1. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial Sevim Uzun, Remco S Djamin, Jan A J W Kluytmans, Paul G H Mulder, Nils E van’t Veer, Anton A M Ermens, Aline J Pelle, Henk C Hoogsteden, Joachim G J V Aerts*, Menno M van der Eerden* Lancet Respir Med 2014; 2: 361–68 R4 김다래 /Prof. 황인경

2. INTRODUCTION COPD AE –important implications for the natural course of COPD –cause high mortality rates in patients with COPD Prevention of COPD AE –improvement of mortality rates –improvement of health-related quality of life –deceleration of further decline of lung function Prevention of COPD AE with longterm macrolide treatment is a recent development and the beneficial effect of this treatment has been postulated to result from both an antimicrobial and an immunomodulatory effect. 1.Limitation of this study at least 1 COPD AE in previous year continuous supplemental oxygen 2. increasing consumption of azithromycin → induction of macrolide resistance

3. INTRODUCTION Proposals have been made to reserve longterm macrolide treatment for patients with two or more COPD AE; however, this recommendation was not supported by findings from clinical studies. We did the COpd: infLUence of Macrolides on exacerBation freqUency in patientS (COLUMBUS) trial to investigate whether patients with COPD who had three or more exacerbations in the previous year would have a decreased rate of exacerbation when maintenance macrolide treatment was added to standard care.

4. METHODS Study design and participants Randomisation and masking Procedures Outcomes Statistical analysis Role of the funding source

5. METHODS Study design and participants –between May 19, 2010 and June 18, 2013 –single-centre trial at the Amphia Hospital (Breda, the Netherlands) –prospective, randomised, double-blind, placebo-controlled study Inclusion criteria –18 years or older and diagnosed with COPD –had received treatment for three or more exacerbations of COPD in the previous year for which they received steroids or antibiotic treatment Exclusion criteria –other respiratory diseases (asthma, cystic fibrosis) –presence of bronchiectasis –maintenance antibiotic treatment –use of more than 10mg PDL a day

6. METHODS Randomisation and masking –independent pharmacy randomly assigned patients (1:1) –computer-generated randomisation sequence with permuted blocks of ten (five per treatment group) –azithromycin dihydrate 500 mg vs. placebo –three times a week for 12 months Procedures –Participants were followed up at the outpatient department at scheduled visits at months 3, 6, 9, and 12 –spirometry, the 6 min walk test, WBC, CRP, ESR, mid-regional pro- adrenomedullin, interleukin-6, and cytokine profiles of T-cell subsets –SF-12, the St George’s Respiratory Questionnaire : every 3 months –The type-D scale : at baseline and at 12 months –Sputum culture : at baseline and at every scheduled visit –All exacerbations were defined according to Anthonisen criteria

10. 1-8 : SYMPTOMS COMPONENT

11. 11, 15 : ACTIVITY COMPONENT

12. 9-10, 12-14, 16- 17 : ACTIVITY COMPONENT

14. METHODS Outcomes [Primary endpoint] –rate of exacerbations of COPD in the year of treatment [Secondary outcomes] –time to first exacerbation –hospital admission for acute exacerbations –change in proportion of exacerbations needing admission to hospital versus treatment in an outpatient department compared with the previous year –treatment for an acute exacerbation of COPD –FEV1 after bronchodilation –FVC after bronchodilation –6 min walking test –quality of life as assessed by the SF-12 and the St George’s Respiratory Questionnaire –acquisition of macrolide resistant microorganisms in sputum –adverse events

15. METHODS Statistical analysis –The sample size was calculated with the assumption that the number of exacerbations followed a Poisson distribution with a mean rate of three exacerbations per patient per year in the placebo group. –We analysed exacerbation rate with Poisson regression, with a log-link function and the log of time-in-study as an off set variable, and with covariates of long- term, low-dose prednisolone use, number of exacerbations in the preceding year, age, sex, smoking, and FEV1. –We included all randomly assigned patients in the intention-to-treat analysis. –Time to first exacerbation was analysed with Kaplan- Meier survival analysis and log-rank test. –Secondary continuous outcome variables measured at baseline and at months 3, 6, 9, and 12 were analysed with linear mixed modelling.

16. METHODS Role of the funding source –The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication.

17. RESULTS

18. (87%)(80%)

19. RESULTS

20. 59 일 130 일 Median time to 1 st exacerbation P value=0.001

21. RESULTS This improvement in symptom score might be attributable to the reduction in exacerbations. 1. Azithromycin did not improve generic and disease specific health-related quality of life, as assessed by SF-12 and the St George’s Respiratory Questionnaire. 2. However, we noted a clinically and statistically significant average treatment effect in the symptom component score of the St George’s questionnaire in patients in the azithromycin group compared with those in the placebo group at 12 months.

22. RESULTS

23. COPD patients who 1.refractory to standard care DISCUSSION This study is the first to investigate macrolide treatment in patients with frequent exacerbations of COPD. Our findings show that treatment with azithromycin for 1 year compared with placebo –decreased the rate of exacerbations –increased time to first exacerbation We examined COPD population who were refractory to usual care In SevimIn AlbertIn Seemungal ICS92%77%78% LABA93%74%63% LAMA80%63%33% High

24. DISCUSSION We examined COPD population who have frequent exacerbation Median time to first exacerbation in the azithromycin was substantially shorter in this study In SevimIn AlbertIn Seemungal Exacerbation patients Inclusion criteria: 3 회 이상의 COPD AE(+) Inclusion 전에 COPD AE(-) : 12% Inclusion 전에 3 회 미만의 COPD AE(+) : 65% Reduction in exacerbation rate 93%74%63% High COPD patients who have 2.the frequent exacerbation In SevimIn AlbertIn Seemungal Median time to first exacerbation Azithro : 130 days (vs. 59 days) a thrice-weekly Azithro : 266 days daily Erythro : 271 days daily Shorter COPD patients who have 3.shorter median time to first exacerbation

25. DISCUSSION Macrolide treatment is an important cause of the development of macrolide resistance in oral commensal streptococcal flora. In our study, we could not explain the increase in acquisition of macrolide-resistant bacteria in the placebo group by additional use of macrolides during follow-up for any indication. Macrolides have been extensively investigated on the basis of their postulated immuno-modulatory effects. –decrease the production of pro-inflammatory cytokines in response to viral infections –decrease the hypersecretion of proinflammatory cytokines and chemokines –improve alveolar macrophage phagocytosis function –maintain integrity of the airway epithelium

26. DISCUSSION Limitation of this study –First, we had small numbers of culture-positive sputum samples for assessment of the development of antimicrobial resistance → underestimate macrolide resistance in vivo –Second, although patients were actively asked about hearing loss, no standard audiometry was done –Third, ECGs were not done as standard before and during the study (Ex: acute coronary syndrome)

27. CONCLUSION In conclusion, our results show that long-term treatment with azithromycin could be recommended in patients with COPD with the frequent exacerbator phenotype who are refractory to standard care. However, careful monitoring of the emergence of macrolide resistance is warranted.