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Background: There are no randomized controlled trials of statin therapy in patients with severe bronchiectasis who are chronically infected with Pseudomonas aeruginosa., Methods: Thirty-two patients chronically infected with P aeruginosa were recruited in this double-blind cross-over randomized controlled trial. Sixteen patients were recruited in each arm, were given atorvastatin 80 mg or placebo for 3 months followed by a washout period for 6 weeks, and then crossed over and administered the alternative therapy for 3 months., Results: Twenty-seven patients completed the study. Atorvastatin did not significantly improve the primary end point of cough as measured by the Leicester Cough Questionnaire (mean difference, 1.92; 95% CI for difference, -0.57-4.41; P = .12). However, atorvastatin treatment resulted in an improved St. Georges Respiratory Questionnaire (-5.62 points; P = .016) and reduced serum levels of CXCL8 (P = .04), tumor necrosis factor (P = .01), and intercellular adhesion molecule 1 (P = .04). There was a trend toward improvement in serum C-reactive protein and serum neutrophil counts (P = .07 and P = .06, respectively). We demonstrated in vitro that atorvastatin 10 μM reduced formyl-methionyl-leucyl phenylalanine-induced upregulation of CD11b expression and changes in calcium flux, reflecting an ability to decrease neutrophil activation., Conclusions: We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in patients with bronchiectasis who were infected with P aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation., Trial Registry: ClinicalTrials.gov; No.: NCT01299194; URL: www.clinicaltrials.gov., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bronchiectasis is characterised by chronic cough, sputum production, and recurrent chest infections. Pathogenesis is poorly understood, but excess neutrophilic airway inflammation is seen. Accumulating evidence suggests that statins have pleiotropic effects; therefore, these drugs could be a potential anti-inflammatory treatment for patients with bronchiectasis. We did a proof-of-concept randomised controlled trial to establish if atorvastatin could reduce cough in patients with bronchiectasis., Methods: Patients aged 18-79 years were recruited from a secondary-care clinic in Edinburgh, UK. Participants had clinically significant bronchiectasis (ie, cough and sputum production when clinically stable) confirmed by chest CT and two or more chest infections in the preceding year. Individuals were randomly allocated to receive either high-dose atorvastatin (80 mg) or a placebo, given orally once a day for 6 months. Sequence generation was done with a block randomisation of four. Random allocation was masked to study investigators and patients. The primary endpoint was reduction in cough from baseline to 6 months, measured by the Leicester Cough Questionnaire (LCQ) score, with a lower score indicating a more severe cough (minimum clinically important difference, 1·3 units). Analysis was done by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT01299181., Findings: Between June 23, 2011, and Jan 30, 2011, 82 patients were screened for inclusion in the study and 22 were excluded before randomisation. 30 individuals were assigned atorvastatin and 30 were allocated placebo. The change from baseline to 6 months in LCQ score differed between groups, with a mean change of 1·5 units in patients allocated atorvastatin versus -0·7 units in those assigned placebo (mean difference 2·2, 95% CI 0·5-3·9; p=0·01). 12 (40%) of 30 patients in the atorvastatin group improved by 1·3 units or more on the LCQ compared with five (17%) of 30 in the placebo group (difference 23%, 95% CI 1-45; p=0·04). Ten (33%) patients assigned atorvastatin had an adverse event versus three (10%) allocated placebo (difference 23%, 95% CI 3-43; p=0·02). No serious adverse events were recorded., Interpretation: 6 months of atorvastatin improved cough on a quality-of-life scale in patients with bronchiectasis. Multicentre studies are now needed to assess whether long-term statin treatment can reduce exacerbations., Funding: Chief Scientist's Office., (Copyright © 2014 Mandal et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by .. All rights reserved.)

Background: Mannose-binding lectin (MBL) is a key component of innate immunity. MBL deficiency is common (10-30% of the general population depending on the definition used) and has been associated with disease progression in cystic fibrosis. We aimed to assess the effect of MBL deficiency on disease severity in non-cystic fibrosis bronchiectasis., Methods: We recruited patients with non-cystic fibrosis bronchiectasis and age-matched and sex-matched controls at a specialist bronchiectasis clinic in Edinburgh, UK. We assessed MBL function with genotyping (low-expressing genotype [deficiency] defined as homozygosity for exon 1 mutations [YO/YO] or compound heterozygosity [XA/YO]; YA/YO and XA/XA genotypes were defined as intermediate-expressing with all other genotypes defined as high-expressing) and serum measurements (deficiency defined with two parameters: <500 ng/mL or <200 ng/mL). We assessed rates of exacerbation, chronic bacterial colonisation, and lung function during 4 years of follow-up., Findings: We included 470 patients with bronchiectasis and 414 controls. MBL genotype frequencies and MBL serum concentrations did not differ between patients and controls. 55 (12%) patients with bronchiectasis had low-expressing genotypes. These patients had a mean of 2·7 exacerbations per year (SD 1·8), compared with 1·9 per year (1·2) for 135 patients with intermediate-expressing genotypes and 1·9 per year (1·3) for 280 patients with high-expressing genotypes (p<0·0001). Chronic colonisation with bacteria was most frequent in patients with low-expressing genotypes (47 [85%] patients vs 82 [61%] patients with intermediate-expressing genotypes and 183 [65%] patients with high-expressing genotypes; p=0·0041); especially P aeruginosa colonisation (19 [35%] patients vs 13 [10%] patients and 36 [13%] patients; p<0·0001). Patients with low-expressing genotypes were more likely to be admitted to hospital for severe exacerbations during follow-up (27 [49%] patients vs 42 [31%] patients and 87 [31%] patients; p=0·032). Patients with low-expressing genotypes also had increased scores for radiological severity and worse quality of life compared with the other two groups. MBL serum deficiency (<200 ng/mL) was associated with increased exacerbations, hospital admissions, and radiological severity. When <500 ng/mL was used as the definition of deficiency, the associations with exacerbation frequency and radiological severity were no longer significant., Interpretation: MBL might be an important modifier of disease severity in non-CF bronchiectasis., Funding: UK Medical Research Council, UK Chief Scientists Office., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: Vitamin-D deficiency has been linked to an increased risk of respiratory infections. The objective of this study was to determine the frequency and clinical importance of vitamin-D deficiency in patients with bronchiectasis., Methods: 25-hydroxyvitamin-D was measured by immunoassay in 402 stable patients with bronchiectasis. Patients were classified as vitamin-D deficient (serum 25-hydroxyvitamin-D <25 nmol/l), insufficient (25 nmol/l-74 nmol/l) or sufficient (≥ 75 nmol/l). Disease severity was assessed, including exacerbation frequency, measurement of airway inflammatory markers, sputum bacteriology and lung function over 3 years follow-up., Results: 50% of bronchiectasis patients were vitamin-D deficient, 43% insufficient and only 7% sufficient. This compared to only 12% of age and sex matched controls with vitamin-D deficiency (p<0.0001). Vitamin-D deficient patients were more frequently chronically colonised with bacteria (p<0.0001), 21.4% of vitamin-D deficient subjects were colonised with Pseudomonas aeruginosa compared to 10.4% of insufficient patients and 3.6% of sufficient patients, p=0.003. Vitamin-D deficient patients had lower FEV(1)% predicted (p=0.002), and more frequent pulmonary exacerbations (p=0.04). Vitamin-D deficient patients had higher sputum levels of inflammatory markers and demonstrated a more rapid decline in lung function over 3 years follow-up. Defects in neutrophil function and assessment of airway LL-37 levels did not provide a mechanistic explanation for these findings. Vitamin-D deficient patients had, however, higher levels of Vitamin-D Binding Protein in sputum sol., Conclusions: Vitamin-D deficiency is common in bronchiectasis and correlates with markers of disease severity. The mechanism of this association is unclear.

Rationale: The vicious cycle hypothesis of bronchiectasis argues that bacterial colonization leads to airway inflammation and progressive lung damage. The logical extension of this hypothesis is that acute or chronic antibiotic therapy should improve airway inflammation and clinical outcome. There are little data to support this hypothesis in patients with non-cystic fibrosis (CF) bronchiectasis., Objectives: To determine whether acute or chronic antibiotic therapy improves airway inflammation and clinical outcome in non-CF bronchiectasis., Methods: The relationship between bacterial load and airway and systemic inflammation was investigated in 385 stable patients, 15 stable patients treated with intravenous antibiotics, and 34 patients with an exacerbation of bronchiectasis treated with intravenous antibiotics. Long-term antibiotic therapy was investigated using samples from a 12-month controlled trial of nebulized gentamicin., Measurements and Main Results: In stable patients, there was a direct relationship between airway bacterial load and markers of airway inflammation (P < 0.0001 for all analyses). High bacterial loads were associated with higher serum intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 (P < 0.05 above bacterial load ≥1 × 10(7) cfu/ml). In stable patients, there was a direct relationship between bacterial load and the risk of subsequent exacerbations (odds ratio, 1.20; 95% confidence interval, 1.11-1.29; P < 0.0001) and severe exacerbations (odds ratio, 1.11; 95% confidence interval, 1.01-1.21; P = 0.02). Short- and long-term antibiotic treatments were associated with reductions in bacterial load, airways, and systemic inflammation., Conclusions: High airway bacterial loads in non-CF bronchiectasis are associated with airway and systemic inflammation and a greater risk of exacerbations. Short- and long-term antibiotic therapy reduce markers of airways and systemic inflammation.

Rationale: Bronchiectasis is a chronic debilitating disease with few evidence-based long-term treatments., Objectives: A randomized controlled trial assessing the efficacy of nebulized gentamicin therapy over 1 year in patients with non-cystic fibrosis bronchiectasis., Methods: Sixty-five patients were randomized to either twice-daily nebulized gentamicin, 80 mg, or nebulized 0.9% saline, for 12 months. All were reviewed at three-monthly intervals during treatment and at 3 months' follow-up., Measurements and Main Results: At each review the following were assessed: quantitative and qualitative sputum bacteriology; sputum purulence and 24-hour volume; FEV(1), FVC, and forced expiratory flow, midexpiratory phase; exercise capacity; Leicester Cough Questionnaire and St. George's Respiratory Questionnaire; and exacerbation frequency. Fifty-seven patients completed the study. At the end of 12 months' treatment, compared with the saline group, in the gentamicin group there was reduced sputum bacterial density with 30.8% eradication in those infected with Pseudomonas aeruginosa and 92.8% eradication in those infected with other pathogens; less sputum purulence (8.7% vs. 38.5%; P < 0.0001); greater exercise capacity (510 [350-690] m vs. 415 [267.5-530] m; P = 0.03); and fewer exacerbations (0 [0-1] vs. 1.5 [1-2]; P < 0.0001) with increased time to first exacerbation (120 [87-161.5] d vs. 61.5 [20.7-122.7] d; P = 0.02). The gentamicin group had greater improvements in Leicester Cough Questionnaire (81.4% vs. 20%; P < 0.01) and St. George's Respiratory Questionnaire (87.5% vs. 19.2%; P < 0.004) score. No differences were seen in 24-hour sputum volume, FEV(1), FVC, or forced expiratory flow, midexpiratory phase. No P. aeruginosa isolates developed resistance to gentamicin. At follow-up, all outcome measures were similar to baseline., Conclusions: Regular, long-term nebulized gentamicin is of significant benefit in non-cystic fibrosis bronchiectasis but treatment needs to be continuous for its ongoing efficacy. Clinical trial registered with www.clinicaltrials.gov (NCT 00749866).

This study aimed to establish whether the bacterial density of spontaneous sputum is affected by the time and mode of sample storage. Ten patients with bronchiectasis collected all sputum expectorated over 45 min. The samples were aliquoted and processed at 25 degrees C for qualitative and quantitative bacteriology at 1, 2, 4 and 6 h from expectoration. Further aliquots were stored at 25 degrees C, 4 degrees C and -20 degrees C for 24 and 48 h prior to processing. The species present was identified and median (interquartile range) sputum log(10) bacterial density (c.f.u. ml(-1)) calculated. All samples cultured grew Pseudomonas aeruginosa and for two patients Staphylococcus aureus additionally grew for all samples. There was no significant difference in P. aeruginosa density in samples processed at 1, 2, 4 and 6 h following expectoration [8.2 (7.8-8.3) c.f.u. ml(-1), 8.0 (7.8-8.3) c.f.u. ml(-1), 8.0 (7.9-8.2) c.f.u. ml(-1), 8.1 (7.9-8.2) c.f.u. ml(-1), respectively, P=0.392]. Storage for 24 and 48 h at 4 degrees C did not significantly change the bacterial load compared with processing at 1 h [8.03 (7.6-8.2) c.f.u. ml(-1), P=0.07, and 7.96 (7.49-8.22) c.f.u. ml(-1), P=0.09, respectively]. Storage for 24 and 48 h at -20 degrees C significantly reduced P. aeruginosa density [7.1 (6.1-7.7) c.f.u. ml(-1), P=0.005, and 6.9 (6.2-7.6) c.f.u. ml(-1), P=0.008, respectively]. Storage at 25 degrees C for 24 and 48 h was associated with a significant increase in bacterial load [8.3 (8.1-8.6) c.f.u. ml(-1), P=0.009, and 8.4 (8.1-8.5) c.f.u. ml(-1), P=0.03, respectively]. Bacterial density was not affected by storage for up to 6 h following expectoration at 25 degrees C; beyond this, storage at 4 degrees C is preferred.