Colonisation with Pseudomonas aeruginosa and antibiotic resistance patterns in COPD patients. K. Engler, K. Mühlemann, C. Garzoni, H. Pfahler, T. Geiser, G. von. Swiss Med Wkly. 2012 Jan 30;142:0.
QUESTIONS: P. aeruginosa infections are assumed to play a major role in the frequency of exacerbations and severity of chronic obstructive pulmonary disease(COPD). Colonisation with P. aeruginosa accelerates lung function decline, most probably due to more frequent exacerbations. In this retrospective study we aimed to determine the prevalence of colonisation with P. aeruginosa in COPD patients treated in a tertiary hospital centre.
METHODS: 112 patients diagnosed with COPD testing positive for P. aeruginosa in at least one respiratory sample during the study period (2004–2008) were retrospectively analysed to estimate GOLD stage-specific prevalences, colonisation patterns, morphology and antibiotic resistance profiles of P. aeruginosa strains.
RESULTS: Colonisation with P. aeruginosa was present in all COPD stages, but prevalence significantly increased with disease severity (GOLD 1: 0.7%, GOLD 2: 1.5%; GOLD 3: 1.5%; GOLD 4: 2.6%; p = 0.0003). 41% of COPD patients with P. aeruginosa-positive respiratory samples were chronic carriers, of whom 8% had mucoid strains. Carriage of a mucoid strain was associated with advanced COPD stage GOLD 4 (p = 0.01). Resistance to cephalosporins was most frequently encountered and resistance to ciprofloxacin was found in more advanced stages of COPD.
CONCLUSIONS: Colonisation with P. aeruginosa was present in all COPD severity stages and colonisation with mucoid strains was more frequent in advanced COPD. Resistance to the only oral anti-pseudomonas antibiotic ciprofloxacin was more frequently encountered in severe COPD stages.
Comments: Several studies have shown that exacerbations are more frequent in COPD patients with more severe disease. Considering the potential concerns about increased rates of pneumonia in COPD patients on inhaled corticosteroids and the recent findings of benefits of Azithromycin in reducing COPD exacerbations (although Azithromycin was most effective in patients with less severe disease) this study supports the notion the a sub-population of patients with frequent exacerbations may have chronic colonization with resistant organisms. Further studies are needed to elucidate whether there is benefit to culturing patients with frequent exacerbation to identify those with colonization, identifying microbial species and resistance patterns and considering prophylactic antibiotic therapy based on these results. It is not dissimilar from the debate with regard to CF and/or bronchiectasis patients. The development of inhaled antibiotic therapies such as aztreonam may make such evaluations important for patients with COPD in future.
Low-dose Azithromycin improves phagocytosis of bacteria by both alveolar and monocyte-derived macrophagesin COPD subjects. S. Hodge, PN Reynolds, Respirology. 2012 Jan 31.
SUMMARY AT A GLANCE: Low-dose azithromycin improves the ability of both alveolar macrophages and monocyte derived macrophages to phagocytose bacteria. This further supports the long term use of low dose azithromycin as an attractive adjunct treatment option for reducing inflammation, bacterial colonization and exacerbation rate in COPD.
BACKGROUND AND OBJECTIVE: Chronic inflammation and reduced airways integrity in COPD potentially results from secondary necrosis as a result of impaired phagocytosis of apoptotic material by airway macrophages, and increased bacterial colonization. We have previously shown that administration of low-dose azithromycin to subjects with COPD improved macrophage phagocytosis of apoptotic airway epithelial cells, reduced inflammation and increased expression of macrophage mannose receptor.
Methods: We firstly investigated whether there were defects in the ability of both alveolar (AM) or monocyte-derived macrophages (MDM) to phagocytose bacteria in COPD, as we have previously reported for phagocytosis of apoptotic cells. We then assessed the effects of administration of low-dose azithromycin to COPD patients on the ability of AM and MDM to phagocytose bacteria. Azithromycin (250mg orally daily for five days then 2x weekly (total 12 weeks)) was administered to 11 COPD subjects and phagocytosis of FITC-labelled E. coli assessed by flow cytometry.
Results: COPD subjects had a significant defect in the ability of both AM and MDM to phagocytose bacteria that was significantly improved by administration of low-dose azithromycin.
Conclusions: The data provide further support for the long term use of low dose azithromycin as an attractive adjunct treatment option for COPD. Improved clearance of both apoptotic cells and bacteria in the airway may have a dual effect; reducing the risk of secondary necrosis and release of toxic cell contents that perpetuate inflammation as well as contributing to a reduction in the rate of exacerbations in COPD.
Comments: A recent large US NIH funded study found benefit to treating COPD patients with azithromycin daily for 1 year in reducing exacerbations but many questions remain with regard to the underlying mechanism and perhaps appropriate patient selection. This study adds further insight into the potential mechanisms of action for macrolide antibiotic therapy in COPD patients with frequent exacerbations and indeed suggests underlying biological characteristics (with regard to macrophage function) that may make certain COPD patients more prone to chronic colonization and/or frequent exacerbations.
Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. C.R. Jenkins, B. Celli, J.A. Anderson, G.T. Ferguson, P.W. Jones, .Vestbo, .C. Yates, P.M. Calverley. Eur Respir J. 2012 Jan;39(1):38–45. Epub 2011 Jul 7.
We investigated the impact of season relative to other determinants of chronic obstructive pulmonary disease (COPD) exacerbation frequency in a long-term international study of patients with forced expiratory volume in 1 s (FEV(1)) <60% predicted. COPD exacerbations were defined by worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate) or hospital admission (severe). Seasonality effect was calculated as the proportion of patients experiencing an exacerbation each month. Exacerbations in the northern and southern regions showed an almost two-fold increase in the winter months. No seasonal pattern occurred in the tropics. Overall, 38% of exacerbations were treated with antibiotics only, 19% with systemic corticosteroids only and 43% with both, while 20% required hospital admission irrespective of the season. Exacerbation frequency was associated with older age, lower body mass index, lower FEV(1)% pred and history of prior exacerbations. Females and patients with worse baseline breathlessness, assessed using the Medical Research Council (MRC) dyspnoea scale, exacerbated more often (rate ratio (RR) for male versus female 0.7, 95% CI 0.7–0.8 (p < 0.001); RR for MRC dyspnoea score 3 versus 1 and 2 combined 1.1, 95% CI 1.1–1.2 (p < 0.001)). The effect of season was independent of these risk factors. COPD exacerbations and hospitalisations were more frequent in winter.
Comments: While it is commonly accepted that exacerbations are more frequent during winter months, the exact reasons for this remain unclear. It is interesting to note that there does not seem to be the same increase in tropical settings during winter months and this observation helps to further refine our thoughts about possible reasons for the increase during this period of the year. Ultimately further investigations in this area may lead to improved prevention strategies for the winter months.
High doses of vitamin d to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. A. Lehouck, C. Mathieu, . Carremans, F. Baeke, J.Verhaegen, J. Van Eldere, B. Decallonne, R. Bouillon, M. Decramer, W. Janssens. Ann Intern Med. 2012 Jan 17;156(2):105–14.
Background: Low serum 25-hydroxyvitamin D (25-[OH]D) levels have been associated with lower FEV(1), impaired immunologic control, and increased airway inflammation. Because many patients with chronic obstructive pulmonary disease (COPD) have vitamin D deficiency, effects of vitamin D supplementation may extend beyond preventing osteoporosis.
Objective: To explore whether supplementation with high doses of vitamin D could reduce the incidence of COPD exacerbations.
Design: Randomized, single-center, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00666367)
Setting: University Hospitals Leuven, Leuven, Belgium. Patients: 182 patients with moderate to very severe COPD and a history of recent exacerbations. Intervention: 100 000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year.
Measurements: The primary outcome was time to first exacerbation. Secondary outcomes were exacerbation rate, time to first hospitalization, time to second exacerbation, FEV(1), quality of life, and death.
Results: Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group (mean between-group difference, 30 ng/mL [95% CI, 27 to 33 ng/mL]; P < 0.001). The median time to first exacerbation did not significantly differ between the groups (hazard ratio, 1.1 [CI, 0.82 to 1.56]; P = 0.41), nor did exacerbation rates, FEV(1), hospitalization, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) at baseline showed a significant reduction in exacerbations in the vitamin D group (rate ratio, 0.57 [CI, 0.33 to 0.98]; P = 0.042). Limitation: This was a single-center study with a small sample size.
Conclusion: High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations. In participants with severe vitamin D deficiency at baseline, supplementation may reduce exacerbations. Primary Funding Source: Applied Biomedical Research Program, Agency for Innovation by Science and Technology (IWT-TBM).
Comments: There has been a great deal of interest in Vitamin D and its potential role in COPD (and just about every other chronic illness). This study demonstrates no benefit except in those that have a severe vitamin D deficiency < 10 ng/mL may benefit. This is a very small sample size and a novel dosing schedule such that it cannot be considered to be a definitive trial by any means. There are other large scale trials addressing this issue and it will be interesting to see if they have similar findings These results do give pause however and suggest that we should not necessarily be jumping to put every COPD patient with low vitamin D levels (or normal levels) on Vitamin D supplementation.