is responsible for chronic infection in many bronchiectasis patients but it is not known whether it is associated with worse clinical outcomes independent of the underlying severity of disease.This ...study analysed data from 2596 bronchiectasis patients included from 10 different bronchiectasis clinical centres across Europe and Israel, with a 5-year follow-up period. Prevalence of
chronic infection and its independent impact on exacerbations, hospitalisations, quality of life and mortality was assessed.The prevalence of
chronic infection was 15.0% (n=389).
was associated with a higher mortality in a univariate analysis (hazard ratio (HR) 2.02; 95% (confidence interval) CI 1.53-2.66; p<0.0001) but an independent impact on mortality was not found in a multivariate analysis (HR 0.98; 95% CI 0.70-1.36; p=0.89).
was independently associated with increased mortality only in patients with frequent exacerbations (two or more per year) (HR 2.03; 95% CI 1.36-3.03; p=0.001). An independent association with worse quality of life of 7.46 points (95% CI 2.93-12.00; p=0.001) was found in a multivariable linear regression.
was therefore found to be independently associated with exacerbation frequency, hospital admissions and worse quality of life. Mortality was increased in patients with
particularly in the presence of frequent exacerbations.
We evaluated the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis, two or more exacerbations in the previous year and ...pre-defined bacteria in sputum.In this phase III, double-blind, placebo-controlled trial, patients were randomised 2:1 to twice-daily ciprofloxacin DPI 32.5 mg or placebo in two treatment regimens consisting of on/off treatment cycles of 14 or 28 days for 48 weeks. The primary end-points were time to first exacerbation and frequency of exacerbations.A total of 416 patients were randomised to the 14-day on/off regimen (ciprofloxacin DPI (n=137) and placebo (n=68)) or the 28-day on/off regimen (ciprofloxacin DPI (n=141) and placebo (n=70)). Ciprofloxacin DPI 14 days on/off significantly prolonged time to first exacerbation
pooled placebo (median time >336
186 days; hazard ratio 0.53, 97.5% CI 0.36-0.80; p=0.0005) and reduced the frequency of exacerbations compared with matching placebo by 39% (mean number of exacerbations 0.6
1.0; incidence rate ratio 0.61, 97.5% CI 0.40-0.91; p=0.0061). Outcomes for ciprofloxacin DPI 28 days on/off were not statistically significantly different from placebo. The safety profile of ciprofloxacin DPI was favourable.Ciprofloxacin DPI was well tolerated and has the potential to be an effective treatment option in non-cystic fibrosis bronchiectasis.
Cellular senescence has been associated with the structural and functional decline observed during physiological lung aging and in chronic obstructive pulmonary disease (COPD). Airway epithelial ...cells are the first line of defense in the lungs and are important to COPD pathogenesis. However, the mechanisms underlying airway epithelial cell senescence, and particularly the role of telomere dysfunction in this process, are poorly understood. We aimed to investigate telomere dysfunction in airway epithelial cells from patients with COPD, in the aging murine lung and following cigarette smoke exposure. We evaluated colocalization of γ-histone protein 2A.X and telomeres and telomere length in small airway epithelial cells from patients with COPD, during murine lung aging, and following cigarette smoke exposure in vivo and in vitro. We found that telomere-associated DNA damage foci increase in small airway epithelial cells from patients with COPD, without significant telomere shortening detected. With age, telomere-associated foci increase in small airway epithelial cells of the murine lung, which is accelerated by cigarette smoke exposure. Moreover, telomere-associated foci predict age-dependent emphysema, and late-generation Terc null mice, which harbor dysfunctional telomeres, show early-onset emphysema. We found that cigarette smoke accelerates telomere dysfunction via reactive oxygen species in vitro and may be associated with ataxia telangiectasia mutated-dependent secretion of inflammatory cytokines interleukin-6 and -8. We propose that telomeres are highly sensitive to cigarette smoke-induced damage, and telomere dysfunction may underlie decline of lung function observed during aging and in COPD.
There is a need for a clear definition of exacerbations used in clinical trials in patients with bronchiectasis. An expert conference was convened to develop a consensus definition of an exacerbation ...for use in clinical research.A systematic review of exacerbation definitions used in clinical trials from January 2000 until December 2015 and involving adults with bronchiectasis was conducted. A Delphi process followed by a round-table meeting involving bronchiectasis experts was organised to reach a consensus definition. These experts came from Europe (representing the European Multicentre Bronchiectasis Research Collaboration), North America (representing the US Bronchiectasis Research Registry/COPD Foundation), Australasia and South Africa.The definition was unanimously approved by the working group as: a person with bronchiectasis with a deterioration in three or more of the following key symptoms for at least 48 h: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise; haemoptysis AND a clinician determines that a change in bronchiectasis treatment is required.The working group proposes the use of this consensus-based definition for bronchiectasis exacerbation in future clinical research involving adults with bronchiectasis.
We evaluated the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis, two or more exacerbations in the previous year and ...predefined sputum bacteria.Patients were randomised 2:1 to twice-daily ciprofloxacin DPI 32.5 mg or placebo in 14- or 28-day on/off treatment cycles for 48 weeks. Primary end-points were time to first exacerbation and frequency of exacerbations. Enrolling countries and α level split (0.049 and 0.001 for 14- and 28-day cycles, respectively) differed from RESPIRE 1.Patients were randomised to ciprofloxacin DPI (14 days on/off (n=176) or 28 days on/off (n=171)) or placebo (14 days on/off (n=88) or 28 days on/off (n=86)). The exacerbation rate was low across treatment arms (mean±sd 0.6±0.9). Active treatment showed trends to prolonged time to first exacerbation (ciprofloxacin DPI 14 days on/off: hazard ratio 0.87, 95.1% CI 0.62-1.21; p=0.3965; ciprofloxacin DPI 28 days on/off: hazard ratio 0.71, 99.9% CI 0.39-1.27; p=0.0511) and reduced frequency of exacerbations (ciprofloxacin DPI 14 days on/off: incidence rate ratio 0.83, 95.1% CI 0.59-1.17; p=0.2862; ciprofloxacin DPI 28 days on/off: incidence rate ratio 0.55, 99.9% CI 0.30-1.02; p=0.0014), although neither achieved statistical significance. Ciprofloxacin DPI was well tolerated.Trends towards clinical benefit were seen with ciprofloxacin DPI, but primary end-points were not met.
When Rene Laennec first described bronchiectatic lesions, he wrote: "Je me contenterai donc de donner deux exemples propres ea faire connaeaitre plus amplement l'alteaieration organique assez rare ...dont il s'agit" 1. Loosely translated, it shows us that during his discovery he had the conviction that bronchiectatic lesions were a rather rare phenomenon. However, at that time, Laennec was the first and only person to characterise these lesions, suggesting that his contemporaries had completely overlooked their existence. What is unsought will go undetected.
IMPORTANCE: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma ...concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. OBJECTIVE: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. DESIGN, SETTING, AND PARTICIPANTS: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. INTERVENTIONS: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). MAIN OUTCOMES AND MEASURES: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. RESULTS: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 95% CI, 2.10-2.38 exacerbations per year) vs 1703 in the placebo group (mean, 2.23 95% CI, 2.09-2.37 exacerbations per year); unadjusted mean difference, 0.01 (95% CI, −0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). CONCLUSIONS AND RELEVANCE: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN27066620
Protease-Antiprotease Imbalance in Bronchiectasis Oriano, Martina; Amati, Francesco; Gramegna, Andrea ...
International journal of molecular sciences,
2021-Jun-01, 2021-06-01, 20210601, Volume:
22, Issue:
11
Journal Article
Peer reviewed
Open access
Airway inflammation plays a central role in bronchiectasis. Protease-antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may ...contribute to bronchiectasis onset and progression. Proteases' over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease-antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
COPD-bronchiectasis overlap syndrome Hurst, John R; Elborn, J Stuart; De Soyza, Anthony
The European respiratory journal
45, Issue:
2
Journal Article
Peer reviewed
Open access
The overlap between chronic obstructive pulmonary disease (COPD) and bronchiectasis is a neglected area of research, and it is not covered by guidelines for clinical practice. Here, we provide a ...position statement from the BRONCH-UK Consortium that is intended to be of interest to both clinicians and researchers. While we are making recommendations based on expert consensus, one of our aims is to provoke debate. Through discussion of COPD-bronchiectasis overlap, we also aim to promote research in the area, driving improvements in patient care.
To characterise
populations during chronic lung infections of non-cystic fibrosis bronchiectasis patients, we used whole-genome sequencing to 1) assess the diversity of
and the prevalence of ...multilineage infections; 2) seek evidence for cross-infection or common source acquisition; and 3) characterise
adaptations.189 isolates, obtained from the sputa of 91 patients attending 16 adult bronchiectasis centres in the UK, were whole-genome sequenced.Bronchiectasis isolates were representative of the wider
population. Of 24 patients from whom multiple isolates were examined, there were seven examples of multilineage infections, probably arising from multiple infection events. The number of nucleotide variants between genomes of isolates from different patients was in some cases similar to the variations observed between isolates from individual patients, implying the possible occurrence of cross-infection or common source acquisition.Our data indicate that during infections of bronchiectasis patients,
populations adapt by accumulating loss-of-function mutations, leading to changes in phenotypes including different modes of iron acquisition and variations in biofilm-associated polysaccharides. The within-population diversification suggests that larger scale longitudinal surveillance studies will be required to capture cross-infection or common source acquisition events at an early stage.
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