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

Abstract

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.

Keywords: circadian rhythm; cystic fibrosis; cystic fibrosis transmembrane regulator; sleep; sleep-wake disorders.

Figure 1

Sleep phase measurements and clinical data for patients with cystic fibrosis (CF). A, We found no relationship between lung function, prior acute pulmonary exacerbations, or weight with sleep latency or total sleep duration in patients with CF. Compared with control subjects, patients with CF had longer sleep latency that was significant without adjustment and prolonged sleep duration that was borderline in significance (Table 2). However, both latency and duration were significantly longer in patients with CF after adjustment for age, sex, and height (Table 3). B, Timing of sleep onset, midsleep, and wake times were independent of FEV₁ % predicted, number of acute pulmonary exacerbations in the prior year, and weight among patients with CF. Volunteers without CF had earlier times for all three sleep events. The differences were significant without adjustment (Table 2), and the associations were strengthened after adjustments for age, sex, and height, as appropriate (Table 3, e-Table 1A-C). APE = acute pulmonary exacerbation; CF = cystic fibrosis.

Figure 2

Relationship between prior acute pulmonary exacerbations and FEV₁ % predicted. FEV₁ % predicted, normalized using National Health And Nutrition Examination Survey III equations, and the number of acute pulmonary exacerbations in the prior year (truncated to a maximum of five) are the two most important predictors of survival in CF. Patients with CF who participated in this study had a wide range of FEV₁ % predicted values and number of prior acute pulmonary exacerbations requiring hospitalization. Using quasi-Poisson regression, we detected a strong inverse relationship. Note that acute pulmonary exacerbation counts were jittered to better show individual values. See Figure 1 legend for expansion of abbreviations.