Management of bronchiectasis in adults Chalmers, James D; Aliberti, Stefano; Blasi, Francesco
The European respiratory journal,
05/2015, Volume:
45, Issue:
5
Journal Article
Peer reviewed
Open access
Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis ...represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis. The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce airway inflammation; and to improve physical functioning and quality of life. Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has benefited greatly from the introduction of evidence-based guidelines in some European countries and randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation. This review provides a critical update on the management of bronchiectasis focussing on emerging evidence and recent randomised controlled trials.
By 21 May 2020, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) had caused more than 5 million cases of coronavirus 2019 (COVID-19) across more than 200 countries. Most countries with ...significant outbreaks have introduced social distancing or "lockdown" measures to reduce viral transmission. So the key question now is when, how and to what extent these measures can be lifted.Publicly available data on daily numbers of newly confirmed cases and mortality were used to fit regression models estimating trajectories, doubling times and the reproduction number (R
) of the disease, before and under the control measures. These data ran up to 21 May 2020, and were sufficient for analysis in 89 countries.The estimates of R
before lockdown based on these data were broadly consistent with those previously published: between 2.0 and 3.7 in the countries with the largest number of cases available for analysis (USA, Italy, Spain, France and UK). There was little evidence to suggest that the restrictions had reduced R far below 1 in many places, with France having the most rapid reductions: R
0.76 (95% CI 0.72-0.82) based on cases, and 0.77 (95% CI 0.73-0.80) based on mortality.Intermittent lockdown has been proposed as a means of controlling the outbreak while allowing periods of increased freedom and economic activity. These data suggest that few countries could have even 1 week per month unrestricted without seeing resurgence of the epidemic. Similarly, restoring 20% of the activity that has been prevented by the lockdowns looks difficult to reconcile with preventing the resurgence of the disease in most countries.
Bronchiectasis is characterised by pathological dilation of the airways. More specifically, the radiographic demonstration of airway enlargement is the common feature of a heterogeneous set of ...conditions and clinical presentations. No approved therapies exist for the condition other than for bronchiectasis caused by cystic fibrosis. The heterogeneity of bronchiectasis is a major challenge in clinical practice and the main reason for difficulty in achieving endpoints in clinical trials. Recent observations of the past 2 years have improved the understanding of physicians regarding bronchiectasis, and have indicated that it might be more effective to classify patients in a different way. Patients could be categorised according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism) or by clinical phenotypes (defined by relevant and common features of the disease). In doing so, more specific therapies needed to effectively treat patients might finally be developed. Here, we describe some of the recent advances in endotyping, genetics, and disease heterogeneity of bronchiectasis including observations related to the microbiome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic lung diseases are the third leading cause of death worldwide and are increasing in prevalence over time. Although much of our traditional understanding of health and disease is derived from ...study of the male of the species - be it animal or human - there is increasing evidence that sex and gender contribute to differences in disease risk, prevalence, presentation, severity, treatment approach, response and outcomes. Chronic obstructive pulmonary disease, asthma and bronchiectasis represent the most prevalent and studied chronic lung diseases and have key sex- and gender-based differences which are critical to consider and incorporate into clinical and research approaches. Mechanistic differences present opportunities for therapeutic development whereas behavioural and clinical differences on the part of patients and providers present opportunities for greater education and understanding at multiple levels. In this review, we seek to summarise the sex- and gender-based differences in key chronic lung diseases and outline the clinical and research implications for stakeholders.
Macrolide antibiotics are well known for their antibacterial properties, but extensive research in the context of inflammatory lung disease has revealed that they also have powerful immunomodulatory ...properties. It has been demonstrated that these drugs are therapeutically beneficial in various lung diseases, with evidence they significantly reduce exacerbations in patients with COPD, asthma, bronchiectasis and cystic fibrosis. The efficacy demonstrated in patients infected with macrolide tolerant organisms such as Pseudomonas aeruginosa supports the concept that their efficacy is at least partly related to immunomodulatory rather than antibacterial effects. Inconsistent data and an incomplete understanding of their mechanisms of action hampers the use of macrolide antibiotics as immunomodulatory therapies. Macrolides recently demonstrated no clinically relevant immunomodulatory effects in the context of COVID-19 infection. This review provides an overview of macrolide antibiotics and discusses their immunomodulatory effects and mechanisms of action in the context of inflammatory lung disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neutrophilic inflammation has a key role in the pathophysiology of multiple chronic lung diseases. The formation of neutrophil extracellular traps (NETs) has emerged as a key mechanism of disease in ...neutrophilic lung diseases including asthma, COPD, cystic fibrosis and, most recently, bronchiectasis. NETs are large, web-like structures composed of DNA and anti-microbial proteins that are able to bind pathogens, prevent microbial dissemination and degrade bacterial virulence factors. The release of excess concentrations of proteases, antimicrobial proteins, DNA and histones, however, also leads to tissue damage, impaired mucociliary clearance, impaired bacterial killing and increased inflammation. A number of studies have linked airway NET formation with greater disease severity, increased exacerbations and overall worse disease outcomes across the spectrum of airway diseases. Treating neutrophilic inflammation has been challenging in chronic lung disease because of the delicate balance between reducing inflammation and increasing the risk of infections through immunosuppression. Novel approaches to suppressing NET formation or the associated inflammation are in development and represent an important therapeutic target. This review will discuss the relationship between NETs and the pathophysiology of cystic fibrosis, asthma, COPD and bronchiectasis, and explore the current and future development of NET-targeting therapies.
Bronchiectasis is a heterogenous disease with multiple underlying causes. The pathophysiology is poorly understood but neutrophilic inflammation and dysfunctional killing of pathogens is believed to ...be key. There are, however, no licensed therapies for bronchiectasis that directly target neutrophilic inflammation. In this review, we discuss our current understanding of neutrophil dysfunction and therapeutic targeting in bronchiectasis. Immunometabolic reprogramming, a process through which inflammation changes inflammatory cell behaviour by altering intracellular metabolic pathways, is increasingly recognised across multiple inflammatory and autoimmune disease. Here we show evidence that much of the neutrophil dysfunction observed in bronchiectasis is consistent with immunometabolic reprogramming. Previous attempts to develop therapies targeting neutrophils have focused on reducing neutrophil numbers, resulting in increased infections. New approaches are needed and we propose that targeting metabolism could theoretically reverse neutrophil dysfunction and dysregulated inflammation. As an exemplar, AMPK activation has already been shown to reverse phagocytic dysfunction and neutrophil extracellular trap formation in models of pulmonary disease. AMPK modulates multiple metabolic pathways including glycolysis which is critical for energy generation in neutrophils. AMPK activators can reverse metabolic reprogramming and are already in clinical use and/or development. We propose the need for a new immunomodulatory, rather than anti-inflammatory, approach to enhance bacterial clearance and reduce bronchiectasis disease severity.
Background. The 2005 American Thoracic Society/Infectious Diseases Society of America guidelines introduced a concept of healthcare-associated pneumonia (HCAP) to define patients at higher risk of ...antibiotic-resistant pathogens, thus requiring broad spectrum therapy. There has been no systematic evaluation of the ability of this definition to identify antibiotic-resistant pathogens. Methods. We conducted a systematic review and meta-analysis of studies comparing the frequency of resistant pathogens (defined as methicillin-resistant Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa) in populations with HCAP compared with populations with community-acquired pneumonia (CAP). Predictive accuracy was evaluated using the area under the receiver operator characteristic curve (AUC). The frequencies of pathogens in each group were pooled using a random effects model. Results. Twenty-four studies were included (n = 22 456). Overall study quality was poor. HCAP was associated with an increased risk of methicillin-resistant S. aureus (odds ratio OR, 4.72; 95% confidence interval CI, 3.69–6.04) enterobactericeae (OR, 2.11; 95% CI, 1.69–2.63), and P. aeruginosa (OR, 2.75; 95% CI, 2.04–3.72; all P < .0001), but these analyses were confounded by publication bias. The discriminatory ability of HCAP for resistant pathogens was low (AUC, 0.70; 95% CI, 0.69–0.71) and was lower in high-quality (AUC, 0.66; 95% CI, 0.62–0.70) and prospective studies (AUC, 0.64; 95% CI 0.62–0.66). After adjustment for age and comorbidities, mortality was not increased in HCAP (OR, 1.20; 95% CI, 0.85–1.70; P = .30). Conclusions. The HCAP concept is based on predominantly low-quality evidence and does not accurately identify resistant pathogens. Mortality in HCAP does not appear to be due to a higher frequency of resistant pathogens.
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