Abstract
Background
Nontuberculous mycobacteria (NTM), predominately Mycobacterium avium complex (MAC), cause chronic pulmonary disease. Improvements in symptoms and health-related quality of life (HRQoL) are important treatment outcomes, but no validated patient-reported outcome (PRO) measure exists.
Research Question
What are the validity and responsiveness of the Quality of Life-Bronchiectasis (QOL-B) questionnaire respiratory symptoms scale and key HRQoL measures during the first 6 months of MAC pulmonary disease (MAC-PD) treatment?
Study Design and Methods
Comparison of Two- vs Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease (MAC2v3) is an ongoing randomized, multisite pragmatic clinical trial. Patients with MAC-PD were randomized to azithromycin-based two-drug or three-drug therapy; treatment groups were combined for this analysis. PROs were measured at baseline, 3 months, and 6 months. The QOL-B respiratory symptoms, vitality, physical functioning, health perceptions, and NTM symptom domain scores (on a scale of 0-100, with 100 being best) were analyzed separately. We performed psychometric and descriptive analyses in the population enrolled as of the time of analysis and calculated the minimal important difference (MID) using distribution-based methods. Finally, we evaluated responsiveness using paired t tests and latent growth curve analysis in the subset with longitudinal surveys completed by the time of analysis.
Results
The baseline population included 228 patients, of whom 144 had completed longitudinal surveys. Patients predominately were female (82%) and had bronchiectasis (88%); 50% were 70 years of age or older. The respiratory symptoms domain showed good psychometric properties (no floor or ceiling effects; Cronbach’s α, 0.85) and an MID of 6.4 to 6.9. Vitality and health perceptions domain scores performed similarly. Respiratory symptoms domain scores improved by 7.8 points (P < .0001) and 7.5 points (P < .0001), and the physical functioning domain score improved by 4.6 points (P < .003) and 4.2 points (P = .01) at 3 and 6 months, respectively. Latent growth curve analysis confirmed a nonlinear, statistically significant improvement in respiratory symptoms and physical functioning domain scores by 3 months.
Interpretation
The QOL-B respiratory symptoms and physical functioning scales exhibited good psychometric properties in patients with MAC-PD. Respiratory symptoms scores improved beyond the MID by 3 months after treatment initiation.
Trial Registry
ClinicalTrials.gov; No.: NCT03672630; URL: www.clinicaltrials.gov
Key Words: Mycobacterium avium complex, patient-reported outcome measures
Take-home Points.
Study Question: What patient-reported outcome domains have shown good psychometric properties for Mycobacterium avium complex pulmonary disease (MAC-PD), including score improvement with treatment?
Results: The Quality of Life-Bronchiectasis (QOL-B) respiratory symptom scale is a valid and responsive measure in patients initiating therapy for MAC-PD, with improvements demonstrated after 3 months of treatment. The QOL-B physical functioning and health perceptions scale scores improved after 6 months of treatment.
Interpretation: Patient-reported outcome measures may be used to monitor treatment response in patients with MAC-PD.
A key component of patient-focused research is the use of patient-reported outcomes (PROs), which are any outcome reported directly by patients themselves, including assessments of health status, quality of life, or symptoms. Nontuberculous mycobacteria (NTM), predominately Mycobacterium avium complex (MAC), can cause chronic, debilitating pulmonary disease in about half of infected patients. Key symptoms of this orphan disease include cough, extreme fatigue, and shortness of breath.1 When initiated, treatment consists of three to five antibiotics for 18 to 24 months.2 The goals of therapy often are to suppress disease, to stop progression, and to help the patient feel better. Although most patients show a microbiologic response, the cure rate is low. Given that improvements in daily symptoms and functioning are critical measures of treatment success from the patient’s perspective, data supporting the use of PROs in clinical practice are needed. Further, the United States Food and Drug Administration recently determined that validated PROs should be the primary outcome for registration trials of antimycobacterial drugs for MAC pulmonary disease (MAC-PD).3
Most patients with MAC-PD have underlying bronchiectasis.4,5 The Quality of Life-Bronchiectasis (QOL-B) instrument, validated in patients with bronchiectasis,6,7 and the NTM Module instrument, with preliminary validation reported in patients with MAC-PD,8, 9, 10 capture 12 domains, including respiratory symptoms, vitality (fatigue), health perception, and NTM-specific symptoms. Prior research in an observational setting indicated that the respiratory symptoms scale improved 12 months after initiating treatment.8 For this analysis, our primary objectives were to evaluate the psychometric performance of the respiratory symptoms scale and to evaluate the trajectory of symptom response during the first 6 months of MAC treatment. We also sought to evaluate other potentially relevant health-related quality of life (HRQoL) domains.
Study Design and Methods
Study Design
The study population consists of a time-defined (enrolled as of June 8, 2022) cohort of patients from 26 participating sites in the United States and Canada in the Patient-Centered Outcomes Research Insitute (PCORI)-funded Comparison of Two- vs Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease (MAC2v3) prospective, randomized, pragmatic clinical trial (ClinicalTrials.gov Identifier: NCT03672630). From this population, we defined two cohorts: (1) the cross-sectional cohort included all who completed baseline PRO surveys and (2) the longitudinal cohort included the subset in the study long enough to have completed 3- and 6-month surveys as of June 8, 2022. Oregon Health & Science University serves as the coordinating center and host of the data repository as part of the MAC2v3 protocol 18819 approved by the Oregon Health & Science University Institutional Review Board. The institutional review boards at all participating sites approved the study or waived oversight to the WCG Institutional Review Board (e-Table 1); patients consent to their data entering into a data repository. All patients enrolled in MAC2v3 meet American Thoracic Society/Infectious Disease Society of America disease criteria for MAC-PD, with pulmonary symptoms, nodular-bronchiectatic disease on CT scan, and at least two sputum cultures with positive results or one BAL culture with positive results.4 Exclusion criteria include cystic fibrosis and cavitary disease that requires more aggressive therapy. Patients are randomized to two-drug (azithromycin plus ethambutol) or three-drug (azithromycin plus ethambutol plus rifampin) therapy for MAC and are followed up for 12 months per usual standard of care. For the purposes of this analysis, we pooled the data. We did not evaluate treatment regimen as a predictor of trajectory because the trial is ongoing and the protocol does not include any planned interim analyses. Baseline demographic and clinical data were collected via chart review.
HRQoL Measures and Scoring
PROs were administered electronically via a Research Electronic Data Capture11 tool hosted at Oregon Health & Science University or on paper and entered into the Research Electronic Data Capture tool at baseline (0) and 1, 3, 6, and 12 months after treatment start. The primary PRO of interest was the QOL-B respiratory symptoms scale score, which contains nine items including severity or frequency of cough, sputum production, shortness of breath, wheezing, chest pain, and chest congestion. We also evaluated the NTM Module NTM symptoms domain score (seven items, including taste or smell sensitivity, feverishness, memory problems, and sleep problems) and QOL-B vitality domain score (three items: frequency of tired, energetic, and exhausted), health perceptions domain score (four items, including health status and extent of health concerns), and physical functioning domain score (five items, including difficulty and limitations with physical activity). Finally, we collected visual analog scale (VAS) scores for overall MAC symptoms (e-Fig 1A). VASs record patient ratings on a horizontal scale with markings at one-point increments from 0 to 10, with 0 being no MAC symptoms and 10 being the worst possible MAC symptoms. The rating then is converted to a scale of 0 to 100. The VAS was modified for use in the Research Electronic Data Capture tool, with a slider for patients to indicate no MAC symptoms to worst possible MAC symptoms that populates a box with a number between 0 and 100 (e-Fig 1B).
Statistical Analysis
We performed psychometric analyses of validity by examining item distributions and floor and ceiling effects (proportion with the minimum and maximum scores, considering > 10% to indicate an inability to discriminate between respondents at either end of the scale). We calculated reliability as internal consistency by Cronbach’s α reliability coefficients. The target range for Cronbach’s α was 0.70, with a maximum of 0.90 to avoid redundancy of items.12,13 We evaluated construct validity for the respiratory symptoms scale based on acid-fast bacillus smear results from the most recent MAC culture showing positive findings obtained before treatment start and pretreatment pulmonary function testing measured by FEV1 and FVC % predicted. We hypothesized that positive smear results indicating a higher bacillary burden would be associated with worse scores, and selected a cutoff of 70% predicted for FEV1 and FVC to define abnormal lung function associated with worse scores.
Because the interval between treatment start and the month 1 survey varied in some because of staggered medication start or treatment delays, we dropped this data point from this analysis. We selected 6 months as an appropriate interval to evaluate responsiveness based on culture conversion data.14 Descriptive analysis included calculation of mean ± SD at months 0, 3, and 6. The mean within-person change from baseline to 3 and 6 months was evaluated using the paired t test. Based on prior validation studies in populations with bronchiectasis, we calculated the proportion with each increases of eight or more points in each domain (considering this a clinically important change).7 The minimal important difference (MID) was calculated using distribution-based methods15: (1) 0.5 SD of the change between baseline and 3 months and (2) 1 SEM at baseline. Using self-reported VAS scores, we explored an anchor-based calculation of MIDs. The literature for fatigue and dyspnea suggests that a minimum 15- to 20-point change on a scale of 0 to 100 is meaningful16,17; accordingly, we conducted a linear regression and calculated the change in respiratory symptoms domain score for a 20-point change in VAS.
We conducted latent growth curve analysis to evaluate the trajectory of the respiratory symptoms domain and other domains’ response after treatment start using all three data points. Baseline and time-invariant categorical predictors of interest included age (< 70 vs ≥ 70 years), sex (male or female), diagnosis through sputum culture alone or BAL, underlying COPD (yes or no), and underlying bronchiectasis (yes or no). For each model, we fixed the intercept loadings to 1 (constant) and initially fixed the loading for time (change) to time 1 (0 months), time 2 (3 months), and time 3 (6 months) to model linear change over time. Alternative models were fit specifying nonlinear change across time by freely estimating the shape loading at time 2. First, we examined whether a linear model was the best fit, after determining that no correlation existed between intercept and shape. Models were fit using full information maximum likelihood estimation, and we evaluated standard model fit statistics, that is, global χ2 test of model fit (n.s. = good fit), root mean square error of approximation (< 0.08 = fair, < 0.05 = good, and < 0.01 = excellent), Bentler’s comparative fit index (> 0.90 = adequate and > 0.95 = good), the Tucker-Lewis fit index (evaluated same as Bentler’s comparative fit index), and standardized root mean square residual (< 0.08 = adequate and < 0.05 = good). As soon as a model was determined to be a good fit, we estimated the mean and variance of the slope or shape, that is, how much variability in slope or shape we observed between participants. Finally, we explored explanatory group predictors of the intercept and slope or shape. All analyses were conducted using SAS version 9.4 software (SAS Institute) and Mplus version 8 software (Muthén & Muthén).
Results
Patient Population
Through June 8, 2022, 228 patients were included in the cross-sectional cohort, and of these, 144 patients were included in the longitudinal cohort. Seven of the patients in the longitudinal cohort were missing baseline clinical comorbidities at the time of analysis and were excluded from the longitudinal predictors analysis. The cross-sectional patient population (Table 1) was predominately female (n = 188 [82.2%]) and had a bronchiectasis diagnosis (n = 183/209 [87.6%]); the population also evenly represented those older than and younger than 70 years, and 21.5% (n = 49) met case criteria with BAL-only positive results for MAC vs those with positive results on acid-fast bacillus sputum cultures. The subset with longitudinal data had similar characteristics.
Table 1.
Characteristics of Patients From the MAC2v3 Study Included in the Cross-sectional and Time-Defined Longitudinal Subpopulation
| Characteristic | Cross-sectional Population (N = 228) | Longitudinal Subpopulation (n = 144) |
|---|---|---|
| Female sex | 188 (82.2) | 124 (86.1) |
| Age ≥ 70 y | 114 (50.0) | 70 (48.6) |
| Met case criteria with BAL only | 49 (21.5) | 36 (25.0) |
| Bronchiectasis | 183 of 209 (87.6) | 122 of 137 (89.1) |
| COPD | 26 of 210 (12.4) | 14 of 137 (10.2) |
| Asthma | 53 of 209 (25.4) | 32 of 137 (23.3) |
Data are presented as No. (%) or No. of Total No. (%). MAC2v3 = Comparison of Two- vs Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease.
Psychometric Properties
We did not observe floor or ceiling effects for respiratory symptoms, vitality, NTM symptoms, or health perception domain scores. However, 16.7% scored 100 (best possible score) on the physical functioning scale. Cronbach’s α indicated excellent reliability for all domains (range, 0.71-0.94) (Table 2).
Table 2.
Psychometric Properties of Select QOL-B and NTM Symptoms Domains for 228 Patients Initiating Treatment for MAC-PD
| Measure and HRQoL Domain | Mean Scores | Floor Effect (Score = 0) | Ceiling Effect (Score = 100) | Cronbach’s α |
|---|---|---|---|---|
| QOL-B | ||||
| Respiratory symptoms | 64.7 ± 17.0 | 0 (0) | 1 (0.4) | 0.85 |
| Physical functioning | 58.9 ± 33.0 | 17 (7.5) | 38 (16.7) | 0.94 |
| Vitality | 59.0 ± 13.6 | 0 (0) | 2 (0.9) | 0.81 |
| Health perception | 47.3 ± 17.7 | 1 (0.4) | 1 (0.4) | 0.81 |
| NTM symptoms | 78.5 ± 16.6 | 0 (0) | 14 (6.2) | 0.71 |
Data are presented as No. (%) or mean ± SD, unless otherwise indicated. Domain score range is 0-100, with higher being better. N = 185 for respiratory symptoms domain Cronbach’s α calculation only because 16% of patients skipped the sputum color question because it was not applicable (ie, lack of sputum production). HRQoL = health-related quality of life; MAC-PD = Mycobacterium avium complex pulmonary disease; NTM = nontuberculous mycobacteria; QOL-B = Quality of Life-Bronchiectasis.
Construct Validity
Smear results were reported for 203 patients (89.0%), and among those, 86 patients (42.3%) showed positive smear results. No significant differences were found in patients with smear-positive results vs those with smear-negative results in any domain. Lung function data were available for 158 patients (69.3%). Abnormal lung function was observed for 46 patients (29.1%) by FEV1 % predicted and 20 patients (12.7%) by FVC % predicted. Comparing by FEV1 % predicted scores of < 70 vs ≥ 70, respiratory symptoms (60.7 vs 67.1; P = .03) and physical functioning (51.8 vs 65.4; P = .01) domain scores were significantly lower for those with abnormal lung function. Vitality (60.9 vs 57.8; P = .18), health perceptions (48.9 vs 45.6; P = .31), and NTM symptoms (79.2 vs 78.2; P = .73) domain scores were not significantly different. Scores by FVC % predicted followed a similar pattern, a statistically significant difference also was found in health perception domain scores (57.0 in those with FVC % predicted of < 70 vs 45.1 in those with FVC % predicted of ≥ 70; P = .006) (Table 3).
Table 3.
Construct Validity of Select QOL-B and NTM Symptoms Domains in Patients With MAC-PD
| Measure and HRQoL Domain | AFB Smear Results |
FEV1 % Predicted |
FVC % Predicted |
||||||
|---|---|---|---|---|---|---|---|---|---|
| Positive (n = 86) | Negative (n = 117) | P Value | < 70 (n = 46) | ≥70 (n = 112) | P Value | < 70 (n = 20) | ≥ 70 (n =138) | P Value | |
| QOL-B | |||||||||
| Respiratory symptoms | 65.1 ± 17.0 | 64.0 ± 17.0 | .66 | 60.7 ± 17.3 | 67.1 ± 16.4 | .03 | 56.2 ± 17.0 | 66.6 ± 16.5 | .009 |
| Physical functioning | 55.6 ± 32.1 | 61.6 ± 33.1 | .20 | 51.8 ± 32.1 | 65.4 ± 30.9 | .01 | 44.8 ± 31.5 | 63.9 ± 31.1 | .01 |
| Vitality | 59.4 ± 14.4 | 58.6 ± 12.4 | .70 | 60.9 ± 13.8 | 57.7 ± 13.1 | .18 | 61.1 ± 11.7 | 58.3 ± 13.5 | .38 |
| Health perception | 46.8 ± 19.1 | 47.0 ± 16.6 | .96 | 48.9 ± 19.1 | 45.6 ± 17.9 | .31 | 57.1 ± 15.8 | 45.1 ± 18.2 | .006 |
| NTM symptoms | 79.7 ± 14.5 | 77.4 ± 17.5 | .33 | 79.2 ± 15.9 | 78.2 ± 17.1 | .73 | 76.8 ± 18.0 | 78.7 ± 16.6 | .64 |
Dara are presented as mean ± SD. Boldface values indicate statistical significance at P < .05. AFB = acid-fast bacillus; HRQOL = health-related quality of life; MAC-PD = Mycobacterium avium complex pulmonary disease; NTM = nontuberculous mycobacteria; QOL-B = Quality of Life-Bronchiectasis.
Mean Domain Scores and Change Over Time
Examining the mean baseline domain scores and change at each time point, we observed statistically significant improvements in respiratory symptoms and physical functioning domain scores at 3 months, with the vitality domain scores improving at 6 months. Health perceptions and NTM symptom domain scores did not change over time. The proportion with an eight-point increase in domain scores at 6 months ranged from 20.8% (NTM symptoms domain) to 40.9% (vitality domain). The MID by the 0.5-SD method ranged from 6.8 to 9.3 over the selected domains and by the SEM method ranged from 6.2 to 9.2. Specifically for the respiratory symptoms domain, the MID was 6.9 and 6.4 by the two statistical methods, respectively. The linear regression of the respiratory symptoms domain score on VAS showed that a 20-point decrease (improvement) in the VAS predicted a 7.3-point (using baseline scores), 7.9-point (3-month scores), and 7.0-point (6-month scores) change in respiratory symptoms domain scores (Table 4).
Table 4.
Baseline Mean and Mean Change in Select QOL-B and NTM Symptom Domain Scores in 144 Patients 3 and 6 Months After Initiating Treatment for MAC-PD and Minimal Important Difference by Distribution-Based Methods
| Measure and HRQoL Domain | Baseline | 3-mo Change | P Value | 6-mo Change | P Value | 6-mo Change ≥ 8 Points | Minimal Important Difference 0.5-SD (3-mo Change) | Minimal Important Difference SEM (Baseline N = 228) |
|---|---|---|---|---|---|---|---|---|
| QOL-B | ||||||||
| Respiratory symptoms | 65.1 (16.5) | 7.8 ± 13.8 | < .001 | 7.5 ± 13.6 | < .001 | 54 (37.5) | 6.9 | 6.4 |
| Physical functioning | 60.3 (32.6) | 4.6 ± 18.5 | .003 | 4.2 ± 20.4 | .01 | 46 (32.2) | 9.3 | 8.0 |
| Vitality | 57.9 (14.2) | 2.1 ± 16.4 | .12 | 3.1 ± 17.0 | .03 | 58 (40.9) | 8.2 | 6.2 |
| Health perception | 47.6 (17.0) | –1.1 ± 14.3 | .34 | –1.5 ± 14.7 | .23 | 48 (33.3) | 7.2 | 7.4 |
| NTM symptoms | 78.1 (17.0) | 1.8 ± 13.6 | .12 | 0.9 ± 12.4 | .37 | 30 (20.8) | 6.8 | 9.2 |
Data are presented as mean ± SD or No. (%). Increase in score indicates improvement in HRQoL. P value for paired t test comparing 3- and 6-mo values with baseline values. Boldface values indicate statistical significance at P < .05. HRQOL = health-related quality of life; MAC-PD = Mycobacterium avium complex pulmonary disease; NTM = nontuberculous mycobacteria; QOL-B = Quality of Life-Bronchiectasis.
Latent Growth Curve Model Selection and Mean Estimation
For the respiratory symptoms and physical functioning domains, the nonlinear model releasing time 2 (month 3) was a better fit than the linear model (e-Table 2) and was somewhat better for the NTM symptoms domain. The linear and nonlinear models were similar for the vitality and health perceptions domains. For all but the physical functioning domain, the variance of the intercept was significant, but the variance of the shape was not (Table 5). This suggests that substantial variability exists in the month 0 (baseline) scores between individuals, but that little variability exists in the change in shape or slope over time. After fitting a model to release the time 3 loading, the mean change in respiratory symptoms domain score from time 1 to time 2 was +7.9 (SE, 1.1; P < .001). When releasing time 1 loading, the mean change from time 2 to time 3 was not significant (–0.31; SE, 0.90; P = .73). We observed a similar pattern for physical functioning, whereas the vitality, NTM symptoms, and health perceptions domain scores were stable over time. See Figure 1 for the final nonlinear model (fit with and without predictors and explanatory groups) for the respiratory symptoms domain score and Figure 2 for the mean modeled change in scores over time.
Table 5.
Mean and Variance at Month 0 and Slope and Change Over Time for Key QOL-B and NTM Symptom Module Domains After 6 Months of MAC-PD Treatment in Patients Enrolled in the MAC2v3 Pragmatic Clinical Trial
| Variable by Measure and HRQoL Domain | Mean (SE) | P Value | Variance (SE) | P Value |
|---|---|---|---|---|
| QOL-B | ||||
| Respiratory symptoms | ||||
| Intercept | 65.10 (1.373) | < .001 | 147.169 (22.188) | < .001 |
| Slope | ||||
| T1-T2 | 7.845 (1.146) | < .001 | 6.078 (15.422) | .693 |
| T2-T3 | –0.309 (0.895) | .73 | –0.047 (0.335) | .889 |
| Physical functioning | ||||
| Intercept | 60.289 (2.706) | 0 | –17.940 (11.675) | .124 |
| Slope | ||||
| T1-T2 | 4.676 (1.539) | .002 | –79.394 (52.026) | .127 |
| T2-T3 | –0.235 (1.501) | .876 | –0.372 (4.528) | .93 |
| Vitality | ||||
| Intercept | 57.870 (1.181) | < .001 | 41.605 (13.426) | < .001 |
| Slope | ||||
| T1-T2 | 2.161 (1.415) | .127 | 19.502 (13.975) | .163 |
| T2-T3 | 0.773 (0.895) | .288 | 6.390 (8.236) | .438 |
| Health perception | ||||
| Intercept | 47.608 (1.413) | < .001 | 172.980 (25.429) | < .001 |
| Slope | ||||
| T1-T2 | –1.138 (1.166) | .329 | –0.547 (13.285) | .967 |
| T2-T3 | –0.820 (1.070) | .444 | 13.375 (19.438) | .491 |
| NTM Symptoms | ||||
| Intercept | 78.142 (1.412) | < .001 | 186.736 (26.231) | < .001 |
| Slope | ||||
| T1-T2 | 1.781 (1.117) | .111 | 14.489 (32.125) | .652 |
| T2-T3 | –0.900 (0.920) | .328 | 1.146 (4.473) | .798 |
Positive mean change indicates improvement. Boldface values indicate statistical significance at P < .05. HRQoL = health-related quality of life; MAC-PD = Mycobacterium avium complex pulmonary disease; MAC2v3 = Comparison of Two- vs Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease; NTM = nontuberculous mycobacteria; QOL-B = Quality of Life-Bronchiectasis; T1 = month 0; T2 = month 3; T3 = month 6.
Figure 1.
Final nonlinear model, with or without time variant explanatory group for the Quality of Life-Bronchiectasis questionnaire respiratory symptoms domain. RSS = Respiratory symptoms scale score; time 1 = month 0; time 2 = month 3; time 3 = month 6; F = latent construct (factor). ∗Statistically significant interval change (P < .05).
Figure 2.
Graph showing modeled mean score change from baseline in select Quality of Life-Bronchiectasis and NTM Symptoms domains after initiating treatment for Mycobacterium avium complex pulmonary disease. ∗Statistically significant interval change (P < .05). NTM = nontuberculous mycobacteria.
Latent Growth Curve Modeling With Predictors
We fit four additional models with preplanned predictors, demographics (age and sex together), sputum vs BAL diagnosis, presence of COPD, and presence of bronchiectasis. Women reported significantly higher respiratory symptoms domain scores (+13) at baseline, but the remaining scores and trajectory of respiratory symptoms domain scores were similar across all characteristics. Patients with a BAL-only MAC diagnosis reported higher vitality domain scores at baseline and a less steep slope compared with those with a positive acid-fast bacillus sputum results diagnosis. Patients with COPD reported significantly lower baseline physical functioning domain scores (–17), whereas those with bronchiectasis reported significantly higher scores (+23), although the trajectory was not significantly different (Table 6).
Table 6.
Unstandardized Predictors of Intercept (Baseline Scores) and Slope and Shape (Trajectory) in Nonlinear Models of Key QOL-B and NTM Symptom Module Domain Scores After 6 Months of MAC-PD Treatment in Patients Enrolled in the MAC2v3 Pragmatic Clinical Trial
| Variable by Measure and HRQoL Domain | Intercept Estimate (SE) | P Value | Shape Estimate (SE) | P Value |
|---|---|---|---|---|
| QOL-B respiratory symptoms | ||||
| Age ≥ 70 y vs < 70 ya | 2.703 (2.636) | .305 | –0.549 (1.067) | .607 |
| Female vs male sexa | 13.398 (3.857) | .001 | –1.944 (1.639) | .235 |
| BAL only vs sputum culture | –4.166 (3.151) | .186 | 0.466 (1.186) | .694 |
| Copd (yes/no) | –7.433 (4.534) | .101 | –2.120 (1.564) | .175 |
| Bronchiectasis (yes/no) | 1.055 (4.449) | .813 | 1.827 (1.523) | .23 |
| QOL-B physical functioning | ||||
| Age ≥ 70 y vs < 70 ya | –1.929 (5.405) | .721 | –0.615 (1.370) | .654 |
| Female vs male sexa | 6.468 (7.990) | .418 | –0.081 (2.168) | .97 |
| Bal only vs sputum culture | 9.431 (6.228) | .13 | –0.871 (1.530) | .569 |
| Copd (yes/no) | –17.578 (9.003) | .051 | –5.493 (2.940) | .062 |
| Bronchiectasis (yes/no) | 22.894 (8.722) | .009 | –2.919 (1.864) | .117 |
| QOL-B vitality | ||||
| Age ≥ 70 y vs < 70 ya | 1.276 (3.211) | .691 | –1.358 (1.759) | .44 |
| Female vs male sexa | –3.878 (3.716) | .297 | 1.684 (1.923) | .381 |
| Bal only vs sputum culture | 9.999 (2.378) | 0 | –3.215 (1.531) | .036 |
| Copd (yes/no) | 1.303 (4.093) | .897 | 0.008 (2.765) | .998 |
| Bronchiectasis (yes/no) | 3.961 (3.727) | .288 | –2.204 (2.235) | .324 |
| QOL-B health perception | ||||
| Age ≥ 70 y vs < 70 ya | –3.884 (2.899) | .18 | 3.671 (1.285) | .004 |
| Female vs male sexa | –8.716 (3.889) | .025 | 4.281 (1.963) | .029 |
| Bal only vs sputum culture | –6.103 (3.129) | .051 | –0.922 (1.619) | .569 |
| Copd (yes/no) | –0.628 (4.838) | .897 | 3.194 (1.972) | .105 |
| Bronchiectasis (yes/no) | –8.002 (4.550) | .079 | –1.160 (2.233) | .604 |
| NTM symptoms | ||||
| Age ≥ 70 y vs < 70 ya | 2.539 (2.853) | .373 | –1.277 (1.102) | .246 |
| Female vs male sexa | 2.703 (4.136) | .513 | –0.666 (1.474) | .651 |
| Bal only vs sputum culture | … | … | … | … |
| Copd (yes/no) | –6.429 (8.676) | .459 | –0.694 (5.462) | .899 |
| Bronchiectasis (yes/no) | … | … | … | … |
Boldface values indicate statistical significance at P < .05. HRQoL = health-related quality of life; MAC-PD = Mycobacterium avium complex pulmonary disease; MAC2v3 = Comparison of Two- vs Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease; NTM = nontuberculous mycobacteria; QOL-B = Quality of Life-Bronchiectasis.
Age and sex modeled together.
Discussion
The QOL-B respiratory symptoms scale showed good psychometric properties in patients with MAC-PD. Most importantly, we observed statistically significant improvements in patient-reported QOL-B respiratory symptoms and physical functioning domain scores in patients initiating treatment for nodular-bronchiectatic MAC-PD. The observed QOL-B respiratory symptoms domain score increase of 7.8 points at 3 months was more than the MID calculated by two different statistical measures (6.9 and 6.4). Further, modeling confirmed that the QOL-B respiratory symptoms and physical functioning trajectories were nonlinear, with rapid improvement observed by 3 months after treatment start.
Respiratory symptoms, including chronic cough, coughing up sputum without or with blood (hemoptysis), and shortness of breath, are reported commonly by patients with MAC-PD.1,4,14,18 They are among the key symptoms required for patients to meet the case definition of MAC-PD and are monitored for improvement during treatment in clinical practice.4 Generally around 10% to 20% of patients in the United States with MAC-PD have COPD, and most (75%-85%) have underlying bronchiectasis, as reflected in this study population.5,19,20 Given the overlap in MAC-PD respiratory symptoms with those of underlying COPD and bronchiectasis, existing measures may be considered for clinical outcomes and trial end points. Further, the Food and Drug Administration has encouraged the use of PRO instruments as a primary efficacy end point for MAC-PD clinical trials; however to date no PRO instruments for any NTM pulmonary disease that are fit for purpose are available.3
The QOL-B and NTM Module are multidimensional tools developed using a detailed conceptual framework and input from patients with bronchiectasis (QOL-B) and NTM (NTM Module) and physician specialists.6,7,9 In the current study, psychometric evaluation of the QOL-B respiratory symptoms scale in patients with MAC-PD showed no floor or ceiling effects, and the scale was reliable by Cronbach’s α. The St. George’s Respiratory Questionnaire was included as a secondary outcome in a recent randomized clinical trial of amikacin liposome inhalation suspension plus guideline-based therapy (GBT) vs GBT alone in the treatment of patients with MAC-PD and Mycobacterium abscessus pulmonary disease that is refractory to previous treatment.19 In that study, the least squares mean difference from baseline in St. George’s Respiratory Questionnaire score was not statistically different, although the improvement was four points (reaching the MID) in the amikacin liposome inhalation suspension plus GBT arm and 0.4 in the GBT-alone arm. Unlike treatment-naïve patients, patients who are refractory to treatment frequently do not respond microbiologically even after changes in therapy and have a higher symptom burden, likely associated with a higher underlying disease burden.19,21 Most treatment-naïve patients showing a microbiologic response do so in the first 6 months after therapy initiation, and in an observational clinic cohort of treatment-naïve patients with nodular bronchiectatic MAC-PD, 30% converted to negative culture results by 3 months.14 We observed a more rapid QOL-B respiratory symptoms domain score response curve in the current study population. Accordingly, our results suggest that symptoms may respond faster than culture conversion and potentially can shorten the duration of efficacy trials if their measure is used as a primary outcome. Further, the respiratory symptoms domain score trajectory was similar for the patient characteristics we could evaluate, supporting the use of respiratory symptoms in heterogeneous patient populations.
Physical functioning domain scores also improved in our study patients; this is important from a clinical perspective because poor physical functioning is associated with poorer outcomes, including mortality in patients with chronic lung disease.22 A ceiling effect was observed on the QOL-B physical functioning scale, in which 16.7% scored 100 and would have no room for improvement with treatment, but the scale was reliable. The 6-min walk distance independently predicted mortality (adjusted hazard ratio, 0.938; 95% CI, 0.896-0.981) in a cohort of patients with bronchiectasis who also predominately showed NTM pulmonary infections.23 In addition, fatigue is both a common symptom of MAC-PD and a potential side effect of long-term antibiotic therapy. In the current population, no floor or ceiling effects were observed for the QOL-B vitality scale score and it was reliable. Despite the lack of improvement on average in the QOL-B vitality scale score in the current study, 40% of patients improved by at least eight points, suggesting that many patients experienced less fatigue. Results were similar for the QOL-B physical functioning domain score, which on average improved by 4.2 points at 6 months, and 32% of patients improved by at least eight points. The QOL-B vitality and physical functioning domains may be better measures of long-term HRQoL after treatment completion or could be used to identify new regimens with less toxicity than GBT.
Notably, we did not observe an improvement in NTM symptoms domain scores in the overall population, and only 20% improved by eight points. The NTM symptoms domain is a distinct cluster of symptoms including feverishness, sensitivity to smells and tastes, and cognitive fogging (eg, memory loss, confusion, challenges sustaining attention). The psychometric validation of this instrument has been reported in several populations with NTM pulmonary disease.10,24 However, patients may not experience these symptoms consistently, as evidenced by high scores (mean score, 76 of 100, with 100 being no symptoms) reported in the preliminary validation population and in the current study population (mean baseline score, 78.5).24 It is possible that these symptoms improve more slowly over time or reflect a relatively small subpopulation.
Our study has several strengths. We evaluated HRQoL outcomes using the QOL-B, developed and evaluated in patients with bronchiectasis. Nearly all (90%) of the patients in our trial population had a diagnosis of bronchiectasis, and we evaluated the QOL-B scores in this population with MAC-PD using modern psychometric methods.25 The study design was longitudinal and enrolled treated patients, which enabled us to evaluate the responsiveness of the selected PRO domains. Latent growth curve techniques allow for modeling of nonlinear effects. Study limitations include the fact that the QOL-B is not fully validated in patients with MAC-PD, although we were able to evaluate reliability and to validate the respiratory symptoms scale partially in our study. Second, we will not be able to evaluate microbiologic or radiographic response data or to compare treatment regimens until the study is completed. As a result, it was not possible to correlate changes in symptoms with changes in bacillary burden (eg, conversion to negative culture results), and it remains unclear whether patients failing to respond microbiologically or radiographically improved symptomatically. Finally, patients from the MAC2v3 who were included were those with the most common MAC-PD phenotype (nodular bronchiectatic disease) and may not be representative of those with cavitary disease or other species of clinical importance (eg, M abscessus).
Interpretation
In conclusion, the QOL-B respiratory symptom scale is a valid and responsive measure in patients initiating therapy for MAC-PD. Importantly, we observed statistically significant improvements in the QOL-B respiratory symptoms scale scores that exceeded the statistical MID of 6 to 7 within 3 months of initiating treatment for MAC-PD. The physical functioning, vitality, health perceptions, and NTM symptoms scales generally showed good psychometric properties, but only the physical functioning and vitality scale scores improved by 6 months after treatment initiation. Further research is needed to confirm MIDs using anchor-based methods, and the respiratory symptoms scale should be evaluated in treatment-refractory populations and NTM pulmonary disease caused by other NTM species to allow for use as a clinical trial end point for Food and Drug Administration labeling. Importantly, PROs that exhibit good psychometric properties and measure symptoms and outcomes that are meaningful to patients also should be evaluated for use in clinical practice.
Funding/Support
Research reported in this article was funded through a Patient-Centered Outcomes Research Institute Award [Grant PCS-2017C2-7764]. Research Electronic Data Capture is supported by the the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health [Grant UL1TR002369]. E. H. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health [Grant K01HL150275].
Financial/Nonfinancial Disclosures
The authors have reported to CHEST the following: E. H. has served on advisory boards for AN2 and MannKind. K. L. W. has received consulting fees and grant support from Insmed, RedHill, AN2, Mannkind, and Spero. A. L. Q. has received consulting fees from Vertex Pharmaceuticals and Insmed. C. L. D. has served on advisory boards for AN2, AstraZeneca, Hyfe, Insmed, MannKind, Matinas, Paratek, and Spero and as a consultant to Genentech and Pfizer and has received research grant or contract support from AN2, Beyond Air, Bugworks, Insmed, Juvabis, and Paratek. None declared (N. F. D., H. F., A. E. B.).
Acknowledgments
Author contributions: E. H. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. E. H. drafted the manuscript. All other authors contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript.
Role ofsponsors: The statements and conclusions in this manuscript are solely the responsibility of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute, its Board of Governors or Methodology Committee. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
∗Collaborators from the MAC2v3 Investigators: Luke Strnad, MD, Cara Varley, MD, MPH, Jodi Lapidus, PhD (Oregon Health & Science University); Julie Philley, MD, Pamela McShane, MD, Megan Devine, MD (University of Texas Health at Tyler Health Science Center); David E. Griffith, MD, Shannon H. Kasperbauer, MD, Gwen Huitt, MD, Jared J. Eddy, MD, Mphil (National Jewish Health); Theodore K. Marras, MD (University Health Network and University of Toronto); Sarah K. Brode, MD, MPH (University Health Network, West Park Healthcare Centre, University of Toronto); Dorreen Addrizzo-Harris, MD, Amy Springer, MSN, FNP-C (New York University); Patrick Flume, MD, Christina Mingora, MD, Yursa Alkabab, MD, Susan Dorman, MD (Medical University of South Carolina); Ted Naureckas,MD (University of Chicago); Timothy R. Aksamit, MD (Mayo Clinic); Stephen Ruoss, MD (Stanford University); Douglas B. Hornick, MD (University of Iowa); Mehdi Mirsaeidi, MD (University of Miami/Miami VA); Matthias Salathe, MD, Stephen Waller, MD, Andreas Schmid, MD (University of Kansas); Wael ElMaraachli, MD, Anne Cowell, MD (University of California, San Diego); Neeta Thakur, MD, MPH, Payam Nahid, MD, MPH, Shoshana Zha, MD (University of California, San Francisco); Elisa H. Ignatius, MD, Jonathan Zenilman, MD, Keira Cohen, MD, Daniel C. Belz, MD, MPH (John Hopkins); Juzar Ali, MD, Nicole Lapinel, MD ((Lousiana State University Health Science Center); Colin Swenson, MD (Emory University School of Medicine); Rebecca Kapolka, MD (Emory University); David Horne, MD (University of Washington); Daniel Salerno, MD (Temple University); Angela DiMango, MD (Columbia University); Dafne Moretta , MD (Loma Linda University Health); Laren Tan, MD, Brian Furukawa, MD (Loma Linda University); Nicholas Wysham, MD (The Vancouver Clinic); Peader Noone, MD, Leigh Anne Daniels, MD, (University of North Carolina); Chris Saddler, MD, Elizabeth Ann Misch, MD (University of Wisconsin); Lisa Hayes, MD,Marcia Epstein, MD, Angela Kim, MD (Northwell); Janet N. Myers, MD (Kaiser Permanente Moanalua Medical Center).
Other contributions: The authors thank the investigators, study coordinators, project staff, and most of all the patient participants who have contributed to the MAC2v3 clinical trial.
Additional information: The e-Figure and e-Tables are available online under “Supplementary Data.”
Footnotes
A. L. Q. is currently at Joe DiMaggio Cystic Fibrosis, Pulmonary and Sleep Center (Hollywood, FL).
Contributor Information
Emily Henkle, Email: henkle@ohsu.edu.
MAC2v3 Investigators:
Luke Strnad, Cara Varley, Jodi Lapidus, Julie Philley, Pamela McShane, Megan Devine, David E. Griffith, Shannon H. Kasperbauer, Gwen Huitt, Jared J. Eddy, Theodore K. Marras, Sarah K. Brode, Dorreen Addrizzo-Harris, Amy Springer, Patrick Flume, Christina Mingora, Yursa Alkabab, Susan Dorman, Ted Naureckas, Timothy R. Aksamit, Stephen Ruoss, Douglas B. Hornick, Mehdi Mirsaeidi, Matthias Salathe, Stephen Waller, Andreas Schmid, Wael ElMaraachli, Anne Cowell, Neeta Thakur, Payam Nahid, Shoshana Zha, Elisa H. Ignatius, Jonathan Zenilman, Keira Cohen, Daniel C. Belz, Juzar Ali, Nicole Lapinel, Colin Swenson, Rebecca Kapolka, David Horne, Daniel Salerno, Angela DiMango, Dafne Moretta, Laren Tan, Brian Furukawa, Nicholas Wysham, Peader Noone, Leigh Anne Daniels, Chris Saddler, Elizabeth Ann Misch, Lisa Hayes, Marcia Epstein, Angela Kim, and Janet N. Myers
Supplementary Data
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