Characterization of sleep in emerging adults with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor

Abstract

•Emerging adults (18–25 years of age) have high rates of sleep dysfunction.•CFTR dysfunction has been implicated as a direct cause of sleep disorders.•Elexacaftor/tezacaftor/ivacaftor may improve sleep in emerging adults with CF.•Clinical practice guidelines are needed for sleep disturbances in people with CF. Sleep disturbances are common among youth and adults with cystic fibrosis (CF). Prior to the availability of the most highly effective modulator therapy, elexacaftor/tezacaftor/ivacaftor, 90% of patients with CF identified a need for support to improve sleep quality [[1]Sadicario J.S. Islam L. Bostetter A. Chaudary N. Identifying patient priorities for psychosocial support in an adult cystic fibrosis clinic.Pediatr Pulmonol. 2019; 54: 421PubMed Google Scholar]. In the post elexacaftor/tezacaftor/ivacaftor era, 77% of CF program directors in the United States agreed that sleep disorders are a problem in CF; however, only 10% of programs reported regularly conducting routine, formal sleep screening [[2]Thomas C.S. Brown R.F. Sleep screening for cystic fibrosis patients: a survey of cystic fibrosis programs.Pediatr Pulmonol. 2020; 55: 3358-3363Crossref Scopus (3) Google Scholar]. For adults with CF, studies have reported increased sleep disordered breathing [[3]Shakkottai A. Nasr S.Z. Hassan F. Irani S. O'Brien L.M. Chervin R.D. Sleep-disordered breathing in cystic fibrosis.Sleep Med. 2020; 74: 57-65Crossref Scopus (6) Google Scholar,[4]Reiter J. Gileles-Hillel A. Cohen-Cymberknoh M. et al.Sleep disorders in cystic fibrosis: a systematic review and meta-analysis.Sleep Med Rev. 2020; 51101279Crossref Scopus (21) Google Scholar], a delayed circadian rhythm [[5]Jensen J.L. Jones C.R. Kartsonaki C. Packer K.A. Adler F.R. Liou T.G. Sleep phase delay in cystic fibrosis: a potential new manifestation of cystic fibrosis transmembrane regulator dysfunction.Chest. 2017; 152: 386-393Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar], increased symptoms of restless legs syndrome [[6]Jurisch P. Gall H. Richter M.J. et al.Increased frequency of the restless legs syndrome in adults with cystic fibrosis.Respir Med. 2019; 151: 8-10Abstract Full Text Full Text PDF Scopus (4) Google Scholar,[7]Mulette P. Ravoninjatovo B. Guguen C. et al.Insomnia in adults with cystic fibrosis: strong association with anxiety/depression and impaired quality of life.BMC Pulm Med. 2021; 21: 108Crossref Scopus (2) Google Scholar], and insomnia [[7]Mulette P. Ravoninjatovo B. Guguen C. et al.Insomnia in adults with cystic fibrosis: strong association with anxiety/depression and impaired quality of life.BMC Pulm Med. 2021; 21: 108Crossref Scopus (2) Google Scholar]. Sleep has been associated with health-related quality of life (HRQOL) outcomes, including physical, mental, and social health in children [[8]Vandeleur M. Walter L.M. Armstrong D.S. Robinson P. Nixon G.M. Horne R.S.C. Quality of life and mood in children with cystic fibrosis: associations with sleep quality.J Cyst Fibros. 2018; 17: 811-820Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,[9]McMurray J. Widger K. Stephenson A.L. Stremler R. Actigraphic and patient and family reported sleep outcomes in children and youth with cystic fibrosis: a systematic review.J Cyst Fibros. 2022; 21: e49-e82Abstract Full Text Full Text PDF Scopus (0) Google Scholar] and adults [[7]Mulette P. Ravoninjatovo B. Guguen C. et al.Insomnia in adults with cystic fibrosis: strong association with anxiety/depression and impaired quality of life.BMC Pulm Med. 2021; 21: 108Crossref Scopus (2) Google Scholar,[10]Forte G.C. Barni G.C. Perin C. Casarotto F.C. Fagondes S.C. Dalcin Pde T. Relationship between clinical variables and health-related quality of life in young adult subjects with cystic fibrosis.Respir Care. 2015; 60: 1459-1468Crossref PubMed Scopus (12) Google Scholar,[11]Íscar-Urrutia M. Madrid-Carbajal C.J. Rubinos-Cuadrado G. et al.Objective and subjective sleep efficiency in adult patients with cystic fibrosis and impact on quality of life.Lung. 2018; 196: 761-767Crossref Scopus (7) Google Scholar]. Factors associated with sleep disturbances include mucus, reflux, cough, anxiety, depression, and pain [[4]Reiter J. Gileles-Hillel A. Cohen-Cymberknoh M. et al.Sleep disorders in cystic fibrosis: a systematic review and meta-analysis.Sleep Med Rev. 2020; 51101279Crossref Scopus (21) Google Scholar], with self-reported medical marijuana used by >50% of patients with CF for insomnia [[12]Stephen M.J. Chowdhury J. Tejada L.A. Zanni R. Hadjiliadis D. Use of medical marijuana in cystic fibrosis patients.Complement Med Ther. 2020; 20: 323Crossref PubMed Scopus (6) Google Scholar]. CF transmembrane conductance regulator (CFTR) protein is found in the retina and anterior hypothalamus and CFTR dysfunction has been implicated as a cause of sleep dysfunction, with evidence to suggest the CFTR gene may impact regulation of circadian rhythms [[13]Louis M. Staiano P. Micalo L. Chaudary N. Cystic fibrosis and sleep circadian rhythms.Pulm Ther. 2022; 8: 139-147Crossref Scopus (0) Google Scholar]. Use of elexacaftor/tezacaftor/ivacaftor may have a direct impact on sleep beyond the well described benefits of decreased respiratory symptoms including improvements in forced expiratory volume (FEV1) and reductions in pulmonary exacerbations [[14]Graeber S.Y. Vitzthum C. Pallenberg S.T. et al.Effects of elexacaftor/tezacaftor/ivacaftor therapy on CFTR function in patients with cystic fibrosis and one or two F508del alleles.Am J Respir Crit Care Med. 2022; 205: 540-549Crossref PubMed Google Scholar]. One study reported improvements in sleep quality in children and adults taking ivacaftor [[15]McCormick J. Cho D.Y. Lampkin B. et al.Ivacaftor improves rhinologic, psychologic, and sleep-related quality of life in G551D cystic fibrosis patients.Int Forum Allergy Rhinol. 2019; 9: 292-297Crossref PubMed Scopus (34) Google Scholar]. Emerging adulthood (18 to 25 years of age) is a distinct and critical developmental period characterized by identity development, a stage in which young people explore questions of who they are and who they would like to be [[16]Potterton R. Austin A. Robinson L. Webb H. Allen K.L. Schmidt U. Identity development and social-emotional disorders during adolescence and emerging adulthood: a systematic review and meta-analysis.J Youth Adolesc. 2022; 51: 16-29Crossref Scopus (3) Google Scholar]. In addition to identity formation, emerging adults are also exploring and committing to complex choices about education, work, and relationships [[17]Arnett J.J. Emerging adulthood. a theory of development from the late teens through the twenties.Am Psychol. 2000; 55: 469-480Crossref PubMed Scopus (9003) Google Scholar]. Emerging adults with CF must navigate these significant life changes while simultaneously transitioning to independently managing their complex chronic illness [[18]Skedgell K.K. Cao V.T. Gallagher K.A. Anderson B.J. Hilliard M.E. Defining features of diabetes resilience in emerging adults with type 1 diabetes.Pediatr Diabetes. 2021; 22: 345-353Crossref Scopus (6) Google Scholar]. Sleep is also unique among emerging adults, with higher rates of insufficient sleep duration, poor quality sleep, and delayed circadian rhythms [[19]Nicholson L. Bohnert A.M. Crowley S.J. A developmental perspective on sleep consistency: preschool age through emerging adulthood.Behav Sleep Med. 2023; 21: 97-116Crossref Scopus (3) Google Scholar]. We report characterization of patient perspectives on sleep and daytime functioning in emerging adults with CF on elexacaftor/tezacaftor/ivacaftor. This cross-sectional characterization study used an online survey. People with CF (pwCF) ages 18 to 25 years inclusive, English speaking, and currently stable on elexacaftor/tezacaftor/ivacaftor for FDA-approved indications and receiving FDA-approved dosing were recruited from National Jewish Health. Exclusion criteria included pulmonary exacerbation (≥10% decline in percent predicted FEV1 and/or use of systemic antibiotics and/or use of systemic steroids) and/or hospitalization in past month, transplant recipient, diagnosed significant mental health disorder (e.g., schizophrenia, bipolar, PTSD) known to interfere with sleep, and requirement of guardian to support activities of daily living. Participants aged 18 to 25 years inclusive and English speaking without CF (controls) were recruited through peer nomination. Exclusion criteria included a diagnosed chronic illness with daily therapies/medications known to interfere with sleep (e.g., diabetes, hypertension, asthma, GERD), or a diagnosed significant mental health disorder known to interfere with sleep. Sleep. Ten items from validated measures were used to screen for the presence and frequency of symptoms of sleep disordered breathing (snoring, apnea, tired/sleepy during day) [[20]Manzar M.D. Hameed U.A. Alqahtani M. et al.Obstructive sleep apnea screening in young people: psychometric validation of a shortened version of the STOP-BANG questionnaire using categorical data methods.Ann Thorac Med. 2020; 15: 215-222Crossref Scopus (2) Google Scholar], restless legs syndrome [[21]Ferri R. Lanuzza B. Cosentino F.I. et al.A single question for the rapid screening of restless legs syndrome in the neurological clinical practice.Eur J Neurol. 2007; 14: 1016-1021Crossref PubMed Scopus (96) Google Scholar,[22]Fulda S. Allen R.P. Earley C.J. et al.We need to do better: a systematic review and meta-analysis of diagnostic test accuracy of restless legs syndrome screening instruments.Sleep Med Rev. 2021; 58101461Crossref Scopus (10) Google Scholar], and parasomnias (sleep walking/sleep terrors) [[23]Meltzer L.J. Brimeyer C. Russell K. et al.The children's report of sleep patterns: validity and reliability of the sleep hygiene index and sleep disturbance scale in adolescents.Sleep Med. 2014; 15: 1500-1507Crossref PubMed Scopus (31) Google Scholar]. Participants were asked about use of over-the-counter (OTC) sleep aids, melatonin, or marijuana/CBD to facilitate sleep. If endorsed, participants were asked the frequency of use (every night, several nights per week, several nights per month, once a month, less than once a month). PwCF were asked 7 questions about their sleep now, compared to before starting elexacaftor/tezacaftor/ivacaftor. Health-Related Quality of Life (HRQOL). Patient Reported Outcome Measurement Information System (PROMIS®) short forms (4 items each) were used to evaluate HRQOL: Sleep Disturbance, Sleep Related Impairment, Depression, Anxiety, Emotional Support, Informational Support, and Pain Interference [24Buysse D.J. Yu L. Moul D.E. et al.Development and validation of patient-reported outcome measures for sleep disturbance and sleep-related impairments.Sleep. 2010; 33: 781-792Crossref PubMed Scopus (468) Google Scholar, 25Cella D. Riley W. Stone A. et al.The patient-reported outcomes measurement information system (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008.J Clin Epidemiol. 2010; 63: 1179-1194Abstract Full Text Full Text PDF PubMed Scopus (2800) Google Scholar, 26Pilkonis P.A. Choi S.W. Reise S.P. Stover A.M. Riley W.T. Cella D. Item banks for measuring emotional distress from the patient-reported outcomes measurement information system (PROMIS(R)): depression, anxiety, and anger.Assessment. 2011; 18: 263-283Crossref PubMed Scopus (1165) Google Scholar]. Raw scores were converted to T-scores (mean=50, SD=10) using www.assessmentcenter.net. Demographic Information. Participants self-reported demographic variables. Clinical Data Capture. The electronic medical record was reviewed to collect health information on pwCF, including CF mutations, CF complications, comorbidities, and medications. Descriptive statistics were used to describe participant characteristics and changes in sleep since starting elexacaftor/tezacaftor/ivacaftor. Chi-square analyses were used to compare the percent of pwCF and Control participants on categorical variables. One-way ANOVA was used to compare group differences on continuous HRQOL variables, with Cohen's d effect sizes to examine the magnitude of difference [small=0.2, medium=0.5, large=0.8] [[27]Cohen J. Statistical power analysis for the behavioral sciences.2nd ed. Lawrence Erlbaum Associates, Mahwah, NJ1988Google Scholar]. Pearson correlation was used to examine the association between sleep and HRQOL measures. Continuous variables were normally distributed and free from outliers. Study participants included 34 pwCF and 42 controls. Demographic characteristics are shown in Table 1. Overall, study participants ranged in age from 18 to 25 years (M±SD 23.2 ± 1.9 years), 52.6% were female (n = 40), 85.1% White (n = 63), and 14.5% Hispanic (n = 11). PwCF had a mean BMI of 22.6 ± 3.4 (range 16.0 to 34.1) and a mean FEV1% predicted of 92.3 ± 21.9 (range 36.6 to 128.0). CF characteristics were similar to the general population of pwCF [[28]Cystic Fibrosis Foundation Patient Registry 2021 Annual Data Report Bethesda, Maryland ©2022 Cystic Fibrosis Foundation.Google Scholar] (Table 1).Table 1Characterization of study participants by group [percent (n) unless otherwise stated].CF Group (n = 34)Control Group (n = 42)Test statisticPDemographic CharacteristicsMean Age ± SD22.8 ± 1.923.5 ± 1.9t(74) = −1.640.11GenderX2(2) = 1.290.53 Male44.1 (15)47.6 (20) Female52.9 (18)52.4 (22) Other2.9 (1)–RaceX2(3) = 7.030.07 White97.0 (32)75.3 (31) Black–9.8 (4) Asian–4.9 (2) Multi-racial/Other3.0 (1)9.8 (4)EthnicityX2(1) = 0.370.55 Hispanic88.2 (30)83.3 (35) Non-Hispanic11.8 (4)16.7 (7)Currently WorkingX2(2) = 1.480.48 Full-time52.9 (18)66.7 (28) Part-time20.6 (7)14.3 (6) Not working26.5 (9)19.0 (8)Attending SchoolX2(2) = 5.590.06 Full-time26.5 (9)31.0 (13) Part-time2.9 (1)19.0 (8) Not attending school70.6 (24)50.0 (21)Partner StatusX2(2) = 3.450.18 Single44.1 (15)59.5 (25) Married20.6 (7)7.1 (3) Partnered35.3 (12)33.3 (14)ChildrenX2(1) = 1.560.21 No91.2 (31)97.6 (41) Yes8.8 (3)2.4 (1)Living SituationX2(1) = 0.640.42 Home with parent(s)/guardian(s)29.4 (10)21.4 (9) Independently (including college)70.6 (24)78.6 (33)CF Mutations–– F508del94.1 (32)– G551D8.8 (3)– 1898 + 1G→T5.9 (2)–CF Complications–– Pancreatic insufficiency100.0 (34)– Diabetes44.1 (15)– Impaired glucose tolerance44.1 (15)– Osteopenia38.2 (13)– Non-cirrhosis liver disease29.4 (10)– Arthritis20.6 (7)–Comorbidities–– Chronic sinusitis94.1 (32)– Asthma82.4 (28)– GERD58.8 (20)– Depression44.1 (15)– Anxiety32.4 (11)– Hypertension14.7 (5)–Medications–– Nasal steroids38.2 (13)– Monteleukast32.4 (11)– OTC antihistamine32.4 (11)– SSRI17.6 (6)– Sleep prescription*8.8 (3)–Non-Prescription Sleep AidsOTC Sleep AidX2 = 0.740.39 No73.5 (25)64.3 (27) Yes26.5 (9)35.7 (15)Frequency OTC Sleep AidX2 = 4.560.10 Several nights per week22.2 (2)6.7 (1) At least once a month66.7 (6)40.0 (6) Less than once a month11.1 (1)53.3 (8)Melatonin UseX2 = 0.630.43 No70.6 (24)61.9 (26) Yes29.4 (10)38.1 (16)Frequency Melatonin UseX2 = 2.090.35 Several nights per week10.0 (1)18.8 (3) At least once a month30.0 (3)50.0 (8) Less than once a month60.0 (6)31.3 (5)Marijuana/CBD Use for SleepX2 = 1.810.18 No64.7 (22)78.6 (33) Yes35.3 (12)21.4 (9)Frequency Marijuana/CBD UseX2 = 3.860.15 Several nights per week75.0 (9)44.4 (4) At least once a month16.7 (2)55.6 (5) Less than once a month8.3 (1)0.0 (0)*Trazodone, clonazepam, amitriptyline. Open table in a new tab *Trazodone, clonazepam, amitriptyline. Snoring was more common among controls (pwCF=5.9%, controls=23.8%), X2(1)=4.54, p = 0.03, with no group difference in observed apnea frequency (pwCF=5.9%, controls=2.4%), X2(1)=0.61, p = 0.44. More pwCF reported daytime fatigue/sleepiness (pwCF=50.0%, controls=19.0%), X2(1)=8.16, p = 0.004. Although not significant, more pwCF reported symptoms of restless leg syndrome (pwCF=38.2%, controls=26.2%), X2(1)=1.26, p = 0.26, and parasomnias (sleep walking/sleep terrors) (pwCF=47.1%, controls=33.3%), X2(1)=1.48, p = 0.22. Although not significant, more control participants used OTC sleep aids (pwCF=26.5%, controls=35.7%) and melatonin (pwCF=29.4%, controls=38.1%) to facilitate sleep (Table 1). More pwCF used marijuana/CBD (pwCF=35.5%, controls=21.4%) to facilitate sleep, with 75% of pwCF using marijuana/CBD for sleep several nights per week (vs. 44.4% of controls). Notably, although fewer pwCF used OTC sleep aids, their use was more frequent than controls. Similarly, although fewer pwCF used melatonin, they used significantly higher doses (pwCF=8.3 ± 5.8 mg, controls=3.8 ± 2.9 mg), t(24)=2.69, p = 0.01. Eighty-eight to 97% of pwCF reported either no change or improvements in sleep since starting elexacaftor/tezacaftor/ivacaftor (Fig. 1). The most notable change was a decrease in the frequency of medications to facilitate sleep, with almost a third of pwCF reporting improvements. Open ended responses also noted “feeling less mucus in my lungs,” “needing less sleep,” and “wake up from coughing better.” Since starting elexacaftor/tezacaftor/ivacaftor, 29% (n = 10) of pwCF reported no change in sleep, 35% (n = 12) reported ≥1 area of improvement, and no worsening symptoms, 18% (n = 6) reported ≥1 area of improvement and 1 worsening symptom, and 18% (n = 6) reported ≥1 area of sleep getting worse, and no improvements. As seen in Table 2, compared to controls, pwCF reported significantly greater sleep disturbances (d = 0.46) and more pain (d = 0.66). Although not statistically significant, small to medium effect sizes highlighted more sleep-related daytime impairment (d = 0.35) and less social support in terms of the availability of helpful information or advice (d = -0.37) in pwCF compared to controls.Table 2PROMIS health-related quality of life (HRQOL) mean (SD) T-scores by group.CF Group (n = 34)Control Group (n = 42)FPCohen's dSleep Disturbance51.2 (6.0)48.2 (7.0)3.910.050.46Sleep-Related Impairment55.2 (7.4)52.5 (8.1)2.240.140.35Anxiety56.5 (9.5)54.9 (8.7)0.600.440.18Depressive Symptoms51.8 (9.7)51.1 (9.1)0.100.760.07Emotional Support55.6 (9.1)55.7 (8.2)0.010.94−0.01Informational Support56.0 (10.5)59.3 (7.1)2.760.10−0.37Pain49.8 (8.7)44.9 (5.9)8.730.0040.66 Open table in a new tab For pwCF, greater sleep disturbances were associated with increased anxiety (r = 0.58, p<0.001) and depressive symptoms (r = 0.50, p = 0.002), lower emotional support (r = -0.35, p = 0.04) and information support (r = -0.39, p = 0.02), and more pain (r = 0.32, p = 0.06). Greater sleep-related impairment was associated with increased anxiety (r = 0.59, p<0.001) and depressive symptoms (r = 0.49, p = 0.003), and lower information support (r = -0.36, p = 0.04). For control participants, greater sleep disturbances were associated with increased anxiety (r = 0.46, p = 0.02) and depressive symptoms (r = 0.44, p = 0.003). Greater sleep-related impairment was associated with increased anxiety (r = 0.46, p = 0.02) and depressive symptoms (r = 0.64, p<0.001). This study highlights that elexacaftor/tezacaftor/ivacaftor may improve sleep in some emerging adults with CF. Despite this improvement, sleep remains a significant concern, with pwCF more frequently using sleep aids, reporting poorer quality sleep, and more impacts on quality of life than age-matched controls. Due to the small sample size, many of the group comparisons were not significantly different, however, the results were clinically meaningful and may be statistically significant if repeated in a larger sample. Study limitations also include the correlational study design, self-selection bias, recall bias potentially influenced by time on elexacaftor/tezacaftor/ivacaftor (i.e., questions only asked after participants were already on treatment), and overall transformative health improvements frequently experienced by people taking this therapy, as well as the lack of data on control participant BMI that may be related to sleep disordered breathing. As a preliminary characterization of this sample, further research is needed that will objectively characterize sleep with actigraphy and polysomnography, and further explore the relationship between sleep disturbances and HRQOL among pwCF. Future studies should also include information about symptoms of daytime sleepiness, alcohol use, exercise, caffeine consumption, and screen time. Further investigation of the impact of elexacaftor/tezacaftor/ivacaftor on sleep is warranted, including a comparison with pwCF who are not eligible for CFTR modulator therapy. Together this knowledge can facilitate development of clinical practice guidelines for the screening and treatment of sleep disturbances in pwCF.