Timothy J. CraigProfessor of Medicine and PediatricsDistinguished Educator Penn State UniversityHershey, PA, USA

Presentation Overview

Allergic Rhinitis and Sleep Disturbance Mechanisms of Sleep Disturbance in

Allergic Rhinitis Impact of AR-associated Sleep

Disturbances

GSKMerckNovartisGenentechForest

Are all potential

Allergic Rhinitis Adversely Impacts Sleep in Adults and Children/Adolescents

40

36

32

28

0

10

20

30

40

50

96 93

79

0

20

40

60

80

100

120 N=476 Adults/Adolescents/Children with AR

Pati

en

ts w

ith

Mod

era

te o

r S

evere

Im

pact

(%)

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.

N=221 Adolescents/Children with AR

Pati

en

ts w

ith

Im

pact

(%)

School/WorkPerformance

NormalActivities

Sleep

Allergic Rhinitis Symptoms are Associated with Sleep Complaints

Leger et al. Arch Intern Med. 2006;166:1744.

17.2

27.125.4

19.6

12.8

20.518.3

23.3

40.3

63.2

46.8

28.7

42.841.6

0

10

20

30

40

50

60

70 Controls (n=502)

AR Patients (n=591)

Su

bje

cts

wit

h c

om

pla

int

(%)

Difficulty FallingAsleep

NocturnalAwakening

EarlyAwakening

NonrestorativeSleep

Feeling ofLack of Sleep

Snoring ESS score>10

Prevalence of Sleep Complaints in Patients with Allergic Rhinitis and Controls

*P<0.001 vs controls.

* *

*

*

*

*

*

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.

24.3

0.5

10.4

16

32.6

3.8

23.2

35.8

0

5

10

15

20

25

30

35

40 Controls (n=502)

AR Patients (n=591)

Su

bje

cts

wit

h d

isord

er

(%)

Insomnia SevereInsomnia

Sleep ApneaSyndrome

Hypersomnia

*

*

*

*

All of the below items often interefere with sleep except?

1. Inflammatory components of the allergic response

2. Symptoms of allergic rhinitis3. Nasal congestion4. High Apnea and Hyponea Index

Answer

Allergic Patients Experience More Apnea/Hypopnea than Non-allergic Controls

P<0.001

0

0.2

0.4

0.6

0.8

1.0

Allergic rhinitis group Control group

AH

I

Before allergy season

During allergy season

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 hypopneaepisodes (assessed by polysomnography) divided by hours of sleep.

Patients with rhinitis had 10 times moremicroarousals (average of 50) than controls (n=14)

Lavie et al. Acta Otolaryngol. 1981;92;529.

Allergic Rhinitis is Associated with Increased Microarousals

Lavie et al. Acta Otolaryngol. 1981;92;529.

Microarousals Correlate with Impaired Breathing

Microarousals in Allergic Rhinitis Correlate with Impaired Breathing

Similarities between the twoObese 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

Pathophysiology of AR and impact on Sleep

Symptoms of AR and impact on Sleep

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/InflammationEosinophil

CysLTs, GM-CSF,

TNF-, IL-1, IL-3, PAF, ECP, MBP

MonocyteCysLTs, TNF-, PAF, IL-1, IL-10

LymphocyteIL-4, IL-13, IL-5, IL-3, GM-CSF,

IL-6

Degranulation

Mast cell

Allergen Chemotactic

factors

(CysLTs, PAF, IL-5)

HistamineProteases

Neosynthesis

CysLTsProstaglandinsPAFBradykininILsTNF-GM-CSF

Early-Phase Response

Mast Cell

BasophilHistamine, CysLTs,

TNF-, IL-4, IL-5, IL-6

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-L

T (

pg

/mL)

0

20

40

60

SDB Mild SDB Controls

*

Increased Cysteinyl Leukotrienes Levels Are Associated with Sleep-Disordered Breathing

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

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

Inflammatory Cytokines are Correlated with Increased REM Latency and Reduced Time in REM

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

IL-1β

IL-4

IL-10

REM Latency

Time in REM

Corr

ela

tion

*P<0.01.Krouse et al. Otolaryngol Head Neck Surg. 2002;126:607.

* *

*

Inflammatory Cytokines Increase REM Latency and Reduce REM Duration

Concentrations of Bradykinin-Like Immunoreactivity in

Nasal Lavage Fluid Before and After Sleep

0

1000

2000

PM AM

Bra

dykin

in (

pg

/mL)

Control

OSA Control

OSA

**

*P<0.05 vs control.Rubinstein. Laryngoscope. 1995;105:175.

Increased Levels of Bradykinin Are Associated with Obstructive Sleep Apnea

Multiple Pro-Inflammatory Factors in Allergic Rhinitis Affect Sleep and Symptoms

Mediator Effect on Sleep

HistamineBalance 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 durationIL-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.

Nasal Obstruction Causes Sleep Disturbances

Zwillich et al. Am Rev Respir Dis. 1981;124:158.

N=10 normal men.

Nasal Congestion: Independent Risk Factor for Habitual Snoring

0

1.0

2.0

3.0

4.0

5.0

6.0

None Intermittent Chronic

Baseline

5-year follow-up

Ris

k f

or

hab

itu

al

sn

ori

ng

*Statistically significant vs no congestion.Young et al. Arch Intern Med. 2001;161:1514.

Nighttime Congestion

* *

*

*

95% CI1.26-2.08 1.27-2.10

95% CI2.06-6.25 2.78-8.78

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.

Incre

ase in

ob

str

ucti

ve

sle

ep

ap

neas/h

ou

r

Increase in nasal resistance (%)

0 10 20 30 40 50 60 700

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

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.

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.

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

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

To what extent do ocular symptoms impact sleep performance ?

1. Significantly2. Moderately3. Marginally4. Not at All

Answer-

Impact of Ocular Allergies on Sleep and Quality of Life: Eye Allergy Patient Impact Questionnaire (EAPIQ)

EAPIQ: Impact on Daily Activities

45%

73%

55%58%61%70%

0%

20%

40%

60%

80%

100%

GoingOutdoors

Reading Driving Concentratingon Daily Tasks

Sleeping Puttingon/wearingmake-up

Perc

en

t of

Pati

en

ts

(%)

Adapted from Klein et al. ARVO. 2003.

N=124

Impact of Seasonal Allergic Conjunctivitis on Sleep and Quality of Life in Private Eye Clinics in Oxfordshire, UK

RQLQ Domain(range 0 to 6)

SAC Controls P value

Activities 2.40 ± 1.52 0.41 ± 0.85 <0.001

Sleep 1.37 ± 1.34 0.22 ± 0.57 <0.001

Non-nose/eye symptoms 1.42 ± 1.22 0.22 ± 0.47 <0.001

Practical problems 2.27 ± 1.54 0.43 ± 0.81 <0.001

Nasal symptoms 2.32 ± 1.40 0.58 ± 0.85 <0.001

Eye symptoms 2.47 ± 1.44 0.37 ± 0.64 <0.001

Emotional 1.46 ± 1.32 0.19 ± 0.53 <0.001

Overall Score 2.02 ± 1.13 0.35 ± 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

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

Allergic Rhinitis Impairs Learning in Paediatric Patients

40

44

48

52

56

60Mean 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.

PlaceboLoratadine10 mL syrup (10 mg)

Diphenhydramine25 mg

Com

posit

e learn

ing

score

(%

)

Healthycontrols

†

*

Habitual Snoring is Associated with Poor Academic Performance in Primary School Children

0

2

4

6

Never Occasionally

Frequently Always

Od

ds R

ati

o f

or

Poor

Acad

em

ic P

erf

orm

an

ce

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

*

*

*

*

*

OSA

Matched controls

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

Nasal Allergies Impact Patients’ Mood and Feelings

4429 26

13 8

36

36 38

2315

0

20

40

60

80

100Sometimes

Frequently

Allergies in America Survey. At: http://www.myallergiesinamerica.com/.

Su

bje

cts

(%

)

Tired Miserable Irritable Depressed/Blue

Embarassed

Q30. During allergy season, how often did you feel [ITEM]-frequently, sometimes, rarely or never? N=2500

Sleep-Disordered Breathing Increases Risk of Psychiatric Disorders

0

5

10

15

20

25

No apnea (n=3,525,276)

Apnea (n=122,052)

Sharafkhaneh et al. Sleep. 2005;28:1405.

*

**

*

*

*

Pati

en

ts w

ith

dis

ord

er

(%)

*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.

Depression Anxiety PTSD Psychosis BipolarDisorder

Dementia

Incidence of Psychiatric Disorders in Patients without and with Diagnosed Sleep Apnea†

Sleep-Disordered Breathing Increases Risk of Behavioral Problems in Children

0

5

10

15

20

25

30

No SDB (n=667)

SDB (n=162)

Prevalence of Behavioral Problems According to Sleep-Disordered Breathing

Su

bje

cts

wit

h

Beh

avio

r (%

)

**

**

*P≤0.01 vs no SDB.Rosen et al. Pediatrics. 2004;114:1640.

Hyperactivity EmotionalLability

OppositionalBehavior

Delinquent/AggressiveBehavior

Obesity and OSA in children: The inflammatory cascade that can lead to metabolic syndrome

Kheirandish-Gozal. Pediatr Pulmonol. 2011; 46:313–323

Obesity and OSA in children: The inflammatory cytokines that can lead to metabolic syndrome

Kheirandish-Gozal. Pediatr Pulmonol. 2011; 46:313–323.

Nurses Health Study: Snoring Increases the Risk of Associated Diseases

Condition Increased Risk with More Frequent Snoring

Coronary Heart Disease1 Stroke1

Hypertension2

Diabetes3

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.

Nurses Health Study: Snoring Increases Risk of CV Disease

0

1

2

3Never

Occasionally

Regularly

Ad

juste

d O

dd

s R

ati

o f

or

CV

D

iseases

Coronary heart diseaseTotal 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.

Nurses Health Study: Snoring Increases Risk of Hypertension

0

1

2NonsnoringOccasional snoringRegular snoring

Ad

juste

d O

dd

s R

ati

o f

or

Hyp

ert

en

sio

n

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.

Nurses Health Study: Snoring Increases Risk of Type II Diabetes

0

1

2

3

Ad

juste

d O

dd

s R

ati

o f

or

Typ

e I

I D

iab

ete

s

Never Regular

Snoring CategoryAl-Delaimy et al. Am J Epidemiol. 2002;155:387.

Multivariate-Adjusted Odds Ratio for Type II Diabetes by Snoring Category

P<0.0001for trend

OccasionalN=69,582 subjects.

In summary

1. Rhinitis can cause sleep disturbance2. 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

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

Thank you

Have a great day.

Ant questions?

tcraig@psu.edu

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.