Module 1:

Allergic Rhinitis
an educational program of:

Updated: June 2011

 Global Resources in Allergy
(GLORIA™)
Global Resources In Allergy (GLORIA™) is the
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Organization (WAO). Its curriculum educates
medical professionals worldwide through
regional and national presentations. GLORIA
modules are created from established
guidelines and recommendations to address
different aspects of allergy-related patient care.
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The World Allergy Organization is an

international coalition of 89 regional
and national allergy and clinical
immunology societies.
 WAO’s Mission
WAO’s mission is to be a global
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allergy, advancing excellence in clinical
care, education, research and training
through a world-wide alliance of allergy
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Module 1: Allergic Rhinitis

Revised in 2007 by:

Omer Kalayci, MD
Ankara, Turkey

Alkis Togias, MD
Bethesda, MD, USA
 The full GLORIA Module on Allergic
Rhinitis
consists of 105 slides.

The WAO GLORIA presenter will select

slides
from this set for presentation today.

These slides will be available for download

for
your own teaching
at: [Link]/gloria
 GLORIA resource documents
• Allergic Rhinitis and Its Impact on Asthma
(ARIA): JACI 2001:56: 813-824
• Contemporary Approaches to Ocular Allergy
Management: American College of Allergy,
Asthma and Immunology, 1998.
• Consensus Statement on the Treatment of
Allergic Rhinitis. Allergy 2000: 55: 116-134
• World Allergy Forum program series: WAO
2000-2003
• Rhinitis: Symptomatic disorder of the nose
characterized by itching, nasal discharge,
sneezing and nasal airway obstruction

• Allergic rhinitis: Induction of rhinitis

symptoms after allergen exposure by an IgE-
mediated immune reaction; accompanied by
inflammation of the nasal mucosa and nasal
airway hyperreactivity.
 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
 Rhinitis phenotypes
less common forms
• Occupational: May be allergic or non-allergic
• Drug-induced: Aspirin, some vasodilators
• Hormonal: Pregnancy, menstruation, hormonal
contraceptives, thyroid disorders
• Food-induced (gustatory)
• Cold air-induced (skier’s nose)
• Atrophic (rhinitis of the elderly)
Conditions that mimic rhinitis
• Cystic fibrosis
• Mucociliary defects

• Cerebrospinal rhinorrhoea

• Anatomic abnormalities

• Foreign bodies

• Tumors

• Granulomas: Sarcoid, Wegener’s, Midline Granuloma

 Non-allergic,
non-infectious rhinitis
(a poorly-defined phenotype)

Pathophysiologic hypotheses
• Non-inflammatory (vasomotor)
– Sensorineural hyperresponsiveness
– Hyperesthesia
– Dysautonomia
• Local allergic reaction
 Non-inflammatory rhinitis
1

*
0.75

Ratio of
eosinophils/ 0.5
epithelial
cells
in mucosal
scrapings 0.25

0
Healthy Non-allergic Allergic
Controls Rhinitis Rhinitis
N = 25 N = 18 N = 25
Numata T et al:Int Arch Allergy Immunol 1999;119:304-313
S. Karger AG, Basel
 Local allergic reaction
(nasal challenges with allergen in non-allergic rhinitics)

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Carney et al. Clin Exp Allergy 2002;32:1436

 IgE can be produced in the nasal mucosa
In situ hybridization for I mRNA - tissue obtained from subjects with alleric rhinitis

Not exposed to
ragweed

Exposed to
ragweed
I RNA+ cells
(germline
transcript)

Cameron et al J Immunol 2003;171:3816

 Prevalence of rhinitis in adults
NUMBER OF
AUTHOR YEAR AGE RANGE COUNTRY PREVALENCE
SUBJECTS

Droste 1996 20-70 2,167 Netherlands 29.5%

Sakurai 1998 19-65 (males) 2,307 Japan 35.5%

Ng 1994 20-74 2,868 Singapore 10.8%

Bachert 2006 > 15 4,959 Belgium 39.3%

Dinmezel 2005 20-44 995 Turkey 27.7%

United
Sibbald 1991 16-65 2,969 24%
Kingdom

Turkeltaub 1991 12-74 12,742 United States 30.5%

 Allergic vs. nonallergic rhinitis
N = 10,854; >12 years old; NHANES II data (USA, 1976-80)
Positive skin tests Negative (or equivocal) skin tests
AGE

Seasonal symptoms 12-24

or 25-49
Diagnosis of “hay fever”
(9.8%) 50-74

Perennial symptoms 12-24

and no 25-49
Diagnosis of “hay fever”
(20.4%) 50-74

0 25 50 75 100
% of subjects in each group

apted from Gergen and Turkeltaub Arch Int Med 1991;151:487

pyright © 1991, American Medical Association
 Current Prevalence of Allergic
Rhinoconjunctivitis
ISAAC phase 1 & 3 (7 years apart)
Age: 6-7 years

Copyright permission for reproduction pending

Adapted from Lancet 2006;368:733-743

 Current Prevalence of Allergic
Rhinoconjunctivitis
ISAAC phase 1 & 3 (7 years apart)
Age: 13-14 years

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pending

Adapted from Lancet 2006;368:733-743

 Allergic rhinitis: impact

• High prevalence
• Impaired quality of life
• Work and school absence
• Impaired learning
• Impaired sleeping
• Associated asthma, sinusitis, otitis
 Short form health survey (SF-36)
profiles of patients with allergic rhinitis
90 controls (n=139)
allergic rhinitis (n=312)
†
85 * scale: 0 to 100
80

Declining 75 *
health *
status 70 *
65 *

60

55 *

50
Physical Role– Bodily General Vitality Social Role– Mental Change in
Functioning Physical Pain Health Emotional Health Health
Functioning
Domains

Adapted from Meltzer EO et al. J Allergy Clin Immunol. 1997;99:S815

 Impairment due to allergic rhinitis:
work productivity and activity impairment questionnaire

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nner LA et al. Am J Managed Care 1999;5(Suppl):S235

Allergic rhinitis co-morbidities

• Conjunctivitis
• Sinusitis
• Otitis Media
• Cough
• Asthma
 Co-existence of allergic conjunctivitis
with other allergic diseases
45 p=0.006
40
35
30
% with 25
conjunctivitis
20
15
10
5
0
All rhinitis Asthma Eczema All rhinitis + asthma
n=316 n= 324 n=149 n=203

Adapted from Gradman J and Wolthers OD Pediatr Allergy Immunol.

2006;17:524-6
 Presence of sinus disease based on CT findings in
patients with allergic rhinitis and controls
Total
With positive sinus CT
40
p=0.017
35

30

25 67.5%

Number of subjects 20

15

10
33.4%
5

0
Allergic rhinitis Controls

errettini et al., Allergy. 1999;54:242-8.

 Allergic rhinitis as a risk factor for chronic sinusitis
Ear Nose Throat-related flight disqualifying events that developed over a 5-
year period in Naval Flight Personnel with only allergic rhinitis (N=465)
versus controls (N=12,628)

Relative Risk 95% CI

Chonic Sinusitis 4.5 (1.7-11.6)

Alternobaric Disease 1.6 (0.4-6.6)

Polyposis 1.2 (0.2-8.7)

Conductive Hearing
0.9 (0.1-6.6)
Loss
Requirement for ENT
3.4 (0.4-27.1)
Surgery

Walker C. et al. Aviat Space Environ Med. 1998; 69:952

 Allergic rhinitis: the basis of
co-morbidity with otitis media
with effusion

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Adapted from Sobotta, Atlas der Anatomie des Menschen. Bd. 1, 21;
2000.
 Risk factors for otitis media in children
O: otitis media with effusion (N=172)
C: controls (N=200 )

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apted form Caffarelli et al., Clin Exp Allergy 1998;28:591-596

 Risk factors for otitis media in children

Multivariate logistic regression for risk of OME

Case-control study in children 1-7 years (N=88 cases, N=88 controls)

hantzi FM et al. Allergy 2006;61:332

 Nasal treatment improves cough
in patients with seasonal allergic rhinitis
(15-day treatment)

1.0
*
0.8
Mean baseline score: 2.3
Mean improvement 0.6
Mometasone, N=122
from baseline
in the cough Placebo, N=123
0.4
symptom score
0.2

0.0

Adapted from Gawchik S et al. Ann Allergy Asthma Immunol 2003;90:416

 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)

25

OR=11 no rhinitis, N=5198

20
rhinitis, N=1412
15

Asthma (%)
OR=17
10

0
Atopic Non atopic

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

 Association of rhinitis with incident asthma
in an adult cohort
(173 incident cases and 2,177 controls; approx. 10-yr follow-up )

Test for trend, p < 0.001 Test for trend, p < 0.001
9

odds ratio
6
for the
association
with asthma 3

ld
ne
ne

re
e
t

nt
t en

mi

ra t
no
no

ve
s te

de
si s

se
rs i

mo
on

pe
i nc

rhinitis

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

 In patients with rhinitis:
• Routinely query for symptoms suggestive of asthma

• Perform chest examination

• Consider lung function testing

• Consider tests for bronchial hyperresponsiveness in selected cases

 Allergic rhinitis classification
Intermittent Persistent
Symptoms Symptoms
• < 4 days / week • > 4 days / week
• or < 4 weeks • or > 4 weeks

Mild Moderate- severe

• Sleep: normal • Sleep: disturbed
• Daily activities (incl. sports): • Daily activities: Restricted
normal • Work and school activities:
• Work-school activities: disrupted
normal • Severe symptoms: yes
• Severe symptoms: no
 Seasonal allergic rhinitis ≠ intermittent
perennial allergic rhinitis ≠ persistent

Intermittent Persistent

Seasonal
Allergic 133 60
Rhinitis (n=193)

Perennial
Allergic 151 57
Rhinitis (n=208)

Bauchau, V. & Durham, S. R. Allergy 2005; 60 (3), 350-353.

Globally important sources of allergens

• House dust mites

• Grass, tree and weed
pollen
• Pets
• Cockroaches
• Molds
 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 skin prick testing
Skin prick test / positive result
 Concept of In Vitro IgE assays

Substrate

Enzyme

Secondary Ab

Sample to be
measured
Primary Ab
In Vitro specific IgE assay (standard curve)
4.5
4
3.5
spectrophotometric outcome (OD)

3
2.5
2
1.5
1
0.5
0
0 200 400 600 800 1000 1200
IgE IU/ml
Immunoassay vs skin test for diagnosis
of allergy

Immunoassay Skin test

• Not influenced by • Higher sensitivity
medication
• Not influenced by skin • Immediate results
disease • Requires expertise
• Does not require expertise • Cheaper
• Quality control possible
• Expensive
 Other diagnostic tests

• Nasal secretion / scraping cytology

• Nasal allergen challenge
• Nasal endoscopy
• CT scan
– anatomic abnormalities
– concomitant presence of sinusitis
 The nasal allergic response
allergen preformed & cytokines
newly formed chemokines
IgE mediators/cytokines

Endothelial allergen
cell activation
mast cell
dendritic cell
Leukocyte
infiltration and activation IL-4 T-lymphocyte
(lymphocytes, eosinophils, basophils) IL-13

B-lymphocyte

IMMEDIATE (early) LATE-PHASE

RESPONSE RESPONSES

Sneezing Nasal obstruction Nasal

Pruritus Rhinorrhea hyperresponsiveness
Rhinorrhea
Nasal obstruction IgE
Ocular symptoms To allergens To irritants and to
(priming) atmospheric changes
 The immediate (early phase) allergic
reaction in the nose
brain PRURITUS

sensory
nerves

epithelium

SNEEZING blood vessels

glands (mucous)

OBSTRUCTION

RHINORRHEA histamine

sulfidopeptide leukotrienes
 Cellular infiltration and activation at the site
of an allergic reaction

usse WW, Lemanske RF Jr. N Engl J Med. 2001;344:350-62.

 Nasal hyperresponsiveness in allergic rhinitis
7

Sneezes 4
induced by p<0.0001
histamine* 3 N = 25

1
N = 18
* same dose in both groups 0
Perennial Healthy
Allergic
Rhinitis
anico AM et al:Int Arch Allergy Immunol 1999;118:154-158
Karger AG, Basel
 Nasal priming in the natural
presentation of seasonal allergic rhinitis

The ratio of symptoms

to pollen counts almost
doubles between the
beginning to the end
of the pollen season

Norman P. J Allergy 1969;44:129

MANAGEMENT OF
ALLERGIC RHINITIS
 Management of
Allergic Rhinitis: ARIA Guidelines
moderate
mild severe
moderate persistent
severe persistent
mild intermittent
intermittent intranasal steroid
oral or local nonsedative H1-blocker

intranasal decongestant (<10 days) or oral decongestant

leukotriene receptor antagonists
avoidance of allergens, irritant and pollutants

immunotherapy

Modified from Bousquet J et al. J Allergy Clin Immunol. 2001;108:S147.

 Stepwise management of allergic rhinitis

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Modified from ARIA workshop, 2001

 Environmental control
1. Allergens
• House dust mites
• Pets
• Cockroaches
• Molds
• Pollen

2. Pollutants and Irritants

 Allergen avoidance
• Pets
• Remove pets from bedrooms and, even better, from the entire home
• Vacuum carpets, mattresses and upholstery regularly
• Wash pets regularly (±)
• Molds
• Ensure dry indoor conditions
• Use ammonia to remove mold from bathrooms and other wet spaces
• Cockroaches
• Eradicate cockroaches with appropriate gel-type, non-volatile, insecticides
• Eliminate dampness, cracks in floors, ceilings, cover food; wash surfaces, fabrics to
remove allergen
• Pollen
• Remain indoors with windows closed at peak pollen times
• Wear sunglasses
• Use air-conditioning, where possible
• Install car pollen filter
House dust mite allergen avoidance
– Provide adequate ventilation to decrease humidity

– Wash bedding regularly at 60°C

– Encase pillow, mattress and quilt in allergen impermeable

covers

– Use vacuum cleaner with HEPA filter

– Dispose of feather bedding

– Remove carpets

– Remove curtains, pets and stuffed toys from bedroom

2003;349:237
 Bed covers in persistent
allergic rhinitis
Der p1 and Der f1 in mattress (µg/g of dust)

No. of patients 79 87

Base-line concentration 4.12 (2.93-5.79) 5.91 (4.00-8.73) 0.18

12-Mo concentration 1.29 (0.95-1.75) 4.84 (3.62-6.47) <0.001

Mean change (95%Cl) .31 (0.21 to 0.46) 0.82 (0.58 to 1.15)

P value <0.001 0.25

Difference between 0.38 (0.23 to 0.64) <0.001

changes (95%Cl)§

erreehorst et al. N Engl J Med. 2003;349:237

 Bed covers in persistent allergic rhinitis
Variable Impermeable- Control Group P
Cover Group Value
Primary end point
Rhinitis-spcific visual-analogue scale

No. of patients 114 118

Base-line score 52.18+2.79 49.82+2.76 0.56

12-Mo score 42.35+2.79 38.96+2.68 0.38

Mean change (95%Cl) -9.83 (-15.28 to- -10.86 (-16.64 to-5.09)

P value 4.39) <0.001
<0.001
Difference between changes 1.03 (-6.87 to 8.94) 0.80
(95%Cl)

erreehorst et al. N Engl J Med. 2003;349:237

2004;351:1068-80
 Environmental intervention in urban US
children with asthma
937 subjects
randomized

469 assigned
468 assigned
to environmental
to control
intervention

444 included in 407 included in 425 included in 414 included in

Year 2 analyses Year 2 analyses Year 1 analyses Year 2 analyses

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

 Environmental intervention in
urban US children with asthma

• Tailored to • Cockroaches
• Skin test profile • Pets
• Environmental exposure • Rodents
• Caretaker’s report
• Mold
• House dust mite
• Passive smoking

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

 Environmental intervention in
urban US children with asthma

The difference
between treatment
arms was
statistically
significant
(p<0.001) in both
phases of the study

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

 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
 Agents and actions
Oral Nasal Cys-LT1 Nasal Oral Nasal
Nasal Nasal
antihistam antihistam receptor decongesta decongesta ipratropiu
steroids cromones
ines ines antagonists nts nts m

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

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

 Oral antihistamines
• First generation agents • Newer agents

Chlorpheniramine Acrivastine
Brompheniramine Azelastine
Diphenydramine Cetirizine
Promethazine Desloratadine
Tripolidine Fexofenadine
Hydroxyzine Levocetirizine Loratadine

Azatadine Mizolastine
Nasal antihistamines

• Azelastine

• Levocabastine

• Olopatadine
 Simplified two-state model of the
histamine H1-receptor

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Simons, F. E. R. N Engl J Med 2004;351:2203

 Efficacy of an antihistamine over 6 months in
persistent allergic rhinitis
Sneezing Rhinorrhea Pruritus Nose Pruritus Eyes Congestion

* * * *
1.0

0.8 * * * * *
* *
mean
0.6
* *
Individual
symptom
score
improvement 0.4

0.2

0
1 wk 6 mo 1 wk 6 mo 1 wk 6 mo 1 wk 6 mo 1 wk 6 mo
* P<0.05 4 wk 4 wk 4 wk 4 wk 4 wk

Baseline total symptom score: 8.95

Levocetirizine, 5 mg, N = 276
Placebo, N = 271

Bachert C et al. J Allergy Clin Immunol 2004:114:838

 Efficacy of an antihistamine in the treatment of
allergic rhinitis with perennial symptoms

(n= 337)
(n= 339)

imons FER et al., J Allergy Clin Immunol 2003;111:617

 Newer antihistamines are equally effective
in the treatment of allergic rhinitis
0

Placebo
-0.5
N =201
Change from -1.0 Fexofenadine 120 mg
baseline in N =211
total symptom -1.5
Fexofenadine 180 mg
score N =202
-2.0
(AM, instantaneous,
Cetirizine 10 mg
trough) N =207
-2.5
*
-3.0 * *
Baseline symptoms
*: <0.05 compared to placebo Study duration

owarth P et al. J Allergy Clin Immunol 1999;104:927

 Effectiveness of a nasal antihistamine in
allergic rhinitis with seasonal symptoms

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Storms WW et al. Ear Nose Throat J. 1994;73:382.

Newer generation oral antihistamines
somnolence/drowsiness
Active Placebo Data Source

Cetirizine
13.7% 6.3% [Link]
10 mg qd

Desloratadine
2.1% 1.8% [Link]
5 mg qd

Fexofenadine
1.3% 0.9% [Link]
60 mg bid
Bachert et al
Levocetirizine
6.8% 1.8% JACI
5 mg qd 2004;114:838

Loratadine
8% 6% [Link]
10 mg qd
Newer generation oral antihistamines

• First line treatment for mild allergic rhinitis

• Effective for
– Rhinorrhea
– Nasal pruritus
– Sneezing

• Less effective for

– Nasal blockage

• Possible additional anti-allergic and anti-inflammatory effect

• In-vitro effect > in-vivo effect

• Minimal or no sedative effects

• Once daily administration

• Rapid onset and 24 hour duration of action

 Decongestants: alpha-2
adrenergic agonists

• Oral • Nasal

Pseudoephedrine Phenylephrine

Oxymetazoline

Xylometazoline
 Decongestants: alpha-2
adrenergic agonists
nasal septum
nasal airway lumen

nasal vasoconstriction
turbinates
 Effect of a nasal decongestant under MRI imaging

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Adapted from Ng BA et al. Ear, Nose and Throat J 1999;78:159

 Efficacy of pseudoephedrine in
seasonal allergic rhinitis
Pseudoephedrine 120 mg twice daily, N=211
1.0 Placebo, N=212

*
0.8

*
0.6
Mean reduction *
in “nasal stuffiness” score
from baseline 0.4

0.2

0.0
Day 4 Endpoint Overall
(15 days)
Adapted from Bronsky E. et al. J Allergy Clin Immunol 1995;96:139
 Nasal obstruction: antihistamine vs decongestant vs
vombination in allergic rhinitis with perennial symptoms

Cetirizine 5mg twice daily, N=70

2.1 Pseudoephedrine 120 mg twice daily , N=70

Combination, N=70
1.7

Nasal
1.3
obstruction
severity score 0.9
(scale: 0-3)
0.5

0 2 4 6 8 10 12 14 16 18 20 21

Day

Bertrand et al. Rhinology 1996;34:91

 Decongestants
EFFICACY:
• 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
Mechanism of action of ipratropium bromide

indirect effect:
cholinergic
brain
sensory
Acetylcholine

X
nerves
on
muscarinic vidian nerve epithelium
receptors

X
RHINORRHEA

direct effect of mediators:

submucosal glands not cholinergic
 Efficacy of ipratropium bromide against
rhinorrhea in allergic rhinitis with perennial symptoms
6.0 3.0

5.0 2.5

* *
4.0 * 2.0
* *
* * Mean Severity
Mean Duration
3.0 Score 1.5
(hours/day)
(scale: 0-5)
2.0 1.0

1.0 0.5

0 0
Baseline Wk 1 Wk 2 Wk 3 Wk 4 Baseline Wk 1 Wk 2 Wk 3 Wk 4
Ipratropium, 42 µg/nostril three times daily, N=42
Ipratropium, 21 µg/nostril three times daily, N=39
Placebo, N=42
* p<0.05 against Placebo

apted from Meltzer E at al. J Allergy Clin Immunol 1992;90:242

 Anticholinergic treatment:
ipratropium bromide
• Nasal glands are activated by muscarinic, cholinergic receptors

• Ipratropium bromide is a nonselective muscarinic receptor antagonist

• Ipratropium bromide applied intranasally blocks rhinorrhea induced

by
cholinergic stimulation

• Ipratropium bromide has negligent systemic anticholinergic activity

• Topical adverse effects: excessive dryness, epistaxis

 Anti-leukotriene agents

CysLT1 Receptor 5-Lipoxygenase

Antagonists Inhibitors

Montelukast * Zileuton
Pranlukast *
Zafirlukast

* Approved for allergic rhinitis

 Cysteinyl-leukotriene production
and the CysLT1 receptor
CysLT1
receptor

cytosolic
phospholipase A2
leukotriene C4

arachidonic
nucleus acid leukotriene C4
+ leukotriene D4
5-lipoxygenase
activating leukotriene E4
protein
5-lipoxygenase leukotriene C4 mast cells
leukotriene A4 synthase basophils
eosinophils
macrophages
 Efficacy of a CysLT1 receptor antagonist
in allergic rhinitis with seasonal symptoms
Daytime Nasal Symptoms Score
(0-3 point scale)
0

Change from -0.2

baseline
(mean, 95% -0.4
CI)
-0.6
* *
placebo, N=149

montelukast, N=155
mean baseline=2.0 loratadine, N=301
*p<0.01 vs placebo

Adapted from Nayak, et al. Ann Allergy Asthma Immunol. 2002;88: 592
Additive effects of CysLT1 receptor antagonists and
H1 receptor antagonists in allergic rhinitis ?

improvement no change worsening

70
*
60
* *
*
50

% of 40
subjects 30

20

10

0
placebo montelukast montelukast loratadine montelukast
10 mg 20 mg 10 mg 10 mg
+
loratadine
10 mg
Adapted from Meltzer EO, et al. J Allergy Clin Immunol. 2000;105:917
 Equipotency of CysLT1 receptor antagonist/antihistamine and
decongestant/antihistamine
on nasal peak inspiratory flow

230
220
210
200
Liters/min 190
180
170 Fexofenadine/Pseudoephedrine, N = 34

160 Loratadine/Montelukast, N = 34

150
B 1 2 3 4 5 6 7 8 9 10 11 12
Treatment Days

Adapted from Moinuddin R et al. Ann Allergy Asthma Immunol 2004;92:73

 Anti-leukotriene treatment in
allergic rhinitis
Efficacy

• 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 vorticosteroids
Beclomethasone dipropionate
Budesonide
Ciclesonide*
Flunisolide
Fluticasone propionate
Mometasone furoate
Triamcinolone acetonide

* Currently only approved for asthma

 Molecular effects of corticosteroids

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dapted from Barnes PJ. Eur J Pharmacol. 2006;533:2

 Nasal corticosteroids
1 2
3

reduction of reduction of
mucosal inflammation mucosal mast cells
• suppression of
glandular activity
and vascular leakage
• induction of
reduction of reduction of vasoconstriction
late phase reactions acute allergic reactions
priming
nasal hyperresponsiveness

reduction of
symptoms and exacerbations
 Efficacy of nasal corticosteroid sprays in children with
allergic rhinitis and seasonal symptoms

eltzer E. et al. J Allergy Clin Immunol. 1999;104:107.

 Onset of action of intranasal budesonide
Against allergen exposure
(controlled environmental exposure - peak nasal inspiratory
flow)

ay JH. et al. J Allergy Clin Immunol. 2000;105:489.

 Comparative efficacy of
nasal corticosteroids

Mandl M. et al. Ann Allergy Asthma Immunol 1997;79:370

 Various treatment combinations in
seasonal allergic rhinitis
Nasal congestion score, Scale: 0-3

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dapted from Di Lorenzo et al. Clin Exp Allergy 2004;934:259

 Various treatment combinations in
seasonal allergic rhinitis
total symptom score
Scale: 0-12

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dapted from Di Lorenzo et al. Clin Exp Allergy 2004;934:259

 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
 Nasal corticosteroids
• Overall safe to use
• Adverse Effects
– Nasal irritation
– Epistaxis
– Septal perforation (extremely rare)
– HPA axis suppression (inconsistent and not
clinically
significant)
– Suppressed growth (only in one study with
beclomethasone)
 Nasal corticosteroid vs placebo: effects on 12-hour
urinary free Cortisol in 2-3 year-old children
6-week treatment
Value of 1 indicates
no change from baseline

1.0

0.8

0.6 0.98 0.94

Adjusted Geometric Mean SE=1.14 SE=1.15
of the Change from Baseline0.4
N=31 N=29

0.2

0
Fluticasone Placebo
Proprionate
Nasal Spray
200 µg daily
Adapted from Galant, S. P. et al. Pediatrics 2003;112:96
 Allergen immunotherapy
(vaccines)

• Subcutaneous

• Sublingual

• Nasal
 Possible mechanisms of immune response
regulation by allergen immunotherapy

Th1
Treg-lymphocyte

DC Th2
Th0-lymphocyte
Possible mechanism: allergen immunotherapy
induces regulatory T-lymphocytes

B
interleukin 10 lymphocyte
TGF
IgG4
Treg
lymphocyte

interleukin 10 TH2
TGF lymphocyte
 Subcutaneous immunotherapy:
effect on serum specific IgE
Initiation of
immunotherapy
70

60
August
50
Anti - ragweed November
IgE 40
(ng/ml) 30

20

10
baseline year 1 year 2 year 6 year 7 year 8

apted from: Peng et al. J Allergy Clin Immunol 1992;89:519

 Long-term efficacy of subcutaneous immunotherapy

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Durham et al. N Eng J Med 1999;341:468

 Sublingual immunotherapy in
grass pollen-induced allergic rhinitis
SLIT, N=316
Placebo, N=318

Need:
Overall p value
Treatment: grass allergen
tablets
Dose?
Frequency?
Started how long before season?

ahl R et al., J Allergy Clin Immunol. 2006;118:434.

 Humanized monoclonal
anti-IgE antibody: omalizumab

IgE

Omalizumab

C3
region
 Efficacy of omalizumab in seasonal allergic rhinitis
(ragweed pollen season)
1.4
• SQ treatments every 3-4 weeks x 3-4
1.2
• First dose prior to the pollen season
1.0
Average 0.8 Placebo, N=136
weekly
symptom 0.6 Omalizumab
score 50mg, N=137
0.4
150mg, N=134
0.2 300mg. N=129

0.0
4 13 20 27 3 10 17 24 1 8 15 22 29
Aug Sep Oct

Casale T, et al. JAMA 2001;286:2956

Copyright © 2001 American Medical Association. All Rights reserved
 Omalizumab and subcutaneous
immunotherapy in children: study design
SIT (birch) + placebo
n = 54

SIT (birch) + omalizumab

n = 55
Prescreening
Randomization
SIT (grass) + omalizumab n = 59

SIT (grass) + placebo n = 53

SIT titration SIT maintenance + study drug

Week 0 Week 12 Week 36

Kuehr J et al. J Allergy Clin Immunol 2002;109:274

 Omalizumab and subcutaneous
immunotherapy in children: symptom load
(rescue medications + symptom severity scores)
grass pollen season

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Kuehr J et al. J Allergy Clin Immunol 2002;109:274

 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
World Allergy Organization (WAO)
For more information on the World Allergy
Organization (WAO), please visit
[Link] or contact the:

WAO Secretariat
555 East Wells Street, Suite 1100
Milwaukee, WI 53202
United States
Tel: +1 414 276 1791
Fax: +1 414 276 3349
Email: info@[Link]