ORCID Profile
0000-0002-9553-5870
Current Organisations
Prince Charles Hospital
,
Queensland Lung Transplant Service
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Publisher: Wiley
Date: 06-02-2020
DOI: 10.1111/RESP.13774
Publisher: BMJ
Date: 08-2001
Abstract: Nitric oxide (NO) is a product of the enzyme nitric oxide synthase (NOS) and is found in normal and asthmatic human airways. The administration of L-arginine results in an increase in airway NO production in asthmatic subjects. This is thought to occur because L-arginine is the substrate for NOS. However, studies in the systemic vasculature suggest that other mechanisms may be responsible. Eight patients with steroid naive asthma each received 2.5 g L-arginine, 2.5 g D-arginine, and 2.0% saline by ultrasonic nebuliser on separate days in a randomised, single blind manner. Exhaled NO was measured by chemiluminescence and spirometric tests were performed before and for 3 hours after each administration. The mean concentration of NO after exposure was calculated from the area under the curve. L-arginine, D-arginine, and 2.0% saline induced a mean (95% CI) maximal bronchoconstriction of 11.9% (-1.7 to 25.4), 10.0% (2.8 to 17.2), and 8.5% (-2.5 to 19.5) of the starting forced expiratory volume in one second (FEV(1)), respectively. Exhaled NO declined in proportion to the degree of bronchoconstriction (r=0.60, p<0.01). Bronchoconstriction and the acute reduction in exhaled NO resolved within 15 minutes. The mean post-exposure concentration of NO was 15.75 parts per billion (ppb) after L-arginine, 15.16 ppb after D-arginine, and 12.74 ppb after 2.0% saline. The mean (95% CI) difference between L-arginine and placebo was 3.01 (0.32 to 5.7) ppb, between D-arginine and placebo 2.42 (0.10 to 4.74) ppb, and between L- and D-arginine 0.59 (-1.56 to 2.74) ppb. Exhaled NO decreased with acute bronchoconstriction and returned to baseline with the resolution of bronchoconstriction. Exhaled NO increased following the administration of both L-arginine and D-arginine. Since NOS is stereospecific, this finding suggests that the increase in exhaled NO is not entirely mediated through an increase in NOS enzyme activity. We suggest that arginine may react in a non-stereospecific fashion with reactive oxygen species present in asthmatic airways.
Publisher: Elsevier BV
Date: 03-1998
DOI: 10.1016/S0954-6111(98)90281-5
Abstract: von Willebrand factor (vWF) is a large glycoprotein secreted predominantly by endothelial cells in both the systemic and pulmonary circulations and has a central role in the formation of the platelet plug. It has been put forward as a possible marker of endothelial cell injury, but is not ideal in that it is not specific for either the pulmonary or systemic circulation and may be released as part of the acute phase response from otherwise healthy endothelial cells. We undertook two studies (i) to assess within-subject to assess within-subject variation in plasma von Willebrand factor antigen (vWF:Ag) levels over time and to assess between-subject variation in a healthy patient population, and (ii) as part of a descriptive study of acute bronchitis, to assess whether plasma vWF:Ag levels altered in such a common and minor insult. A random s le of patients aged 45-74 years were taken from a local general practice. vWF:Ag levels were measured on three occasions, and spirometry was performed. The descriptive study was undertaken on patients in the general practice diagnosed with acute bronchitis without pre-existing pulmonary disease. Plasma vWF:Ag was measured on presentation and 14 and 42 days later. In 219 randomly selected patients the mean plasma vWF:Ag was similar at all three visits, the within-subject standard deviation being 0.09 U ml(-1) and 1.12 U ml(-1) respectively). There was no correlation between plasma vWF:Ag and C-reactive protein on presentation. We conclude that there is relatively little variation in an in idual's plasma vWF:Ag level but that levels increase significantly with age. The observed elevation occurring with acute bronchitis is a true phenomenon the absence of an associated acute phase response suggests that endothelial cell injury is the mechanism for the rise. These observations are important in the context of vWF as a marker of endothelial cell damage, as a common and supposedly minor insult such as acute bronchitis may markedly raise plasma levels.
Publisher: Wiley
Date: 28-09-2019
DOI: 10.1111/RESP.13412
Abstract: The past four decades have yielded advances in molecular biology allowing detailed characterization of the cellular genome and the transcriptome: the complete set of RNA species transcribed by a cell or tissue. Through transcriptomics and next-generation sequencing, we can now attain an unprecedented level of detail in understanding cellular phenotypes through examining the genes expressed in specific physiological and pathological states. In this review, we provide an overview of transcriptomics and RNA-sequencing in the analysis of whole tissue and single cells. We describe the techniques and pitfalls involved in the isolation and sequencing of single cells, and what additional benefits this application can provide. Finally, we look to how these technologies are being applied in pulmonary research, and how they may translate in the near future into clinical practice.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.HEALUN.2012.10.006
Abstract: Because infection has been associated with the development of bronchiolitis obliterans syndrome (BOS), we hypothesized that post-transplant hypogammaglobulinemia would be associated with infection and BOS. Cross-sectional levels of serum immunoglobulins were measured on 2 occasions in our transplant cohort and models developed to explain serum immunoglobulin levels and BOS-free survival. A total of 139 patients (median age, 46.6 years) were evaluated at 47 months (range, 15-74 months) after transplant, and 87 were re-evaluated at 72 months (40-107 months). Of this cohort, 44% were immunoglobulin (Ig) G deficient and levels remained stable across the study period, and 27% were IgA deficient and levels fell slightly over time (p = 0.003). Both immunoglobulin classes were lower in patients with a history of invasive fungal infection, whereas IgA levels were lower in patients with a history of community-acquired respiratory viral infection. Low IgG was independently associated with shorter BOS-free survival (hazard ratio, 0.79 95% confidence interval, 0.71-0.88 p<0.001). Serum immunoglobulin deficiency is common after lung transplantation and is associated with community-acquired respiratory viral infection, invasive fungal infection, and BOS.
Publisher: Wiley
Date: 07-2008
Publisher: Wiley
Date: 07-02-2019
DOI: 10.1111/RESP.13498
Publisher: BMJ
Date: 12-2020
DOI: 10.1136/BMJOPEN-2020-040798
Abstract: Interstitial lung diseases are characterised by scarring of lung tissue that leads to reduced transfer of oxygen into the blood, decreased exercise capacity and premature death. Ambulatory oxygen therapy may be used to treat exertional oxyhaemoglobin desaturation, but there is little evidence to support its efficacy and there is wide variation in clinical practice. This study aims to compare the clinical efficacy and cost-effectiveness of ambulatory oxygen versus ambulatory air in people with fibrotic interstitial lung disease and exertional desaturation. A randomised, controlled trial with blinding of participants, clinicians and researchers will be conducted at trial sites in Australia and Sweden. Eligible participants will be randomised 1:1 into two groups. Intervention participants will receive ambulatory oxygen therapy using a portable oxygen concentrator (POC) during daily activities and control participants will use an identical POC modified to deliver air. Outcomes will be assessed at baseline, 3 months and 6 months. The primary outcome is change in physical activity measured by number of steps per day using a physical activity monitor (StepWatch). Secondary outcomes are functional capacity (6-minute walk distance), health-related quality of life (St George Respiratory Questionnaire, EQ-5D-5L and King’s Brief Interstitial Lung Disease Questionnaire), breathlessness (Dyspnoea-12), fatigue (Fatigue Severity Scale), anxiety and depression (Hospital Anxiety and Depression Scale), physical activity level (GENEActive), oxygen saturation in daily life, POC usage, and plasma markers of skeletal muscle metabolism, systematic inflammation and oxidative stress. A cost-effectiveness evaluation will also be undertaken. Ethical approval has been granted in Australia by Alfred Hospital Human Research Ethics Committee (HREC/18/Alfred/42) with governance approval at all Australian sites, and in Sweden (Lund Dnr: 2019-02963). The results will be published in peer-reviewed scientific journals, presented at conferences and disseminated to consumers in publications for lay audiences. ClinicalTrials.gov Registry ( NCT03737409 ).
Publisher: American Thoracic Society
Date: 11-2022
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.HEALUN.2006.06.002
Abstract: Scedosporium species (sp) can cause disseminated disease in lung transplant recipients with almost universal mortality. We present 2 cases of disseminated disease, which responded to voriconazole therapy. In the first case, polymerase chain reaction was used to make a rapid diagnosis and allow differentiation from Aspergillus sp. In this patient, Scedosporium sp could be isolated in the urine despite therapy, and direct irrigation of the renal tract with voriconazole was used with apparent efficacy. In the other case, withdrawal of therapy resulted in clinical relapse, suggesting that lifelong therapy is probably required.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 17-02-2022
DOI: 10.1111/RESP.14229
Abstract: An epidemic of silicosis has emerged due to a failure to control risks associated with exposure to high-silica content respirable dust generated while working with artificial stone products. Methods for quantification of alveolar crystal burden are needed to advance our understanding of the pathobiology of silica-related lung injury as well as assisting in the diagnosis, clinical management and prognostication of affected workers. The objective of this study was to develop and validate novel methods to quantify alveolar crystal burden in bronchoalveolar lavage (BAL) fluid from patients with artificial stone silicosis. New methods to quantify and analyse alveolar crystal in BAL from patients with artificial stone silicosis were developed. Crystals were isolated and counted by microscopy and alveolar crystal burden was calculated using a standard curve generated by titration of respirable α-Quartz. The utility of the assay was then assessed in 23 patients with artificial stone silicosis. Alveolar crystal burden was greater in patients with silicosis (0.44 picograms [pg]/cell [0.08-3.49]) compared to patients with other respiratory diagnoses (0.057 pg/cell [0.01-0.34] p < 0.001). Alveolar crystal burden was positively correlated with years of silica exposure (ρ = 0.49, p = 0.02) and with decline in diffusing capacity of the lungs for carbon monoxide (ρ = -0.50, p = 0.02). Alveolar crystal burden quantification differentiates patients with silicosis from patients with other respiratory disorders. Furthermore, crystal burden is correlated with the rate of decline in lung function in patients with artificial stone silicosis.
Publisher: European Respiratory Society (ERS)
Date: 16-01-2020
Publisher: American Society for Clinical Investigation
Date: 14-10-2019
DOI: 10.1172/JCI128323
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2019
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.HEALUN.2019.02.005
Abstract: The new anti-fibrotics pirfenidone and nintedanib are now in widespread use for idiopathic pulmonary fibrosis (IPF), but they may have an adverse impact on pathways involved in wound-healing. This study aimed to establish the safety of anti-fibrotic therapy in the peri-transplant period, particularly with regard to healing of the bronchial anastomosis. In this work we assessed a retrospective cohort of patients who had undergone lung transplantation with a diagnosis of pulmonary fibrosis between January 2012 and December 2017. Pre-transplant use of pirfenidone and nintedanib was identified. Anastomotic dehiscence of any extent was determined at bronchoscopy. Known risk factors for anastomotic dehiscence were evaluated in both anti-fibrotic and control groups. Two hundred twenty-six patients (160 males mean age 59.7 ± 7.8 years) underwent transplantation in Australia for pulmonary fibrosis during the study period. Forty (17.7%) were receiving anti-fibrotics at the time of transplantation (29 with pirfenidone and 11 with nintedanib). There were 7 anastomotic dehiscence events, with overall incidence rates of 7.5% and 2.2% in the anti-fibrotic and control groups, respectively (p = 0.08). All episodes of dehiscence in the anti-fibrotic group and 2 of 4 in the comparator group occurred <6 weeks post-transplant. Survival at 30days was 100% and 96% (p = 0.21) and at 1 year was 93% and 88% (p = 0.01) in the anti-fibrotic and comparator groups, respectively. Two patients with dehiscence died. The other 5 anastomotic defects resolved, with 1 requiring stent insertion. The incidence of bronchial dehiscence after transplantation for IPF is low and is not significantly higher in patients receiving anti-fibrotic therapy at the time of transplantation.
Publisher: Wiley
Date: 19-04-2021
DOI: 10.1111/RESP.14062
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.HEALUN.2012.02.004
Abstract: We have previously reported that T-cell pro-inflammatory cytokines in the airways are associated with acute lung transplant rejection. However, during acute rejection episodes, we found no significant differences in airway intraepithelial T cell pro-inflammatory cytokines from stable and rejecting patients due to broad cytokine variability between patient groups. To overcome this limitation, we hypothesized that there would be an increase in pro-inflammatory intraepithelial T-cells in the graft compared with native airway during acute rejection. Bronchial brushings from patients with stable graft function, evidence of acute rejection, bronchiolitis obliterans syndrome, infection, and healthy controls were stimulated and pro-inflammatory cytokines in intraepithelial T cells from graft and native airway were determined using multiparameter flow cytometry. There was a significant increase in intraepithelial T-cell interferon-γ and tumor necrosis factor (TNF)-α in the graft of patients with acute rejection compared with intraepithelial T cells obtained from the native airway, but no changes were noted among other patient groups. The increase in intraepithelial T-cell TNF-α was more pronounced the higher the acute rejection grade. The graft airway epithelium is enriched with T cells producing interferon-γ and TNF-α during acute graft rejection. Therapeutic targeting of these pro-inflammatory cytokines and improved monitoring using this assay may reduce acute lung transplant rejection.
Publisher: Springer Science and Business Media LLC
Date: 12-09-2019
DOI: 10.1007/S12325-019-01086-2
Abstract: Rheumatoid arthritis (RA) is the most common of the connective tissue diseases (CTD), affecting up to 0.75% of the United States (U.S.) population with an increasing prevalence. Interstitial lung disease is prevalent and morbid condition in RA (RA-ILD), affecting up to 60% of patients with RA, leading to premature death in 10% and accruing an average of US$170,000 in healthcare costs per patient over a 5-year period. Although there have been significant advances in the management of this joint disease, there are no ongoing randomized clinical trials looking at pharmacologic treatments for RA-ILD, and there currently are no U.S. Food and Drug Administration-approved drugs for RA-ILD. We describe the Treatment for Rheumatoid Arthritis and Interstitial Lung Disease 1 (TRAIL1) trial, a multicenter randomized, double-blind, placebo-controlled, phase 2 study of the safety, tolerability and efficacy of pirfenidone in patients with RA-ILD. The study will enroll approximately 270 subjects across a network of sites who have RA and ILD as defined by a fibrotic abnormality involving greater than 10% of the lung parenchyma. The primary endpoint of the study is the incidence of the composite endpoint of decline in percent predicted forced vital capacity of 10 or greater or death during the 52-week study period. A number of secondary and exploratory endpoints have been chosen to evaluate the safety and efficacy in different domains. The TRAIL1 trial is designed to evaluate the safety and efficacy of pirfenidone in RA-ILD, a disease with significant impact on patients' quality of life and outcome. In addition to investigating the safety and efficacy of pirfenidone, this trial looks at a number of exploratory endpoints in an effort to better understand the impact of therapy on areas such as changes in quantitative high-resolution computed tomography scores and a patient's quality of life. Biospecimens will be collected in order to investigate biomarkers that could potentially predict the subtype of disease, its behavior over time, and its response to therapy. Finally, by creating a network of institutions and clinician investigators with an interest in RA-ILD, this trial will pave the way for future studies of investigational agents in an effort to reduce or eliminate the burden of disease for those suffering from RA-ILD. Genentech, a member of the Roche Group. Clinicaltrials.gov, identifier NCT02808871.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-05-2010
Publisher: Wiley
Date: 23-01-2020
DOI: 10.1111/RESP.13766
Publisher: Springer Science and Business Media LLC
Date: 25-10-2022
DOI: 10.1007/S00403-022-02403-6
Abstract: Organ transplant recipients (OTRs) are at greater risk of basal cell carcinomas (BCCs) than non-OTRs, but histopathologic differences between BCCs in OTRs and the general population are largely unknown. We compared clinicopathologic features of BCCs in OTRs vs the general population in Queensland, Australia. Details of BCC tumors (site, size, level of invasion, subtype, biopsy procedure) were collected from histopathology reports in two prospective skin cancer studies, one in OTRs and one general-population-based. We used log-binomial regression models to estimate age- and sex-adjusted prevalence ratios (PR) with 95% confidence intervals (CIs) for BCC features. Overall, there were 702 BCCs in 200 OTRs and 1725 BCCs in 804 population cases. Of these, 327 tumors in 128 OTRs were higher risk BCCs (any head and neck BCC ≥ 2 cm on trunk/extremities), more per person than 703 higher risk BCCs in 457 cases in the general population (chi-square p = 0.008). Among head/neck BCCs, OTRs were more likely than general population cases to have BCCs on scalp/ear than on face/lip/neck (PR = 1.5, 95%CI 1.2–1.8). Although aggressive subtypes were less common among higher risk BCCs in OTRs, BCCs invading beyond the dermis were almost twice as prevalent in OTRs (PR = 1.8, 95% CI 1.3–2.6) than the general population.
Publisher: Frontiers Media SA
Date: 14-02-2022
DOI: 10.3389/FCELL.2022.819726
Abstract: Therapeutic benefits of mesenchymal stem cells (MSCs) are now widely believed to come from their paracrine signalling, i.e. secreted factors such as cytokines, chemokines, and extracellular vesicles (EVs). Cell-free therapy using EVs is an active and emerging field in regenerative medicine. Typical 2D cultures on tissue culture plastic is far removed from the physiological environment of MSCs. The application of 3D cell culture allows MSCs to adapt to their cellular environment which, in turn, influences their paracrine signalling activity. In this study we evaluated the impact of 3D MSCs culture on EVs secretion, cargo proteome composition, and functional assessment in immunomodulatory, anti-inflammatory and anti-fibrotic properties. MSC-EVs from 2D and 3D cultures expressed classical EV markers CD81, CD63, and CD9 with particle diameter of & nm. There were distinct changes in immunomodulatory potencies where 3D cultures exhibited reduced indoleamine 2,3-dioxygenase (IDO) activity and significantly reduced macrophage phagocytosis. Administration of 2D and 3D EVs following double dose bleomycin challenge in aged mice showed a marked increase of bodyweight loss in 3D group throughout days 7–28. Histopathological observations of lung tissues in 3D group showed increased collagen deposition, myofibroblast differentiation and leukocytes infiltrations. Assessment of lung mechanics showed 3D group did not improve lung function and instead exhibited increased resistance and tissue d ing. Proteome profiling of MSC-EV composition revealed molecular enrichment of EV markers (compared to parental cells) and differential proteome between EVs from 2D and 3D culture condition associated with immune-based and fibrosis/extracellular matrix/membrane organization associated function. This study provides insight into distinct variation in EV protein composition dependent on the cellular microenvironment of the parental cells, which could have implications in their therapeutic effect and potency. Overall, this work suggests that EVs produced from 3D MSC cultures did not enhance typical MSC-EV properties expected from 2D cultures (immunomodulation, anti-fibrotic, anti-inflammatory). The outcome highlights critical differences between MSC-EVs obtained from different culture microenvironments, which should be considered when scaling up MSC culture for clinical manufacturing.
Publisher: AMPCo
Date: 20-11-2018
DOI: 10.5694/MJA17.00799
Abstract: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with debilitating symptoms of dyspnoea and cough, resulting in respiratory failure, impaired quality of life and ultimately death. Diagnosing IPF can be challenging, as it often shares many features with other interstitial lung diseases. In this article, we summarise recent joint position statements on the diagnosis and management of IPF from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia, specifically tailored for physicians across Australia and New Zealand. Main suggestions: A comprehensive multidisciplinary team meeting is suggested to establish a prompt and precise IPF diagnosis. Antifibrotic therapies should be considered to slow disease progression. However, enthusiasm should be tempered by the lack of evidence in many IPF subgroups, particularly the broader disease severity spectrum. Non-pharmacological interventions including pulmonary rehabilitation, supplemental oxygen, appropriate treatment of comorbidities and disease-related symptoms remain crucial to optimal management. Despite recent advances, IPF remains a fatal disease and suitable patients should be referred for lung transplantation assessment.
Publisher: Elsevier BV
Date: 09-2021
Publisher: BMJ
Date: 11-2019
DOI: 10.1136/BMJRESP-2019-000500
Abstract: The primary aim was to determine the healthcare utilisation benefits including respiratory-related hospital admissions, hospital admission days and emergency department presentations in the 0–12 and 12–24 months postpulmonary rehabilitation compared with the 12 months preprogramme. An observational, data-linkage design of 11 standardised pulmonary rehabilitation programmes were used. All programmes were 8 weeks in duration with two supervised exercise sessions per week and were required to use the national pulmonary rehabilitation recommendations with regard to programme organisation, exercise training guidelines and multidisciplinary education. For each participant with chronic obstructive pulmonary disease (COPD), healthcare utilisation data were collected for the 12 months preprogramme and 24 months postprogramme. 426 participants (231 males, FEV 1 49.3 (19.6) % predicted) were studied. The number of respiratory admissions articipant/year decreased from 0.7 (1.1) in the 12 months preprogramme to 0.5 (1.9) in the 12 months postprogramme, p=0.083 but increased in the 12–24 months postprogramme to 1.0 (2.3), p .001. The hospital days articipant/year improved from 4.0 (7.8) days in the 12 months preprogramme to 2.5 (8.5) days in the 12 months postprogramme, p .001 but increased in the 12–24 months postprogramme to 6.1 (16.6) days, p=0.004. The emergency department presentations articipant/year improved from 1.15 (1.75) in the 12 months preprogramme to 0.9 (1.8) in the 12 months postprogramme, p=0.003 but increased in the 12–24 months postprogramme to 2.0 (3.3), p .001. Pulmonary rehabilitation significantly improves hospital days and emergency department presentations in the first 12 months postprogramme. Healthcare utilisation benefits in the second 12 months are less clear.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 12-07-2016
DOI: 10.1186/S13287-016-0354-8
Abstract: Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are capable of repairing wounded lung epithelial cells by donating cytoplasmic material and mitochondria. Recently, we characterized two populations of human lung-derived mesenchymal stromal cells isolated from digested parenchymal lung tissue (LT-MSCs) from healthy in iduals or from lung transplant recipients’ bronchoalveolar lavage fluid (BAL-MSCs). The aim of this study was to determine whether LT-MSCs and BAL-MSCs are also capable of donating cytoplasmic content and mitochondria to lung epithelial cells. Cytoplasmic and mitochondrial transfer was assessed by co-culturing BEAS2B epithelial cells with Calcein AM or Mitotracker Green FM-labelled MSCs. Transfer was then measured by flow cytometry and validated by fluorescent microscopy. Molecular inhibitors were used to determine the contribution of microtubules/tunnelling nanotubes (TNTs, cytochalasin D), gap junctions (carbenoxolone), connexin-43 (gap26) and microvesicles (dynasore). F-actin microtubules/TNTs extending from BM-MSCs, LT-MSCs and BAL-MSCs to bronchial epithelial cells formed within 45 minutes of co-culturing cells. Each MSC population transferred a similar volume of cytoplasmic content to epithelial cells. Inhibiting microtubule/TNTs, gap junction formation and microvesicle endocytosis abrogated the transfer of cytoplasmic material from BM-MSCs, LT-MSCs and BAL-MSCs to epithelial cells. In contrast, blocking connexin-43 gap junction formation had no effect on cytoplasmic transfer. All MSC populations donated mitochondria to bronchial epithelial cells with similar efficiency. Mitochondrial transfer was reduced in all co-cultures after microtubule/TNT or endocytosis inhibition. Gap junction formation inhibition reduced mitochondrial transfer in BM-MSC and BAL-MSC co-cultures but had no effect on transfer in LT-MSC co-cultures. Connexin-43 inhibition did not impact mitochondrial transfer. Finally, bronchial epithelial cells were incapable of donating cytoplasmic content or mitochondria to any MSC population. Similar to their bone marrow counterparts, LT-MSCs and BAL-MSCs can donate cytoplasmic content and mitochondria to bronchial epithelial cells via multiple mechanisms. Given that BM-MSCs utilize these mechanisms to mediate the repair of damaged bronchial epithelial cells, both LT-MSCs and BAL-MSCs will probably function similarly.
Publisher: Rockefeller University Press
Date: 09-01-2020
DOI: 10.1084/JEM.20191236
Abstract: The ontogeny of airway macrophages (AMs) in human lung and their contribution to disease are poorly mapped out. In mice, aging is associated with an increasing proportion of peripherally, as opposed to perinatally derived AMs. We sought to understand AM ontogeny in human lung during healthy aging and after transplant. We characterized monocyte/macrophage populations from the peripheral blood and airways of healthy volunteers across infancy/childhood (2–12 yr), maturity (20–50 yr), and older adulthood (& yr). Single-cell RNA sequencing (scRNA-seq) was performed on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. During healthy aging, the proportions of blood and bronchoalveolar lavage (BAL) classical monocytes peak in adulthood and decline in older adults. scRNA-seq of BAL cells from lung transplant recipients indicates that after transplant, the majority of AMs are recipient derived. These data show that during aging, the peripheral monocyte phenotype is consistent with that found in the airways and, furthermore, that the majority of human AMs after transplant are derived from circulating monocytes.
Publisher: American Thoracic Society
Date: 15-02-2011
Publisher: American Medical Association (AMA)
Date: 07-2018
Publisher: Wiley
Date: 06-11-2022
DOI: 10.1111/RESP.14404
Abstract: Identification of an exposure is integral to the diagnosis, management, and prognostication of chronic hypersensitivity pneumonitis (CHP). Standardized questionnaires may aid in the identification of exposures, however, there currently are no evidence‐based patient‐validated questionnaires available. Key qualifiers (including duration and frequency) which indicate exposure relevance are also poorly defined. This study assessed the use of a standardized CHP exposure questionnaire in the identification of exposures and diagnostic confidence of CHP. People with a multi‐disciplinary meeting (MDM) diagnosis from five Australian interstitial lung disease (ILD) expert centres who provided informed consent were included. Participants completed a previously developed standardized CHP Exposure Questionnaire. Responses were collected with the participant's MDM data, including diagnosis, diagnostic confidence, and clinician‐elicited exposures. One hundred thirty participants (IPF = 58, CHP = 24, CTD‐ILD = 17, unclassifiable = 19, other = 12) were included. In 33% of CHP participants, a standardized questionnaire elicited an exposure where the clinician did not. 63% of these had provisional low confidence CHP and an exposure history would have increased the diagnostic confidence in these cases. Using the standardized questionnaire, 96% of CHP participants reporting any exposure, compared with 75% of non‐HP ILD participants. CHP participants were 3.5 times more likely ( p = 0.004) to report their symptoms improved on avoidance, and 2.3 times more likely ( p = 0.018) to report daily frequent exposure, compared with non‐HP ILDs. A standardized questionnaire which elicits exposure characteristics in addition to presence or absence of relevant exposures can increase the diagnostic confidence of CHP and reduce the proportion of antigen‐indeterminate CHP.
Publisher: BMJ
Date: 12-2021
DOI: 10.1136/BMJRESP-2021-001127
Abstract: Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens, including danazol, may be effective in lengthening telomeres in peripheral blood cells. This study aims to assess the safety and efficacy of danazol in adults and children with PF associated with telomere shortening. A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two ided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2 mg/kg/day orally in two ided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4 mg/kg/day (maximum 800 mg daily) orally in two ided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population. Ethics approval has been granted in Australia by the Metro South Human Research Ethics Committee (HREC/2020/QMS/66385). The study will be conducted and reported according to Standard Protocol Items: Recommendations for Interventional Trials guidelines. Results will be published in peer-reviewed journals and presented at international and national conferences. NCT04638517 Australian New Zealand Clinical Trials Registry (ACTRN12620001363976p).
Publisher: Oxford University Press (OUP)
Date: 23-02-2020
DOI: 10.1111/BJD.18812
Abstract: Lung transplant recipients are at high risk of skin cancer, but precise annual incidence rates of treated skin cancers per patient are unknown. To perform a prospective assessment of the total burden of histologically confirmed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) and associated factors in lung transplant recipients. A population-based cohort of 125 Queensland lung transplant recipients aged 18 years and over, recruited between 2013 and 2015, were followed to the end of 2016. All underwent dermatological skin examinations at baseline and annually thereafter and patients self-reported all interim treated skin cancers, which were verified against pathology databases. Standard skin cancer risk factors were obtained via questionnaire, and details of medications were acquired from hospital records. During a median follow-up time of 1·7 years, 29 (23%) and 30 (24%) lung transplant recipients with a median duration of immunosuppression of 3·3 years developed SCC and BCC, respectively. The general population age-standardized incidence rates of SCC and BCC were 201 and 171 per 1000 person-years, respectively (based on first primary SCC or BCC during follow-up) however, on accounting for multiple primary tumours, corresponding incidence rates were 447 and 281 per 1000 person-years. Risk of multiple SCCs increased around sixfold in those aged ≥ 60 years and in those with previous skin cancer, and increased around threefold in those treated with the antifungal medication voriconazole. Multiple BCC risk rose threefold from age 60 years and tenfold for patients with previous skin cancer. Lung transplant recipients have very high incidence of multiple primary skin cancers. Close surveillance and assiduous prevention measures are essential. Linked Comment: Proby and Harwood. Br J Dermatol 2020 183:416-417.
Publisher: Wiley
Date: 09-07-2014
DOI: 10.1111/RESP.12343
Abstract: Idiopathic pulmonary fibrosis (IPF) is a degenerative disease characterized by fibrosis following failed epithelial repair. Mesenchymal stromal cells (MSC), a key component of the stem cell niche in bone marrow and possibly other organs including lung, have been shown to enhance epithelial repair and are effective in preclinical models of inflammation-induced pulmonary fibrosis, but may be profibrotic in some circumstances. In this single centre, non-randomized, dose escalation phase 1b trial, patients with moderately severe IPF (diffusing capacity for carbon monoxide (DLCO ) ≥ 25% and forced vital capacity (FVC) ≥ 50%) received either 1 × 10(6) (n = 4) or 2 × 10(6) (n = 4) unrelated-donor, placenta-derived MSC/kg via a peripheral vein and were followed for 6 months with lung function (FVC and DLCO ), 6-min walk distance (6MWD) and computed tomography (CT) chest. Eight patients (4 female, aged 63.5 (57-75) years) with median (interquartile range) FVC 60 (52.5-74.5)% and DLCO 34.5 (29.5-40)% predicted were treated. Both dose schedules were well tolerated with only minor and transient acute adverse effects. MSC infusion was associated with a transient (1% (0-2%)) fall in SaO2 after 15 min, but no changes in haemodynamics. At 6 months FVC, DLCO , 6MWD and CT fibrosis score were unchanged compared with baseline. There was no evidence of worsening fibrosis. Intravenous MSC administration is feasible and has a good short-term safety profile in patients with moderately severe IPF.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 10-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-07-2009
Publisher: Elsevier BV
Date: 11-2021
Publisher: Hindawi Limited
Date: 25-08-2019
DOI: 10.1155/2019/6748242
Abstract: Background . Damage to the endothelium has been established as a key pathological process in lung transplantation and ex vivo lung perfusion (EVLP), a new technology that provides a platform for the assessment of injured donor lungs. Damage to the lung endothelial glycocalyx, a structure that lines the endothelium and is integral to vascular barrier function, has been associated with lung dysfunction. We hypothesised that endothelial glycocalyx shedding occurs during EVLP and aimed to establish a porcine model to investigate the mechanism underlying glycocalyx breakdown during EVLP. Methods . Concentrations of endothelial glycocalyx breakdown products, syndecan-1, hyaluronan, heparan sulphate, and CD44, were measured using the ELISA and matrix metalloproteinase (MMP) activity by zymography in the perfusate of both human ( n = 9) and porcine ( n = 4) lungs undergoing EVLP. Porcine lungs underwent prolonged EVLP (up to 12 hours) with perfusion and ventilation parameters recorded hourly. Results . During human EVLP, endothelial glycocalyx breakdown products in the perfusate increased over time. Increasing MMP-2 activity over time was positively correlated with levels of syndecan-1 ( r = 0.886 p = 0.03 ) and hyaluronan ( r = 0.943 p = 0.02 ). In the porcine EVLP model, hyaluronan was the only glycocalyx product detectable during EVLP (1 hr: 19 (13–84) vs 12 hr: 143 (109–264) ng/ml p = 0.13 ). Porcine hyaluronan was associated with MMP-9 activity ( r = 0.83 p = 0.02 ) and also with dynamic compliance ( r = 0.57 p = 0.03 ). Conclusion . Endothelial glycocalyx products accumulate during both porcine and human EVLP, and this accumulation parallels an accumulation of matrix-degrading enzyme activity. Preliminary evidence in our porcine EVLP model suggests that shedding may be related to organ function, thus warranting additional study.
Publisher: Elsevier BV
Date: 2019
Publisher: Elsevier BV
Date: 10-2021
Publisher: Wiley
Date: 15-02-2020
DOI: 10.1111/ALL.14202
Abstract: Silicosis is an ancient and potentially fatal pneumoconiosis caused by exposure to respirable crystalline silica. Silicosis is historically a disease of miners however, failure to recognize and control the risk associated with silica exposure in contemporary work practices such as sandblasting denim jeans and manufacturing of artificial stone benchtops has led to re-emergence of silicosis around the world. This review outlines the mineralogy, epidemiology, clinical and radiological features of the various forms of silicosis and other silica-associated diseases. Perspective is provided on the most recent studies shedding light on pathogenesis, including the central role of innate immune effector cells and subsequent inflammatory cascades in propagating pulmonary fibrosis and the extrapulmonary manifestations, which uniquely characterize this pneumoconiosis. Clinical conundrums in differential diagnosis, particularly between silicosis and sarcoidosis, are highlighted, as is the importance of obtaining a careful occupational history in the patient presenting with pulmonary infiltrates and/or fibrosis. While silicosis is a completely preventable disease, unfortunately workers around the world continue to be affected and experience progressive or even fatal disease. Although no treatments have been proven, opportunities to intervene to prevent progressive disease, founded in a thorough cellular and molecular understanding of the immunopathology of silicosis, are highlighted.
Publisher: Oxford University Press (OUP)
Date: 04-12-2020
Abstract: Cytomegalovirus (CMV) remains a significant burden in lung transplant recipients. Deficiencies in T-cell immunity posttransplant increase the risk of CMV-associated complications. However, it is not clear if underlying poor pretransplant immunity increases risk. To assess this, we recruited 39 prospective lung transplant patients and performed QuantiFERON-CMV on their peripheral blood. More than a third of prospective CMV-seropositive transplant recipients were CMV non-immune reactive (CMV-NIR) pretransplant. CMV-NIR status was associated with a significantly higher incidence of CMV reactivation posttransplant, demonstrating that dysfunctional CMV immunity in prospective lung transplant recipients is associated with an increased risk of viral reactivation posttransplant.
Publisher: Oxford University Press (OUP)
Date: 28-05-2010
DOI: 10.1111/J.1365-2249.2010.04186.X
Abstract: Immunosuppression therapy following lung transplant fails to prevent chronic rejection/bronchiolitis obliterans syndrome, which we have shown is associated with lack of suppression of peripheral blood T cell granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We hypothesized that these proinflammatory mediators may increase with time post-transplant in otherwise stable patients before clinical signs of declining lung function, and patients experiencing declining lung function would show a further increase in these mediators. Intracellular cytokine profiles and granzyme B were investigated in T cells in whole blood and airways from lung transplant patients using flow cytometry. There was a significant negative correlation between forced expiratory volume in 1 s (FEV1), drug dose and time post-transplant. A significant correlation between increased granzyme B, IFN-γ, interleukin (IL)-2 and TNF-α and time post-transplant was noted in peripheral blood T cells but not lung T cells from stable patients. Patients with similar drug dose but experiencing declining FEV1 showed a further increase in peripheral blood T cell IFN-γ, IL-2 and TNF-α. Time post-lung transplant correlates with increasing peripheral blood T cell granzyme B and proinflammatory cytokines. Declining FEV1 is associated with a further increase in these proinflammatory mediators. Drugs that reduce these inflammatory mediators effectively may reduce the incidence of chronic graft rejection.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.HEALUN.2011.06.007
Abstract: Long-term survival after lung transplantation is hindered by the development of bronchiolitis obliterans syndrome (BOS), and recent evidence suggests that dysregulated epithelial repair may underlie its development. Because matrix metalloproteinase (MMP) -2 and MMP-9 secretion is integral to repair, we hypothesized that airway epithelial cells from patients with BOS would over-express these matrix-degrading enzymes. Cells obtained from bronchial and bronchiolar brushings from patients with and without BOS (without acute rejection or infection) were analyzed via quantitative polymerase chain reaction and immunocytochemistry for MMP-2, and MMP-9 gene and protein expression. The expression of tissue inhibitor of metalloproteinase (TIMP)2 and TIMP1 was also assessed. MMP activity in bronchoalveolar lavage was determined via gelatin zymography. MMP-2 and MMP-9 production was significantly higher in bronchoalveolar lavage (3.85- and 11.59-fold, p < 0.001) and airway epithelium (MMP-2 bronchial: 6.33-fold, bronchiolar: 3.57-fold, both p < 0.001 MMP-9 bronchial: 32.55-fold, p < 0.001 bronchiolar: 8.60-fold, p = 0.01) in patients with BOS, but expression in patients without BOS was not different from healthy controls. TIMP expression was similar in patients with and without BOS. Immunostaining confirmed that the airway epithelium was a direct source of MMP-2 and MMP-9 expression in patients with BOS. In patients with BOS, the airway epithelium over-expresses MMPs, even in the absence of acute rejection or infection. Dysregulated epithelial repair may be a key feature of BOS.
Publisher: BMJ
Date: 10-2001
Abstract: Nitric oxide (NO) is detectable in the exhaled breath, is involved in airway defence and inflammation, and probably modulates bronchial smooth muscle tone. Given the sensitivity of nitrogen oxides to local redox conditions, we postulated that exposure to oxidant or antioxidant compounds could alter concentrations of NO in the exhaled breath (eNO). We assessed the effect of nitrogen dioxide (NO(2)) and ascorbic acid exposure on eNO in healthy human subjects. Ten healthy subjects were randomised to undergo a 20 minute single blind exposure to NO(2) (1.5 parts per million) or medical air in a crossover fashion. Exhaled NO and pulmonary function were measured before and for 3 hours after exposure. In a separate double blind crossover study 20 healthy subjects received ascorbic acid 500 mg twice daily or placebo for 2 weeks with a 6 week interim washout. Serum ascorbic acid levels and eNO were measured before and after each supplementation phase. NO(2) induced a decrease of 0.62 (95% CI 0.32 to 0.92) ppb in the mean post-exposure eNO (p<0.01) with no change in forced expiratory volume in 1 second (FEV(1)). Oral supplementation with ascorbic acid increased the mean serum ascorbic acid concentration by 7.4 (95% CI 5.1 to 9.7) microg/ml (63%) but did not alter eNO. NO(2) exposure causes a decrease in eNO, an effect which may be mediated through changes in epithelial lining fluid redox state or through a direct effect on epithelial cells. In contrast, ascorbic acid does not appear to play a significant role in the metabolism of NO in the epithelial lining fluid.
Publisher: Oxford University Press (OUP)
Date: 02-2017
DOI: 10.1002/SCTM.16-0372
Abstract: Chronic lung transplant rejection (termed chronic lung allograft dysfunction [CLAD]) is the main impediment to long-term survival after lung transplantation. Bone marrow-derived mesenchymal stromal cells (MSCs) represent an attractive cell therapy in inflammatory diseases, including organ rejection, given their relative immune privilege and immunosuppressive and tolerogenic properties. Preclinical studies in models of obliterative bronchiolitis and human trials in graft versus host disease and renal transplantation suggest potential efficacy in CLAD. The purpose of this phase 1, single-arm study was to explore the feasibility and safety of intravenous delivery of allogeneic MSCs to patients with advanced CLAD. MSCs from unrelated donors were isolated from bone marrow, expanded and cryopreserved in a GMP-compliant facility. Patients had deteriorating CLAD and were bronchiolitis obliterans (BOS) grade ≥ 2 or grade 1 with risk factors for rapid progression. MSCs (2 x 106 cells per kilogram patient weight) were infused via a peripheral vein twice weekly for 2 weeks, with 52 weeks follow-up. Ten Patients (5 male, 8 bilateral, median [interquartile range] age 40 [30–59] years, 3 BOS2, 7 BOS3) participated. MSC treatment was well tolerated with all patients receiving the full dosing schedule without any procedure-related serious adverse events. The rate of decline in forced expiratory volume in one second slowed after the MSC infusions (120 ml/month preinfusion vs. 30 ml/month postinfusion, p = .08). Two patients died at 152 and 270 days post-MSC treatment, both from progressive CLAD. In conclusion, infusion of allogeneic bone marrow-derived MSCs is feasible and safe even in patients with advanced CLAD.
Publisher: Wiley
Date: 27-08-2017
DOI: 10.1111/RESP.13146
Abstract: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease (ILD) of unknown aetiology with a median survival of only 2-5 years. It is characterized by progressive dyspnoea and worsening lung function, ultimately resulting in death. Until recently, there were no effective therapies for IPF however, with the publication of two landmark clinical trials in 2014, the anti-fibrotic therapies, nintedanib and pirfenidone, have gained widespread approval. This position paper aims to highlight the current evidence for the treatment of IPF, with particular application to the Australian and New Zealand population. We also consider areas in which evidence is currently lacking, especially with regard to the broader IPF severity spectrum and treatment of co-morbid conditions. The utility of non-pharmacological therapies including pulmonary rehabilitation, oxygen as well as symptom management thought to be important in the holistic care of IPF patients are also discussed.
Publisher: Elsevier BV
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 10-11-2017
Publisher: Elsevier BV
Date: 10-2021
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.HEALUN.2018.09.009
Abstract: Lung transplant recipients (LTRs) are at very high risk of skin cancer. Omega-3 fatty acids (FAs) are anti-inflammatory and immune-modulating and could potentially reduce this risk. We assessed the feasibility of omega-3 FA supplementation to reduce skin cancer among these patients. LTRs aged 18 Among 106 eligible lung transplant recipients, 49 consented to take part (46%) with 25 allocated to omega-3 FA and 24 to placebo supplements. Of these, 22 (88%) and 20 (83%), respectively, completed the trial. After 12 months, median plasma EPA increased substantially in the intervention group (125.0 to 340.0 µmol/L), but not the placebo group (98.0 to 134.5 µmol/L). In the intervention group, 6 patients developed skin cancers compared with 11 in the placebo group, giving an odds ratio (95% confidence interval) of 0.34 (0.09 to 1.32). There were no serious, active intervention-related adverse events. This pilot trial among LTRs showed acceptable recruitment and high retention and adherence. We demonstrated a signal for reduction of new skin cancer cases in those taking omega-3 FA supplements, which supports the notion that a larger, more definitive trial is warranted.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.HEALUN.2021.05.016
Abstract: Chronic Lung Allograft Dysfunction (CLAD) limits long-term survival following lung transplantation. Colonization of the allograft by Pseudomonas aeruginosa is associated with an increased risk of CLAD and inferior overall survival. Recent experimental data suggests that 'cloaking' antibodies targeting the O-antigen of the P. aeruginosa lipopolysaccharide cell wall (cAbs) attenuate complement-mediated bacteriolysis in suppurative lung disease. In this retrospective cohort analysis of 123 lung transplant recipients, we evaluated the prevalence, risk factors and clinical impact of serum cAbs following transplantation. cAbs were detected in the sera of 40.7% of lung transplant recipients. Cystic fibrosis and younger age were associated with increased risk of serum cAbs (CF diagnosis, OR 6.62, 95% CI 2.83-15.46, p < .001 age at transplant, OR 0.69, 95% CI 0.59-0.81, p < .001). Serum cAbs and CMV mismatch were both independently associated with increased risk of CLAD (cAb, HR 4.34, 95% CI 1.91-9.83, p < .001 CMV mismatch (D+/R-), HR 5.40, 95% CI 2.36-12.32, p < .001) and all-cause mortality (cAb, HR 2.75, 95% CI 1.27-5.95, p = .010, CMV mismatch, HR 3.53, 95% CI 1.62-7.70, p = .002) in multivariable regression analyses. Taken together, these findings suggest a potential role for 'cloaking' antibodies targeting P. aeruginosa LPS O-antigen in the immunopathogenesis of CLAD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2005
Publisher: European Respiratory Society (ERS)
Date: 12-07-2022
DOI: 10.1183/16000617.0250-2021
Abstract: Workers in the mining and construction industries are at increased risk of respiratory and other diseases as a result of being exposed to harmful levels of airborne particulate matter (PM) for extended periods of time. While clear links have been established between PM exposure and the development of occupational lung disease, the mechanisms are still poorly understood. A greater understanding of how exposures to different levels and types of PM encountered in mining and construction workplaces affect pathophysiological processes in the airways and lungs and result in different forms of occupational lung disease is urgently required. Such information is needed to inform safe exposure limits and monitoring guidelines for different types of PM and development of biomarkers for earlier disease diagnosis. Suspended particles with a 50% cut-off aerodynamic diameter of 10 µm and 2.5 µm are considered biologically active owing to their ability to bypass the upper respiratory tract's defences and penetrate deep into the lung parenchyma, where they induce potentially irreversible damage, impair lung function and reduce the quality of life. Here we review the current understanding of occupational respiratory diseases, including coal worker pneumoconiosis and silicosis, and how PM exposure may affect pathophysiological responses in the airways and lungs. We also highlight the use of experimental models for better understanding these mechanisms of pathogenesis. We outline the urgency for revised dust control strategies, and the need for evidence-based identification of safe level exposures using clinical and experimental studies to better protect workers’ health.
Publisher: Wiley
Date: 21-03-2013
DOI: 10.1111/RESP.12050
Abstract: Mesenchymal stem cells (MSC) are a population of tissue-resident adult progenitor cells that were originally identified in bone marrow, but have now been identified in many organs including the lung. Although their precise role in organ function remains incompletely defined, mounting evidence suggests that they are an important component of the parenchymal progenitor cell niche and orchestrate organ homeostasis and repair following injury. In this review, what is known about MSC biology will be outlined with particular emphasis on lung biology, and the therapeutic potential of MSC-based cell therapy will also be highlighted.
Publisher: Wiley
Date: 06-2008
DOI: 10.1111/J.1399-3062.2007.00290.X
Abstract: Pulmonary aspergillosis in immunosuppressed patients is associated with significant mortality and morbidity. We assessed the prophylactic and therapeutic effect of nebulized hotericin B (AmB) on mortality of immunosuppressed animals with pulmonary aspergillosis in this meta-analysis. Literature search was based on MEDLINE (1966 to January 15, 2007), EMBASE, and Cochrane-Controlled Trials Register (2006 issue 4) databases. Only randomized-controlled studies comparing nebulized AmB with placebo on immunosuppressed animals were included. Two reviewers reviewed and extracted the data independently. Eight studies including 839 immunosuppressed animals were considered. The overall mortality of the immunosuppressed animals with pulmonary aspergillosis treated with nebulized AmB was reduced (69.4% versus 87.7%, odds ratio [OR] 0.12, 95% confidence interval [CI]: 0.08-0.19 P < 0.0001). The effect of nebulized AmB on mortality was more significant when the drug was administered as prophylaxis before the inoculation of Aspergillus fumigatus (OR 0.07, 95% CI: 0.03-0.12, P = 0.0001 I(2) = 0) than as a therapeutic agent (OR 0.20, 95% CI: 0.11-0.36, P < 0.0001 I(2) = 0) (ratio of the 2 ORs = 2.86, 95% CI: 1.03-6.11 P = 0.04). The effectiveness of AmB desoxycholate (OR 0.16, 0.06-0.38, P < 0.0001 I(2) = 0) and lipid-associated (liposomal, or lipid complex or colloidal dispersion) hotericin (OR 0.11, 95% CI: 0.06-0.20, P < 0.0001 I(2) = 0) was not significantly different (ratio of the 2 ORs = 1.46, 95% CI: 0.49-4.39 P = 0.50). Three studies evaluated the potential side effects of nebulized hotericin and showed that there was no significant renal toxicity but the hotericin desoxycholate had some detrimental effects on pulmonary surfactant function. The use of nebulized hotericin, either as a prophylactic or therapeutic agent, is effective in reducing mortality of immunosuppressed animals with pulmonary aspergillosis. A large randomized controlled trial is needed to confirm whether combining nebulized hotericin with systemic antifungal agents will reduce mortality in immunosuppressed patients with suspected or proven pulmonary aspergillosis.
Publisher: Elsevier BV
Date: 03-2016
Publisher: Wiley
Date: 25-06-2020
DOI: 10.1002/RCR2.607
Publisher: European Respiratory Society (ERS)
Date: 19-03-2008
DOI: 10.1183/09031936.00127107
Abstract: Improved survival following extreme preterm birth complicated by bronchopulmonary dysplasia (BPD) is resulting in an increasing number of affected infants surviving to adulthood. The aim of the present pilot study was to describe the functional and structural pulmonary sequelae of moderate and severe BPD in a population of adult survivors. All babies were cared for at one institution (King Edward Memorial Hospital, Subiaco, Australia). Subjects born between 1980 and 1987 with birthweight <1,500 g and requiring supplementary oxygen at 36 weeks post-menstrual age were identified from a complete neonatal database and recruited prospectively. Local physicians were concurrently asked to refer suitable patients. Demographics, respiratory symptoms and examination results, pulmonary function tests and computed tomography images were acquired. In total, 21 subjects were studied. Of these, 12 were female, the median (range) age was 19 (17-33) yrs and 15 (71%) had persistent respiratory symptoms. The median (range) forced expiratory volume in one second (FEV(1)) z-score was -0.77 (-8.20-1.37), the forced expiratory flow at 25-75% of forced vital capacity was -1.81 (-6.00-0.75) and the diffusing capacity of the lung for carbon monoxide was -5.04 (-13.17- -1.24). Computed tomography was carried out on 19 subjects and all had abnormal findings, with emphysema being the most common, present in 84% of subjects. The extent of radiological emphysema was inversely related to the FEV(1) z-score. Young adult survivors of moderate and severe bronchopulmonary dysplasia may be left with residual functional and characteristic structural pulmonary abnormalities, most notably emphysema.
Publisher: Elsevier BV
Date: 03-2017
Publisher: American Thoracic Society
Date: 05-2022
Publisher: Wiley
Date: 07-2013
DOI: 10.1111/CTR.12163
Abstract: Lung transplant recipients report reduced exercise capacity despite satisfactory graft function. We analysed changes in lung function, six-min walk distance (6MWD), and quadriceps strength in the first 26-wk post-transplant and examined what factors predict 6MWD recovery. All lung transplant recipients at a single institution between June 2007 and January 2011 were considered for inclusion. Lung function, 6MWD, and quadriceps strength corrected for body weight (QS%) were recorded pre- and two-, six-, 13-, and 26-wk post-transplant. Fifty recipients, of mean (± SD) age 42 (± 13) yr, were studied. Mean FEV1 % and 6MWD improved from 26.4% to 88.9% and from 397 to 549 m at 26 wk, respectively (both p < 0.001). QS% declined in the first two wk but had improved to above pre-transplant levels by 26 wk (p = 0.027). On multivariate analysis (n = 35), lower pre-transplant exercise capacity and greater recovery in muscle strength explained most of the improvement in exercise capacity. Delayed recovery of exercise capacity after lung transplantation is unrelated to delay in improvement in graft function, but occurs secondary to the slow recovery of muscle strength. Our findings show that additional controlled trials are needed to better understand the influence of exercise rehabilitation on improvement in exercise capacity post-transplantation.
Publisher: Wiley
Date: 05-05-2020
DOI: 10.1002/RCR2.566
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.HEALUN.2010.03.015
Abstract: Gastroesophageal reflux disease (GORD) and microaspiration may be associated with acute graft dysfunction and development of obliterative bronchiolitis (OB) after lung transplantation. The "gold standard" for diagnosis of GORD is the 24-hour esophageal pH-monitoring study, although no simple, non-invasive screening test is routinely employed. Oil red O staining of alveolar macrophages in bronchoalveolar lavage (BAL) fluid identifies exogenous lipid and may be a surrogate marker for microaspiration. In this study we aimed to assess the utility of the lipid index in identifying patients with significant GORD. Our investigation was a prospective analysis of 34 lung transplant patients who were transplanted between April 1999 and July 2006 at a single institution. All patients with recurrent respiratory infections, recurrent acute rejection, unexplained graft dysfunction or newly diagnosed OB had Oil red O staining of alveolar macrophages on BAL specimens at bronchoscopy and 24-hour esophageal pH monitoring. A quantitative assessment called the lipid index was performed resulting in a score from 0 to 400. Abnormal 24-hour pH studies were defined as acid exposure >3.4% in the distal and/or >1% in the proximal esophageal site. Thirty-four patients with a mean age 36.1 years and mean post-operative day of 571 +/- 648 had lipid indices of 143 +/- 94 (range 3 to 341). Twenty-four-hour pH studies revealed a distal mean of 16.1 +/- 6.2% and proximal mean of 6.4 +/- 3.7%. A lipid index >150 was 82.3% sensitive and 76.4% specific for an abnormal 24-hour pH result. Foreign material present on cytology of bronchial fluid seen in 28% of patients showed poor correlation with Oil red O stains and pH studies. The lipid index is an effective, non-invasive screening test that provides direct evidence of esophageal aspiration. Patients with high positive results should proceed to surgical assessment for Nissen fundoplication.
Publisher: Oxford University Press (OUP)
Date: 05-07-2018
DOI: 10.1093/CID/CIY549
Abstract: Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of antiviral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. Although adoptive T-cell therapy has been successfully used in hematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus-specific T-cell response in vivo and the perceived risk of graft rejection. In this prospective study, 22 SOT recipients (13 renal and 8 lung and 1 heart transplants) with recurrent or ganciclovir-resistant CMV infection were recruited, and 13 of them were treated with in vitro-expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms, and immune reconstitution. Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the 13 treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia and CMV-associated end-organ disease and/or the cessation or reduced use of antiviral drugs. Furthermore, four of these patients showed coincident increased frequency of CMV-specific T cells in peripheral blood after completion of T-cell therapy. The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT recipients with recurrent and/or drug-resistant CMV infection or disease. ACTRN12613000981729.
Publisher: Wiley
Date: 24-11-2020
DOI: 10.1111/RESP.13977
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 04-2003
Abstract: Exhaled nitric oxide (NO) is thought to be a marker of asthmatic inflammation. Levels in cystic fibrosis (CF) are generally low. This study aimed to measure exhaled NO in CF patients at high risk of developing ABPA and patients at low risk. We studied nine patients at high risk of developing ABPA and 36 at low risk. The two groups were similar in age and spirometry. All patients in the high-risk group were taking oral or inhaled glucocorticoids, compared to 56% in the low-risk group (P=0.02). The exhaled NO levels were lower in the high-risk group than in the low-risk group (2.0 vs. 3.6 ppb), mean difference (95% CI) 1.6 (-3.6 to 0.4) ppb, P=0.001. On subgroup analysis of patients on oral glucocorticoids, the exhaled NO levels were significantly lower in patients with a high risk of developing ABPA (n=7) than patients with a low risk (n=8) (P=0.011). The number of patients who were on inhaled, but not oral glucocorticoids was too small to analyse usefully. Exhaled NO levels were lower in CF patients with a high risk of developing ABPA and on glucocorticoids. This may be because oral glucocorticoids exert a greater effect on exhaled NO than inhaled glucocorticoids. Alternatively, inducible nitric oxide synthase may be down-regulated by Aspergillus toxin.
Publisher: American Thoracic Society
Date: 15-03-2009
Publisher: Oxford University Press (OUP)
Date: 04-07-2016
DOI: 10.1002/STEM.2419
Abstract: Stromal support is critical for lung homeostasis and the maintenance of an effective epithelial barrier. Despite this, previous studies have found a positive association between the number of mesenchymal stromal cells (MSCs) isolated from the alveolar compartment and human lung diseases associated with epithelial dysfunction. We hypothesised that bronchoalveolar lavage derived MSCs (BAL-MSCs) are dysfunctional and distinct from resident lung tissue MSCs (LT-MSCs). In this study, we comprehensively interrogated the phenotype and transcriptome of human BAL-MSCs and LT-MSCs. We found that MSCs were rarely recoverable from the alveolar space in healthy humans, but could be readily isolated from lung transplant recipients by bronchoalveolar lavage. BAL-MSCs exhibited a CD90Hi, CD73Hi, CD45Neg, CD105Lo immunophenotype and were bipotent, lacking adipogenic potential. In contrast, MSCs were readily recoverable from healthy human lung tissue and were CD90Hi or Lo, CD73Hi, CD45Neg, CD105Int and had full tri-lineage potential. Transcriptional profiling of the two populations confirmed their status as bona fide MSCs and revealed a high degree of similarity between each other and the archetypal bone-marrow MSC. 105 genes were differentially expressed 76 of which were increased in BAL-MSCs including genes involved in fibroblast activation, extracellular matrix deposition and tissue remodelling. Finally, we found the fibroblast markers collagen 1A1 and α-smooth muscle actin were increased in BAL-MSCs. Our data suggests that in healthy humans, lung MSCs reside within the tissue, but in disease can differentiate to acquire a profibrotic phenotype and migrate from their in-tissue niche into the alveolar space.
Publisher: American Thoracic Society
Date: 04-2015
Publisher: Oxford University Press (OUP)
Date: 03-08-2009
DOI: 10.1111/J.1365-2249.2009.04008.X
Abstract: Bronchiolitis obliterans syndrome (BOS) is characterized by persistent alloreactive, infective and non-specific epithelial injury, loss of epithelial integrity and dysregulated repair. We have reported increased apoptosis of epithelial cells collected from the large airway in lung transplant recipients. As part of the alloreactive response, T cells induce apoptosis of target epithelial cells by secreting granzyme b. We hypothesized that granzyme b would be increased in lung transplant patients with acute rejection and BOS and that commonly used immunosuppressive agents would fail to suppress this serine protease adequately. We investigated intracellular T cell granzyme b in blood, bronchoalveolar lavage (BAL) and large airway brushing (23 controls, 29 stable transplant, 23 BOS, 28 acute rejection, 31 infection) using flow cytometry and assessed the effect of clinically relevant concentrations of cyclosporin A, tacrolimus, methylprednisolone and a protease inhibitor, gabexate mesilate, on in vitro granzyme b production. Granzyme b was increased significantly in all compartments of all transplant groups compared to controls. Surprisingly, granzyme b was even higher in patients with BOS than in patients with acute rejection. In longitudinal analysis in three patients, blood granzyme b increased prior to or at the onset of BOS. In vitro, methylprednisolone and gabexate mesilate had no effect and cyclosporin A and tacrolimus only a moderate effect on production of granzyme b by CD8+ T cells. Increased T cell granzyme b production may contribute to BOS pathogenesis and is not curtailed by current immunosuppressants. Longitudinal investigation of granzyme b in blood may provide an adjunctive non-invasive method for predicting BOS/OB.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2014
DOI: 10.1038/SREP03993
Publisher: Springer Science and Business Media LLC
Date: 10-11-2021
DOI: 10.1186/S12890-021-01704-2
Abstract: Interstitial lung disease is a debilitating condition associated with significant dyspnoea, fatigue, and poor exercise tolerance. Pulmonary rehabilitation is an effective and key intervention in people with interstitial lung disease. However, despite the best efforts of patients and clinicians, many of those who participate are not achieving clinically meaningful benefits. This assessor-blinded, multi-centre, randomised controlled trial aims to compare the clinical benefits of high intensity interval exercise training versus the standard pulmonary rehabilitation method of continuous training at moderate intensity in people with fibrotic interstitial lung disease. Eligible participants will be randomised to either a standard pulmonary rehabilitation group using moderate intensity continuous exercise training or high intensity interval exercise training. Participants in both groups will undertake an 8-week pulmonary rehabilitation program of twice-weekly supervised exercise training including aerobic (cycling) and strengthening exercises. In addition, participants in both groups will be prescribed a home exercise program. Outcomes will be assessed at baseline, upon completion of the intervention and at six months following the intervention by a blinded assessor. The primary outcome is endurance time on a constant work rate test. Secondary outcomes are functional capacity (6-min walk distance), health-related quality of life (Chronic Respiratory Disease Questionnaire (CRQ), St George’s Respiratory Questionnaire idiopathic pulmonary fibrosis specific version (SGRQ-I), breathlessness (Dyspnoea 12, Modified Medical Research Council Dyspnoea Scale), fatigue (fatigue severity scale), anxiety (Hospital Anxiety and Depression Scale), physical activity level (GeneActiv), skeletal muscle changes (ultrasonography) and completion and adherence to pulmonary rehabilitation. The standard exercise training strategies used in pulmonary rehabilitation may not provide an optimal exercise training stimulus for people with interstitial lung disease. This study will determine whether high intensity interval training can produce equivalent or even superior changes in exercise performance and symptoms. If high intensity interval training proves effective, it will provide an exercise training strategy that can readily be implemented into clinical practice for people with interstitial lung disease. Trial registration ClinicalTrials.gov Registry (NCT03800914). Registered 11 January 2019, t2/show/NCT03800914 Australian New Zealand Clinical Trials Registry ACTRN12619000019101. Registered 9 January 2019, www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376050& isReview=true
Publisher: American Physiological Society
Date: 11-2001
DOI: 10.1152/JAPPL.2001.91.5.1924
Abstract: Nasal nitric oxide (NO) exchange dynamics are poorly understood but potentially are of importance, inasmuch as they may provide insight into the NO-related physiology of the bronchial tree. In healthy human volunteers, NO output was assessed by isolating the nasal cavity through elevation of the soft palate and application of tight-fitting nasal olives. Mean NO output was 334 nl/min and was a positive function of gas flow. With the use of a mathematical model and the introduction of nonzero concentrations of NO, the diffusing capacity for NO in the nose (D NO ) and the mucosal NO concentration (C w ) were determined. D NO ranged from 0.52 to 2.98 × 10 −3 nl · s −1 · ppb −1 and C w from 1,236 to 8,947 ppb. C w declined with increasing gas flow, while D NO was constant. NO output declined with luminal hypoxia, particularly at oxygen tensions %. Measurement of nasal D NO and C w is easy using this method, and the range of intersubject values of C w raises the possibility of interin idual differences in NO-dependent nasal physiology.
Publisher: Wiley
Date: 24-02-2021
DOI: 10.1111/RESP.14018
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1111/J.1600-6143.2012.04193.X
Abstract: Donation-after-Determination-of-Cardiac-Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5-year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes. Between 2006 and 2011 there were 174 actual DDCD category III donors (with an additional 37 potentially suitable donors who did not arrest in the mandated 90 min postwithdrawal window), of whom 71 donated lungs for 70 bilateral LTx and two single LTx. In 2010 this equated to an "extra" 28% of donors utilized for LTx. Withdrawal to pulmonary arterial flush was a mean of 35.2 ± 4.0 min (range 18-89). At 24 h, the incidence of grade 3 primary graft dysfunction was 8.5%[median PaO(2)/FiO(2) ratio 315 (range 50-507)]. Overall the incidence of grade 3 chronic rejections was 5%. One- and 5-year actuarial survival was 97% and 90%, versus 90% and 61%, respectively, for 503 contemporaneous brain-dead donor lung transplants. Category III DDCD LTx therefore provides a significant, practical, additional quality source of transplantable lungs.
Publisher: Wiley
Date: 19-08-2019
DOI: 10.1111/RESP.13686
Publisher: Springer Science and Business Media LLC
Date: 26-10-2009
Abstract: The study of small airway diseases such as post-transplant bronchiolitis obliterans syndrome (BOS) is h ered by the difficulty in assessing peripheral airway function either physiologically or directly. Our aims were to develop robust methods for s ling small airway epithelial cells (SAEC) and to establish submerged SAEC cultures for downstream experimentation. SAEC were obtained at 62 post-transplant bronchoscopies in 26 patients using radiologically guided bronchial brushings. Submerged cell cultures were established and SAEC lineage was confirmed using expression of clara cell secretory protein (CCSP). The cell yield for SAEC (0.956 ± 0.063 × 10 6 ) was lower than for large airway cells (1.306 ± 0.077 × 10 6 ) but did not significantly impact on the culture establishment rate (79.0 ± 5.2% vs. 83.8 ± 4.7% p = 0.49). The presence of BOS significantly compromised culture success (independent of cell yield) for SAEC (odds ratio (95%CI) 0.067 (0.01-0.40)) but not LAEC (0.3 (0.05-1.9)). Established cultures were successfully passaged and expanded. Primary SAEC can be successfully obtained from human lung transplant recipients and maintained in culture for downstream experimentation. This technique will facilitate the development of primary in vitro models for BOS and other diseases with a small airway component such as asthma, cystic fibrosis and COPD.
Publisher: Elsevier BV
Date: 10-2020
Publisher: European Respiratory Society (ERS)
Date: 10-2005
DOI: 10.1183/09031936.05.00126704
Abstract: Cross-infection with Pseudomonas aeruginosa is an emerging issue in the care of patients with cystic fibrosis (CF). This study sought to determine the extent of, and patient factors associated with, cross-infection in a tertiary referral adult CF centre. P. aeruginosa isolates were genotyped into two groups between November 2001 and February 2003, using pulsed-field gel electrophoresis after DNA digestion by the SpeI endonuclease, and identified as clustered if there was >80% homology in the macrorestriction profiles. Patient factors and measures of disease severity were identified a priori. In total, 157 out of 227 patients had a P. aeruginosa isolate genotyped. Of these, 94 patients (60%) were infected with clustered genotypes and 47 (30%) were infected with the newly described "Midlands 1" (Md1) genotype. A further 18 patients were infected with the previously identified "Liverpool" genotype and two with the "Manchester" genotype. Logistic regression analysis revealed that the predominant predictor of infection with Md1 was age at the time of referral to the centre, suggesting that infection may have occurred prior to referral in some patients. Md1 demonstrated a relatively benign anti-biogram and did not appear to be associated with more severe disease. In conclusion, the present study provides further evidence of the emerging importance of Pseudomonas aeruginosa cross-infection in cystic fibrosis.
Publisher: Elsevier BV
Date: 10-2018
Publisher: American Thoracic Society
Date: 15-03-2013
Publisher: Elsevier BV
Date: 05-2022
Publisher: Wiley
Date: 22-10-2008
DOI: 10.1111/J.1440-1843.2008.01368.X
Abstract: Gastroesophageal reflux (GOR) has been implicated in the pathogenesis of bronchiolitis obliterans syndrome (BOS), possibly due to pulmonary aspiration of refluxed acid. Risk of aspiration of gastric contents is increased during sleep due to decreased oesophageal clearance mechanisms and may be further increased by the presence of OSA. This study investigated the relationship between nocturnal GOR, OSA and BOS in a group of lung transplant patients. Fourteen lung transplant patients underwent overnight polysomnography with simultaneous dual oesophageal pH monitoring. Patients had an FEV(1) of 84 +/- 15% of their best post-transplant FEV(1). Six of the 14 patients were in various stages of BOS. The average proportion of time spent overnight with a pH of 5 events per hour). There were no relationships between severity of OSA or GOR and severity of BOS. Both nocturnal GOR and OSA were common in this group of patients but their occurrences were not related. Neither was there any relationship between the presence of nocturnal GOR or OSA and severity of BOS.
Publisher: Elsevier BV
Date: 10-1999
DOI: 10.1016/S0954-6111(99)90040-9
Abstract: Although some risk factors for accelerated decline in forced expiratory volume in 1 s (FEV1) such as cigarette smoking, are well defined, it is not possible to identify those in iduals with the most rapid rates of decline. Von Willebrand factor (vWF) is a product of both the pulmonary and systemic endothelium, and serum levels are raised during episodes of acute bronchitis. We hypothesized that raised serum levels of vWF may indicate sub-clinical pulmonary injury and so may predict subsequent accelerated decline in FEV1. The aims of this study were 1. to define the prevalence of chronic respiratory symptoms and obstructive airway disease in an inner-city British population and 2. to determine whether elevated levels of von Willebrand factor (vWF) identify those in iduals at risk for more rapid decline in FEV1 over time. In 1987, all 2013 in iduals aged 45 to 74 years at an inner-city general practice were mailed a respiratory symptom questionnaire. One in six of the responders were asked to attend for spirometry and for assessment of serum vWF. In 1996, those in iduals who had spirometry and vWF assessed in 1987 were traced, and repeat spirometry was performed. In 1987, 1527 of 2013 (75.8%) in iduals completed the questionnaire. Forty-two point two percent of responders reported shortness of breath on hills, 34.7% reported wheeze and 31.6% reported mucus hypersecretion. Smokers were more likely to report these symptoms. Two hundred and ten of the 251 (84%) in iduals approached had spirometry and vWF assessed. Eleven percent of these had both an FEV1 < 75% predicted and a forced expiratory ratio (FEV1 forced vital capacity (FVC)) < 70%. Sub-normal spirometry was associated with wheeze, mucus hypersecretion, cigarette smoking and increasing age. By 1996, 32 (15%) of the original group of 210 in iduals had died, and 117 of the remaining 178 (66%) had spirometry repeated. FEV1 < 75% predicted was a strong predictor of interim mortality, independent of age, sex and smoking history. The average decline in FEV1 was 46.7 ml yr-1. There was no significant correlation between serum vWF levels and subsequent decline in FEV1. Chronic respiratory symptoms and spirometric evidence of airflow limitation are common in inner-city residents of the U.K., and are associated with smoking history. Much of this disease is unrecognised by health professionals. An FEV1 < 75% predicted is a strong independent predictor of subsequent mortality. The measurement of serum vWF levels is unhelpful in identifying those in iduals at increased risk of accelerated decline in FEV1.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2020
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 10-2019
Publisher: Future Medicine Ltd
Date: 04-2022
Abstract: Chronic lung allograft dysfunction (CLAD) affects approximately 50% of all lung transplant recipients by 5 post-operative years and is the leading cause of death in lung transplant recipients. Early CLAD diagnosis or ideally prediction of CLAD is essential to enable early intervention before significant lung injury occurs. New technologies have emerged to facilitate biomarker discovery, including epigenetic modification and single-cell RNA sequencing. This review examines new and existing technologies for biomarker discovery and the current state of research on biomarkers for identifying lung transplant rejection.
Publisher: Public Library of Science (PLoS)
Date: 21-12-2012
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CHEMOSPHERE.2019.05.235
Abstract: Arsenic (As) contamination of the groundwater in the Mekong Delta is a serious problem affecting millions of people who rely on this important resource for drinking and agriculture. In this study, borehole cores up to a depth of 40 m were collected in the Vietnamese-side of the delta, and the solid-phase partitioning of As with depth was investigated to understand the factors and processes controlling the release of this toxic element under oxic, acidic and reducing conditions. The results showed that in most of the sediments, substantial amounts of As are partitioned with exchangeable phases that are easily released into solution. Two borehole cores obtained between the Hau and Tien Rivers also had significantly high As partitioned with organic/sulfide phases and one of these cores had abundant As-bearing pyrite in 1-m thick peat layers. Leaching experiments in deionized (DI) water coupled with principal component analysis suggest that As release was controlled by sorption-desorption reactions with clays hyllosilicates (i.e., kaolinite, muscovite and clinochlore), proton-promoted dissolution of iron-oxyhydroxides, and oxidation of pyrite/organic matter. The mobility of As was further promoted under acidic conditions in the presence of chloride (Cl
Publisher: BMJ
Date: 08-1998
DOI: 10.1136/THX.53.8.677
Abstract: Cigarette smoking is associated with a number of common pulmonary diseases including chronic airflow limitation and bronchial carcinoma. Lower respiratory tract (LRT) nitric oxide (NO) concentrations are reduced in habitual cigarette smokers between cigarettes, and although this finding has been implicated in the pathogenesis of smoking related disease, the underlying mechanisms are unclear. A study was undertaken to determine the nature and time course for changes in LRT NO concentrations following acute inhalation of cigarette smoke. Twenty four healthy habitual smokers were studied. The concentration of LRT NO in exhaled breath before, one and ten minutes after smoking a single cigarette was measured using chemiluminescence. LRT NO concentrations increased in all subjects from a mean (SE) of 2.6 (0.27) to 4.8 (0.26) ppb (p < 0.0001) at one minute, and at 10 minutes remained significantly raised above the baseline level at 3.2 (0.25) ppb (p = 0.003). The mean (95% CI) increases in NO concentrations were 2.2 (1.7 to 2.7) and 0.6 (0.2 to 1.0) ppb, respectively. These findings were unexpected in both their direction and time course. They suggest a novel mechanism for the handling of NO in the human lung. We hypothesise that NO is trapped in the epithelial lining fluid (ELF) of the normal human respiratory tract in bioequivalent forms such as S-nitrosothiols or peroxynitrite and that this trapping mechanism is sensitive to the redox state of the ELF. LRT NO concentrations will thus increase with oxidant exposure and decline as pulmonary antioxidant defence mechanisms take effect. These findings may have implications for the pathogenesis and diagnosis of oxidant mediated pulmonary disease.
Publisher: Wiley
Date: 10-09-2017
DOI: 10.1111/RESP.13163
Abstract: Interstitial lung diseases (ILD) are a erse group of pulmonary diseases for which accurate diagnosis is critical for optimal treatment outcomes. Diagnosis of ILD can be challenging and a multidisciplinary approach is recommended in international guidelines. The purpose of this position paper is to review the evidence for the use of the multidisciplinary meeting (MDM) in ILD and suggest an approach to its governance and constitution, in an attempt to provide a standard methodology that could be applied across Australia and New Zealand. This position paper is endorsed by the Thoracic Society of Australia and New Zealand (TSANZ) and the Lung Foundation Australia (LFA).
Publisher: Wiley
Date: 10-2010
DOI: 10.1111/J.1445-5994.2010.02314.X
Abstract: Reversible posterior leukoencephalopathy syndrome (RPLS) is a potentially devastating early complication of calcineurin inhibitor (CNI) therapy in solid organ transplantation. Management centres on cessation of CNI therapy however, this strategy is complicated in lung transplantation because of the threat of allograft rejection, or, if CNI is replaced with mammalian target of rapamycin-based immunosuppression, poor wound healing and bronchial dehiscence. We describe four cases of RPLS after lung transplantation, emphasizing the diagnostic and management approach required to maintain a healthy allograft and ensure that RPLS is, as the name suggests, reversible.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.HEALUN.2015.08.015
Abstract: The objective of this study was to review the international experience in lung transplantation using lung donation after circulatory death (DCD). In this retrospective study, data from the International Society for Heart and Lung Transplantation (ISHLT) DCD Registry were analyzed. The study cohort included DCD lung transplants performed between January 2003 and June 2013, and reported to the ISHLT DCD Registry as of April 2014. The participating institutions included 10 centers in North America, Europe and Australia. The control group was a cohort of lung recipients transplanted using brain-dead donors (DBDs) during the same study period. The primary end-point was survival after lung transplantation. There were 306 transplants performed using DCD donors and 3,992 transplants using DBD donors during the study period. Of the DCD transplants, 94.8% were Maastricht Category III, whereas 4% were Category IV and 1.2% Category V (euthanasia). Heparin was given in 54% of the cases, donor extubation occurred in 90% of the cases, and normothermic ex vivo lung perfusion (EVLP) was used in 12%. The median time from withdrawal of life support therapy (WLST) to cardiac arrest was 15 minutes (5th to 95th percentiles of 5 to 55 minutes), and from WLST to cold flush was 33 minutes (5th to 95th percentiles of 19.5 to 79.5 minutes). Recipient age and medical diagnosis were similar in DCD and DBD groups (p = not significant [NS]). Median hospital length of stay was 18 days in DCD lung transplants and 16 days in DBD transplants (p = 0.016). Thirty-day survival was 96% in the DCD group and 97% in the DBD group. One-year survival was 89% in the DCD group and 88% in the DBD group (p = NS). Five-year survival was 61% in both groups (p = NS). The mechanism of donor death within the DCD group seemed to influence recipient early survival. The survival rates through 30 days were significantly different by donor mechanism of death (p = 0.0152). There was no significant correlation between the interval of WLST to pulmonary flush with survival (p = 0.11). This large study of international, multi-center experience demonstrates excellent survival after lung transplantation using DCD donors. It should be further evaluated whether the mechanism of donor death influences survival after DCD transplant.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1111/J.1600-6143.2010.03422.X
Abstract: Influenza A H1N1 2009 led to 189 deaths during the Australian pandemic. Community-acquired respiratory viruses not only can cause prolonged allograft dysfunction in lung transplant recipients but have also been linked to bronchiolitis obliterans syndrome (BOS). We report the impact of the 2009 H1N1 pandemic on Australian lung transplant recipients. An observational study of confirmed H1N1 cases was conducted across five Australian lung transplant programs during the pandemic. An electronic database collected patient demographics, clinical presentation, management and outcomes up to a year follow-up. Twenty-four H1N1 cases (mean age 43 ± 14 years, eight females) were identified, incidence of 3%. Illness severity varied from upper respiratory tract symptoms only in 29% to lung allograft dysfunction (≥10% decline FEV1) in 75% to death in 5 (21%) cases (pre-existing BOS grade 3, n = 4). Treatment with oseltamivir occurred in all but one case confirmed after death, reduced immunosuppression, n = 1, augmented corticosteroid therapy, n = 16, and mechanical/noninvasive ventilation, n = 4. There was BOS grade decline within a year in six cases (32%). In conclusion, Australian lung transplant recipients were variably affected by the H1N1 pandemic mirroring the broader community with significant morbidity and mortality. After initial recovery, a considerable proportion of survivors have demonstrated BOS progression.
Publisher: AMPCo
Date: 11-2009
Publisher: Elsevier BV
Date: 2021
Publisher: Wiley
Date: 28-06-2022
DOI: 10.1111/RESP.14320
Abstract: See related article
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.HEALUN.2009.03.013
Abstract: There is a growing expectation that cell-based therapies will prove effective for a wide range of conditions including lung diseases such as cystic fibrosis. The promise of these therapies will depend largely on effective delivery and engraftment. In this study, in the setting of human lung transplantation, we sought to determine whether exogenous epithelial cells are able to engraft the transplanted organ and if cells of a similar phenotype could be detected in peripheral blood. Cells obtained from bronchial brushings and peripheral blood were analyzed via dual fluorescent in situ hybridization/fluorescent immunohistochemistry (FISH/IHC), short tandem repeat polymerase chain reaction (STR-PCR) and flow cytometry. In 2 of 3 gender-mismatched patients we observed limited (5.9% to 6.8% by STR-PCR and 3.5% to 4% by FISH/IHC) engraftment of the bronchial epithelium by exogenous epithelial cells. Engrafting cells were CD34(-) CD15(-) CD68(-) c-Kit(-), but expressed CXCR4 on the cell surface. Cells with a similar phenotype were also identified in peripheral blood. In 8 patients, at 2 to 66 months post-transplant, 0.57 +/- 0.17% of CD14(-) peripheral blood mononuclear cells were of epithelial lineage. Almost all were CD45(+) and most expressed CXCR4 on the cell membrane. Cells of epithelial lineage were also identified in peripheral blood in healthy in iduals but in much lower numbers (0.08 +/- 0.01%, p < 0.05). Cells of epithelial lineage are detectable in peripheral blood and are able to engraft the bronchial epithelium in humans. Cell numbers are increased in lung transplantation.
Publisher: CSIRO Publishing
Date: 28-10-2021
DOI: 10.1071/AH20337
Abstract: Objectives Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease presenting in people aged ≥50 years. There is currently no cure for IPF, but two medications (pirfenidone and nintedanib) have been shown to slow the functional decline of the lungs. In 2017, these two medications were listed on the Pharmaceutical Benefits Scheme (PBS) for subsidisation in Australia. This study evaluated local trends in the use of these two medications. Methods Prescription data for this analysis were obtained from the PBS Item Reports for the period May 2017–May 2020. Population data were extracted from the Australian Bureau of Statistics data cubes. A descriptive approach was used to conduct and report the analysis to illustrate trends in the use of these two medications and associated costs. Results There were 44 010 prescriptions processed for the treatment for IPF in the 3-year period. Nintedanib use was higher than pirfenidone use, accounting for 54% of prescriptions. New South Wales accounted for 35% of the total prescriptions but, when standardised against population size, the Australian Capital Territory accounted for the highest proportion of prescriptions (24%). Prescriptions for nintedanib and pirfenidone were associated with a total cost of A$131 377 951 over the period 2017–20. Conclusion This study provides initial information on prescription rates, practices and expenditure for pirfenidone and nintedanib. In addition, we provide some insight into possible pharmacological and epidemiological trends based on jurisdictional differences. Together, the results from this study provide a platform for future research given the dearth of information on IPF in Australia. What is known about the topic? Data regarding trends in the utilisation of antifibrotics for the treatment of IPF in Australia are currently limited. What does this paper add? This study demonstrated that nintedanib use was slightly higher than pirfenidone use, and that there were variations in jurisdictional prescribing practices. The highest number of prescriptions and costs were attributable to New South Wales but, when standardised against population size, the Australian Capital Territory had the highest number of prescriptions and costs. What are the implications for practitioners? This study provides some insights into the use of pirfenidone and nintedanib, as well as pharmacoepidemiological trends, in Australia, which is useful for economic evaluation and modelling future health expenditure.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Elsevier BV
Date: 10-2017
Publisher: American Physiological Society
Date: 12-2020
DOI: 10.1152/AJPLUNG.00218.2020
Abstract: Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) s les, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function were compared with effects of BALF collected from healthy volunteers. CF BALF s les that cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp− CF BALF s les identified a number of differentially expressed transcripts, including those involved in interferon signaling, antimicrobial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Elsevier BV
Date: 2016
DOI: 10.1038/MTM.2016.58
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.HEALUN.2022.06.022
Abstract: Lung retransplantation is a complex surgical decision that represents the only potential treatment option for recipients suffering from lung allograft failure. We sought to describe the modern landscape of lung retransplantation and to compare the relative importance of selected clinical, donor, and recipient factors on mortality in the year following lung retransplantation. We conducted a retrospective cohort study of first-time adult recipients of deceased donor lung retransplants reported to the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry from May 2005 through June 2017. In addition to describing the characteristics of lung retransplant recipients, we examined 1 year survival overall, and by initial transplant-retransplant procedure type, recipient age, retransplant indication, and time-to-lung retransplantation (i.e., inter-transplant interval). We used the Somers' D Our cohort included 1,597 lung retransplant recipients. 2005 was the first year with more than 100 retransplants, and since 2007, 138 to 188 retransplants (approximately 4%-6% of all transplants) were reported annually to the ISHLT Registry. The median inter-transplant interval was 3.4 years (interquartile range: 1.6-6.2 years). Forty-three percent of the cohort had an obliterative bronchiolitis retransplant indication, whereas 17% had primary graft failure. One-third (32%) were retransplanted within 2 years of their primary transplant, and 64% received a double lung transplant both times, whereas 36% received consecutive single lung transplants. Six-month and 1 year survival (82% and 76%) were higher for double-double lung retransplant recipients than for single-single recipients (76% and 69%). The 3 strongest prognostic factors for 1 year mortality were the inter-transplant interval (decreasing hazard with longer intervals), donor age (increasing hazard with older age), and need for mechanical ventilation preceding lung retransplantation. Retransplants comprise approximately 5% of annual lung transplants worldwide. The factor most strongly associated with 1 year mortality in this population was the duration of time since the primary lung transplant, with a persistent reduction in risk as more time elapses.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.JID.2021.03.034
Abstract: Solid organ transplant recipients (SOTRs) have elevated risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), especially in high UVR environments. We assessed whether polygenic risk scores can improve the prediction of BCC and SCC risks and multiplicity over and above the traditional risk factors in SOTRs in a high UV setting. We built polygenic risk scores for BCC (n = 594,881) and SCC (n = 581,431) using UK Biobank and 23andMe datasets, validated them in the Australian QSkin Sun and Health Study cohort (n > 6,300), and applied them in SOTRs in the skin tumor in allograft recipients cohort from Queensland, Australia, a high UV environment. About half of the SOTRs with a high genetic risk developed BCC (absolute risk = 45.45%, 95% confidence interval = 33.14-58.19%) and SCC (absolute risk = 44.12%, 95% confidence interval = 32.08-56.68%). For both cancers, SOTRs in the top quintile were at >3-fold increased risk relative to those in the bottom quintile. The respective polygenic risk scores improved risk predictions by 2% for BCC (area under the curve = 0.77 vs. 0.75, P = 0.0691) and SCC (area under the curve = 0.84 vs. 0.82, P = 0.0260), over and above the established risk factors, and 19.03% (for BCC) and 18.10% (for SCC) of the SOTRs were reclassified in a high/medium/low risk scenario. The polygenic risk scores also added predictive accuracy for tumor multiplicity (BCC R
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1111/J.1600-6143.2009.02558.X
Abstract: Bronchiolitis obliterans syndrome (BOS) compromises lung transplant outcomes and is characterised by airway epithelial damage and fibrosis. The process whereby the normal epithelial configuration is replaced by fibroblastic scar tissue is poorly understood, but recent studies have implicated epithelial mesenchymal transition (EMT). The primary aim of this study was to assess the utility of flow cytometry in detecting and quantifying EMT in bronchial epithelial cells. Large airway brushings were obtained at 33 bronchoscopies in 16 BOS-free and 6 BOS grade 1-3 patients at 2-120 months posttransplant. Flow cytometry was used to assess expression of the mesenchymal markers alphaSMA, S100A4 and ED-A FN and HLA-DR. TGF beta 1 and HGF were measured in Bronchoalveolar lavage (BAL). Expression of all three mesenchymal markers was increased in BOS, as was HLA-DR. BAL HGF, but not TGF beta 1 was increased in BOS. Longitudinal investigation of one patient revealed a 100% increase in EMT markers concurrent with a 6-fold increase in BAL TGF beta 1 and the diagnosis of BOS at 17 months posttransplant. Flow cytometric evaluation of bronchial epithelium may provide a novel and rapid means to assess lung allografts at risk of BOS.
Publisher: Wiley
Date: 22-02-2016
DOI: 10.1111/TID.12497
Abstract: Fungal infection is a common cause of mortality and morbidity in lung transplant recipients (LuTR). Treatment failure to first-line antifungals because of resistance or intolerance is an increasing problem. Posaconazole (PCZ), a triazole antifungal, is an attractive treatment option. We performed a single-center retrospective study to describe the use, tolerability, efficacy, and drug interaction effect (with tacrolimus) of PCZ oral suspension in LuTR. Seventy-eight patients were treated with PCZ oral suspension for prophylaxis (n = 15), pre-emptive treatment (n = 31), and treatment of possible (n = 7) and probable (n = 25) invasive fungal infection. A range of fungal isolates was encountered. Resolution was observed in 52.4% (probable, possible, and pre-emptive treatment groups). Aggregate all-cause 1-year mortality was 12.8%. PCZ was well tolerated with 11.5% of patients experiencing adverse effects. Despite dose adjustment strategies, 11.7% of patients experienced supratherapeutic tacrolimus levels, which in 5 cases was associated with a rise (mean 21.6 μmol/L) in serum creatinine. PCZ is well tolerated and appears effective in the management of fungal infection after lung transplantation. Patients receiving concurrent tacrolimus require careful therapeutic drug monitoring.
Publisher: Elsevier BV
Date: 04-2022
Publisher: Springer International Publishing
Date: 2015
Publisher: BMJ
Date: 03-04-2015
Publisher: Elsevier BV
Date: 08-2016
Publisher: Frontiers Media SA
Date: 16-04-2021
DOI: 10.3389/FIMMU.2021.658062
Abstract: Chronic lung allograft dysfunction (CLAD) represents the major impediment to long term survival following lung transplantation. Donor and recipient telomere length have been shown to associate with lung transplant outcomes, including CLAD. In this study we aimed to measure the telomere lengths of bronchial and bronchiolar airway cells in lung allografts early after transplantation and to investigate associations with CLAD and all-cause mortality. This prospective, longitudinal study was performed at The Prince Charles Hospital, Australia. Airway cells were collected via bronchial and bronchiolar airway brushings at post-transplant bronchoscopies. The relative telomere length in airway cells was determined by quantitative PCR based on the T/S ratio. All patients were censored for CLAD and all-cause mortality in August 2020. In total 231 bronchoscopies incorporating transbronchial brush and bronchial brush were performed in 120 patients. At the time of censoring, 43% and 35% of patients, respectively, had developed CLAD and had died. Airway bronchiolar and bronchial telomere lengths were strongly correlated (r=0.78, p& .001), confirming conservation of telomere length with airway branch generation. Both the bronchiolar (r = -0.34, p& .001) and bronchial (r = -0.31, p& .001) telomere length decreased with age. Shorter airway telomere length was associated with older donor age and higher donor pack-year smoking history. Neither the bronchiolar nor the bronchial airway telomere length were associated with the development of CLAD (HR 0.39 (0.06-2.3), p=0.30 HR 0.66 (0.2-1.7), p=0.39, respectively) or all-cause mortality (HR 0.92 (0.2-4.5), p=0.92 HR 0.47 (0.1-1.9), p=0.28, respectively). In this cohort, airway telomere length was associated with donor age and smoking history but was not associated with the future development of CLAD or all-cause mortality.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.HEALUN.2010.10.018
Abstract: Lymphocytic bronchiolitis (LB) is the strongest risk factor for subsequent allograft loss due to bronchiolitis obliterative syndrome (BOS) however, it is poorly assessed by transbronchial biopsy (TBBx) because of s ling error, interpretation error and the presence of non-alloimmune airway inflammation. We hypothesized that flow cytometric evaluation of bronchiolar brushings (transbronchial brush, TBBr) may be a better approach. Transbronchial brushings (2 to 3 cm from the pleural surface under radiologic guidance) were obtained prior to TBBx in 32 patients and analyzed by flow cytometry. We assessed the proportion of nucleated cells that were CD3(+)CD103(+) (epithelial-specific T cells). No adverse events occurred 0.5% (0.27 to 0.84) of the cells were epithelial-specific T cells and numbers increased with episodes of Grade A1 rejection (p < 0.01) and in patients with BOS (p = 0.02). Viral and invasive fungal infection were associated with marked infiltration with CD103(-) T cells (p < 0.01). TBBr is simple to obtain, low risk, quantitative, and can discriminate between infective and alloimmune LB. It may be a valuable addition to current lung allograft assessment.
Publisher: Wiley
Date: 03-2015
DOI: 10.1038/CTI.2015.5
Publisher: European Respiratory Society (ERS)
Date: 15-05-2014
Publisher: Springer Science and Business Media LLC
Date: 05-09-2020
DOI: 10.1007/S00403-020-02136-4
Abstract: Various treatments of keratotic skin lesions and early skin cancers are performed in organ transplant recipients (OTRs) at high risk of skin malignancies but the frequency of their use is unknown. We prospectively assessed the frequency of use of cryotherapy, diathermy, and topical therapies and also investigated their associations with background incidence of histologically-confirmed squamous-cell carcinoma (SCC) and basal cell carcinoma (BCC) in a cohort of OTRs in Queensland, Australia. Median follow-up ranged from 1.7 to 3.2 years across organ transplant groups. Among 285 kidney, 125 lung and 203 liver transplant recipients [382 (62%) male, 380 (62%) immunosuppressed 5 years, 394 (64%) previously diagnosed with skin cancer], 306 (50%) reported treatment of skin lesions with major types of non-excision therapies during follow-up: 278 (45%) cryotherapy or diathermy 121 (20%) topical treatments. Of these 306, 150 (49%) developed SCC at double the incidence of those who did not receive these treatments, as assessed by incidence rate ratio (IRR) adjusted for age, sex, type of organ transplant, skin color and history of skin cancer at baseline, calculated by multivariable Poisson regression (IRR adj = 2.1, 95% confidence interval (CI) 1.4–3.1). BCC incidence was not associated with these therapies. Skin lesions in OTRs that are treated with cryotherapy, diathermy, or topical treatment warrant judicious selection and careful follow-up.
Publisher: Wiley
Date: 18-12-2021
DOI: 10.1111/BJH.17182
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-10-2020
DOI: 10.1126/SCIIMMUNOL.ABC1884
Abstract: The ACOD1/itaconate axis is a pulmonary regulatory pathway that controls the severity of fibrosis and is a potential therapeutic target in IPF.
Publisher: Wiley
Date: 08-2011
DOI: 10.1111/J.1754-9485.2011.02285.X
Abstract: This study aimed to describe the structural pulmonary sequelae of bronchopulmonary dysplasia (BPD) in adulthood. Fifty-one adult survivors (36 females and 15 males median age 20 years) of BPD underwent high-resolution inspiratory and expiratory computed tomography of the chest. The scans were evaluated independently by two thoracic radiologists blinded to the patient's clinical details using a standardised scoring system. Abnormal findings were seen in 50 (98%), the most common of which were subpleural triangular opacities (94%), linear opacities (90%), air trapping (65%) and emphysema (47%). The kappa values were derived by simplifying the score for each finding as present or absent. The kappa values for these findings were 0.65, 0.20, 0.58 and 0.54, respectively. Common findings were triangular, linear opacities and gas trapping. Emphysema diagnosis was more prevalent than previous studies, which may have been enhanced by improved technical factors.
Publisher: American Thoracic Society
Date: 2016
Publisher: Springer International Publishing
Date: 31-08-2019
Publisher: American Thoracic Society
Date: 09-2012
Publisher: BMJ
Date: 21-09-2014
DOI: 10.1136/THORAXJNL-2014-205587
Abstract: Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations. Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been conducted. To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations, antibiotic use for exacerbations and quality of life (QOL) (St George's Respiratory Questionnaire, SGRQ). Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and ≥2 pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18-85 years of age, baseline FEV1 ≥40% and ≤85% predicted and a baseline SGRQ score ≥30. 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol (rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022). SGRQ score was improved on mannitol compared with low-dose mannitol control (-2.4 units, p=0.046). Adverse events were similar between groups. Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated. NCT00669331.
Publisher: Humana Press
Date: 27-09-2013
Publisher: American Thoracic Society
Date: 15-07-2013
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
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Daniel Chambers.