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Co-morbitities of Asthma - Allergic Rhinitis, Rhinosinusitis, OME, OSA Co-morbitities of Asthma - Allergic Rhinitis, Rhinosinusitis, OME, OSA Ruby Pawankar, MD, Ph.D Nippon Medical School, Tokyo, Japan rpawankar @gmail.com Ruby Pawankar, MD, Ph.D Nippon Medical School, Tokyo, Japan rpawankar @gmail.com

Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

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Page 1: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Co-morbitities of Asthma -Allergic Rhinitis,

Rhinosinusitis, OME, OSA

Co-morbitities of Asthma -Allergic Rhinitis,

Rhinosinusitis, OME, OSA

Ruby Pawankar, MD, Ph.D

Nippon Medical School,

Tokyo, Japan

rpawankar @gmail.com

Ruby Pawankar, MD, Ph.D

Nippon Medical School,

Tokyo, Japan

rpawankar @gmail.com

Page 2: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

IntroductionIntroduction� Asthma and allergic rhinitis (AR) are global health

problems that causes major illness and disability worldwide.

� WHO estimates 300 million worldwide have asthma and 400 million people worldwide have AR

� Impairment of quality of life is seen in both adults and children with asthma and AR and asthma.

� Patients have several co-morbidities -sleep disorders, emotional problems, impairment in activities and social functioning.

� The economic impact direct and indirect costs are substantial.

Page 3: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Co-morbidities of AsthmaCo-morbidities of Asthma

Modified from Spector SL. JACI. 1997;99:S773-S780.

Sinusitis

OME

OSAS

AR

Comorbidities

• Allergic Rhinitis• Sinusitis• Otitis media with effusion• Sleep disorders

Page 4: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Asthma and ARAsthma and AR

Page 5: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Allergic Rhinitis Is a Risk Factor for Asthma

Allergic Rhinitis Is a Risk Factor for Asthma

23-year follow-up of college freshmen undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years. Adapted from Settipane RJ et al Allergy Proc 1994;15:21-25.

12

10

8

6

4

2

0

% of patients

whodeveloped

asthma

10.5

Allergic rhinitisat baseline

(n=162)

3.6

No allergic rhinitisat baseline

(n=528)

p<0.002

Allergic rhinitis increased the risk of asthma ~ 3-fold

Page 6: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

* Only 50% of study children skin tested.Wright et al. Pediatrics. 1994; 94:895.

Prevalence of Rhinitis in ChildrenPrevalence of Rhinitis in Children

� Physician diagnosed allergic rhinitis in children

- By 6 years of age 42%

• Began in first year 77%

• Began after first year 57%

• Prick skin test positive * 20%� Development of asthma by 6 years

– When rhinitis began in first year 23% (p<.005)

– When rhinitis began after first year 13%

When rhinitis began in the 1st year of life, the de velopment of asthma was twice as high as when it started after t he 1st year

Page 7: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Prevalence of Asthma in Adults and Children With AR

Diagnosed with asthma

Asthma symptoms in past 12 months

Res

pond

ents

, %

32

39

21

28

0

10

20

30

40

50

60

Adults with AR (N = 2,500) Children with AR (N = 500 )

More children than adults with AR have been diagnos ed with asthma or had asthma symptoms in the past 12 months

Page 8: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Adapted from Casale TB, et al. Clin Rev Allergy Immunol 2001 and

Kay AB N Engl J Med 2001

Early-phaseresponse

Late-phaseresponseT cells Inflammatory

mediators

Allergen

Cytokines

Preformed MediatorsCysteinyl leukotrienes

ProstaglandinsPlatelet-activating factor

Eosinophils

Membrane-bound IgE

Mastcell

Common Inflammatory Cells and Mediators

Page 9: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Bronchial biopsies in patients with SAR

0

10

20

30

40

50

60

Cel

ls/m

m2

con

nec

tive

tis

sue

out inpollen season

EG1+

CD45RO+

CD8+

CD4+

Chakir et al, Allergy Clin Immunol 2000

Page 10: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

nose bronchi

0

20

40

60

80Asthmatics

untreated

CS-dependent

nose bronchi

0

20

40

60

80Controls

Eos

inop

hils

(/m

m2)

Eosinophilic inflammation in submucosa

Chanez et al, Am J Respir Crit Care Med 1999

Page 11: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Bronchial Allergen Challenge ProducedNasal Inflammation

Bronchial Allergen Challenge ProducedNasal Inflammation

Eos

inop

hils

(10

6C

ells

/mm

2 ) 600

500

400

300

200

100

0

Blood(N = 16)

Bronchial Subepithelium

(N = 16)

T0

11

T0 = before challenge; T24 = 24-hr postchallenge.* P <.05 vs control (T0);

†P <.01 vs allergic patients (T0).Braunstahl et al. Am J Respir Crit Care Med. 2000;161:2051-2057.

Nasal Lamina Propria(N = 16)

Eos

inop

hils

(N

o. C

ells

/mm

2 )

Eos

inop

hils

(N

o. C

ells

/mm

2 )

T24

Allergic Patients Control Patients

1600

1200

800

400

0

100

80

60

40

20

0

T0 UnchallengedLeft Lung

T0 T24Allergen-ChallengedRight Middle

Lobe

T24

†* *

*

Page 12: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

22% 41%

48% 33%

44% 38%

51% 35%

0% 20% 40% 60% 80% 100%

Impact of AR on Asthma in Child’s Quality of Life

Impact of AR on Asthma in Child’s Quality of Life

Participation in leisure & sports . . .

Concentration at work/ school

Ability to enjoy social activities

Ability to get a good night’s sleep

A great deal and Quite a lotA great deal and Quite a lot A little bitA little bit

85%85%

82%82%

83%83%

63%63%

Total disrupted:Total disrupted:

Erkka V and Pawankar R, 2007. Br. Pulm Med

The co-existence of AR with asthma grossly worsened the QOL

Page 13: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Price D, et al. Clin Exp Allergy 2005, in press.(Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in a general practice in the UK)

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

% of patients

hospitalizedannually

0.76

Patients with asthma + allergic rhinitis

(n=4611)

0.45

Patientswith asthma(n=22,692)

p<0.006

Increased Risk of Hospitalization for Asthma in AR Patients

Patients with AR and asthma had an increased risk o f hospitalization

Page 14: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Treating Allergic Rhinitis Decreased Asthma-Related Resource Utilization Treating Allergic Rhinitis Decreased Asthma-Related Resource Utilization

Retrospective cohort study of costs over a period of up to one year incurred by patients 12 to 60 years of age with both allergic rhinitis and asthma.Adapted from Crystal-Peters J et al J Allergy Clin Immunol 2002;109(1):57-62.

0.9

2.5

2.0

1.5

1.0

0.5

0

% ofpatients

Patients untreated forallergic rhinitis (n=1357)

Patients treated forallergic rhinitis (n=3587)

2.3

p<0.01

61% fewer hospitalizations in patients treated for AR

Page 15: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Asthma, AR and SinusitisAsthma, AR and Sinusitis

Page 16: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Ulanovski et al. Am J Rhinol. 2008;22:122.

Subjects ≤≤≤≤25 years of age(n=35)

Pat

ient

s w

ith

Acu

te R

hino

sinu

sitis

(%

)

Total population(N=136)

Controls (n=82)AR (n=54)

P=0.09

P<0.001

Acute Rhinosinusitis Is More Commonin Patients With AR

Acute Rhinosinusitis Is More Commonin Patients With AR

Page 17: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Prevalence of Sinus Mucosal Disease in Patientswith Perennial Allergic Rhinitis

In a study comparing the prevalence of sinusitis in patients with perennial allergic rhinitis (PAR) versus normal controls, Berrettini et al. found a prevalence of 67.5% in 40 patients with PAR versus 33.4% in 30 nonallergic controls.This difference was statistically significant.

Sinusitis - defined by sinus CT scan or rhinoscopy. Thirty-six of the 40 patients with PAR also had positive endoscopic findings.

Page 18: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Increased Risk and Duration of Respiratory Infections in Children

with AR

Increased Risk and Duration of Respiratory Infections in Children

with AR

Tot

al R

I (nu

mbe

r)

Allergic children(n=46)

RI D

urat

ion

(day

s)

P=0.0001

Non-allergic children(n=71)

Allergic children(n=46)

Non-allergic children(n=71)

P=0.009

Ciprandi et al. Pediatr Allergy Immunol. 2006;17:389-391.

Upper Respiratory Infections in Children 5.1 in asthmatic children vs 3.8 in controls

Page 19: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Complications of Acute Rhinosinusitis

Complications of Acute Rhinosinusitis

� Orbital cellulitis (ethmoid)� Meningitis� Subdural/epidural empyema

(frontal)� Brain abscess (frontal)� Cavernous sinus thrombosis

(sphenoid)� Osteomyelitis (frontal)� Asthma exacerbation

Page 20: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Upper Respiratory Infections in Children

Upper Respiratory Infections in Children

� 5.1 in asthmatic children

vs� 3.8 in controls

Minor et al. J. Pediatr. 1974; 85:472-477.

Page 21: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema
Page 22: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Chronic SinusitisChronic Sinusitis

� 50% with chronic sinusitis have OME

� 53% have abnormal sinus radiographs

– 27% near total opacification

G. Shapiro. J. Allergy Clin. Immunol. 1988; 81:1025.

Page 23: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Influx of Eosinophils into the Maxillary Sinuses After Nasal Allergen ChallengeInflux of Eosinophils into the Maxillary Sinuses After Nasal Allergen Challenge

0

100

200

300

400

500

600

700

Pre Dil A1 A2 A3 1 2 3 4 5 6 7 8

Time (hrs)

Tot

al E

osin

ophi

ls

IpsilateralContralateral

*

* *

*

**

*p<0.05 vs DilN=15

*

Page 24: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

RightMaxillary

Sinus

LeftMaxillary

Sinus

Central Nervous System

LeftNostril

RightNostril

Efferent PathwaysAfferent PathwaysAxon Reflexes

Nasal and Sinus Reflexes

Page 25: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

AR and Otitis Media with EffusionAR and Otitis Media with Effusion

Page 26: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Nasal Allergy and Chronic OME in various Paediatric populationsNasal Allergy and Chronic OME

in various Paediatric populations

OME = Otitis Media with Effusion.Tomonaga et al. Acta Otolaryngol. (Stockh) 1988; 458 (suppl):41.

School Children Allergic Rhinitis Children Chroni c OME Children

50% Allergic Rhinitis21% OME

6% OME

1.9% OME + Allergic Rhinitis

17% Allergic Rhinitis

Page 27: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Eustachian Tube Obstruction:Ragweed Pollen Season

Eustachian Tube Obstruction:Ragweed Pollen Season

05

10152025303540

Pre-SeasonalPeak-SeasonalPost-Seasonal

Eustachian Tube

Obstruction (%)

15/58

32/96p<.001

9/62

p<.02

Hurst, Venge. Otolaryngol. Head Neck Surg. 1993; 108:711.

Page 28: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Eosinophils

T-lymphocytes

NonAtopic

CD3+ cells in MEE

Atopic

Same trend for IL-4 and IL-5

Asthma and OME

Nguyen LHP, et al. J Allergy Clin Immunol 2004; 114: 1110.

Page 29: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Asthma and OME

Similar allergic inflammation in the middle ear and the airways

Page 30: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Sinusitis, Asthma and OME in house dust mite AR patients

Sinusitis, Asthma and OME in house dust mite AR patients

Pawankar R et al.

0

5

10

15

20

25

30

35

40

SinusitisAsthmaOME

% of total HDM - AR patients

Page 31: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

Chronic allergic respiratory syndrome

Modified from Stokes JR and Casale T. AR, asthma and OSA- the link. In- Allergy Frontiers Epigenetics to Future Perspective. Eds- Pawankar. Holgate Rosenwasser

SinusitisOME

Page 32: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema

SummarySummary

� Asthma is rarely found in isolation and needs to be considered in the context of systemic allergic disease associated with numerous comorbid disorders

� Upper airway co-morbidities of asthma include AR, sinusitis, and OME( with consequent disordered sleep/ behavioral effects)

� Treating the underlying inflammation is key to relieving symptoms & reducing consequences / co-morbidities in patients with asthma

Page 33: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema
Page 34: Co-morbitities of Asthma - Allergic Rhinitis ... rhinosinusitis-Pawankar.pdfComplications of Acute Rhinosinusitis Orbital cellulitis (ethmoid) Meningitis Subdural/epidural empyema