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Abstract
Rationale: Chronic infection with Pseudomonas aeruginosa is associated with an increased exacerbation frequency, a more rapid decline in lung function, and increased mortality in patients with bronchiectasis.
Objectives: To perform a randomized placebo-controlled study assessing the efficacy and safety of inhaled colistin in patients with bronchiectasis and chronic P. aeruginosa infection.
Methods: Patients with bronchiectasis and chronic P. aeruginosa infection were enrolled within 21 days of completing a course of antipseudomonal antibiotics for an exacerbation. Participants were randomized to receive colistin (1 million IU; n = 73) or placebo (0.45% saline; n = 71) via the I-neb twice a day, for up to 6 months.
Measurements and Main Results: The primary endpoint was time to exacerbation. Secondary endpoints included time to exacerbation based on adherence recorded by the I-neb, P. aeruginosa bacterial density, quality of life, and safety parameters. All analyses were on the intention-to-treat population. Median time (25% quartile) to exacerbation was 165 (42) versus 111 (52) days in the colistin and placebo groups, respectively (P = 0.11). In adherent patients (adherence quartiles 2–4), the median time to exacerbation was 168 (65) versus 103 (37) days in the colistin and placebo groups, respectively (P = 0.038). P. aeruginosa density was reduced after 4 (P = 0.001) and 12 weeks (P = 0.008) and the St. George’s Respiratory Questionnaire total score was improved after 26 weeks (P = 0.006) in the colistin versus placebo patients, respectively. There were no safety concerns.
Conclusions: Although the primary endpoint was not reached, this study shows that inhaled colistin is a safe and effective treatment in adherent patients with bronchiectasis and chronic P. aeruginosa infection.
Clinical trial registered with http://www.isrctn.org/ (ISRCTN49790596)
Chronic infection with Pseudomonas aeruginosa affects 12–27% of adults with bronchiectasis and is associated with increased exacerbation frequency and poor clinical outcomes. The evidence base supporting the use of nebulized antibiotics in these patients is weak.
This randomized controlled study shows improved clinical and patient-reported outcomes with colistin administered through the I-neb adaptive aerosol delivery device in adherent patients with bronchiectasis and chronic P. aeruginosa infection.
Individuals with bronchiectasis present with symptoms of persistent or recurrent bronchial sepsis related to irreversibly damaged and dilated bronchi (1). Recent data showing a direct relationship between bacterial load, airway inflammation, and risk of exacerbation are consistent with the “vicious cycle hypothesis” of bronchiectasis (2, 3) and support the rationale for antibiotic prophylaxis (4).
Chronic infection with Pseudomonas aeruginosa affects 12–27% of adults with bronchiectasis (5–10) and is associated with an increased exacerbation frequency (8), an accelerated rate of FEV1 decline (7), more extensive bronchiectasis on computed tomography (11), and increased mortality (12). Because of the worse clinical outcomes associated with chronic infection with P. aeruginosa, the British Thoracic Society guidelines on bronchiectasis recommend the prescription of nebulized antibiotics in such patients if they have a high infection frequency (1). However, the evidence base for this recommendation is weak. Studies evaluating nebulized tobramycin demonstrated excellent microbiologic outcomes, but the formulations tested were poorly tolerated (13–15). A subsequent study of nebulized gentamicin in patients with predominantly Haemophilus influenzae (46%) or P. aeruginosa (42%) reported better tolerability and marked improvements in bacterial load, exacerbation frequency, exercise tolerance, and patient-reported outcomes (16). Recent phase II studies of dry powder and liposomal formulations of inhaled ciprofloxacin have shown encouraging results including marked reductions in P. aeruginosa bacterial density (17, 18), but an international phase III study of nebulized aztreonam conducted in similar patients failed to meet its efficacy endpoints and was associated with a high incidence of adverse events (AEs) (19).
Nebulized colistin is commonly prescribed for patients with bronchiectasis in Europe (20), but has not been evaluated in a clinical study setting to date. We performed a randomized, double-blind, placebo-controlled study of nebulized colistin administered through the I-neb adaptive aerosol delivery device (Philips Respironics, Chichester, UK) in patients with bronchiectasis and chronic P. aeruginosa infection. The I-neb is a unique device that monitors the time and peak flow of the first three breaths during nebulization and then pulses aerosol at the start of the inspiratory phase to optimize drug delivery (21). Nebulization is silent, it takes approximately 3 minutes, and the device informs the patient when the dose has been delivered. It also provides a precise record of nebulizer use through an electronic download.
Some of the results of this study have been previously reported in the form of abstracts (22–24).
The study was conducted at 35 centers in the United Kingdom, Russia, and Ukraine. Participants were 18 years of age or older, had bronchiectasis confirmed by computed tomography, had two or more positive respiratory tract cultures for P. aeruginosa in the preceding 12 months, and were within 21 days of completing a course of antipseudomonal antibiotics for the treatment of an exacerbation. P. aeruginosa also had to be cultured from a sputum sample taken at the screening visit.
Participants provided written informed consent. The study was approved by the central Independent Ethics Committee for each country.
Participants were randomly allocated (1:1) to colistin, 1 million international units, in 1-ml 0.45% saline or placebo (1 ml 0.45% saline). The investigator and study participants were masked to treatment allocation.
The first dose was administered under supervision and patients with 15% or more reduction in FEV1 within 30 minutes of nebulization were withdrawn. Those that remained in the study administered the study drug twice a day for 6 months or until they developed an exacerbation.
Exacerbations were defined as the presence of three or more of the following signs or symptoms for at least 24 hours: increased cough, increased sputum volume, increased sputum purulence, hemoptysis, increased dyspnea, increased wheezing, fever (≥38°C) or malaise, and the treating physician agreed that antibiotic therapy was required.
Study visits were scheduled at Weeks 4, 12, and 26, or earlier if the patient developed an exacerbation. At study visits, patients completed the St. George’s Respiratory Questionnaire (SGRQ) (25) (Week 12, Week 26, or exacerbation visits), submitted a sputum sample for quantitative culture and susceptibility testing, submitted a 24-hour sputum collection (baseline and Week 4 visits), performed spirometry, and reported AEs. In addition, adherence data were downloaded from the I-neb.
The primary endpoint was the time to exacerbation. The secondary efficacy endpoints were time to exacerbation based on adherence recorded by the I-neb, severity of exacerbation, CFUs of P. aeruginosa, 24-hour sputum weight, and SGRQ total score. Secondary safety endpoints included bronchoconstriction in the 30 minutes post first dose of study drug, FEV1, sensitivity of P. aeruginosa to colistin, CFUs of other potentially pathogenic microorganisms, and AE reporting.
To have 80% power to detect a 75% difference in median time to exacerbation, 67 patients per treatment group were required. The calculation assumed a two-sided significance test performed at the 5% level, a median time to exacerbation of 60 days in the placebo group (16), and study duration of 6 months per patient. To allow for dropouts, 7.5% more patients were recruited to the study (n = 144).
All analyses were performed on the intention-to-treat (ITT) population using SAS statistical software, release 9.1.3 (SAS Corporation, Cary, NC). A Kaplan-Meier survival curve of time to exacerbation was plotted for each treatment group and the median time to exacerbation was estimated using survival analysis. The log-rank test was used to compare the treatment groups and the analysis was stratified by center. Time to exacerbation in relation to adherence recorded by the I-neb was summarized in quartiles based on percentage adherence and treatment differences were analyzed as per the primary endpoint.
Additional information on the study methods is available in the online supplement.
A total of 230 patients were screened for eligibility and 144 patients were randomized (Figure 1); all participants received at least one dose of the assigned study drug (colistin, n = 73; placebo, n = 71) and were included in the ITT analyses. Eleven patients in each group did not complete the study. Table 1 shows the baseline characteristics; there were no between-group differences for any parameter. Adherence data recorded by the I-neb are summarized in Table 2.
Figure 1. Flow diagram of patients enrolled in a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of up to 6 months of therapy with inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. *Treatment difference in incidence of treatment-emergent adverse events leading to discontinuation (P = 0.56). †Patient (placebo) was withdrawn from the study after one dose of investigation medicinal product because she did not meet the entry criteria (>15% fall in FEV1 within 30 min of the first dose). AE = adverse event; ITT = intention-to-treat.
[More] [Minimize]| Colistin Group (n = 73) | Placebo Group (n = 71) | |
|---|---|---|
| Sex, n (%) | ||
| Male | 27 (37%) | 34 (48%) |
| Female | 46 (63%) | 37 (52%) |
| Age, yr, mean (SD) | 58.3 (15.3) | 60.3 (15.8) |
| FEV1, L, mean (SD) | 1.55 (0.89) | 1.56 (0.65) |
| Predicted FEV1, %, mean (SD) | 55.9 (24.3) | 57.6 (24.9) |
| Weight of sputum collected over 24 h (g) before baseline visit, mean (SD) | 28.0 (25.9) | 28.6 (20.1) |
| Azithromycin therapy, n (%) | 6 (8%) | 5 (7%) |
| Prior inhaled antibiotic therapy | 0 | 0 |
| Colistin Group (n = 73) | Placebo Group (n = 71) | |
|---|---|---|
| Level of adherence, n (%)* | ||
| <60% | 4 (5.7) | 7 (10.0) |
| 60 to <70% | 6 (8.6) | 4 (5.7) |
| 70 to <80% | 6 (8.6) | 5 (7.1) |
| 80 to <90% | 11 (15.7) | 15 (21.4) |
| ≥90% | 43 (61.4) | 39 (55.7) |
| Mean (SD) | 87.3 (15.4) | 85.0 (18.4) |
| Median (range) | 92.7 (27.5–109.3) | 91.7 (25.0–117.4) |
| 25% quartile | 82.4 | 80.8 |
| 75% quartile | 97.0 | 97.5 |
| Not recorded | 3 | 1 |
A total of 36 of 73 (49%) patients in the colistin group experienced an exacerbation compared with 42 of 71 (59%) in the placebo group; a Kaplan-Meier plot of the estimate of the time to exacerbation is depicted in Figure 2A. The median time (25% quartile) to exacerbation was 165 days (42 d) in the colistin group and 111 days (52 d) in the placebo group (P = 0.11).
Figure 2. Kaplan-Meier plot of estimate of time to first exacerbation within (A) the whole intention-to-treat population, and (B) adherence quartiles 2–4 of the intention-to-treat population.
[More] [Minimize]To examine the effects of adherence on efficacy, the time to exacerbation was summarized in quartiles based on percentage adherence. Treatment comparisons showed a statistically significant result in favor of the active treatment in the second adherence quartile (81–92.1%; n = 34; P = 0.017). At this level of adherence, 6 of 17 (35%) patients in the colistin group experienced an exacerbation compared with 14 of 17 (82%) in the placebo group. It was not possible to determine a median time to exacerbation in the colistin group because of the number of patients completing 6 months of therapy; in the placebo group it was 89 days. The respective 25% quartiles for time to exacerbation were 26 and 22 days. Within the first quartile (adherence <81%; n = 34), third quartile (adherence 92.1–97.1%; n = 36), and fourth quartile (adherence >97.1%; n = 36) there was no evidence of a treatment group difference.
Data from quartiles 2–4 were combined (adherence ≥81%). At this level of adherence, 27 of 54 (50%) patients in the colistin group experienced an exacerbation compared with 37 of 52 (71%) in the placebo group; a Kaplan-Meier plot of the estimate of the time to exacerbation is depicted in Figure 2B. The median time (25% quartile) to exacerbation was 168 days (65 d) in the colistin group and 103 days (37 d) in the placebo group (P = 0.038).
A post hoc analysis was performed in patients with greater than or equal to 80% adherence, a cut-off used to distinguish adherent from nonadherent patients (17, 26, 27). At this level of adherence, 27 of 54 (50%) patients in the colistin group experienced an exacerbation compared with 39 of 54 (72%) in the placebo group. The median time (25% quartile) to exacerbation was 168 days (65 d) in the colistin group and 103 days (37 d) in the placebo group (P = 0.028).
In the whole ITT population, inhaled colistin resulted in significant reductions in P. aeruginosa bacterial density after 4 and 12 weeks treatment compared with placebo (−1.7 [2.2] vs. −0.3 [1.9] log10 CFU/g, P = 0.001, at 4 wk; −1.6 [2.2] vs. −0.5 [2.3] log10 CFU/g, P = 0.008, at 12 wk) (Figure 3).
Figure 3. Change from baseline in log10 CFUs Pseudomonas aeruginosa within the whole intention-to-treat population. The treatment difference in change from baseline in P. aeruginosa CFUs was analyzed using the Wilcoxon rank sum test. Error bars denote SEM.
[More] [Minimize]In the whole ITT population, colistin-treated patients experienced a mean (SD) change in SGRQ total score from baseline to Week 12 and Week 26 of −2.8 (14.5) and −10.4 (19.6) units, respectively. The corresponding results for the placebo group were −2.2 (10.5) and −0.4 (13.2) units, respectively. The estimated mean treatment differences in change in SGRQ total score from baseline to Week 12 and Week 26 were −1.09 (95% confidence interval [CI], −5.18 to 2.99) and −10.51 (95% CI, −17.87 to −3.14), respectively. This treatment difference reached statistical significance at Week 26 (P = 0.006) (Figure 4).
Figure 4. Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score within the whole intention-to-treat population. An analysis of covariance with treatment and center included in the model was used to examine treatment differences between groups for SGRQ total score. Error bars denote SEM.
[More] [Minimize]In the whole ITT population, the mean (SD) change in 24-hour sputum weight from baseline to Week 4 was −3.6 g (22.4) in the colistin group compared with −1.6 g (9.9) in the placebo group. The estimated mean treatment difference was −1.9 (95% CI, −8.3 to 4.5; P = 0.56).
In the whole ITT population, most exacerbations (75% and 79% in the colistin and placebo groups, respectively) were treated with oral antibiotics.
One patient in the placebo group experienced a reduction in FEV1 of greater than or equal to 15% within 30 minutes of the first dose and discontinued treatment. However, five (7%) patients in the colistin group subsequently developed bronchoconstriction that led to discontinuation of treatment.
In the colistin group, mean (SD) changes from baseline to Weeks 4, 12, and 26 in FEV1 (L) were −0.03 (0.40), 0.01 (0.43), and −0.10 (0.45), respectively. The corresponding results for the placebo group were 0.02 (0.18), −0.09 (0.34), and 0.00 (0.26), respectively. The estimated mean treatment differences in change in FEV1 (L) from baseline to Weeks 4, 12, and 26 were −0.05 (95% CI, −0.17 to 0.07), 0.11 (95% CI, −0.17 to 0.07), and −0.10 (95% CI, −0.22 to 0.02), respectively. These treatment differences did not reach statistical significance.
No colistin-resistant strains of P. aeruginosa were identified during the study (Table 3). There were no significant differences in treatment-emergent pathogens between treatment groups (Table 4).
| Colistin Group | Placebo Group | |||||||
|---|---|---|---|---|---|---|---|---|
| N | MIC50 | MIC90 | MIC Range | N | MIC50 | MIC90 | MIC Range | |
| Baseline | 73 | 0.25 | 1.5 | 0.032–2.0 | 70 | 0.5 | 2.0 | 0.047–2.0 |
| 1 mo | 44 | 0.38 | 1.5 | 0.064–2.0 | 49 | 0.5 | 2.0 | 0.064–3.0 |
| Final visit | 47 | 0.25 | 1.5 | 0.047–3.0 | 53 | 0.38 | 1.5 | 0.047–2.0 |
| Microorganism | Colistin Group | Placebo Group | ||||
|---|---|---|---|---|---|---|
| Baseline | 1 Mo | Final Visit | Baseline | 1 Mo | Final visit | |
| Achromobacter xylosoxidans | 1 (1.4%) | 1 (1.8%) | 0 | 2 (2.8%) | 1 (2.0%) | 1 (1.6%) |
| Acinetobacter spp. | 0 | 0 | 0 | 2 (2.8%) | 0 | 0 |
| Aeromonas sp. | 0 | 0 | 0 | 0 | 1 (2.0%) | 0 |
| Aspergillus spp. | 2 (2.8%) | 0 | 5 (7.5%) | 4 (5.7%) | 2 (3.9%) | 3 (4.8%) |
| Candida spp. | 2 (2.8%) | 1 (1.8%) | 2 (3.0%) | 4 (5.7%) | 1 (2.0%) | 3 (4.8%) |
| Coliform | 1 (1.4%) | 0 | 0 | 0 | 0 | 1 (1.6%) |
| Haemophilus influenzae | 0 | 0 | 0 | 1 (1.4%) | 1 (2.0%) | 3 (4.8%) |
| Klebsiella pneumoniae | 0 | 0 | 0 | 1 (1.4%) | 0 | 0 |
| Moraxella catarrhalis | 3 (4.2%) | 0 | 2 (3.0%) | 2 (2.9%) | 1 (2.0%) | 4 (6.5%) |
| Providencia rettgeri | 0 | 0 | 1 (1.5%) | 0 | 0 | 0 |
| Serratia marcescens | 0 | 0 | 0 | 0 | 0 | 1 (1.6%) |
| Staphylococcus aureus | 3 (4.2%) | 3 (5.5%) | 5 (7.5%) | 5 (7.1%) | 8 (15.7%) | 2 (3.2%) |
| Stenotrophomonas maltophilia | 0 | 0 | 0 | 0 | 0 | 1 (1.6%) |
| Streptococcus pneumoniae | 2 (2.8%) | 1 (1.8%) | 2 (3.0%) | 0 | 1 (2.0%) | 1 (1.6%) |
| Number of patient samples | 71 | 55 | 67 | 70 | 51 | 62 |
AEs are summarized in Table 5. A total of 143 AEs were reported in 47 patients (64%) in the colistin group and 108 AEs in 38 patients (54%) in the placebo group (P = 0.25). No suspected unexpected serious adverse reactions were reported. There were three deaths, which were all considered unlikely related to study drug by the investigator. One death (preferred term: cardiopulmonary failure) occurred in the colistin group and two deaths (preferred terms: bronchiectasis and respiratory failure in one patient and acute coronary syndrome in one patient) occurred in the placebo group.
| Colistin Group (n = 73) | Placebo Group (n = 71) | |
|---|---|---|
| Number of patients reporting TEAEs | ||
| Any TEAEs, n (%) | 47 (64.4) | 38 (53.5) |
| Deaths, n (%) | 1 (1.4) | 2 (2.8) |
| SAEs, n (%) | 6 (8.2) | 4 (5.6) |
| AE leading to withdrawal, n (%) | 7 (9.6) | 6 (8.5) |
| Severe AEs, n (%) | 7 (9.6) | 3 (4.2) |
| Related AEs, n (%) | 18 (24.7) | 9 (12.7) |
| Total number of TEAEs reported | 143 | 108 |
| By severity, events (%) | ||
| Mild | 92 (64.3) | 67 (62.0) |
| Moderate | 41 (28.7) | 37 (34.3) |
| Severe | 10 (7.0) | 4 (3.7) |
| Serious, events (%) | 9 (6.3) | 6 (5.6) |
| SUSARs | 0 | 0 |
| Relationship to study treatment, events (%) | ||
| Unlikely | 108 (75.5) | 88 (81.5) |
| Possible | 31 (21.7) | 11 (10.2) |
| Probable | 3 (2.1) | 9 (8.3) |
| Definite | 1 (0.7) | 0 |
| Action taken with study drug, events (%) | ||
| None | 129 (90.2) | 97 (89.8) |
| Interrupted | 4 (2.8) | 2 (1.9) |
| Discontinued | 10 (7.0) | 9 (8.3) |
| IMP-related TEAE leading to discontinuation, events (%) | 8 (5.6) | 6 (5.6) |
| Statistical analysis of TEAEs, SAEs, and SUSARs | ||
| Treatment difference in overall incidence of TEAEs* | P = 0.25 | |
| Treatment difference in incidence of TEAEs leading to discontinuation* | P = 1.00 | |
| Treatment difference in overall incidence of study drug-related TEAEs leading to discontinuation* | P = 0.75 | |
Colistin administered through the I-neb increases time to exacerbation compared with placebo in adherent patients with bronchiectasis and chronic P. aeruginosa infection.
Use of the I-neb allowed a detailed analysis of the relationship between adherence to study drug and treatment outcome, and had a major impact on the interpretation of the results. The study failed to meet its primary endpoint of time to exacerbation within the whole ITT population because of the greater number of exacerbations experienced by poorly adherent patients assigned colistin (8 of 16 [50%]) compared with placebo (5 of 18 [28%]). When patients in adherence quartile 1 were excluded from the analysis (adherence <81%), there was a statistically significant and clinically meaningful treatment difference of 65 days in time to exacerbation between the colistin and placebo groups. Near identical results were found in patients with greater than or equal to 80% adherence, a cut-off used to distinguish adherent from nonadherent patients (17, 26, 27), indicating that individuals need to be adherent to gain clinical benefit from nebulized colistin. More impressive increases in time to exacerbation were reported with inhaled gentamicin and azithromycin, but these studies involved patients with bronchiectasis with lower rates of P. aeruginosa infection (12–42% of participants) (16, 28, 29). However, a remarkably similar treatment difference of 76 days was found between the active and placebo groups in the recent phase II study evaluating the effect of nebulized liposomal ciprofloxacin in 42 patients with bronchiectasis and P. aeruginosa infection (18).
In the whole ITT population analysis, there was a significant reduction in P. aeruginosa density after 4 and 12 weeks of treatment with colistin compared with placebo. Although the magnitude of change was modest compared with the 4 log10 reduction reported after a month of liposomal ciprofloxacin (18), it is likely the CFU change with colistin was affected by the prescription of exacerbation antipseudomonal antibiotics that triggered entry to the study. This novel study design was implemented to provide a uniform starting point for the primary endpoint of time to first exacerbation.
In the whole ITT population analysis, there was a significant improvement in SGRQ total score following 26 weeks treatment with nebulized colistin compared with placebo. A reduction in SGRQ total score of 4 units is clinically significant (30), thus the 10.5-unit reduction seen with nebulized colistin strongly suggests it had a meaningful impact on quality of life. This finding is consistent with the SGRQ outcomes reported with nebulized gentamicin (16) and with one of the three recently published macrolide studies in which a reduction of 6.1 units was observed per 6 months of treatment compared with a 2.1-unit reduction in the placebo group (29). Because exacerbation frequency is known to have a negative impact on quality of life in patients with bronchiectasis (31, 32), the reduction in exacerbation frequency with long-term antibiotic therapy may explain the improvement in SGRQ total score in these studies.
There were no safety concerns related to the use of nebulized colistin. The incidence of AEs leading to discontinuation was extremely low and similar between treatment groups. There were no concerns with respect to renal toxicity or neuropathy. The low rate of bronchospasm related to colistin on initial testing and throughout the study is reassuring. There was no significant change in FEV1, which is consistent with other recent studies of inhaled antibiotics in bronchiectasis (16–18). There was no evidence that use of nebulized colistin for up to 6 months led to the development of colistin-resistant isolates of P. aeruginosa or overgrowth of other bacteria. This is in contrast to the 28% increase in the proportion of macrolide-resistant commensal oropharyngeal streptococci reported after 12 months of erythromycin (33) and a macrolide resistance rate of 88% following 12 months of azithromycin (29) in patients with bronchiectasis. Aspergillus species were isolated from 2.8% of sputum samples at baseline and 7.5% at the final visit of colistin-treated patients. Although similar rates of Aspergillus species isolation were seen in the placebo group, Aspergillus species are isolated more frequently following the prescription of inhaled antipseudomonal antibiotics in patients with cystic fibrosis (34).
In summary, colistin administered through the I-neb adaptive aerosol delivery device is associated with improvements in P. aeruginosa bacterial density, time to exacerbation, and quality of life in adherent patients with bronchiectasis and chronic P. aeruginosa infection.
The authors acknowledge the help of Dr. Catriona Urquhart (provided by Profile Pharma Ltd.) in the preparation and revision of the manuscript. They also thank the patients, and the following study investigators that contributed to the study: Professor S. Andreychyn (Ukraine), Professor Y. Antonovsky (Russia), Dr. V. Blazhko (Ukraine), Dr. K. Bogatska (Ukraine), Professor M. Britton (UK), Professor E. Bukreeva (Russia), Dr. J. Calvert (UK), Dr. A. Chauhan (UK), Professor P. Chizhov (Russia), Professor I. Chopey (Ukraine), Dr. C. Davies (UK), Dr. A. De Soyza (UK), Professor A. Doroshenkova (Russia), Dr. J. Duckers (UK), Dr. F. Edenborough (UK), Dr. E. Evans (UK), Professor O. Fediv (Ukraine), Dr. C. Haworth (UK), Dr. T. Howes (UK), Dr. S. Kharkivska (Ukraine), Dr. E. Khodosh (Ukraine), Prof. V. Kostromina (Ukraine), Dr. L. Kuitert (UK), Dr. C. Llewellyn-Jones (UK), Professor N. Monogarova (Ukraine), Professor A. Morice (UK), Dr. M. Nordstrom (UK), Professor V. Nosov (Russia), Dr. G. Phillips (UK), Professor L. Prystupa (Ukraine), Dr. G. Robinson (UK), Professor V. Rodionova (Ukarine), Professor E. Schmelev (Russia), Dr. S. Scott (UK), Dr. K. Sridharan (UK), Professor V. Sushko (Ukraine), Dr. E. Thomas (UK), Dr. P. Walker (UK), Dr. A. Wilson (UK).
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Supported by Profile Pharma Ltd., Chichester, United Kingdom. The statistical analysis was performed by Wilkinson Associates. D.B. is supported by the NHIR Respiratory Disease Biomedical Research Unit at Royal Brompton and Harefield Hospital NHS Foundation Trust, United Kingdom.
Author Contributions: C.S.H. and D.B. participated in the study conception. P.W. participated in the data analysis. C.S.H., J.E.F., P.W., R.F.K., and D.B. participated in the study design, data interpretation, and writing of the manuscript, and have read and approved the final version for submission. C.S.H. and D.B., as the co-chief investigators, had unrestricted access to the data and had final responsibility for the manuscript.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201312-2208OC on March 13, 2014
Author disclosures are available with the text of this article at www.atsjournals.org.
