious infection settings and especially in CF lung disease. This review discusses the implications of cyanogenesis in the CF airway in terms of bacterial ecology, host immune response, progression of lung disease and potential treatment options.
Publisher: Elsevier BV
Date: 09-2017
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.JHIN.2009.05.021
Abstract: A genotypically indistinguishable strain of Pseudomonas aeruginosa (Australian epidemic strain III: AES III) has previously been found in a proportion of adults with cystic fibrosis (CF) in Tasmania, Australia. The aim of this study was to identify a source of these infections within the major tertiary referral hospital for the State of Tasmania, and to determine if this strain could be isolated from settings other than the CF lung. A total of 120 isolates of P. aeruginosa were collected from clinical and environmental sources within the hospital and from environmental locations in the hospital vicinity. These isolates were genotyped by random lification of polymorphic DNA (RAPD)-polymerase chain reaction (PCR) and antimicrobial susceptibility testing was performed using the Clinical and Laboratory Standards Institute method. Confirmation of similar genotypes identified by RAPD-PCR was performed using pulsed-field gel electrophoresis with restriction enzyme SpeI. AES III was not recovered from any source other than the respiratory secretions of CF patients. P. aeruginosa in the non-CF settings was found to be panmictic, and no cross-infection or acquisition of hospital environment strains by patients was observed.
Publisher: Springer Science and Business Media LLC
Date: 23-05-2012
Publisher: Wiley
Date: 05-2007
Publisher: Wiley
Date: 12-2003
DOI: 10.1111/J.1445-5994.2003.00485.X
Abstract: Bronchodilator reversibility (BDR) and inhaled corticosteroid (ICS) use were assessed for volunteers who responded to an advertisement requesting current or ex-smokers who were experiencing breathlessness to attend for lung function testing. One hundred and fifty-four volunteers responded. Forced expiratory volume (FEV1) was measured before and after 400 microg of salbutamol. Significant BDR was assessed according to guidelines of: (i) the American Thoracic Society (> or =12% plus 200 mL of baseline FEV1 or forced vital capacity), (ii) the British-Thoracic Society (BTS) (> or =15% plus 200 mL of baseline FEV1), (iii) the European Thoracic Society (> or =10% predicted FEV1), and (iv) the most commonly used criteria in Australia and New Zealand (> or =15% of baseline FEV1). One hundred and twenty-three subjects (33 female 40 current smokers median pack years 48 (range 5-144)) were suitable for analysis (i.e. had no history of asthma, demonstrable airflow limitation and a forced expiratory ratio (FER) of <70%). Twenty (16%) patients had an FEV1 within the normal range but FER of <70%, 24 (20%) patients had mild disease (FEV1 60-80% predicted), 31 (24%) patients had moderate disease (FEV1 40-59% predicted), and 48 (39%) patients had severe disease (FEV1 <40% predicted), according to BTS criteria. Significant BDR was evident in: (i) 58 (47%) subjects by American criteria, (ii) 26 (21%) subjects by British criteria, (iii) 19 (15%) subjects by European criteria and (iv) 36 (29%) subjects by Australasian criteria. ICS use was reported by 71 (58%) subjects overall and was weakly, but significantly, related to poorer FEV1 (r = -0.2 P < 0.01), and greater BDR (r = 0.3 P < 0.005). Chronic obstructive pulmonary disease in Australian volunteers with no history of asthma encompasses many in iduals with significant BDR. Interestingly, most volunteers reported ICS use and this was related to poorer spirometry and greater BDR. However, until the underlying immuno-pathology has been determined they cannot be assumed to have "asthma" or even an "asthmatic element".
Publisher: Wiley
Date: 09-2000
DOI: 10.1046/J.1440-1843.2000.00265.X
Abstract: As part of the European Community Respiratory Health Survey (ECRHS) in 1992-1993 we assessed management practices and treatment perceptions among young asthmatic adults in Melbourne, Australia. We conducted a postal questionnaire survey of 4500 randomly selected adults (aged 20-44 years), drawn from three electoral districts, of whom 3200 (71%) subjects responded. A randomly selected s le of 1642 respondents, 'enriched' by a further 433 symptomatic subjects, was invited to complete a second phase respiratory questionnaire. The questionnaire was completed by 757 subjects who underwent laboratory testing. A further 119 subjects who were unable to attend the laboratory completed an identical questionnaire by telephone interview (42% response rate). In the second phase, 16% of subjects reported 'current asthma' (group I) as defined by physician confirmation and a recent attack (within 1 year), 10% had confirmed asthma but reported no recent attack (group II) and 74% did not have asthma (group III). Inhaled corticosteroid use was significantly higher in group I than in group II subjects (45% vs 24%, P<0.01), but only 11% of asthmatic subjects overall reported daily prophylactic use. Regular treatment in any form was considered to be 'bad' by 65% of asthmatic subjects and only 43% took medication as prescribed all of the time. Despite national education c aigns, the majority of young asthmatic adults in Melbourne did not adhere to prescribed treatment, but continued to rely upon beta2-agonists alone with neglect of regular inhaled corticosteroid which has probably contributed to Australia's continued high asthma morbidity and mortality rates.
Publisher: Wiley
Date: 09-2015
DOI: 10.1111/IMJ.12816
Abstract: To determine predictors of short- and long-term outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) (AECOPD) presenting to hospital. A prospective clinical audit of AECOPD attendances to the only public acute general hospital in Southern Tasmania, Australia. Out of 416 attendances with AECOPD to the emergency department (ED) between November 2006 and July 2008, 150 patients with 218 attendances were followed to March 2009. Predictors of hospital admission from ED, in-hospital death, length of hospital stay, post-discharge mortality and re-attendance rate for AECOPD were the main outcomes. There were no clear differences between patients admitted to hospital and those sent home from ED. Predictors of in-hospital death were initial physiologic parameters, that is, arterial pH, PaCO2 , oxygen saturation and blood pressure. Longer hospital stay was associated with older age, current smoking, hyperglycaemia, lower blood pressure and lower oxygen saturation. Risk of mortality after discharge was associated with a history of myocardial infarction, nursing home residence and severity of COPD. Re-attendance rate was associated with osteoporosis, younger age and severity of COPD. Further investigation into the process of decision making about which AECOPD patients are admitted from the ED is required. Short-term outcomes, in-hospital death and length of hospital stay are mainly predicted by severity of the acute exacerbation and patient demographics. Although severity of COPD was a predictor of long-term outcomes, the main predictors of these were presence of co-morbidities.
Publisher: Elsevier BV
Date: 2002
Abstract: Iron deficiency (ID) is common in patients with cystic fibrosis (CF) and may be related to GI factors and chronic inflammation. Pseudomonas aeruginosa (PA) infection is predominantly responsible for chronic lung suppuration in patients with CF, but its survival is critically dependent on the availability of extracellular iron, which it obtains via highly efficient mechanisms. To determine whether ID in CF patients is directly related to the severity of suppurative lung disease. We determined the iron status of 30 randomly selected adult CF patients (13 women) and assessed the relationship to lung disease severity and GI factors by determining their daily sputum volume, FEV(1) percent predicted, C-reactive protein (CRP) level, erythrocyte sedimentation rate, and degree of pancreatic supplementation. Additionally, we measured the sputum concentrations of iron and ferritin in a randomly selected subgroup of 13 of the 30 subjects. Adult CF Service in a tertiary-care center. Seventy-four percent of subjects experienced ID (ie, serum iron levels < or = 12 micromol/L and/or transferrin saturation levels < or = 16%). There was no relationship found with the degree of pancreatic supplementation. The daily sputum volume was strongly associated with low serum iron levels, transferrin saturation, ferritin/CRP ratio, and FEV(1) percent predicted (p < 0.05). Serum iron levels and transferrin saturation were negatively related to CRP (r = -0.8 and r = -0.7, respectively p < 0.01) and erythrocyte sedimentation rate (r = -0.5 and r = -0.4, respectively p < 0.05). FEV(1) percent predicted was positively related to serum iron level (r = 0.5 p < 0.01), transferrin saturation (r = 0.4 p < 0.05), and ferritin/CRP ratio (r = 0.7 p < 0.05). Sputum iron concentration (median, 63 micromol/L range, 17 to 134 micromol/L) and ferritin concentration (median, 5,038 microg/L range, 894 to 6,982 microg/L) exceeded plasma levels and negatively correlated with FEV(1) percent predicted (r = -0.6 and r = -0.5, respectively p < or = 0.05). In our CF patients, ID was directly related to the increased severity of suppurative lung disease but not to the degree of pancreatic insufficiency. Iron loss into the airway may contribute to ID and may facilitate PA infection.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
Publisher: Elsevier BV
Date: 2011
Publisher: Cold Spring Harbor Laboratory
Date: 25-10-2023
Publisher: Microbiology Society
Date: 08-2010
Abstract: The virulence factor genotypes of a large cohort of clinical, nosocomial environment and community environment isolates (184 in total) of Pseudomonas aeruginosa from Tasmania, Australia, were determined by PCR. The virulence factor genotype of the majority of isolates was highly conserved, with the exception of the virulence gene exoU , which demonstrated low prevalence (33 isolates 18 %) in the population tested. Isolates collected from the environment of intensive therapy wards (intensive care unit and neurosurgical units) of the major tertiary referral hospital in Tasmania were found to be more likely ( P .001 and P .05, respectively) to possess the virulence factor gene exoU than all other isolates. Adult cystic fibrosis isolates showed a decreased prevalence of the exoU gene ( P .01) when compared to other clinical isolates ( P .01), which may indicate decreased virulence. No specific virulence factor genotype was associated with the cystic fibrosis epidemic strains tested.
Publisher: Wiley
Date: 05-2009
Publisher: Informa UK Limited
Date: 05-2014
DOI: 10.2147/COPD.S63911
Publisher: AMPCo
Date: 10-2011
DOI: 10.5694/MJA10.11229
Abstract: To assess mortality trends among people with cystic fibrosis (CF) in Australia. We augmented Australian summary data for deaths from CF registered during 1979-2005 with information from Australian transplant centres on lung transplantation among CF patients for 1989-2005 to allow us to follow trends in all "mortality events" (death or lung transplantation). Age at death or lung transplantation. Between 1979 and 2005, the mean age at death increased from 12.2 years to 27.9 years for males and from 14.8 years to 25.3 years for females. Overall, female deaths in childhood (0-14 years) occurred at an age-standardised rate of 0.40 per 100,000 (95% CI, 0.34-0.45) during 1979-2005, which exceeded the corresponding rate for males of 0.24 (95% CI, 0.20-0.28) per 100,000. Among 0-14-year-old boys, event rates declined markedly after 1989, but they declined later and more gradually for girls, with the result that the age-standardised rate for girls was 2.38 times that of boys during 1989-2005 (95% CI, 1.69-3.36). The pattern of CF mortality in Australia has changed substantially. Mortality rates continue to be higher for girls than for boys, but death in childhood has become uncommon. Survival has increased since 1979, but females continue to have reduced length of life.
Publisher: Informa UK Limited
Date: 27-01-2019
Publisher: Wiley
Date: 04-11-2003
DOI: 10.1046/J.1440-1843.2003.00495.X
Abstract: Exhaled nitric oxide (eNO) has been used as a surrogate of airway inflammation in mild asthma. However, whether eNO levels reflect disease activity in symptomatic asthmatics receiving moderate doses of inhaled corticosteroid (ICS) is more uncertain. To examine the relationship between eNO levels, sputum and blood eosinophils (SpE and PbE), PD(20) methacholine as a marker of airway hyperresponsiveness (AHR) and clinical status in 28 ICS-treated asthmatic subjects with persistent asthma compared to that in 25 symptomatic asthmatics managed with beta2-agonists alone. As expected, eNO levels were normalized in ICS-treated subjects and significantly elevated in the beta2-agonist only group (P < 0.001). SpE, PbE and PD20M did not differ between asthmatic groups but FEV1 was significantly worse in ICS-treated subjects (P < 0.01). Exhaled NO levels correlated with PbE within both asthmatic groups (P < 0.005), but with SpE only in ICS-untreated subjects (r(s) = 0.6, P < 0.05). In contrast, PD20M was negatively correlated with eNO and PbE in ICS-treated subjects only (r(s) = - 0.4, r(s) = - 0.4, respectively, P < 0.05). SpE and PbE were strongly correlated in both asthmatic groups (r(s) = 0.8, r(s) = 0.7, respectively, P < 0.005). Exhaled NO levels, SpE and PbE were all positively associated with increased nocturnal awakenings ( P < 0.05) in ICS-treated subjects, but not in ICS-untreated subjects. In ICS-treated asthma, eNO reflects clinical activity, PbE and AHR but not eosinophilic airway inflammation. Exhaled NO levels are quantitatively and relationally different in asthmatic subjects treated with ICS and continue to have potential for use as a surrogate of asthma pathophysiology in this group.
Publisher: Wiley
Date: 09-2008
DOI: 10.1111/J.1440-1843.2008.01380.X
Abstract: Bronchodilator reversibility (BDR) is common in smoking-related COPD, but the airway pathology underlying this has not been described. In particular, it is not known whether BDR is associated with underlying airway eosinophilia and whether BDR is predictive of a better response to inhaled corticosteroid (ICS) treatment. A double-blind, placebo-controlled, randomized 2:1 study of fluticasone propionate (FP), 500 microg twice daily versus placebo over 6 months was performed in subjects with mild to moderate COPD. Subjects with a clinical history of asthma were excluded, but not on BDR criteria alone. Induced sputum, BAL and endobronchial biopsies (EBB) were performed in 36 subjects at baseline, and 30 of these provided a second full set of s les (FP, n = 19 placebo, n = 11). Baseline BDR was not related to airway eosinophilia and did not predict response to ICS. Post-bronchodilator FEV(1) increased in the FP group compared with the placebo group (P = 0.05), and there were within-treatment group reductions in total symptom scores with FP (P < 0.05). Compared with placebo, FP reduced macrophage numbers but increased neutrophil numbers in EBB (P = 0.01 and P = 0.003, respectively). BAL neutrophil and epithelial cell numbers were also reduced with FP (P = 0.03 for both). There were within-treatment group reductions in the numbers of EBB mast cells and CD8+ve lymphocytes with FP (P = 0.007). BDR was not related to any particular inflammatory phenotype or any clinical or anti-inflammatory response to ICS in these subjects with mild to moderate COPD.
Publisher: Elsevier BV
Date: 05-2013
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2009
End Date: 2011
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2005
End Date: 2007
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: National Health and Medical Research Council
View Funded Activity