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

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.

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

Asthma and ARAsthma and AR

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

* 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

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

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

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

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

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

†

†* *

*

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

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

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

Asthma, AR and SinusitisAsthma, AR and Sinusitis

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

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.

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

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

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.

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.

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

*

RightMaxillary

Sinus

LeftMaxillary

Sinus

Central Nervous System

LeftNostril

RightNostril

Efferent PathwaysAfferent PathwaysAxon Reflexes

Nasal and Sinus Reflexes

AR and Otitis Media with EffusionAR and Otitis Media with Effusion

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

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.

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.

Asthma and OME

Similar allergic inflammation in the middle ear and the airways

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

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

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