Transcript Allergic diseases

Basics in paediatric allergology: IgE-mediated allergy in
respiratory illness
Prof. Dieter Koller, M.D.
University Children´s Hospital of Vienna,
Austria
Themes
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Definition of allergy
Overview on IgE-mediated allergies
Methods in diagnosis
Skin Prick testing, intradermal testing, atopy patch test,
provocation testing
Allergy prevention
Primary, sekundary,tertiary prevention
Overview on studies dealing with prevention
Treatment
Symptomatic
causale (specific immuntherapy SCIT und SLIT)
Studies dealing with SCIT und SLIT
Allergic reaction
• Manifestation of symptoms after repeated
exposure to an allergen after (latent)
period of sensitization
• IgE-mediated release of mediators and
zytokines from effector cells like mast
cells, eosinophils and T-lymphocytes
• Symptoms may occur in single organ but
also systemically (allergic
• Symptome zwar abhängig vom Zielorgan
-systemisch allergische Reaktion jedoch
immer möglich (z.B. allergische Rhinitis u.
zeitgleiche Asthmasymptome)
Pseudoallergy and/or
anaphylaktoid reactions
• Symptoms similiar to allergic reaction –but
not immunological mediated (Allergy tests
negative)- and partially dependent on
dosis
Histamine intolerance
Reaction auf radiocontrast agents,i.v.
anaesthetics, antibiotics
Food adverse reactions to additives
Atopy:„a-topos“:
“ being on the wrong place“ :
ill-making reaction of the immune
systeme
Clemes von Pirquet (Head of the University Children´s Hospital Vienna19111929) defined the terminus Allergy/Atopy
Definition
• Atopy: enhanced production of IgE in
asymptomatic subjects
• Allergy: Presence of symptoms
corresponding to specific IgE antibodies
Manifestations of allergic diseases
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Eyes - allergic conjunctivitis
Nose - allergic rhinitis
larynx- angioedema
Lung - allergic bronchial asthma
Skin – urticaria, rash
Gastrointestinal - diarrhea, abdominal
cramps
• Systemic - Anaphylaxis
House dust mite
Sensitization potency of allergens
depends on
Intrinsic factors
molecular weight
concentration
solubility
stability
biochemichal activity
extrinsic factors
genetics and sex
Nicotin exposure
pollution
season of birth
Infections, exposure to
endotoxins
Flow of systemic allergic
reactions
• Seconds to minutes after exposure of
minimal amounts of allergen,
sometimes after up to two hours
• Biphasic reactions:
rapide – improvement after treatment
– further reaction
• Prolonged reaction:
Perstistence of symptoms under
treatment
Allergic diseases
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Bronchial asthma (extrinsic)
Allergic rhinoconjunctivitis (hay fever)
Atopic dermatitis
Food allergy
Insect sting allergy
Oral Allergy Syndrome (cross reactivity between
pollens and certain fruits, like tree pollens and nuts,
latex and banana, mango, house dust mite and
snails, mussels, shrimps)
Prevalence of allergic diseases in the
paediatric population
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Atopic eczema: 10%
Allergic rhinoconjunctivitis: 10-20%
Bronchial asthma : 10%
Insect sting Allergy: 0.8 -1%
Food allergy: 3-4%
Anaphylaxis:1-4%
Drug allergy: ?
(in 90% of children with positive history no
detection of specific)
Genetics of allergic diseases
• Until now, 79 genes have been identified to associated
with the asthma and/or atopy phenotype in different
populations.
• Two major genes with association to the same
phenotype independent of the population:
 Arg 110Gln = variation of IL-13 (Th2-cytokine) encoded
Gene is associated with increaseed IgE production
 R510X = Gene variation causing lost of function of
filagrin – atopic eczema
Diagnostic procedure
Patients´ history
in vivo, in vitro testing
Provocation testing
Anamnesis
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Which symptoms
Since when
When
How long
How frequent
Where
Which medication so far (improvement?)
Which symptoms may be associated with
allergic diseases
 Eczema
 Erythema
 recurrent diarrhea
 dystrophia
 Itching
 urticaria
 abdominal pain
 Wheezing
 shortness of breath
 chronic sticky nose
 sneezing
 recurrent redness of eyes or itching
 coughing
Diagnostics in allergy
• In vivo (Skin-Prick testing,intradermal testing)
• In vitro (spezific IgE, total IgE, tryptase …)
Skin Prick Testing (SPT)
SKIN PRICK TESTING
8 a old child; rhinoconjunctivitis since 2 years , end of
May to middle of June
When are skin prick test false
positive/negative?
• Medication: antihistamines, steroids,
immunosuppression
• diseases: mastocytosis, atopic eczem, chronic
urticaria, sunburn
Positive SPT result
• negative = no wheal reaction, similar to the negative control
• positive = wheal reaction of at least 3mm and equivalent to the
histamine reaction.
Intradermal testing
• Suspicion of hymenoptera allergy (drug
allergy)
• More sensitive than SPT but also more
painful
In-vitro- testing
• total IgE 
• specific IgE 
• ECP (eosinophil cationic protein)
• tryptase
Total IgE: Indications
• Indirect-diagnostic parameter if
aspergillosis, parasitic infections, Jobsyndrome
• Detection of atopy(„nice to know but no
need to know“)
• Total IgE is no screening test (sensitivity
<60%)
Primary indications for IgE
measurement
• Contraindications for skin prick testing
• Diagnostics in infants and toddlers
Indication for using recombinant
allergens (component)
• ???? (no therapeutic consequences)
• Exception:
hymenoptera allergy (Api m1, Ves v1,
Ves v5)
peanut allergy (Ara h2 – high risk for
severe reactions)
In-Vitro-diagnostics
- advantages • Accurate and reproducable results
• WHO controlled standards
• Simple quantification (classes, Kilounits/l)
In-Vitro-diagnostics
- disadvantages • Measurement of circulating IgE-Ab, only
• The level of antibodies does not correlate with
clinical severity.
Provocation testing
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Nasal
Conjunktivale
Bronchial
Oral
S.c.
i.v.
Nasal provocation testing
• Especially with perennial allergens (mould,
house dust mite)
• Information about clinical relevance
• Discrepancy between symptoms and SPT/IgE
conjunctival provocation testing
• No screening test
• Detection of allergic reactions of the eyes
• Very sensitive, prove of allergy also when
SPT or IgE negative
• Einfach und meist risikolos
Bronchial provocation testing
• Can a suspected allergen induce an
asthma attack and in which dosage?
Why early diagnosis?
The pattern of atopic sensitization is
associated with the development of asthma
in childhood
S Illi, E von Mutius, S Lau et al.
J Allergy Clin Immunol
2001;108:709-14
Aim and methods
• Prospective evaluation of relationship
between the development of asthma and
sensitization (MAS study)
• Longitudinal observation with
questionnaires, allergy and lung function
testing in 1300 children with and without
atopy risk from birth till the age of 7 years.
Conclusion!
• In children with a positive family history for
atopy an early sensitization against
allergens is a significant risk factor for the
development of brochial asthma.
Prevention of allergic diseases
• Primary prevention
- Avoidance of sensitization
• Secondary prevention
- Avoidance of allergic disease in sensitized
subjects
• Tertiary prevention
- Reduction of symptoms in existent allergic
disease and prevention of secondary
disorders (allergen avoidance in asthma)333
Benefits of high altitude allergen
avoidance in atopic adolescents with
moderate to severe asthma, over and
above treatment with high dose inhaled
steroids
Grottendorst DC, Dahlen SE,Van den Mos
JW
Clin Exp Allergy 2002;31(3):400-8
Conclusion
• Short-term allergen avoidance in high
altitude compined with regular asthma
medication results in significant
improvement of symptoms and in reduction
of bronchial hyperreactivity as well as a
decrease of inflammatory markers.
Effect of mattress and pillow encasings on
children with asthma and house dust mite
allergy
Halken S, Host A, Niklassen U,
Hansen LG, Nielsen F et al.
J Allergy Clin Immunol
2003,111(1):169-76
Conclusion
• Encasings for mattresses and pillows results
in children with brochial asthma and house
dust mite allergy in a significant reduction
of allergen exposure and a significant
reduction of steroid dosage.
Fazit !
• Allergen avoidance in combination with
drug therapy reduces the severity of
symptoms effectively and for a long time.
TREATMENT
Austrian Allergy Report 2006, T Dorner, A Rieder, K Lawrence,M Kunze,
Treatment of allergic diseases
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Symptomatic: topical and/or systemic
antihistamines (H1-receptorblockers)
Dinatriumcromoglycate (nose, eye, lung)
topical steroids (nose, eye, lung, skin)
Causal:
Allergen avoidance if possible
Spezific immuntherapy – SIT
Allergic rhinitis and its impact on
asthma
ARIA
Bousquet J et al. J Allergy Clin Immunol 2001
108 (5 Suppl): S 147-334
A.R.I.A.
Allergic Rhinitis and its Impact on Asthma
WHO – Position Statement
• AR and asthma: „One Airway- One Disease“
• Early treatment of AR reduces the development of
asthma or diminishes the severity of symptoms.
• Optimal management of AR can improve
co-existent asthma
• SIT is an additive therapy and should be offered
early in the course of disease
Bousquet J, van Cauwenberge P J Allergy Clin Immunol, 2001;108:S 147-S 334
Stufenplan nach ARIA
moderatelsevere
persistent
mild
persistent
Moderatesevere
recurrent
Mild
recurrent
+ topical steroids
Cromones
Non-sedating antihistamines
Decongestiva ( nose drops <10 days)
Allergen avoidance
Spezific Immuntherapy
Causal treatment
• Specific immunotherapy
• Allergen avoidance
Specific immunotherapy
(SIT)
Vaczinationsimmunotherapy(VIT)
Hyposensitization
Indications
• IgE-mediated disease (Rhinoconjunctivitis,allergic
bronchial asthma)
• At least 2 years seasonal or perennial symptoms
when allergen avoidance can not b achieved or
symptoms persist
• Older then 5 years of age
• Atopic family history – early initiation to prevent the
developement of asthma and polysensitization
ftallergie
Contraindications
• Immunodeficieny
• Severe, uncontrolled bronchial asthma
• severe cardiovascular diseases
Applications
• Subcutaneous
• Sublingual (drops)
• Soluble tablets
Specific subcutaneous
immunotherapy (SCIT)
 Clinical improvement
 Immunological effect (vaczination)
 Long-term effect
 Prevention of new sensitizations
 Prevention of asthma
SCIT
• Clinical efficacy
Grass pollen immunotherapy as an effective therapy for childhood
seasonal allergic asthma
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Roberts G, Hurley C, Turcanu V, Lack G, J Allergy Clin Immunol. 2006 Feb;117(2):263-8.
Conclusion
• SCIT with grass pollens leads to significant
improvement of rhinitis- and asthma
symptoms in children.
• In comparison to placebo skin test,
conjunctival and bronchial reactivity
decreased.
SCIT
• Prevention of new sensitizations
Development of new sensitizations after SCIT with house
dust mites
number
of
patients
New
sensitization
+
New
sensitization
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HDM SCIT-
22
12
10
controls
22
22
0
Des Roches A. et al. JACI 1997;99:450-53
SCIT
• Prevention of bronchial asthma
AIM:
Influence of SCIT with birch and/or grass pollens in
children hayfever on the brochial hyperreactivity
and the development of asthma
Development of asthma after 3 years
treatment
100
% of ptt.
80
Odds-ratio = 2. 52
(1.3 – 5.1) p = <0.05
N=60
N=40
60
N=32
40
N=19
20
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SIT
No asthma
Control
Asthma
PAT-Prevention of Asthma by Treatment
Specific immunotherapy has long-term preventive effect of seasonal and
perennial asthma: 10-year follow-up on the PAT study.
Jacobsen L, Niggemann B, Dreborg S et al. Allergy. 2007 Aug;62(8):943-8.
Immunological mechanisms of SCIT
IgE
IL-4
B-cell
Allergen
APC
Th2
CD80/86
CD28
Eosinophil
IL-5
HLA
TCR
CD4
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IT
T cell
IT
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Allergic+ reaction
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TGF- b
Tr1
IL-10
Th1
IFN-g
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B-cell
IgG
Sublingual Immunotherapy
(SLIT)
• Drops for sublingual application
• Allergen dosage much higher than used in SCIT
• Mechanism not totally solved
SLIT: indications
• Repeated systemic reactions during SCIT??
• Incompliant patients, trypanophobia???
Allergic Rhinitis and its Impact on Asthma ARIA Bousquet J, Cauwenberge P
editors, J Allergy Clin Imunol 2001;108:S 147-336
Demands when prescribing SLIT
• cumulative allergen-dosage at least 100-fold
higher than using SCIT
• Accurate information of the patient about
potential side-effects (treatment will be
performed at home)
Allergic Rhinitis and its Impact on Asthma ARIA Bousquet J, Cauwenberge P
editors, J Allergy Clin Imunol 2001;108:S 147-336
Ann Allergy Asthma Immunol. 2006;97:141-48
Rhinitis score
Rescue medication score
Different IgG- antibody response after SCIT and SLIT
Until now, unsolved questions
regarding SLIT in children
• Ideal dosage duration of therapy ?
• Direct comparison SLIT and SCIT
regarding efficacy, prevention and
immunological effects?
• Reproducability of studies in a larger
study population?
Other immunomodulatory
therapies
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Recombinant allergens 
Anti-IgE 
DNA immunisation
Modified allergens
Adjuvants (IL-12, mycobacterial)
Peptid-Immunotherapy