[
Original Research Bronchiectasis
]
A Preliminary Quality of Life Questionnaire-Bronchiectasis A Patient-Reported Outcome Measure for Bronchiectasis Alexandra L. Quittner, PhD; Kristen K. Marciel, PhD; Matthias A. Salathe, MD, FCCP; Anne E. O’Donnell, MD, FCCP; Mark H. Gotfried, MD, FCCP; Jonathan S. Ilowite, MD, FCCP; Mark L. Metersky, MD, FCCP; Patrick A. Flume, MD; Sandra A. Lewis, MS; Matthew McKevitt, PhD; A. Bruce Montgomery, MD; Thomas G. O’Riordan, MD; and Alan F. Barker, MD, FCCP
BACKGROUND: The Quality of Life Questionnaire-Bronchiectasis (QOL-B) is the first diseasespecific, patient-reported outcome measure for patients with bronchiectasis. Content validity, cognitive testing, responsivity to open-label treatment, and psychometric analyses are presented.
Reviews of literature, existing measures, and physician input were used to generate the initial QOL-B. Modifications following preliminary cognitive testing (N 5 35 patients with bronchiectasis) generated version (V) 1.0. An open-ended patient interview study (N 5 28) provided additional information and was content analyzed to derive saturation matrices, which summarized all disease-related topics mentioned by each participant. This resulted in QOL-B V2.0. Psychometric analyses were carried out using results from an open-label phase 2 trial, in which 89 patients were enrolled and treated with aztreonam for inhalation solution. Responsivity to open-label treatment was observed. Additional analyses generated QOL-B V3.0, with 37 items on eight scales: respiratory symptoms; physical, role, emotional, and social functioning; vitality; health perceptions; and treatment burden. For each scale, scores are standardized on a 0-to-100-point scale; higher scores indicate better health-related quality of life. No total score is calculated. A final cognitive testing study (N 5 40) resulted in a minor change to one social functioning scale item (QOL-B V3.1).
METHODS:
Content validity, cognitive testing, responsivity to open-label treatment, and initial psychometric analyses supported QOL-B items and structure. RESULTS:
CONCLUSIONS: This interim QOL-B is a promising tool for evaluating the efficacy of new therapies for patients with bronchiectasis and for measuring symptoms, functioning, and quality of life in these patients on a routine basis. A final psychometric validation study is needed and is forthcoming. TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT00805025; URL: www.clinicaltrials.gov CHEST 2014; 146(2):437-448
Manuscript received August 21, 2013; revision accepted February 10, 2014; originally published Online First March 13, 2014. ABBREVIATIONS: 6MWT 5 6-min walk test; AZLI 5 aztreonam for inhalation solution; CF 5 cystic fibrosis; CFQ-R 5 Cystic Fibrosis Questionnaire-Revised; HRCT 5 high-resolution CT; PRO 5 patientreported outcome; QOL-B 5 Quality of Life-Bronchiectasis; SGRQ 5 St. George’s Respiratory Questionnaire; V 5 version AFFILIATIONS: From the Department of Psychology and Pediatrics (Drs Quittner and Marciel), and the Division of Pulmonary, Allergy,
Critical Care and Sleep Medicine (Dr Salathe), Department of Medicine, University of Miami, Coral Gables, FL; the Division of Pulmonary, Critical Care and Sleep Medicine (Dr O’Donnell), Department of Medicine, Georgetown University, Washington, DC; Pulmonary Associates (Dr Gotfried), and University of Arizona (Dr Gotfried), Phoenix, AZ; the Department of Medicine (Dr Ilowite), Division of Pulmonary and Critical Care, Winthrop University Hospital, Mineola, NY; the Division of Pulmonary and Critical Care (Dr Metersky), University of Connecticut School of Medicine, University of Connecticut, Farmington,
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Bronchiectasis, an obstructive lung disease, is defined by dilated airways on high-resolution CT (HRCT) chest scans. The disease is associated with significant morbidity. Symptoms typically include chronic cough, sputum production, dyspnea, fatigue, and persistent lower respiratory tract infections.1-4 Acute exacerbations of airway infections are common, associated with worsening symptoms, and typically treated with antibiotics, and they sometimes result in hospitalization. The development of new therapies for treating bronchiectasis has been hampered by the lack of disease-specific, practical, and well-validated primary end points. Commonly used measures have serious limitations in clinical trials.5 Changes in measures of lung function (eg, FEV1 %) are often subtle, and FEV1 is not strongly associated with a reduction in airway bacteria or an improvement in patients’ health status after treatment.6,7 The 6-min walk test (6MWT) has fallen into disfavor because of variability in the way the test is administered and because the results may be confounded by concomitant lung disease or other age-related comorbidities. Radiographic studies (eg, HRCT scans) have been used to develop severity scores, but changes do not correlate strongly with clinical improvement. It has been suggested that their lack of correlation is because some patients with bronchiectasis have debilitating respiratory symptoms with only focal structural airway damage
Materials and Methods QOL-B development (Table 1) was based on established processes.18 Three interview studies (preliminary and secondary cognitive testing and open-ended concept elicitation) and a validation study (open-label, 28-day course of aztreonam for inhalation solution (AZLI) (Cayston; Gilead Sciences, Inc) (e-Fig 1) were conducted. AZLI is approved for treatment of patients with CF with chronic Pseudomonas aeruginosa infection.19,20 Study Designs Cognitive testing interviews (lasting approximately 1.5 h) were audio recorded. Interviews used standard cognitive-testing procedures to determine what participants were thinking when responding to each item, how responses were chosen, what would elicit an adjacent response, relevance of items, and need for additional topics.21-23 Most recent BMI,
CT; the Division of Pulmonary and Critical Care Medicine (Dr Flume), Medical University of South Carolina, Charleston, SC; Gilead Sciences (Ms Lewis and Drs McKevitt, Montgomery, and O’Riordan), Seattle, WA; ; Cardeas Pharma (Dr Montgomery), Seattle, WA; and the Department of Medicine (Dr Barker), Division of Pulmonary and Critical Care, Oregon Health and Science University, Portland, OR. Part of this article has been presented previously in abstract form at American Thoracic Society International Conferences (May 19, 2009, San Diego, CA; May 19, 2010, New Orleans, LA; and May 20, 2013, Philadelphia, PA), a European Respiratory Society Annual Congress (September 13, 2009, Vienna, Austria), and CHEST conferences
438 Original Research
visible by HRCT scans.8 Use of acute exacerbations as a primary end point is complicated by the lack of a standardized definition and by the requirement for lengthy periods of assessment. Further, analyses could be affected by seasonal differences in exacerbation rates, and using this end point implies that patients feel well between episodes, when in fact most are symptomatic. Prior to developing the Quality of Life QuestionnaireBronchiectasis (QOL-B), existing patient-reported outcome (PRO) measures were evaluated; both the Leicester Cough Questionnaire9 and the St. George’s Respiratory Questionnaire10 (SGRQ) have been studied in bronchiectasis.11-13 Limitations have included minimal respiratory symptom coverage (Leicester Cough Questionnaire; Chronic Respiratory Questionnaire14), variable or lengthy recall intervals (SGRQ), and substantial response burden (some Chronic Respiratory Questionnaire and SGRQ forms). Our review strongly suggested that a new PRO was needed for bronchiectasis.15 The Cystic Fibrosis Questionnaire-Revised (CFQ-R)16,17 contained the most complete and relevant items measuring respiratory symptoms (because of the common occurrence of bronchiectasis in patients with cystic fibrosis [CF]). Therefore, items from the CFQ-R and the relevant literature were used as a starting point for developing the QOL-B, the first bronchiectasis-specific PRO instrument to our knowledge. spirometry (performed during preliminary study24), and sputum culture results were obtained (retrospective chart review). In the preliminary cognitive-testing study, revisions were made on the basis of responses and were tested at subsequent sites; QOL-B version (V) 1.0 was developed after analyzing all interviews. In concept-elicitation interviews (lasting 1-1.5 h), interviewers probed several dimensions of severity: (1) the frequency with which symptoms and other impacts occurred, (2) the level of difficulty managing symptoms, and (3) the extent to which symptoms affected daily activities (work, social roles). Audiotapes were transcribed and responses were coded (Atlas.ti V5.0; Scientific Software Development). Relevant topics were selected based on the frequency of patient endorsement (more than two patients) and physician review. The phase 2 clinical trial was conducted at 21 centers in the United States (December 2008 to October 2009), with six visits over 70 days,
(October 30-November 4, 2010, Vancouver, BC, Canada; and October 22-26, 2011, Honolulu, HI). FUNDING/SUPPORT: The studies described here were sponsored by Gilead Sciences, Inc and Behavioral Health Systems Research. CORRESPONDENCE TO: Alexandra L. Quittner, PhD, Child Division, University of Miami, 5665 Ponce de Leon Blvd, Coral Gables, FL 33146; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1891
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TABLE 3
] Internal Consistency of QOL-B Scales QOL-B Version 2.0
QOL-B Scale
QOL-B Version 3.0
No. Respondents (N 5 131)
Cronbach’s a
No. Respondentsb (N 5 40)
Cronbach’s a
Respiratory symptoms
117
0.78
36
0.82
Physical functioning
119
0.92
38
0.94
Vitality
122
0.70
40
0.85
Role functioning
124
0.89
40
0.86
Health perceptions
121
0.77
40
0.77
Emotional functioning
122
0.86
40
0.72
Social functioning
125
0.69c
36
0.66
Treatment burden
108
0.83
36
0.84
a
See Table 1 for expansion of abbreviations. aTotal number of patients screened for the phase 2 open-label AZLI trial; analyses included data for patients who were not missing measurements at screening visit. bTotal number of participants in the second cognitive testing study. cAnalyses did not include one new item that had been added to QOL-B version 2.0.
and carrying” was changed to “carrying,” and “affectionate/intimate” was changed to “intimate.” Two items were reworded to better represent the participants’ experiences: “chest pain with coughing” was changed to “chest pain”; and examples of planning for the future were modified slightly. An item was added to the social functioning scale to address concerns about being around other people who were sick. Revisions generated QOL-B V2.0 (36 items on eight scales) (Table 1). Anger, weight gain/loss, digestive symptoms, changes in appetite, and sensitivity to smell were mentioned by small numbers of participants and were not added to the QOL-B because the participants considered these issues unrelated to their bronchiectasis. Items address-
TABLE 4
ing sinus problems or a runny nose were not added because upper respiratory problems are very common in the general adult population in the United States.28 The concept-elicitation study did not require participants to have documented gram-negative endobronchial infection; however, consistent topics were elicited from participants with (n 5 10 of 22) or without (n 5 12) such infections (e-Table 2). Phase 2 Open-Label AZLI Study
Although QOL-B V1.0 was administered in the phase 2 study, analyses presented herein include only data from the 35 items retained on V2.0 ( Table 1 ). Responses were scored in accordance with V2.0 scales and syntax.
] Test-Retest Reliability: Intraclass Correlation Coefficients between Screening (Visit 1; D 14) and Baseline (Visit 2; D 0) for QOL-B Version 2.0 Scale Scores for Clinically Stable Patients
QOL-B Scale
No. Respondents (N 5 89)
Intraclass Correlation Coefficient
Respiratory symptoms
85
0.80
Physical functioning
88
0.88
Vitality
87
0.67
Role functioning
87
0.84
Health perceptions
88
0.78
Emotional functioning
88
0.82
Social functioninga
87
0.85
Treatment burden
74
0.76
Total N is the number of patients enrolled and subsequently treated with AZLI in the open-label phase 2 clinical trial. Intraclass correlation coefficients were determined from screening and baseline measurements; both occurred before AZLI treatment. Analyses included patients with specified QOL-B scale measurements at both screening and baseline. See Table 1 for expansion of abbreviations. aAnalyses did not include one new item that had been added to QOL-B version 2.0.
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TABLE 1
] (continued)
Step
Scales
Number of Items
Modifications of Instrument
Step 3b: Psychometric and responsivity analyses; data from 131 patients screened for a phase 2 open-label AZLI clinical trial; 108 patients enrolled and treated with AZLI; 2008-2009; 21 sites in the United States (clinicaltrials. gov:NCT00805025) QOL-B version 2.0
Eight scales:
36 items
Same scales as version 1.0
Changes from previous version: 15 items deleted from six different scales (eight were not supported by participants’ comments as being important to the experience of having bronchiectasis, and seven were redundant with other items) Three items moved to a different scale One item added Seven items reworded
Step 4: Additional analyses of previous studies; feedback from regulatory agency QOL-B version 3.0
Eight scales:
37 items
Same scales as version 1.0
Changes from previous version: One item moved to a different scale One item added Two items reworded (specific examples added to better define meaning of items) Scoring changed for one item: two mucous colors were combined for scoring Response options changed for 19 items
Step 5: Second cognitive testing study; 40 participants; 2012; four sites in the United States QOL-B version 3.1
Eight scales: Same scales as version 1.0
37 items
Changes from previous version: Response options and wording changed for one item on social functioning scale
AZLI 5 aztreonam for inhalation solution; CFQ-R 5 Cystic Fibrosis Questionnaire-Revised; QOL-B 5 Quality of Life Questionnaire-Bronchiectasis.
including 14 days of observation, 28 days of open-label AZLI treatment (75 mg, administered tid) with an investigative eFlow nebulizer (PARI Innovative Manufacturers, Inc), and 28 days of follow-up (e-Fig 1). Psychometric analyses used QOL-B responses from 131 screened patients and/or 89 AZLI-treated patients (e-Fig 2), as identified for each analysis. Procedures for all studies were approved by institutional review boards (e-Appendix 1). Participants provided written informed consent prior to participation.
440 Original Research
Study Participants Interview studies included adults with bronchiectasis, who had not been exposed previously to the QOL-B. Patients with CF were excluded from all studies. For each study, the same research team conducted and analyzed the interviews. For the phase 2 trial, eligible patients (ⱖ 18 years old) had bronchiectasis confirmed by chest HRCT scans (during the prior 6 months), which were read/scored by two independent radiologists (BioClinica, Inc) using established criteria (scores ranged
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Analyses
from 0 to 243; smaller values indicated less severe disease25). Patients had mucopurulent sputum production daily and a history of positive sputum culture for a gram-negative organism within 5 years, were culture positive for gram-negative organism at screening, and had had previous antibiotic treatment of bronchiectasis. Key exclusion criteria included hospitalization or hemoptysis . 30 mL (prior 14 days), serious adverse event during observation period, antibiotic use for respiratory symptoms (excluding chronic, stable azithromycin use) or change in corticosteroid/bronchodilator regimen (prior 14 days or during observation period), FEV1 , 25% predicted, or change in FEV1 (L) . 10% and 150 mL during observation period.
Statistical analyses were performed with the IBM SPSS Statistics program, V19 (interview studies) and SAS V9.1 (SAS Institute Inc) (phase 2 study). Comparisons used Pearson’s correlation coefficients (r), unless noted. Internal consistency was measured for each scale using Cronbach’s a; values ⱖ 0.70 indicated that items within a scale were correlated with each other.26 QOL-B test-retest reliability (reproducibility) was calculated using intraclass correlation coefficients to compare the results for each scale over a 2-week interval; values ⱖ 0.70 indicated good score stability/reproducibility (results from visits 1 and 2 were used) (phase 2 trial).27
Results
Concept-Elicitation Study
Preliminary Cognitive Testing Study
The concept-elicitation study included 28 participants (Table 2); 82% were currently receiving bronchiectasis treatment(s). Participants mentioned 73 disease-related topics, with 71 topics mentioned by the first 14 participants, the last two topics mentioned by the 16th and 23rd participants, and no new topics elicited from the final five participants. This indicated that saturation of disease-related topics had been reached. Topics are presented by decreasing incidence (e-Table 1) and in a saturation grid (e-Table 2).
The initial QOL-B (56 items, 11 scales; 1-week recall period) (Table 1) was assessed in a preliminary cognitive testing study conducted sequentially at three sites (35 participants) (Table 2). Three items were added on the basis of participants’ responses, including “feeling anxious,” “I am concerned that my health will get worse,” and an item addressing intimacy. Nine items were deleted, including an item addressing dyspnea when sitting, which few participants experienced. Instructions and response options were well understood. The resulting QOL-B (V1.0; 50 items, eight scales) (Table 1) was administered during the phase 2 trial. Results were analyzed concurrently with the conceptelicitation study, which is presented first.
TABLE 2
After analysis, one item was reworded to match the terms used by the participants: “dyspnea (shortness of breath)” was changed to “shortness of breath” (Table 1). Two items were rewritten to reflect a single concept that best captured the participants’ concerns: “lifting
] Comparison of Patient Characteristics
Characteristics
Preliminary Cognitive Testing Study
Patients, No.
35
Open-Ended Concept-Elicitation Interview Study 28
Age, mean (SD), y
65.0 (13.4)
60.1 (16.8)
Age, range, y
26-87
25-98
FEV1 % predicted, mean (SD)
57.1 (25.5)
65.0 (23.1)
FEV1 % predicted, range
17-103
30-110
a
BMI, mean (SD)
25.1 (6.2)
26.4 (7.5)
Female, No. (%)
20 (57)
23 (82.1)
Bronchiectasis confirmed
Investigator selection
Investigator selection
Gram-negative organism,c No. (%)
11 (45.8)
10 (45.5)
b
Phase 2 Open-Label AZLI Clinical Trial
Second Cognitive Testing Study
89
40
64 (14.7) 24-84 60.4 (21.3) 27-114 24.8 (5.5) 62 (69.7) Documented HRCT scan 89 (100)
64.6 (12.3) 36-84 69.07 (19.83) 6.8-117 25.15 (6.08) 33 (82.5) Documented CT scan 14 (35.9)
HRCT 5 high-resolution CT. See Table 1 for expansion of other abbreviation. aFEV % predicted values available for 35, 22, 89, and 39 patients in the four studies. 1 bIn the preliminary cognitive testing and concept-elicitation interview studies, patients with bronchiectasis were selected by investigators; diagnosis by CT scan was confirmed for 77.1% of participants (n 5 27 of 35) in the preliminary study and 62.1% (n 5 18 of 29) in the open-ended conceptelicitation study; the remaining participants were selected on the basis of medical history (no CT scan was available at study site). cCultures available for 24, 22, 89, and 39 patients in the four studies; percentages were calculated using the number of patients with cultures.
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TABLE 3
] Internal Consistency of QOL-B Scales QOL-B Version 2.0
QOL-B Scale
QOL-B Version 3.0
No. Respondents (N 5 131)
Cronbach’s a
No. Respondentsb (N 5 40)
Cronbach’s a
Respiratory symptoms
117
0.78
36
0.82
Physical functioning
119
0.92
38
0.94
Vitality
122
0.70
40
0.85
Role functioning
124
0.89
40
0.86
Health perceptions
121
0.77
40
0.77
Emotional functioning
122
0.86
40
0.72
Social functioning
125
0.69c
36
0.66
Treatment burden
108
0.83
36
0.84
a
See Table 1 for expansion of abbreviations. aTotal number of patients screened for the phase 2 open-label AZLI trial; analyses included data for patients who were not missing measurements at screening visit. bTotal number of participants in the second cognitive testing study. cAnalyses did not include one new item that had been added to QOL-B version 2.0.
and carrying” was changed to “carrying,” and “affectionate/intimate” was changed to “intimate.” Two items were reworded to better represent the participants’ experiences: “chest pain with coughing” was changed to “chest pain”; and examples of planning for the future were modified slightly. An item was added to the social functioning scale to address concerns about being around other people who were sick. Revisions generated QOL-B V2.0 (36 items on eight scales) (Table 1). Anger, weight gain/loss, digestive symptoms, changes in appetite, and sensitivity to smell were mentioned by small numbers of participants and were not added to the QOL-B because the participants considered these issues unrelated to their bronchiectasis. Items address-
TABLE 4
ing sinus problems or a runny nose were not added because upper respiratory problems are very common in the general adult population in the United States.28 The concept-elicitation study did not require participants to have documented gram-negative endobronchial infection; however, consistent topics were elicited from participants with (n 5 10 of 22) or without (n 5 12) such infections (e-Table 2). Phase 2 Open-Label AZLI Study
Although QOL-B V1.0 was administered in the phase 2 study, analyses presented herein include only data from the 35 items retained on V2.0 ( Table 1 ). Responses were scored in accordance with V2.0 scales and syntax.
] Test-Retest Reliability: Intraclass Correlation Coefficients between Screening (Visit 1; D 14) and Baseline (Visit 2; D 0) for QOL-B Version 2.0 Scale Scores for Clinically Stable Patients
QOL-B Scale
No. Respondents (N 5 89)
Intraclass Correlation Coefficient
Respiratory symptoms
85
0.80
Physical functioning
88
0.88
Vitality
87
0.67
Role functioning
87
0.84
Health perceptions
88
0.78
Emotional functioning
88
0.82
Social functioninga
87
0.85
Treatment burden
74
0.76
Total N is the number of patients enrolled and subsequently treated with AZLI in the open-label phase 2 clinical trial. Intraclass correlation coefficients were determined from screening and baseline measurements; both occurred before AZLI treatment. Analyses included patients with specified QOL-B scale measurements at both screening and baseline. See Table 1 for expansion of abbreviations. aAnalyses did not include one new item that had been added to QOL-B version 2.0.
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Patient characteristics were comparable to those in the interview studies, except the presence of gram-negative organisms was required for enrollment (Table 2). P aeruginosa (n 5 73 of 89 [82.0%]) and Achromobacter xylosoxidans (n 5 11 of 89 [12.4%]) were the most commonly reported gram-negative organisms (e-Table 3). Minor floor effects (scores 5 0 at screening) were observed for the vitality (7.2% respondents) and physical and social functioning (6.4% each) scales. Ceiling effects (scores 5 100 at screening) were observed for . 10% of respondents on only two scales: treatment burden (17.4%) and emotional functioning (16.0%). Evidence of strong internal consistency was found, with Cronbach’s a ranging from 0.69 to 0.92; all scales except for social functioning were ⱖ 0.70 (Table 3). Test-retest reliability was also excellent, with intraclass correlation coefficients ranging from 0.67 to 0.88; all except for vitality were ⱖ 0.70 (Table 4). At screening, only the QOL-B V2.0 physical and role functioning scores discriminated between patients on the basis of lung function, with scores significantly lower for patients with FEV1 ⱕ 50% predicted than for patients with FEV1 . 50% predicted (Table 5). At screening, strong evidence of convergent validity was found between QOL-B respiratory symptoms and SGRQ scores (r 5 20.53 to 20.73; each, P , .001), with modest associations found between respiratory symptoms and HRCT scan overall severity scores (r 5 20.24, P 5 .009) (Table 6). Significant correlations were not found between respiratory symptoms scores and FEV1 % predicted or 6MWT. Modest to strong associations were found between physical functioning scores and HRCT scan overall severity scores, FEV1 % predicted, 6MWT, and SGRQ scores. Responsiveness of the QOL-B to 28 days of open-label AZLI was assessed by comparing QOL-B scores before and after treatment (Table 7). QOL-B V2.0 scores improved significantly after open-label AZLI treatment (P , .05) for all scales except for treatment burden. Across the study, improvements in mean respiratory symptoms scores were accompanied by decreases in mean P aeruginosa and A xylosoxidans sputum density; however, for individual subjects, the changes in respiratory symptoms scores did not correlate with changes in P aeruginosa colony-forming units (r 5 20.126) (Fig 1). Mean (SD) baseline HRCT scan overall severity scores were 43.6 (22.52) (range, 1.5-117.8) and also did not correlate with change from baseline QOL-B V2.0 respi-
TABLE 5
] QOL-B Version 2.0 Scale Scores at Screening by Disease Severity (FEV1 % Predicted)
QOL-B Scale
FEV1 ⱕ 50% FEV1 . 50% Predicted (N 5 48) Predicted (N 5 72)
P Value
Respiratory symptoms No. Mean (SD)
47
71
…
51.3 (20.22)
50.6 (19.35)
.74
47
72
…
32.6 (27.26)
50.5 (30.84)
.002
Physical functioning No. Mean (SD) Vitality No. Mean (SD)
47
72
…
43.1 (19.08)
45.2 (23.46)
.56
Role functioning No. Mean (SD)
47
72
…
51.1 (28.46)
62.3 (26.90)
.040
Health perceptions No. Mean (SD)
47
72
…
37.2 (19.99)
39.1 (20.93)
.56
Emotional functioning No. Mean (SD)
47
72
…
69.0 (26.16)
74.5 (22.82)
.32
Social functioninga No. Mean (SD)
47
72
…
41.6 (25.64)
47.2 (27.96)
.29
Treatment burden No. Mean (SD)
43
61
…
64.3 (25.72)
68.1 (27.85)
.36
N 5 131 patients were screened for the phase 2 AZLI trial. FEV1 % predicted values were available for 120 patients at screening. QOL-B scores were from screening (visit 1, before AZLI treatment). P values were based on Wilcoxon rank sum test. For patients with FEV1 ⱕ 50% predicted vs FEV1 . 50% predicted: mean (SD) FEV1 (L) 5 1.0 (0.3) vs 1.9 (0.6); mean (SD) FEV1 % predicted 5 37.9 (8.6) vs 74.9 (17.7); mean (SD) log10 Pseudomonas aeruginosa CFU/g 5 4.3 (3.1) vs 4.2 (3.0); and mean (SD) log10 of all CFU/g 5 14.3 (4.5) vs 13.9 (3.2). CFU 5 colony-forming unit. See Table 1 for expansion of other abbreviations. aAnalyses did not include one new item that had been added to QOL-B version 2.0.
ratory symptoms score after 4 weeks of AZLI treatment (r 5 20.04, P 5 .7, n 5 82). Improvements on the respiratory symptoms scale were not driven by responses on any single item; statistically significant improvements were observed for most items on the scale (e-Table 4).
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TABLE 6
] Pearson’s Correlation Coefficients for QOL-B V2.0 Scale Scores at Screening and Other Indices of Health Status
Other Indexes of Health Status
QOL-B Scale (N 5 131) Respiratory symptoms (No.) (n 5 124) P value Physical functioning (No.) (n 5 125) P value Vitality (No.) (n 5 125) P value Emotional functioning (No.) (n 5 125) P value Social functioninge (No.) (n 5 125) P value
HRCT Overall Severitya (n 5 119)
FEV1 % Predictedb (n 5 120)
6-Min Walk Test (n 5 121)
SGRQ Symptomsc (n 5 121)
SGRQ Activityc (n 5 117)
SGRQ Impactsc (n 5 119)
20.24 (117)d
0.06 (118)d
0.07 (119)d
20.73 (119)d
20.53 (116)
20.62 (118)
.009
.49
.43
, .001
, .001
, .001
20.21 (118)
0.32 (119)
0.45 (120)
20.68 (120)
20.85 (117)
20.76 (119)
.023
, .001
, .001
, .001
, .001
, .001
20.18 (118)
0.07 (119)
0.24 (120)
20.58 (120)
d
d
.049
.45
20.18 (119)
0.12 (119)
d
.009 0.17 (120)
d
d
20.64 (117)
d
20.68 (119)
, .001
, .001
, .001
20.38 (120)
20.41 (117)
20.54 (119)d
.06
.20
.06
, .001
, .001
, .001
20.22 (118)
0.12 (119)
0.13 (120)
20.64 (120)
20.48 (117)
20.69 (119)d
.018
.19
.16
, .001
, .001
, .001
N 5 131 patients were screened for the phase 2 AZLI trial; correlations were based on responses at screening (visit 1). SGRQ 5 St. George’s Respiratory Questionnaire. See Tables 1 and 2 for expansion of other abbreviations. aThe HRCT scan overall severity score was summed from lobe scores for six different lobes of the lung, including the right upper lobe, the right middle lobe, the right lower lobe, the left upper lobe, the lingular lobe, and the left lower lobe.24 The following scores were calculated and summed to provide a score for each lobe: bronchiectasis score, mucous plugging score, peribronchial thickening, parenchyma, and hyperinflation (air trapping). For each patient, the lobe scores (range, 0-40.5) of the two primary readers were averaged before the values were summed to give the HRCT scan overall severity score (possible range, 0-243; observed range, 1.5-117.8). bHankinson’s equations were used to calculate FEV % normal predicted for each patient.28 1 cThe SGRQ contains 50 items with a total of 76 weighted responses. Items are distributed on three domains: symptoms, activity, and impact. Each item on the SGRQ has been assigned a particular weight, based on responses from patients with asthma and COPD.9 Scores are standardized on a 0-to-100-point scale. dComparison prespecified by the study protocol. eAnalyses did not include one new item that had been added to QOL-B version 2.0.
Cough (11.2% of patients) and dyspnea (10.1%) were the most commonly reported adverse events (e-Table 5). Mild dysphonia (3.3%) was the only treatment-related event reported for three or more patients. Five patients (5.6%) experienced adverse events assessed by investigators as severe; the events were primarily respiratory and musculoskeletal disorders, and all were considered unrelated to treatment. Additional Analyses
Feedback from a regulatory agency about using the QOL-B respiratory symptoms scale as a primary clinical trial end point led to additional changes (QOL-B V3.0; 37 items; eight scales) (Table 1). Dyspnea was moved from the physical functioning to the respiratory symptoms scale. An item was added to measure shortness of breath 444 Original Research
with minimal exertion; “shortness of breath when talking” was selected because it was mentioned in the concept-elicitation study and represented the very severe end of the continuum. Second Cognitive Testing Study
The second cognitive testing study (40 participants) (Table 2) confirmed the usefulness of the changes made to generate QOL-B V3.0. No new content emerged in participant interviews. One item was modified (QOL-B V3.1); the parenthetical example of “sexual activity” was added to an item addressing intimacy with a partner (social functioning scale), and a response of “not applicable” was added (for participants without partners). Internal consistency (Cronbach’s a) of the V3.0 scales was ⱖ 0.70 for all scales except for social functioning (Table 4).
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TABLE 7
] Responsiveness of QOL-B Version 2.0 Scale Scores to Open-Label Treatment with AZLI in the Phase 2 Clinical Trial
QOL-B Scale
Baseline: Visit 2
After 4 Wk of Open-Label AZLI Treatment: Visit 4
Change From Visit 2 to Visit 4
P Value
84
84
84
…
49.5 (18.39)
65.8 (19.15)
16.3 (19.54)
, .001
Respiratory symptoms No. Mean (SD) Physical functioning No. Mean (SD)
86
86
86
44.7 (29.52)
52.2 (32.75)
7.6 (20.31)
…
85
85
85
…
46.7 (19.76)
54.1 (21.94)
7.4 (22.61)
.002
.001
Vitality No. Mean (SD) Role functioning No. Mean (SD)
85
85
85
…
58.4 (27.98)
63.1 (29.70)
4.7 (19.13)
.046
86
86
86
…
42.1 (19.76)
49.0 (23.35)
6.9 (19.15)
.002
Health perceptions No. Mean (SD) Emotional functioning No. Mean (SD)
86
86
86
…
79.8 (21.08)
83.4 (19.44)
3.6 (14.56)
.024
85
85
85
…
47.8 (27.91)
54.9 (26.52)
7.1 (19.08)
.002
Social functioninga No. Mean (SD) Treatment burden No. Mean (SD)
73
73
66.2 (25.35)
65.0 (22.58)
73 21.2 (18.48)
… .37
N 5 89 enrolled and AZLI-treated patients. P values were based on the Wilcoxon rank sum test. Specific analyses included patients whose compliance with dosing was ⱖ 80%. Patients who withdrew during the treatment period were included if they received at least 7 days of study drug, with compliance of ⱖ 80%. If patients withdrew prior to visit 4, the withdrawal values were carried over to the end of the treatment period. See Table 1 for expansion of abbreviations. aAnalyses did not include one new item that had been added to version 2.0.
Recall Period
Discussion
The QOL-B was designed to measure changes in chronic symptoms over the previous week. The accuracy of this recall period was evaluated in the preliminary cognitive testing study. Mean (SD) respiratory symptoms scores were 62.2 (21.4) with a single 24-h recall period and 60.0 (20.8) with a 1-week recall. Responses on eight of 10 items on the QOL-B V1.0 respiratory symptoms scale were comparable across the two recall periods; chest congestion and coughing up mucus were given slightly higher scores (fewer symptoms) on the single 24-h recall. Weekly and 24-h scores were highly correlated (paired correlation r 5 0.94, P , .00l, n 5 35).
The QOL-B is a self-administered, comprehensive, multidimensional PRO that evaluates the effects of bronchiectasis on patients’ symptoms and daily functioning. Items are ordered sequentially to provide a mix of positively and negatively worded statements to minimize response biases and fatigue. This also supports respondents’ engagement with an instrument that measures difficult issues related to living with a chronic disease.29,30 Each QOL-B scale has independently demonstrated good psychometric properties that support construct
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treatment. Only the social functioning and vitality scales did not meet or exceed well-established thresholds for these coefficients and thus these scales should be used with caution. The overall lack of notable ceiling or floor effects indicated that respondents have room to either improve or worsen. Thus, the QOL-B development pathway was based on guidance from the Food and Drug Administration18 and the European Medicines Agency31 and will be submitted to these agencies for consideration as an efficacy end point in bronchiectasis clinical trials. It is important to have an instrument that measures changes in both respiratory symptoms and physical functioning, because lung function measurements or changes in HRCT scans have not proven to be reliable or sensitive indicators of quality-of-life improvements after treatment of this population.5,7,8 For the respiratory symptoms scale, weekly and 24-h recall periods were comparable, consistent with studies of respiratory symptoms in CF and asthma.32,33 Weekly administration of a PRO is less burdensome than daily diary administration, particularly in longer clinical trials, and tools that are less burdensome for patients should be prioritized.
Figure 1 – A, Change in P aeruginosa and A xylosoxidans sputum density. B, Change in baseline QOL-B respiratory symptoms scores. C, Correlation between change from baseline QOL-B respiratory symptoms scores and P aeruginosa sputum density. Number of patients with data: 86, 83, 80, and 79 at d 14, 28, 42, and 46, respectively, for QOL-B V2.0 respiratory symptoms scores; 45, 46, 45, and 43 for change in P aeruginosa sputum density; and eight, five, seven, and seven for change in A xylosoxidans sputum density. A change of one response category 5 4.76 points for six of seven items on the QOL-B V2.0 respiratory symptoms scale and 3.57 points for the seventh item. A xylosoxidans 5 Achromobacter xylosoxidans; AZLI 5 aztreonam for inhalation solution; CFU 5 colony-forming unit; P aeruginosa 5 Pseudomonas aeruginosa; QOL-B 5 Quality of Life Questionnaire-Bronchiectasis; V 5 version.
validity, including adequate internal consistency, testretest reliability with good reproducibility over a 2-week interval, convergent validity with established measures, and responsivity to open-label antibiotic 446 Original Research
A limitation of this series of studies is that the psychometric analyses were conducted on an intermediate QOL-B version; analyses will be repeated with V3.0 data from two phase 3 AZLI clinical trials,34,35 and minimal important difference scores will be evaluated. The minimal important difference estimates in the phase 2 study described herein were not considered definitive. In addition, it is possible that a more quantitative approach, such as Rasch methods, would have identified slightly different items for inclusion. A further limitation is that there was no placebo arm in the phase 2 trial. One should not draw the conclusion that there was a causal relationship between AZLI treatment and symptom improvement; despite improvements in QOL-B respiratory symptoms scores after AZLI treatment, the improvements did not correlate with reductions in bacterial sputum density. Further, a lack of efficacy in treating non-CF bronchiectasis was reported in the recently completed phase 3 AZLI trials.36 It is possible that there was some sampling bias in the populations selected for the QOL-B development studies; however, we purposefully sought to include patients who varied in demographic and medical characteristics and who were receiving treatment at a variety
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of medical centers. Further, the patient characteristics of the clinical trial population appeared to be comparable to those in the other studies, except the presence of gram-negative organisms was required for enrollment in the trial.
Conclusions In conclusion, the QOL-B was developed using a detailed conceptual framework, input from patients and medical experts, and a series of rigorous qualita-
Acknowledgments Author contributions: All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A. L. Q., K. K. M., M. A. S., A. E. O., M. H. G., J. S. I., M. L. M., P. A. F., S. A. L., M. M., A. B. M., T. G. O., and A. F. B. contributed to the conception and design, acquisition, or analysis and interpretation of data; drafting of the submitted article or critical revision of the article for important intellectual content; and approval of the final version to be submitted. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Quittner has been a consultant to Gilead Sciences, Inc; Bayer HealthCare Pharmaceuticals; and Abbott Pharmaceuticals (now AbVie). Dr Marciel has been a consultant to Gilead Sciences, Inc. Dr O’Donnell has received research funding from, and has been a consultant to, Gilead Sciences, Inc. Dr Gotfried has received research support from Gilead Sciences, Inc, and Bayer HealthCare Pharmaceuticals. Dr Flume has participated as an investigator in a clinical trial of non-CF bronchiectasis sponsored by Gilead Sciences, Inc. Ms Lewis and Drs McKevitt, Montgomery, and O’Riordan were employees of Gilead Sciences, Inc, while these studies were conducted and are shareholders in Gilead Sciences, Inc. Dr Barker has been a consultant to Bayer; conducted clinical research for Gilead Sciences, Inc; and received an honorarium from UpToDate. Drs Salathe, Ilowite, and Metersky have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: Two sponsors were responsible for the work presented in this manuscript. The sponsor for the initial development of the QOL-B study was Behavioral Health Systems Research, which is the sole proprietorship of Dr Alexandra L. Quittner. She was awarded an investigator-initiated grant to perform all of the phases of instrument development leading up to the open-label
tive and quantitative studies to establish the content validity, reliability, and convergent validity of this instrument. It has been translated into more than 40 languages, and these translations have been piloted for use in multiple countries.37,38 Validation of the interim QOL-B was promising for evaluating the efficacy of new medications for patients with bronchiectasis and evaluating the symptoms and functioning of patients on a routine basis. A final psychometric validation is forthcoming.
responsivity phase. Dr Quittner was responsible for the design, implementation, conduct and analysis of the open-ended interviews and cognitive testing phases of the study. In addition, Gilead Sciences was the sponsor for the Phase 2 open-label treatment study which yielded the initial psychometric properties on the instrument. Content analysis of the open-ended interviews and transcription and analysis of the cognitive testing interviews were performed by Dr Quittner. Statistical analysis of the open label clinical study was performed by Gilead Sciences. Gilead paid a medical writer to assist with preparation of the manuscript and four of the authors who reviewed and revised the manuscript were either current or former employees of Gilead Sciences. Dr Quittner was responsible for organizing and editing the manuscript and collating feedback from the other authors to produce the final draft of the manuscript. Additional information: The e-Appendix, e-Figures, and e-Tables can be found in the Supplemental Materials section of the online article.
References 1. Nicotra MB, Rivera M, Dale AM, Shepherd R, Carter R. Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort. Chest. 1995;108(4):955-961. 2. King PT, Holdsworth SR, Freezer NJ, Villanueva E, Gallagher M, Holmes PW. Outcome in adult bronchiectasis. COPD. 2005;2(1):27-34. 3. King P, Holdsworth S, Freezer N, Holmes P. Bronchiectasis. Intern Med J. 2006;36(11):729-737. 4. O’Donnell AE. Bronchiectasis. Chest. 2008;134(4):815-823. 5. Smith MP, Hill AT. Evaluating success of therapy for bronchiectasis: what end points to use? Clin Chest Med. 2012;33(2):329-349. 6. Barker AF, Couch L, Fiel SB, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med. 2000;162(2 pt 1): 481-485.
7. Lee AL, Button BM, Ellis S, et al. Clinical determinants of the 6-minute walk test in bronchiectasis. Respir Med. 2009;103(5):780-785. 8. Eshed I, Minski I, Katz R, Jones PW, Priel IE. Bronchiectasis: correlation of high-resolution CT findings with health-related quality of life. Clin Radiol. 2007;62(2):152-159. 9. Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax. 2003;58(4):339-343. 10. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145(6):1321-1327. 11. Murray MP, Turnbull K, MacQuarrie S, Pentland JL, Hill AT. Validation of the Leicester Cough Questionnaire in noncystic fibrosis bronchiectasis. Eur Respir J. 2009;34(1):125-131. 12. Wilson CB, Jones PW, O’Leary CJ, Cole PJ, Wilson R. Validation of the St. George’s Respiratory Questionnaire in bronchiectasis. Am J Respir Crit Care Med. 1997;156(2 Pt 1):536-541. 13. Chan SL, Chan-Yeung MM, Ooi GC, et al. Validation of the Hong Kong Chinese version of the St. George Respiratory Questionnaire in patients with bronchiectasis. Chest. 2002;122(6):2030-2037. 14. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax. 1987;42(10):773-778. 15. Turner RR, Quittner AL, Parasuraman BM, Kallich JD, Cleeland CS; Mayo/FDA Patient-Reported Outcomes Consensus Meeting Group. Patient-reported outcomes: instrument development and selection issues. Value Health. 2007;10(suppl 2):S86-S93. 16. Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life Res. 2003;12(1):63-76.
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17. Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of The Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest. 2005;128(4):2347-2354. 18. U.S. Department of Health and Human Services; Food and Drug Administration. Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER); Center for Devices and Radiological Health (CDRH). Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims. US Food and Drug Administration website. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/UCM193282. pdf. Published December 2009. Accessed August 26, 2013. 19. McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine is effective in intensively-treated patients with cystic fibrosis. Am J Respir Crit Care Med. 2008;178(9): 921-928.
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20. Retsch-Bogart GZ, Quittner AL, Gibson RL, et al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest. 2009;135(5):1223-1232. 21. Schwarz N, Sudman S. Answering Questions: Methodology for Determining Cognitive and Communicative Processes in Survey Research. San Francisco, CA: Jossey-Bass; 1996. 22. Lessler JT, Forsyth BH. A coding system for appraising questionnaires. In: Schwarz N, Sudman S, eds. Answering Questions: Methodology for Determining Cognitive and Communicative Process in Survey Research. San Francisco, CA: Jossey-Bass; 1996:259-292. 23. Quittner AL, Sweeny S, Watrous M, et al. Translation and linguistic validation of
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a disease-specific quality of life measure for cystic fibrosis. J Pediatr Psychol. 2000;25(6):403-414. Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. Brody AS, Kosorok MR, Li Z, et al. Reproducibility of a scoring system for computed tomography scanning in cystic fibrosis. J Thorac Imaging. 2006;21(1):14-21. Ware J Jr, Brook RH, Davies-Avery A, et al. Conceptualization and measurement of health for adults in the health insurance study: vol 1, model of health and methodology. R-1987/1-HEW. Santa Monica, CA: Rand Corp; 1980. http://www.rand.org/pubs/reports/2006/ R1987.1.pdf. Published May 1980. Accessed August 26, 2013. Landis JR , Koch GG . The measurement of observer agreement for categorical data. Biometrics. 1977;33(1): 159-174. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Health, United States, 2005, with chartbook on trends in the health of Americans. Centers for Disease Control website. http://www.cdc.gov/ nchs/data/hus/hus05.pdf. Accessed August 26, 2013. Fayers P, Machin D. Quality of Life. 2nd ed. Chichester, West Sussex, England: John Wiley & Sons, Ltd.; 2007:64. Epstein JL, McPartland JM. The concept and measurement of the quality of school life. Am Educ Res J. 1976;13(1):15-30. European Medicines Agency (EMA) Committee for Medicinal Products for Human Use. (CHMP). Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products. London, England: European Medicines Agency; 2005. http://www.
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ema.europa.eu/docs/en_GB/document_ library/Scientific_guideline/2009/09/ WC500003637.pdf. Published July 27, 2005. Accessed August 26, 2013. Bennett AV, Patrick DL, Lymp JF, Edwards TC, Goss CH. Comparison of 7-day and repeated 24-hour recall of symptoms of cystic fibrosis. J Cyst Fibros. 2010;9(6):419-424. Juniper EF, O’Byrne PM, Ferrie PJ, King DR, Roberts JN. Measuring asthma control. Clinic questionnaire or daily diary? Am J Respir Crit Care Med. 2000;162(4 pt 1):1330-1334. A study to see if AZLI (an inhaled antibiotic) is effective in treating adults with non-CF bronchiectasis–AIR-BX1. NCT01313624. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2011. http://clinicaltrials.gov/ct2/ show/NCT01313624. Updated August 26, 2013. A study to see if AZLI (an inhaled antibiotic) is effective in treating adults with non-CF bronchiectasis–AIR-BX2. NCT01314716. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2011. http://clinicaltrials.gov/ ct2/show/NCT01314716. Updated August 26, 2013. Barker A, O’Donnell A, Thompson PJ, et al. Two phase 3 placebo-controlled trials of aztreonam lysine for inhalation (AZLI) for non-cystic fibrosis bronchiectasis (NCFB) (abstract P4136). Eur Respir J. 2013;42(suppl 57):877s-878s. Quittner AL, Marciel KK, Barker AF. Quality of life questionnaire-bronchiectasis. University of Miami website. http://www. psy.miami.edu/qol_b/. Accessed August 26, 2013. Olveira C, Olveira G, Espildora F, et al. Validation of a quality of life questionnaire for bronchiectasis: psychometric analyses of the Spanish QOL-B-V3.0 [published online ahead of print October 19, 2013]. Qual Life Res. doi:10.1007/ s11136-013-0560-0.
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Original Research Bronchiectasis
]
A Preliminary Quality of Life Questionnaire-Bronchiectasis A Patient-Reported Outcome Measure for Bronchiectasis Alexandra L. Quittner, PhD; Kristen K. Marciel, PhD; Matthias A. Salathe, MD, FCCP; Anne E. O’Donnell, MD, FCCP; Mark H. Gotfried, MD, FCCP; Jonathan S. Ilowite, MD, FCCP; Mark L. Metersky, MD, FCCP; Patrick A. Flume, MD; Sandra A. Lewis, MS; Matthew McKevitt, PhD; A. Bruce Montgomery, MD; Thomas G. O’Riordan, MD; and Alan F. Barker, MD, FCCP
BACKGROUND: The Quality of Life Questionnaire-Bronchiectasis (QOL-B) is the first diseasespecific, patient-reported outcome measure for patients with bronchiectasis. Content validity, cognitive testing, responsivity to open-label treatment, and psychometric analyses are presented.
Reviews of literature, existing measures, and physician input were used to generate the initial QOL-B. Modifications following preliminary cognitive testing (N 5 35 patients with bronchiectasis) generated version (V) 1.0. An open-ended patient interview study (N 5 28) provided additional information and was content analyzed to derive saturation matrices, which summarized all disease-related topics mentioned by each participant. This resulted in QOL-B V2.0. Psychometric analyses were carried out using results from an open-label phase 2 trial, in which 89 patients were enrolled and treated with aztreonam for inhalation solution. Responsivity to open-label treatment was observed. Additional analyses generated QOL-B V3.0, with 37 items on eight scales: respiratory symptoms; physical, role, emotional, and social functioning; vitality; health perceptions; and treatment burden. For each scale, scores are standardized on a 0-to-100-point scale; higher scores indicate better health-related quality of life. No total score is calculated. A final cognitive testing study (N 5 40) resulted in a minor change to one social functioning scale item (QOL-B V3.1).
METHODS:
Content validity, cognitive testing, responsivity to open-label treatment, and initial psychometric analyses supported QOL-B items and structure. RESULTS:
CONCLUSIONS: This interim QOL-B is a promising tool for evaluating the efficacy of new therapies for patients with bronchiectasis and for measuring symptoms, functioning, and quality of life in these patients on a routine basis. A final psychometric validation study is needed and is forthcoming. TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT00805025; URL: www.clinicaltrials.gov CHEST 2014; 146(2):437-448
Manuscript received August 21, 2013; revision accepted February 10, 2014; originally published Online First March 13, 2014. ABBREVIATIONS: 6MWT 5 6-min walk test; AZLI 5 aztreonam for inhalation solution; CF 5 cystic fibrosis; CFQ-R 5 Cystic Fibrosis Questionnaire-Revised; HRCT 5 high-resolution CT; PRO 5 patientreported outcome; QOL-B 5 Quality of Life-Bronchiectasis; SGRQ 5 St. George’s Respiratory Questionnaire; V 5 version AFFILIATIONS: From the Department of Psychology and Pediatrics (Drs Quittner and Marciel), and the Division of Pulmonary, Allergy,
Critical Care and Sleep Medicine (Dr Salathe), Department of Medicine, University of Miami, Coral Gables, FL; the Division of Pulmonary, Critical Care and Sleep Medicine (Dr O’Donnell), Department of Medicine, Georgetown University, Washington, DC; Pulmonary Associates (Dr Gotfried), and University of Arizona (Dr Gotfried), Phoenix, AZ; the Department of Medicine (Dr Ilowite), Division of Pulmonary and Critical Care, Winthrop University Hospital, Mineola, NY; the Division of Pulmonary and Critical Care (Dr Metersky), University of Connecticut School of Medicine, University of Connecticut, Farmington,
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Bronchiectasis, an obstructive lung disease, is defined by dilated airways on high-resolution CT (HRCT) chest scans. The disease is associated with significant morbidity. Symptoms typically include chronic cough, sputum production, dyspnea, fatigue, and persistent lower respiratory tract infections.1-4 Acute exacerbations of airway infections are common, associated with worsening symptoms, and typically treated with antibiotics, and they sometimes result in hospitalization. The development of new therapies for treating bronchiectasis has been hampered by the lack of disease-specific, practical, and well-validated primary end points. Commonly used measures have serious limitations in clinical trials.5 Changes in measures of lung function (eg, FEV1 %) are often subtle, and FEV1 is not strongly associated with a reduction in airway bacteria or an improvement in patients’ health status after treatment.6,7 The 6-min walk test (6MWT) has fallen into disfavor because of variability in the way the test is administered and because the results may be confounded by concomitant lung disease or other age-related comorbidities. Radiographic studies (eg, HRCT scans) have been used to develop severity scores, but changes do not correlate strongly with clinical improvement. It has been suggested that their lack of correlation is because some patients with bronchiectasis have debilitating respiratory symptoms with only focal structural airway damage
Materials and Methods QOL-B development (Table 1) was based on established processes.18 Three interview studies (preliminary and secondary cognitive testing and open-ended concept elicitation) and a validation study (open-label, 28-day course of aztreonam for inhalation solution (AZLI) (Cayston; Gilead Sciences, Inc) (e-Fig 1) were conducted. AZLI is approved for treatment of patients with CF with chronic Pseudomonas aeruginosa infection.19,20 Study Designs Cognitive testing interviews (lasting approximately 1.5 h) were audio recorded. Interviews used standard cognitive-testing procedures to determine what participants were thinking when responding to each item, how responses were chosen, what would elicit an adjacent response, relevance of items, and need for additional topics.21-23 Most recent BMI,
CT; the Division of Pulmonary and Critical Care Medicine (Dr Flume), Medical University of South Carolina, Charleston, SC; Gilead Sciences (Ms Lewis and Drs McKevitt, Montgomery, and O’Riordan), Seattle, WA; ; Cardeas Pharma (Dr Montgomery), Seattle, WA; and the Department of Medicine (Dr Barker), Division of Pulmonary and Critical Care, Oregon Health and Science University, Portland, OR. Part of this article has been presented previously in abstract form at American Thoracic Society International Conferences (May 19, 2009, San Diego, CA; May 19, 2010, New Orleans, LA; and May 20, 2013, Philadelphia, PA), a European Respiratory Society Annual Congress (September 13, 2009, Vienna, Austria), and CHEST conferences
438 Original Research
visible by HRCT scans.8 Use of acute exacerbations as a primary end point is complicated by the lack of a standardized definition and by the requirement for lengthy periods of assessment. Further, analyses could be affected by seasonal differences in exacerbation rates, and using this end point implies that patients feel well between episodes, when in fact most are symptomatic. Prior to developing the Quality of Life QuestionnaireBronchiectasis (QOL-B), existing patient-reported outcome (PRO) measures were evaluated; both the Leicester Cough Questionnaire9 and the St. George’s Respiratory Questionnaire10 (SGRQ) have been studied in bronchiectasis.11-13 Limitations have included minimal respiratory symptom coverage (Leicester Cough Questionnaire; Chronic Respiratory Questionnaire14), variable or lengthy recall intervals (SGRQ), and substantial response burden (some Chronic Respiratory Questionnaire and SGRQ forms). Our review strongly suggested that a new PRO was needed for bronchiectasis.15 The Cystic Fibrosis Questionnaire-Revised (CFQ-R)16,17 contained the most complete and relevant items measuring respiratory symptoms (because of the common occurrence of bronchiectasis in patients with cystic fibrosis [CF]). Therefore, items from the CFQ-R and the relevant literature were used as a starting point for developing the QOL-B, the first bronchiectasis-specific PRO instrument to our knowledge. spirometry (performed during preliminary study24), and sputum culture results were obtained (retrospective chart review). In the preliminary cognitive-testing study, revisions were made on the basis of responses and were tested at subsequent sites; QOL-B version (V) 1.0 was developed after analyzing all interviews. In concept-elicitation interviews (lasting 1-1.5 h), interviewers probed several dimensions of severity: (1) the frequency with which symptoms and other impacts occurred, (2) the level of difficulty managing symptoms, and (3) the extent to which symptoms affected daily activities (work, social roles). Audiotapes were transcribed and responses were coded (Atlas.ti V5.0; Scientific Software Development). Relevant topics were selected based on the frequency of patient endorsement (more than two patients) and physician review. The phase 2 clinical trial was conducted at 21 centers in the United States (December 2008 to October 2009), with six visits over 70 days,
(October 30-November 4, 2010, Vancouver, BC, Canada; and October 22-26, 2011, Honolulu, HI). FUNDING/SUPPORT: The studies described here were sponsored by Gilead Sciences, Inc and Behavioral Health Systems Research. CORRESPONDENCE TO: Alexandra L. Quittner, PhD, Child Division, University of Miami, 5665 Ponce de Leon Blvd, Coral Gables, FL 33146; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1891
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TABLE 3
] Internal Consistency of QOL-B Scales QOL-B Version 2.0
QOL-B Scale
QOL-B Version 3.0
No. Respondents (N 5 131)
Cronbach’s a
No. Respondentsb (N 5 40)
Cronbach’s a
Respiratory symptoms
117
0.78
36
0.82
Physical functioning
119
0.92
38
0.94
Vitality
122
0.70
40
0.85
Role functioning
124
0.89
40
0.86
Health perceptions
121
0.77
40
0.77
Emotional functioning
122
0.86
40
0.72
Social functioning
125
0.69c
36
0.66
Treatment burden
108
0.83
36
0.84
a
See Table 1 for expansion of abbreviations. aTotal number of patients screened for the phase 2 open-label AZLI trial; analyses included data for patients who were not missing measurements at screening visit. bTotal number of participants in the second cognitive testing study. cAnalyses did not include one new item that had been added to QOL-B version 2.0.
and carrying” was changed to “carrying,” and “affectionate/intimate” was changed to “intimate.” Two items were reworded to better represent the participants’ experiences: “chest pain with coughing” was changed to “chest pain”; and examples of planning for the future were modified slightly. An item was added to the social functioning scale to address concerns about being around other people who were sick. Revisions generated QOL-B V2.0 (36 items on eight scales) (Table 1). Anger, weight gain/loss, digestive symptoms, changes in appetite, and sensitivity to smell were mentioned by small numbers of participants and were not added to the QOL-B because the participants considered these issues unrelated to their bronchiectasis. Items address-
TABLE 4
ing sinus problems or a runny nose were not added because upper respiratory problems are very common in the general adult population in the United States.28 The concept-elicitation study did not require participants to have documented gram-negative endobronchial infection; however, consistent topics were elicited from participants with (n 5 10 of 22) or without (n 5 12) such infections (e-Table 2). Phase 2 Open-Label AZLI Study
Although QOL-B V1.0 was administered in the phase 2 study, analyses presented herein include only data from the 35 items retained on V2.0 ( Table 1 ). Responses were scored in accordance with V2.0 scales and syntax.
] Test-Retest Reliability: Intraclass Correlation Coefficients between Screening (Visit 1; D 14) and Baseline (Visit 2; D 0) for QOL-B Version 2.0 Scale Scores for Clinically Stable Patients
QOL-B Scale
No. Respondents (N 5 89)
Intraclass Correlation Coefficient
Respiratory symptoms
85
0.80
Physical functioning
88
0.88
Vitality
87
0.67
Role functioning
87
0.84
Health perceptions
88
0.78
Emotional functioning
88
0.82
Social functioninga
87
0.85
Treatment burden
74
0.76
Total N is the number of patients enrolled and subsequently treated with AZLI in the open-label phase 2 clinical trial. Intraclass correlation coefficients were determined from screening and baseline measurements; both occurred before AZLI treatment. Analyses included patients with specified QOL-B scale measurements at both screening and baseline. See Table 1 for expansion of abbreviations. aAnalyses did not include one new item that had been added to QOL-B version 2.0.
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TABLE 1
] (continued)
Step
Scales
Number of Items
Modifications of Instrument
Step 3b: Psychometric and responsivity analyses; data from 131 patients screened for a phase 2 open-label AZLI clinical trial; 108 patients enrolled and treated with AZLI; 2008-2009; 21 sites in the United States (clinicaltrials. gov:NCT00805025) QOL-B version 2.0
Eight scales:
36 items
Same scales as version 1.0
Changes from previous version: 15 items deleted from six different scales (eight were not supported by participants’ comments as being important to the experience of having bronchiectasis, and seven were redundant with other items) Three items moved to a different scale One item added Seven items reworded
Step 4: Additional analyses of previous studies; feedback from regulatory agency QOL-B version 3.0
Eight scales:
37 items
Same scales as version 1.0
Changes from previous version: One item moved to a different scale One item added Two items reworded (specific examples added to better define meaning of items) Scoring changed for one item: two mucous colors were combined for scoring Response options changed for 19 items
Step 5: Second cognitive testing study; 40 participants; 2012; four sites in the United States QOL-B version 3.1
Eight scales: Same scales as version 1.0
37 items
Changes from previous version: Response options and wording changed for one item on social functioning scale
AZLI 5 aztreonam for inhalation solution; CFQ-R 5 Cystic Fibrosis Questionnaire-Revised; QOL-B 5 Quality of Life Questionnaire-Bronchiectasis.
including 14 days of observation, 28 days of open-label AZLI treatment (75 mg, administered tid) with an investigative eFlow nebulizer (PARI Innovative Manufacturers, Inc), and 28 days of follow-up (e-Fig 1). Psychometric analyses used QOL-B responses from 131 screened patients and/or 89 AZLI-treated patients (e-Fig 2), as identified for each analysis. Procedures for all studies were approved by institutional review boards (e-Appendix 1). Participants provided written informed consent prior to participation.
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Study Participants Interview studies included adults with bronchiectasis, who had not been exposed previously to the QOL-B. Patients with CF were excluded from all studies. For each study, the same research team conducted and analyzed the interviews. For the phase 2 trial, eligible patients (ⱖ 18 years old) had bronchiectasis confirmed by chest HRCT scans (during the prior 6 months), which were read/scored by two independent radiologists (BioClinica, Inc) using established criteria (scores ranged
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Analyses
from 0 to 243; smaller values indicated less severe disease25). Patients had mucopurulent sputum production daily and a history of positive sputum culture for a gram-negative organism within 5 years, were culture positive for gram-negative organism at screening, and had had previous antibiotic treatment of bronchiectasis. Key exclusion criteria included hospitalization or hemoptysis . 30 mL (prior 14 days), serious adverse event during observation period, antibiotic use for respiratory symptoms (excluding chronic, stable azithromycin use) or change in corticosteroid/bronchodilator regimen (prior 14 days or during observation period), FEV1 , 25% predicted, or change in FEV1 (L) . 10% and 150 mL during observation period.
Statistical analyses were performed with the IBM SPSS Statistics program, V19 (interview studies) and SAS V9.1 (SAS Institute Inc) (phase 2 study). Comparisons used Pearson’s correlation coefficients (r), unless noted. Internal consistency was measured for each scale using Cronbach’s a; values ⱖ 0.70 indicated that items within a scale were correlated with each other.26 QOL-B test-retest reliability (reproducibility) was calculated using intraclass correlation coefficients to compare the results for each scale over a 2-week interval; values ⱖ 0.70 indicated good score stability/reproducibility (results from visits 1 and 2 were used) (phase 2 trial).27
Results
Concept-Elicitation Study
Preliminary Cognitive Testing Study
The concept-elicitation study included 28 participants (Table 2); 82% were currently receiving bronchiectasis treatment(s). Participants mentioned 73 disease-related topics, with 71 topics mentioned by the first 14 participants, the last two topics mentioned by the 16th and 23rd participants, and no new topics elicited from the final five participants. This indicated that saturation of disease-related topics had been reached. Topics are presented by decreasing incidence (e-Table 1) and in a saturation grid (e-Table 2).
The initial QOL-B (56 items, 11 scales; 1-week recall period) (Table 1) was assessed in a preliminary cognitive testing study conducted sequentially at three sites (35 participants) (Table 2). Three items were added on the basis of participants’ responses, including “feeling anxious,” “I am concerned that my health will get worse,” and an item addressing intimacy. Nine items were deleted, including an item addressing dyspnea when sitting, which few participants experienced. Instructions and response options were well understood. The resulting QOL-B (V1.0; 50 items, eight scales) (Table 1) was administered during the phase 2 trial. Results were analyzed concurrently with the conceptelicitation study, which is presented first.
TABLE 2
After analysis, one item was reworded to match the terms used by the participants: “dyspnea (shortness of breath)” was changed to “shortness of breath” (Table 1). Two items were rewritten to reflect a single concept that best captured the participants’ concerns: “lifting
] Comparison of Patient Characteristics
Characteristics
Preliminary Cognitive Testing Study
Patients, No.
35
Open-Ended Concept-Elicitation Interview Study 28
Age, mean (SD), y
65.0 (13.4)
60.1 (16.8)
Age, range, y
26-87
25-98
FEV1 % predicted, mean (SD)
57.1 (25.5)
65.0 (23.1)
FEV1 % predicted, range
17-103
30-110
a
BMI, mean (SD)
25.1 (6.2)
26.4 (7.5)
Female, No. (%)
20 (57)
23 (82.1)
Bronchiectasis confirmed
Investigator selection
Investigator selection
Gram-negative organism,c No. (%)
11 (45.8)
10 (45.5)
b
Phase 2 Open-Label AZLI Clinical Trial
Second Cognitive Testing Study
89
40
64 (14.7) 24-84 60.4 (21.3) 27-114 24.8 (5.5) 62 (69.7) Documented HRCT scan 89 (100)
64.6 (12.3) 36-84 69.07 (19.83) 6.8-117 25.15 (6.08) 33 (82.5) Documented CT scan 14 (35.9)
HRCT 5 high-resolution CT. See Table 1 for expansion of other abbreviation. aFEV % predicted values available for 35, 22, 89, and 39 patients in the four studies. 1 bIn the preliminary cognitive testing and concept-elicitation interview studies, patients with bronchiectasis were selected by investigators; diagnosis by CT scan was confirmed for 77.1% of participants (n 5 27 of 35) in the preliminary study and 62.1% (n 5 18 of 29) in the open-ended conceptelicitation study; the remaining participants were selected on the basis of medical history (no CT scan was available at study site). cCultures available for 24, 22, 89, and 39 patients in the four studies; percentages were calculated using the number of patients with cultures.
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TABLE 3
] Internal Consistency of QOL-B Scales QOL-B Version 2.0
QOL-B Scale
QOL-B Version 3.0
No. Respondents (N 5 131)
Cronbach’s a
No. Respondentsb (N 5 40)
Cronbach’s a
Respiratory symptoms
117
0.78
36
0.82
Physical functioning
119
0.92
38
0.94
Vitality
122
0.70
40
0.85
Role functioning
124
0.89
40
0.86
Health perceptions
121
0.77
40
0.77
Emotional functioning
122
0.86
40
0.72
Social functioning
125
0.69c
36
0.66
Treatment burden
108
0.83
36
0.84
a
See Table 1 for expansion of abbreviations. aTotal number of patients screened for the phase 2 open-label AZLI trial; analyses included data for patients who were not missing measurements at screening visit. bTotal number of participants in the second cognitive testing study. cAnalyses did not include one new item that had been added to QOL-B version 2.0.
and carrying” was changed to “carrying,” and “affectionate/intimate” was changed to “intimate.” Two items were reworded to better represent the participants’ experiences: “chest pain with coughing” was changed to “chest pain”; and examples of planning for the future were modified slightly. An item was added to the social functioning scale to address concerns about being around other people who were sick. Revisions generated QOL-B V2.0 (36 items on eight scales) (Table 1). Anger, weight gain/loss, digestive symptoms, changes in appetite, and sensitivity to smell were mentioned by small numbers of participants and were not added to the QOL-B because the participants considered these issues unrelated to their bronchiectasis. Items address-
TABLE 4
ing sinus problems or a runny nose were not added because upper respiratory problems are very common in the general adult population in the United States.28 The concept-elicitation study did not require participants to have documented gram-negative endobronchial infection; however, consistent topics were elicited from participants with (n 5 10 of 22) or without (n 5 12) such infections (e-Table 2). Phase 2 Open-Label AZLI Study
Although QOL-B V1.0 was administered in the phase 2 study, analyses presented herein include only data from the 35 items retained on V2.0 ( Table 1 ). Responses were scored in accordance with V2.0 scales and syntax.
] Test-Retest Reliability: Intraclass Correlation Coefficients between Screening (Visit 1; D 14) and Baseline (Visit 2; D 0) for QOL-B Version 2.0 Scale Scores for Clinically Stable Patients
QOL-B Scale
No. Respondents (N 5 89)
Intraclass Correlation Coefficient
Respiratory symptoms
85
0.80
Physical functioning
88
0.88
Vitality
87
0.67
Role functioning
87
0.84
Health perceptions
88
0.78
Emotional functioning
88
0.82
Social functioninga
87
0.85
Treatment burden
74
0.76
Total N is the number of patients enrolled and subsequently treated with AZLI in the open-label phase 2 clinical trial. Intraclass correlation coefficients were determined from screening and baseline measurements; both occurred before AZLI treatment. Analyses included patients with specified QOL-B scale measurements at both screening and baseline. See Table 1 for expansion of abbreviations. aAnalyses did not include one new item that had been added to QOL-B version 2.0.
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Patient characteristics were comparable to those in the interview studies, except the presence of gram-negative organisms was required for enrollment (Table 2). P aeruginosa (n 5 73 of 89 [82.0%]) and Achromobacter xylosoxidans (n 5 11 of 89 [12.4%]) were the most commonly reported gram-negative organisms (e-Table 3). Minor floor effects (scores 5 0 at screening) were observed for the vitality (7.2% respondents) and physical and social functioning (6.4% each) scales. Ceiling effects (scores 5 100 at screening) were observed for . 10% of respondents on only two scales: treatment burden (17.4%) and emotional functioning (16.0%). Evidence of strong internal consistency was found, with Cronbach’s a ranging from 0.69 to 0.92; all scales except for social functioning were ⱖ 0.70 (Table 3). Test-retest reliability was also excellent, with intraclass correlation coefficients ranging from 0.67 to 0.88; all except for vitality were ⱖ 0.70 (Table 4). At screening, only the QOL-B V2.0 physical and role functioning scores discriminated between patients on the basis of lung function, with scores significantly lower for patients with FEV1 ⱕ 50% predicted than for patients with FEV1 . 50% predicted (Table 5). At screening, strong evidence of convergent validity was found between QOL-B respiratory symptoms and SGRQ scores (r 5 20.53 to 20.73; each, P , .001), with modest associations found between respiratory symptoms and HRCT scan overall severity scores (r 5 20.24, P 5 .009) (Table 6). Significant correlations were not found between respiratory symptoms scores and FEV1 % predicted or 6MWT. Modest to strong associations were found between physical functioning scores and HRCT scan overall severity scores, FEV1 % predicted, 6MWT, and SGRQ scores. Responsiveness of the QOL-B to 28 days of open-label AZLI was assessed by comparing QOL-B scores before and after treatment (Table 7). QOL-B V2.0 scores improved significantly after open-label AZLI treatment (P , .05) for all scales except for treatment burden. Across the study, improvements in mean respiratory symptoms scores were accompanied by decreases in mean P aeruginosa and A xylosoxidans sputum density; however, for individual subjects, the changes in respiratory symptoms scores did not correlate with changes in P aeruginosa colony-forming units (r 5 20.126) (Fig 1). Mean (SD) baseline HRCT scan overall severity scores were 43.6 (22.52) (range, 1.5-117.8) and also did not correlate with change from baseline QOL-B V2.0 respi-
TABLE 5
] QOL-B Version 2.0 Scale Scores at Screening by Disease Severity (FEV1 % Predicted)
QOL-B Scale
FEV1 ⱕ 50% FEV1 . 50% Predicted (N 5 48) Predicted (N 5 72)
P Value
Respiratory symptoms No. Mean (SD)
47
71
…
51.3 (20.22)
50.6 (19.35)
.74
47
72
…
32.6 (27.26)
50.5 (30.84)
.002
Physical functioning No. Mean (SD) Vitality No. Mean (SD)
47
72
…
43.1 (19.08)
45.2 (23.46)
.56
Role functioning No. Mean (SD)
47
72
…
51.1 (28.46)
62.3 (26.90)
.040
Health perceptions No. Mean (SD)
47
72
…
37.2 (19.99)
39.1 (20.93)
.56
Emotional functioning No. Mean (SD)
47
72
…
69.0 (26.16)
74.5 (22.82)
.32
Social functioninga No. Mean (SD)
47
72
…
41.6 (25.64)
47.2 (27.96)
.29
Treatment burden No. Mean (SD)
43
61
…
64.3 (25.72)
68.1 (27.85)
.36
N 5 131 patients were screened for the phase 2 AZLI trial. FEV1 % predicted values were available for 120 patients at screening. QOL-B scores were from screening (visit 1, before AZLI treatment). P values were based on Wilcoxon rank sum test. For patients with FEV1 ⱕ 50% predicted vs FEV1 . 50% predicted: mean (SD) FEV1 (L) 5 1.0 (0.3) vs 1.9 (0.6); mean (SD) FEV1 % predicted 5 37.9 (8.6) vs 74.9 (17.7); mean (SD) log10 Pseudomonas aeruginosa CFU/g 5 4.3 (3.1) vs 4.2 (3.0); and mean (SD) log10 of all CFU/g 5 14.3 (4.5) vs 13.9 (3.2). CFU 5 colony-forming unit. See Table 1 for expansion of other abbreviations. aAnalyses did not include one new item that had been added to QOL-B version 2.0.
ratory symptoms score after 4 weeks of AZLI treatment (r 5 20.04, P 5 .7, n 5 82). Improvements on the respiratory symptoms scale were not driven by responses on any single item; statistically significant improvements were observed for most items on the scale (e-Table 4).
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TABLE 6
] Pearson’s Correlation Coefficients for QOL-B V2.0 Scale Scores at Screening and Other Indices of Health Status
Other Indexes of Health Status
QOL-B Scale (N 5 131) Respiratory symptoms (No.) (n 5 124) P value Physical functioning (No.) (n 5 125) P value Vitality (No.) (n 5 125) P value Emotional functioning (No.) (n 5 125) P value Social functioninge (No.) (n 5 125) P value
HRCT Overall Severitya (n 5 119)
FEV1 % Predictedb (n 5 120)
6-Min Walk Test (n 5 121)
SGRQ Symptomsc (n 5 121)
SGRQ Activityc (n 5 117)
SGRQ Impactsc (n 5 119)
20.24 (117)d
0.06 (118)d
0.07 (119)d
20.73 (119)d
20.53 (116)
20.62 (118)
.009
.49
.43
, .001
, .001
, .001
20.21 (118)
0.32 (119)
0.45 (120)
20.68 (120)
20.85 (117)
20.76 (119)
.023
, .001
, .001
, .001
, .001
, .001
20.18 (118)
0.07 (119)
0.24 (120)
20.58 (120)
d
d
.049
.45
20.18 (119)
0.12 (119)
d
.009 0.17 (120)
d
d
20.64 (117)
d
20.68 (119)
, .001
, .001
, .001
20.38 (120)
20.41 (117)
20.54 (119)d
.06
.20
.06
, .001
, .001
, .001
20.22 (118)
0.12 (119)
0.13 (120)
20.64 (120)
20.48 (117)
20.69 (119)d
.018
.19
.16
, .001
, .001
, .001
N 5 131 patients were screened for the phase 2 AZLI trial; correlations were based on responses at screening (visit 1). SGRQ 5 St. George’s Respiratory Questionnaire. See Tables 1 and 2 for expansion of other abbreviations. aThe HRCT scan overall severity score was summed from lobe scores for six different lobes of the lung, including the right upper lobe, the right middle lobe, the right lower lobe, the left upper lobe, the lingular lobe, and the left lower lobe.24 The following scores were calculated and summed to provide a score for each lobe: bronchiectasis score, mucous plugging score, peribronchial thickening, parenchyma, and hyperinflation (air trapping). For each patient, the lobe scores (range, 0-40.5) of the two primary readers were averaged before the values were summed to give the HRCT scan overall severity score (possible range, 0-243; observed range, 1.5-117.8). bHankinson’s equations were used to calculate FEV % normal predicted for each patient.28 1 cThe SGRQ contains 50 items with a total of 76 weighted responses. Items are distributed on three domains: symptoms, activity, and impact. Each item on the SGRQ has been assigned a particular weight, based on responses from patients with asthma and COPD.9 Scores are standardized on a 0-to-100-point scale. dComparison prespecified by the study protocol. eAnalyses did not include one new item that had been added to QOL-B version 2.0.
Cough (11.2% of patients) and dyspnea (10.1%) were the most commonly reported adverse events (e-Table 5). Mild dysphonia (3.3%) was the only treatment-related event reported for three or more patients. Five patients (5.6%) experienced adverse events assessed by investigators as severe; the events were primarily respiratory and musculoskeletal disorders, and all were considered unrelated to treatment. Additional Analyses
Feedback from a regulatory agency about using the QOL-B respiratory symptoms scale as a primary clinical trial end point led to additional changes (QOL-B V3.0; 37 items; eight scales) (Table 1). Dyspnea was moved from the physical functioning to the respiratory symptoms scale. An item was added to measure shortness of breath 444 Original Research
with minimal exertion; “shortness of breath when talking” was selected because it was mentioned in the concept-elicitation study and represented the very severe end of the continuum. Second Cognitive Testing Study
The second cognitive testing study (40 participants) (Table 2) confirmed the usefulness of the changes made to generate QOL-B V3.0. No new content emerged in participant interviews. One item was modified (QOL-B V3.1); the parenthetical example of “sexual activity” was added to an item addressing intimacy with a partner (social functioning scale), and a response of “not applicable” was added (for participants without partners). Internal consistency (Cronbach’s a) of the V3.0 scales was ⱖ 0.70 for all scales except for social functioning (Table 4).
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TABLE 7
] Responsiveness of QOL-B Version 2.0 Scale Scores to Open-Label Treatment with AZLI in the Phase 2 Clinical Trial
QOL-B Scale
Baseline: Visit 2
After 4 Wk of Open-Label AZLI Treatment: Visit 4
Change From Visit 2 to Visit 4
P Value
84
84
84
…
49.5 (18.39)
65.8 (19.15)
16.3 (19.54)
, .001
Respiratory symptoms No. Mean (SD) Physical functioning No. Mean (SD)
86
86
86
44.7 (29.52)
52.2 (32.75)
7.6 (20.31)
…
85
85
85
…
46.7 (19.76)
54.1 (21.94)
7.4 (22.61)
.002
.001
Vitality No. Mean (SD) Role functioning No. Mean (SD)
85
85
85
…
58.4 (27.98)
63.1 (29.70)
4.7 (19.13)
.046
86
86
86
…
42.1 (19.76)
49.0 (23.35)
6.9 (19.15)
.002
Health perceptions No. Mean (SD) Emotional functioning No. Mean (SD)
86
86
86
…
79.8 (21.08)
83.4 (19.44)
3.6 (14.56)
.024
85
85
85
…
47.8 (27.91)
54.9 (26.52)
7.1 (19.08)
.002
Social functioninga No. Mean (SD) Treatment burden No. Mean (SD)
73
73
66.2 (25.35)
65.0 (22.58)
73 21.2 (18.48)
… .37
N 5 89 enrolled and AZLI-treated patients. P values were based on the Wilcoxon rank sum test. Specific analyses included patients whose compliance with dosing was ⱖ 80%. Patients who withdrew during the treatment period were included if they received at least 7 days of study drug, with compliance of ⱖ 80%. If patients withdrew prior to visit 4, the withdrawal values were carried over to the end of the treatment period. See Table 1 for expansion of abbreviations. aAnalyses did not include one new item that had been added to version 2.0.
Recall Period
Discussion
The QOL-B was designed to measure changes in chronic symptoms over the previous week. The accuracy of this recall period was evaluated in the preliminary cognitive testing study. Mean (SD) respiratory symptoms scores were 62.2 (21.4) with a single 24-h recall period and 60.0 (20.8) with a 1-week recall. Responses on eight of 10 items on the QOL-B V1.0 respiratory symptoms scale were comparable across the two recall periods; chest congestion and coughing up mucus were given slightly higher scores (fewer symptoms) on the single 24-h recall. Weekly and 24-h scores were highly correlated (paired correlation r 5 0.94, P , .00l, n 5 35).
The QOL-B is a self-administered, comprehensive, multidimensional PRO that evaluates the effects of bronchiectasis on patients’ symptoms and daily functioning. Items are ordered sequentially to provide a mix of positively and negatively worded statements to minimize response biases and fatigue. This also supports respondents’ engagement with an instrument that measures difficult issues related to living with a chronic disease.29,30 Each QOL-B scale has independently demonstrated good psychometric properties that support construct
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treatment. Only the social functioning and vitality scales did not meet or exceed well-established thresholds for these coefficients and thus these scales should be used with caution. The overall lack of notable ceiling or floor effects indicated that respondents have room to either improve or worsen. Thus, the QOL-B development pathway was based on guidance from the Food and Drug Administration18 and the European Medicines Agency31 and will be submitted to these agencies for consideration as an efficacy end point in bronchiectasis clinical trials. It is important to have an instrument that measures changes in both respiratory symptoms and physical functioning, because lung function measurements or changes in HRCT scans have not proven to be reliable or sensitive indicators of quality-of-life improvements after treatment of this population.5,7,8 For the respiratory symptoms scale, weekly and 24-h recall periods were comparable, consistent with studies of respiratory symptoms in CF and asthma.32,33 Weekly administration of a PRO is less burdensome than daily diary administration, particularly in longer clinical trials, and tools that are less burdensome for patients should be prioritized.
Figure 1 – A, Change in P aeruginosa and A xylosoxidans sputum density. B, Change in baseline QOL-B respiratory symptoms scores. C, Correlation between change from baseline QOL-B respiratory symptoms scores and P aeruginosa sputum density. Number of patients with data: 86, 83, 80, and 79 at d 14, 28, 42, and 46, respectively, for QOL-B V2.0 respiratory symptoms scores; 45, 46, 45, and 43 for change in P aeruginosa sputum density; and eight, five, seven, and seven for change in A xylosoxidans sputum density. A change of one response category 5 4.76 points for six of seven items on the QOL-B V2.0 respiratory symptoms scale and 3.57 points for the seventh item. A xylosoxidans 5 Achromobacter xylosoxidans; AZLI 5 aztreonam for inhalation solution; CFU 5 colony-forming unit; P aeruginosa 5 Pseudomonas aeruginosa; QOL-B 5 Quality of Life Questionnaire-Bronchiectasis; V 5 version.
validity, including adequate internal consistency, testretest reliability with good reproducibility over a 2-week interval, convergent validity with established measures, and responsivity to open-label antibiotic 446 Original Research
A limitation of this series of studies is that the psychometric analyses were conducted on an intermediate QOL-B version; analyses will be repeated with V3.0 data from two phase 3 AZLI clinical trials,34,35 and minimal important difference scores will be evaluated. The minimal important difference estimates in the phase 2 study described herein were not considered definitive. In addition, it is possible that a more quantitative approach, such as Rasch methods, would have identified slightly different items for inclusion. A further limitation is that there was no placebo arm in the phase 2 trial. One should not draw the conclusion that there was a causal relationship between AZLI treatment and symptom improvement; despite improvements in QOL-B respiratory symptoms scores after AZLI treatment, the improvements did not correlate with reductions in bacterial sputum density. Further, a lack of efficacy in treating non-CF bronchiectasis was reported in the recently completed phase 3 AZLI trials.36 It is possible that there was some sampling bias in the populations selected for the QOL-B development studies; however, we purposefully sought to include patients who varied in demographic and medical characteristics and who were receiving treatment at a variety
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of medical centers. Further, the patient characteristics of the clinical trial population appeared to be comparable to those in the other studies, except the presence of gram-negative organisms was required for enrollment in the trial.
Conclusions In conclusion, the QOL-B was developed using a detailed conceptual framework, input from patients and medical experts, and a series of rigorous qualita-
Acknowledgments Author contributions: All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A. L. Q., K. K. M., M. A. S., A. E. O., M. H. G., J. S. I., M. L. M., P. A. F., S. A. L., M. M., A. B. M., T. G. O., and A. F. B. contributed to the conception and design, acquisition, or analysis and interpretation of data; drafting of the submitted article or critical revision of the article for important intellectual content; and approval of the final version to be submitted. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Quittner has been a consultant to Gilead Sciences, Inc; Bayer HealthCare Pharmaceuticals; and Abbott Pharmaceuticals (now AbVie). Dr Marciel has been a consultant to Gilead Sciences, Inc. Dr O’Donnell has received research funding from, and has been a consultant to, Gilead Sciences, Inc. Dr Gotfried has received research support from Gilead Sciences, Inc, and Bayer HealthCare Pharmaceuticals. Dr Flume has participated as an investigator in a clinical trial of non-CF bronchiectasis sponsored by Gilead Sciences, Inc. Ms Lewis and Drs McKevitt, Montgomery, and O’Riordan were employees of Gilead Sciences, Inc, while these studies were conducted and are shareholders in Gilead Sciences, Inc. Dr Barker has been a consultant to Bayer; conducted clinical research for Gilead Sciences, Inc; and received an honorarium from UpToDate. Drs Salathe, Ilowite, and Metersky have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: Two sponsors were responsible for the work presented in this manuscript. The sponsor for the initial development of the QOL-B study was Behavioral Health Systems Research, which is the sole proprietorship of Dr Alexandra L. Quittner. She was awarded an investigator-initiated grant to perform all of the phases of instrument development leading up to the open-label
tive and quantitative studies to establish the content validity, reliability, and convergent validity of this instrument. It has been translated into more than 40 languages, and these translations have been piloted for use in multiple countries.37,38 Validation of the interim QOL-B was promising for evaluating the efficacy of new medications for patients with bronchiectasis and evaluating the symptoms and functioning of patients on a routine basis. A final psychometric validation is forthcoming.
responsivity phase. Dr Quittner was responsible for the design, implementation, conduct and analysis of the open-ended interviews and cognitive testing phases of the study. In addition, Gilead Sciences was the sponsor for the Phase 2 open-label treatment study which yielded the initial psychometric properties on the instrument. Content analysis of the open-ended interviews and transcription and analysis of the cognitive testing interviews were performed by Dr Quittner. Statistical analysis of the open label clinical study was performed by Gilead Sciences. Gilead paid a medical writer to assist with preparation of the manuscript and four of the authors who reviewed and revised the manuscript were either current or former employees of Gilead Sciences. Dr Quittner was responsible for organizing and editing the manuscript and collating feedback from the other authors to produce the final draft of the manuscript. Additional information: The e-Appendix, e-Figures, and e-Tables can be found in the Supplemental Materials section of the online article.
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