Impact of Treatable Traits on Asthma Control and Quality of Life.

BACKGROUND: Many adult patients with asthma have uncontrolled disease and impaired quality of life, despite current asthma-specific drug therapies. OBJECTIVE: This study aimed to investigate the prevalence of 9 traits in patients with asthma, their associations with disease control and quality of life, and referral rates to nonmedical health care professionals. METHODS: Retrospectively, data from patients with asthma were collected in 2 Dutch hospitals (Amphia Breda and RadboudUMC Nijmegen). Adult patients without exacerbation <3 months who were referred for a first-ever elective, outpatient, hospital-based diagnostic pathway were deemed eligible. Nine traits were assessed: dyspnea, fatigue, depression, overweight, exercise intolerance, physical inactivity, smoking, hyperventilation, and frequent exacerbations. To assess the likelihood of having poor disease control or decreased quality of life, the odds ratio (OR) was calculated per trait. Referral rates were assessed by checking patients' files. RESULTS: A total of 444 adults with asthma were studied (57% women, age: 48 ± 16 years, forced expiratory volume in 1 second: 88% ± 17% predicted). Most patients (53%) were found to have uncontrolled asthma (Asthma Control Questionnaire ≥1.5 points) and decreased quality of life (Asthma Quality of Life Questionnaire <6 points). Generally, patients had 3.0 ± 1.8 traits. Severe fatigue was most prevalent (60%) and significantly increased the likelihood of having uncontrolled asthma (OR: 3.0, 95% confidence interval [CI]: 1.9-4.7) and decreased quality of life (OR: 4.6, 95% CI: 2.7-7.9). Referrals to nonmedical health care professionals were low; most referrals were to a respiratory-specialized nurse (33%). CONCLUSION: Adult patients with asthma with a first-ever referral to a pulmonologist frequently exhibit traits justifying the deployment of nonpharmacological interventions, especially in those with uncontrolled asthma. However, referrals to appropriate interventions appeared infrequent.

Differences in Pulmonary and Extra-Pulmonary Traits between Women and Men with Chronic Obstructive Pulmonary Disease.

Background: Evidence suggests sex-related differences in chronic obstructive pulmonary disease (COPD). Whether these differences are reflected in the prevalence of treatable traits remains unknown. Methods: Two samples of patients referred to secondary (n = 530) or tertiary care (n = 2012) were analyzed. Men and women were matched for age, forced expiratory volume in 1 s and body mass index. Sex-related differences were tested using t-tests, Mann-Whitney U, or chi-square tests. Results: Frequent exacerbations (30.5 vs. 19.7%), high cardiovascular risk (88.1 vs. 66.2%) and activity-related severe dyspnea (50.9 vs. 34.8%) were more prevalent in women in secondary care (p < 0.05). Severe hyperinflation (43.0 vs. 25.4%), limited diffusing capacity (79.6 vs. 70.1%), impaired mobility (44.0 vs. 28.7%), frequent exacerbations (66.8 vs. 57.4%), frequent hospitalizations (47.5 vs. 41.6%), severe activity-related dyspnea (89.1 vs. 85.0%), symptoms of anxiety (56.3 vs. 42.0%) and depression (50.3 vs. 44.8%), and poor health status (79.9 vs. 71.0%) were more prevalent in women in tertiary care (p < 0.05). Severe inspiratory muscle weakness (14.6 vs. 8.2%) and impaired exercise capacity (69.1 vs. 59.6%) were more prevalent among men (p < 0.05) in tertiary care. Conclusions: Sex-related differences were found, with most traits more prevalent and severe among women. Care providers should be aware of these differences to adjust treatment.

"Can Do, Do Do" Quadrants and 6-Year All-Cause Mortality in Patients With COPD.

BACKGROUND: Physical capacity (PC; "can do") and physical activity (PA; "do do") are prognostic indicators in COPD and can be used to subdivide patients with COPD into four exclusive subgroups (the so-called "can do, do do" quadrants). This concept may be useful to understand better the impact of PC and PA on all-cause mortality in patients with COPD. RESEARCH QUESTION: What is the 6-year all-cause mortality risk of the "can do, do do" quadrants of patients with COPD? STUDY DESIGN AND METHODS: This retrospective study used data from patients with COPD who underwent a comprehensive assessment at their first-ever outpatient consultation. PC was assessed using the 6-min walk distance and physical activity was assessed using an accelerometer (steps per day). All-cause mortality data were obtained from the Municipal Personal Records Database. Receiver operating characteristic curves were used to determine threshold values for PC and PA to predict 6-year all-cause mortality. Using the derived threshold values, male and female patients were divided into the four "can do, do do" quadrants. RESULTS: Data from 829 patients were used for analyses. Best discriminatory values for 6-year mortality were 404 m and 4,125 steps/day for men and 394 m and 4,005 steps/day for women. During a median follow-up of 55 months (interquartile range, 37-71 months), 129 patients (15.6%) died. After controlling for established prognostic factors, patients in the "can do, don't do" quadrant and "can do, do do" quadrant showed significantly lower mortality risk compared with patients in the "can't do, don't do" quadrant: hazard ratios of 0.36 (95% CI, 0.14-0.93) and 0.24 (95% CI, 0.09-0.61) for men and 0.37 (95% CI, 0.38-0.99) and 0.29 (95% CI, 0.10-0.87) for women, respectively. No significant differences were found between the "can't do, do do" and "can't do, don't do" quadrants. INTERPRETATION: Patients with COPD with a preserved PC seem to have a significantly lower 6-year mortality risk compared with patients with a decreased PC, regardless of physical activity level.

Prevalence of hyperventilation in patients with asthma.

OBJECTIVE: Asthma is frequently accompanied by dysfunctional breathing of which hyperventilation has been recognized as a subtype. The prevalence of hyperventilation in stable asthma has been scantily studied using blood gas analysis. Hence, a reliable estimate of its prevalence is lacking. It is unknown whether the Nijmegen Questionnaire (NQ) is a useful screening tool for hyperventilation in asthma. Therefore, the primary aim of this study was to determine the prevalence of hyperventilation in a large sample of patients with asthma in a stable state of disease. Secondary aims were to compare the clinical characteristics between patients with and without hyperventilation, and, to examine the concurrent validity of the NQ to detect hypocapnia in patients with asthma. METHODS: A real-world, observational, multicenter study was conducted. Capillary blood gas analysis was performed in adults with a confirmed diagnosis of stable asthma. A subset of patients completed the NQ. RESULTS: A blood gas analysis was obtained in 1006 patients. In 17% of the patients an acute hyperventilation was found, and in another 23% a chronic hyperventilation was uncovered. Patients with a chronic hyperventilation blood gas were more often female, were younger and had a better spirometric outcomes. The NQ appeared not to correlate with PCO2. CONCLUSION: Hyperventilation is common in patients with stable asthma. Chronic hyperventilation is more often found in females of younger age and with the best spirometric outcomes compared to patients without hyperventilation. The NQ is not a suitable screening tool for the presence of hyperventilation in stable asthmatics.

Characteristics and treatable traits of patients with chronic obstructive pulmonary disease (COPD) with and without paid employment.

INTRODUCTION: Patients with COPD are vulnerable to workforce detachment. Better knowledge of features associated with paid work loss might be of help to design and select appropriate interventions. METHOD: This cross-sectional study aimed to explore the presence of treatable traits in COPD patients without paid work. Patients with COPD below 65 years at first referral to a hospital-based patient clinic were included. Using binary logistic regression analysis, the relationship between paid work and the following characteristics was explored: low daily physical activity, exercise, active smoking, Medical Research Council dyspnea scale (MRC), poor nutritional status, exacerbations, and fatigue (checklist individual strength (CIS)). Variables were adjusted for age, sex, forced expiratory volume in 1 s (FEV 1), and education level. RESULTS: In total, 191 patients (47.3%) were without paid work. The following treatable traits were related to not being in paid work: < 5000 steps/day (OR 2.36, 95% CI (1.52-3.68)), MRC ≥ 3 (OR 1.78, 95%CI (1.14-2.77)), CIS ≥ 36 points (OR 1.78, 95% CI (1.10-2.87)), six-minute walk distance (6MWD) < 70% of predicted (OR 2.62, 95% CI (1.69-4.06)), and ≥ 2 exacerbations per year (OR 1.80, 95% CI (1.12-2.92)). Significant differences were also seen in age (OR 1.06, 95% CI (1.02-1.10) per year), FEV 1% predicted (OR 0.98, 95% CI (0.97-1.00) per % predicted increase), and medium/high education level (OR 0.62, 95% CI (0.41-0.93)). When adjusting for all variables the only treatable trait that remained significant was 6MWD. CONCLUSION: Patients without paid work are more likely to have treatable traits with 6MWD revealing the most significant association.

Long-Term Azithromycin Maintenance Treatment in Patients with Frequent Exacerbations of Chronic Obstructive Pulmonary Disease.

Macrolides are effective in reducing the number of exacerbations in COPD patients with the frequent exacerbator phenotype. Our study did not show a persistent effect of azithromycin on exacerbation frequencies after more than one year of usage.

"Can Do" Versus "Do Do" in Patients with Asthma at First Referral to a Pulmonologist.

BACKGROUND: Pharmacotherapy is key in asthma control, including preventing lung function decline, in primary care. However, patients' physical functioning (eg, physical capacity [PC] [=can do] and physical activity [PA] [=do do]) correlates poorly with lung function. Therefore, a better insight into the physical function of patients with asthma is needed, using the "can do, do do" concept. OBJECTIVE: To explore the "can do, do do" concept in adult patients with asthma at referral for the first time to an outpatient consultation of a pulmonologist. METHODS: PC was measured using the six-minute walk test and PA by using an accelerometer. Patients were classified into quadrants: low PC (6-minute walking distance <70% predicted), low PA (<7000 steps/d, "'can't do, don't do"); preserved PC, low PA ("can do, don't do"); low PC, preserved PA ("'can't do, do do"); or preserved PC, preserved PA ("can do, do do"). RESULTS: A total of 479 patients with asthma had a median (interquartile range) 6-minute walking distance of 74% (66%-82%) predicted, and walked 6829 (4593-9075) steps/d. Only 29% were classified as "can do, do do," whereas 30% were classified as "can't do, don't do." The Asthma Control Questionnaire and the Asthma Quality of Life Questionnaire scores were worst in the "can't do" groups. CONCLUSIONS: Low PC and/or PA was found in most patients with asthma at the index referral to a pulmonologist. An impaired PC is accompanied by a significantly reduced asthma control and disease-specific quality of life. This justifies further studies on safety and efficacy of nonpharmacological interventions, such as physiotherapy.

Treatable traits qualifying for nonpharmacological interventions in COPD patients upon first referral to a pulmonologist: the COPD sTRAITosphere.

INTRODUCTION: The present study assessed the prevalence of nine treatable traits (TTs) pinpointing nonpharmacological interventions in patients with COPD upon first referral to a pulmonologist, how these TTs co-occurred and whether and to what extent the TTs increased the odds having a severely impaired health status. METHODS: Data were collected from a sample of 402 COPD patients. A second sample of 381 patients with COPD was used for validation. Nine TTs were assessed: current smoking status, activity-related dyspnoea, frequent exacerbations <12 months, severe fatigue, depressed mood, poor physical capacity, low physical activity, poor nutritional status and a low level of self-management activation. For each TT the odds ratio (OR) of having a severe health status impairment was calculated. Furthermore, a graphic representation was created, the COPD sTRAITosphere, to visualise TTs prevalence and OR. RESULTS: On average 3.9±2.0 TTs per patient were observed. These TTs occurred relatively independently of each other and coexisted in 151 unique combinations. A significant positive correlation was found between the number of TTs and Clinical COPD Questionnaire total score (r=0.58; p<0.001). Patients with severe fatigue (OR: 8.8), severe activity-related dyspnoea (OR: 5.8) or depressed mood (OR: 4.2) had the highest likelihood of having a severely impaired health status. The validation sample corroborated these findings. CONCLUSIONS: Upon first referral to a pulmonologist, COPD patients show multiple TTs indicating them to several nonpharmacological interventions. These TTs coexist in many different combinations, are relatively independent and increase the likelihood of having a severely impaired health status.

Prevalence and abundance of selected genes conferring macrolide resistance genes in COPD patients during maintenance treatment with azithromycin.

OBJECTIVES: Maintenance treatment with macrolide antibiotics has shown to be effective in reducing exacerbations in COPD patients. A major concern with prolonged treatment with antibiotics is the development of bacterial resistance. In this study we determined the effect of azithromycin on the development and acquisition of resistance to macrolides in the nasopharyngeal flora in COPD patients. METHODS: This study was part of the COLUMBUS trial, a randomised, double-blind, placebo-controlled trial to measure the effect of maintenance treatment with azithromycin in 92 COPD patients on the exacerbation rates during a 12-month period. In order to determine resistance to macrolides, we used a targeted metagenomic approach to measure the presence and relative abundance of specific macrolide resistance genes ermB, ermF and mefA in throat samples collected at different time-points during this 12-month period. RESULTS: There was no increased risk for acquisition of macrolide resistance genes in the azithromycin group compared to the placebo group in COPD patients. However, loss of the macrolide resistance gene ermB was increased overtime in the placebo treated group compared to the azithromycin group (n = 5 for the placebo group versus n = 0 for the azithromycin group at 12 months; p = 0.012). The change in relative abundance of the three macrolide-resistance genes showed that all but one (ermF) increased during treatment with azithromycin. CONCLUSIONS: The acquisition rate of macrolide resistance genes in COPD patients treated with azithromycin maintenance therapy was limited, but the relative abundance of macrolide resistance genes increased significantly over time compared to placebo. This study was part of the COLUMBUS trial ( Clinicaltrials.gov , NCT00985244 ).

Fatigue is highly prevalent in patients with COPD and correlates poorly with the degree of airflow limitation.

BACKGROUND: The objective of this study was to compare fatigue levels between subjects with and without COPD, and to investigate the relationship between fatigue, demographics, clinical features and disease severity. METHODS: A total of 1290 patients with COPD [age 65 ± 9 years, 61% male, forced expiratory volume in 1 s (FEV1) 56 ± 19% predicted] and 199 subjects without COPD (age 63 ± 9 years, 51% male, FEV1 112 ± 21% predicted) were assessed for fatigue (Checklist Individual Strength-Fatigue), demographics, clinical features and disease severity. RESULTS: Patients with COPD had a higher mean fatigue score, and a higher proportion of severe fatigue (CIS-Fatigue score 35 ± 12 versus 21 ± 11 points, p < 0.001; 49 versus 10%, p < 0.001). Fatigue was significantly, but poorly, associated with the degree of airflow limitation [FEV1 (% predicted) Spearman correlation coefficient = -0.08, p = 0.006]. Multiple regression indicated that 30% of the variance in fatigue was explained by the predictor variables. CONCLUSIONS: Severe fatigue is prevalent in half of the patients with COPD, and correlates poorly with the degree of airflow limitation. Future studies are needed to better understand the physical, psychological, behavioural, and systemic factors that precipitate or perpetuate fatigue in COPD.

Blood eosinophil count and GOLD stage predict response to maintenance azithromycin treatment in COPD patients with frequent exacerbations.

INTRODUCTION: Maintenance treatment with macrolides are useful in preventing COPD exacerbations. We investigated which characteristics of COPD patients with frequent exacerbations predicted the best response to maintenance treatment with azithromycin. METHODS: This study was part of the COLUMBUS trial, a prospective randomized, double-blind, placebo-controlled study in 92 COPD patients with frequent exacerbations. During the 1-year treatment period, follow-up data were collected for spirometry, mMRC scores, sputum cultures and blood inflammatory markers. RESULTS: In the azithromycin group a significant lower number of exacerbations per patient was observed in patients with the following characteristics: baseline blood eosinophil count ≥2.0% (x̄ = 1.26), compared to an eosinophil count < 2.0% (x̄ = 2.50; p = 0.02), GOLD stage 1-2 (x̄ = 1.06), versus GOLD stage 4 (x̄ = 2.62; p = 0.02) and GOLD group C (x̄ = 0.45) compared to group D (x̄ = 2.18; p < 0.01). Moreover, the number of hospitalizations was significantly lower in patients, with a blood eosinophil count ≥2.0% (x̄ = 0.26) compared to an eosinophil count < 2.0% (x̄ = 0.90; p = 0.01) and in GOLD stages 1-2 (x̄ = 1.06) compared to stage 4 (x̄ = 2.62; p = 0.04). CONCLUSION: In conclusion, azithromycin maintenance treatment appears to be effective in COPD patients with frequent exacerbations, who are either classified in GOLD stage 1-2 or GOLD C and those with a blood eosinophil count of ≥2.0%.

"Can do" versus "do do": A Novel Concept to Better Understand Physical Functioning in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Physical capacity (PC) and physical activity (PA) represent associated but separate domains of physical function. It remains unknown whether this framework may support a better understanding of the impaired physical function in patients with chronic obstructive pulmonary disease (COPD). The current study had two aims: (1) to determine the distribution of patients with COPD over the PC-PA quadrants, and (2) to explore whether differences exist in clinical characteristics between these quadrants. METHODS: In this retrospective study, PC was measured using the six-minute walk distance (6MWD), and PA was assessed with an accelerometer. Moreover, patients' clinical characteristics were obtained. Patients were divided into the following quadrants: (I) low PC (6MWD <70% predicted), low PA, using a step-defined inactivity index (<5000 steps/day, "can't do, don't do" quadrant); (II) preserved PC, low PA ("can do, don't do" quadrant); (III) low PC, preserved PA ("can't do, do do" quadrant); and (IV) preserved PC, preserved PA ("can do, do do" quadrant). RESULTS: The distribution of the 662 COPD patients over the quadrants was as follows: "can't do, don't do": 34%; "can do, don't do": 14%; "can't do, do do": 21%; and "can do, do do": 31%. Statistically significant differences between quadrants were found for all clinical characteristics, except for educational levels. CONCLUSIONS: This study proves the applicability of the PC-PA quadrant concept in COPD. This concept serves as a pragmatic clinical tool, that may be useful in the understanding of the impaired physical functioning in COPD patients and therefore, may improve the selection of appropriate interventions to improve physical function.

Fatigue is Highly Prevalent in Patients with Asthma and Contributes to the Burden of Disease.

The 2018 update of the Global Strategy for Asthma Management and Prevention does not mention fatigue-related symptoms. Nevertheless, patients with asthma frequently report tiredness, lack of energy, and daytime sleepiness. Quantitative research regarding the prevalence of fatigue in asthmatic patients is lacking. This retrospective cross-sectional study of outpatients with asthma upon referral to a chest physician assessed fatigue (Checklist Individual Strength-Fatigue (CIS-Fatigue)), lung function (spirometry), asthma control (Asthma Control Questionnaire (ACQ)), dyspnea (Medical Research Council (MRC) scale), exercise capacity (six-minute walk test (6MWT)), and asthma-related Quality-of-Life (QoL), Asthma Quality of Life Questionnaire (AQLQ) during a comprehensive health-status assessment. In total, 733 asthmatic patients were eligible and analyzed (47.4 ± 16.3 years, 41.1% male). Severe fatigue (CIS-Fatigue ≥ 36 points) was detected in 62.6% of patients. Fatigue was not related to airflow limitation (FEV1, ρ = -0.083); was related moderately to ACQ (ρ = 0.455), AQLQ (ρ = -0.554), and MRC (ρ = 0.435; all p-values < 0.001); and was related weakly to 6MWT (ρ = -0.243, p < 0.001). In stepwise multiple regression analysis, 28.9% of variance in fatigue was explained by ACQ (21.0%), MRC (6.5%), and age (1.4%). As for AQLQ, 42.2% of variance was explained by fatigue (29.8%), MRC (8.6%), exacerbation rate (2.6%), and age (1.2%). Severe fatigue is highly prevalent in asthmatic patients; it is an important determinant of disease-specific QoL and a crucial yet ignored patient-related outcome in patients with asthma.

Circulating desmosine as a biomarker of azithromycin treatment response: a post hoc analysis of the COLUMBUS randomised controlled trial.

Circulating desmosine is not reduced by treatment with azithromycin in COPD but elevated desmosine may identify a patient group with a greater treatment response http://ow.ly/vN6N30mhBA1.

Prognostic assessment in COPD without lung function: the B-AE-D indices.

Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function.The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.

Occurrence of virus-induced COPD exacerbations during four seasons.

In this study, we investigated the occurrence of viral infections in acute exacerbations of chronic obstructive pulmonary disease (COPD) during four seasons. Viral infections were detected by the use of real-time reverse transcriptase polymerase chain reaction on pharyngeal swabs. During a 12-month period pharyngeal swabs were obtained in 136 exacerbations of 63 patients. In 35 exacerbations (25.7%) a viral infection was detected. Most viral infections occurred in the winter (n = 14, 40.0%), followed by summer (n = 9, 25.7%), autumn (n = 6, 17.1%), and spring (n = 6, 17.1%). Rhinovirus was the most frequently isolated virus (n = 19, 51.4%), followed by respiratory syncytial virus (n = 6, 16.2%), human metapneumovirus (n = 5, 13.5%), influenza A (n = 4, 10.8%), parainfluenza 4 (n = 2, 5.4%), and parainfluenza 3 (n = 1, 2.7%). This study showed that virus-induced COPD exacerbations occur in all four seasons with a peak in the winter months. However, the distribution of rhinovirus infections showed a different pattern, with most infections occurring in July.

[Acute respiratory insufficiency due to COPD: invasive mechanical ventilation or not?]. / Acute respiratoire insufficiëntie door COPD: beslissen over wel of niet beademen.

The decision to move to a form of mechanical ventilation in patients with acute respiratory failure due to an acute exacerbation of COPD is influenced by expectations about survival and quality of life after discharge from the ICU. Physicians tend to be too pessimistic about the survival outcome of an ICU stay with invasive mechanical ventilation. The forced expiratory volume in 1 second (FEV1) is not an adequate prognostic parameter. In order to prevent undertreatment of patients with respiratory failure due to an exacerbation of COPD, knowledge of prognostic parameters and quality of life in these patients is very important. End of life care should be integrated into the standard care of COPD patients.

Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care. METHODS: We did a randomised, double-blind, placebo-controlled, single-centre trial in The Netherlands between May 19, 2010, and June 18, 2013. Patients (≥18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone (≤10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00985244. FINDINGS: We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1·94 (95% CI 1·50-2·52) for the azithromycin group and 3·22 (2·62-3·97) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0·58, 95% CI 0·42-0·79; p=0·001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0·015). INTERPRETATION: Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care. FUNDING: SoLong Trust.

Influence of macrolide maintenance therapy and bacterial colonisation on exacerbation frequency and progression of COPD (COLUMBUS): study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by progressive development of airflow limitation that is poorly reversible. Because of a poor understanding of COPD pathogenesis, treatment is mostly symptomatic and new therapeutic strategies are limited. There is a direct relationship between the severity of the disease and the intensity of the inflammatory response. Besides smoking, one of the hypotheses for the persistent airway inflammation is the presence of recurrent infections. Macrolide antibiotics have bacteriostatic as well as anti-inflammatory properties in patients with cystic fibrosis and other inflammatory pulmonary diseases. There is consistent evidence that macrolide therapy reduces infectious exacerbations, decreases the requirement for additional antibiotics and improves nutritional measures. Because of these positive effects we hypothesised that maintenance macrolide therapy may also have beneficial effects in patients with COPD who have recurrent exacerbations. The effects on development of bacterial resistance to macrolides due to this long-term treatment are unknown. Until now, studies investigating macrolide therapy in COPD are limited. The objective of this study is to assess whether maintenance treatment with macrolide antibiotics in COPD patients with three or more exacerbations in the previous year decreases the exacerbation rate in the year of treatment and to establish microbial resistance due to the long-term treatment. METHODS/DESIGN: The study is set up as a prospective randomised double-blind placebo-controlled single-centre trial. A total of 92 patients with COPD who have had at least three exacerbations of COPD in the previous year will be included. Subjects will be randomised to receive either azithromycin 500 mg three times a week or placebo. Our primary endpoint is the reduction in the number of exacerbations of COPD in the year of treatment. DISCUSSION: We investigate whether long-term therapy with macrolide antibiotics can prevent exacerbations in patients with COPD. Additionally, our study aims to assess the effect of long-term use of macrolide on the development of antimicrobial resistance and on inflammatory parameters related to COPD. We believe this study will provide more data on the effects of macrolide treatment in patients in COPD and will add more knowledge on its working mechanisms. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00985244.