Abstract
People with CF (PwCF), particularly those with advanced lung disease (ALD), experience frequent respiratory symptoms. A major CF breakthrough was the approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019, which has been shown to improve symptoms and lung function in the CF population, and decrease pulmonary exacerbations. The purpose of this study was to analyze longitudinal changes in respiratory symptoms over 24 months in ETI-treated and untreated PwCF with ALD Symptoms were measured among CF adults with ppFEV1 < 40% (N=48, 24 ETI-treated, 24 untreated) using the CFRSD-CRISS and the CFQ-R [respiratory]. Two multilevel growth models assessed the rate of change in symptoms overall and within the ETI-treated and untreated groups. PwCF on ETI had significantly lower symptom severity over 24 months than those not on ETI as measured by the CRISS and CFQ-R. The ETI-treated group maintained an −11.7 and +19.3 point difference(p<0.01) in CRISS and CFQ-R scores over the study compared to the non-ETI group, achieving minimal clinically important differences on average between groups on both instruments. No change in the symptom burden trajectory between groups was observed (p=0.58). Even with ALD, ETI-treated PwCF have a lower respiratory burden than those not on ETI. This may be confounded by survivorship bias in the non-ETI group. Of note, in this ALD cohort, neither instrument demonstrated ceiling effects. Our results suggest that, while ETI has significantly improved the lived experience, PwCF with ALD are still plagued by respiratory symptoms.
Keywords: cystic fibrosis, elexacaftor/tezacaftor/ivacaftor, Cystic fibrosis transmembrane conductance regulator modulator, respiratory symptoms
Introduction
People with Cystic Fibrosis (PwCF) experience frequent respiratory symptoms, including cough, mucus production and fatigue, all particularly problematic in those with advanced lung disease (ALD) [1]. CF-associated symptoms are emotionally and physically burdensome, and symptom reduction is reported as the most important outcome to PwCF [2]. In 2019 elexacaftor/tezacaftor/ivacaftor (ETI) was first approved in the United States (US) for PwCF with at least one F508del mutation. ETI has proven to significantly decrease the frequency of pulmonary exacerbations, reduce respiratory symptoms, and increase lung function in PwCF [3,4]. Recent data suggests that in ETI-treated PwCF, respiratory symptoms may be minimal, incurring a potential loss of sensitivity to changes on the key symptom scales and reaching a “ceiling” effect [5,6], a finding with potentially broad implications for drug development and study.
It remains unclear whether this “ceiling” effect on symptoms can be generalized in PwCF with ALD [defined as ppFEV1 < 40%] [7], who were excluded in the phase 3 clinical trials. Additionally, despite a quarter of adults with CF in the U.S in 2021 having a ppFEV1 < 50% [8], there is no literature describing the effects of ETI on respiratory symptoms in PwCF with ALD over time. This study aimed to compare change in respiratory symptoms over 24 months in PwCF with ALD prescribed ETI versus those not prescribed ETI.
Methods
Study population
This study (N=48) was a longitudinal analysis of PwCF with ALD who underwent serial testing with patient-reported outcome measures as part of a multicenter cohort study (K23HL138154). Adults with a ppFEV1 < 40% predicted were enrolled from three CFF accredited centers in the US during periods of stability from 2017–2020. Adults were clustered by ETI status: not prescribed (n=24, enrolled in 2017) and prescribed ETI (n=24, enrolled in 2020). PwCF not prescribed ETI were enrolled in the observational study prior to ETI availability; no minimum time on ETI was required for enrollment. The Institutional Review Boards at the University of Washington (ID: STUDY00002616), University of Minnesota (ID: STUDY00005671), and University of Pittsburgh (ID: STUDY18110085) approved this study.
Timing of Assessments and Measures
Symptoms were assessed using two instruments: the cystic fibrosis respiratory symptom diary (CFRSD) – chronic respiratory infection symptom scale (CRISS) and the Cystic Fibrosis Questionnaire-Revised [respiratory] (CFQ-R). The CFRSD-CRISS assesses eight specific respiratory symptoms that are totaled for a CRISS score ranging 0–100, where higher numbers indicate worse symptom burden. The CFQ-R [respiratory] is a subscale of the CFQ-R and analyzes six respiratory symptoms that are totaled and scores range 0–100 where lower numbers indicate worse symptom burden. Henceforth, “CFQ-R” will refer to the respiratory subscale. Instruments were administered five times: enrollment, and 6, 12, 18, and 24 months.
Statistical Analysis
Data were assessed for normality and missingness. Descriptive statistics were used to analyze the data, as well as differences between two groups. Multilevel growth models were used to assess the rate of change in CRISS and CFQ-R score between and within groups over 24 months. Post hoc analyses of gender differences and rate of change over 12 months were performed. An alpha of 0.05 was considered significant. All data were analyzed using R-studio version 4.2.1.
Results
A total of 48 participants were included. At enrollment, the mean ppFEV1 was 33.4% and 31.4% in the ETI and non-ETI cohorts, respectively (Table 1). In the entire cohort, the mean CRISS score was 36.7 and CFQ-R score was 60.4 over the 24-month study; the most severe symptom(s) experienced on the CRISS were fatigue and mucus production, and on the CFQ-R was cough (Table 2). Over the 24-month study, one participant (4%) in the ETI cohort died (due to acute infection) and none underwent lung transplant, while in the non-ETI cohort one (4%) died and six (25%) underwent transplant.
Table 1.
, Demographic Characteristics
| N (%) | ||
|---|---|---|
| Gender | ||
| Male | 27 (56%) | |
| Female | 21 (44%) | |
|
| ||
| Race | ||
| White | 40 (83%) | |
| Black | 5 (17%) | |
| Hispanic | 1 (2%) | |
| Native American or | 2 (4%) | |
| Alaskan | 0 (0%) | |
|
| ||
| Insurance | ||
| Private | 17 (34%) | |
| Medicaid | 20 (40%) | |
| Medicare | 13 (26%) | |
|
| ||
| Work Status | ||
| Working full or part-time | 21 (44%) | |
| Full-time homemaker | 3 (6.25%) | |
| Not working or attending | ||
| school d/t health | 20 (42%) | |
| Not working, other | 5 (10%) | |
|
| ||
| Education | ||
| Some High School or Less | 2 (4%) | |
| High School | 9 (19%) | |
| Vocational | 1 (2%) | |
| Some College | 17 (35%) | |
| College | 12 (25%) | |
| Graduate School | 5 (10%) | |
|
| ||
| Hospitalizations (person-months) | ||
| 103 | ||
| ETI group | 178 | |
| Non-ETI group | ||
|
| ||
| Mean | Min, Max | |
|
| ||
| ppFEV1 | 32 | 20, 43 |
|
| ||
| BMI | 22.5 | 17.1, 33 |
Table 2.
, Respiratory symptoms averages over 24 months
| Whole Cohort | ETI | Non-ETI | |
|---|---|---|---|
| CFRSD-CRISS (Higher=Worse) | |||
|
| |||
| Difficulty Breathing | 1.0 | 0.7 | 1.3 |
| Feverish | 0.2 | 0.1 | 0.3 |
| Fatigue | 1.4 | 1.2 | 1.6 |
| Chills/Sweats | 0.2 | 0.1 | 0.3 |
| Increased Cough | 1.1 | 0.8 | 1.4 |
| Increased Mucus | 1.4 | 1.0 | 1.7 |
| Chest Tightness | 0.9 | 0.6 | 1.1 |
| Wheezing | 0.6 | 0.4 | 0.7 |
| Total CRISS Score | 36.7 | 30.8 | 42.5 |
| Women | 42.6 | 37.2 | 46.8 |
| Men | 32.6 | 27.8 | 37.4 |
|
| |||
| CFQ-R Respiratory (Lower=Worse) | |||
|
| |||
| Congestion | 2.7 | 3.0 | 2.4 |
| Increased Cough | 2.4 | 2.8 | 2.1 |
| Increased Mucus | 2.5 | 2.9 | 2.3 |
| Wheezing | 3.2 | 3.3 | 3.0 |
| Difficulty Breathing | 3.0 | 3.3 | 2.8 |
| Woken up at night d/t | 3.2 | 3.6 | 3.0 |
| coughing | |||
|
| |||
| Total Respiratory | 60.4 | 70.0 | 50.7 |
| Score | |||
| Women | 53.3 | 62 | 44.6 |
| Men | 65.7 | 74.4 | 57 |
Participants on ETI experienced less severe respiratory symptoms in each symptom domain on both instruments over the study than non-ETI participants (Table 2). The mean CRISS and CFQ-R scores over 24-months for ETI-treated participants were 30.8 and 70.0, compared to 42.5 and 50.7, respectively (p<0.001). There were no significant differences in the symptom growth trajectory between groups over 24-months (p=0.58), however, the ETI-treated group maintained an −11.7 and +19.3 point difference(p<0.01) in CRISS and CFQ-R scores over the study compared to the non-ETI group, achieving minimal clinically important differences on average between groups on both instruments (Figure 1) [9,10]. Controlling for gender, both women and men on ETI maintained a −9.6 and +17.4 point difference in CRISS and CFQ-R over 24 months compared to women and men not on ETI. However, women experience worse symptom burden than men. Women had +9.4 and −12.4 point difference on CRISS and CFQ-R compared to men, regardless of ETI status. Women on ETI did not have statistically different (p>0.05) symptom burden than men not on ETI on both instruments over 24 months. Missingness did not contribute to observed trends, an analysis limited to enrollment to 12-months produced the same pattern: ETI-treated participants had significantly lower symptoms (p<0.001) on both instruments overtime with no change in growth trajectory (p<0.74) compared to non-ETI.
Figure 1.
Sympton trajectories
Discussion
This study is the first to show that ETI treatment is associated with improved respiratory symptoms over time in PwCF with ALD, as measured by two commonly used instruments, the CFRSD-CRISS and the CFQ-R. The findings are consistent with those of Middleton et al. in a non-ALD cohort using the CFQ-R [3] while also introducing the CFRSD-CRISS as a valid and reliable tool for detecting differences in respiratory symptom patterns in ETI-treated PwCF. Importantly, these data also clearly demonstrate that symptoms persist in PwCF and ALD even when treated with ETI. Of note, women treated with ETI had the same symptom burden on both instruments as men not treated with ETI, highlighting continued gender differences in symptom experience in the era of highly-effective modulator therapy. Additionally, neither instrument demonstrated ceiling effects, suggesting that there remains an unmet need to address respiratory burden in this population. There is continued value in using existing patient reported outcomes (the CFQ-R and CFRSD-CRISS), particularly in more ALD, women and non-ETI treated patients.
Our study has many strengths. Participants were enrolled in a study with standardized symptom measures and protocols for symptom collection at multiple centers. Our study also has several important limitations. First, in the non-ETI treated cohort, patients progressed to either lung transplant or death while those in the ETI cohort had no pulmonary deaths or transplants, consistent with current literature on the impact of ETI on advanced disease [11,12,13]. This may have biased the longitudinal data with differential drop off. Our analysis of data up to 12-months supports that the direction of this potential bias is null of less difference between ETI and non-ETI symptom reporting, as the sickest people died or underwent transplant.
Even with ALD, ETI-treated PwCF have a lower respiratory burden than non-ETI PwCF. The ETI cohort had consistently lower symptom burden over 24-months. However, neither group had changes in symptom burden trajectory. Our results show that symptom burden will not continue to improve the longer a PwCF is treated with ETI. This finding is consistent with current clinical trial data, including findings that symptoms did not progress/worsen during the phase 3 program in PwCF. Our findings convey that the ETI treatment effect on symptom burden plateaus over time, and that PwCF with ALD continue to be plagued by respiratory symptoms.
Highlights.
ETI decreases respiratory symptoms in adults with CF with advanced lung disease over 24-months
Women on ETI have no significant difference in symptoms than men not on ETI in advanced CF disease
No ceiling affect noted on CFRSD-CRISS and CFQ-R in adults with CF with advanced lung disease
Acknowledgements:
This work was supported by the CFF [RAMOS20A0-KB, RAMOS17A0, BOMBER19R0], and the NIH [K23HL138154; P30 DK089507; T32NR016913]. We appreciate the dedication of time by patients and research coordinators. The content is solely the responsibility of the authors and does not represent the NIH official views.
Footnotes
Declaration of Competing Interest
Authors Eliana R. Gill, Lauren E. Bartlett, Tijana Milinic, Nora Burdis, Joseph M. Pilewski, Jordan M. Dunitz, Siddhartha G. Kapnadak, Christopher H. Goss, and Kathleen J. Ramos report no conflicts of interest.
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