Inhaled corticosteroids for chronic obstructive pulmonary disease-the shifting treatment paradigm

Chronic obstructive pulmonary disease (COPD) guidelines suggest using inhaled corticosteroids (ICS) in patients with severe airflow limitation or those at high risk of exacerbations. This recommendation is based on evidence demonstrating that ICS, especially when prescribed in fixed-dose combinations (FDC) with long-acting β2 agonists (LABA), improve quality of life (QoL), decrease exacerbations and hospitalisations, and have been associated with a trend towards a reduction in all-cause mortality. Audit shows that routine prescribing practice frequently uses inhaler therapies outside current guidelines recommendations; severe to very severe disease constitutes about 20% of all COPD patients, but up to 75% of COPD patients are prescribed an ICS, with significant numbers given ICS/LABA as first-line maintenance therapy. The role of ICS in the treatment paradigm for COPD is changing, driven by the growing evidence of increased risk of pneumonia, and the introduction of a new class of FDC; LABA and long-acting muscarinic antagonists (LAMA), which simplify dual bronchodilation and present a plausible alternative therapy. As the evidence base for dual therapy bronchodilation expands, it is likely that maximal bronchodilation will move up the treatment algorithm and ICS reserved for those with more severe disease who are not controlled on dual therapy. This change has already manifested in local COPD algorithms, such as those at Tayside, and represents a significant change in recommended prescribing practice. This review reassesses the role of ICS in the shifting treatment paradigm, in the context of alternative treatment options that provide maximal bronchodilation

Optimisation, harmonisation and standardisation of the direct mycobacterial growth inhibition assay using cryopreserved human peripheral blood mononuclear cells.

A major challenge to tuberculosis (TB) vaccine development is the lack of a validated immune correlate of protection. Mycobacterial growth inhibition assays (MGIAs) represent an unbiased measure of the ability to control mycobacterial growth in vitro. A successful MGIA could be applied to preclinical and clinical post-vaccination samples to aid in the selection of novel vaccine candidates at an early stage and provide a relevant measure of immunogenicity and protection. However, assay harmonisation is critical to ensure that comparable information can be extracted from different vaccine studies. As part of the FP7 European Research Infrastructures for Poverty Related Diseases (EURIPRED) consortium, we aimed to optimise the direct MGIA, assess repeatability and reproducibility, and harmonise the assay across different laboratories. We observed an improvement in repeatability with increased cell number and increased mycobacterial input. Furthermore, we determined that co-culturing in static 48-well plates compared with rotating 2 ml tubes resulted in a 23% increase in cell viability and a 500-fold increase in interferon-gamma (IFN-γ) production on average, as well as improved reproducibility between replicates, assay runs and sites. Applying the optimised conditions, we report repeatability to be <5% coefficient of variation (CV), intermediate precision to be <20% CV, and inter-site reproducibility to be <30% CV; levels within acceptable limits for a functional cell-based assay. Using relevant clinical samples, we demonstrated comparable results across two shared sample sets at three sites. Based on these findings, we have established a standardised operating procedure (SOP) for the use of the direct PBMC MGIA in TB vaccine development

Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trial

Background: Mycobacterium tuberculosis is the main causative agent of tuberculosis. BCG, the only licensed vaccine, provides inadequate protection against pulmonary tuberculosis. Controlled human infection models are useful tools for vaccine development. We aimed to determine a safe dose of aerosol-inhaled live-attenuated Mycobacterium bovis BCG as a surrogate for M tuberculosis infection, then compare the safety and tolerability of infection models established using aerosol-inhaled and intradermally administered BCG. Methods: This phase 1 controlled human infection trial was conducted at two clinical research facilities in the UK. Healthy, immunocompetent adults aged 18–50 years, who were both M tuberculosis-naive and BCG-naive and had no history of asthma or other respiratory diseases, were eligible for the trial. Participants were initially enrolled into group 1 (receiving the BCG Danish strain); the trial was subsequently paused because of a worldwide shortage of BCG Danish and, after protocol amendment, was restarted using the BCG Bulgaria strain (group 2). After a dose-escalation study, during which participants were sequentially allocated to receive either 1 × 103, 1 × 104, 1 × 105, 1 × 106, or 1 × 107 colony-forming units (CFU) of aerosol BCG, the maximum tolerated dose was selected for the randomised controlled trial. Participants in this trial were randomly assigned (9:12), by variable block randomisation and using sequentially numbered sealed envelopes, to receive aerosol BCG (1 × 107 CFU) and intradermal saline or intradermal BCG (1 × 106 CFU) and aerosol saline. Participants were masked to treatment allocation until day 14. The primary outcome was to compare the safety of a controlled human infection model based on aerosol-inhaled BCG versus one based on intradermally administered BCG, and the secondary outcome was to evaluate BCG recovery in the airways of participants who received aerosol BCG or skin biopsies of participants who received intradermal BCG. BCG was detected by culture and by PCR. The trial is registered at ClinicalTrials.gov, NCT02709278, and is complete. Findings: Participants were assessed for eligibility between April 7, 2016, and Sept 29, 2018. For group 1, 15 participants were screened, of whom 13 were enrolled and ten completed the study; for group 2, 60 were screened and 33 enrolled, all of whom completed the study. Doses up to 1 × 107 CFU aerosol-inhaled BCG were sufficiently well tolerated. No significant difference was observed in the frequency of adverse events between aerosol and intradermal groups (median percentage of solicited adverse events per participant, post-aerosol vs post-intradermal BCG: systemic 7% [IQR 2–11] vs 4% [1–13], p=0·62; respiratory 7% [1–19] vs 4% [1–9], p=0·56). More severe systemic adverse events occurred in the 2 weeks after aerosol BCG (15 [12%] of 122 reported systemic adverse events) than after intradermal BCG (one [1%] of 94; difference 11% [95% CI 5–17]; p=0·0013), but no difference was observed in the severity of respiratory adverse events (two [1%] of 144 vs zero [0%] of 97; 1% [−1 to 3]; p=0·52). All adverse events after aerosol BCG resolved spontaneously. One serious adverse event was reported—a participant in group 2 was admitted to hospital to receive analgesia for a pre-existing ovarian cyst, which was deemed unrelated to BCG infection. On day 14, BCG was cultured from bronchoalveolar lavage samples after aerosol infection and from skin biopsy samples after intradermal infection. Interpretation: This first-in-human aerosol BCG controlled human infection model was sufficiently well tolerated. Further work will evaluate the utility of this model in assessing vaccine efficacy and identifying potential correlates of protection

Evaluation of the non-specific effects of Bacille Calmette-Guérin (BCG) vaccination in healthy UK adults

Tuberculosis is the leading single infectious disease killer in the world, and the global burden of LTBI and TB disease, with the addition of antimicrobial drug resistance means there is a desperate need for a safe and effective TB vaccine. BCG is the only licensed vaccine and extremely variable in efficacy. However, BCG potentially exerts a non-specific beneficial effect - protecting infants from other causes of death such as respiratory infections and fever. Data from randomised and observational studies in support have been variable in quality; however the WHO reviewed the data and concluded that the effect was likely real, but that more robust data was needed. The aim of this my study was to evaluate the potential non-specific effects of BCG using an in-vitro whole blood growth inhibition assay as a surrogate marker of an individual’s ability to control growth of bacteria before and after vaccination with BCG. Identification of improved control of bacterial net growth following vaccination with BCG would provide evidence to support large, costly, randomised control trials in TB high burden countries. The assay did not demonstrate improved control of growth of four pathogens in the whole blood GIA following BCG vaccination and was subject to bacterial inoculum batch effect and other variables such as haemoglobin. A PBMC GIA potentially detected a subtle improvement in control of bacteria in the same volunteer cohort, but requires further optimisation. Volunteers who received BCG vaccination had an expected clinical and immunological reaction to vaccination with BCG. Pilot data exploring innate immune ‘memory’ through secondary antigenic stimulation of PBMCs did not demonstrate a significant increase in cytokine production, but numbers were small and more work is necessary.</p

Evaluation of the non-specific effects of Bacille Calmette-Guérin (BCG) vaccination in healthy UK adults

Tuberculosis is the leading single infectious disease killer in the world, and the global burden of LTBI and TB disease, with the addition of antimicrobial drug resistance means there is a desperate need for a safe and effective TB vaccine. BCG is the only licensed vaccine and extremely variable in efficacy. However, BCG potentially exerts a non-specific beneficial effect - protecting infants from other causes of death such as respiratory infections and fever. Data from randomised and observational studies in support have been variable in quality; however the WHO reviewed the data and concluded that the effect was likely real, but that more robust data was needed. The aim of this my study was to evaluate the potential non-specific effects of BCG using an in-vitro whole blood growth inhibition assay as a surrogate marker of an individualâs ability to control growth of bacteria before and after vaccination with BCG. Identification of improved control of bacterial net growth following vaccination with BCG would provide evidence to support large, costly, randomised control trials in TB high burden countries. The assay did not demonstrate improved control of growth of four pathogens in the whole blood GIA following BCG vaccination and was subject to bacterial inoculum batch effect and other variables such as haemoglobin. A PBMC GIA potentially detected a subtle improvement in control of bacteria in the same volunteer cohort, but requires further optimisation. Volunteers who received BCG vaccination had an expected clinical and immunological reaction to vaccination with BCG. Pilot data exploring innate immune âmemoryâ through secondary antigenic stimulation of PBMCs did not demonstrate a significant increase in cytokine production, but numbers were small and more work is necessary.</p

Smolting in post-sexually mature male Atlantic salmon (Salmo salar L.) parr in the wild

Conflicts can arise in developmental pathways that prevent an individual entering different developmental life stages that result in the expression of different phenotypes within a specific time period. In salmonids, theory suggests that sexual maturation may inhibit subsequent smolting within the same 12-month period and that this is partly the result of the time and the apparently conflicting physiological changes for these processes to occur, and partly because of the energy requirements for these physiologically taxing processes. This study tested whether sexually mature male Atlantic salmon (Salmo salar L.) parr, caught in the autumn, would subsequently smolt the following spring. Through individual identification using PIT telemetry, minimum estimates of 3.0% (n = 6/203) and 5.9% (n = 1/17) of Atlantic salmon parr that were sexually mature in two river catchments during the autumn were subsequently identified as smolts in the following spring. We therefore suggest that, in line with previous studies on domesticated Atlantic salmon and laboratory-based experiments, there is no developmental conflict but that life-history expression is mediated by environmental and genetic processes