1,474 research outputs found
Challenges in the development of new therapies for bronchiectasis
No full textIntroduction: Bronchiectasis is a neglected condition for which there are no licensed therapies. Increasing recognition of the disease has led to a surge in interest over recent years, with a number of active drug development programmes.Areas covered: Disappointing results with therapies successful in cystic fibrosis (CF) have forced a re-evaluation of how we develop new treatments for bronchiectasis. Bronchiectasis presents a unique array of challenges. These include a heterogeneous and poorly characterized patient population, a lack of agreed standards of care and a lack of understanding of the natural history. Pre-clinical development is limited by the lack of an adequate animal model of disease, and by our limited understanding of pathogenesis. There is no agreement on how to define key clinical trials end points including exacerbations and quality of life. The difficulty in translating positive Phase II data into successful Phase III trials suggests the need for better early phase trial end points.Expert opinion: Extrapolating from CF and chronic obstructive pulmonary disease has been a necessity but now risks holding back development if we do not recognize the unique challenges in bronchiectasis. This article comprehensively reviews the barriers to new drug development for bronchiectasis.</p
A Molecular Approach to the Diagnosis, Assessment, Monitoring and Treatment of Pulmonary Non-Tuberculous Mycobacterial Disease
No full textIntroduction: Non-Tuberculous Mycobacteria (NTM) can cause disease of the lungs and sinuses, lymph nodes, joints and central nervous system as well as disseminated infections in immunocompromised individuals. Efforts to tackle infections in NTM are hampered by a lack of reliable biomarkers for diagnosis, assessment of disease activity, and prognostication.
Aims: The broad aims of this thesis are:
1. to develop molecular assays capable of quantifying the 6 most common pathogenic mycobacteria (M. abscessus, M. avium, M. intracellulare, M. malmoense, M. kansasii, M. xenopi) and calculate comparative sensitivities and specificities for each assay.
2. to assess patients’ clinical course over 12 – 18 months by performing the developed molecular assays against DNA extracted from sputum from patients with NTM infection.
3. to assess dynamic bacterial changes of the lung microbiome in patients on treatment for NTM disease and those who are treatment na ve.
Methods: DNA was extracted from a total of 410 sputum samples obtained from 38 patients who were either:
• commencing treatment for either M. abscessus or Mycobacterium avium complex.
• considered colonised with M. abscessus or Mycobacterium avium complex (i.e. cultured NTM but were not deemed to have infection as they did not meet ATS or BTS criteria for disease).
• Diagnosed with cystic fibrosis (CF) or non-CF bronchiectasis but had never cultured NTM.
For the development of quantitative molecular assays, NTM hsp65 gene sequences were aligned and interrogated for areas of variability. These variable regions enabled the creation of species specific probes. In vitro sensitivity and specificity for each probe was determined by testing each probe against a panel of plasmids containing hsp65
gene inserts from different NTM species. Quantification accuracy was determined by using each assay against a mock community containing serial dilutions of target DNA.
Each sample was tested with the probes targeting: M. abscessus, M. avium and M. intracellulare producing a longitudinal assessment of NTM copy number during each patient’s clinical course.
In addition, a total of 64 samples from 16 patients underwent 16S rRNA gene sequencing to characterise longitudinal changes in the microbiome of both NTM disease and controls.
Results: In vitro sensitivity for the custom assays were 100% and specificity ranged from 91.6% to 100%. In terms of quantification accuracy, there was no significant difference between the measured results of each assay and the expected values when performed in singleplex. The assays were able to accurately determine NTM copy number to a theoretical limit of 10 copies/μl.
When used against samples derived from human sputum and using culture results as a gold standard, the sensitivity of the assay for M. abscessus was found to be 0.87 and 0.86 for MAC. The specificity of the assay for M. abscessus was 0.95 and 0.62 for MAC. The negative predictive value of the assay for M. abscessus was 0.98 and 0.95 for MAC. This resulted in an AUC of 0.92 for M. abscessus and 0.74 for MAC.
Longitudinal analysis of the lung microbiome using 16SrRNA gene sequencing showed that bacterial burden initially decreases after initiation of antibiotic therapy but begins to return to normal levels over several months of antibiotic therapy. This effect is mirrored by changes in alpha diversity. The decrease in bacterial burden and loss of alpha diversity was found to be secondary to significant changes in specific genera such as Veillonella and Streptococcus. The abundance of other Proteobacteria such as Pseudomonas remain relatively constant.
Conclusion: The molecular assay has shown high in vitro sensitivity and specificity for the detection and accurate quantification of the 6 most commonly pathogenic NTM species. The assays successfully identified NTM DNA from human sputum samples.
A notable association between NTM copy number and the cessation of one or more antibiotics existed (i.e. when one antibiotic was stopped because of patient intolerance, NTM copy number increased, often having been unrecordable prior to this). The qPCR assays developed in this thesis provide an affordable, real time and rapid measurement of NTM burden allowing clinicians to act on problematic results sooner than currently possible.
There was no significant difference between the microbiome in bronchiectasis and cystic fibrosis nor was there a significant difference between the microbiome in patients requiring treatment for NTM and those who did not. Patients receiving treatment experienced an initial decrease in bacterial burden over the first weeks of treatment followed by a gradual increase towards baseline over the next weeks to months. This change was mirrored in measures of alpha diversity. Changes in abundance and diversity were accounted for by decreases in specific bacteria whilst the abundance of other bacteria increased, occupying the microbial niche created. These bacteria (for example Pseudomonas spp) are often associated with morbidity.Open Acces
Clinimetrics properties of objective outcome measures in the BronchUK study
No full textJudy M. Bradley*1; Kathryn Ferguson2; Katherine O’Neill*1; DeniseCosgrove2; Adam T. Hill*3; Michael R. Loebinger*4; Mary Carroll*5;James D. Chalmers*6; Timothy Gatheral*7; Chris Johnson*8; AnthonyDe Soyza*9; John R. Hurst*10; Andrew Bailey11; Joseph S. Elborn*11Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine,Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UnitedKingdom; 2Belfast Health and Social Care Trust, Belfast, United Kingdom; 3RoyalInfirmary and University of Edinburgh, Edinburgh, United Kingdom; 4RoyalBrompton Hospital and Imperial College London, London, United Kingdom;5University Hospital Southampton NHS Foundation Trust, Southampton, UnitedKingdom; 6University of Dundee, College of Medicine, Dundee, United Kingdom;7Department of Respiratory Medicine, University Hospitals of Morecambe Bay NHSFoundation Trust, Morecambe Bay, United Kingdom; 8Cambridge Centre for LungInfection, Papworth Hospital, Cambridge, United Kingdom; 9Institute of CellularMedicine, Newcastle University, National Institute of Health Research BiomedicalResearch Centre, Newcastle, United Kingdom; 10UCL Respiratory, UniversityCollege London, London, United Kingdom; 11Frontier Science (Scotland) Ltd.,Kincraig, United Kingdom*On behalf of BRONCH-UK consortiumJudy M. Bradley*1; Katherine O’Neill*1; Kathryn Ferguson2; Adam T.Hill*3; Michael R. Loebinger*4; Mary Carroll*5; Timothy Gatheral*6;Anthony De Soyza*7; James D. Chalmers*8; Chris Johnson*9; John R.Hurst*10; Jeremy Brown10; Andrew Bailey11; Joseph S. Elborn*11Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine,Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UnitedKingdom; 2Belfast Health and Social Care Trust, Belfast, United Kingdom; 3RoyalInfirmary and University of Edinburgh, Edinburgh, United Kingdom; 4RoyalBrompton Hospital and Imperial College London, London, United Kingdom;5University Hospital Southampton NHS Foundation Trust, Southampton,United Kingdom; 6Department of Respiratory Medicine, University Hospitalsof Morecambe Bay NHS Foundation Trust, Morecambe Bay, United Kingdom;7Institute of Cellular Medicine, Newcastle University, National Institute of HealthResearch Biomedical Research Centre, Newcastle, United Kingdom; 8Universityof Dundee, College of Medicine, Dundee, United Kingdom; 9Cambridge Centrefor Lung Infection, Papworth Hospital, Cambridge, United Kingdom; 10UCLRespiratory, University College London, London, United Kingdom; 11FrontierScience (Scotland) Ltd., Kincraig, United Kingdom*On behalf of BRONCH-UK consortium<br/
Hyperthermia treatment of tumors by mesenchymal stem cell-delivered superparamagnetic iron oxide nanoparticles
No full textTammy L Kalber,1,2,* Katherine L Ordidge,1,2,* Paul Southern,3 Michael R Loebinger,1 Panagiotis G Kyrtatos,2,3 Quentin A Pankhurst,3,* Mark F Lythgoe,2,* Sam M Janes1,* 1Lungs for Living Research Centre, UCL Respiratory, University College London, 2UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, 3Healthcare Biomagnetics Laboratory, University College London, London, UK *These authors contributed equally to this work Abstract: Magnetic hyperthermia – a potential cancer treatment in which superparamagnetic iron oxide nanoparticles (SPIONs) are made to resonantly respond to an alternating magnetic field (AMF) and thereby produce heat – is of significant current interest. We have previously shown that mesenchymal stem cells (MSCs) can be labeled with SPIONs with no effect on cell proliferation or survival and that within an hour of systemic administration, they migrate to and integrate into tumors in vivo. Here, we report on some longer term (up to 3 weeks) post-integration characteristics of magnetically labeled human MSCs in an immunocompromized mouse model. We initially assessed how the size and coating of SPIONs dictated the loading capacity and cellular heating of MSCs. Ferucarbotran® was the best of those tested, having the best like-for-like heating capability and being the only one to retain that capability after cell internalization. A mouse model was created by subcutaneous flank injection of a combination of 0.5 million Ferucarbotran-loaded MSCs and 1.0 million OVCAR-3 ovarian tumor cells. After 2 weeks, the tumors reached ~100 µL in volume and then entered a rapid growth phase over the third week to reach ~300 µL. In the control mice that received no AMF treatment, magnetic resonance imaging (MRI) data showed that the labeled MSCs were both incorporated into and retained within the tumors over the entire 3-week period. In the AMF-treated mice, heat increases of ~4°C were observed during the first application, after which MRI indicated a loss of negative contrast, suggesting that the MSCs had died and been cleared from the tumor. This post-AMF removal of cells was confirmed by histological examination and also by a reduced level of subsequent magnetic heating effect. Despite this evidence for an AMF-elicited response in the SPION-loaded MSCs, and in contrast to previous reports on tumor remission in immunocompetent mouse models, in this case, no significant differences were measured regarding the overall tumor size or growth characteristics. We discuss the implications of these results on the clinical delivery of hyperthermia therapy to tumors and on the possibility that a preferred therapeutic route may involve AMF as an adjuvant to an autologous immune response. Keywords: mesenchymal stem cells, SPIONs, hyperthermia, MRI, tumor therap
Research priorities in bronchiectasis:a consensus statement from the EMBARC Clinical Research Collaboration
No full textBronchiectasis is a disease of renewed interest in light of an increase in prevalence and increasing burden on international healthcare systems. There are no licensed therapies, and large gaps in knowledge in terms of epidemiology, pathophysiology and therapy. The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) is a European Respiratory Society (ERS) Clinical Research Collaboration, funded by ERS to promote high-quality research in bronchiectasis. The objective of this consensus statement was to define research priorities in bronchiectasis. From 2014 to 2015, EMBARC used a modified Delphi process among European bronchiectasis experts to reach a consensus on 55 key research priorities in this field. During the same period, the European Lung Foundation collected 711 questionnaires from adult patients with bronchiectasis and their carers from 22 European countries reporting important research priorities from their perspective. This consensus statement reports recommendations for bronchiectasis research after integrating both physicians and patients priorities, as well as those uniquely identified by the two groups. Priorities identified in this consensus statement provide the clearest possible roadmap towards improving our understanding of the disease and the quality of care for patients with bronchiectasis.</p
Clinimetrics properties of patient reported outcome measures to measure health-related quality of life in the BronchUK study
No full textJudy M. Bradley*1; Katherine O’Neill*1; Kathryn Ferguson2; Adam T.Hill*3; Michael R. Loebinger*4; Mary Carroll*5; Timothy Gatheral*6;Anthony De Soyza*7; James D. Chalmers*8; Chris Johnson*9; John R.Hurst*10; Jeremy Brown10; Andrew Bailey11; Joseph S. Elborn*11Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine,Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UnitedKingdom; 2Belfast Health and Social Care Trust, Belfast, United Kingdom; 3RoyalInfirmary and University of Edinburgh, Edinburgh, United Kingdom; 4RoyalBrompton Hospital and Imperial College London, London, United Kingdom;5University Hospital Southampton NHS Foundation Trust, Southampton,United Kingdom; 6Department of Respiratory Medicine, University Hospitalsof Morecambe Bay NHS Foundation Trust, Morecambe Bay, United Kingdom;7Institute of Cellular Medicine, Newcastle University, National Institute of HealthResearch Biomedical Research Centre, Newcastle, United Kingdom; 8Universityof Dundee, College of Medicine, Dundee, United Kingdom; 9Cambridge Centrefor Lung Infection, Papworth Hospital, Cambridge, United Kingdom; 10UCLRespiratory, University College London, London, United Kingdom; 11FrontierScience (Scotland) Ltd., Kincraig, United Kingdom*On behalf of BRONCH-UK consortiu
Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection: Design of a dose-finding study (iBEST-1)
No full textIn patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate. We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection. In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7–28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis. As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area
Mrs. Sophia M. Loebinger, Treasurer of the National Progressive Suffragettes Union
No full textTitle from unverified data provided by the Bain News Service on the negatives or caption cards.Forms part of: George Grantham Bain Collection (Library of Congress).General information about the Bain Collection is available at http://hdl.loc.gov/loc.pnp/pp.ggbai
The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC): experiences from a successful ERS Clinical Research Collaboration.
No full textIn contrast to airway diseases like chronic obstructive pulmonary disease or asthma, and rare diseases such as cystic fibrosis, there has been little research and few clinical trials in bronchiectasis. Guidelines are primarily based on expert opinion and treatment is challenging because of the heterogeneous nature of the disease. In an effort to address decades of underinvestment in bronchiectasis research, education and clinical care, the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) was established in 2012 as a collaborative pan-European network to bring together bronchiectasis researchers. The European Respiratory Society officially funded EMBARC in 2013 as a Clinical Research Collaboration, providing support and infrastructure to allow the project to grow. EMBARC has now established an international bronchiectasis registry that is active in more than 30 countries both within and outside Europe. Beyond the registry, the network participates in designing and facilitating clinical trials, has set international research priorities, promotes education and has participated in producing the first international bronchiectasis guidelines. This manuscript article the development, structure and achievements of EMBARC from 2012 to 2017. EDUCATIONAL AIMS: To understand the role of Clinical Research Collaborations as the major way in which the European Respiratory Society can stimulate clinical research in different disease areasTo understand some of the key features of successful disease registriesTo review key epidemiological, clinical and translational studies of bronchiectasis contributed by the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) project in the past 5 yearsTo understand the key research priorities identified by EMBARC for the next 5 years
BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs
No full textBackground: A clinical study to investigate the leukotriene B4 (LTB4)-receptor antagonist BIIL 284 in cystic fibrosis (CF) patients was prematurely terminated due to a significantly increased risk of adverse pulmonary events. We aimed to establish the effect of BIIL284 in models of Pseudomonas aeruginosa lung infection, thereby contributing to a better understanding of what could have led to adverse pulmonary events in CF patients. Methods: P. aeruginosa DNA in the blood of CF patients during and after acute pulmonary exacerbations and in stable patients with non-CF bronchiectasis (NCFB) and healthy individuals was assessed by PCR. The effect of BIIL 284 treatment was tested in an agar bead murine model of P. aeruginosa lung infection. Bacterial count and inflammation were evaluated in lung and other organs. Results: Most CF patients (98%) and all patients with NCFB and healthy individuals had negative P. aeruginosa DNA in their blood. Similarly, the P. aeruginosa-infected mice showed bacterial counts in the lung but not in the blood or spleen. BIIL 284 treatment decreased pulmonary neutrophils and increased P. aeruginosa numbers in mouse lungs leading to significantly higher bacteremia rates and lung inflammation compared to placebo treated animals. Conclusions: Decreased airway neutrophils induced lung proliferation and severe bacteremia in a murine model of P. aeruginosa lung infection. These data suggest that caution should be taken when administering anti-inflammatory compounds to patients with bacterial infections
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