Allergic Rhinitis and Asthma

-the link
Ruby Pawankar, MD, Ph.D
Nippon Medical School,
Tokyo, Japan
rpawankar @gmail.com

Ruby Pawankar, NMS

 The Global Burden of Asthma
 Asthma is one of the most common
chronic diseases in the world, especially
in children
 An estimated 300 million people are
affected worldwide
 Asthma prevalence increases as
communities adopt western lifestyles and
become urbanised
 Asthma mortality is also increasing and
is alarmingly high
Ruby Pawankar, NMS
 Allergic rhinitis

 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.

Ruby Pawankar, NMS

International Study of Asthma &
Allergies in Childhood (ISAAC III)
Asthma Allergic Rhinoconjunctivitis

Ruby Pawankar, NMS

 Impairment Due to Allergic Rhinitis:
work productivity and activity impairment questionnaire

Ability to do daily activities 96

Work productivity 91

Classroom productivity 93

Any work time missed 23

Any classroom time missed 23

0 25 50 75 100
% of patients

AR markedly impairs the QOL of patients

Tanner LA et al. Am J Managed Care 1999;5(Suppl):S235 Ruby Pawankar, NMS

 ASIAN SURVEY : Impact of AR on
Asthma in Child’s Quality of Life

A great deal and Quite a lot A little bit Totaldisrupted:

disrupted:
Total

Ability to get a good 85%

85%
night’s sleep 51% 35%

Participation in 82%
82%
leisure & sports . . . 44% 38%

Concentration at 83%
83%
work/ school 48% 33%

Ability to enjoy 63%

63%
social activities 22% 41%

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

Most patients (73%) had pre-existing AR when diagnosed with asthma.

most troublesome symptom was wheezing (17%) and coughing (17%).

Erkka V and Pawankar R, 2007 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
80% of asthmatics have rhinitis and 40% of
rhinitis patients have asthma
12
p<0.002
10
10.5
% of
8
patients
who
6
developed
asthma 4

3.6
2

0
No allergic rhinitis Allergic rhinitis
at baseline at baseline
(n=528) (n=162)
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. Ruby Pawankar, NMS
 Allergic Rhinitis: Risk Factor for Asthma
Development
Perennial rhinitis often preceeds asthma
10 year prognosis for childhood (3-17 years old) allergic rhinitis

% 70
60 seasonal AR
50
perennial AR
40
30 asthma
20
10 symptom-free

0
SAR n = 110 PAR n = 44
Type AR at the beginning of the study

Linna, et al. Acta Pediatr 1992 Ruby Pawankar, NMS

 Allergic rhinitis as a risk factor for
the development of asthma
Incidence of asthma over an 8-year period in the
Copenhagen Allergy Study

30

25

20
% of subjects 15

10

0
pollen animal mite

no rhinitis rhinitis
at baseline at baseline

Linneberg et al. Allergy 2002;57:1048

Ruby Pawankar, NMS
 Risk factor 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%

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

94:895. Ruby Pawankar, NMS
 Allergic Rhinitis and Asthma
Have Comon Triggers
 Outdoor allergens
– Pollens
– Molds

 Indoor allergens
– House-dust mites
– Animal dander
– Insects (e.g., cockroach
allergen)

 Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)
(e.g., aspirin)

Ruby Pawankar, NMS

Early and Late Phase Responses in Allergic
Rhinitis and Asthma
Upper Score for nasal Immediate (early) phase Late phase
Airways symptoms
(Allergic Sneezing
rhinitis) Nasal pruritus
Congestion
Rhinorrhea
Antigen 1 3–4 8–12 24
challenge
Time postchallenge (hours)

Lower 100
Airways
(Asthma) FEV1
50
(% change)

0
0 1 2 3 4 5 6 7 8 9 10 24
Time (hours)

Adapted from Varner AE, et al. Asthma and Rhinitis 2000

and Togias A. JACI 2000 Ruby Pawankar, NMS
 Common Inflammatory Cells and
Mediators
Membrane-bound
IgE
Preformed Mediators
Mast Cysteinyl leukotrienes Early-phase
cell Prostaglandins response
Platelet-activating factor

Allergen

Eosinophils

Inflammatory Late-phase
T cells Cytokines response
mediators

Adapted from Casale TB, et al. Clin Rev Allergy Immunol 2001 and
Kay AB N Engl J Med 2001 Ruby Pawankar, NMS
 Bronchial biopsies in patients with SAR
60
connective tissue CD4+
50
CD8+
40 CD45RO+
EG1+
30
2
Cells/mm

20

10

0 out in
pollen season
Ruby Pawankar, NMS
Chakir et al, Allergy Clin Immunol 2000
 Eosinophilic inflammation in
submucosa
Controls Asthmatics
80 80
untreated
CS-dependen
60 60
Eosinophils (/mm2)

40 40

20 20

0 0

nose bronchi nose bronchi

Chanez et al, Am J Respir Crit Care Med 1999 Ruby Pawankar, NMS
 Nasal provocation results
in bronchial inflammation
n = 14
2
p = 0.03

1.5

Sputum
eosinophils (%) 1

.5

0
baseline 24 hrs after nasal
allergen challenge

Ruby Pawankar, NMS

 Bronchial Allergen Challenge Produced
Nasal Inflammation
Allergic Patients Control Patients

Blood Bronchial Nasal Lamina Propria

(N = 16) Subepithelium (N = 16)
1600 (N = 1
† 6)
Eosinophils (106 Cells/mm2)

600 * 100 *

Eosinophils (No. Cells/mm2)

Eosinophils (No. Cells/mm2)

†
500
1200 80

400
60
300 800
40
200
400
20
100
*
0 0 0

T0 T24 T0 Unchallenged Allergen- T0 T24

Left Lung Challenged
Right Middle
Lobe
T0 = before challenge; T24 = 24-hr postchallenge.
T24
* P <.05 vs control (T0); †P <.01 vs allergic patients (T0). Braunstahl
et al. Am J Respir Crit Care Med. 2000;161:2051-2057.
Ruby Pawankar, N1M
8S
 Correlation between nasal and
bronchial inflammation
Gaga et al. Clin Exp Allergy 2000
40 (n= 17)
35
30
25
EOS in nasal
mucosa 20
(asthmatics)
15
10
5
r= 0.851, p<0.001
0
0 5 10 15 20 25 30
EOS in bronchial mucosa (asthmatics)

There exists nasal inflammation in asthma despite the presence

of allergic rinitis in atopic individuals (20 to 66 yr old)
Ruby Pawankar, NMS
 Nasal Steroids Reduced Asthma Symptoms in
Patients With Seasonal AR and Seasonal Asthma
Placebo (n = 14) Cromolyn (n = 14)

Flunisolide (n = 19) BDP (n = 11)

Treatment
1400
(Mean Weekly Difference From Baseline)

15 200
Asthma Chest Symptom* Score

Daily
1000 Ragweed
10 Pollen
800 Count
(Grain/ m 3 )

5 600

400
0
200

-5 Prepeak Peak Postpeak 0

7/11 7/17 7/24 7/31 8/7 8/14 8/21 8/28 9/4 9/11
*Chest tightness and wheezing.1984 9/18
Welsh et al. Mayo Clin Proc. 1987;62:125-134
Ruby Pawankar, N2M
0S
 Antihistamine Improved Asthma Symptoms
in Patients With Seasonal AR and Asthma

8 Placebo (n = 93) Cetirizine (10 mg/d) (n = 93)

7
Total Asthma Score

6
5
4
* * * * *
3
2
1
0
0 1 2 3 4 5 6
Week
* P <.05 vs placebo.
Grant et al. J Allergy Clin Immunol. 1995;95:923-932.
Ruby Pawankar, N2M
1S
 Inhibition of the bronchial allergic reaction by an
antileukotriene and an antihistamine

100
early
N = 16
late
75
% inhibition of
the allergen
induced drop 50
in FEV1

25

0
montelukast loratadine montelukast
and
loratadine

Ruby Pawankar, NMS

 Percentage of Children After 3 Years of
SIT 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 Same mediators

• Upper and lower airways are contiguous • IgE
• Functional linkage - nose vs. mouth breathing •Cytokines
• Similar histology • Histamine
• Leukotrienes

Allergic
Same cells
•Mast cells
Rhinitis Same drugs
• Eosinophils • Anti-IgE
• Th2 cells Asthma • Steroids (ICS/INS)
•CD34 Stem cells • Antihistamines (?)
(the bone marrow + AR
• Antileukotrienes
connection)

Asthma
Ruby Pawankar, NMS
 Increased Risk of ER Visits for Asthma in
AR Patients
4.0
p=0.029
3.5 3.6
3.0
2.5
% of
patients 2.0
1.5 1.7
1.0
0.5
0
Patients Patients with asthma
with asthma + allergic rhinitis
(n=597) (n=893)

Patients with AR and asthma had an increased risk of ER visits

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)
Ruby Pawankar, NMS
 Increased Risk of Hospitalization for
Asthma in AR Patients
0.8 p<0.006

0.7 0.76
0.6
% of
patients 0.5
hospitalized 0.45
0.4
annually
0.3
0.2
0.1
0
Patients Patients with asthma
with asthma + allergic rhinitis
(n=22,692) (n=4611)

Patients with AR and asthma had an increased risk of hospitalization

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) Ruby Pawankar, NMS
 Treating Allergic Rhinitis Decreased
Asthma-Related Resource Utilization

2.5 p<0.01

2.0 2.3

% of 1.5
patients 0.9
1.0

0.5

0
Patients untreated for Patients treated for
allergic rhinitis (n=1357) allergic rhinitis (n=3587)

61% fewer hospitalizations in patients treated for AR

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.
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, NMS
 Interactions Nose – Lower Airways:
Possible Mechanisms of Relationship

 Mouth breathing
Central
sensitization and   Air warming &
nasopharyngo- humidification
bronchial reflexes
 
Particle/irritant
trapping

Drainage of  ( Nitric oxide)

inflammatory Systemic
material propagation of
(para)nasal
inflammation

Adapted from Togias A. JACI 2003 Ruby Pawankar, NMS

 Link between Rhinitis and Asthma
CCR3
CCR4
C CR5 Bone marrow
E25 IL-4

Allergic Rhinitis Mc Th2

IL-3
IL-5
IL-4, IL-5
GM-CSF CysLT1 R
Histamine IL-6, IL-13,
Tryptase RANTES CysLT2 R
Allergen IL-5 R, IL-3 R
Cys LTs Eotaxin
PGs GM-CSF R
IL-4, IL-5 Eo /Ba
IL-6, IL-13, progenitor
VCAM
GM-CSF VLA-4
-1
TNF-
CCR3
Asthma CysLT1 R
Upregulated CysLT2 R
Adhesion Blood vessel
Molecules & Eosinophil
chemoattractacta
nts
Eosinophil

c Pawankar R 2006-.Clin Exp Allergy 36(1): 1-4, 2006. Ruby Pawankar, NMS
 Asthma and Rhinitis
One Airway, One Disease?

Togias: ‘Asthma and rhinitis are

manifestations of one syndrome, the chronic
allergic respiratory syndrome’
JACI 2003
Ruby Pawankar, NMS
Ruby Pawankar, NMS
Ruby Pawankar, NMS