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The Affect of Allergic Rhinitis on Sleep and Potential Complications IN CHILDREN

Timothy J. Craig Professor of Medicine and Pediatrics Distinguished Educator Penn State University Hershey, PA, USA. The Affect of Allergic Rhinitis on Sleep and Potential Complications IN CHILDREN. Presentation Overview. Allergic Rhinitis and Sleep Disturbance

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The Affect of Allergic Rhinitis on Sleep and Potential Complications IN CHILDREN

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  1. Timothy J. Craig Professor of Medicine and Pediatrics Distinguished Educator Penn State University Hershey, PA, USA The Affect of Allergic Rhinitis on Sleep and Potential Complications IN CHILDREN

  2. Presentation Overview • Allergic Rhinitis and Sleep Disturbance • Mechanisms of Sleep Disturbance in Allergic Rhinitis • Impact of AR-associated Sleep Disturbances

  3. GSK Merck Novartis Genentech Forest Are all potential Conflicts of Interest

  4. Allergic Rhinitis Adversely Impacts Sleep in Adults and Children/Adolescents N=221 Adolescents/Children with AR N=476 Adults/Adolescents/Children with AR Patients with Moderate or Severe Impact (%) Patients with Impact (%) School/WorkPerformance NormalActivities Sleep Sleep DailyActivities School/WorkPerformance Lifestyle O’Connor and Punekar. J Allergy Clin Immunol. 2006;117:S322. Abstract 1244. Scadding and Punekar. EAACI Abstract Book. 2006;211. Abstract 741.

  5. Subjects with complaint (%) Difficulty FallingAsleep NocturnalAwakening EarlyAwakening NonrestorativeSleep Feeling ofLack of Sleep Snoring ESS score>10 Allergic Rhinitis Symptoms are Associated with Sleep Complaints Prevalence of Sleep Complaints in Patients with Allergic Rhinitis and Controls * * * * * * * *P<0.001 vs controls. Leger et al. Arch Intern Med. 2006;166:1744.

  6. * * * Subjects with disorder (%) * Insomnia SevereInsomnia Sleep ApneaSyndrome Hypersomnia Allergic Rhinitis Symptoms are Associated with Sleep Disorders Prevalence of Sleep Disorders in Patients with Allergic Rhinitis and Controls *P≤0.003 vs controls. Leger et al. Arch Intern Med. 2006;166:1744.

  7. All of the below items often interefere with sleep except? • Inflammatory components of the allergic response • Symptoms of allergic rhinitis • Nasal congestion • High Apnea and Hyponea Index Answer

  8. Allergic Patients Experience More Apnea/Hypopnea than Non-allergic Controls Allergic patients had more apnea/hypopnea episodes than non-allergic controls P<0.001 AHI=apnea/hypopnea index, determined as the total number of apnea and hypopneaepisodes (assessed by polysomnography) divided by hours of sleep. Stuck et al. J Allergy Clin Immunol. 2004;113:663.

  9. Allergic Rhinitis is Associated with Increased Microarousals Patients with rhinitis had 10 times moremicroarousals (average of 50) than controls (n=14) Lavie et al. Acta Otolaryngol. 1981;92;529.

  10. Microarousals in Allergic Rhinitis Correlate with Impaired Breathing Microarousals Correlate with Impaired Breathing Lavie et al. Acta Otolaryngol. 1981;92;529.

  11. Similarities between the two Obese man with severe OAS • Increase in IL-1 • Increase in TNF • Increase in Il-6 • Increase in T-helper 2 cyokines • Decrease in T-helper 1 cytokines A young girl snoring and with rhinitis • Increase in IL-1 • Increase in TNF • Increase in Il-6 • Increase in T-helper 2 cytokines • Decrease in T-helper 1 cytokines

  12. Pathophysiology of AR and impact on Sleep Symptoms of AR and impact on Sleep Mechanisms of Sleep Disturbance in Allergic Rhinitis

  13. Inflammation

  14. Pathophysiology of Allergic Rhinitis and Impact on Sleep Early-Phase Response Mast Cell Late-Phase Response Cellular Infiltration/Inflammation Eosinophil • Histamine • Proteases CysLTs, GM-CSF, TNF-, IL-1, IL-3, PAF, ECP, MBP Degranulation Allergen Basophil Chemotactic factors (CysLTs, PAF, IL-5) Histamine, CysLTs,TNF-, IL-4, IL-5, IL-6 Mast cell Monocyte • CysLTs • Prostaglandins • PAF • Bradykinin • ILs • TNF- • GM-CSF CysLTs, TNF-, PAF, IL-1, IL-10 Neosynthesis Lymphocyte IL-4, IL-13, IL-5, IL-3, GM-CSF, IL-6 Bascom et al. Am Rev Respir Dis. 1988;138:406. Bascom et al. J Allergy Clin Immunol. 1988;81:580. Pearlman. J Allergy Clin Immunol 1999;104:S132. Quraishi et al. J Am Osteopath Assoc. 2004;104(suppl 5):S7.

  15. Increased Cysteinyl Leukotrienes Levels Are Associated with Sleep-Disordered Breathing cys-LT (pg/mL) Increased Levels of Cysteinyl Leukotrienes in Exhaled Breath Condensate from Children with Sleep-Disordered Breathing * * P<0.01 for SDB vs mild SDB vs controls. SDB=sleep-disordered breathing. Goldbart et al. Chest. 2006;130:143.

  16. Sleep disturbance cause an increase in on IL-6 With sleep restriction Without sleep restriction Vgontzas AN. Zoumakis E. Bixler EO. Lin HM. Follett H. Kales A. Chrousos GP. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. [Journal Article. Research Support, U.S. Gov't, P.H.S.] Journal of Clinical Endocrinology & Metabolism. 89(5):2119-26, 2004 May.

  17. Vgontzas AN. Zoumakis E. Bixler EO. Lin HM. Follett H. Kales A. Chrousos GP. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. [Journal Article. Research Support, U.S. Gov't, P.H.S.] Journal of Clinical Endocrinology & Metabolism. 89(5):2119-26, 2004 May. Changes of TNF over 24 hour clock before and with sleep restriction Sleep restriction Before restriction

  18. Inflammatory Cytokines Increase REM Latency and Reduce REM Duration Inflammatory Cytokines are Correlated with Increased REM Latency and Reduced Time in REM * * * Correlation Time in REM REM Latency *P<0.01. Krouse et al. Otolaryngol Head Neck Surg. 2002;126:607.

  19. Concentrations of Bradykinin-Like Immunoreactivity in Nasal Lavage Fluid Before and After Sleep Increased Levels of Bradykinin Are Associated with Obstructive Sleep Apnea * * Bradykinin (pg/mL) Control OSA Control OSA PM AM *P<0.05 vs control. Rubinstein. Laryngoscope. 1995;105:175.

  20. Multiple Pro-Inflammatory Factors in Allergic Rhinitis Affect Sleep and Symptoms Ferguson. Otolaryngol Head Neck Surg. 2004;130:617.

  21. Nasal Congestion

  22. Nasal Obstruction Causes Sleep Disturbances N=10 normal men. Zwillich et al. Am Rev Respir Dis. 1981;124:158.

  23. Nasal Congestion: Independent Risk Factor for Habitual Snoring Nighttime Congestion 95% CI 2.06-6.25 2.78-8.78 * Risk for habitual snoring * 95% CI 1.26-2.08 1.27-2.10 * * *Statistically significant vs no congestion. Young et al. Arch Intern Med. 2001;161:1514.

  24. 1.0 0.8 0.6 0.4 0.2 0 0 10 20 30 40 50 60 70 Nasal Congestion in Patients with SAR is Associated with Obstructive Sleep Apneas* Apneas were longer and more frequent in patients with obstruction than in those without obstruction Increase in obstructive sleep apneas/hour Increase in nasal resistance (%) *5 men with SAR. McNicholas et al. Am Rev Respir Dis. 1982;126:625.

  25. Nasal Obstruction and Obstructive Sleep Apnea in Childhood: Clinical Practice Guideline • Prevalence in high-risk pediatric subjects (adenotonsillar hypertrophy) • Primary snoring: 3%-12% • Obstructive sleep apnea syndrome: 2% • Sequelae of obstructive sleep apnea syndrome in children • Poor learning • Behavioral problems • Attention deficit-hyperactivity disorder Section on Pediatric Pulmonology and Subcommittee on Obstructive Sleep Apnea Syndrome. Pediatrics. 2002;109:704.

  26. Nasal Obstruction and Obstructive Sleep Apnea in Childhood: Clinical Practice Guideline • Adenotonsillectomy is the most common and most effective first-line treatment for children with obstructive sleep apnea syndrome • Symptom and polysomnographic resolution occur in 75%-98% of the cases • Efficacy of adenotonsillectomy suggests that upper airway obstruction is the primary cause of obstructive sleep apnea syndrome in children Section on Pediatric Pulmonology and Subcommittee on Obstructive Sleep Apnea Syndrome. Pediatrics. 2002;109:704.

  27. The affect of OSA on asthma and benefits of T+A

  28. The affect OSA has on asthma and the benefit of T+A

  29. Symptoms of Allergic Rhinitis

  30. To what extent do ocular symptoms impact sleep performance ? • Significantly • Moderately • Marginally • Not at All Answer-

  31. Impact of Ocular Allergies on Sleep and Quality of Life: Eye Allergy Patient Impact Questionnaire (EAPIQ) N=124 Percent of Patients (%) Adapted from Klein et al. ARVO. 2003.

  32. Impact of Seasonal Allergic Conjunctivitis on Sleep and Quality of Life in Private Eye Clinics in Oxfordshire, UK SAC sufferers report a 6 times greater effect on sleep compared with controls N=310 Pitt et al. Ophthalmic Epidemiol. 2004;11:17.

  33. Impact of Poor Sleep • Impaired Social Functioning: • daytime fatigue/somnolence • Impaired performance • Impaired learning • Emotional/behavioral impact • Delayed onset • Sleep fragmentation • Arousals/microarousals • Sleep Disordered Breathing • Snoring • Obstructive Sleep Apnea • Associated Diseases: • Hypertension • Cardiovascular disease • Stroke • Diabetes • Psychological disorders

  34. Allergic Rhinitis Impairs Learning in Paediatric Patients Mean Learning Scores in Children 10-12 Years of Age (N=73) Composite learning score (%) * † Healthy controls Loratadine 10 mL syrup (10 mg) Placebo Diphenhydramine 25 mg *P=0.007 vs healthy controls. †P=0.002 vs healthy controls. Vuurman et al. Ann Allergy. 1993;71:121.

  35. Habitual Snoring is Associated with Poor Academic Performance in Primary School Children Odds Ratio for Poor Performance by Snoring Category Snoring Category * * * Odds Ratio for Poor Academic Performance * * Mathematics Science Spelling P≤0.038 vs never. Urschitz et al. Am J Respir Crit Care Med. 2003;168:464.

  36. Sleep apnea affects cognitive skills in children Kheirandish-Gozal. European Respiratory Journal. 36(1):164-9, 2010 Jul. OSA Matched controls

  37. Nasal Allergies Impact Patients’ Mood and Feelings Q30. During allergy season, how often did you feel [ITEM]-frequently, sometimes, rarely or never? N=2500 Subjects (%) Tired Irritable Miserable Embarassed Depressed/Blue Allergies in America Survey. At: http://www.myallergiesinamerica.com/.

  38. Sleep-Disordered Breathing Increases Risk of Psychiatric Disorders Incidence of Psychiatric Disorders in Patients without and with Diagnosed Sleep Apnea† * * * Patients with disorder (%) * * * Depression Anxiety PTSD Psychosis BipolarDisorder Dementia *P<0.001 vs no apnea. PTSD=post-traumatic stress disorder. †Apnea defined by diagnosis of sleep apnea associated with insomnia, hypersomnia, or other unspecified. Sharafkhaneh et al. Sleep. 2005;28:1405.

  39. Sleep-Disordered Breathing Increases Risk of Behavioral Problems in Children Prevalence of Behavioral Problems According to Sleep-Disordered Breathing * * * * Subjects with Behavior (%) Hyperactivity EmotionalLability OppositionalBehavior Delinquent/AggressiveBehavior *P≤0.01 vs no SDB. Rosen et al. Pediatrics. 2004;114:1640.

  40. Obesity and OSA in children: The inflammatory cascade that can lead to metabolic syndrome Kheirandish-Gozal. Pediatr Pulmonol. 2011; 46:313–323

  41. Obesity and OSA in children: The inflammatory cytokines that can lead to metabolic syndrome Kheirandish-Gozal. Pediatr Pulmonol. 2011; 46:313–323.

  42. Nurses Health Study: Snoring Increases the Risk of Associated Diseases 1. Hu et al. JAm Coll Cardiol. 2000;35:308. 2. Hu et al. Am J Epidemiol. 1999;150:806. 3. Al-Delaimy et al. Am J Epidemiol. 2002;155:387.

  43. Nurses Health Study: Snoring Increases Risk of CV Disease Age-Adjusted Odds Ratio for CV Disease by Snoring Category Adjusted Odds Ratio for CV Diseases Stroke Total CV Events Coronary heart disease N=71,779 subjects. Hu et al. JAm Coll Cardiol. 2000;35:308.

  44. Nurses Health Study: Snoring Increases Risk of Hypertension Multivariate-Adjusted Odds Ratio for Hypertension by Snoring Category Adjusted Odds Ratio for Hypertension Baseline 8-Year Follow-up N=73,231 subjects. Hu et al. Am J Epidemiol. 1999;150:806.

  45. Nurses Health Study: Snoring Increases Risk of Type II Diabetes Multivariate-Adjusted Odds Ratio for Type II Diabetes by Snoring Category P<0.0001for trend Adjusted Odds Ratio for Type II Diabetes Occasional Never Regular N=69,582 subjects. Snoring Category Al-Delaimy et al. Am J Epidemiol. 2002;155:387.

  46. In summary 1. Rhinitis can cause sleep disturbance 2. Inflammation, congestion and other rhinitis symptoms can all worsen sleep and cause day time somnolence and fatigue 3. The end results of rhinitis is poor performance, decrease productivity and reduced quality of life 4. The long term effects may be obesity and metabolic syndrome

  47. Thank you to my colaborators: • Stephanie Teets • Stan Golden • Josh Berlin • Sujani Kukumanu • Katherine Hughs • Casey Glass • Joel Torretti • Faina Gurevich • Wenxin Wei • Jeff McCann • Chris Hanks • Carah Santos • Niti Sardana

  48. Thank you Have a great day. Ant questions? tcraig@psu.edu

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