Circadian Rhythm Disorders in Children With Cystic Fibrosis Under CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) Modulators

Result of the Horne and Ostberg questionnaire.

Cystic fibrosis (CF) is a rare disease affecting one out of 4,500 newborns in France (INSERM
 2021). Despite major advances in patient care over the past two decades, with significant
 improvements in life expectancy, cystic fibrosis remains a pathology that considerably
 impairs quality of life.
 
 Several studies have reported the possibility of respiratory and non-respiratory sleep
 disorders (SD) in patients with CF. Respiratory disorders are reported to affect 30% of
 children with CF (Barbosa 2020). Among non-respiratory SD, sleep onset and maintenance
 insomnia are well known in these patients, while chronotype abnormalities (circadian rhythm
 disorders) are understudied. Chronotype refers to a person's tendency to be more efficient in
 the morning or evening.
 
 The existence of chronotype abnormalities has been suggested in CF patients, but no precise
 data are available (Louis 2022). The involvement of CFTR (Cystic Fibrosis Transmembrane
 Conductance Regulator) protein dysfunction in the central nervous system (CNS) has been
 hypothesized as a contributory factor. In vivo, in a mouse model of CF, dysregulation of
 clock genes such as Clock, Cry2 and Per2 was found in the CNS (Barbato 2019). Among them,
 certain genes such as Rev-erbα could regulate endobronchial inflammation and contribute to
 the severity of respiratory pathology. All in all, chronotype abnormalities could be at the
 origin of sleep debt, impaired cognitive functions or metabolic disturbances.
 
 In the era of highly effective modulator therapy (HEMT) for the treatment of CF, the impact
 of these new therapies on chronotype has been understudied. Assuming that chronotype
 abnormalities are a direct consequence of CFTR protein dysfunction in the retina and anterior
 hypothalamus, HEMT should improve sleep quality. However, between 20% and 30% of adult and
 pediatric patients express an increase in chronotype abnormalities following initiation of
 treatment.
 
 Paradoxically, the perceived gain in respiratory quality of life is counterbalanced by the
 occurrence of these disorders. Some patients would effectively reverse their treatment in
 order to limit the phenomenon. A single polysomnographic study evaluated the effect of HEMT
 Kaftrio-Kalydeco on sleep in adults with CF (Welsner 2022). After 3 months of treatment,
 patients had a significant reduction in respiratory events, with no change in total sleep
 time, sleep efficiency or sleep architecture. Chronotype was not mentioned. Currently, no
 studies on chronotype in children or adults with CF have been carried out. Our hypothesis is
 that CF patients treated with HEMT would develop an abnormal chronotype of late sleep onset.
 
 The aim of this study is to evaluate the chronotype of children with CF treated with HEMT.
 Chronotype abnormalities could have major consequences for quality of life, the immune
 system, cognitive functions and metabolism. Systematic detection of these disorders via
 anamnesis, followed by diagnosis by questionnaire, actimetrics and/or urinary melatonin
 dosage, would enable their early management, starting with the reversal of Kaftrio-Kalydeco
 intake between morning and evening.