Corticosteroids and Leukotriene Modifiers in Pediatric SDB

  • Aviv D. GoldbartEmail author
  • Leila Kheirandish-Gozal
Part of the Respiratory Medicine book series (RM)


Two major mechanisms have been proposed to explain the morbid consequences of sleep-disordered breathing (SDB), namely oxidative stress and increased activation of inflammatory processes [1, 2], which may be further modulated by genetic, lifestyle, and environmental factors [1, 3]. Current data suggests that no more than a quarter of all children undergoing tonsillectomy and adenoidectomy (T&A) due to SDB are cured [4]. Therefore, extensive research efforts have been implemented during the last decade to identify new nonsurgical solutions for children with SDB that target those inflammatory processes. At least two types of medications have been studied in children thus far. This chapter describes the potential role(s) of corticosteroids and leukotrienes in the pathophysiology of SDB and also discusses relevant therapeutic considerations pertaining to these agents. To this effect, we briefly describe the role of inflammation in SDB and the optional interventions by focusing on (1) SDB and inflammation: the upper airway and the systemic involvement, (2) leukotrienes and their receptors: upper airway and systemic expression, (3) steroid receptors and the upper airway, and (4) anti-inflammatory treatments for children with SDB.


Obstructive Sleep Apnea Exhale Breath Condensate Continuous Positive Airway Pressure Treatment hsCRP Level Mild Obstructive Sleep Apnea 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Capdevila OS, Kheirandish-Gozal L, Dayyat E, Gozal D. Pediatric obstructive sleep apnea: complications, management, and long-term outcomes. Proc Am Thorac Soc. 2008;5(2):274–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Gozal D, Crabtree VM, Sans Capdevila O, Witcher LA, Kheirandish-Gozal L. C-reactive protein, obstructive sleep apnea, and cognitive dysfunction in school-aged children. Am J Respir Crit Care Med. 2007;176(2):188–93.PubMedCrossRefGoogle Scholar
  3. 3.
    Gozal D, Kheirandish L. Oxidant stress and inflammation in the snoring child: confluent pathways to upper airway pathogenesis and end-organ morbidity. Sleep Med Rev. 2006;10(2):83–96.PubMedCrossRefGoogle Scholar
  4. 4.
    Bhattacharjee R, Kheirandish-Gozal L, Spruyt K, Mitchell RB, Promchiarak J, Simakajornboon N, Kaditis AG, Splaingard D, Splaingard M, Brooks LJ, Marcus CL, Sin S, Arens R, Verhulst SL, Gozal D. Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study. Am J Respir Crit Care Med. 2010;182(5): 676–83.PubMedCrossRefGoogle Scholar
  5. 5.
    Suzuki M, Watanabe T, Mogi G. Clinical, bacteriological, and histological study of adenoids in children. Am J Otolaryngol. 1999;20:85–90.PubMedCrossRefGoogle Scholar
  6. 6.
    Nistico L, Kreft R, Gieseke A, Coticchia JM, Burrows A, Khampang P, Liu Y, Kerschner JE, Post JC, Lonergan S, Sampath R, Hu FZ, Ehrlich GD, Stoodley P, Hall-Stoodley L. An adenoid reservoir for pathogenic biofilm bacteria. J Clin Microbiol. 2011;49(4): 1411–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Carpagnano GE, Kharitonov SA, Resta O, Foschino-Barbaro MP, Gramiccioni E, Barnes PJ. Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients. Chest. 2002;122: 1162–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Entzian P, Linnemann K, Schlaak M, Zabel P. Obstructive sleep apnea syndrome and circadian rhythms of hormones and cytokines. Am J Respir Crit Care Med. 1996;153:1080–6.PubMedGoogle Scholar
  9. 9.
    Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, Somers VK. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation. 2002;105(21):2462–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation. 2003;107:1129–34.PubMedCrossRefGoogle Scholar
  11. 11.
    Shadan FF, Jalowayski AA, Fahrenholz J, Kline LE, Dawson A. Nasal cytology: a marker of clinically silent inflammation in patients with obstructive sleep apnea and a predictor of noncompliance with nasal CPAP therapy. J Clin Sleep Med. 2005;1:266–70.PubMedGoogle Scholar
  12. 12.
    Tauman R, Ivanenko A, O’Brien LM, Gozal D. Plasma C-reactive protein levels among children with sleep-disordered breathing. Pediatrics. 2004;113: e564–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Kaditis AG, Alexopoulos EI, Kalampouka E, Kostadima E, Germenis A, Zintzaras E, Gourgoulianis K. Morning levels of C-reactive protein in children with obstructive sleep-disordered breathing. Am J Respir Crit Care Med. 2005;171:282–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Larkin EK, Rosen CL, Kirchner HL, Storfer-Isser A, Emancipator JL, Johnson NL, Zambito AM, Tracy RP, Jenny NS, Redline S. Variation of C-reactive protein levels in adolescents: association with sleep-disordered breathing and sleep duration. Circulation. 2005;111:1978–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Tauman R, Gulliver TE, Krishna J, Montgomery-Downs HE, O’Brien LM, Ivanenko A, Gozal D. Persistence of obstructive sleep apnea syndrome in children after adenotonsillectomy. J Pediatr. 2006;149:803–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Tauman R, O’Brien LM, Gozal D. Hypoxemia and obesity modulate plasma C-reactive protein and interleukin-6 levels in sleep-disordered breathing. Sleep Breath. 2007;11:77–84.PubMedCrossRefGoogle Scholar
  17. 17.
    Peters-Golden M, Henderson Jr WR. Leukotrienes. N Engl J Med. 2007;357:1841–54.PubMedCrossRefGoogle Scholar
  18. 18.
    Murphy RC, Gijón MA. Biosynthesis and metabolism of leukotrienes. Biochem J. 2007;405:379–95.PubMedCrossRefGoogle Scholar
  19. 19.
    Shirasaki H, Kanaizumi E, Watanabe K, Matsui T, Sato J, Narita S, Rautiainen M, Himi T. Expression and localization of the cysteinyl leukotriene 1 receptor in human nasal mucosa. Clin Exp Allergy. 2002;32:1007–12.PubMedCrossRefGoogle Scholar
  20. 20.
    Figueroa DJ, Breyer RM, Defoe SK, Kargman S, Daugherty BL, Waldburger K, Liu Q, Clements M, Zeng Z, O’Neill GP, Jones TR, Lynch KR, Austin CP, Evans JF. Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med. 2001;163:226–33.PubMedGoogle Scholar
  21. 21.
    Borish L. The role of leukotrienes in upper and lower airway inflammation and the implications for treatment. Ann Allergy Asthma Immunol. 2002;88:16–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Ciprandi G, Frati F, Marcucci F, Sensi L, Tosca MA, Milanese M, Ricca V. Nasal cytokine modulation by montelukast in allergic children: a pilot study. Eur Ann Allergy Clin Immunol. 2003;35:295–9.PubMedGoogle Scholar
  23. 23.
    Bisgaard H, Loland L, Oj JA. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med. 1999;160:1227–31.PubMedGoogle Scholar
  24. 24.
    Goldbart AD, Goldman JL, Li RC, Brittian KR, Tauman R, Gozal D. Differential expression of cysteinyl leukotriene receptors 1 and 2 in tonsils of children with obstructive sleep apnea syndrome or recurrent infection. Chest. 2004;126:13–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Figueroa DJ, Borish L, Baramki D, Philip G, Austin CP, Evans JF. Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis. Clin Exp Allergy. 2003;33:1380–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Li AM, Hung E, Tsang T, Yin J, So HK, Wong E, Fok TF, Ng PC. Induced sputum inflammatory ­measures correlate with disease severity in children with obstructive sleep apnoea. Thorax. 2007;62(1): 75–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Goldbart AD, Goldman JL, Veling MC, Gozal D. Leukotriene modifier therapy for mild sleep-disordered breathing in children. Am J Respir Crit Care Med. 2005;172:364–70.PubMedCrossRefGoogle Scholar
  28. 28.
    Ebenfelt A, Ivarsson M. Neutrophil migration in tonsils. J Anat. 2001;198(Pt 4):497–500.PubMedCrossRefGoogle Scholar
  29. 29.
    Kaditis AG, Ioannou MG, Chaidas K, Alexopoulos EI, Apostolidou M, Apostolidis T, Koukoulis G, Gourgoulianis K. Cysteinyl leukotriene receptors are expressed by tonsillar T cells of children with obstructive sleep apnea. Chest. 2008;134(2):324–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Shahid SK, Kharitonov SA, Wilson NM, Bush A, Barnes PJ. Increased interleukin-4 and decreased interferon-gamma in exhaled breath condensate of children with asthma. Am J Respir Crit Care Med. 2002;165:1290–3.PubMedCrossRefGoogle Scholar
  31. 31.
    Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med. 2001;163:1693–722.PubMedGoogle Scholar
  32. 32.
    Kharitonov SA, Barnes PJ. Exhaled markers of inflammation. Curr Opin Allergy Clin Immunol. 2001;1:217–24.PubMedGoogle Scholar
  33. 33.
    Goldbart AD, Krishna J, Li RC, Serpero LD, Gozal D. Inflammatory mediators in exhaled breath condensate of children with obstructive sleep apnea syndrome. Chest. 2006;130:143–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Petrosyan M, Perraki E, Simoes D, Koutsourelakis I, Vagiakis E, Roussos C, Gratziou C. Exhaled breath markers in patients with obstructive sleep apnoea. Sleep Breath. 2008;12(3):207–15.PubMedCrossRefGoogle Scholar
  35. 35.
    Dayyat E, Serpero LD, Kheirandish-Gozal L, Goldman JL, Snow A, Bhattacharjee R, Gozal D. Leukotriene pathways and in vitro adenotonsillar cell proliferation in children with obstructive sleep apnea. Chest. 2009;135(5):1142–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Kim J, Bhattacharjee R, Dayyat E, Snow AB, Kheirandish-Gozal L, Goldman JL, Li RC, Serpero LD, Clair HB, Gozal D. Increased cellular proliferation and inflammatory cytokines in tonsils derived from children with obstructive sleep apnea. Pediatr Res. 2009;66:423–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Goldbart A, Tal A. Elevated circulating leukotrienes in children with sleep disordered breathing. Am J Respir Crit Care Med. 2007;175:A.278.Google Scholar
  38. 38.
    Goldbart A, Tal A. Circulating cysteinyl LT-1 receptor in children with mild sleep disordered breathing. Sleep. 2006;29:A.287.Google Scholar
  39. 39.
    Kaditis AG, Alexopoulos E, Chaidas K, Ntamagka G, Karathanasi A, Tsilioni I, Kiropoulos TS, Zintzaras E, Gourgoulianis K. Urine concentrations of cysteinyl leukotrienes in children with obstructive sleep-disordered breathing. Chest. 2009;135(6):1496–501.PubMedCrossRefGoogle Scholar
  40. 40.
    Adcock IM, Lane SJ. Corticosteroid-insensitive asthma: molecular mechanisms. J Endocrinol. 2003; 178:347–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Christodoulopoulos P, Leung DY, Elliott MW, Hogg JC, Muro S, Toda M, Laberge S, Hamid QA. Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma. J Allergy Clin Immunol. 2000;106:479–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Gagliardo R, Chanez P, Vignola AM, Bousquet J, Vachier I, Godard P, Bonsignore G, Demoly P, Mathieu M. Glucocorticoid receptor alpha and beta in glucocorticoid dependent asthma. Am J Respir Crit Care Med. 2000;162:7–13.PubMedGoogle Scholar
  43. 43.
    Goldbart AD, Veling MC, Goldman JL, Li RC, Brittian KR, Gozal D. Glucocorticoid receptor subunit expression in adenotonsillar tissue of children with obstructive sleep apnea. Pediatr Res. 2005;57: 232–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Kheirandish-Gozal L, Serpero LD, Dayyat E, Kim J, Goldman JL, Snow A, Bhattacharjee R, Gozal D. Corticosteroids suppress in vitro tonsillar proliferation in children with obstructive sleep apnoea. Eur Respir J. 2009;33:1077–84.PubMedCrossRefGoogle Scholar
  45. 45.
    Al-Ghamdi SA, Manoukian JJ, Morielli A, Oudjhane K, Ducharme FM, Brouillette RT. Do systemic corticosteroids effectively treat obstructive sleep apnea secondary to adenotonsillar hypertrophy? Laryngoscope. 1997;107:1382–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Brouillette RT, Manoukian JJ, Ducharme FM, Oudjhane K, Earle LG, Ladan S, Morielli A. Efficacy of fluticasone nasal spray for pediatric obstructive sleep apnea. J Pediatr. 2001;138:838–44.PubMedCrossRefGoogle Scholar
  47. 47.
    Alexopoulos EI, Kaditis AG, Kalampouka E, Kostadima E, Angelopoulos NV, Mikraki V, Skenteris N, Gourgoulianis K. Nasal corticosteroids for children with snoring. Pediatr Pulmonol. 2004;38: 161–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Kheirandish-Gozal L, Gozal D. Intranasal budesonide treatment for children with mild obstructive sleep apnea syndrome. Pediatrics. 2008;122: e149–55.PubMedCrossRefGoogle Scholar
  49. 49.
    Goldbart A, Tal A. Leukotriene modifier therapy for sleep disordered breathing: a double blind double placebo controlled study. Am J Respir Crit Care Med. 2009;179:A.6344.Google Scholar
  50. 50.
    Kheirandish L, Goldbart AD, Gozal D. Intranasal steroids and oral leukotriene modifier therapy in residual sleep-disordered breathing after tonsillectomy and adenoidectomy in children. Pediatrics. 2006;117: e61–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Sleep Wake Disorders Unit, Department of Pediatrics, Saban Pediatric CenterSoroka University Medical CenterBeer-ShevaIsrael
  2. 2.Section of Sleep Medicine, Department of Pediatrics, Pritzker School of MedicineUniversity of ChicagoChicagoUSA

Personalised recommendations