ORCID Profile
0000-0001-6150-6927
Current Organisations
NUIG
,
Monash University
,
The Alfred Hospital
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Publisher: Wiley
Date: 17-09-2021
DOI: 10.1002/PPUL.25667
Abstract: Exercise testing is important in people with cystic fibrosis (pwCF). The aim was to develop an incremental maximal step test to assess exercise capacity across the range of pwCF, without floor or ceiling effects, within restrictions of space, and infection prevention. The step test was developed in adults with stable CF. Subjects assisted in selecting: step height, start rate, increments, stage and test duration parameters. Equipment to externally pace and time the test and measure exercise parameters were selected. Reasons for stopping, criteria for achieving a maximal test, and key outcome measures were determined. Documentation to record and standardize the test and instructions to set up the metronome and timer App were developed. Infection control practices were considered. Eight subjects were recruited to develop the Alfred Step Test Exercise Protocol (A‐STEP) on a 20 cm portable step. The A‐STEP package included a pretest information sheet, clinical assessment and instructions, recording worksheet, and the metronome/timer instructions. The test started at 18 steps/min. Each level increased by two steps/min to a maximum of 48 steps (Level 16). Results were presented as mean ( SD ) [range] for: age 30.63 (5.89) [21–39] years FEV 1 58.13 (18.33) [32–89]% levels: 10.31 (3.29) [6–15.5]. The A‐STEP required space of 2 m 2 and complied with current infection control guidelines. The A‐STEP is a new incremental maximal step test to assess exercise capacity in pwCF, without floor or ceiling effects. It addresses the issues of space restrictions and the need for strict infection prevention in the clinical setting.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.JCF.2017.08.002
Abstract: G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4month double-blind, placebo-controlled, crossover study of ivacaftor with 28days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene licon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing. No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P=0.95, square root ECV=-4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time (P<0.0001, Mann Whitney U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P=0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered (P=0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor (P=0.004, two-tailed paired Student's t-test). The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.
Publisher: Wiley
Date: 13-04-2022
DOI: 10.1002/RCR2.942
Abstract: Acute carbon monoxide (CO) poisoning is known to cause neurological, metabolic and cardiorespiratory sequalae. However, data on chronic CO exposure are scant, particularly in the context of vaping, which recent literature suggests may be a greater source of CO than tobacco cigarette smoking. During a series of admissions at the time of vaping, our patient repeatedly presented with significant CO poisoning and developed pulmonary arterial hypertension with resultant high‐output right heart failure. On each occasion, our patient's levels of carboxyhaemoglobin were both higher and took longer to resolve than 12 smokers who underwent arterial blood gas testing at two time points. Our observation may reveal an association between vaping, chronic carboxyhaemoglobinemia and the development of cardiorespiratory disease. Thus, further studies into the safety of vaping and chronic CO exposure are urged.
Publisher: European Respiratory Society (ERS)
Date: 11-2021
Publisher: Massachusetts Medical Society
Date: 25-10-2018
Publisher: Springer Science and Business Media LLC
Date: 20-09-2007
Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a progressive diffuse disease involving the lung parenchyma. Despite recent advances, the molecular mechanisms of the initiation and progression of this disease remain elusive. Previous studies have demonstrated TGFβ1 as a key effector cytokine in the development of lung fibrosis. In this study we have used a transgenic mouse based strategy to identify the effect of overexpression of this key effector mediator on the development of pulmonary fibrosis in response to exogenous injury. We bred two lines (line 25 and 18) of transgenic mice (Tr+) that overexpressed active TGFβ1. Three-month old transgenic and wild type mice were subsequently wounded with intraperitoneal bleomycin. Mice were sacrificed at 6 weeks post-bleomycin and their lungs analysed histologically and biochemically. The severity of lung fibrosis was significantly greater in the Tr+ mice compared to the wild type mice. Using an oligonucleotide microarray based strategy we identified discrete patterns of gene expression contributing to TGFβ1 associated pulmonary fibrosis. This data emphasises the importance of a host predisposition in the form of endogenous TGFβ1, in the development of pulmonary fibrosis in response to an exogenous injury.
Publisher: BMJ
Date: 08-2019
DOI: 10.1136/BMJRESP-2019-000456
Abstract: Acute neurological events may present as an extrapulmonary complication in patients with cystic fibrosis (CF). These events can be secondary to a range of different aetiologies. A retrospective analysis of 476 medical records of CF patients attending a large teaching hospital between 2000 and 2018 was performed. Patients presenting with acute neurological events who had MRI brain imaging were evaluated. Patients who had headaches without associated neurological symptoms were excluded from this analysis. Acute neurological presentations, excluding headaches without associated neurological symptoms, were reported in 27 index patients out of the 476 patients. Of these, 16 patients had MRI brain imaging for review. Three patients suffered pathology secondary to vascular events, both ischaemic and haemorrhagic four patients had evidence of ischaemia or infarction not consistent with a vascular territory stroke and the remaining patients experienced a range of different neurological events. The most common presentation among these patients was seizure activity, followed by a transient motor or sensory deficit. Neurological complications are recognised among in iduals with CF. Although rare, they can be secondary to a range of different aetiologies, including dysfunctional cell energetics. Additional studies are required to further evaluate this association.
Publisher: European Respiratory Society (ERS)
Date: 07-2021
DOI: 10.1183/23120541.00120-2021
Abstract: Quality of life has improved dramatically over the past two decades in people with cystic fibrosis (CF). Quantification has been enabled by patient-reported outcome measures (PROMs) however, many are lengthy and can be challenging to use in routine clinical practice. We propose a short-form PROM that correlates well with established quality-of-life measures. We evaluated the utility of a 10-item score (AWESCORE) by measuring reliability, validity and responsiveness in adults with CF. The questions were developed by thematic analysis of survey questions to patients in a single adult CF centre. Each question was scored using a numerical rating scale 0 to 10. Total scores ranged from 0 to 100. Test–retest reliability was assessed over 24 h. To determine validity, comparisons were sought between stable subjects and those in pulmonary exacerbation, and between AWESCORE and Cystic Fibrosis Questionnaire – Revised (CFQ-R). Responsiveness to pulmonary exacerbation in in idual subjects was evaluated. Five domains, each with two questions, were identified for respiratory, physical, nutritional, psychological and general health. A total of 246 consecutive adults attending the outpatient clinic completed the AWESCORE. Scores were higher during clinical stability compared to pulmonary exacerbation (mean± sd): 73±11 versus 48±11 (p .001). Each domain scored worse during an acute exacerbation (p .001). No differences in reliability were observed in scores on retesting using Bland–Altman comparison. The CFQ-R scores (mean± sd : 813±125) and AWESCORE (81±13) were moderately correlated (Pearson's r=0.649 p=0.002). The AWESCORE is valid, reliable and responsive to altered health status in CF.
Publisher: Informa UK Limited
Date: 2008
DOI: 10.1080/01902140802093162
Abstract: The quality of tissue studied impacts greatly on oligonucleotide microarray results, emphasizing the importance of harvesting techniques. The analyzed RNA extracted from human lung s les preserved via 4 different storage conditions (RNAlater, phosphate-buffered saline, TRIzol, liquid nitrogen). RNA was assessed by denaturing gel electrophoresis, Agilent bioanalysis, real-time polymerase chain reaction (PCR), and Test3 Affymetrix chip hybridization. Results revealed better quality RNA from RNAlater s les on gel electrophoresis and bioanalysis. RNAlater s les also showed greater yield (r18s via PCR P < .05) and resulted in better Test3 chips hybridization (p < .05), suggesting RNAlater was superior at preserving lung tissue nucleic acid.
Publisher: Springer Science and Business Media LLC
Date: 12-02-2007
Abstract: Osteoporosis, a disease of decreased bone mineral density represents a significant and growing burden in the western world. Aging population structure and therapeutic use of glucocorticoids have contributed in no small way to the increase in the incidence of this disease. Despite substantial investigative efforts over the last number of years the exact molecular mechanism underpinning the initiation and progression of osteoporosis remain to be elucidated. This has meant that no significant advances in therapeutic strategies have emerged, with joint replacement surgery being the mainstay of treatment. In this study we have used an integrated genomics profiling and computational biology based strategy to identify the key osteoblast genes and gene clusters whose expression is altered in response to dexamethasone exposure. Primary human osteoblasts were exposed to dexamethasone in vitro and microarray based transcriptome profiling completed. These studies identified approximately 500 osteoblast genes whose expression was altered. Functional characterization of the transcriptome identified developmental networks as being reactivated with 106 development associated genes found to be differentially regulated. Pathway reconstruction revealed coordinate alteration of members of the WNT signaling pathway, including frizzled-2, frizzled-7, DKK1 and WNT5B, whose differential expression in this setting was confirmed by real time PCR. The WNT pathway is a key regulator of skeletogenesis as well as differentiation of bone cells. Reactivation of this pathway may lead to altered osteoblast activity resulting in decreased bone mineral density, the pathological hallmark of osteoporosis. The data herein lend weight to the hypothesis that alterations in developmental pathways drive the initiation and progression of osteoporosis.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.HLC.2017.08.018
Abstract: Epidemiology and treatment strategies continue to evolve in pulmonary arterial hypertension (PAH). We sought to define the characteristics and survival of patients with idiopathic, heritable and drug-induced PAH in the current management era. Consecutive cases of idiopathic, heritable and drug-induced PAH were prospectively enrolled into an Australian and New Zealand Registry. Between January 2012 and December 2016, a total of 220 incident cases were enrolled (mean age 57.2±18.7years, female 69.5%) and followed for a median duration of 26 months (IQR17-39). Co-morbidities were common such as obesity (34.1%), systemic hypertension (30.5%), coronary artery disease (16.4%) and diabetes mellitus (19.5%). Initial combination therapy was used in 54 patients (dual, n=50 triple, n=4). Estimated survival rates at 1-year, 2-years and 3-years were 95.6% (CI 92.8-98.5%), 87.3% (CI 82.5-92.4%) and 77.0% (CI 70.3-84.3%), respectively. Multivariate analysis showed that male sex and lower 6-minute distance at diagnosis independently predicted worse survival, whereas obesity was associated with improved survival. Co-morbidities other than obesity did not impact survival. Initial dual oral combination therapy was associated with a trend towards better survival compared with initial oral monotherapy (adjusted HR=0.27, CI 0.06-1.18, p=0.082) CONCLUSIONS: The epidemiology and survival of patients with idiopathic PAH in Australia and New Zealand are similar to contemporary registries reported in Europe and North America. Male sex and poorer exercise capacity are predictive of mortality whereas obesity appears to exert a protective effect. Despite current therapies, PAH remains a life-threatening disease associated with significant early mortality.
Publisher: Wiley
Date: 09-2013
DOI: 10.1086/674308
Publisher: Wiley
Date: 02-2008
Publisher: Elsevier BV
Date: 05-2021
DOI: 10.1016/J.JCF.2020.12.006
Abstract: The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied. We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Wiley
Date: 05-10-2021
DOI: 10.1111/RESP.14162
Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious condition occurring in 2%–4% of patients after acute pulmonary embolism. Pulmonary endarterectomy (PEA) is a potential cure for technically operable disease. The epidemiology and long‐term outcomes of CTEPH have not been previously described in Australia and New Zealand. Data were extracted from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry for patients diagnosed with CTEPH between January 2004 and March 2020. Baseline characteristics, treatment strategies, outcome data and long‐term survival are reported. A total of 386 patients were included with 146 (37.8%) undergoing PEA and 240 (62.2%) in the non‐PEA group. PEA patients were younger (55 ± 16 vs. 62 ± 16 years, p 0.001) with higher baseline 6‐min walk distance (6MWD 405 ± 122 vs. 323 ± 146 m, p = 0.021), whilst both groups had similar baseline pulmonary haemodynamics. Pulmonary hypertension‐specific therapy was used in 54% of patients post‐PEA and 88% in the non‐PEA group. The 1‐, 3‐ and 5‐year survival rates were 93%, 87% and 84% for the PEA group compared to 86%, 73% and 62%, respectively, for the non‐PEA group ( p 0.001). Multivariate survival analysis showed baseline 6MWD was an independent predictor of survival in both operated and medically managed patients. In this first multicentre report of CTEPH in Australia and New Zealand, long‐term survival is comparable to that in other contemporary CTEPH registries. However, PEA was only performed in a minority of CTEPH patients (37.8%) and significantly less than overseas reports. Greater awareness of PEA and improved patient access to experienced CTEPH centres are important priorities.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2010
Publisher: Wiley
Date: 06-2014
DOI: 10.1086/676663
Publisher: Elsevier BV
Date: 08-2005
Abstract: Although most patients wish to be fully informed about bad news such as a diagnosis of cancer, a significant minority prefer no or minimal information. We examined the value of asking patients about their disclosure preferences at the outset of hospitalization. Consecutive patients admitted to a respiratory and a geriatric unit were asked whether and how they would wish to be told of cancer or Alzheimer disease. Of the 207 patients interviewed, 174 (84%) wanted to be told about cancer or dementia the proportion who would wish to be told did not differ between older patients (89 of 108 patients 82%) and younger patients (85 of 99 patients 86% p = 0.34). Thirty patients (15%) sought reassurance during or after the interview, and 13 patients (6%) reported that they had been bothered by the questions. Of the 207 patients, cancer or dementia was diagnosed in 23 patients (11%). Preferences for disclosure or nondisclosure were honored for 20 patients (87%). Seeking preferences regarding truth disclosure at the outset of hospitalization is helpful and feasible in everyday practice, and the results can be used by clinicians to improve communication with patients and families in accordance with patients' own wishes.
Publisher: AMPCo
Date: 08-2008
DOI: 10.5694/J.1326-5377.2008.TB01957.X
Abstract: Two children with advanced lung disease underwent successful cadaveric bilateral lobar lung transplantation, using lungs "cut down" from deceased adult donors - the first reported use of the technique in Australia. This approach, while it cannot address the lack of donor organs, may enable us to redress any size bias limiting paediatric lung transplantation.
Publisher: SAGE Publications
Date: 2018
Abstract: Over 2000 genotypes in the cystic fibrosis (CF) gene have been described. These genotypic differences result in variable clinical manifestations of CF, with severity of disease dependent on CF transmembrane conductance (CFTR) protein function. CFTR is widely distributed in nucleated cells, including cardiac myocytes, but the effect of genotype on cardiac function is not known. This retrospective review of echocardiographic data is from a single adult CF centre between 2000 and 2015. Patients were cohorted based on the functional classification of genotype. ‘Severe’ patients had both CF genes from functional classification groups 1-3 ‘mild’ patients had one or no gene from these groups, or in the event of the second gene being unknown were pancreatic sufficient. Genotype and echocardiography were recorded during the inclusion period in 100 patients, 79 of whom were classified as having severe genotypes. Although the severe group were younger they had a lower fractional shortening (33.66 ± 6.6 vs 36.9 ± 6.3, P .05), left atrial area (14.9 ± 3.6 versus 18.0 ± 4.2 cm 2 P .01) and volume (39.9 ± 18.7 versus 51.0 ± 18.7 mL P .05) and showed a trend to lower left ventricular ejection fraction. This study is the first to show that in CF, severity of genotype (functional classification) is associated with cardiac impairment. Patients with severe CF genotype and cardiac dysfunction should be identified to evaluate cardiac response to gene-modifying treatments prior to consideration for lung transplantation.
Publisher: Wiley
Date: 07-2022
DOI: 10.1111/IMJ.15836
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.RMED.2022.106784
Abstract: In many patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH), bronchial artery hypertrophy is observed. Patients with bronchial dilatation have been shown to be at increased risk of hemoptysis introducing the risk of airway obstruction. In this study from an academic tertiary referral center, we aimed to assess the incidence of massive hemoptysis in our CTEPH patients, the success of bronchial artery embolization (BAE), recurrence, and hemoptysis-related mortality. Retrospective cohort study of all adults with CTEPH who underwent BAE for massive hemoptysis between 1 January 2015 and 30 July 2021. Primary endpoints were hemoptysis relapse and hemoptysis-related mortality. There were 367 patients who were being treated and managed with a diagnosis of CTEPH at our institution. There were 24 bronchial artery embolization procedures performed for all causes. A total of 3 patients during this time met inclusion criteria with acute massive hemoptysis and CTEPH. All patients were taking therapeutic-dose anticoagulation. Technical success after BAE was 100%. No hemoptysis recurrence was demonstrated at 17, 24, and 40-months follow-up respectively. No patient died from hemoptysis. However, 1 patient died 24 months after the embolization procedure due to a non-hemoptysis cause. This study highlights the low but important incidence of massive hemoptysis in patients with CTEPH. Unlike other causes of hemoptysis, this unique cohort requires balancing anticoagulation and hemorrhage control. Given the high degree of success, BAE is a viable option, allowing continuation or early re-establishment of anticoagulation.
Publisher: Wiley
Date: 18-07-2022
DOI: 10.1002/PPUL.26069
Abstract: To evaluate feasibility of the Alfred Step Test Exercise Protocol (A‐STEP) for the assessment of exercise capacity in adults and children with cystic fibrosis (CF) in adults to test whether demographics and/or lung function correlated with exercise capacity. Adults and children with stable CF from two centres completed the A‐STEP (a recently developed incremental maximal‐effort step test). Feasibility was evaluated by: usefulness for exercise capacity assessment (measures of exercise capacity were: level reached, exercise‐induced desaturation, and achievement of at least one maximal effort criteria) safety operational factors time to complete floor and/or ceiling effects. We used multiple linear regression to test whether demographics and/or lung function correlated with exercise capacity. A total of 49 participants: 38 adults (18 male), percent predicted (pp) forced expiration in one second (FEV 1 ) 29–109, aged 22–48 years and 11 children (6 male), ppFEV 1 68–107, aged 10–15 years were included. Levels reached (mean ( SD ) [range]) were 10.2 (2.4) [6–15] (adults), 10.1 (2.5) [7–14] (children) desaturation (change between baseline and peak‐exercise SpO 2 ): was 8.4 (3.8 [0–15]% (adults), 2.0 (2.0) [0–7]% (children). A total of 8 (21%) adults and no children desaturated % SpO 2 . At least one criterion for maximal effort was reached by 33 (84%) adults and 10 (91%) children. There were no adverse events. The A‐STEP was straightforward to use and carried out by one operator. A total of 26 (68.4%) adults and 7 (63.6%) children completed the test within the recommended 8–12 min. All participants completed a minimum of 6 levels, and completed the test before the final 16th level. In adults, ppFEV 1 and ppFVC correlated with the level reached ( r = 0.55 p = .001 and r = 0.66, p = .0001) and desaturation ( r = 0.55, p = .001 and r = 0.45, p = .005). In adults and children with stable CF, the A‐STEP was feasible, safe, and operationally easy to use for the assessment of exercise capacity, without floor or ceiling effects. In adults, lung function correlated with exercise capacity.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.CHEST.2019.08.2203
Abstract: Pulmonary arterial hypertension (PAH) prognosis has improved with targeted therapies however, the long-term outlook remains poor. Objective multiparametric risk assessment is recommended to identify patients at risk of early morbidity and mortality, and for optimization of treatment. The US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk score is a new model proposed for the follow-up of patients with PAH but has not been externally validated. The REVEAL 2.0 risk score was applied to a mixed prevalent and incident cohort of patients with PAH (n = 1,011) from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) Registry. Kaplan-Meier survival was estimated for each REVEAL 2.0 risk score strata and for a simplified three-category (low, intermediate, and high risk) model. Sensitivity analysis was performed on an incident-only cohort. The REVEAL 2.0 model effectively discriminated risk in the large external PHSANZ Registry cohort, with a C statistic of 0.74 (both for full eight-tier and three-category models). When applied to incident cases only, the C statistic was 0.73. The three-category REVEAL 2.0 model demonstrated robust separation of 12- and 60-month survival estimates (all risk category comparisons P < .001). Although the full eight-tier REVEAL 2.0 model separated patients at low, intermediate, and high risk, survival estimates overlapped within some of the intermediate- and high-risk strata. The REVEAL 2.0 risk score was validated in a large external cohort from the PHSANZ Registry. The REVEAL 2.0 model can be applied for risk assessment of patients with PAH at follow-up. The simplified three-category model may be preferred for clinical use and for future comparison with other prognostic models.
Publisher: Wiley
Date: 30-01-2020
DOI: 10.1111/RESP.13768
Abstract: Early diagnosis of PAH is clinically challenging. Patterns of diagnostic delay in Australian and New Zealand PAH populations have not been explored in large-scale studies. We aimed to evaluate the magnitude, risk factors and survival impact of diagnostic delay in Australian and New Zealand PAH patients. A cohort study of PAH patients from the PHSANZ Registry diagnosed from 2004 to 2017 was performed. Diagnostic interval was the time from symptom onset to diagnostic right heart catheterization as recorded in the registry. Factors associated with diagnostic delay were analysed in a multivariate logistic regression model. Survival rates were compared across patients based on the time to diagnosis using Kaplan-Meier method and Cox regression. A total of 2044 patients were included in analysis. At diagnosis, median age was 58 years (IQR: 43-69), female-to-male ratio was 2.8:1 and majority of patients were in NYHA FC III-IV (82%). Median diagnostic interval was 1.2 years (IQR: 0.6-2.7). Age, CHD-PAH, obstructive sleep apnoea and peripheral vascular disease were independently associated with diagnostic interval of ≥1 year. No improvement in diagnostic interval was seen during the study period. Longer diagnostic interval was associated with decreased 5-year survival. PAH patients experience significant diagnostic interval, which has not improved despite increased community awareness. Age, cardiovascular and respiratory comorbidities are significantly associated with longer time to diagnosis. Mortality rates appear higher in patients who experience longer diagnostic interval.
Publisher: European Respiratory Society (ERS)
Date: 27-04-2020
DOI: 10.1183/13993003.01654-2019
Abstract: Pulmonary vascular resistance (PVR) Wood units is a criterion of the haemodynamic definition of pulmonary arterial hypertension (PAH). However, this cut-off is conservative and arbitrarily defined. Data is lacking on the natural history, response to therapy and survival of patients diagnosed with precapillary pulmonary hypertension (PH) with mild or borderline elevation of PVR. In Australia, PAH therapy could be prescribed solely on mean pulmonary arterial pressure (PAP) and pulmonary arterial wedge pressure (PAWP) criteria. Using the Australian and New Zealand Pulmonary Hypertension Registry, we aimed to study a population diagnosed with PAH between January 2004 and December 2017 with the pre-defined haemodynamic characteristics of mean PAP ≥25 mmHg, PAWP ≤15 mmHg and PVR Wood units. Eighty-two patients met the pre-defined haemodynamic inclusion criteria (mean age 63±11 years 67 females). Underlying aetiologies included idiopathic disease (n=39), connective tissue disease (CTD n=42) and HIV infection (n=1). At diagnosis, mean PAP was 27 mmHg (interquartile range (IQR) 25–30 mmHg), PAWP 13 mmHg (IQR 11–14 mmHg) and PVR 2.2 Wood units (IQR 1.9–2.7 Wood units). Baseline 6-min walk distance (6MWD) was 352 m (IQR 280–416 m) and 77% of subjects were in New York Heart Association (NYHA) functional class 3 or 4. All patients were commenced on initial monotherapy with an endothelin receptor antagonist (ERA n=66) or phosphodiesterase type-5 inhibitor (PDE5i n=16). At first re-evaluation, 6MWD increased by 46 m (IQR 7–96 m) and 35% of subjects demonstrated improvement in NYHA functional class. After a median follow-up of 65 months (IQR 32–101 months), 18 out of 82 subjects (22.0%) had died, with estimated 1-year and 5-year survival rates of 98% and 84%, respectively. Death attributed to PAH occurred in six out of these 18 patients (33.3%, 7% of total cohort). Patients with precapillary PH and “borderline” PVR falling outside the current definition have adverse outcomes. Such patients appear to respond to PAH therapy however, this requires further study in randomised trials.
Publisher: European Respiratory Society (ERS)
Date: 2023
Publisher: European Respiratory Society (ERS)
Date: 05-03-2020
DOI: 10.1183/13993003.02443-2019
Abstract: Cystic fibrosis (CF) is a common multi-system genetically inherited condition, predominately found in in iduals of Caucasian decent. Since the identification of the cystic fibrosis (CF) transmembrane conductance regulator ( CFTR ) gene in 1989, and the subsequent improvement in understanding of CF pathophysiology, significant increases in life-expectancy have followed. Initially this was related to improvements in the management and systems of care for treating the various affected organ systems. These cornerstone treatments are still essential for CF patients born today. However, over the last decade, the major advance has been in therapies that target the resultant genetic defect: the dysfunctional CFTR protein. Small molecule agents that target this dysfunctional protein via a variety of mechanisms have led to lung function improvements, reductions in pulmonary exacerbation rates and increases in weight and quality-of-life indices. As more patients receive these agents earlier and earlier in life, it is likely that general CF care will increasingly pivot around these specific therapies, although it is also likely that effects other than those identified in the initial trials will be discovered and need to be managed. Despite great excitement for modulator therapies, they are unlikely to be suitable or available for all whether this is due to a lack of availability for specific CFTR mutations, drug-reactions or the health economic set-up in certain countries. Nevertheless, the CF community must be applauded for its ongoing focus on research and development for this life-limiting disease. With time, personalised in idualised therapy would ideally be the mainstay of CF care.
Publisher: European Respiratory Society (ERS)
Date: 26-11-2020
DOI: 10.1183/23120541.00203-2020
Abstract: Lumacaftor/ivacaftor (LUM/IVA) has been shown to improve clinical outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with forced expiratory volume in 1 s (FEV 1 ) % pred %. We assessed the clinical utility of LUM/IVA in all eligible adult CF patients with FEV 1 % pred % treated for at least 1 year under a single-centre managed access programme. Following clinical optimisation, eligible patients (n=40) with FEV 1 % pred % were commenced on LUM/IVA and monitored for tolerance and clinical outcomes, including health service utilisation, pulmonary function, weight and body composition. 24 patients reached 1 year of treatment by the time of evaluation. Six patients discontinued due to adverse events (five for increased airways reactivity) and three underwent lung transplantation. In comparison with the year prior to LUM/IVA commencement, significant reductions (median per year) were observed in the treatment year in the number of pulmonary exacerbations requiring hospitalisation (from 3 to 1.5 p=0.0002), hospitalisation days (from 27 to 17 p=0.0002) and intravenous antibiotic (IVAB) usage days (from 45 to 27 p=0.0007). Mean± sd change in FEV 1 % pred was −2.10±1.18% per year in the year prior, with the decline reversed in the year following (+1.45±1.13% per year p=0.035), although there was significant heterogeneity in in idual responses. Mean± sd weight gain at 1 year was 2.5±4.1 kg (p=0.0007), comprising mainly fat mass (mean 2.2 kg). The proportion of patients severely underweight (body mass index .5 kg·m −2 ) decreased from 33% at baseline to 13% at 1 year (p=0.003). This real-world evaluation study demonstrated benefits over several clinical domains (infective exacerbations requiring hospitalisation, IVABs, pulmonary function decline and nutritional parameters) in CF patients with severe lung disease.
Publisher: Elsevier BV
Date: 12-2016
Publisher: Wiley
Date: 03-2011
DOI: 10.1111/J.1445-5994.2010.02333.X
Abstract: IVI epoprostenol is the only therapy for pulmonary arterial hypertension (PAH) with a randomized controlled trial demonstrating improved survival, when used as first-line monotherapy. In Australia it is used as salvage therapy for those failing treatment with other targeted therapies or presenting in World Health Organization functional class (FC) IV. Report experience with IVI epoprostenol, administered as salvage therapy for the treatment of adults with PAH in a single Australian PAH centre. Retrospective case series of all patients commenced on IVI epoprostenol for PAH, between 2002 and 2010. Review of case notes with collection of data at baseline and after treatment, including FC, 6-min walk test (6MWT), right ventricular systolic pressure (RVSP) on echocardiogram, patient survival and treatment complications. Change in indices was assessed using the Wilcoxon Sign Rank Test and is expressed as median (inter-quartile range). A total of 23 patients was included. Treatment was generally well tolerated with few major complications. At the end of the study period, nine patients were successfully bridged to transplant, five had a sustained response to IVI epoprostenol, six had an incomplete response but were clinically stabilized, two died awaiting transplant and one died who was not a candidate for transplantation. Overall, when measured at best level post initiation of IVI epoprostenol, there were significant improvements in FC -1 [0 to -1] (P < 0.0001), 6MWT (m) +117 [70-264] (P= 0.002) and RVSP (mmHg) -7.0 [4.0 to -45] (P= 0.03). Findings support efficacy of epoprostenol as salvage therapy for patients with PAH.
Publisher: Massachusetts Medical Society
Date: 26-08-2021
Publisher: Elsevier BV
Date: 10-2020
Publisher: Portland Press Ltd.
Date: 17-07-2017
DOI: 10.1042/CS20170995
Abstract: G551D, a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in CF is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline (%Δ) of VO2max (maximal oxygen consumption, primary outcome) during cardiopulmonary exercise testing (CPET), relevant other CPET physiological variables, lung function, body mass index (BMI), sweat chloride and disease-specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore)). %ΔVO2max was unchanged compared with placebo as was %Δminute ventilation. However, %Δexercise time (mean 7.3, CI 0.5–14,1, P=0.0222) significantly increased as did %ΔFEV1 (11.7%, range 5.3–18.1, P& ·005) and %ΔBMI (1.2%, range 0.1–2.3, P=0·0393) whereas sweat chloride decreased (mean −43.4 range −55.5–18.1 mmol·l−1, P& ·005). Total and activity based domains in both CFQ-R and AWEscore also increased. A positive treatment effect on spirometry, BMI (increased), SCT (decreased) and total and activity based CF-specific QOL measures was expected. However, the lack of discernible improvement in VO2max and VE despite other positive changes including spirometric lung function and exercise time with a 28-day ivacaftor intervention suggests that ventilatory parameters are not the sole driver of change in exercise capacity in this study cohort. Investigation over a more prolonged period may delineate the potential interdependencies of the observed discordances over time. Trial registration number: ClinicalTrials.gov-NCT01937325.
No related grants have been discovered for Dominic Keating.