Pathogenetic Mechanisms of Adenotonsillar Hypertrophy in Children with Sleep Disordered Breathing

Objectives:1)To assess the hypothesis that levels of inflammatory and oxidative stress markers in the exhaled breath condensate of children with OSA are higher than those of control subjects, as well as their relationship with OSA severity.2)To evaluate the role of endogenous glucocorticoid levels in the pathogenesis of tonsillar hypertrophy in children with OSA.Material:1)Phase A: Twelve children with moderate- to- severe OSA (mean age ± SD: 6.3 ± 1.7 years, AHI: 13.6 ± 10.1 episodes/ hour), 22 children with mild OSA (6.7± 2.1 years, AHI 2.8 ± 1 episodes/ hour) and 16 control children (7.7 ± 2.4 years, ΑΗΙ: 0.6 ± 0.3 episodes/ hour).2)Phase B: Seventy children (2-13 y.o.) were recruited: 30 with moderate-to-severe OSA (apnea-hypopnea index-AHI >5 episodes/h), 26 with mild OSA (AHI > 1 and ≤ 5) and 14 controls (no snoring, with various sleep problems; AHI ≤ 1). Methods:1)Morning levels of hydrogen peroxide (H2O2) and sum of nitrite and nitrate (NOx) were measured in the exhaled breath condensate (EBC) of children with symptoms of SDB and of controls with sleep problems without history of habitual snoring who underwent overnight polysomnography and were expressed in μΜ.2) Children with and without snoring underwent polysomnography, tonsillar size grading and measurement of morning serum cortisol.Results:1)Children with moderate-to severe OSA had higher log-transformed H2O2 concentrations in EBC compared to subjects with mild OSA, or to control participants: 0.4 ± 1.1 versus -0.9 ± 1.3 (p=0.015), or versus -1.2 ± 1.2 (p=0.003), respectively. AHI and % sleep time with oxygen saturation of hemoglobin 5 επεισόδια/ώρα), 26 με ήπιο ΣΑΑΥ (AHI > 1 και ≤ 5 επεισόδια/ώρα) και 14 μάρτυρες (χωρίς ροχαλητό: AHI ≤ 1 επεισόδιο/ώρα). Μέθοδος:1)Μετρήθηκαν οι συγκεντρώσεις υπεροξειδίου του υδρογόνου (Η2Ο2) και αθροίσματος νιτρωδών και νιτρικών (ΝΟx) σε πρωινό δείγμα ΣΕΑ που ελήφθη από παιδιά με συμπτώματα ΑΔΑΥ και μάρτυρες με διαταραχές ύπνου χωρίς ροχαλητό που υποβλήθηκαν σε νυχτερινή πολυκαταγραφική μελέτη, εκφραζόμενες σε μΜ.2)Παιδιά χωρίς και με ροχαλητό υπεβλήθηκαν σε πολυκαταγραφική μελέτη, αξιολόγηση του μεγέθους των αμυγδαλών και μέτρηση επιπέδων κορτιζόλης σε δείγμα πρωινού ορού.Αποτελέσματα:1)Τα παιδιά με μέτριο προς σοβαρό ΣΑΑΥ παρουσίαζαν υψηλότερες τιμές Η2Ο2 στο ΣΕΑ μετά λογαριθμική μετατροπή σε σχέση με τα παιδιά με ήπια ΑΑΥ ή τους μάρτυρες: 0.4 ± 1.1 έναντι -0.9 ± 1,3 (p=0.015), ή έναντι -1.2 ± 1.2 (p=0.003), αντίστοιχα. Ο δείκτης απνοιών-υποπνοιών (ΑΗΙ) και ο ελάχιστος κορεσμός της αιμοσφαιρίνης ήταν σημαντικοί προγνωστικοί παράγοντες των τιμών Η2Ο2 μετά τη στατιστική διόρθωση για την ηλικία και το ΒΜΙ z- score (p< 0.05). Δε διαπιστώθηκαν σημαντικές διαφορές μεταξύ των τριών ομάδων της μελέτης ως προς τα επίπεδα ΝΟx στο ΣΕΑ.2)Υπερτροφία αμυγδαλών διαπιστώθηκε στο 56.7%, 53.8% και 42.9% των συμμετεχόντων σε κάθε ομάδα αντίστοιχα. Η εφαρμογή γραμμικού μοντέλου ανέδειξε ότι η αλληλεπίδραση μεταξύ βαρύτητας του ΣΑΑΥ και αμυγδαλικής υπερτροφίας επηρεάζει σημαντικά τα επίπεδα κορτιζόλης ορού (p=0.04), μετά από διόρθωση για την παχυσαρκία, το φύλο και την ηλικία. Μεταξύ των παιδιών με υπερτροφία αμυγδαλών, τα άτομα με μέτριο- σοβαρό ΣΑΑΥ (n=17, AHI 14.7 ± 10.6 ), ήπιο ΣΑΑΥ (n=14; AHI 2.3 ± 1.2) και οι υγιείς μάρτυρες (n=6; AHI 0.7 ± 0.2) διέφεραν στατιστικά σημαντικά ως προς τα επίπεδα κορτιζόλης (p=0.02). Τα παιδιά με μέτριο- σοβαρό ΣΑΑΥ είχαν χαμηλότερη κορτιζόλη (16.9 ± 8.7 mcg/dL) από ότι αυτά με ήπιο ΣΑΑΥ (23.3 ± 4.2 mcg/dL, p=0.01) ή τους μάρτυρες χωρίς ΣΑΑΥ (23.6 ± 5.3 mcg/dL, p=0.04). Αντίθετα, παιδιά με αμυγδαλές φυσιολογικού μεγέθους και μέτριο- σοβαρό ΣΑΑΥ, ήπιο ΣΑΑΥ ή μάρτυρες δε διέφεραν ως προς τα επίπεδα κορτιζόλης.Συμπεράσματα:1)Παιδιά με μέτρια προς σοβαρή ΑΑΥ παρουσιάζουν αυξημένα επίπεδα Η2Ο2 σε πρωινό δείγμα ΣΕΑ και αυτό αποτελεί έμμεσο δείκτη επικράτησης των οξειδωτικών έναντι των αντιοξειδωτικών συστημάτων στον αεραγωγό.2)Παιδιά με μέτριο- σοβαρό ΣΑΑΥ και φαινότυπο υπερτροφικών αμυγδαλών έχουν χαμηλά επίπεδα πρωινής κορτιζόλης ορού και πιθανώς μειωμένη ανασταλτική επίδραση των γλυκοκορτικοειδών στον αύξηση των αμυγδαλώ

Interactions of Obstructive Sleep-Disordered Breathing With Recurrent Wheezing or Asthma and Their Effects on Sleep Quality

Snoring is the most characteristic symptom of obstructive sleep-disordered breathing ( SDB) and recurrent wheezing is the most common clinical manifestation of asthma. The purpose of the present review is to outline the impact of SDB and recurrent wheezing/ asthma on sleep quality and to summarize the epidemiologic and pathophysiologic evidence supporting an association between the two disorders. Enlarged tonsils and adenoid or obesity predispose to obstructive sleep apneas and hypopneas which are accompanied by arousals, restless sleep, and frequently daytime sleepiness, inattention, hyperactivity, and academic difficulties. Subjects with history of wheezing are also at risk for sleep disturbance and daytime cognitive dysfunction. Asthmatic children have more frequent snoring, apneas, and hypopneas during sleep than non-asthmatic subjects and tonsillar hypertrophy mediates at least in part this epidemiologic association. In addition, preliminary evidence indicates that treatment of sleep apnea with adenotonsillectomy results in improved control of coexisting asthma. Elevated concentrations of leukotrienes and oxidative stress markers have been detected in the exhaled breath condensate of children with asthma and probably contribute to bronchoconstriction. Moreover, sleep apneic children have increased expression of leukotrienes and leukotriene receptors in adenotonsillar tissue. Viral respiratory infections may induce inflammation and oxidative stress in the asthmatic airway enhancing not only bronchospasm, but also biosynthesis of leukotrienes within pharyngeal lymphoid tissues, which promote adenotonsillar enlargement and sleep apnea. In conclusion, taking under consideration the epidemiologic association between obstructive SDB and asthma, when one of the two disorders is diagnosed, the possibility of the other disease being present should be entertained. Pediatr Pulmonol. 2011; 46:1047-1054. (C) 2011 Wiley Periodicals, Inc

Infants with viral bronchiolitis demonstrate two distinct patterns of nocturnal oxyhaemoglobin desaturation

AimThis study aimed to demonstrate that viral bronchiolitis is associated with intermittent oxygen saturation of haemoglobin (SpO(2)) drops (3%) and low basal SpO(2) between episodes of haemoglobin desaturation. MethodsInfants with bronchiolitis underwent pulse oximetry during the first night following hospital admission and a subgroup of them underwent repeat oximetry before hospital discharge. Oximetry was also performed in infants with partial upper airway obstruction (UAO) and without lung disease and in control participants without UAO or lung disease. ResultsWe enrolled 53 infants: 21 with bronchiolitis, 11 with UAO and 21 healthy controls. Participants with bronchiolitis had lower basal SpO(2) (median 93.7% [10th-90th percentiles: 91.1-96.8]) than the subjects with UAO (96.9% [95.3-98.1]; p&lt;0.01) or the controls (98.7% [96.9-99.3]; p&lt;0.01). The bronchiolitis group was not different from the UAO group regarding the desaturation index (23.3 episodes/hour [10.3-46.6] and 15.5 episodes/hour [5.4-36.4], respectively; p=0.08), but differed significantly from the controls (3.1 episodes/hour [0.3-5.5]; p&lt;0.01). The basal SpO(2) and desaturation index improved in 10 subjects with bronchiolitis who had follow-up oximetry before discharge, but these indices remained abnormal when compared to values in the control group. ConclusionBronchiolitis was characterised by low nocturnal basal SpO(2) and intermittent SpO(2) drops

Viral Croup: Diagnosis and a Treatment Algorithm

Viral croup is a frequent disease in early childhood. Although it is usually self-limited, it may occasionally become life-threatening. Mild croup is characterized by the presence of stridor without intercostal retractions, whereas moderate-to-severe croup is accompanied by increased work of breathing. A single dose of orally administered dexamethasone (0.15-0.6mg/kg) is the mainstay of treatment with addition of nebulized epinephrine only in cases of moderate-to-severe croup. Nebulized budesonide (2mg) can be given alternatively to children who do not tolerate oral dexamethasone. Exposure to cold air or administration of cool mist are treatment interventions for viral croup that are not supported by published evidence, but breathing heliox can potentially reduce the work of breathing related to upper airway obstruction. In summary, corticosteroids may decrease the intensity of viral croup symptoms irrespective to their severity on presentation to the emergency department. Pediatr Pulmonol. 2014; 49:421-429. (c) 2013 Wiley Periodicals, Inc

Family History of Adenotonsillectomy as a Risk Factor for Tonsillar Hypertrophy and Snoring in Childhood

ObjectiveAccumulating evidence supports a role for familial predisposition in the pathogenesis of OSA. In this study, it was hypothesized that parental history of adenoidectomy and/or tonsillectomy (AT), which is the standard treatment for pediatric OSA is a risk factor for tonsillar hypertrophy and habitual snoring (&gt;3 nights/week) in the offspring. MethodsChildren were recruited from the emergency department and the pediatric pulmonology clinic. Paternal or maternal history of AT (explanatory variables) and habitual snoring (outcome) were recorded and presence of tonsillar hypertrophy (outcome) was assessed. ResultsTwo hundred ninety-two children (2-14 y.o.) were recruited; 37 (12.7%) of them had paternal history of AT, 39 (13.4%) maternal history of AT, 60 (20.5%) tonsillar hypertrophy, and 48 (16.4%) habitual snoring. Maternal and paternal history of AT were significantly associated with the presence of tonsillar hypertrophy even after adjustment for age, gender, obesity, passive smoking, and physician-diagnosed wheezing requiring treatment with inhaled medications over the past year [odds ratios (95% confidence interval): 3.52 (1.54-8.06); P&lt;0.01 and 4.70 (2.13-10.36); P&lt;0.01, respectively]. Only maternal history of AT predicted history of snoring [4.12 (1.86-9.12); P&lt;0.01]. When entered in the same multivariate logistic regression analysis model, tonsillar hypertrophy was a stronger predictor of habitual snoring than maternal history of AT [4.00 (1.97-8.14) vs. 2.73 (1.20-6.20)]. ConclusionsChildren with parental history of AT have more frequently tonsillar hypertrophy than those without such history. Tonsillar hypertrophy mediates at least in part the association between maternal history of AT and habitual snoring in childhood. Pediatr Pulmonol. 2014; 49:366-371. (c) 2013 Wiley Periodicals, Inc

Nocturnal enuresis is associated with moderate-to-severe obstructive sleep apnea in children with snoring

BACKGROUND: Conflicting data suggest that prevalence of monosymptomatic primary nocturnal enuresis (NE) increases with increasing severity of obstructive sleep apnea (OSA) in childhood and especially in girls. We hypothesized that NE is associated with increased risk of moderate-to-severe GSA (obstructive apnea-hypopnea index (AHI) &gt;5 episodes/hour) among children with snoring. METHODS: Data of children (&gt;= 5 y old) with snoring who were referred for polysomnography over 12 y were reviewed. RESULTS: Data of 525 children with mean age (+/- SD) 7.5 (+/- 2.2) y and median obstructive AHI (10th-90th percentiles) 1.9 (0.4-7.3) episodes/hour were analyzed. Three hundred and fifty-five children (67.6%) had NE and 87 (16.6%) had moderate-to-severe GSA. There was no interaction between NE and gender regarding the association with moderate-to-severe GSA (P &gt; 0.05). NE was associated significantly with presence of moderate-to-severe GSA after adjustment for tonsillar hypertrophy, obesity, gender, and age (adjusted odds ratio = 1.92 (1.08-3.43); P = 0.03). Presence of NE had high sensitivity (78.2%) and low positive predictive value (19.2%) for detecting moderate-to-severe GSA and low specificity (34.5%) and high negative predictive value (88.8%) for ruling it out. CONCLUSION: Children with snoring and without NE referred for polysomnography are less likely to have moderate-to-severe GSA compared to those with NE

Obstructive Sleep Apnea, Excessive Daytime Sleepiness, and Morning Plasma TNF-alpha Levels in Greek Children

Background: Obstructive sleep apnea (OSA) has been associated with increased frequency of excessive daytime sleepiness (EDS). Increased plasma TNF-alpha levels may mediate this association in adults, but conflicting results have been reported in children. We hypothesized that: (i) the higher the OSA severity in childhood, the higher the frequency of EDS and morning plasma TNF-alpha levels; and (ii) high TNF-alpha levels predict presence of EDS. Methods: Children without and with snoring underwent polysomnography. EDS was determined by parental response to specific questions, and plasma TNF-alpha levels were measured. Results: Children with moderate-to-severe OSA (n = 24; 5.7 +/- 2 years; apnea-hypopnea index [AHI] 11.5 +/- 5.1/h), but not participants with mild OSA (n = 22; 6 +/- 2.5 years; AHI 2.1 +/- 1/h) were at significantly higher risk for EDS than controls (n = 22; 6.8 +/- 2.1 years; AHI 0.5 +/- 0.3/h) (OR [95% CI] adjusted for age, gender, and obesity: 9.2 [1.7-50.2] and 3.8 [0.7-21.8], respectively). The 3 groups did not differ regarding TNF-alpha concentration (0.63 +/- 0.2 vs 0.65 +/- 0.18 vs 0.63 +/- 0.17 pg/mL; P &gt; 0.05). TNF-alpha levels were associated significantly with body mass index z-score (P &lt; 0.05) and not with polysomnography indices (P &gt; 0.05). Subjects with high TNF-alpha levels (&gt; 0.57 pg/mL) were not at higher risk for EDS than participants with low levels (OR [95% CI] adjusted for age, gender, and obesity: 1.7 [0.5-5.7]). Conclusions: Increasing severity of OSA is associated with increasing frequency of EDS, but not with elevated plasma TNF-alpha concentration. High TNF-a levels cannot be used as predictor for the presence of EDS in children with sleep apnea

Low Morning Serum Cortisol Levels in Children with Tonsillar Hypertrophy and Moderate-to-Severe OSA

Background: Hypertrophic tonsillar tissue in children with obstructive sleep apnea (OSA) has enhanced expression of glucocorticoid receptors, which may reflect low endogenous cortisol levels. We have evaluated the effect of the interaction between tonsillar hypertrophy and OSA severity on morning serum cortisol levels. Methods: Children with and without snoring underwent polysomnography, tonsillar size grading, and measurement of morning serum cortisol. Results: Seventy children (2-13 years old) were recruited: 30 with moderate-to-severe OSA (apnea-hypopnea index [AHI] &gt; 5 episodes/h), 26 with mild OSA (AHI &gt; 1 and &lt;= 5), and 14 controls (no snoring; AHI &lt;= 1). Tonsillar hypertrophy was present in 56.7%, 53.8%, and 42.9% of participants in each group, respectively. Application of a general linear model demonstrated a significant effect of the interaction between severity of OSA and tonsillar hypertrophy on cortisol levels (P = 0.04), after adjustment for obesity, gender, and age. Among children with tonsillar hypertrophy, subjects with moderate-to-severe OSA (n = 17; AHI 14.7 +/- 10.6), mild OSA (n = 14; AHI 2.3 +/- 1.2), and control participants (n = 6; AHI 0.7 +/- 0.2) were significantly different regarding cortisol levels (P = 0.02). Subjects with moderate-to-severe OSA had lower cortisol (16.9 +/- 8.7 mcg/dL) than those with mild OSA (23.3 +/- 4.2; P = 0.01) and those without OSA (controls) (23.6 +/- 5.3 mcg/dL; P = 0.04). In contrast, children with normal-size tonsils and moderate-to-severe OSA, mild OSA, and controls did not differ in cortisol levels. Conclusions: Children with moderate-to-severe obstructive sleep apnea and the phenotype of hypertrophic tonsils have reduced morning serum cortisol levels and potentially decreased glucocorticoid inhibitory effects on tonsillar growth

Low-grade albuminuria in children with obstructive sleep apnea

Small urinary protein loss (low-grade albuminuria or microalbuminuria) may reflect altered permeability of the glomerular filtration barrier. In the present study, it was hypothesized that children with obstructive sleep apnea have an increased risk of microalbuminuria compared with control subjects without sleep-disordered breathing. Albumin-to-creatinine ratio was measured in morning spot urine specimens collected from consecutive children with or without snoring who were referred for polysomnography. Three groups were studied: (i) control subjects (no snoring, apneahypopnea index&lt;1episodeh1; n=31); (ii) mild obstructive sleep apnea (snoring, apneahypopnea index=15episodesh1; n=71); and (iii) moderate-to-severe obstructive sleep apnea (snoring, apneahypopnea index&gt;5episodes.h1; n=27). Indications for polysomnography in control subjects included nightmares, somnambulism and morning headaches. An albumin-to-creatinine ratio&gt;median value in the control group (1.85mg of albumin per g of creatinine) was defined as elevated. Logistic regression analysis revealed that children with moderate-to-severe obstructive sleep apnea, but not those with mild obstructive sleep apnea, had increased risk of elevated albumin-to-creatinine ratio relative to controls (reference) after adjustment for age, gender and presence of obesity: odds ratio 3.8 (95% confidence interval 1.112.6); P=0.04 and 1.5 (0.63.7); 0.05, respectively. Oxygen desaturation of hemoglobin and respiratory arousal indices were significant predictors of albumin-to-creatinine ratio (r=0.31, P=0.01; and r=0.43, P&lt;0.01, respectively). In conclusion, children with moderate-to-severe obstructive sleep apnea are at significantly higher risk of increased low-grade excretion of albumin in the morning urine as compared with control subjects without obstructive sleep apnea. These findings may reflect altered permeability of the glomerular filtration barrier related to nocturnal hypoxemia and sympathetic activation which are induced by obstructive sleep apnea