Overview of Allergic Disorders

Spectrum of allergic disease

 Allergy: The clinical expression of

atopic disease, including asthma,
rhinitis, eczema and food allergy

 Atopy: A tendency for exaggerated IgE

antibody responses, defined clinically
by the presence of one or more positive
skin prick tests (or by allergen-specific
IgE serum levels) to common inhaled
allergens, i.e. a predisposition to
develop allergy (1)
(1) Holgate ST, Church MK, Lichenstein LM. Allergy. 2nd Edition. Mosby International Ltd. 2001. Page 3.

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Prevalence of allergic disease (I)

 About 40% of the population is atopic,

i.e. their ability to produce IgE is
increased
 Manifestations of allergic diseases are
observed in up to a third of the overall
population
 In Europe the prevalence rates of
seasonal allergic rhinitis are 10–20%
 Atopic dermatitis has become a major
public health problem in Europe

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Prevalence of allergic disease (II)

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 Increasing prevalence
of allergic disease
 Increased prevalence of asthma seems to be due
to unidentified factors related to modern Western
lifestyles: the Hygiene Hypothesis
 Prevalence of allergic asthma increased nearly
two-fold during the 1980s (1)
 Prevalence of seasonal allergic rhinitis (hay fever)
has increased since the early 20th century
 Cumulative incidence of atopic dermatitis before
the age of 7 years has increased dramatically – It
may further lead to development of asthma later
in life (2)

(1) The European Allergy White Paper: The UCB Institute of Allergy 1997.
(2) Schultz Larsen F. In: Epidemiology of Clinical Allergy. Burr ML (ed), Basel, Karger 1993;31:9-28.

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 Why allergic diseases are
on the increase

 Genetic factors
 Environmental factors
 Outdoor pollution
 Indoor pollution
 Changes in lifestyle and hygiene conditions

Polluted Birch pollen House-dust mite

- higher allergic potency

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 The Allergic March

 The ’allergic march‘ is the term describing the

common progression from atopic dermatitis
to allergic asthma

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 Allergies begin in children

Evolution of sensitisation to Evolution of sensitisation to house dust

grass pollen between the ages mite between the ages of 0 and 6 years
of 0 and 6 years

% sensitised % sensitised
15
2
5
2
0 10
1
5
1
5
0
5

0 1 2 3 5 6 0 1 2 3 5 6
Age (years)
Bergmann RL et al. Clin Exp Allergy 1998;28:965-70. Age (years)
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Allergy:
One disease with many faces (I)
ALLERGIC RHINITIS ALLERGIC URTICARIA

ATOPIC DERMATITIS ALLERGIC ASTHMA

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Allergy:
One disease with many faces (II)

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Link between rhinitis and
other conditions
“The united airways concept”

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 Allergic rhinitis
 Allergic rhinitis is clinically defined as a
symptomatic disorder of the nose, induced
after allergen exposure, by an IgE-mediated
inflammation of the nasal membranes
 Symptoms include rhinorrhoea, nasal
obstruction, nasal itching and sneezing
 There are two types:
 Intermittent Allergic Rhinitis (< 4 days/week
or < 4 weeks/year)
 Persistent Allergic Rhinitis (> 4 days/week
and > 4 weeks/year) (1)

(1) Management of allergic rhinitis and its impact on asthma workshop report. ARIA in collaboration with the WHO. 2001.

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 Allergic conjunctivitis

 Allergic conjunctivitis – characterised by

burning, itching, tightness, conjunctival
hyperaemia, lacrimation and swelling around
the eyes
 Conjunctivitis is a very common condition and
affects people of all ages and is often
associated with allergic rhinitis
 Nasal and ocular symptoms have a similar
pathophysiology and are collectively referred to
as rhinoconjunctivitis (1)

(1) Lee AW et al. Atlas of Allergies. Fireman P. 2nd Edition. Mosby-Wolfe 1999;12:187-204.

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 Atopic dermatitis and urticaria
 Atopic dermatitis is a common inflammatory
disorder, characterised by severe pruritus,
chronically relapsing course, a distinctive
distribution of eczematous skin lesions, and
often, personal or family history of atopic
diseases (1)
 Urticaria is characterised by transient swellings
anywhere on the skin surface. Wheals are
usually itchy with raised pale centres and
surrounded by
a red flare (2)

(1) Holgate ST et al. Allergy. 2nd Edition. Mosby International Ltd. 2001. Page 105.
(2) Holgate ST et al. Allergy. 2nd Edition. Mosby International Ltd. 2001. Page 93.

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 Asthma
 Asthma – a chronic inflammation of the airways
in which inflammation is the central event which
leads to the development of bronchial
hyperreactivity and asthmatic symptoms

 Asthma has the following characteristics:

 Airway obstruction (or narrowing) that is
reversible in most patients either spontaneously
or upon treatment
 Airway inflammation
 Increased airway responsiveness to various
stimuli (1)

(1) The European Allergy White Paper: The UCB Institute of Allergy 1997.

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 The allergic reaction process
Two phases of an allergic process:
Immediate (early) allergic response – consists
mainly of allergen-provoked, IgE-mediated
release of histamine and other inflammatory
mediators from mast cells
Late phase response – migration of various
leucocytes, particularly eosinophils, and other
cells to the site of inflammation, their
attachment to tissues and the release of further
substances which maintain the inflammatory
reaction (1)

(1) Fasce L et al. Int Arch Allergy Immunol 1996;109:272-6.

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Immediate allergic response

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Allergy is more than histamine

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 Minimal Persistent Inflammation

 Minimal Persistent Inflammation (MPI) is

an inflammatory process present in
allergic individuals, even asymptomatic
individuals who are exposed to allergens
 MPI is characterised by infiltration of
inflammatory cells (eosinophils and
neutrophils) and by ICAM-1 expression on
epithelial cells (1)

(1) Ciprandi G. J Allergy Clin Immunol 1995;96:971-9.

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Minimal Persistent Inflammation

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Minimal Persistent Inflammation

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Allergic Rhinitis
Definition of allergic rhinitis

 An inflammatory disorder of the nose

induced by an Ig E-mediated inflammation
following allergen exposure of the mucous
membranes lining the nose;
characteristized by sneezing and nasal
obstruction

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Allergic rhinitis:Symptoms and
relationship to allergic conjunctivitis

 Major symptoms
 Rhinorrhea
 Nasal itching
 Nasal obstruction
 Sneezing

 42% of patients with allergic rhinitis experience

symptoms of allergic conjunctivitis (ACAAI),
and conjunctivitis is a tpical feature of the
patient with seasonal pollen allergy.

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Allergic rhinitis:
Traditional classification

 Seasonal Allergic Rhinitis (SAR)

 Perennial Allergic Rhinitis (PAR)

 Occupational Allergic Rhinitis

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CHARACTERISTIC SEASONAL PERENNIAL
obstruction Variable Usual, common

Secretion Watery, common Seromucous, post-

nasal drip, variable
Sneezing Always Variable

Smell disturbance Variable Common

CO-MORBIDITIES

Eye symptoms Common Rare

Asthma Variable Common

Chronic sinusitits Occasional Frequent

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Classifications of allergic rhinitis:

 Seasonal - Intermitent - acute -occasional

 Occasional symptoms lasting less than a
month
 <4 days per week or
 < 4 weeks
 Perennial -persistent-chronic-long duration
 Symptoms lasting longer than a month
 >4 days per week and
 > 4 weeks

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New classification of allergic rhinitis:
Severity

 Mild
 Few troublesome symptoms, not interfering
with daily activities and/or sleep

 Moderate - Severe
 Troblesome symptoms which do interfere with
daily activities and/or sleep
 Patient needs treatment to function adequately

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 ARIA Classification
Intermittent Persistent
. < 4 days per week . > 4 days per week
. or < 4 weeks . and > 4 weeks

Mild Moderate-severe
one or more items
normal sleep
. abnormal sleep
& no impairment of daily
activities, sport, leisure . impairment of daily
activities, sport, leisure
& normal work and school
& no troublesome symptoms . abnormal work and school
. troublesome symptoms

in untreated patients
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Differential diagnosis of allergic rhinitis:
Non-allergic rhinitis

 Infectious: Viral, bacterial, fungal

 Drug-induced: Aspirin, other medications
 Occupational (may be both allergic or non-
allergic)
 Hormonal: Puberty, pregnancy, menstruation,
endocrine disorders
 Other causes: Foods, irritants, emotion, Non-
Allergic Rhinitis with Eosinophilia Syndrome
(NARES) gastro-esophageal reflux, atrophic
 Idiopathic: Cause not known

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Differential diagnosis of allergic rhinitis

 Polyps
 Ciliary Defects
 Cerebrospinal Rhinorrhea
 Tumors: Benign, Malignant
 Mechanical: Deviated Septum, Foreign
Bodies, Choanal Atresia
 Granulomas: Sarcoid, Infectious,
Wegener’s Midline Destructive

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Epidemiology of allergic rhinitis:
Children
 Prevalence of rhinits symptoms in the International
Study of Asthma and Allergies in Childhood, ISAAC,
varied between 0.8% and 14.95% in 6-7 year olds and
between 1.4% and 39.7% in 13-14 year olds.

 Low prevalence: Indonesia, Georgia, Greece

 High prevalence: Australia, UK and Latin America

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Epidemiology of allergic rhinitis:
Adults

 Not equivalent to ISAAC study

 National survey show prevalence rates

between 5.9% (France) and 29% (UK) with
a mean of 16%

 Persistent (perennial) rhinitis more

common in adults than children

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Globally important allergens

House dust mites

Grass, tree and weed
pollens
Pets
Cockroaches
Moulds

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Diagnosis of allergic rhinitis:1

 Essential
 Detailed personal and family allergic history
and physical examination
 Nasal examination -- anterior rhinoscopy
 History of eye symptoms
 Allergy skin tests, e.g. skin prick/puncture
tests and/or
 Measurement of allergen specific IgE antibody
(Radioallergosorbent test)

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Diagnosis of allergic rhinitis:2

 Additional diagnostic tests which may be

performed if required:

 Total IgE
 Fibreoptic rhinoscopy
 Nasal secretions/scrapings for cytology
 Nasal challenge with allergen, including
rhinomanometry
 CT scan

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Allergy skin prick testing

 Skin prick test/positive result

Advantages: - ease of use

- relatively low cost
- high information value

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Radioallergosorbent tests

 In vitro test methods

 determine specific IgE against major
allergens
 Advantages:
 safe
 high degree of precision & standardization
 not influenced by ongoing symptoms or
treatment
 Disadvantages:
 absence of immediate results
 high costs

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Immunopathology of allergic rhinitis

 Allergic rhinitis is characterized by an inflammatory

infiltrate in the nasal mucosa which includes:

 Chemotaxis, selective recruitment and transendothelial

migration and activation of eosinophils, basophils, mast
cell precursors, macrophages, Langerhans cells and
lymphocytes, particularly T-helper cells;

 Migration and activation of mast cells, eosinophils,

Langerhans cells and lymphocytes towards and into the
epithelium;

 Regulation of local and systemic IgE synthesis: systemic

levels of IgE and IgE antibody are increased as a reaction
to allergen exposure

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Immunopathology of allergic disease:
Major mediators - Histamine

 Pre-formed mediator
 Released from activated mast cells
 Major mediator in early phase reaction
 causes sneezing, itching, rhinorrhoea and
nasal obsruction
 Pro-inflammatory activity

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Immunopathology of allergic disease:
Major mediators - Leukotrienes

 Newly generated mediators

 Important role in late phase reaction
 Cause nasal obstruction, mucus secretion,
inflammatory cell recruitment

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Allergic Rhinitis: Co-morbidity asthma

 40 - 50% of patients with allergic rhinitis

have asthma
 Rhinitis occurs in > 75% of allergic
asthmatics
 Additional investigations recommended
 History of asthma
 Chest examination
 Lung function before and after bronchodilator

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Allergic Rhinitis: Co-morbidity sinusitis

 Strong association (>50%) between

sinusitis and allergic rhinitis in children
and adults

 Additional features/investigations
recommended
 Sinusitis history - fever, headache, facial pain,
muco-purulent nasal discharge
 Sinus X-rays or CT scan

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Treatment of allergic disease:
Allergen avoidance - 1

Allergen avoidance is the first step in the

management of allergic disease

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Treatment of allergic disease:
Allergen avoidance - 2

 House dust mites

 Wash bedding weekly at 60º C
 Encase pillow, mattress and quilt in allergen
impermeable covers
 Dispose of feather bedding
 Use vacuum cleaner with HEPA filter
 Replace carpets with linoleum or wooden floors
 Remove curtains, pets and soft toys from bedroom
 Provide adequate ventilation to decrease humidity

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Treatment of allergic disease:
Allergen avoidance - 3

 Pollens
 Remain indoors at peak pollen times
 Wear sunglasses and masks
 Use air-conditioning if possible
 Install car pollen filters
 Pets
 Exclude pets from bedrooms and if possible
from homes
 Vacuum carpets, mattresses and upholstery
regularly

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Treatment of allergic disease:
Allergen avoidance - 4

 Cockroaches
 Eradicate with appropriate insecticides

 Moulds
 Use dehumidifier, ensure dry housing
 Use ammonia to remove mould from
bathrooms and other wet spaces

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Treatment of allergic rhinitis:
Decongestants

Topical Spray Oral Tablets

 Very effective in treating  Less effective than sprays:

nasal obstruction no rhinitis meicamentosa

 Limit treatment to 3-10  Effective when combined

days with oral antihistamines

 Application for > 10 days  Usually avoided in: children

may lead to unwanted <1 year, pregnancy,
effects hypertension, cardiopathy.
Prostatism, glaucoma

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Treatment of allergic rhinitis:
Anti-allergic compounds

 Disodium cromoglycate and nedocromil

 Less effective than antihistamines

 Require regular administration: DSCG four
times/day, nedocromil two times/day
 Excellent safety profile for use in children and
pregnancy

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Treatment of allergic rhinitis:
Anti-cholinergic compounds

 Ipratropium bromide

 Effective in controlling watery nasal

discharge but not sneezing or obstruction

 Unwanted effects include nasal dryness,

irritation and burning, stuffy nose, dry
mouth and headache

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Treatment of allergic rhinitis:
Topical antihistamines

 Azelastine and levocabastine

 Rapid onset of action (15 minutes)

 Twice daily administration
 Recommended for organ-limited disease
 May be used “on demand” in addition to a
continous medication
 Good safety profile

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Treatment of allergic rhinitis: First
generation oral antihistamines

 Chlorpheniramine, diphendramine,
promethazine, tripolidine

 Use limited by sedative and

anticholinergic effects

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Treatment of allergic rhinitis:
Properties required of ideal second
generation antihistamines
Pharmacological: Pharmacokinetics:
 potent, non-competitive  rapid onset and 24
H1-receptor blockade hour duration fo action
 additive anti-allergic  once daily
activities administration
 no interference of activity  no tachyphylaxis
by foods
 known therapeutic dose
Lack of unwanted effects
 no sedation
 no anticholinergic effect
 no weight gain
 no cardiac toxicity

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Treatment of allergic rhinitis: Second
generation oral antihistamines

 Acrivastine, astemizole*, azelastine,

cetirizine, ebastine, epinastin,
fexofenadine, ketotifen, levocetirizine,
loratadine, terfenadine*, mizolastine

 Greatly reduced unwanted effects

 First line treatment for intermittent or mild
persistent Allergic Rhinitis

 * Withdrawn from some markets due to rare cardiotoxic

effects

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Treatment of allergic disease:
Anti-leukotrienes

 Ineffective alone

 May have additive effect with

antihistamines

 May be effective in aspirin-induced

rhinitis and asthma

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Treatment of allergic rhinitis:
Topical corticosteroids - 1
 Beclomethasone dipropionate, bidesonide,
flunisolide, fluocortinbutyl, fluticasone
propionate, mometasone furoate,
triamcinolone acetonide

 Potent anti-inflammatory agents

 Effective in treatment of all nasal symptoms
including blockage
 Once or twice daily administration
 Superior to antihistamines for all nasal symptoms
 First line pharmacotherapy for moderate-severe
persistent allergic rhinitis
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Treatment of allergic rhinitis:
Topical corticosteroids - 2

 Safety
 Occasional unwanted effects

 Rarely affect HPA axis (some exceptions)

 Anecdotally, perforation of the nasal septum

has been reported

 One study reports decrease in growth in

children taking beclomethasone dipropionate

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Treatment of allergic rhinitis:
Systemic corticosteroids

 Short courses of oral corticosteroids (< 3 weeks)

can be prescribed for severe refractory symptoms

 Can be repeated every 3 months

 Can be used with caution in children and in

pregnancy, if no alternative available

 Intramuscular injection of corticosteroid

suspensions should be avoided

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Treatment of allergic disease:
Injection allergen immunotherapy

 Recommended for clinically relevant IgE

mediated disease. May involve multiple
allergens; usually restricted to two
allergens in Europe
 Risk:benefit ratio must be considered in all
cases
 Highly effective in carefully selected
patients

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Treatment of allergic disease: High
dose sub-lingual immunotherapy

 Controlled studies have shown that

high-dose sublingual/swallow
immunotherapy is a viable alternative to
injection allergen immunotherapy for
mild intermittent allergic disease

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Evidence-based stepwise guidelines
for the management of allergic rhinitis

 A rational basis upon which to commence

and manage treatment; relating clinical
symptoms to underlying pathology

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 TREATMENT OF ALLERGIC RHINITIS
(ARIA 2001)
Moderate-
severe
Mild persistent
Moderate- persistent
severe
Mild intermittent
intermittent topical steroid
topical cromolin
Systemic (topical) nonsedating antihistamine
Nasal decongestant (<10 days) or oral decongestantt
Allergen avoidance
Immunotherapy

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