Sleep measures and morning plasma TNF-alpha levels in children with sleep-disordered breathing

Abstract

Background: Sleep disordered breathing in children is associated with severity-dependent increases in excessive daytime sleepiness (EDS). TNF-alpha is an inflammatory cytokine that has been implicated in EDS. Since, at any given level of apnea-hypopnea index, there is significant variability in EDS, we hypothesized that morning tumor necrosis factor (TNF)-alpha plasma levels may provide a biologic correlate of EDS.

Methods: Children being evaluated for sleep disordered breathing underwent a blood draw after nocturnal polysomnography, and TNF-alpha plasma concentrations were assayed using ELISA. In a subset of 15 children with sleep disordered breathing and in 15 matched control subjects, whole blood cultures in the presence of lipopolysaccharide and Multiple Sleep Latency Test were conducted. Furthermore, 22 children with obstructive sleep apnea had TNF-alpha levels assayed and underwent nocturnal polysomnography and Multiple Sleep Latency Test before and after adenotonsillectomy.

Results: In 298 children, morning TNF-alpha levels were globally increased in the presence of obstructive sleep apnea, particularly in more severe cases, and correlated with obstructive apnea-hypopnea index and sleep pressure score, a measure of respiratory-induced sleep fragmentation, but not with nadir Sa02. A stepwise logistic regression analysis revealed that sleep pressure score and body mass index accounted for 36.2% of the adjusted variance in TNF-alpha levels (P < 0.0001). Furthermore, multiple sleep latencies were correlated with whole blood culture-derived TNF-alpha levels (n = 15), and morning TNF-alpha levels decreased after adenotonsillectomy in 22 children.

Conclusions: TNF-alpha levels are increased in pediatric obstructive sleep apnea, are primarily driven by sleep fragmentation and body mass index, and are closely associated with the degree of sleepiness, as measured by Multiple Sleep Latency Test. Furthermore, surgical treatment of obstructive sleep apnea results in significant reductions in TNF-alpha levels with reciprocal prolongations in sleep latency.

Figure 1

Scattergrams of individual tumor necrosis factor (TNF)-α morning plasma levels plotted against corresponding obstructive apnea-hypopnea index (OAHI), nadir SaO₂, and sleep pressure score (SPS) in 270 habitually snoring children and 28 nonsnoring control subjects. Linear regression lines are shown and were highly signicant for OAHI (r²: 0.24; P < 0.001) and SPS (r²: 0.52; P < 0.000001) but not with nadir SaO₂ (r²: 0.05; p > 0.05). The vertical lines show OAHI = 5 and SPS = 0.25 as cutoffs for disease severity. The right bottom panel shows log TNF-α plotted against log SPS, with the vertical line representing SPS = 0.25 whereas the curvilinear line represents the sigmoidal t function (r²: 0.64; P < 0.00000001). Please note the marked take off of TNF-α morning plasma concentrations once SPS exceeds the 0.25 cutoff value (7).

Figure 2

Scattergrams of individual basal and after lipopolysaccharide stimulation tumor necrosis factor (TNF)-α supernatant levels obtained by ex vivo blood cultures and plotted against corresponding mean sleep latencies (MSL) in 15 children with obstructive sleep apnea and 15 age-, sex-, ethnicity-, and body mass index-matched control subjects.

Figure 3

Tumor necrosis factor (TNF)-α morning plasma levels and mean sleep latencies (MSL) in 22 children with obstructive sleep apnea before (PRE) and after (POST) surgical adenotonsillectomy. (PRE vs POST for both TNF-α levels and MSL: P < 0.001)