Upcoming Scenarios for the Comprehensive Management of Obstructive Sleep Apnea: An Overview of the Spanish Sleep Network.

Sleep is considered an essential part of life and plays a vital role in good health and well-being. Equally important as a balanced diet and adequate exercise, quality and quantity of sleep are essential for maintaining good health and quality of life. Sleep-disordered breathing is one of the most prevalent conditions that compromises the quality and duration of sleep, with obstructive sleep apnea (OSA) being the most prevalent disorder among these conditions. OSA is a chronic and highly prevalent disease that is considered to be a true public health problem. OSA has been associated with increased cardiovascular, neurocognitive, metabolic and overall mortality risks, and its management is a challenge facing the health care system. To establish the main future lines of research in sleep respiratory medicine, the Spanish Sleep Network (SSN) promoted the 1st World Café experts' meeting. The overall vision was established by consensus as "Sleep as promoter of health and the social impact of sleep disturbances". Under this leitmotiv and given that OSA is the most prevalent sleep disorder, five research lines were established to develop a new comprehensive approach for OSA management: (1) an integrated network for the comprehensive management of OSA; (2) the biological impact of OSA on comorbidities with high mortality, namely, cardiovascular and metabolic diseases, neurocognitive diseases and cancer; (3) Big Data Analysis for the identification of OSA phenotypes; (4) personalized medicine in OSA; and (5) OSA in children: current needs and future perspectives.

ERS statement on obstructive sleep disordered breathing in 1- to 23-month-old children.

The present statement was produced by a European Respiratory Society Task Force to summarise the evidence and current practice on the diagnosis and management of obstructive sleep disordered breathing (SDB) in children aged 1-23 months. A systematic literature search was completed and 159 articles were summarised to answer clinically relevant questions. SDB is suspected when symptoms or abnormalities related to upper airway obstruction are identified. Morbidity (pulmonary hypertension, growth delay, behavioural problems) and coexisting conditions (feeding difficulties, recurrent otitis media) may be present. SDB severity is measured objectively, preferably by polysomnography, or alternatively polygraphy or nocturnal oximetry. Children with apparent upper airway obstruction during wakefulness, those with abnormal sleep study in combination with SDB symptoms (e.g. snoring) and/or conditions predisposing to SDB (e.g. mandibular hypoplasia) as well as children with SDB and complex conditions (e.g. Down syndrome, Prader-Willi syndrome) will benefit from treatment. Adenotonsillectomy and continuous positive airway pressure are the most frequently used treatment measures along with interventions targeting specific conditions (e.g. supraglottoplasty for laryngomalacia or nasopharyngeal airway for mandibular hypoplasia). Hence, obstructive SDB in children aged 1-23 months is a multifactorial disorder that requires objective assessment and treatment of all underlying abnormalities that contribute to upper airway obstruction during sleep.

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.

When and why to treat the child who snores?

Obstructive sleep-disordered breathing (SDB) can result in cardiovascular and neurocognitive morbidity as well as adversely affect behavior, growth, quality of life, and nocturnal continence. This article summarizes the latest evidence regarding the morbidity related to obstructive SDB, commenting on the impact of severity of obstruction, that is, the difference in effects seen of moderate to severe obstructive sleep apnea syndrome (OSAS) compared to those of mild OSAS or primary snoring. The impact of therapy is discussed, focusing on which children are likely to benefit from treatment interventions; namely those with moderate or severe OSAS irrespective of the presence of morbidity, children with mild OSAS with associated morbidity or predictors of SDB persistence such as obesity, and children with complex conditions accompanied by upper airway obstruction like craniosynostosis and Prader-Willi syndrome. The co-existing conditions which may improve when treatment for obstructive SDB is offered are reviewed, while the clinical parameters associated with spontaneous improvement or resolution of obstructive SDB are discussed. The intention being to enable clinicians to make informed decisions on who should be treated, when and why. Pediatr Pulmonol. 2017;52:399-412. © 2016 Wiley Periodicals, Inc.

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.

Biomarkers of Alzheimer Disease in Children with Obstructive Sleep Apnea: Effect of Adenotonsillectomy.

STUDY OBJECTIVE: Obese children are at increased risk for developing obstructive sleep apnea (OSA), and both of these conditions are associated with an increased risk for end-organ morbidities. Both OSA and obesity (OB) have been associated with increased risk for Alzheimer disease (AD). This study aimed to assess whether OSA and OB lead to increased plasma levels of 2 AD markers amyloid ß protein 42 (Aß42) and pre-senilin 1 (PS1). METHODS: Fasting morning plasma samples from otherwise healthy children with a diagnosis of OB, OSA, or both (OSA+OB), and controls, and in a subset of children with OSA after adenotonsillectomy (T&A) were assayed for Aß42 and PS1 levels using commercial enzyme-linked immunosorbent assay kits. RESULTS: 286 children (mean age of 7.2 ± 2.7 y) were evaluated. Compared to control subjects, OB children had similar Aß42 (108.3 ± 31.7 pg/mL versus 83.6 ± 14.6 pg/mL) and PS1 levels (0.89 ± 0.44 ng/mL versus 0.80 ± 0.29 pg/mL). However, OSA children (Aß42: 186.2 ± 66.7 pg/mL; P < 0.001; PS1: 3.42 ± 1.46 ng/mL; P < 0.001), and particularly OSA+OB children had significant elevations in both Aß42 (349.4 ± 112.9 pg/mL; P < 0.001) and PS1 (PS1: 4.54 ± 1.16 ng/mL; P < 0.001) circulating concentrations. In a subset of 24 children, T&A resulted in significant reductions of Aß42 (352.0 ± 145.2 versus 151.9 ± 81.4 pg/mL; P < 0.0001) and PS1 (4.82 ± 1.09 versus 2.02 ± 1.18 ng/mL; P < 0.0001). CONCLUSIONS: Thus, OSA, and particularly OSA+OB, are associated with increased plasma levels of AD biomarkers, which decline upon treatment of OSA in a representative, yet not all- encompassing subset of patients, suggesting that OSA may accelerate AD-related processes even in early childhood. However, the cognitive and overall health-related implications of these findings remain to be defined.

Obstructive sleep disordered breathing in 2- to 18-year-old children: diagnosis and management.

This document summarises the conclusions of a European Respiratory Society Task Force on the diagnosis and management of obstructive sleep disordered breathing (SDB) in childhood and refers to children aged 2-18 years. Prospective cohort studies describing the natural history of SDB or randomised, double-blind, placebo-controlled trials regarding its management are scarce. Selected evidence (362 articles) can be consolidated into seven management steps. SDB is suspected when symptoms or abnormalities related to upper airway obstruction are present (step 1). Central nervous or cardiovascular system morbidity, growth failure or enuresis and predictors of SDB persistence in the long-term are recognised (steps 2 and 3), and SDB severity is determined objectively preferably using polysomnography (step 4). Children with an apnoea-hypopnoea index (AHI) >5 episodes·h(-1), those with an AHI of 1-5 episodes·h(-1) and the presence of morbidity or factors predicting SDB persistence, and children with complex conditions (e.g. Down syndrome and Prader-Willi syndrome) all appear to benefit from treatment (step 5). Treatment interventions are usually implemented in a stepwise fashion addressing all abnormalities that predispose to SDB (step 6) with re-evaluation after each intervention to detect residual disease and to determine the need for additional treatment (step 7).

Evaluation of circulating markers of hepatic apoptosis and inflammation in obese children with and without obstructive sleep apnea.

OBJECTIVE: Hepatocyte apoptosis and macrophage activation contribute to the disease progression of nonalcoholic fatty liver disease (NAFLD). Obstructive sleep apnea (OSA) in obese children is associated with the severity of NAFLD. The aim of this study was to evaluate plasma levels of soluble Fas (sFas), soluble Fas ligand (sFasL), cytokeratin 18 (CK18) (markers of apoptosis), and soluble CD163 (sCD163) (marker of macrophage activation) in obese children with and without OSA. METHODS: Consecutive obese children who were evaluated for OSA were recruited. The diagnosis of OSA was made using overnight polysomnography (PSG). Fasting blood samples were used to determine plasma CK18, sFas, sFasL, and sCD163 levels using specific sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: Fifty-eight subjects were included in the analysis with a mean age of 8.9 ± 3.2 years and a mean body mass index (BMI) z-score of 2.4 ± 0.49. Circulating sFas and sFasL levels were significantly lower in subjects with mild and severe OSA compared with those without OSA (p < 0.005 for both). In addition, sCD163 levels increased with an increasing severity of OSA (no OSA = 1.6 ± 0.25 mg/L, mild OSA = 2.3 ± 0.45, and severe OSA = 3.0 ± 0.52; p < 0.001), and they correlated with the apnea-hypopnea index (AHI) [rho (95% confidence interval, CI) of 0.71 (0.41, 1.00), p-value <0.001]. In six patients with severe OSA from whom samples were taken before and after tonsillectomy, the sCD163 level decreased significantly after treatment, and there was a trend toward an increase in sFasL. CONCLUSION: Markers of apoptosis and macrophage activation are altered in obese children with OSA, indicating increased apoptotic and inflammatory pressures.

Treatment outcomes of obstructive sleep apnoea in obese community-dwelling children: the NANOS study.

The first line of treatment of obstructive sleep apnoea syndrome (OSAS) in children consists of adenotonsillectomy (T&A). The aim of the present study was to evaluate treatment outcomes of OSAS among obese children recruited from the community.A cross-sectional, prospective, multicentre study of Spanish obese children aged 3-14 years, with four groups available for follow-up: group 1: non-OSAS with no treatment; group 2: dietary treatment; group 3: surgical treatment; and group 4: continuous positive airway pressure treatment.117 obese children (60 boys, 57 girls) with a mean age of 11.3±2.9 years completed the initial (T0) and follow-up (T1) assessments. Their mean body mass index (BMI) at T1 was 27.6±4.7 kg·m(-2), corresponding to a BMI Z-score of 1.34±0.59. Mean respiratory disturbance index (RDI) at follow-up was 3.3±3.9 events·h(-1). Among group 1 children, 21.2% had an RDI ≥3 events·h(-1) at T1, the latter being present in 50% of group 2, and 43.5% in group 3. In the binary logistic regression model, age emerged as a significant risk factor for residual OSAS (odds ratio 1.49, 95% confidence interval 1.01-2.23; p<0.05) in obese children surgically treated, and RDI at T0 as well as an increase in BMI emerged as significant risk factors for persistent OSAS in obese children with dietary treatment (OR 1.82, 95% CI 1.09-3.02 (p<0.03) and OR 8.71, 95% CI 1.24-61.17 (p=0.03)).Age, RDI at diagnosis and obesity are risk factors for relatively unfavourable OSAS treatment outcomes at follow-up.

Inflammatory markers and obstructive sleep apnea in obese children: the NANOS study.

INTRODUCTION: Obesity and obstructive sleep apnea syndrome (OSA) are common coexisting conditions associated with a chronic low-grade inflammatory state underlying some of the cognitive, metabolic, and cardiovascular morbidities. AIM: To examine the levels of inflammatory markers in obese community-dwelling children with OSA, as compared to no-OSA, and their association with clinical and polysomnographic (PSG) variables. Methods. In this cross-sectional, prospective multicenter study, healthy obese Spanish children (ages 4-15 years) were randomly selected and underwent nocturnal PSG followed by a morning fasting blood draw. Plasma samples were assayed for multiple inflammatory markers. RESULTS: 204 children were enrolled in the study; 75 had OSA, defined by an obstructive respiratory disturbance index (RDI) of 3 events/hour total sleep time (TST). BMI, gender, and age were similar in OSA and no-OSA children. Monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in OSA children, with interleukin-6 concentrations being higher in moderate-severe OSA (i.e., AHI > 5/hrTST; P < 0.01), while MCP-1 levels were associated with more prolonged nocturnal hypercapnia (P < 0.001). CONCLUSION: IL-6, MCP-1, and PAI-1 are altered in the context of OSA among community-based obese children further reinforcing the proinflammatory effects of sleep disorders such as OSA. This trial is registered with ClinicalTrials.gov NCT01322763.

Obstructive sleep apnea in obese community-dwelling children: the NANOS study.

INTRODUCTION: Obesity in children is assumed to serve as a major risk factor in pediatric obstructive sleep apnea syndrome (OSAS). However, the prevalence of OSAS in otherwise healthy obese children from the community is unknown. AIM: To determine the prevalence of OSAS in obese children identified and recruited from primary care centers. METHODS: A cross-sectional, prospective, multicenter study. Spanish children ages 3-14 y with a body mass index (BMI) greater than or equal to the 95th percentile for age and sex were randomly selected, and underwent medical history, snoring, and Pediatric Sleep Questionnaire (PSQ) assessments, as well as physical examination, nasopharyngoscopy, and nocturnal polysomnography (NPSG) recordings. RESULTS: Two hundred forty-eight children (54.4% males) with mean age of 10.8 ± 2.6 y were studied with a BMI of 28.0 ± 4.7 kg/m(2) corresponding to 96.8 ± 0.6 percentile when adjusted for age and sex. The mean respiratory disturbance index (RDI), obstructive RDI (ORDI), and obstructive apnea-hypopnea index (OAHI) were 5.58 ± 9.90, 5.06 ± 9.57, and 3.39 ± 8.78/h total sleep time (TST), respectively. Using ≥ 3/h TST as the cutoff for the presence of OSAS, the prevalence of OSAS ranged from 21.5% to 39.5% depending on whether OAHI, ORDI, or RDI were used. CONCLUSIONS: The prevalence of obstructive sleep apnea syndrome (OSAS) in obese children from the general population is high. Obese children should be screened for the presence of OSAS. ClinicalTrials.gov identifier: NCT01322763.

Respiratory polygraphy for follow-up of obstructive sleep apnea in children.

OBJECTIVES: (1) To evaluate the effectiveness of adenotonsillectomy for the treatment of Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) in children. (2) To evaluate the usefulness of respiratory polygraphy (RP) for controlling post-adenotonsillectomy effects. METHODS: The children studied were referred to the Burgos Sleep Unit (SU) with clinical suspicion of OSAHS before undergoing adenotonsillectomy. For all patients, a clinical history was taken and a general physical examination, as well as a specific ear, nose, and throat examination was done. RP before adenotonsillectomy, and seven months afterwards, was also done. OSAHS was diagnosed if the Apnea Hypopnea Index (AHI) was ≥ 4.6. RESULTS: Of the 100 children studied, 68 were male and 32 female, with an age of 4.17 ± 2.05 years. Using RP, 86 of them were diagnosed with OSAHS before undergoing adenotonsillectomy. There was a significant improvement in all clinical and polygraphic variables after adenotonsillectomy. The pre and post surgery AHI index was 11.9 ± 11.0 and 2.6 ± 1.5, respectively, with a significant mean difference (9.4 ± 10.9, p<0.01). The residual OSAHS was 11.6% (CI 95%: 4.3-19%). CONCLUSIONS: Respiratory polygraphy is a useful tool for monitoring the effectiveness of surgical treatment and the detection of residual OSAHS in children with adenotonsillar hypertrophy.