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 work productivity productivity and and activity activity impairment impairment questionnaire questionnaire

Ability to do daily activities Work productivity Classroom productivity Any work time missed Any classroom time missed
23 91

96

93

23

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 Childs Quality of Life

A great deal and Quite a lot
Ability to get a good nights sleep Participation in leisure & sports . . . Concentration at work/ school Ability to enjoy social activities

A little bit

Totaldisrupted: disrupted: Total 85% 85%

51%

35%

44%

38%

82% 82%

48%

33%

83% 83%

22% 20%

41% 40% 60% 80%

63% 63%

0%

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 10 p<0.002 10.5

% of patients who developed asthma

8 6 4 2 0 No allergic rhinitis at baseline (n=528) Allergic rhinitis at baseline (n=162) 3.6

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 50 40 30 20 10 0 SAR n = 110 PAR n = 44
Type AR at the beginning of the study

seasonal AR perennial AR asthma symptom-free

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 5 0 pollen no rhinitis at baseline animal rhinitis at baseline mite

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 Began after first year Prick skin test positive *
Development of asthma by 6 years When rhinitis began in first year When rhinitis began after first year 13%

77% 57% 20%

23% (p<.005)

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

Allergic Rhinitis and Asthma Have Comon Triggers

Outdoor allergens
Pollens Molds

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

Nonsteroidal AntiAntiinflammatory Drugs (NSAIDs)

(e.g., aspirin)
Ruby Pawankar, NMS

Early and Late Phase Responses in Allergic Rhinitis and Asthma

Upper Airways
(Allergic rhinitis)

Score for nasal symptoms

Sneezing Nasal pruritus Congestion Rhinorrhea

Immediate (early) phase

Late phase

Antigen challenge

34

812

24

Time postchallenge (hours)

Lower Airways
(Asthma)

100

FEV1 (% change)

50

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 Mast cell Preformed Mediators
Cysteinyl leukotrienes Prostaglandins Platelet-activating factor

Early-phase response

Allergen
Eosinophils

T cells

Cytokines

Inflammatory mediators

Late-phase response

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 40 30 20 10 0

CD8+ CD45RO+ EG1+

Cells/mm

out in pollen season

Ruby Pawankar, NMS

Chakir et al, Allergy Clin Immunol 2000

Eosinophilic inflammation in submucosa

Controls
80

Asthmatics
80 untreated CS-dependent 60

60 Eosinophils (/mm2)

40

40

20

20

nose

bronchi

nose

Chanez et al, Am J Respir Crit Care Med 1999

bronchi Ruby Pawankar, NMS

Nasal provocation results in bronchial inflammation

2

n = 14 p = 0.03

1.5

Sputum eosinophils (%) 1

.5

baseline

24 hrs after nasal allergen challenge

Ruby Pawankar, NMS

Bronchial Allergen Challenge Produced Nasal Inflammation

Allergic Patients Control Patients

Blood (N = 16) Eosinophils (106 Cells/mm2) Eosinophils (No. Cells/mm2)

600 500 400 300 200 100 0 T0 T24

Eosinophils (No. Cells/mm2)

1600

Bronchial Subepithelium (N = 16)

Nasal Lamina Propria (N = 16)

100 80 60 40 20 0

1200

800

400

*
0 T0
Unchallenged AllergenLeft Lung Challenged Right Middle Lobe

T0

T24

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.

T24

18 Ruby Pawankar, NMS

Correlation between nasal and bronchial inflammation

Gaga et al. Clin Exp Allergy 2000
40 35 30 EOS in nasal mucosa (asthmatics) 25 20 15 10 5 0 0 5 10 15 20 25 30 EOS in bronchial mucosa (asthmatics) r= 0.851, p<0.001
(n= 17)

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) Flunisolide (n = 19) Treatment Asthma Chest Symptom* Score (Mean Weekly Difference From Baseline) Cromolyn (n = 14) BDP (n = 11)

1400 15 200 1000 10 800 5 600 400 0 200 -5

7/11 7/17 7/24 7/31 Prepeak 8/7 8/14 9/18 Peak 8/21 8/28 Postpeak 9/4 9/11 Daily Ragweed Pollen Count (Grain/ m 3 )

*Chest tightness and wheezing. 1984 Welsh et al. Mayo Clin Proc. 1987;62:125-134

20 Ruby Pawankar, NMS

Antihistamine Improved Asthma Symptoms in Patients With Seasonal AR and Asthma

8
Total Asthma Score

Placebo (n = 93)

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

7 6 5 4 3 2 1 0 0 1 2 3
Week
* P <.05 vs placebo. Grant et al. J Allergy Clin Immunol. 1995;95:923-932.

21 Ruby Pawankar, NMS

Inhibition of the bronchial allergic reaction by an antileukotriene and an antihistamine

100 N = 16 75 % inhibition of the allergen induced drop 50 in FEV1 25 late early

0 montelukast loratadine montelukast and loratadine

Ruby Pawankar, NMS

Percentage of Children After 3 Years of SIT vs. Control With or Without Asthma

Mller 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 cells
Mast cells Eosinophils Th2 cells CD34 Stem cells (the bone marrow connection)

Allergic Rhinitis Asthma + AR Asthma

Same drugs
Anti-IgE Steroids (ICS/INS) Antihistamines (?) Antileukotrienes

Ruby Pawankar, NMS

Increased Risk of ER Visits for Asthma in AR Patients

4.0 3.5 3.0 3.6 2.5 2.0 1.5 1.0 0.5 0 Patients with asthma (n=597) Patients with asthma + allergic rhinitis (n=893) 1.7 p=0.029

% of patients

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 0.7 0.6 p<0.006 0.76

% of patients hospitalized annually

0.5 0.4 0.3 0.2 0.1 0 Patients with asthma (n=22,692) Patients with asthma + allergic rhinitis (n=4611) 0.45

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 Ruby Pawankar, 55 years of age with asthma and allergic rhinitis in a general practice in the UK)

NMS

Treating Allergic Rhinitis Decreased Asthma-Related Resource Utilization

2.5 2.0 2.3 p<0.01

% of patients

1.5 1.0 0.5 0 Patients untreated for allergic rhinitis (n=1357) Patients treated for allergic rhinitis (n=3587) 0.9

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 Air warming & humidification Particle/irritant trapping ( Nitric oxide) Drainage of inflammatory material Systemic propagation of (para)nasal inflammation
Adapted from Togias A. JACI 2003 Ruby Pawankar, NMS

Central sensitization and nasopharyngobronchial reflexes

Link between Rhinitis and Asthma

IL-4 CCR3 CCR4 CCR5

Bone marrow

Allergic Rhinitis

E25

Mc

Th2
IL-4, IL-5 IL-6, IL-13, RANTES Eotaxin IL-3 IL-5 GM-CSF CysLT1 R CysLT2 R IL-5 R, IL-3 R GM-CSF R

Allergen

Histamine Tryptase Cys LTs PGs IL-4, IL-5 IL-6, IL-13, GM-CSF TNF-
Upregulated Adhesion Molecules & chemoattractacta nts

VCAM -1

Eo /Ba progenitor
VLA-4 CCR3 CysLT1 R CysLT2 R

Asthma

Blood vessel

Eosinophil Eosinophil

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