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Ruby Pawankar, NMS
Allergic Rhinitis and AsthmaAllergic Rhinitis and AsthmaAllergic Rhinitis and AsthmaAllergic Rhinitis and Asthma
----the linkthe linkthe linkthe link
Ruby Pawankar, MD, Ph.D
Nippon Medical School,
Tokyo, Japan
rpawankar @gmail.com
Ruby Pawankar, NMS
The Global Burden of AsthmaThe Global Burden of Asthma
� Asthma is one of the most common Asthma is one of the most common chronic diseases in the world, especially chronic diseases in the world, especially in childrenin children
�� An estimated 300 million people are An estimated 300 million people are affected worldwideaffected worldwide
�� Asthma prevalence increases as Asthma prevalence increases as communities adopt western lifestyles and communities adopt western lifestyles and become urbanisedbecome urbanised
�� Asthma mortality is also increasing and is Asthma mortality is also increasing and is alarmingly highalarmingly high
Ruby Pawankar, NMS
● Allergic rhinitis is a global health problem affecting 10 to 50 % of the population
● Its prevalence is increasing. ● Although it is not usually a severe disease,
rhinitis alters social life and affects school performance and work productivity.
● Costs incurred by rhinitis are substantial.● Most importantly, Allergic rhinitis is a risk
factor for asthma.
Allergic rhinitis
Ruby Pawankar, NMS
Asthma Allergic Rhinoconjunctivitis
International Study of Asthma & Allergies in Childhood (ISAAC III)International Study of Asthma & Allergies in Childhood (ISAAC III)
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Impairment Due to Allergic Rhinitis: work productivity and activity impairment questionn aireImpairment Due to Allergic Rhinitis: work productivity and activity impairment questionn aire
23
23
93
91
96
0 25 50 75 100
Tanner LA et al. Am J Managed Care 1999;5(Suppl):S235
% of patients
Ability to do daily activities
Work productivity
Classroom productivity
Any work time missed
Any classroom time missed
AR markedly impairs the QOL of patients
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22% 41%
48% 33%
44% 38%
51% 35%
0% 20% 40% 60% 80% 100%
ASIAN SURVEY : Impact of AR on Asthma in Child’s Quality of LifeASIAN SURVEY : 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
Most patients (73%) had pre-existing AR when diagnosed with asthma. most troublesome symptom was wheezing (17%) and coughing (17%).
Ruby Pawankar, NMS
Asthma and Rhinitis
• Common Triggers
• Epidemiological Link
• Common inflammatory processes
• Pathophysiological links
• Treatment Outcomes
Ruby Pawankar, NMS
Allergic Rhinitis Is a Risk Factor for Asthma
Allergic Rhinitis Is a Risk Factor for Asthma
� 80% of asthmatics have rhinitis and 40% of rhinitis patients have 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
Ruby Pawankar, NMS
Perennial rhinitis often preceeds asthma
0
10
20
30
40
50
60
70%
SAR n = 110 PAR n = 44
Type AR at the beginning of the study
seasonal AR
perennial AR
asthma
symptom-free
Allergic Rhinitis: Risk Factor for Asthma Development
10 year prognosis for childhood (3-17 years old) allergic rhinitis
Linna, et al. Acta Pediatr 1992
Ruby Pawankar, NMS
0
5
10
15
20
25
30
Linneberg et al. Allergy 2002;57:1048
Allergic rhinitis as a risk factor forthe development of asthma
Incidence of asthma over an 8-year period in the
Copenhagen Allergy Study
% of subjects
pollen animal mite
no rhinitis
at baseline
rhinitis
at baseline
Ruby Pawankar, NMS
� 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%
* Only 50% of study children skin tested.Wright et al. Pediatrics. 1994; 94:895.
Risk factor in ChildrenRisk factor in Children
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� Outdoor allergensOutdoor allergensOutdoor allergensOutdoor allergens
– PollensPollensPollensPollens
– MoldsMoldsMoldsMolds
� Indoor allergensIndoor allergensIndoor allergensIndoor allergens
– HouseHouseHouseHouse----dust mitesdust mitesdust mitesdust mites
– Animal danderAnimal danderAnimal danderAnimal dander
– Insects (e.g., cockroach Insects (e.g., cockroach Insects (e.g., cockroach Insects (e.g., cockroach allergen)allergen)allergen)allergen)
� Nonsteroidal AntiNonsteroidal AntiNonsteroidal AntiNonsteroidal Anti----inflammatory Drugs (NSAIDs) inflammatory Drugs (NSAIDs) inflammatory Drugs (NSAIDs) inflammatory Drugs (NSAIDs) (e.g., aspirin)(e.g., aspirin)(e.g., aspirin)(e.g., aspirin)
Allergic Rhinitis and Asthma Have Comon Triggers
Allergic Rhinitis and Asthma Allergic Rhinitis and Asthma Have Comon TriggersHave Comon Triggers
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Early and Late Phase Responses in Allergic Rhinitis and Asthma
Early and Late Phase Responses in Allergic Rhinitis and Asthma
Adapted from Varner AE, et al. Asthma and Rhinitis 2000and Togias A. JACI 2000
(Asthma)
Score for nasal symptoms
SneezingNasal pruritus
CongestionRhinorrhea
Time postchallenge (hours)
1Antigen challenge
3–4 8–12 24
Immediate (early) phase Late phase
FEV1
(% change)
Time (hours)
0
50
100
1 10 240 2 3 4 5 6 7 8 9
Upper Airways
Lower Airways
(Allergic rhinitis)
Ruby Pawankar, NMS
Adapted from Casale TB, et al. Clin Rev Allergy Immunol 2001 and
Kay AB N Engl J Med 2001
Early-phaseresponse
Late-phaseresponse
T cells Inflammatorymediators
Allergen
Cytokines
Preformed MediatorsCysteinyl leukotrienes
ProstaglandinsPlatelet-activating factor
Eosinophils
Membrane-bound IgE
Mastcell
Common Inflammatory Cells and Mediators
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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
Ruby Pawankar, NMSnose 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
Ruby Pawankar, NMS
0
.5
1
1.5
2
Sputum
eosinophils (%)
baseline 24 hrs after nasal
allergen challenge
n = 14
p = 0.03
Nasal provocation results in bronchial inflammation
Ruby Pawankar, NMS
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
18
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
†
†* *
*
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Correlation between nasal and bronchial inflammationGaga et al. Clin Exp Allergy 2000
40
35
30
25
20
15
10
5
0
EOS in nasal EOS in nasal mucosa mucosa
(asthmatics)(asthmatics)
0
r= 0.851, p<0.001r= 0.851, p<0.001
EOS in bronchial mucosa (asthmatics)EOS in bronchial mucosa (asthmatics)
5 10 15 20 25 30
(n= 17)
There exists nasal inflammation in asthma despite the presThere exists nasal inflammation in asthma despite the preseence nce of allergic rinitis in atof allergic rinitis in atoopic individuals (20 to 66 yr old)pic individuals (20 to 66 yr old)
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Nasal Steroids Reduced Asthma Symptoms inPatients With Seasonal AR and Seasonal Asthma
Nasal Steroids Reduced Asthma Symptoms inPatients With Seasonal AR and Seasonal Asthma
20
*Chest tightness and wheezing.Welsh et al. Mayo Clin Proc. 1987;62:125-134
Treatment
Placebo (n = 14)
Flunisolide (n = 19)
Cromolyn (n = 14)
BDP (n = 11)
Ast
hma
Che
st S
ympt
om*
Sco
re
(Mea
n W
eekl
y D
iffer
ence
Fro
m B
asel
ine)
15
10
5
0
-5
1400
200
1000
800
600
400
200
0
7/11 7/17 7/24 7/31 8/7 8/14 8/21 8/28 9/4 9/11 9/18
Prepeak PostpeakPeak
DailyRagweed
PollenCount
(Grain/ m 3 )
1984
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Antihistamine Improved Asthma Symptomsin Patients With Seasonal AR and Asthma
Antihistamine Improved Asthma Symptomsin Patients With Seasonal AR and Asthma
21
* P <.05 vs placebo.Grant et al. J Allergy Clin Immunol. 1995;95:923-932.
0
1
2
3
4
5
6
7
8
0 1 2 3 4 5 6
Placebo (n = 93) Cetirizine (10 mg/d) (n = 93)
Week
Tot
al A
sthm
a S
core
*****
Ruby Pawankar, NMS
0
25
50
75
100
montelukast loratadine montelukast
and
loratadine
Inhibition of the bronchial allergic reaction by anantileukotriene and an antihistamine
early
lateN = 16
% inhibition
of the allergen
induced drop
in FEV1
Ruby Pawankar, NMS
Percentage of Children After 3 Years ofSIT vs. Control With or Without AsthmaPercentage of Children After 3 Years ofSIT vs. Control With or Without Asthma
Möller C, et al. J Allergy Clin Immunol. 2002; 109:251-256.
Ruby Pawankar, NMS
Asthma and allergic rhinitis – Two related conditions linked by one common airway
Anatomy/Physiology• Upper and lower airways are contiguous
• Functional linkage - nose vs. mouth breathing
• Similar histology
Same mediators• IgE
•Cytokines
• Histamine
• Leukotrienes
Same drugs• Anti-IgE
• Steroids (ICS/INS)
• Antihistamines (?)
• Antileukotrienes
Asthma
Allergic Rhinitis
Asthma+ AR
Same cells• Mast cells
• Eosinophils
• Th2 cells
• CD34 Stem cells (the bone marrow connection)
Ruby Pawankar, NMS
% of patients
Patients with asthma + allergic rhinitis
(n=893)
Patientswith asthma
(n=597)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
p=0.029
1.7
3.6
Bousquet J, et al. Poster presented at the (EAACI) 2004 (Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic rhinitis over 52 weeks)
Increased Risk of ER Visits for Asthma in AR Patients
Patients with AR and asthma had an increased risk o f ER visits
Ruby Pawankar, NMSPrice 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
Ruby Pawankar, NMS
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
Ruby Pawankar, NMS
Asthma and Allergic Rhinitis – Two Related Conditions Linked by One Common Airway
Module 1: The underlying mechanisms of the United Airway concept
Asthma and Allergic Rhinitis: WAO Online Lecture Series
Ruby Pawankar, NMSAdapted from Togias A. JACI 2003
Interactions Nose – Lower Airways : : Possible Mechanisms of Relationship
Central sensitization and nasopharyngo-bronchial reflexes
Drainage of inflammatory material
� Mouth breathing
� ↓↓↓↓ Air warming & humidification
� ↓↓↓↓ Particle/irritant trapping
� (↓↓↓↓ Nitric oxide)
Systemic propagation of (para)nasal inflammation
Ruby Pawankar, NMS
Link between Rhinitis and Asthma
Eosinophil
CCR3CCR4CCR5
VLA-4VCAM-1
Th2
CCR3CysLT1 RCysLT2 R
CysLT1 RCysLT2 RIL-5 R, IL-3 RGM-CSF R
IL-4, IL-5IL-6, IL-13,RANTESEotaxin
Eo /Ba progenitor
IL-3IL-5GM-CSF
Asthma
Allergic Rhinitis
Eosinophil
E25 Mc
HistamineTryptaseCys LTsPGsIL-4, IL-5IL-6, IL-13,GM-CSFTNF-α
IL-4Bone marrow
Blood vessel
Allergen
UpregulatedAdhesion Molecules & chemoattractactants
Pawankar R 2006-.Clin Exp Allergy 36(1): 1-4, 2006.c
Ruby Pawankar, NMS
One Airway, One Disease?One Airway, One Disease?
Togias: ‘Asthma and rhinitis are manifestations of one syndrome, the chronic
allergic respiratory syndrome’JACI 2003
Asthma and Rhinitis
Ruby Pawankar, NMS
Ruby Pawankar, NMS