Are rhinitis and asthma two manifestations of one disease?

Stephen R. Durham

Allergy and Clinical ImmunologyRoyal Brompton Hospital andImperial College London

WAO Cancun Dec 7th 2011

Relationship between rhinitis and asthma – implications for treatment

Is there a relationship between rhinitis and asthma ?

Is the relationship causal ?

Does treating rhinitis improve asthma?

Jarvis D et al Allergy 2011 Nov 4. [Epub ahead of print]

Asthma in adults and its association with chronic rhinosinusitis: The GA(2)LEN survey in Europe.

52,000 adults (18 -75 yr) 19 centres,12 countries.

Strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20-3.76).

Association stronger in those with CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57-13.17).

Allergic rhinitis is a risk factor for asthmaAllergic rhinitis increased the risk of asthma ~3-fold

23-year follow-up of college freshmen undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years.

12

10

8

6

4

2

0% o

f pati

ents

who

dev

elop

ed a

sthm

a

10.5

Allergic rhinitisat baseline

(n=162)

3.6

No allergic rhinitisat baseline

(n=528)

p<0.002

Settipane RJ et al Allergy Proc 1994;15:21-25.

The nose is that part of the lung which is accessible to the finger

Rhinitis / Asthma : Similarities Frequently coexist Respiratory pseudostratified epithelium IgE-dependent mechanisms Th2 T lymphocyte activation Eosinophil rcruitment Mast cell / basophil activation and

transepithelial migration

Rhinitis / Asthma: Differences

Epithelium intact Basement membrane normal No airway smooth muscle Venous sinusoids Submucosal glands prominent Remodelling absent Antihistamines effective 2-agonists ineffective

Epithelium disrupted Basement membrane abnormal Bronchial smooth muscle No venous sinusoids Submucosal glands few Remodelling present Antihistamines ineffective (?) 2-agonists effective

Rhinitis Asthma

Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways.

Braunstahl G-J, Overbeek SE, KleinJan A, Prins J-B, Hoogsteden HC, Fokkens WJ.

J Allergy Clin Immunol 2001;107:469-76.

Study design

AgNasal Ag provocation Nasal Ag provocation

Nasal mucosa Bronchial mucosa

T 24h

T 0h

ICAM-1 VCAM-1 ICAM-1 VCAM-1

0 24

0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

100

Allergic Rhinitis

Controls (n=9)

0 24 0 24

0 24

0 24

0 24

ICAM-1/CD31 VCAM-1/CD31 ELAM-1/CD31

ICAM-1/CD31 VCAM-1/CD31 ELAM-1/CD31

Per

cent

pos

itive

Per

cent

pos

itive

NoseBronchus

NoseBronchus

*

***

** * p<0.05

Influence of nasal challenge on expression of adhesion molecules on blood vessels in the

nasal ( ) and bronchial ( ) mucosa

Treatment of allergic rhinitis

mildintermittent

mildpersistentmoderate

severeintermittent

moderatesevere

persistent

Allergen and irritant avoidance

Immunotherapy

Intra-nasal steroid (+/- antileukotriene)

Oral or topical antihistamine

http://www.whiar.org/

Does treating hayfever help patients with asthma?

Antihistamines Leukotriene antagonists

Nasal corticosteroids

Allergen immunotherapy

High-dose H1 receptor antagonist treatment in persistent asthma

Simons FER. Clin Exp Allergy 1999; 29: S98–104

Effect of cetirizine in patients with seasonal rhinitis and concomitant asthma

placebocetirizine

1 2 3 4 5 6

1 2 3 4 5 6

2

4

6

8

0

2

4

6

8

0

10

Study week

Study week

Mea

n to

tal

rhin

itis s

core

Mea

n to

tal

asth

ma

scor

e

Grant et al. J Allergy Clin Immmunol 1995; 97: 923–732

Does treating hayfever help patients with asthma?

Antihistamines

Leukotriene antagonists

Nasal corticosteroids

Allergen immunotherapy

Philip G. Curr Med Res Opin. 2004 Oct;20(10):1549-58.

Montelukast: Effect on hayfever in patients with asthma (n=631)

* p < 0.001 compared with placebo

Philip G. Curr Med Res Opin. 2004 Oct;20(10):1549-58.

Montelukast: Effect on hayfever in patients with asthma (n=631)

Philip G. Curr Med Res Opin. 2004 Oct;20(10):1549-58.

Does treating hayfever help patients with asthma?

Antihistamines

Leukotriene antagonists

Nasal corticosteroids Allergen immunotherapy

Welsh PW, Stricker WE, Chu CP, Naessens JM,Reese ME, Reed CE and Marcoux.

Efficacy of beclomethasone nasal solution flunisolide,and cromolyn in relieving symptoms of ragweed allergy. Mayo Clin Proc.1987;62:125-34.

All three treatments superior to placebo (p< 0.001). Glucocorticoids more effective than cromolyn (p<0.001). All 3 intranasal treatments ALSO reduced seasonal asthma.

Study randomised but NOT blinded:

100

80

60

40

20

0

7.11 7.24 8.7 8.21 9.49.187.17 7.31 8.14 8.28 9.111984

Treatment

Mea

n w

eekl

y ha

y fe

ver r

aw sc

ore

NasalcromPlacebo

NasalideBeconase aqueous

Welsh PW. Mayo Clinic Proceedings 1987; 62: 125-34.

Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed rhinitis

Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed asthma

15

10

5

0

-5

Asth

ma

scor

e m

ean

wee

kly

diffe

renc

e fr

om b

asel

ine

Treatment

NasalcromPlacebo

NasalideBeconase aqueous

Welsh PW. Mayo Clinic Proceedings 1987; 62: 125-34.

Dahl R. Allergy 2005: 60: 875–881

- DBPC double-dummy study in seasonal rhinitis and asthma- no effect of intranasal steroids on asthma outcomes- no effect of inhaled steroids on nasal outcomes- but ? too mild disease to show an effect

Intranasal and inhaled fluticasone propionate for pollen-induced rhinitis and asthma

Dahl R. Allergy 2005: 60: 875–881

Geometric mean PD20 methacholine measured at baseline () and after 4 weeks treatment () (*** p < 0.001 IHFP ± INFP vs INFP or placebo). INFP, fluticasone proprionate nasal spray; IHFP, inhaled fluticasone propionate.

Does treating hayfever help patients with asthma?

Antihistamines

Leukotriene antagonists

Nasal corticosteroids

Allergen immunotherapy

Allergens of Proven Efficacy in Double-Blind Placebo-Controlled Studies

Birch Cat Mites Grass

Walker SM. J Allergy Clin Immunol 2001; 107: 87-93

% re

duct

ion

from

bas

elin

e (1

998/

1996

)

Subcutaneous immunotherapy for hayfever:effect on symptoms and rescue medication

0

-50

-100

P = .01

P = .007

Immunotherapy group

Placebo group

Symptoms Medication

Walker SM et al JACI 2001; 107: 87-93

50% decrease in nasal Symptoms85% decrease in asthma symptoms

P = .04

Immunotherapy

P = .01 P = ns

Winter SummerSummer

1996 1996 1998

Winter SummerSummer

1996 1996 1998

Placebo

>16.0

16.0

8.0

4.0

2.0

1.0

Met

hach

olin

e PC

20, m

g/m

L

Walker SM. J Allergy Clin Immunol 2001; 107: 87-93

Effect of immunotherapy on airway responsiveness to methacholine

Does treating hayfever help patients with asthma?

Antihistamines

Leukotriene antagonists

Nasal corticosteroids

Allergen immunotherapy

Adams RJ et al. J Allergy Clin Immunol 2002; 109: 636-42.

Retrospective study of 13,844 asthmatics 1031 had emergency dept visit (7.4%) Relative risk-INS 1/yr = 0.7, >3/yr = 0.5 RR anti-histamine = 0.9

Effect of rhinitis treatment on asthmaexacerbations

Adams RJ et al. J Allergy Clin Immunol 2002; 109: 636-42.

Corren J. J Allergy Clin Immunol 2004; 113: 415-9.

Corren J. J Allergy Clin Immunol 2004; 113: 415-9.

Rhinitis therapy and the prevention of hospital care for asthma: A case-control study

Adjusted odds ratios for asthma-related hospital care in relation to intranasal corticosteroid and second generation antihistamine use during 1-year period before the index date

Is there a relationship between rhinitis and asthma ? Yes

Is the relationship causal ? Yes

Does treating rhinitis Maybeimprove asthma?

Relationship between rhinitis and asthma – implications for treatment

Patients with rhinitis should be evaluated for asthma

Patients with asthma should be evaluated for rhinitis

A strategy should combine the treatment of upper and lower airways in terms of efficacy and safety

Recommendations