Persistent sleep-disordered breathing independently contributes to metabolic syndrome in prepubertal children.

BACKGROUND: Obstructive sleep apnea (OSA) is a risk factor for metabolic syndrome (MetS) in adults, but its association in prepubertal children is still questionable due to the relatively limited cardiometabolic data available and the phenotypic heterogeneity. OBJECTIVE: To identify the role of OSA as a potential mediator of MetS in prepubertal children. METHODS: A total of 255 prepubertal children from the Childhood Adenotonsillectomy Trial were included, with standardized measurements taken before OSA treatment and 7 months later. MetS was defined if three or more of the following criteria were present: adiposity, high blood pressure, elevated glycemia, and dyslipidemia. A causal mediation analysis was conducted to assess the effect of OSA treatment on MetS. RESULTS: OSA treatment significantly impacted MetS, with the apnea-hypopnea index emerging as mediator (p = .02). This mediation role was not detected for any of the individual risk factors that define MetS. We further found that the relationship between MetS and OSA is ascribable to respiratory disturbance caused by the apnea episodes, while systemic inflammation as measured by C-reactive protein, is mediated by desaturation events and fragmented sleep. In terms of evolution, patients with MetS were significantly more likely to recover after OSA treatment (odds ratio = 2.56, 95% confidence interval [CI] 1.20-5.46; risk ratio = 2.06, 95% CI 1.19-3.54) than the opposite, patients without MetS to develop it. CONCLUSION: The findings point to a causal role of OSA in the development of metabolic dysfunction, suggesting that persistent OSA may increase the risk of MetS in prepubertal children. This mediation role implies a need for developing screening for MetS in children presenting OSA symptoms.

An explainable deep-learning model to stage sleep states in children and propose novel EEG-related patterns in sleep apnea.

Automatic deep-learning models used for sleep scoring in children with obstructive sleep apnea (OSA) are perceived as black boxes, limiting their implementation in clinical settings. Accordingly, we aimed to develop an accurate and interpretable deep-learning model for sleep staging in children using single-channel electroencephalogram (EEG) recordings. We used EEG signals from the Childhood Adenotonsillectomy Trial (CHAT) dataset (n = 1637) and a clinical sleep database (n = 980). Three distinct deep-learning architectures were explored to automatically classify sleep stages from a single-channel EEG data. Gradient-weighted Class Activation Mapping (Grad-CAM), an explainable artificial intelligence (XAI) algorithm, was then applied to provide an interpretation of the singular EEG patterns contributing to each predicted sleep stage. Among the tested architectures, a standard convolutional neural network (CNN) demonstrated the highest performance for automated sleep stage detection in the CHAT test set (accuracy = 86.9% and five-class kappa = 0.827). Furthermore, the CNN-based estimation of total sleep time exhibited strong agreement in the clinical dataset (intra-class correlation coefficient = 0.772). Our XAI approach using Grad-CAM effectively highlighted the EEG features associated with each sleep stage, emphasizing their influence on the CNN's decision-making process in both datasets. Grad-CAM heatmaps also allowed to identify and analyze epochs within a recording with a highly likelihood to be misclassified, revealing mixed features from different sleep stages within these epochs. Finally, Grad-CAM heatmaps unveiled novel features contributing to sleep scoring using a single EEG channel. Consequently, integrating an explainable CNN-based deep-learning model in the clinical environment could enable automatic sleep staging in pediatric sleep apnea tests.

Effect of Hypertonic Saline on Lung Function as Add-on Treatment in People With Cystic Fibrosis Receiving Dornase Alfa: A Cystic Fibrosis Foundation Patient Registry Analysis.

BACKGROUND: Introduction of novel therapies for cystic fibrosis (CF) raises the question of whether traditional treatments can be withdrawn. Nebulized hypertonic saline (HS) potentially could be discontinued in patients receiving dornase alfa (DA). RESEARCH QUESTION: In the era before modulators, did people with CF who are F508del homozygous (CFF508del) and who received DA and HS have better preserved lung function than those treated with DA only? STUDY DESIGN AND METHODS: Retrospective analysis of the Cystic Fibrosis Foundation Patient Registry data (2006-2014). Among 13,406 CFF508del with data for at least 2 consecutive years, 1,241 CFF508del had spirometry results and were treated with DA for 1 to 5 years without DA or HS during the preceding (baseline) year. Absolute FEV1 % predicted change while receiving DA and HS, relative to treatment with DA only, was the main outcome. A marginal structural model was applied to assess the effect of 1 to 5 years of HS treatment while controlling for time-dependent confounding. RESULTS: Of 1,241 CFF508del, 619 patients (median baseline age, 14.6 years; interquartile range, 6-53 years) received DA only and 622 patients (median baseline age, 14.55 years; interquartile range, 6-48.1 years) were treated with DA and HS for 1 to 5 years. After 1 year, patients receiving DA and HS showed FEV1 % predicted that averaged 6.60% lower than that in patients treated with DA only (95% CI, -8.54% to -4.66%; P < .001). Lower lung function in the former relative to the latter persisted throughout follow-up, highlighting confounding by indication. After accounting for baseline age, sex, race, DA use duration, baseline and previous year's FEV1 % predicted, and time-varying clinical characteristics, patients treated with DA and HS for 1 to 5 years were similar to those treated with DA only regarding FEV1 % predicted (year 1: mean FEV1 % predicted change, +0.53% [95% CI, -0.66% to +1.71%; P = .38]; year 5: mean FEV1 % predicted change, -1.82% [95% CI, -4.01% to +0.36%; P = .10]). INTERPRETATION: In the era before modulators, CFF508del showed no significant difference in lung function when nebulized HS was added to DA for 1 to 5 years.

Pediatric sleep apnea: Characterization of apneic events and sleep stages using heart rate variability.

Heart rate variability (HRV) is modulated by sleep stages and apneic events. Previous studies in children compared classical HRV parameters during sleep stages between obstructive sleep apnea (OSA) and controls. However, HRV-based characterization incorporating both sleep stages and apneic events has not been conducted. Furthermore, recently proposed novel HRV OSA-specific parameters have not been evaluated. Therefore, the aim of this study was to characterize and compare classic and pediatric OSA-specific HRV parameters while including both sleep stages and apneic events. A total of 1610 electrocardiograms from the Childhood Adenotonsillectomy Trial (CHAT) database were split into 10-min segments to extract HRV parameters. Segments were characterized and grouped by sleep stage (wake, W; non-rapid eye movement, NREMS; and REMS) and presence of apneic events (under 1 apneic event per segment, e/s; 1-5 e/s; 5-10 e/s; and over 10 e/s). NREMS showed significant changes in HRV parameters as apneic event frequency increased, which were less marked in REMS. In both NREMS and REMS, power in BW2, a pediatric OSA-specific frequency domain, allowed for the optimal differentiation among segments. Moreover, in the absence of apneic events, another defined band, BWRes, resulted in best differentiation between sleep stages. The clinical usefulness of segment-based HRV characterization was then confirmed by two ensemble-learning models aimed at estimating apnea-hypopnea index and classifying sleep stages, respectively. We surmise that basal sympathetic activity during REMS may mask apneic events-induced sympathetic excitation, thus highlighting the importance of incorporating sleep stages as well as apneic events when evaluating HRV in pediatric OSA.

Nocturnal oximetry parameters as predictors of sleep apnea severity in resource-limited settings.

Nocturnal oximetry is an alternative modality for evaluating obstructive sleep apnea syndrome (OSAS) severity when polysomnography is not available. The Oxygen Desaturation (≥3%) Index (ODI3) and McGill Oximetry Score (MOS) are used as predictors of moderate-to-severe OSAS (apnea-hypopnea index-AHI >5 episodes/h), an indication for adenotonsillectomy. We hypothesised that ODI3 is a better predictive parameter for AHI >5 episodes/h than the MOS. All polysomnograms performed in otherwise healthy, snoring children with tonsillar hypertrophy in a tertiary hospital (November 2014 to May 2019) were analysed. The ODI3 and MOS were derived from the oximetry channel of each polysomnogram. Logistic regression was applied to assess associations of ODI3 or MOS (predictors) with an AHI >5 episodes/h (primary outcome). Receiver operating characteristic (ROC) curves and areas under ROC curves were used to compare the ODI3 and MOS as predictors of moderate-to-severe OSAS. The optimal cut-off value for each oximetry parameter was determined using Youden's index. Polysomnograms of 112 children (median [interquartile range] age 6.1 [3.9-9.1] years; 35.7% overweight) were analysed. Moderate-to-severe OSAS prevalence was 49.1%. The ODI3 and MOS were significant predictors of moderate-to-severe OSAS after adjustment for overweight, sex, and age (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.19-1.51); and OR 4.10, 95% CI 2.06-8.15, respectively; p < 0.001 for both). Area under the ROC curve was higher for the ODI3 than for MOS (0.903 [95% CI 0.842-0.964] versus 0.745 [95% CI 0.668-0.821]; p < 0.001). Optimal cut-off values for the ODI3 and MOS were ≥4.3 episodes/h and ≥2, respectively. The ODI3 emerges as preferable or at least a complementary oximetry parameter to MOS for detecting moderate-to-severe OSAS in snoring children when polysomnography is not available.

A 2D convolutional neural network to detect sleep apnea in children using airflow and oximetry.

The gold standard approach to diagnose obstructive sleep apnea (OSA) in children is overnight in-lab polysomnography (PSG), which is labor-intensive for clinicians and onerous to healthcare systems and families. Simplification of PSG should enhance availability and comfort, and reduce complexity and waitlists. Airflow (AF) and oximetry (SpO2) signals summarize most of the information needed to detect apneas and hypopneas, but automatic analysis of these signals using deep-learning algorithms has not been extensively investigated in the pediatric context. The aim of this study was to evaluate a convolutional neural network (CNN) architecture based on these two signals to estimate the severity of pediatric OSA. PSG-derived AF and SpO2 signals from the Childhood Adenotonsillectomy Trial (CHAT) database (1638 recordings), as well as from a clinical database (974 recordings), were analyzed. A 2D CNN fed with AF and SpO2 signals was implemented to estimate the number of apneic events, and the total apnea-hypopnea index (AHI) was estimated. A training-validation-test strategy was used to train the CNN, adjust the hyperparameters, and assess the diagnostic ability of the algorithm, respectively. Classification into four OSA severity levels (no OSA, mild, moderate, or severe) reached 4-class accuracy and Cohen's Kappa of 72.55% and 0.6011 in the CHAT test set, and 61.79% and 0.4469 in the clinical dataset, respectively. Binary classification accuracy using AHI cutoffs 1, 5 and 10 events/h ranged between 84.64% and 94.44% in CHAT, and 84.10%-90.26% in the clinical database. The proposed CNN-based architecture achieved high diagnostic ability in two independent databases, outperforming previous approaches that employed SpO2 signals alone, or other classical feature-engineering approaches. Therefore, analysis of AF and SpO2 signals using deep learning can be useful to deploy reliable computer-aided diagnostic tools for childhood OSA.

Heart rate variability as a potential biomarker of pediatric obstructive sleep apnea resolution.

STUDY OBJECTIVES: Pediatric obstructive sleep apnea (OSA) affects cardiac autonomic regulation, altering heart rate variability (HRV). Although changes in classical HRV parameters occur after OSA treatment, they have not been evaluated as reporters of OSA resolution. Specific frequency bands (named BW1, BW2, and BWRes) have been recently identified in OSA. We hypothesized that changes with treatment in these spectral bands can reliably identify changes in OSA severity and reflect OSA resolution. METHODS: Four hundred and four OSA children (5-9.9 years) from the prospective Childhood Adenotonsillectomy Trial were included; 206 underwent early adenotonsillectomy (eAT), while 198 underwent watchful waiting with supportive care (WWSC). HRV changes from baseline to follow-up were computed for classical and OSA-related frequency bands. Causal mediation analysis was conducted to evaluate how treatment influences HRV through mediators such as OSA resolution and changes in disease severity. Disease resolution was initially assessed by considering only obstructive events, and was followed by adding central apneas to the analyses. RESULTS: Treatment, regardless of eAT or WWSC, affects HRV activity, mainly in the specific frequency band BW2 (0.028-0.074 Hz). Furthermore, only changes in BW2 were specifically attributable to all OSA resolution mediators. HRV activity in BW2 also showed statistically significant differences between resolved and non-resolved OSA. CONCLUSIONS: OSA treatment affects HRV activity in terms of change in severity and disease resolution, especially in OSA-related BW2 frequency band. This band allowed to differentiate HRV activity between children with and without resolution, so we propose BW2 as potential biomarker of pediatric OSA resolution. CLINICAL TRIAL REGISTRATION: Childhood Adenotonsillectomy Trial, NCT00560859, https://sleepdata.org/datasets/chat.

Bispectral Analysis of Heart Rate Variability to Characterize and Help Diagnose Pediatric Sleep Apnea.

Pediatric obstructive sleep apnea (OSA) is a breathing disorder that alters heart rate variability (HRV) dynamics during sleep. HRV in children is commonly assessed through conventional spectral analysis. However, bispectral analysis provides both linearity and stationarity information and has not been applied to the assessment of HRV in pediatric OSA. Here, this work aimed to assess HRV using bispectral analysis in children with OSA for signal characterization and diagnostic purposes in two large pediatric databases (0-13 years). The first database (training set) was composed of 981 overnight ECG recordings obtained during polysomnography. The second database (test set) was a subset of the Childhood Adenotonsillectomy Trial database (757 children). We characterized three bispectral regions based on the classic HRV frequency ranges (very low frequency: 0-0.04 Hz; low frequency: 0.04-0.15 Hz; and high frequency: 0.15-0.40 Hz), as well as three OSA-specific frequency ranges obtained in recent studies (BW1: 0.001-0.005 Hz; BW2: 0.028-0.074 Hz; BWRes: a subject-adaptive respiratory region). In each region, up to 14 bispectral features were computed. The fast correlation-based filter was applied to the features obtained from the classic and OSA-specific regions, showing complementary information regarding OSA alterations in HRV. This information was then used to train multi-layer perceptron (MLP) neural networks aimed at automatically detecting pediatric OSA using three clinically defined severity classifiers. Both classic and OSA-specific MLP models showed high and similar accuracy (Acc) and areas under the receiver operating characteristic curve (AUCs) for moderate (classic regions: Acc = 81.0%, AUC = 0.774; OSA-specific regions: Acc = 81.0%, AUC = 0.791) and severe (classic regions: Acc = 91.7%, AUC = 0.847; OSA-specific regions: Acc = 89.3%, AUC = 0.841) OSA levels. Thus, the current findings highlight the usefulness of bispectral analysis on HRV to characterize and diagnose pediatric OSA.

Heart rate variability spectrum characteristics in children with sleep apnea.

BACKGROUND: Classic spectral analysis of heart rate variability (HRV) in pediatric sleep apnea-hypopnea syndrome (SAHS) traditionally evaluates the very low frequency (VLF: 0-0.04 Hz), low frequency (LF: 0.04-0.15 Hz), and high frequency (HF: 0.15-0.40 Hz) bands. However, specific SAHS-related frequency bands have not been explored. METHODS: One thousand seven hundred and thirty-eight HRV overnight recordings from two pediatric databases (0-13 years) were evaluated. The first one (981 children) served as training set to define new HRV pediatric SAHS-related frequency bands. The associated relative power (RP) were computed in the test set, the Childhood Adenotonsillectomy Trial database (CHAT, 757 children). Their relationships with polysomnographic variables and diagnostic ability were assessed. RESULTS: Two new specific spectral bands of pediatric SAHS within 0-0.15 Hz were related to duration of apneic events, number of awakenings, and wakefulness after sleep onset (WASO), while an adaptive individual-specific new band from HF was related to oxyhemoglobin desaturations, arousals, and WASO. Furthermore, these new spectral bands showed improved diagnostic ability than classic HRV. CONCLUSIONS: Novel spectral bands provide improved characterization of pediatric SAHS. These findings may pioneer a better understanding of the effects of SAHS on cardiac function and potentially serve as detection biomarkers. IMPACT: New specific heart rate variability (HRV) spectral bands are identified and characterized as potential biomarkers in pediatric sleep apnea. Spectral band BW1 (0.001-0.005 Hz) is related to macro sleep disruptions. Spectral band BW2 (0.028-0.074 Hz) is related to the duration of apneic events. An adaptive spectral band within the respiratory range, termed ABW3, is related to oxygen desaturations. The individual and collective diagnostic ability of these novel spectral bands outperforms classic HRV bands.

Treatment of Obstructive Sleep Apnea in Children: Handling the Unknown with Precision.

Treatment approaches to pediatric obstructive sleep apnea (OSA) have remarkably evolved over the last two decades. From an a priori assumption that surgical removal of enlarged upper airway lymphadenoid tissues (T&A) was curative in the vast majority of patients as the recommended first-line treatment for pediatric OSA, residual respiratory abnormalities are frequent. Children likely to manifest persistent OSA after T&A include those with severe OSA, obese or older children, those with concurrent asthma or allergic rhinitis, children with predisposing oropharyngeal or maxillomandibular factors, and patients with underlying medical conditions. Furthermore, selection anti-inflammatory therapy or orthodontic interventions may be preferable in milder cases. The treatment options for residual OSA after T&A encompass a large spectrum of approaches, which may be complementary, and clearly require multidisciplinary cooperation. Among these, continuous positive airway pressure (CPAP), combined anti-inflammatory agents, rapid maxillary expansion, and myofunctional therapy are all part of the armamentarium, albeit with currently low-grade evidence supporting their efficacy. In this context, there is urgent need for prospective evidence that will readily identify the correct candidate for a specific intervention, and thus enable some degree of scientifically based precision in the current one approach fits all model of pediatric OSA medical care.

Obstructive Sleep Apnea and Inflammation: Proof of Concept Based on Two Illustrative Cytokines.

Obstructive sleep apnea syndrome (OSAS) is a markedly prevalent condition across the lifespan, particularly in overweight and obese individuals, which has been associated with an independent risk for neurocognitive, behavioral, and mood problems as well as cardiovascular and metabolic morbidities, ultimately fostering increases in overall mortality rates. In adult patients, excessive daytime sleepiness (EDS) is the most frequent symptom leading to clinical referral for evaluation and treatment, but classic EDS features are less likely to be reported in children, particularly among those with normal body-mass index. The cumulative evidence collected over the last two decades supports a conceptual framework, whereby sleep-disordered breathing in general and more particularly OSAS should be viewed as low-grade chronic inflammatory diseases. Accordingly, it is assumed that a proportion of the morbid phenotypic signature in OSAS is causally explained by underlying inflammatory processes inducing end-organ dysfunction. Here, the published links between OSAS and systemic inflammation will be critically reviewed, with special focus on the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), since these constitute classical prototypes of the large spectrum of inflammatory molecules that have been explored in OSAS patients.

Exosome and Macrophage Crosstalk in Sleep-Disordered Breathing-Induced Metabolic Dysfunction.

Obstructive sleep apnea (OSA) is a highly prevalent worldwide public health problem that is characterized by repetitive upper airway collapse leading to intermittent hypoxia, pronounced negative intrathoracic pressures, and recurrent arousals resulting in sleep fragmentation. Obesity is a major risk factor of OSA and both of these two closely intertwined conditions result in increased sympathetic activity, oxidative stress, and chronic low-grade inflammation, which ultimately contribute, among other morbidities, to metabolic dysfunction, as reflected by visceral white adipose tissue (VWAT) insulin resistance (IR). Circulating extracellular vesicles (EVs), including exosomes, are released by most cell types and their cargos vary greatly and reflect underlying changes in cellular homeostasis. Thus, exosomes can provide insights into how cells and systems cope with physiological perturbations by virtue of the identity and abundance of miRNAs, mRNAs, proteins, and lipids that are packaged in the EVs cargo, and are secreted from the cells into bodily fluids under normal as well as diseased states. Accordingly, exosomes represent a novel pathway via which a cohort of biomolecules can travel long distances and result in the modulation of gene expression in selected and targeted recipient cells. For example, exosomes secreted from macrophages play a critical role in innate immunity and also initiate the adaptive immune response within specific metabolic tissues such as VWAT. Under normal conditions, phagocyte-derived exosomes represent a large portion of circulating EVs in blood, and carry a protective signature against IR that is altered when secreting cells are exposed to altered physiological conditions such as those elicited by OSA, leading to emergence of IR within VWAT compartment. Consequently, increased understanding of exosome biogenesis and biology should lead to development of new diagnostic biomarker assays and personalized therapeutic approaches. Here, the evidence on the major biological functions of macrophages and exosomes as pathophysiological effectors of OSA-induced metabolic dysfunction is discussed.

Exosomal Cargo Properties, Endothelial Function and Treatment of Obesity Hypoventilation Syndrome: A Proof of Concept Study.

STUDY OBJECTIVES: Longitudinal studies support the usage of positive airway pressure (PAP) therapy in treating obstructive sleep apnea (OSA) to improve cardiovascular disease. However, the anticipated benefit is not ubiquitous. In this study, we elucidate whether PAP therapy leads to immediate improvements on endothelial function, a subclinical marker of cardiovascular status, by examining the effect of circulating exosomes, isolated from patients before and after PAP therapy, on naive endothelial cells. METHODS: We isolated plasma-derived circulating exosomes from 12 patients with severe OSA and obesity hypoventilation syndrome (OHS) before and after 6 weeks of PAP therapy, and examined their effect on cultured endothelial cells using several in vitro reporter assays. RESULTS: We found that circulating exosomes contributed to the induction and propagation of OSA/OHS-related endothelial dysfunction (ie, increased permeability and disruption of tight junctions along with increased adhesion molecule expression, and reduced endothelial nitric oxide synthase expression), and promoted increased monocyte adherence. Further, when comparing exosomes isolated before and after PAP therapy, the disturbances in endothelial cell function were attenuated with treatment, including an overall cumulative decrease in endothelial permeability in all 12 subjects by 10.8% (P = .035), as well as detection of a subset of 4 differentially expressed exosomal miRNAs, even in the absence of parallel changes in systemic blood pressure or metabolic function. CONCLUSIONS: Circulating exosomes facilitate important intercellular signals that modify endothelial phenotype, and thus emerge as potential fundamental contributors in the context of OSA/OHS-related endothelial dysfunction. Exosomes may not only provide candidate biomarkers, but are also a likely and plausible mechanism toward OSA/OHS-induced cardiovascular disease. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Title: AVAPS-AE Efficacy Study, URL: https://clinicaltrials.gov/ct2/show/NCT01368614, Identifier: NCT01368614.

Circulating exosomes in obstructive sleep apnea as phenotypic biomarkers and mechanistic messengers of end-organ morbidity.

Obstructive sleep apnea (OSA), the most severe form of sleep disordered breathing, is characterized by intermittent hypoxia during sleep (IH), sleep fragmentation, and episodic hypercapnia. OSA is associated with increased risk for morbidity and mortality affecting cardiovascular, metabolic, and neurocognitive systems, and more recently with non-alcoholic fatty liver disease (NAFLD) and cancer-related deaths. Substantial variability in OSA outcomes suggests that genetically-determined and environmental and lifestyle factors affect the phenotypic susceptibility to OSA. Furthermore, OSA and obesity often co-exist and manifest activation of shared molecular end-organ injury mechanisms that if properly identified may represent potential therapeutic targets. A challenge in the development of non-invasive diagnostic assays in body fluids is the ability to identify clinically relevant biomarkers. Circulating extracellular vesicles (EVs) include a heterogeneous population of vesicular structures including exosomes, prostasomes, microvesicles (MVs), ectosomes and oncosomes, and are classified based on their size, shape and membrane surface composition. Of these, exosomes (30-100nm) are very small membrane vesicles derived from multi-vesicular bodies or from the plasma membrane and play important roles in mediating cell-cell communication via cargo that includes lipids, proteins, mRNAs, miRNAs and DNA. We have recently identified a unique cluster of exosomal miRNAs in both humans and rodents exposed to intermittent hypoxia as well as in patients with OSA with divergent morbid phenotypes. Here we summarize such recent findings, and will focus on exosomal miRNAs in both adult and children which mediate intercellular communication relevant to OSA and endothelial dysfunction, and their potential value as diagnostic and prognostic biomarkers.

Nocturnal Oximetry-based Evaluation of Habitually Snoring Children.

RATIONALE: The vast majority of children around the world undergoing adenotonsillectomy for obstructive sleep apnea-hypopnea syndrome (OSA) are not objectively diagnosed by nocturnal polysomnography because of access availability and cost issues. Automated analysis of nocturnal oximetry (nSpO2), which is readily and globally available, could potentially provide a reliable and convenient diagnostic approach for pediatric OSA. METHODS: Deidentified nSpO2 recordings from a total of 4,191 children originating from 13 pediatric sleep laboratories around the world were prospectively evaluated after developing and validating an automated neural network algorithm using an initial set of single-channel nSpO2 recordings from 589 patients referred for suspected OSA. MEASUREMENTS AND MAIN RESULTS: The automatically estimated apnea-hypopnea index (AHI) showed high agreement with AHI from conventional polysomnography (intraclass correlation coefficient, 0.785) when tested in 3,602 additional subjects. Further assessment on the widely used AHI cutoff points of 1, 5, and 10 events/h revealed an incremental diagnostic ability (75.2, 81.7, and 90.2% accuracy; 0.788, 0.854, and 0.913 area under the receiver operating characteristic curve, respectively). CONCLUSIONS: Neural network-based automated analyses of nSpO2 recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.

Angiopoietin-2 and soluble Tie-2 receptor plasma levels in children with obstructive sleep apnea and obesity.

OBJECTIVE: Obstructive sleep apnea (OSA) is a prevalent condition, especially in children with obesity, and is associated with increased risk for metabolic syndrome (MetS). Angiopoietins have been identified as potential biomarkers of endothelial dysfunction and MetS. In adults, angiopoietin-2 (Ang-2) and its soluble receptor (sTie-2) are associated with diabetes, hypertension, and obesity and could be increased in children with OSA and obesity, particularly those with evidence of cardiometabolic alterations. METHODS: One hundred twenty-six children (7.4 ± 2.0 years) were consecutively recruited and underwent overnight polysomnography, as well as endothelial function and BMI z score assessments and a fasting blood draw the morning after the sleep study. In addition to lipid profile, glucose and insulin levels, and homeostatic model assessment of insulin resistance (HOMA-IR), Ang-2 and sTie-2 concentrations were determined. RESULTS: Children with obesity and OSA had significantly elevated plasma Ang-2 and sTie-2 levels compared to corresponding controls with and without obesity. Furthermore, endothelial function (Tmax) and HOMA-IR were linearly and independently associated with Ang-2 and sTie-2 levels. In a small subset of children (n = 14), treatment of OSA by adenotonsillectomy resulted in reductions of Ang-2 and sTie-2 (P < 0.01). CONCLUSIONS: Ang-2 and sTie-2 plasma levels are increased in pediatric OSA and obesity, particularly when endothelial dysfunction or insulin resistance is detectable, and appear to decrease upon OSA treatment.

Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Elevated Lipoprotein-Associated Phospholipase A2 Plasma Activity Levels.

BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent condition, especially in obese children, and has been associated with increased risk for endothelial dysfunction and dislipidemia, which are precursors of atherosclerosis. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is recognized as an independent risk factor for cardiovascular risk and atheromatous plaque activity. We hypothesized that Lp-PLA2 levels would be elevated in children with OSA, particularly among obese children who also manifest evidence of endothelial dysfunction. METHODS AND RESULTS: One hundred sixty children (mean age 7.1±2.3 years), either nonobese with (n=40) and without OSA (n=40) or obese with (n=40) and without OSA (n=40) underwent overnight polysomnographic and postocclusive reperfusion evaluation and a fasting blood draw the morning after the sleep study. In addition to lipid profile, Lp-PLA2 plasma activity was assessed using a commercial kit. Obese children and OSA children had significantly elevated plasma Lp-PLA2 activity levels compared to controls. Furthermore, when both obesity and OSA were concurrently present or when endothelial function was present, Lp-PLA2 activity was higher. Treatment of OSA by adenotonsillectomy resulted in reductions of Lp-PLA2 activity (n=37; P<0.001). CONCLUSIONS: Lp-PLA2 plasma activity is increased in pediatric OSA and obesity, particularly when endothelial dysfunction is present, and exhibits decreases on OSA treatment. The short-term and long-term significance of these findings in relation to cardiovascular risk remain undefined.

Montelukast for Children with Obstructive Sleep Apnea: Results of a Double-Blind, Randomized, Placebo-Controlled Trial.

RATIONALE: Obstructive sleep apnea (OSA) is highly prevalent in children and is usually treated by adenotonsillectomy. Nonsurgical therapies for OSA consist primarily of antiinflammatory approaches and have gained popularity, but their efficacy remains to be critically examined. OBJECTIVES: To determine the effect of montelukast on pediatric OSA. METHODS: A prospective randomized double-blind controlled trial of polysomnographically diagnosed OSA in children ages 2-10 years who were treated with either oral montelukast (4 or 5 mg daily) or placebo for 16 weeks. Adherence to the medication was ascertained using automated timed pill dispensers along with weekly telephonic reminders. MEASUREMENTS AND MAIN RESULTS: Ninety-two children diagnosed with OSA were approached, and 64 (69.6%) agreed to participate. Of these, 57 (89.0%) completed the 16-week trial, 28 in the montelukast group and 29 in the placebo group. Age, sex, and percentage of obesity were similar in the two groups, as were initial apnea-hypopnea index (AHI) scores. Overall, intention-to-treat analyses revealed that beneficial effects occurred in 20 children receiving montelukast (71.4%), whereas only 2 (6.9%) of the children receiving placebo showed reductions in AHI score (P < 0.001). Indeed, AHI decreased from 9.2 ± 4.1/hour total sleep time (TST) to 4.2 ± 2.8/hour TST (P < 0.0001) in montelukast-treated children, whereas in children receiving placebo, the AHI did not change (from 8.2 ± 5.0/h TST before to 8.7 ± 4.9/h TST at completion of the trial). CONCLUSIONS: When compared with placebo, montelukast for 16 weeks effectively reduced the severity of obstructive sleep apnea in children 2-10 years of age. These results support a therapeutic role for leukotriene modifiers in pediatric OSA provided that long-term trials confirm current findings. Clinical trial registered with www.clinicaltrials.gov (NCT 00599534).

Circulating Plasma Extracellular Microvesicle MicroRNA Cargo and Endothelial Dysfunction in Children with Obstructive Sleep Apnea.

RATIONALE: Obese children are at increased risk for developing obstructive sleep apnea (OSA), and both of these conditions are associated with an increased risk for endothelial dysfunction (ED) in children, an early risk factor for atherosclerosis and cardiovascular disease. Although weight loss and treatment of OSA by adenotonsillectomy improve endothelial function, not every obese child or child with OSA develops ED. Exosomes are circulating extracellular vesicles containing functional mRNA and microRNA (miRNA) that can be delivered to other cells, such as endothelial cells. OBJECTIVES: To investigate whether circulating exosomal miRNAs of children with OSA differentiate based on endothelial functional status. METHODS: Obese children (body mass index z score >1.65) and nonobese children were recruited and underwent polysomnographic testing (PSG), and fasting endothelial function measurements and blood draws in the morning after PSG. Plasma exosomes were isolated from all subjects. Isolated exosomes were then incubated with confluent endothelial cell monolayer cultures. Electric cell-substrate impedance sensing systems were used to determine the ability of exosomes to disrupt the intercellular barrier formed by confluent endothelial cells. In addition, immunofluorescent assessments of zonula occludens-1 tight junction protein cellular distribution were conducted to examine endothelial barrier dysfunction. miRNA and mRNA arrays were also applied to exosomes and endothelial cells, and miRNA inhibitors and mimics were transfected for mechanistic assays. MEASUREMENTS AND MAIN RESULTS: Plasma exosomes isolated from either obese children or nonobese children with OSA were primarily derived from endothelial cell sources and recapitulated ED, or its absence, in naive human endothelial cells and also in vivo when injected into mice. Microarrays identified a restricted signature of exosomal miRNAs that readily distinguished ED from normal endothelial function. Among the miRNAs, expression of exosomal miRNA-630 was reduced in children with ED and normalized after therapy along with restoration of endothelial function. Conversely, transfection of exosomes from subjects without ED with an miRNA-630 inhibitor induces the ED functional phenotype. Gene target discovery experiments further revealed that miRNA-630 regulates 416 gene targets in endothelial cells that include the Nrf2, AMP kinase, and tight junction pathways. CONCLUSIONS: These observations elucidate a novel role of exosomal miRNA-360 as a putative key mediator of vascular function and cardiovascular disease risk in children with underlying OSA and/or obesity, and identify therapeutic targets.