Dataset Information

Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations.

ABSTRACT:

Rationale

Proline-glycine-proline (PGP), a neutrophil chemoattractant derived from the enzymatic breakdown of collagen, is elevated in sputum of patients with chronic obstructive pulmonary disease (COPD) and may contribute to disease progression. Whether sputum levels of PGP respond to therapy for COPD or predict outcomes is unknown.

Objectives

We conducted a study ancillary to a multicenter trial of the efficacy of azithromycin treatment for 1 year in preventing COPD exacerbations to test whether sputum levels of PGP were altered by treatment or associated with exacerbation frequency.

Methods

We collected remnant sputa from trial participants and assayed them in a blinded fashion for PGP, myeloperoxidase and matrix metalloproteinase (MMP)-9 and for the ability to generate PGP from collagen ex vivo. Once the parent trial was unblinded, the results were correlated with use of azithromycin or placebo and exacerbations in participants.

Results

Azithromycin treatment significantly reduced sputum levels of PGP and myeloperoxidase in patients with COPD, particularly with increased duration of therapy. We found no difference in sputum MMP-9 or PGP generation between participants taking azithromycin or placebo. Sputum PGP levels were highest around the time of an exacerbation and declined with successful treatment.

Conclusions

These data support a role for PGP in the airway and parenchymal neutrophilic inflammation that drives COPD progression and exacerbations, and provide new information on the anti-inflammatory properties of macrolides. PGP may have potential as a target for novel anti-inflammatory therapies in COPD and as a biomarker for clinical trials.

SUBMITTER: O'Reilly PJ

PROVIDER: S-EPMC3884851 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Publications

Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations.

O'Reilly Philip J PJ Jackson Patricia L PL Wells J Michael JM Dransfield Mark T MT Scanlon Paul D PD Blalock J Edwin JE

BMJ open 20131223 12

<h4>Rationale</h4>Proline-glycine-proline (PGP), a neutrophil chemoattractant derived from the enzymatic breakdown of collagen, is elevated in sputum of patients with chronic obstructive pulmonary disease (COPD) and may contribute to disease progression. Whether sputum levels of PGP respond to therapy for COPD or predict outcomes is unknown.<h4>Objectives</h4>We conducted a study ancillary to a multicenter trial of the efficacy of azithromycin treatment for 1 year in preventing COPD exacerbation ...[more]

PMID: 24366582

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Project description:BackgroundAcute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.MethodsWe performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.ResultsA total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).ConclusionsAmong selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Project description:BackgroundChronic obstructive pulmonary disease (COPD) is a prevalent, progressive respiratory disease, and acute exacerbations of COPD (AECOPD) can accelerate the deterioration of the disease. Increasing evidence suggests that airway bacterial dysbiosis is associated with AECOPD. However, the exact relationship between changes in the sputum microbiome during AECOPD and clinical indices remains unclear.MethodsIn this study, a total of 76 sputum samples were collected from patients with AECOPD (n = 28), stable COPD (n = 23), recovery (n = 15) and healthy controls (HCs; n = 10). The sputum microbiome profile was analysed by sequencing the V3‑V4 amplicon of the 16S rRNA (ribosomal RNA) gene.ResultsThe bacterial diversity (Shannon and Simpson's index) was found to be significantly decreased in the AECOPD and recovery groups when compared to that in the stable COPD and HC groups. The most dominant phylum identified in the sputum samples of AECOPD patients was Proteobacteria, accounting for 30% of the microbiome. Compared to the stable COPD groups, the relative abundances of Firmicutes and Bacteroidetes were decreased, whereas those of Proteobacteria and Actinobacteria were increased in AECOPD patients. Furthermore, discriminative bacteria, such as Haemophilus, were identified as being specific taxa in AECOPD patients. Functional analysis showed that genes involved in membrane transport and signal transduction metabolism were enriched in the AECOPD group. Importantly, the proportions of Veillonella were positively correlated with lung function, and Staphylococcus was positively correlated with inflammatory indices.ConclusionOur study revealed variations in the sputum microbiome of AECOPD (based on composition and function) in a Chinese cohort and highlighted its correlation to clinical indices. These results indicated that microbial dysbiosis may contribute to disease progression and provide microbial biomarkers for the diagnosis of AECOPD.

Dataset Information

Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations.

Rationale

Objectives

Methods

Results

Conclusions

Publications

Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations.

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