Rhinitis:

Symptomatic disorder of the nose

characterized by itching, nasal

discharge, sneezing and nasal airway

obstruction

cterized by itching, nasal discharge,

sneezing and nasal airway obstruction

Are rhinitis and asthma two manifestations of one disease?

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

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?

Allergic rhinitis is a risk factor for asthma

Allergic 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 p

atie

nts

wh

o d

eve

lop

ed

ast

hm

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.

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

Rhinitis / Asthma : Similarities

• Frequently coexist

• Respiratory pseudostratified epithelium

• IgE-dependent mechanisms

• Th2 T lymphocyte activation

• Eosinophil rcruitment

• Mast cell / basophil activation and transepithelial migration

Does treating hayfever help patients with asthma?

Antihistamines

Leukotriene antagonists

Nasal corticosteroids

Allergen immunotherapy

Effect of cetirizine in patients with seasonal rhinitis and concomitant asthma

placebo

cetirizine

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

Me

an t

ota

lrh

init

is s

core

Me

an t

ota

las

thm

a sc

ore

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

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.

• Is there a relationship between

rhinitis and asthma ? Yes

• Is the relationship causal ? Yes

• Does treating rhinitis Maybe

improve 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

Rhinitis phenotypes most common forms

• Allergic

• Infectious: Viral (acute), bacterial, fungal

• Non-Allergic, Non-Infectious, Rhinitis

• Non-Allergic Rhinitis with Eosinophilia Syndrome (NARES)

• Chronic Rhinosinusitis with or without Polyps: Hypertrophic,

inflammatory disorder that can affect allergic or non-allergic

individuals

Allergic Rhinitis

• Inflammation to the mucosal lining of the nose caused by inappropriate hypersensitivity reaction to an aeroallergen.

• IgE mediated immune response, with mast cell activation and release of cytokines

Symptoms

• Rhinorrhea

• Cough/sneezing

• Nasal congestion

• Post nasal drip

• Nasal pruritis

• Watery eyes

• General fatigue

• Diminished quality of life

Physical

• General appearance– Allergic shiners, allergic salute, malaise

• Nose– Septal deviation, polyps, drainage, turbinate hypertrophy, hyponasality

• Mouth– Cobblestoning of oropharynx

• Ear– Middle ear pathology

• Neck– Lymphadenopathy, thyroid enlargement

• Chest– wheezing

• Skin– Eczema, dermatographism

Globally important sources of allergens

• House dust mites

• Grass, tree and weed

pollen

• Pets

• Cockroaches

• Molds

Endothelial

cell activation

Leukocyte

infiltration and activation(lymphocytes, eosinophils, basophils)

IMMEDIATE (early)

RESPONSE

LATE-PHASE

RESPONSES

preformed &

newly formed

mediators/cytokines

mast cell

Sneezing

Rhinorrhea

Nasal obstruction

Ocular sympto

Pruritusms

Nasal obstruction

Rhinorrhea

ivNasal

hyperresponseness

To allergens

(priming)

To irritants and to

atmospheric changes

IgE

allergen

dendritic cell

T-lymphocyte

cytokines

chemokines

allergen

B-lymphocyte

IgE

IL-4

IL-13

The nasal allergic response

brain

SNEEZING

PRURITUS

RHINORRHEA

OBSTRUCTION

sensory

nerves

epithelium

glands (mucous)

blood vessels

histamine

sulfidopeptide leukotrienes

The immediate (early phase) allergic

reaction in the nose

Intermittent

Symptoms

• < 4 days / week

• or < 4 weeks

Persistent

Symptoms

• > 4 days / week

• or > 4 weeks

Mild

• Sleep: normal

• Daily activities (incl. sports):

normal

• Work-school activities: normal

• Severe symptoms: no

Moderate- severe

• Sleep: disturbed

• Daily activities: Restricted

• Work and school activities:

disrupted

• Severe symptoms: yes

Allergic rhinitis classification

ALLERGIC RHINITIS AND ITS

IMPACT ON ASTHMA

ARIA

JACI 2001:56: 813-824

Perennial rhinitis: an independent risk factor for asthma

(European Community Respiratory Health Survey)

Adapted from Leynaert B et al. J Allergy Clin Immunol 1999; 104:301

Asthma (%)

Atopic Non atopic

no rhinitis, N=5198

rhinitis, N=1412

OR=11

OR=17

0

5

10

15

20

25

rhinitis

odds ratio

for the

association

with asthma

1

3

6

9

Guerra S et al. J Allergy Clin Immunol 2002;109:419

Test for trend, p < 0.001 Test for trend, p < 0.001

Association of rhinitis with incident asthma in an adult cohort

(173 incident cases and 2,177 controls; approx. 10-yr follow-up)

Diagnosis of allergic rhinitis

• Detailed personal and family allergic history

• Intranasal examination – anterior rhinoscopy

• Symptoms of other allergic diseases

• Allergy skin tests and/or

• In vitro specific IgE tests

Allergy Testing

• Nasal smear

• Skin testing

• In vitro testing

Screening Tests

• Negative result usually requires no additional testing

• Positive result requires further testing of other antigens in the group or family. There may be some cross-reactivity, especially with molds.

• Contain 12 to 14 antigens, (pollen, mold, weeds, dust mite, animal dander)

Allergy skin prick testing

Skin prick test / positive result

Skin prick

• Droplet of antigen is introduced about 1 mm deep into the skin.

• Correlates with RAST, and set endpoint dilutional testing (81-89%). Gungor et al Grade A

• Disadvantages

– Patient discomfort

– Intertester variability

– Non-standardized allergen extracts, and different interpretation scales

Intradermal dilutional testing

• Intradermal testing utilizing serial dilutions to quantify degree of sensitivity to specific antigen.

• Labor intensive

• Patient discomfort due to multiple sticks

• SET – skin endpoint titration

Primary Ab

Secondary Ab

Enzyme

Sample to be

measured

Substrate

Concept of In Vitro IgE assays

Immunoassay

• Not influenced by medication

• Not influenced by skin disease

• Does not require expertise

• Quality control possible

• Expensive

Skin test

• Higher sensitivity

• Immediate results

• Requires expertise

• Cheaper

Immunoassay vs skin test for diagnosis

of allergy

mildintermittent

mildpersistent

moderatesevere

intermittent

moderatesevere

persistent

avoidance of allergens, irritant and pollutants

immunotherapy

intranasal decongestant (<10 days) or oral decongestant

intranasal steroid

oral or local nonsedative H1-blocker

Management of

Allergic Rhinitis: ARIA Guidelines

Modified

leukotriene receptor antagonists

Environmental control

• House dust mites

• Pets

• Cockroaches

• Molds

• Pollen

1. Allergens

2. Pollutants and Irritants

Environmental intervention in urban US

children with asthma

• Tailored to

• Skin test profile

• Environmental exposure

• Caretaker’s report

• House dust mite

• Passive smoking

Adapted from Morgan WJ et al. New Engl J Med 2004;351:1068-80

• Cockroaches

• Pets

• Rodents

• Mold

Environmental control

• The most logical strategy for disease that relates to the indoor environment

• Effectiveness requires comprehensive and multifaceted measures

• More studies are needed to also address the role of indoor pollutants (e.g. NO2, PMs, tobacco smoke, endotoxin)

PHARMACOTHERAPY OF

ALLERGIC RHINITIS

Modified from van Cauwenberge P Allergy 2000;55:116-134

Agents and actions

Oral

antihistam

ines

Nasal

antihistam

ines

Cys-LT1

receptor

antagonists

Nasal

steroids

Nasal

decongest

ants

Oral

decongest

ants

Nasal

ipratropium

Nasal

cromones

Rhinorrhea + + ++ ++ +++ 0 0 +++ +

Congestion + + + +++ ++++ ++ 0 +

Sneezing ++ ++ ++ +++ 0 0 0 +

Pruritus ++ ++ + +++ 0 0 0 +

Ocular symptoms ++ 0 ++ ++ 0 0 0 0

Onset of action 1 hr 15 min 48 hr 12 hr 5-15 min 1 hr 15-30 min -

Duration 12-24 hr 6-12 hr 24 hr 12-48 hr 3-6 hr 12-24 hr 4-12 hr 2-6 hr

Oral antihistamines

• First generation agents

Chlorpheniramine

Brompheniramine

Diphenydramine

Promethazine

Tripolidine

Hydroxyzine

Azatadine

• Newer agents

Acrivastine

Azelastine

Cetirizine

Desloratadine Fexofenadine

Levocetirizine Loratadine

Mizolastine

Efficacy of an antihistamine over 6 months in

persistent allergic rhinitisSneezing Rhinorrhea Pruritus Nose Pruritus Eyes Congestion

*

*

*

*

*

*

*

*

*

*

*

*

*

1.0

0.8

0.6

0.4

0.2

01 wk

4 wk

6 mo 1 wk

4 wk

6 mo 1 wk4 wk

6 mo 1 wk

4 wk

6 mo 1 wk

4 wk

6 mo

mean

Individual

symptom

score

improvement

* P<0.05

fexofenadine120 mg, N = 276

Placebo, N = 271

Baseline total symptom score: 8.95

Placebo

N =201

Fexofenadine 120 mg

N =211

Fexofenadine 180 mg

N =202

Cetirizine 10 mg

N =207*

* *

Change from

baseline in

total symptom

score

(AM, instantaneous,

trough)

0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

Newer antihistamines are equally effective

in the treatment of allergic rhinitis

Baseline symptoms

Study duration

Newer generation oral antihistamines

somnolence/drowsiness

Active Placebo Data Source

Cetirizine

10 mg qd13.7% 6.3% www.PDR.net

Desloratadine

5 mg qd2.1% 1.8% www.PDR.net

Fexofenadine

60 mg bid1.3% 0.9% www.PDR.net

Levocetirizine

5 mg qd6.8% 1.8%

Bachert et al

JACI 2004;114:838

Loratadine

10 mg qd8% 6% www.PDR.net

DecongestantsEFFICACY:

• Oral decongestants: moderate

• Nasal decongestants: high

ADVERSE EFFECTS:

• Oral decongestants: insomnia, tachycardia, hyperkinesia

tremor, increased blood pressure, stroke (?)

• Nasal decongestants: tachyphylaxis, rebound congestion, nasal

hyperresponsiveness, rhinitis medicamentosa

Anti-leukotriene treatment in

allergic rhinitisEfficacy

• Equipotent to H1 receptor antagonists but with onset of action after 2 days

• Reduce nasal and systemic eosinophilia

• May be used for simultaneous treatment of allergic rhinitis and asthma

Safety

• Dyspepsia (approx. 2%)

Nasal corticosteroids

Beclomethasone dipropionate

Budesonide

Ciclesonide*

Flunisolide

Fluticasone propionate

Mometasone furoate

Triamcinolone acetonide

* Currently only approved for asthma

Nasal corticosteroids

• Most potent anti-inflammatory agents

• Effective in treatment of all nasal symptoms including

obstruction

• Superior to anti-histamines and anti-leukotienes

• First line pharmacotherapy for persistent allergic

rhinitis

Allergen immunotherapy

(vaccines)

• Subcutaneous

• Sublingual

• Nasal

DCTh0-lymphocyte

Treg-lymphocyte

Possible mechanisms of immune response

regulation by allergen immunotherapy

Th1

Th2

Possible mechanism: allergen immunotherapy

induces regulatory T-lymphocytes

TH2

lymphocyte

Treg

lymphocyte

B

lymphocyte

interleukin 10

TGF

interleukin 10

TGF

IgG4

Sublingual immunotherapy

• Subcutaneous immunotherapy (SCIT)currentlyrepresents the standard immunotherapymodality,with well ascertained clinical efficacy.

• The first SLIT randomized DBPC-RCT waspublished in 1986. The rationale proposed forSLIT was to improve the safety and to makethe treatment more convenient.

• In SLIT, the allergen extract (prepared as dropsor tablets) is kept under the tongue for 1 to 2minutes and then swallowed; thus, this routeis also called sublingual-swallow. In somestudies a different method was adopted, theallergen was kept under the tongue and thenspat out (sublingual-spit).24 Presently, onlythe sublingual-swallow route is used,therefore the acronym SLIT refers to thesublingual-swallow modality.

Mode of action• Oral mucosa is a natural site of immune tolerance (Langerhans cells,

FcR1, IL-10, IDO [indoleamine• 2,3-dioxygenase]).• Sublingual immunotherapy in optimal doses is effective and may

induce remission after discontinuation and prevent newsensitizations, features consistentwith induction of tolerance.

• Sublingual immunotherapy is associated with:- Retention of allergen in sublingual mucosa for several hours.- Marked early increases in antigen-specific IgE,blunting of seasonal

IgE.- Modest increases in antigen-specific IgG4 and IgEblocking activity.- Inhibition of eosinophils, reduction of adhesion molecules in target

organ.- Some evidence of increase in peripheral T cell IL-10

Selection of patient• To be eligible for SLIT, patients should have:

- A clinical history of allergy.

- Documented ALLERGEN SPECIFIC IgE positive test.

- The allergen used for immunotherapy must be clinicallyrelevant to their clinical history.

- Patients uncontrolled with optimal pharmacotherapy

(SCUAD).

- Patients in whom pharmacotherapy induces undesirable sideeffects.

- Patients refusing injections.

- Patients who do not want to be on constant or longtermpharmacotherapy

Important!

• Age does not seem to be a limitation.

• Monosensitized patients are ideal candidates for SLIT, andrecently single allergen SLIT has been demonstrated to beeffective in polysensitized patients.

• SLIT may be considered as initial treatment. Failure ofpharmacological treatment is not an essential prerequisite forthe use of SLIT.

• SLIT may be proposed as an early treatment in respiratory

allergy therapeutic strategy

Paediatric essentials…

• SLIT is effective in allergic rhinitis in children>= 5

years of age.

• SLIT may be safe in allergic rhinitis in children>= 3

years of age.

• SLIT can be used for allergic rhinitis in childrenwith asthma.

• SLIT should not be suggested as monotherapy for

treating asthma.

• The most important concern that still remainsis to determine the optimal dose of allergenfor SLIT, because the treatment has beenshown effective over a very large range ofdoses (from5–300 times the dose used forSCIT). However, it is clear that the effectivedoses of allergens for SLIT must be higher thanfor SCIT

Omalizumab

IgE

Humanized monoclonal

anti-IgE antibody: omalizumab

C3

region

Anti IgE - omalizumab

• Not licensed to treat allergic rhinitis

• Could be considered in severe cases unresponsive

to conventional treatment

• Could be an adjunct to immunotherapy in severe

cases

NARES

NARES, non-allergic rhinitis with eosinophilia syndrome, is characterized on the basis of 20-25% or greater eosinophils in nasal smears of pt with rhinitis.

There is lack of allergy by skin test, or IgEantibodies.

Prevalence ranges from 13-33% of non-allergic rhinitis.

Idiopathic Rhinitis

Idiopathic rhinitis (IR) is usually diagnosis of exclusion.

Therefore, it is solely diagnosed on patient complaints.

Idiopathic Rhinitis

Exclusion criteria for IR

Positive allergy test

Smoking

Nasal polyps

Pregnancy

Medications affecting nasal function

Beneficial effects of nasal corticosteroid spray (NARES)

Treatment

Immunologic therapy has no benefit to non-allergic rhinitis and therefore it is important to distinguish the disease before considering starting immunotherapy.

Nasal saline lavage has minor decongestant benefits and improves mucociliary function in both allergic and non-allergic rhinitis.

Topical nasal steroids are widely used for treatment of NAR.

They work on the nasal mucosa by decreasing neutrophils and eosinophilchemotaxis, reduced mast cell release and thus decrease edema and inflammation.

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