Sleep Phase Delay in Cystic Fibrosis: A Potential New Manifestation of Cystic Fibrosis Transmembrane Regulator Dysfunction

doi:10.1016/j.chest.2017.03.057

Chest

Volume 152, Issue 2, August 2017, Pages 386-393

Portions of this work were presented in preliminary form during the 11th Australasian Cystic Fibrosis Conference, August 15-18, 2015, Sydney, Australia and during Internal Medicine Grand Rounds at the University of Utah, December 1, 2016, Salt Lake City, UT.

https://doi.org/10.1016/j.chest.2017.03.057 Get rights and content

Background

Cystic fibrosis (CF) transmembrane regulator (CFTR) protein dysfunction causes CF. Improving survival allows detection of increasingly subtle disease manifestations. CFTR dysfunction in the central nervous system (CNS) may disturb circadian rhythm and thus sleep phase. We studied sleep in adults to better understand potential CNS CFTR dysfunction.

Methods

We recruited participants from April 2012 through April 2015 and administered the Munich Chronotype Questionnaire (MCTQ). We compared free-day sleep measurements between CF and non-CF participants and investigated associations with CF survival predictors.

Results

We recruited 23 female and 22 male adults with CF aged 18 to 46 years and 26 female and 22 male volunteers aged 18 to 45 years. Compared with volunteers without CF, patients with CF had delayed sleep onset (0.612 h; P = .015), midsleep (1.11 h; P < .001), and wake (1.15 h; P < .001) times and prolonged sleep latency (7.21 min; P = .05) and duration (0.489 h; P = .05). Every hour delay in sleep onset was associated with shorter sleep duration by 0.29 h in patients with CF and 0.75 h in subjects without CF (P = .007) and longer sleep latency by 7.51 min in patients with CF and 1.6 min in volunteers without CF (P = .035). Among patients with CF, FEV₁ % predicted, prior acute pulmonary exacerbations, and weight were independent of all free-day sleep measurements.

Conclusions

CF in adults is associated with marked delays in sleep phase consistent with circadian rhythm phase delays. Independence from disease characteristics predictive of survival suggests that sleep phase delay is a primary manifestation of CFTR dysfunction in the CNS.

Section snippets

Participants

With University of Utah Investigational Review Board approval (IRB_00005311) and informed consent, we serially recruited adult patients with CF during outpatient visits or hospitalizations for acute pulmonary exacerbations. We recorded age, height, weight, sex, race, ethnicity, CF genotype, and FEV₁.36, 37, 38 We normalized FEV₁ to FEV₁ % predicted using National Health And Nutrition Examination Survey (NHANES) III³⁹ and Global Lung Initiative (GLI) equations.⁴⁰ We counted acute pulmonary

Participants

We recruited 47 patients with CF and 50 volunteers without CF. We discarded two questionnaires from patients and two from volunteers because of incompleteness. Study groups had the same frequencies regarding sex, race, and ethnicity. All were young adults, but there were small differences in distribution of age and height (Table 1, e-Fig 1). All participants were white except one Hispanic female with CF, consistent with the racial distribution of CF in Utah.

Sleep Analyses

Univariable linear regressions showed

Discussion

We performed a pilot study examining sleep timing and duration among patients with CF compared with volunteers without CF. We found that adults with CF have markedly delayed sleep phase and prolonged sleep latency and duration (Table 2). Study patients had a wide range of disease, from normal lung function and no acute pulmonary exacerbations in the year prior to MCTQ administration to an FEV₁ approximately 20% of predicted and more than five exacerbations (Fig 2), providing the opportunity to

Acknowledgments

Author contributions: J. L. J. and T. G. L. are the guarantors of the paper and assume responsibility for the integrity of the work as a whole. All authors participated in performing and completing this project. J. L. J. initiated and persisted in the work despite minimal assistance for more than a year. J. L. J. and C. R. J, C. K., F. R. A., and T. G. L. designed the study and devised the analysis plans. J. L. J. and K. A. P. initiated and managed the institutional review board application,

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Concerning sleep architecture, one study did not observe significant changes in sleep stages [5] whereas another study performed in 19 adult patients found a decrease in the percentage of REM sleep [16]. Circadian phase delay is commonly observed in adolescents and young adults with CF. This circadian phase delay has been analyzed in 45 adults with CF and 50 healthy volunteers by means of the Munich Chronotype Questionnaire [17]. Patients with CF had a significantly delayed sleep onset, mid-sleep and wake times and prolonged sleep latency as compared to controls.
Large gains have been made in the management of respiratory diseases associated with cystic fibrosis (CF). Initial studies evaluating sleep issues in CF focused on respiratory problems of nocturnal hypoxia, alveolar hypoventilation and risk of airway obstruction from nasal polyps with treatment evaluations including long term oxygen therapy or noninvasive ventilation in case of nocturnal hypercapnia. More recent studies include patients whose lung function is better preserved, and have permitted more focus on sleep patterns and sleep quality. This literature identified that reduced sleep duration and poor sleep quality are common and may be explained by chronic pain and cough, frequent stools, gastro-oesophageal reflux, nasal obstruction or sinusitis, and drugs such as corticosteroids or beta-agonists. In the teenage years, poor sleep hygiene, sleep debt and poor sleep quality are associated with depression, poor academic performance, less physical activity, and a decrease in quality of life. Restless leg syndrome also seems to be common in adult patients with CF. These sleep problems seem more important in patients with a low lung function but may also be observed in patients with preserved lung function. The consequences of poor sleep may potentially exaggerate the multi-organ morbidity of CF, such as pain, inflammation, susceptibility to infection, and glucose intolerance, but these aspects are largely under-evaluated. Sleep should be evaluated on a routine basis in CF and prospective studies assessing the benefits of interventions aiming at improving sleep duration and sleep quality urgently needed.
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This article summarizes our current understanding of sleep disorders and sleep health concerns in children with chronic respiratory disorders (asthma, bronchopulmonary dysplasia, cystic fibrosis, and pulmonary hypertension) commonly encountered by sleep medicine clinicians. Special considerations for polysomnography acquisition and interpretation in the setting of chronic respiratory disease are discussed.
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A total of fourteen studies utilized different sleep questionnaires, actigraphy, and other outcomes measurements in children [2,33,37,54,71–80]. Similarly, fifteen studies of adults incorporated sleep questionnaires [27,43,44,47,48,50,81–90]. Finally, ten studies combined results from both children and adults [46,53,91–98].
Cystic fibrosis (CF) is a genetic disorder that leads to airway mucus accumulation, chronic inflammation, and recurrent respiratory infections – all likely impacting sleep. However, controlled studies of sleep in CF patients are limited, and have shown mixed results. We reviewed all publications on CF and sleep indexed in PubMed, CINAHL, and Scopus through April 2019. In the meta-analysis, we calculated pooled weighted mean differences for sleep quality, sleepiness, oximetry, and polysomnographic (PSG) parameters, using fixed or random-effects models as appropriate. A total of 87 manuscripts were reviewed. Compared to controls, children with CF had lower nighttime oxygen saturation nadirs, decreased sleep efficiency and a higher respiratory event index, with no differences in the percentage of REM sleep. Adults with CF had lower oxygen saturation nadirs, with a trend towards reduced sleep efficiency and no differences in REM sleep. In addition, patients with CF cough more during sleep and experience painful events that interfere with sleep. Actigraphy and questionnaires suggest disturbed sleep and daytime sleepiness. Noninvasive ventilation appears to improve gas exchange and symptoms.
We conclude that when sleep is evaluated objectively or subjectively in patients with CF, perturbations are common, emphasizing the importance of their identification and treatment and inclusion as part of routine care. Additional research, with larger sample sizes and standardized outcomes, are necessary.
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Normal cystic fibrosis (CF) transmembrane regulator (CFTR) protein has multiple functions in health and disease. Many mutations in the CFTR gene produce abnormal or absent protein. CFTR protein dysfunction underlies the classic CF phenotype of progressive pulmonary and GI pathology but may underlie diseases not usually associated with CF. This review highlights selected extrapulmonary disease that may be associated with abnormal CFTR. Increasing survival in CF is associated with increasing incidence of diseases associated with aging. CFTR dysfunction in older individuals may have novel effects on glucose metabolism, control of insulin release, regulation of circadian rhythm, and cancer cell pathophysiology. In individuals who have cancers with acquired CFTR suppression, their tumors may more likely exhibit rapid expansion, epithelial-to-mesenchymal transformation, abnormally reduced apoptosis, and increased metastatic potential. The new modulators of CFTR protein synthesis could facilitate the additional exploration needed to better understand the unfolding clinical biology of CFTR in human disease, even as they revolutionize treatment of patients with CF.

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: FUNDING/SUPPORT: This work was funded by the NHLBI/NIH, Bethesda, MD [grant R01 HL 125520], the Cystic Fibrosis Foundation, Bethesda, MD [grants CC132-16AD, LIOU13A0, LIOU14P0], the Ben B. and Iris M. Margolis Family Foundation of Utah, and the Claudia Ruth Goodrich Stevens Endowment Fund.

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Chest

Original Research: Genetic and Developmental DisordersSleep Phase Delay in Cystic Fibrosis: A Potential New Manifestation of Cystic Fibrosis Transmembrane Regulator Dysfunction

Background

Methods

Results

Conclusions

Section snippets

Participants

Participants

Sleep Analyses

Discussion

Acknowledgments

Chest

Lancet Respir Med

Lancet Respir Med

Mol Cell Endocrinol

Mol Brain

Sleep Med Clin

Sleep Med

Sleep Med

J Psychosom Res

Sleep Med Rev

J Pediatr

Chest

Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathologic study

Am J Child

Physiological basis of cystic fibrosis: a historical perspective

Physiol Rev

Identification of the cystic fibrosis gene: genetic analysis

Science

Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA

Science

Identification of the cystic fibrosis gene: chromosome walking and jumping

Science

Predictive 5-year survivorship model of cystic fibrosis

Am J Epidemiol

A CFTR potentiator in patients with cystic fibrosis and the G551D mutation

N Engl J Med

Discovery of clinically approved agents that promote suppression of cystic fibrosis transmembrane conductance regulator nonsense mutations

Am J Respir Crit Care Med

Cystic fibrosis transmembrane conductance regulator protein (CFTR) expression in the developing human brain: comparative immunohistochemical study between patients with normal and mutated CFTR

J Histochem Cytochem Off J Histochem Soc

Expression and localization of the cystic fibrosis transmembrane conductance regulator mRNA and its protein in rat brain

J Clin Invest

Retinal pigment epithelial function: a role for CFTR?

Doc Ophthalmol Adv Ophthalmol

Light and alcohol evoked electro-oculograms in cystic fibrosis

Doc Ophthalmol Adv Ophthalmol

Cystic fibrosis transmembrane conductance regulator expression in human hypothalamus

Neuroreport

CFTR is functionally active in GnRH-expressing GT1-7 hypothalamic neurons

Am J Physiol

Original Research: Genetic and Developmental Disorders
Sleep Phase Delay in Cystic Fibrosis: A Potential New Manifestation of Cystic Fibrosis Transmembrane Regulator Dysfunction