D o m i n i k H a r d e rFacharzt für Hals- Nasen- und Ohrenerkrankungen FMH

Facharzt für Allergologie und klinische Immunologie FMH

Brunnenhof-Praxis, Gäuggelistrasse 20

7000 Chur

Basics of the allergic reaction

and

the allergic rhinitis

ORL-Summerschool 2018

History:

Rhinoconjunktivitis and Asthma poll. since 4 years, mainly April

Patient U.F, 23-y. ?

Reason for Consultation

Hazelnut Pruritus in Mouth

Nussmix Swelling of the lower lip

Allergy !

Patient U.F, 23-y. ?

Ist die erworbene, spezifische Änderung der Immunitätslage im Sinne einer krankmachenden Überempfindlichkeit(Clemens von Pirquet; Wien 1906)

Allergy ?

Is the acquired, specific alteration of the immune status in terms of disease-causing hypersensitivity (Clemens von Pirquet, Vienna 1906)

ImmunsystemUnspecific Immunsystem

„Innate Immunity“Specific Immunsystem„acquired Immunity“

humoral cellular cellular humoral

• Complement

• Cytokins

• MPS

• Granulocytes

• APC

• T-Lymphocytes

• B-Lymphocytes

• Plasma-cells• Immunglobulins

Spezific ImmunesystemExtrazellular Epitops: Bacteria

Viren Within Cell

B-Lymphozyte

T-Lymphozyte = General Manager

IgD

IgA

IgG

Unspecific Immunsystem

IgM

IgE

Intrazellular Epitops: VirusesZytokins

Spezific ImmunesystemExtrazellular Epitops: Bacteria

Viren Within Cell

B-Lymphozyte

T-Lymphozyte = General Manager

IgD

IgA

IgG

Unspecific Immunsystem

IgM

IgE

Intrazellular Epitops: VirusesZytokins

Allergy is generated in the specific part of the

Immunsystem

Cytokines

IL-5

IL-4

IL-5IL-5

IL-5

IL-5

IL-6

IL-4

IL-4IL-6 IL-6

IL-6IL-6

IL-10IL-10

IL-8IL-8IL-7

IL-12

IL-7

IL-12

IL-12

• Cells swim in a soup with cytokines

• low molecular weight polypeptides (10-80 kD, 25-50 AS)

• Cytokine production by cells affects directly their own

environment

• Effective only at short distances

autokrin

parakrin

Cytokines in the Cell environment, decide about cell reaction

• Main Effects:

Regulation of Proteinsynthesis of the affected cells

Apoptoseregulation (programmed Celldeath)

Migrationsregulation

Interleukines, Cytokines und Chemokines

Proinflammatory Immunregulatory Growth factors

• Zytokines of innate immunity

• Production by unspezific Immunsystem (Monocytes und Makrophages) und T-Helpercells

(CD 4)

• Zytokines of the spezific Immunsystem

•Regulation, Growth und Differentiation of Lymphocytes

•Production mainly by T-Helper-Cells (CD 4)

• Stimulation of immature progenitor Cells in bone marrow

•Production by Granulocytes, Makrophages, Monocytes, Fibroblasts, Endothel-cells und T-Helpercells(CD 4)

Zytokine

T-Helper-Cell is able to produce the whole „cytokine repertoire“

Important Cytokines

Proinflammatory Immunregulatory Growth-Factors

•IFN-1

•TNF-alpha

•IL-1

•IL-6

•GM-CSF

•IL-2

•IL-4

•IL-5

•TGF-beta

•IFN-gamma

•IL-10

•IL-12

•IL-13

•IL-3

•GM-CSF

•G-CSF

Chemokines

•chemotactic

•IL-8

•Eotaxin

•RANTES (Regulated on Activation, Normal T Expressed and Secreted)

Most important Cytokines of the T-Helper-Cell

• IL-2 Main- Stimulation for Lymphocytes

• IL-4 B-Cellmaturation, Switch tor IgE-Production, IFN-gamma-Antagonist

• IL-5 Differentiation and Stimulation of Eosinophils !

• IL-10 T-Zellanergie (Specific Immunotherapy)

• IL-12 Stimulator of natural killer cells (NK)

• IFN-g Antiviral, Antiproliferativ, Aktivation of Neutrophils, Aktivation of NK, Switchfactor to

IgG-Production, „Couterplayer of IL-4

• TGF-b Immunmodulatory

Most important Cytokines of the T-Helper-Cell

• IL-2 Main- Stimulation for Lymphocytes

• IL-4 B-Cellmaturation, Switch tor IgE-Production, IFN-gamma-Antagonist

• IL-5 Differentiation and Stimulation of Eosinophils !

• IL-10 T-Zellanergie (Specific Immunotherapy)

• IL-12 Stimulator of natural killer cells (NK)

• IFN-g Antiviral, Antiproliferativ, Aktivation of Neutrophils, Aktivation of NK, Switchfactor to

IgG-Production, „Couterplayer of IL-4

• TGF-b ImmunmodulatoryTH-2 Muster = Allergy

Most important Cytokines of the T-Helper-Cell

• IL-2 Main- Stimulation for Lymphocytes

• IL-4 B-Cellmaturation, Switch tor IgE-Production, IFN-gamma-Antagonist

• IL-5 Differentiation and Stimulation of Eosinophils !

• IL-10 T-Zellanergie (Specific Immunotherapy)

• IL-12 Stimulator of natural killer cells (NK)

• IFN-g Antiviral, Antiproliferativ, Aktivation of Neutrophils, Aktivation of NK, Switchfactor to

IgG-Production, „Couterplayer of IL-4

• TGF-b ImmunmodulatoryTH-1 Muster = Defense

Spezific ImmunesystemExtrazellular Epitops: Bacteria

Viren Within Cell

B-Lymphozyte

T-Lymphozyte = General Manager

IgD

IgA

IgG

Unspecific Immunsystem

IgM

IgE

Intrazellular Epitops: VirusesZytokins

1. Phagocytosis

2.Prozessing

4. Antigenpräsentation

3.Production of proinflammatory Cytokines

Immunanswer after Contact with Antigen

Zellmigration, Priming

Antigenpräsentation

• Immungenetik

• Cytokinenvironment ATOPY

TH-2

Ig E

Type of Antigen- Präsentation

IL-4IL-4

IL-4IL-4

IL-5IL-5

IL-5IL-5

IL-2

IL-2

IL-2

Ishizaka 1967

Mastzelle/ Basophiler

Mastzelle/ Basophiler

Mastzelle/ Basophiler

MastcellSpezific Stimulus

(Allergenbindung to IgE)

AllergyUnspezific Stimulus Reiz

(Direkte Mastzellactivation)

Pseudoallergy

• NSAR

• Opiate

• Codein

• physicalic Factors

Stored Mediatores

HistaminSerotoninChymaseTryptaseCarboxypeptidaseSaure HydrolasenNCF-ACathepsin GHeparinMBP

New produced MediatoresProstaglandin D2Prostaglandin E2Thromboxan A2ProstacyclinLeukotrienePAFBradykininSauerstoffradikaleC3a + C5aSubstanz PNeurokinin AVIPCGRP.....

Mastcell Antigenpräsentation

ATOPY

TH-2

Ig E

• Immungenetik

• Cytokinenvironment

ATOPY ?

B-Lymphozyt

IgG

„Normal“IgE

Allergenexposition by ingestion or inhalation

ATOPY

B-Lymphozyt

IgG

IgEAtopic person

„Normal“

IgE

IgE

=> Tendency to produce IgE instead of IgG

Allergenexposition by ingestion or inhalation

From Atopic dermatitis in infancy…

.... To Asthma, allergic rhinitis or hay fever

„ the atopic March„

Atopic Manifestations and Age

„the atopic March“

House dust mites3-8 %

Tierepithelia2 -9 %

Moulds1 - 5 %

Pollen12 – 18 % of Population

Main inhalative Allergens

SAPALDIA: Swiss Study on Air Pollution and Respiratory Diseases in Adults 1991-1993SCARPOL: Swiss Study on Childhood Allergy and Respiratory Symptoms with Respect to Air Pollution and Climate

1992/1993

Leadpollen 2003 german part of CH

Jan Feb March April Mai Juni Juli Aug Sep Okt Nov Dez

HazelAlder

BirchAsh

Grass

RyeMugwort

Leadpollen are responsible for 95% of inhalative allergies

John Bostock in 1819Describes „hay fever“

28 Cases in England

1819

19818.4%

19714.4%

1900 2000

Aberg et al.Swedish army

CH:1%

CH15-20%

USA5-22%

Incidence of Pollinosis increasing world-wide !

Sapaldia/ Scarpol

• Genetic Factors

• Hygienehypthesis

• Pollution

• Changed Lifestyles (Pets)

Reasons for Increase Factors associated with Allergy-Incidence

Older sisters or brothers

Daily care center

Living on farm

Helminth-Infection

BakterielleExposition (LPS)

Single kid

Urban Lifestyle

„Steril“ Environment

Less Allergy More Allergy

Hygienehypothesis

Prick-Test:

Birchpollen ++

Hazelnut ++Carrots ++

Cherries ++

Patient U.F, 23-y. ?

Prick to Prick – Test with native allergens

Crossreaction

Bet v 1 Mal d 1

Bet v 1 Bet v 1

High Aminoacididentity

Mal d 1Bet v 1

Neudecker et al., J Biol Chem 2001

Bet v 1Bet v 2Profilin…

Mal d 1Mal d 4…

Cor a 1Cor a 2…

Api g 1Api g 4…

Dau c 1Dau c 4…

Proteinsequences with similar Structures

ApiaceaeSellerie, Karotte, Fenchel, Petersilie, Anis, Dill, Koriander, Kümmel, Liebstöckel

RosaceaeApfel, Birne, Aprikose, Pfirsich, Nektarine, Kirsche, Zwetschgen, Erdbeere, Mandel

BetulaceaeHaselnuss

Exotische FrüchteKiwi, Mango, Lychee

SolanaceaeKartoffel

Birch

40-70 % of all Patients with Birchpollenallergy

Mugwort

ApiaceaeSellerie, Karotte, Fenchel, Petersilie, Anis, Dill, Koriander, Kümmel, Liebstöckel

Exotische FrüchteMango, Lychee

SolanaceaePaprika, Chili

CompositaeKamille, Estragon, Wermut, HonigSonnenblumenkerne

PiperaceaePfeffer

Cucurbidaceae Melone, Gurke, Zucchini

20-25% of all Patients with mugwortallergy

Diagnostic Aproach to Allergy

History

Clinical Presentation

Skintests (in vivo)

Serology (in vitro)

Provocation Test in Discrepancy

„Reibe“test

Skin-Pricktest Intracutantest/ Intradermaltest Epicutantest

Typ IV-Allergie

Serology

Detection of allergenspecific IgE

Limits of IgE

Sensitization = Allergy

IgE – is not valid without corresponding History

Positive IgE- Test : without Symptoms latent Sensitisation

Positive IgE- Test : with Symptoms Allergy

In doubt Provocation !

Provocation-tests

ConjunctivalNasalBronchialOralSubcutan (Drugs)Intravenous (Drugs)

Central Competence of the

ENT-Doctors

Therapy of Allergies

Allergenkarenz

Medical Therapy

spezific Immunotherapy (SIT)

Encasing in house dust mite allergy, Nasal douching

Topic vs Systemic

Symptomatic Therapy

• Nasal douching/ Nasal Creme• Topic Vasoconstrictor CAVE• Topic Anticholinergikum• Topic Cortico-Steroid• Topic Antihistamines• Systemic Antihistamines• Systemic Cortico-Steroides• ASS-Desactivation

DymistaFluticasonpropionat/Azelastin

Therapy of Allergies

Allergenavoidance

Drugs

spezific Immunotherapy (SIT)

Allergy

TH2

IL-4, IL-5, IL-13

TH1

INF-

Cell-Apoptosis

Antiviral

Spezific Immunotherapy

Noon / Freeman 1911: Pollen

TH1

INF-

Cell-Apoptosis

Antiviral

Repetitive Exposition to

high doses of causative AllergenAllergy

TH2

IL-4, IL-5, IL-13

TH2

TH1

Ig G4

T reg

IL-4, IL-13IL- 5

Spezific ImmunotherapyIL-10TGF-

Specific Immunotherapy

Maintenance Doseevery 4 – 6 Weaks

within 3 Years

Repetitionof 7 -9 Injections before

PollenseasonWithin 3 Years

oder

Specific Immunotherapy

Induction-Phase Konventionell

Rush

Ultra-Rush Co-Saisonal

Pre-SaisonalSIT- Indication in seasonal allergic RCV

• Classic seasonal History

• Detection of specific IgE (SkinPrickTest, Serology, Provocation)

• Durance 3 Years

• Symptoms increasing

• Unsatisfactory „course“ instead of using appropriate Medication

• Pulmonary involvement (Asthma bronchiale)

Efficiancy of SIT• Insect sting Allergy

• Pollinosis

• House dust mite allergy

• Allergy to Pets

• Mould-Allergy

85-95%

70-90 %

~ 60%

?

?

Succes in 1. Year, mainly. in 2. Year

Nasal > Konjunktival > BHR > OAS

Monosensibilisierte > Polysensibilisierte

Ongoing Efficacy over min. 5- 8 Years in70 – 80% of Patients

SPECIFIC IMMUNOTHERAPY„Realistic Outcome in Pollinosis“

New Sensitizations

Need for Medication Need for Medication

Extrakt Composition

only immunological related Allergens in Maximum 3-4 Allergens (> 20 ug/Allergen) only good standartised Allergenes

Contraindications of SIT

• Activ Autoimmun Diseases • Immunsuppression• Malignomas• Irreversible pulmonal Pathologies

(Bronchiektasen/Emphysem)• Uncontrolled Asthma/ COPD (FEV 1< 70%)• Tuberkulosis, Hepatitis• Cardiovaskular Diseases• Beta-Blocker, ACE-Inhibitors( )

( ) Insectallergie III-IV

Relative Kontraindications

• Pregnancy• Age < 5 Jahre / > 65• Severe atopic Ekzema• Compliance

Rhinoconjunktivitis and Asthma poll. since 4 Years, April

SIT Co-Seasonal with Birchpollen 100%

Improving of associated Food allergy in ca. 50% of cases to be

expected

Patient U.F, 23-y. ?

Efficiency

Adverse reactionsTime of Therapy

SIT

Measures for Optimizing SIT

Efficiency

Adverse reactionsTime of Therapy

Rekombinant manufactured AllergensNo IgE-binding EpitopesOnly T-Cell-binding-Epitopes

SIT

Different Application-Localizations

Different Dosing Schematas

Measures for Optimizing SIT

SubLingual SLITIntralymphatic ILITEpicutan ELIT

D o m i n i k H a r d e rFacharzt für Hals- Nasen- und Ohrenerkrankungen FMH

Facharzt für Allergologie und klinische Immunologie FMH

Brunnenhof-Praxis, Gäuggelistrasse 20

7000 Chur

Thank You