Ehab Dayyat

Pediatric Obstructive Sleep Apnea: Complications, Management, and Long-term Outcomes

Obstructive sleep apnea (OSA) in children has emerged not only as a relatively prevalent condition but also as a disease that imposes a large array of morbidities, some of which may have long-term implications, well into adulthood. The major consequences of pediatric OSA involve neurobehavioral, cardiovascular, and endocrine and metabolic systems. The underlying pathophysiological mechanisms of OSA-induced end-organ injury are now being unraveled, and clearly involve oxidative and inflammatory pathways. However, the roles of individual susceptibility (as dictated by single-nucleotide polymorphisms), and of environmental and lifestyle conditions (such as diet, physical, and intellectual activity), may account for a substantial component of the variance in phenotype. Moreover, the clinical prototypic pediatric patient of the early 1990s has been insidiously replaced by a different phenotypic presentation that strikingly resembles that of adults afflicted by the disease. As such, analogous to diabetes, the terms type I and type II pediatric OSA have been proposed. The different manifestations of these two entities and their clinical course and approaches to management are reviewed.

Obstructive Sleep Apnea and Endothelial Function in School-Aged Nonobese Children Effect of Adenotonsillectomy

Background— Obstructive sleep apnea (OSA) in children is associated with cardiovascular morbidity such as systemic and pulmonary hypertension. However, it remains unclear whether endothelial dysfunction occurs in pediatric OSA and whether it is reversible on effective treatment of OSA. Methods and Results— Consecutive nonobese children (aged 6 to 11 years) who were diagnosed with OSA after overnight polysomnography and control children matched on the basis of age, gender, ethnicity, and body mass index underwent blood draw the next morning for soluble CD40 ligand, asymmetric dimethylarginine (ADMA), and nitrotyrosine levels, as well as 2 iterations of 60-second cuff-occlusion tests for assessment of endothelial function. These tests were repeated 4 to 6 months after adenotonsillectomy. OSA children showed blunted reperfusion kinetics after release of occlusion, which completely normalized in 20 of 26 patients after adenotonsillectomy. All 6 children in whom no improvements occurred had a strong family history of cardiovascular disease (versus 2 of the remaining 20 patients; P<0.04). Plasma nitrotyrosine and ADMA levels were similar in OSA and control children; however, soluble CD40 ligand levels were higher in OSA children and were reduced after treatment, particularly in those with normalized hyperemic responses. Conclusions— Postocclusive hyperemia is consistently blunted in children with OSA, and such altered endothelial function is reversible 4 to 6 months after treatment, particularly if a family history of cardiovascular disease is not present. Although no evidence for either nitric oxide–dependent oxidative/nitrosative stress or for the increased presence of the circulating nitric oxide synthase inhibitor ADMA was found in children with OSA, soluble CD40 ligand levels were increased in OSA and reflected the changes in endothelial function after treatment.

Obstructive Sleep Apnea in Children: Relative Contributions of Body Mass Index and Adenotonsillar Hypertrophy

BACKGROUND The obesity epidemic has prompted remarkable changes in the proportion of obese children who are referred for habitual snoring. However, the contribution of obesity to adenotonsillar hypertrophy remains undefined. METHODS In our study, 206 nonobese habitually snoring children with polysomnographically diagnosed obstructive sleep apnea (OSA) were matched for age, gender, ethnicity, and obstructive apnea-hypopnea index (OAHI) to 206 obese children. Size estimates of tonsils and adenoids, and Mallampati class scores were obtained, and allowed for the assessment of potential relationships between anatomic factors and obesity in pediatric OSA. RESULTS The mean OAHI for the two groups was approximately 10.0 episodes/h total sleep time. There was a modest association between adenotonsillar size and OAHI in nonobese children (r = 0.22; p < 0.001) but not in obese children. The mean (+/- SEM) adenotonsillar size was larger in nonobese children (3.85 +/- 0.16 vs 3.01 +/- 0.14, respectively; p < 0.0001), and conversely Mallampati class scores were significantly higher in obese children (p < 0.0001). CONCLUSION The magnitude of adenotonsillar hypertrophy required for any given magnitude of OAHI is more likely to be smaller in obese children compared to nonobese children. Increased Mallampati scores in obese children suggest that soft-tissue changes and potentially fat deposition in the upper airway may play a significant role in the global differences in tonsillar and adenoidal size among obese and nonobese children with OSA.

Leukotriene Pathways and In Vitro Adenotonsillar Cell Proliferation in Children With Obstructive Sleep Apnea

INTRODUCTION The abundant expression of leukotrienes (LTs) and their receptors in adenotonsillar tissues of children with obstructive sleep apnea (OSA) suggest that LT antagonists could be useful in treating OSA. METHODS The effects of LTD4 and of LT receptor antagonists zileuton, montelukast, and BAY u9773 were examined on mixed cell cultures prepared from dissociated tonsils or adenoids harvested intraoperatively from children with polysomnographically diagnosed OSA. Proliferation was assessed by (3)[H]-thymidine incorporation, and inflammatory cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, IL-8, IL-10, and IL-12) was assessed in supernatants using enzyme-linked immunosorbent assay. RESULTS LTD4 elicited dose-dependent increases in adenotonsillar cell proliferation (p < 0.001; n = 12). All LT antagonists exhibited dose-dependent reductions in adenotonsillar cellular proliferation rates, with montelukast more than BAY u9773 more than zileuton (n = 14/group; p < 0.001). However, BAY u9773 showed partial agonist effects and increased cellular proliferation at higher concentrations (10(-4) mmol/L; p < 0.01; n = 12). LTD4 effects were partially blocked by montelukast and BAY u9773 but not by zileuton. All three antagonists reduced TNF-alpha, IL-6, and IL-12 concentrations, with selective changes in IL-8 and no effects on IL-10 levels. CONCLUSIONS LT pathways mediate intrinsic proliferative and inflammatory signaling pathways in adenotonsillar tissues from children with OSA, and targeted pharmacologic disruption of these pathways may provide nonsurgical alternatives for prevention and treatment of this disease.

Obstructive Sleep Apnea in Poorly Controlled Asthmatic Children: Effect of Adenotonsillectomy

Asthma and obstructive sleep apnea (OSA) in children share multiple epidemiological risk factors and the prevalence of snoring is higher in asthmatic children, suggesting that the latter may be at increased risk for OSA. Since both asthma and OSA are inflammatory disorders, we hypothesized that polysomnographically demonstrated OSA would be more frequent among poorly controlled asthmatics (PCA), and that treatment of OSA, if present, would ameliorate the frequency of acute asthmatic exacerbations (AAE).

Increased Cellular Proliferation and Inflammatory Cytokines in Tonsils Derived From Children With Obstructive Sleep Apnea

Adenotonsillar hypertrophy is the major pathophysiological mechanism underlying obstructive sleep apnea (OSA) and recurrent tonsillitis (RI) in children. The increased expression of various mediators of the inflammatory response in tonsils of patients with OSA prompted our hypothesis that the enhanced local and systemic inflammation in children with OSA would promote tonsillar proliferation. Mixed cell cultures from tonsils recovered during adenotonsillectomy in children with OSA and RI were established, and proliferative rates were assessed. Cells were also cultured to determine the levels of proinflammatory cytokines and antioxidant protein levels and mRNA expression. Global cell proliferative rates from OSA tonsils were significantly higher than RI (p < 0.01), with CD3+, CD4+, and CD8+ cell proliferation being higher in OSA (p < 0.05). Moreover, proinflammatory cytokines, such as TNF-α, IL-6, and IL-1α, were highly expressed in OSA-derived tonsils. Furthermore, thioredoxin (TRX), an antioxidant protein, was also highly expressed in OSA tonsils at the mRNA and protein levels (p < 0.01). Thus, T cells are in a highly proliferative state in the tonsils of children with OSA and are associated with increased production of proinflammatory cytokines and TRX, when compared with children with RI.

Green Tea Catechin Polyphenols Attenuate Behavioral and Oxidative Responses to Intermittent Hypoxia

RATIONALE The intermittent hypoxia (IH) that characterizes sleep-disordered breathing impairs spatial learning and increases NADPH oxidase activity and oxidative stress in rodents. We hypothesized that green tea catechin polyphenols (GTPs) may attenuate IH-induced neurobehavioral deficits by reducing IH-induced NADPH oxidase expression, lipid peroxidation, and inflammation. OBJECTIVES To assess the effects of GTP administered in drinking water on the cognitive, inflammatory, and oxidative responses to long-term (>14 d) IH during sleep in male Sprague-Dawley rats. METHODS Cognitive assessments were conducted in the Morris water maze. We measured levels and expression of malondialdehyde (MDA), prostaglandin E(2), p47(phox) subunit of NADPH oxidase, receptor for advanced glycation end products (RAGE), and glial fibrillary acidic protein expression in rodent brain tissue. MEASUREMENTS AND MAIN RESULTS GTP treatment prevented IH-induced decreases in spatial bias for the hidden platform during the Morris water maze probe trails as well as IH-induced increases in p47phox expression within the hippocampal CA1 region. In untreated animals, IH exposure was associated with doubling of cortical MDA levels in comparison to room air control animals, and GTP-treated animals exposed to IH showed a 40% reduction in MDA levels. Increases in brain RAGE and glial fibrillary acidic protein expression were observed in IH-exposed animals, and these increases were attenuated in animals treated with GTP. CONCLUSIONS Oral GTP attenuates IH-induced spatial learning deficits and mitigates IH-induced oxidative stress through multiple beneficial effects on oxidant pathways. Because oxidative processes underlie neurocognitive deficits associated with IH, the potential therapeutic role of GTP in sleep-disordered breathing deserves further exploration.

Sleep Assessments In Healthy School-Aged Children Using Actigraphy: Concordance with Polysomnography

Actigraphic (ACT) recordings are used widely in schoolchildren as a less intrusive and more extended approach to evaluation of sleep problems. However, critical assessment of the validity and reliability of ACT against overnight polysomnography (NPSG) are unavailable. Thus, we explored the degree of concordance between NPSG and ACT in school‐aged children to delineate potential ACT boundaries when interpreting pediatric sleep. Non‐dominant wrist ACT was recorded simultaneously with NPSG in 149 healthy school‐aged children (aged 4.1–8.8 years, 41.7% boys, 80.4% Caucasian) recruited from the community. Analyses were limited to the Actiware (MiniMitter‐64) calculated parameters originating from 1‐min epoch sampling and medium sensitivity threshold value of 40; i.e. sleep period time (SPT), total sleep time (TST) and wake after sleep onset (WASO). SPT was not significantly different between ACT and NPSG. However, ACT underestimated TST significantly by 32.2 ± 33.4 min and overestimated WASO by 26.3 ± 34.4 min. The decreased precision of ACT was also evident from moderate to small concordance correlation coefficients (0.47 for TST and 0.09 for WASO). ACT in school‐aged children provides reliable assessment of sleep quantity, but is relatively inaccurate during determination of sleep quality. Thus, caution is advocated in drawing definitive conclusions from ACT during evaluation of the sleep‐disturbed child.

Stress, Coping, and Circadian Disruption Among Women Awaiting Breast Cancer Surgery

BackgroundPsychological distress and coping related to a breast cancer diagnosis can profoundly affect psychological adjustment, possibly resulting in the disruption of circadian rest/activity and cortisol rhythms, which are prognostic for early mortality in metastatic colorectal and breast cancers, respectively.PurposeThis study aims to explore the relationships of cancer-specific distress and avoidant coping with rest/activity and cortisol rhythm disruption in the period between diagnosis and breast cancer surgery.MethodsFifty-seven presurgical breast cancer patients provided daily self-reports of cancer-specific distress and avoidant coping as well as actigraphic and salivary cortisol data.ResultsDistress and avoidant coping were related to rest/activity rhythm disruption (daytime sedentariness, inconsistent rhythms). Patients with disrupted rest/activity cycles had flattened diurnal cortisol rhythms.ConclusionsMaladaptive psychological responses to breast cancer diagnosis were associated with disruption of circadian rest/activity rhythms. Given that circadian cycles regulate tumor growth, we need greater understanding of possible psychosocial effects in cancer-related circadian disruption.

Transcriptomic Analysis Identifies Phosphatases as Novel Targets for Adenotonsillar Hypertrophy of Pediatric Obstructive Sleep Apnea

RATIONALE Obstructive sleep apnea (OSA) is a highly prevalent disorder in children, in which enlarged adenotonsillar tissues (AT) play a major pathophysiologic role. Mechanisms leading to the proliferation and hypertrophy of AT in children who subsequently develop OSA remain unknown, and surgical extirpation of AT is associated with potential morbidity and mortality. OBJECTIVES We hypothesized that a computationally based analysis of gene expression in tonsils from children with OSA and children with recurrent tonsillitis without OSA can identify putative mechanistic pathways associated with tonsillar proliferation and hypertrophy in OSA. METHODS Palatine tonsils from children with either polysomnographically documented OSA or recurrent infectious tonsillitis were subjected to whole-genome microarray and functional enrichment analyses followed by significance score ranking based on gene interaction networks. The latter enabled identification and confirmation of a candidate list of tonsil-proliferative genes in OSA. MEASUREMENTS AND MAIN RESULTS In vitro studies using a mixed tonsil cell culture system targeting one of these candidates, phosphoserine phosphatase, revealed that it was more abundantly expressed in tonsils of children with OSA, and that pharmacological inhibition of phosphoserine phosphatase led to marked reductions in T- and B-lymphocyte cell proliferation and increased apoptosis. CONCLUSIONS A systems biology approach revealed a restricted set of candidate genes potentially underlying the heightened proliferative properties of AT in children with OSA. Furthermore, functional studies confirm a novel role for protein phosphatases in AT hypertrophy, and may provide a promising strategy for discovery of novel, nonsurgical therapeutic targets in pediatric OSA.