1. Timothy J. Craig Professor of Medicine and Pediatrics Distinguished Educator Penn State University Hershey, PA, USA

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

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

5. Allergic Rhinitis Symptoms are Associated with Sleep Complaints Leger et al. Arch Intern Med. 2006;166:1744. Subjects with complaint (%) Difficulty Falling Asleep Nocturnal Awakening Early Awakening Nonrestorative Sleep Feeling of Lack of Sleep SnoringESS score >10 Prevalence of Sleep Complaints in Patients with Allergic Rhinitis and Controls *P<0.001 vs controls. * * * * * * *

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

7. All of the below items often interefere with sleep except? 1. Inflammatory components of the allergic response 2. Symptoms of allergic rhinitis 3. Nasal congestion 4. High Apnea and Hyponea Index Answer

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

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

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

13. 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

14. Pathophysiology of AR and impact on Sleep Symptoms of AR and impact on Sleep

16. Pathophysiology of Allergic Rhinitis and Impact on Sleep 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. Late-Phase Response Cellular Infiltration/Inflammation Eosinophil CysLTs, GM-CSF, TNF- , IL-1, IL-3, PAF, ECP, MBP Monocyte CysLTs, TNF- , PAF, IL-1, IL-10 Lymphocyte IL-4, IL-13, IL-5, IL-3, GM-CSF, IL-6 Degranulation Mast cell Allergen Chemotactic factors (CysLTs, PAF, IL-5) Histamine Proteases Neosynthesis CysLTs Prostaglandins PAF Bradykinin ILs TNF-  GM-CSF Early-Phase Response Mast Cell Basophil Histamine, CysLTs, TNF- , IL-4, IL-5, IL-6

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

18. 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. With sleep restriction Without sleep restriction Sleep disturbance cause an increase in on IL-6

19. Changes of TNF over 24 hour clock before and with 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. Sleep restriction Before restriction

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

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

22. Multiple Pro-Inflammatory Factors in Allergic Rhinitis Affect Sleep and Symptoms MediatorEffect on Sleep Histamine Balance between wakefulness and sleep, arousal; ↑ nasal obstruction, rhinorrhea, & pruritus CysLT ↑ Slow-wave sleep, ↑ Sleep-disordered breathing; ↑ Nasal obstruction, rhinorrhea IL-1 ↑ Latency to REM and ↓ REM duration IL-4 IL-10 Bradykinin↑ Sleep apnea; ↑ Nasal obstruction & rhinorrhea Substance P↑ Latency to REM, arousal; ↑ Nasal obstruction Ferguson. Otolaryngol Head Neck Surg. 2004;130:617.

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

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

26. Nasal Congestion in Patients with SAR is Associated with Obstructive Sleep Apneas* *5 men with SAR. McNicholas et al. Am Rev Respir Dis. 1982;126:625. Increase in obstructive sleep apneas/hour Increase in nasal resistance (%) 010203040506070 0 0.2 0.4 0.6 0.8 1.0 Apneas were longer and more frequent in patients with obstruction than in those without obstruction

27. 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.

28. 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.

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

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

32. To what extent do ocular symptoms impact sleep performance ? 1. Significantly 2. Moderately 3. Marginally 4. Not at All Answer-

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

34. Impact of Seasonal Allergic Conjunctivitis on Sleep and Quality of Life in Private Eye Clinics in Oxfordshire, UK RQLQ Domain (range 0 to 6) SACControlsP value Activities2.40 ± 1.520.41 ± 0.85<0.001 Sleep1.37 ± 1.340.22 ± 0.57<0.001 Non-nose/eye symptoms1.42 ± 1.220.22 ± 0.47<0.001 Practical problems2.27 ± 1.540.43 ± 0.81<0.001 Nasal symptoms2.32 ± 1.400.58 ± 0.85<0.001 Eye symptoms2.47 ± 1.440.37 ± 0.64<0.001 Emotional1.46 ± 1.320.19 ± 0.53<0.001 Overall Score2.02 ± 1.130.35 ± 0.49<0.001 N=310 Pitt et al. Ophthalmic Epidemiol. 2004;11:17. SAC sufferers report a 6 times greater effect on sleep compared with controls

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

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

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

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

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

40. Sleep-Disordered Breathing Increases Risk of Psychiatric Disorders Sharafkhaneh et al. Sleep. 2005;28:1405. * * * * * * Patients with disorder (%) *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. DepressionAnxietyPTSDPsychosisBipolar Disorder Dementia Incidence of Psychiatric Disorders in Patients without and with Diagnosed Sleep Apnea †

41. Sleep-Disordered Breathing Increases Risk of Behavioral Problems in Children Prevalence of Behavioral Problems According to Sleep-Disordered Breathing Subjects with Behavior (%) * * * * *P≤0.01 vs no SDB. Rosen et al. Pediatrics. 2004;114:1640. HyperactivityEmotional Lability Oppositional Behavior Delinquent/ Aggressive Behavior

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

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

44. Nurses Health Study: Snoring Increases the Risk of Associated Diseases ConditionIncreased Risk with More Frequent Snoring Coronary Heart Disease 1  Stroke 1  Hypertension 2  Diabetes 3  1. Hu et al. J Am 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.

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

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

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

48. 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

49. 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

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

51. Vgontzas AN. Zoumakis M. Papanicolaou DA. Bixler EO. Prolo P. Lin HM. Vela-Bueno A. Kales A. Chrousos GP. Chronic insomnia is associated with a shift of interleukin-6 and tumor necrosis factor secretion from nighttime to daytime. [Clinical Trial. Controlled Clinical Trial. Journal Article] Metabolism: Clinical & Experimental. 51(7):887-92, 2002 Jul.