Pilot study of nasal expiratory positive airway pressure devices for the treatment of childhood obstructive sleep apnea syndrome.

STUDY OBJECTIVES: Alternative therapies for childhood obstructive sleep apnea syndrome (OSAS) are needed as OSAS may persist despite adenotonsillectomy, and continuous positive airway pressure (CPAP) adherence is low. Nasal expiratory positive airway pressure (NEPAP) devices have not been studied in children. We hypothesized that NEPAP would result in polysomnographic improvement. Further, we aimed to determine NEPAP adherence, effects on sleepiness, behavior, and quality of life. METHODS: A randomized, double-blind, placebo-controlled, crossover pilot study was performed. CPAP candidates, 8-16 years old, underwent NEPAP and placebo polysomnograms. Subjects with ≥ 50% reduction in the apnea hypopnea index (AHI) from placebo to NEPAP night or AHI < 5/h on NEPAP night wore NEPAP at home for 30 days. Adherence was assessed by daily phone calls/emails and collecting used devices. RESULTS: Fourteen subjects (age 13.4 ± 1.9 years, BMI z-scores 2.2 ± 1 [mean ± SD]) were studied. There was significant improvement in the obstructive apnea index with NEPAP vs. placebo: 0.6 (0-21.1)/h vs. 4.2 (0-41.9)/h (median [range], p = 0.010) and trends for improvement in other polysomnographic parameters. However, responses were variable, with 3 subjects not improving and 2 worsening. Older children and those with less hypercapnia had a better response. Eight subjects were sent home with devices; one was lost to follow-up, and adherence in the remainder was 83% of nights; these subjects had a significant improvement in sleepiness and quality of life. CONCLUSIONS: NEPAP devices are a potential alternative therapy for OSAS in a small subset of children. Due to variability in individual responses, efficacy of NEPAP should be evaluated with polysomnography. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, identifier: NCT01768065.

Mitotic asynchrony induces transforming growth factor-ß1 secretion from airway epithelium.

We recently proposed that mitotic asynchrony in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to proinflammatory cross-talk among asynchronously repairing adjacent tissues. Building on our previous finding that mitotic asynchrony is associated with proinflammatory/fibrotic cytokine secretion (e.g., transforming growth factor [TGF]-ß1), here we provide evidence supporting cause-and-effect. Under normal conditions, primary airway epithelial basal cell populations undergo mitosis synchronously and do not secrete proinflammatory or profibrotic cytokines. However, when pairs of nonasthmatic cultures were mitotically synchronized at 12 hours off-set and then combined, the mixed cell populations secreted elevated levels of TGF-ß1. This shows that mitotic asynchrony is not only associated with but is also causative of TGF-ß1 secretion. The secreted cytokines and other mediators from asthmatic cells were not the cause of asynchronous regeneration; synchronously mitotic nonasthmatic epithelia exposed to conditioned media from asthmatic cells did not show changes in mitotic synchrony. We also tested if resynchronization of regenerating asthmatic airway epithelia reduces TGF-ß1 secretion and found that pulse-dosed dexamethasone, simvastatin, and aphidicolin were all effective. We therefore propose a new model for chronic inflammatory and fibrotic conditions where an underlying factor is mitotic asynchrony.

Narcolepsy in the pediatric population.

Narcolepsy is characterized by excessive daytime sleepiness, with or without cataplexy. Associated features include sleep paralysis, hypnagogic or hypnopompic hallucinations, and disturbed nocturnal sleep. Narcolepsy is strongly associated with the HLA DQB1*0602 allele, and its symptoms stem from destruction of hypocretin-secreting neurons in the hypothalamus. Recently identified autoantibodies to Tribbles homologue 2 in some patients, as well as cases associated with H1N1 vaccination, support an autoimmune mechanism. There are many challenges in diagnosing and treating pediatric narcolepsy. Caution must also be used in interpreting polysomnography and multiple sleep latency test results in children. HLA testing is nonspecific, and no commercial test exists to measure cerebrospinal fluid hypocretin levels. Neuroimaging has not yet proven useful in primary narcolepsy. Treatment of sleepiness and cataplexy in children requires extrapolating from adult studies. Hopefully, further insights into the pathophysiology of narcolepsy will allow for new therapeutics to manage the symptoms and modify the course of the disease.