Leukotriene modifier therapy for mild sleep-disordered breathing in children

Abstract

Background: Children with mild sleep-disordered breathing (SDB), who may not be recommended for adenotonsillectomy, frequently exhibit neurocognitive and behavioral morbidity, and may benefit from alternative therapeutic interventions, such as leukotriene modifier therapy.

Methods: Twenty-four children with SDB completed an open-label intervention study for 16 weeks with daily montelukast therapy. Sleep studies and adenoid size estimates from lateral X-ray films of the neck were obtained before and after treatment. In a parallel study, adenoid and tonsillar tissues from children with obstructive sleep apnea or recurrent throat infections were subjected to quantitative polymerase chain reaction, immunohistochemistry, and Western blotting for gene and protein expression of leukotriene receptors LT1-R and LT2-R, and for concentrations of LTB4 and LTC4/D4/E4.

Results: Montelukast treatment induced significant reductions in adenoid size and respiratory-related sleep disturbances, which were absent in 16 children with SDB who did not receive treatment. LT1-R and LT2-R mRNA was similarly abundant in adenoid tissues, but increased LT1-R and LT2-R protein expression and higher levels of LTB4 and LTC4/D4/E4 emerged in children with obstructive sleep apnea.

Conclusions: Oral therapy with a leukotriene modifier appears to be associated with improved breathing during sleep. Double-blind, placebo-controlled trials will be needed to corroborate current findings and solidly establish antiinflammatory strategies, such as leukotriene modifiers, as therapeutic alternatives in children with SDB too mild to justify referral for adenotonsillectomy.

Figure 1.

Lateral neck soft X-ray in a 6-year-old patient with mild sleep-disordered breathing before (Pre) and after (Post) 16-week course of montelukast. Increased upper airway diameter and recession of adenoid tissue are apparent in the post-treatment radiograph. Arrows: A, adenoid; P, pharynx.

Figure 2.

Left upper panel: Representative immunoblots of leukotriene 1 receptor (LT1-R; detected at 38.5 kD) and β-actin in adenoids and tonsils from patients with obstructive sleep apnea (SA) and recurrent tonsillitis (RI). BP indicates blocking peptide for competition assay and M indicates molecular marker. Left lower panel: Mean LT1-R/β-actin demonstrate significantly higher LT1-R expression in adenoid tissues of patients with SA (n = 8) compared with RI (n = 8; p = 0.04). Right upper panel: Representative immunoblots of LT2-R (detected at 59 kD) and β-actin in adenoids and tonsils from patients with SA and RI. Right lower panel: Mean LT2-R/β-actin demonstrate significantly higher LT2-R expression in adenoid tissues of patients with SA (n = 8) compared with RI (n = 8; p = 0.02).

Figure 3.

Double-label immunohistochemistry for LT1-R and myeloperoxidase (MPO) in tonsils obtained from patients with SA and RI reveals the enhanced immunoreactivity of LT1-R in SA. In addition, a higher abundance of LT1-R/MPO coexpression is apparent in the patient with SA. Similar findings were detected in five sets of tonsils from patients with SA and RI.

Figure 4.

Left panel: Individual and mean LTC4/D4/E4 concentrations (pg/ml) in adenotonsillar tissues obtained from children with SA (n = 19) were significantly higher compared with upper airway lymphoid tissues from patients with RI (n = 7; *p < 0.03). Right panel: Individual and mean LTB4 concentrations (pg/ml) in adenotonsillar tissues obtained from children with SA (n = 20) were significantly higher compared with those found in RI (n = 9; p < 0.02).