Simon Finch

A Comprehensive Analysis of the Impact of Pseudomonas aeruginosa Colonization on Prognosis in Adult Bronchiectasis

RATIONALE Eradication and suppression of Pseudomonas aeruginosa is a key priority in national guidelines for bronchiectasis and is a major focus of drug development and clinical trials. An accurate estimation of the clinical impact of P. aeruginosa in bronchiectasis is therefore essential. METHODS Data derived from 21 observational cohort studies comparing patients with P. aeruginosa colonization with those without it were pooled by random effects meta-analysis. Data were collected for key longitudinal clinical outcomes of mortality, hospital admissions, exacerbations, and lung function decline, along with cross-sectional outcomes such as quality of life. MEASUREMENTS AND MAIN RESULTS In the aggregate, the included studies comprised 3,683 patients. P. aeruginosa was associated with a highly significant and consistent increase in all markers of disease severity, including mortality (odds ratio [OR], 2.95; 95% confidence interval [CI], 1.98-4.40; P < 0.0001), hospital admissions (OR, 6.57; 95% CI, 3.19-13.51; P < 0.0001), and exacerbations (mean difference, 0.97/yr; 95% CI, 0.64-1.30; P < 0.0001). The patients with P. aeruginosa also had worse quality of life on the basis of their St. Georges Respiratory Questionnaire results (mean difference, 18.2 points; 95% CI, 14.7-21.8; P < 0.0001). Large differences in lung function and radiological severity were also observed. The definitions of colonization were inconsistent among the studies, but the findings were robust regardless of the definition used. CONCLUSION P. aeruginosa is associated with an approximately threefold increased risk of death and an increase in hospital admissions and exacerbations in adult bronchiectasis.

Comorbidities and the risk of mortality in patients with bronchiectasis: an international multicentre cohort study.

BACKGROUND Patients with bronchiectasis often have concurrent comorbidities, but the nature, prevalence, and impact of these comorbidities on disease severity and outcome are poorly understood. We aimed to investigate comorbidities in patients with bronchiectasis and establish their prognostic value on disease severity and mortality rate. METHODS An international multicentre cohort analysis of outpatients with bronchiectasis from four European centres followed up for 5 years was done for score derivation. Eligible patients were those with bronchiectasis confirmed by high-resolution CT and a compatible clinical history. Comorbidity diagnoses were based on standardised definitions and were obtained from full review of paper and electronic medical records, prescriptions, and investigator definitions. Weibull parametric survival analysis was used to model the prediction of the 5 year mortality rate to construct the Bronchiectasis Aetiology Comorbidity Index (BACI). We tested the BACI as a predictor of outcomes and explored whether the BACI added further prognostic information when used alongside the Bronchiectasis Severity Index (BSI). The BACI was validated in two independent international cohorts from the UK and Serbia. FINDINGS Between June 1, 2006, and Nov 22, 2013, 1340 patients with bronchiectasis were screened and 986 patients were analysed. Patients had a median of four comorbidities (IQR 2-6; range 0-20). 13 comorbidities independently predicting mortality rate were integrated into the BACI. The overall hazard ratio for death conferred by a one-point increase in the BACI was 1·18 (95% CI 1·14-1·23; p<0·0001). The BACI predicted 5 year mortality rate, hospital admissions, exacerbations, and health-related quality of life across all BSI risk strata (p<0·0001 for mortality and hospital admissions, p=0·03 for exacerbations, p=0·0008 for quality of life). When used in conjunction with the BSI, the combined model was superior to either model alone (p=0·01 for combined vs BACI; p=0·008 for combined vs BSI). INTERPRETATION Multimorbidity is frequent in bronchiectasis and can negatively affect survival. The BACI complements the BSI in the assessment and prediction of mortality and disease outcomes in patients with bronchiectasis. FUNDING European Bronchiectasis Network (EMBARC).

Neutrophil Elastase Activity is Associated with Exacerbations and Lung Function Decline in Bronchiectasis

Rationale: Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis. Methods: This was a single‐center prospective cohort study using the TAYBRIDGE (Tayside Bronchiectasis Registry Integrating Datasets, Genomics, and Enrolment into Clinical Trials) registry in Dundee, UK. A total of 433 patients with high‐resolution computed tomography‐confirmed bronchiectasis provided blood samples for desmosine measurement, and 381 provided sputum for baseline elastase activity measurements using an activity‐based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross‐sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3 years. Measurement and Main Results: Elastase activity in sputum was associated with the bronchiectasis severity index (r = 0.49; P < 0.0001) and was also correlated with the Medical Research Council dyspnea score (r = 0.34; P < 0.0001), FEV1% predicted (r = −0.33; P < 0.0001), and the radiological extent of bronchiectasis (r = 0.29; P < 0.0001). During a 3‐year follow‐up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (P < 0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV1 decline (&bgr; coefficient, −0.139; P = 0.001). Elastase showed good discrimination for severe exacerbations with an area under the curve of 0.75 (95% confidence interval [CI], 0.72‐0.79) and all‐cause mortality (area under the curve, 0.70; 95% CI, 0.67‐0.73). Sputum elastase activity increased at exacerbations (P = 0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r = 0.42; P < 0.0001) and was associated with risk of severe exacerbations (hazard ratio 2.7; 95% CI, 1.42‐5.29; P = 0.003) but not lung function decline. Conclusions: Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.

Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts

Introduction Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality. Methods We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies. Results The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in ‘severe’ patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline. Conclusion The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.

Secreted mucins and airway bacterial colonization in non-CF bronchiectasis

Secreted mucins play a key role in antibacterial defence in the airway, but have not previously been characterized in non‐cystic fibrosis (CF) bronchiectasis patients. We aim to investigate the relationship between secreted mucins levels and the presence of bacterial colonization due to potentially pathogenic microorganisms (PPM) in the airways of stable bronchiectasis patients.

The generalizability of bronchiectasis randomized controlled trials: A multicentre cohort study.

INTRODUCTION Randomized controlled trials (RCTs) for bronchiectasis have experienced difficulties with recruitment and in reaching their efficacy end-points. To estimate the generalizability of such studies we applied the eligibility criteria for major RCTs in bronchiectasis to 6 representative observational European Bronchiectasis cohorts. METHODS Inclusion and exclusion criteria from 10 major RCTs were applied in each cohort. Demographics and outcomes were compared between patients eligible and ineligible for RCTs. RESULTS 1672 patients were included. On average 33.0% were eligible for macrolide trials, 15.0% were eligible for inhaled antibiotic trials, 15.9% for the DNAse study and 47.7% were eligible for a study of dry powder mannitol. Within these groups, some trials were highly selective with only 1-9% of patients eligible. Eligible patients were generally more severe with higher mortality during follow-up (mean 17.2 vs 9.0% for macrolide studies, 19.2%% vs 10.7% for inhaled antibiotic studies), and a higher frequency of exacerbations than ineligible patients. As up to 93% of patients were ineligible for studies, however, numerically more deaths and exacerbations occurred in ineligible patient across studies (mean 56% of deaths occurred in ineligible patients across all studies). CONCLUSION Our data suggest that patients enrolled in RCTs in bronchiectasis are only partially representative of patients in clinical practice. The majority of mortality and morbidity in bronchiectasis occurs in patients ineligible for many current trials.

Cardiovascular disease as a complication of community-acquired pneumonia.

Purpose of review Here, we review the incidence, prognosis, potential mechanisms and therapeutic implications of cardiovascular disease in community-acquired pneumonia (CAP). Recent findings Recent evidence suggests that a large proportion of deaths from CAP are attributable to cardiovascular disease, including sudden cardiac death, acute myocardial infarction (MI), arrhythmias and cardiac failure. Up to one-third of patients with CAP may experience cardiovascular complications within 30 days of hospital admission, while data also suggest that CAP managed in the community is associated with increased risk of acute MI. The risk is maximal within a few days of hospitalization with CAP and reduces over time. Most studies suggest that risk is still increased at 1 year, and some suggest risk continues to be increased at 10 years post-CAP. This clearly contributes to the well-recognized increased long-term mortality associated with CAP. The mechanism is not entirely clear, but recent published data have better defined the impact of the host response, including systemic inflammation and platelet activation. The contribution of Streptococcus pneumoniae has also been recently investigated, with animal studies suggesting a direct effect of S. pneumoniae on the myocardium, forming microlesions that heal with resulting myocardial fibrosis. Several studies suggest a key role for the pore-forming toxin pneumolysin in S. pneumoniae-induced cardiac toxicity. Summary Several therapies have been shown to improve the outcomes in cardiovascular disease, but whether these would be effective in improving outcomes in CAP is unknown. In this review, we argue that cardioprotective treatments may hold the greatest promise in terms of reducing long-term mortality in patients with CAP.

Inhaled Corticosteroids for Chronic Obstructive Pulmonary Disease—The Shifting Treatment Paradigm

Abstract 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.

The past decade in bench research into pulmonary infectious diseases: What do clinicians need to know?

Respiratory infections are primarily treated with antibiotics, drugs that are mostly inexpensive and have been widely available since the 1940s and 1950s. Nevertheless, despite antibiotics, the burden of disease in pneumonia, bronchiectasis, cystic fibrosis, COPD and rare respiratory infections remains exceptionally high. There is an urgent need for translational studies to develop new treatments or new biomarkers to improve outcomes in these conditions. The ‘translational gaps’ between bench science and clinical practice are particularly challenging in respiratory infections. This is partly due to the poor representativeness of animal models of infection to human disease, and a long‐term lack of investment into pulmonary infection research.

Sputum colour in non‐CF bronchiectasis: The original neutrophil biomarker

Non-cystic fibrosis bronchiectasis is characterised by neutrophil-driven airways inflammation leading to the clinical syndrome of cough, sputum production and recurrent respiratory infections. Historically, bronchiectasis has been an ‘orphan disease’ with a lack of research and few available treatments. The pathogenesis of bronchiectasis is traditionally viewed in terms of Coles’ ‘vicious cycle’, linking airway structural damage (bronchiectasis), bacterial infection with opportunistic bacteria and airway inflammation, which then drives further structural damage and the continuation of the cycle. Although this has been central to our understanding of bronchiectasis for decades, the scientific data to back up the interdependence of these three components of the cycle have been lacking. There is particularly a need in bronchiectasis to identify patients in an ‘accelerated vicious cycle’ with progressive disease who are at high risk of deteriorating lung function, exacerbations, hospital admissions and death. At present, there are no validated disease severity tools or biomarkers for use in bronchiectasis. Sputum colour has been a widely used indicator of airway inflammation and bacterial infection in bronchiectasis and other inflammatory lung diseases for generations, and few would view sputum colour as a ‘biomarker’. The National Institutes of Health, however, define a biomarker as ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention’. Sputum colour correlates with markers of disease severity in stable patients and changes in sputum colour are part of the definition of exacerbations. Sputum colour changes in response to antibiotic therapy, therefore nicely meeting the definition of biomarker. The distinctive green colour of sputum in patients with bronchiectasis is the result of the accumulation of myeloperoxidase, a green haem-containing protein released from neutrophil primary granules as part of the process of killing phagocytosed bacteria. The accumulation of this protein in sputum is a very good indicator of the presence of activated neutrophils in the airway. Clear or white sputum typically indicates a relatively low number of inflammatory cells while an increase in sputum colour from pale green/yellow to dark green indicates the accumulation of larger numbers of neutrophils. Sputum colour therefore represents a readily available and easily interpreted biomarker detecting the presence of inflammatory cells in the airway. Not only this, but since the primary driver for neutrophil recruitment to the airway appears to be bacteria, and neutrophil markers correlate closely with bacterial load, sputum colour also provides a rapid estimation of the presence of bacterial infection/colonisation. In this issue of Respirology, Goeminne et al. have sought to investigate the value of sputum colour as a marker of airway inflammation in bronchiectasis, presenting useful data that correlate sputum colour, inflammation, neutrophil protease activity and disease severity in a cohort of 49 patients with noncystic fibrosis bronchiectasis. The study was based on the bronchiectasis specific colour chart developed by Murray, using photographs of patients sputum to classify patients into three broad categories: mucoid (white/clear—grade 1), mucopurulent (yellow/pale—grade 2) or purulent (green to dark green—grades 3 and 4). The chart shows excellent interand intraobserver reliability as well as correlating with important clinical measures such as high-resolution computed tomography appearance and the presence of bacterial infection. Goeminne et al. studied a cohort of patients with non-cystic fibrosis bronchiectasis due to a variety of causes and a control group of healthy volunteers matched for age and sex. The patient’s disease severity was assessed using the Leicester Cough Questionnaire, Spirometry and a modified Brody score for high-resolution computed tomography scans. This latter feature is a particular strength of the Goeminne et al.’s study as most recent bronchiectasis studies have used a modified Reiff score, which only captures degree of dilatation and the number of lobes involved while the Brody score takes into account additional features including airway wall thickening, mucous plugging and parenchymal abnormalities. Patient’s sputum was analysed for total cell count, inflammatory cytokines and total proteolytic activity, followed by the specific activity of individual proteases focussing on neutrophil elastase and matrix metalloproteinase-9. The Murray colour chart proved to be an outstanding predictor of bacterial infection, with no patients with mucoid sputum being found to have bacterial infection by standard culture and also airway inflammation, correlating with total neutrophil counts and with protease activity. Proteases released from activated neutrophils appear to play a key role in disease progression in bs_bs_banner