Common AllergyCommon Allergy Update 2001 Update 2001

Asst. Prof. Kiat Ruxrungtham, M.D.Asst. Prof. Kiat Ruxrungtham, M.D.Division of Allergy and Clinical ImmunologyDivision of Allergy and Clinical Immunology

Department of MedicineDepartment of MedicineFaculty of MedicineFaculty of Medicine

Chulalongkorn UniversityChulalongkorn University

โรคภู�มิ�แพ้ที่� พ้บบ�อยโรคภู�มิ�แพ้ที่� พ้บบ�อย โรคภู�มิ�แพ้ที่างจมิ�ก โรคภู�มิ�แพ้ที่างจมิ�ก Allergic Allergic

RhinitisRhinitis โรคหื�ดจากภู�มิ�แพ้ โรคหื�ดจากภู�มิ�แพ้ Allergic Allergic

AsthmaAsthma โรคภู�มิ�แพ้ที่างผิ�วหืนั�ง โรคภู�มิ�แพ้ที่างผิ�วหืนั�ง Atopic Atopic

DermatitisDermatitis โรคลมิพ้�ษโรคลมิพ้�ษ UrticariaUrticaria โรคโรค แพ้อาหืาร แพ้อาหืาร Food AllergyFood Allergy การการแพ้ยาแพ้ยา Drug AllergyDrug Allergy

Allergy Chula 1999

Epidemiology of Allergic Diseasesin Thai Children

13

17.9

40

4.2

13

0 10 20 30 40

Prevalence (%)

AtopicDermatitis

AllergicRhinitis

Asthma1990 1995

พยนต์� บุ�ญญฤทธิ พงษ์� และมนต์รี� ต์��จิ นดา 2533; ปกิ ต์ วิ ชยานนท� และคณะ 2541

Mediators of Mast Cells and BasophilsMediators of Mast Cells and Basophils

Histamine

Tryptase

Chymotryptase

Heparin/Chondroitin

Kininogenase

Chemotactic Factors

ProstaglandinsLeukotrienes

PAFHistamine RFs

IL-3, 4, 5, 6, 7, 8GM-CSF, TNF

Chemokines -MCP1, MIP1

Oxygen radicals

Primary MediatorsPrimary Mediators Secondary MediatorsSecondary Mediators

Sim TC, Grant JA 1996 AllergyChula

Mediators of Mast Cells and Allergy

Mast CellMast CellBasophilBasophil

Blood VesselsBlood VesselsBlood VesselsBlood Vessels

Smooth MusclesSmooth MusclesSmooth MusclesSmooth Muscles

Mucus GlandsMucus GlandsMucus GlandsMucus Glands

Sensory NervesSensory NervesSensory NervesSensory Nerves

LeukocytesLeukocytesLeukocytesLeukocytes

H, PGDH, PGD22, , LTs, PAFLTs, PAF

bradykininbradykinin

HH

H, PGDH, PGD22, , LTs, PAFLTs, PAF

LTB4LTB4PAFPAFIL3, IL5IL3, IL5ChemokinesChemokines

Urticaria, AngioedemaUrticaria, AngioedemaLaryngeal edema, ShockLaryngeal edema, Shock

BronchospasmBronchospasmAbd. pain, VomitingAbd. pain, Vomiting

Diarrhea, RhinorheaDiarrhea, RhinorheaBronchial secretionBronchial secretion

ItchingItching

Inflammation - LPAR Inflammation - LPAR

AllergyChula

Pathogenesis of Allergic DiseasePathogenesis of Allergic Disease

Genetic SusceptibilityGenetic SusceptibilityGenetic SusceptibilityGenetic Susceptibility

Allergic SensitzationAllergic SensitzationAllergic SensitzationAllergic Sensitzation

Upper/lower airway or SkinUpper/lower airway or Skinhyperresponsiveness hyperresponsiveness

Upper/lower airway or SkinUpper/lower airway or Skinhyperresponsiveness hyperresponsiveness

Allergic DiseasesAllergic Diseases

Allergen Exposure

Adjuvant factors:• Tobacco smoke• Air pollutants

Lack of protective factors:• Infection ?• Immunization ?• Nutrition ?

PollutantsInfectionExcercise

Modified from Ulrich Wahn 1998

Vary in spectrum Vary in spectrum and severityand severity

Principle Pathogenesis of Allergic Diseases Principle Pathogenesis of Allergic Diseases

Th-2Th-1

IL-12

IFN-IL-5IL-3GM-CSF

Eosonophil

Mastcell

IL-4 IgE

B-cell

APCAllergen

CD4+ T-cell

Late Phase Reaction

_ +

IgG

Durham and Till 1998, Lu 1998, Drazen 1996

CD8+ cell

AllergyChula

IL-5

B-cell

Allergen

Tryptase, LTs

MBPECP, LTs

Other cells

The Respiratory TractThe Respiratory TractUpper Respiratory Tract

Structures - Nose —> trachea - Sinuses, eustachian tubes - Ciliated mucosal lining

Functions - Conditioning the air - Defense

FiltrationInflammatory reactionImmune reaction

- Smell - Voice

Lower Respiratory Tract

Structures - Trachea —> alveoli

Functions - Inhalation-exhalation - Gas exchange - Acid-base balance

Co-existence of Asthma and ARCo-existence of Asthma and AR

306 former students 306 former students with with Allergic RhinitisAllergic Rhinitis

84 former students 84 former students with with AsthmaAsthma

AsthmaAsthma

nono ARAR

nono

Greisner WA et al Allergy Asthma Proc 1998; 19:185-8

86 %86 %79 %79 %

21 %21 %

23-Years Follow-up Study of Former Brown University Students (N=738)

Ragweed Hay Fever with Seasonal AsthmaRagweed Hay Fever with Seasonal AsthmaUpper-Lower Airway Linked

PlaceboPlacebo

Welsh et al. Mayo Clin Proc 1987;62:125-34

AR in Patients with Mild AsthmaAR in Patients with Mild AsthmaTreatment with intranasal corticosteroids :Treatment with intranasal corticosteroids :

Effect on lower airway responsiveness

0

1

2

3

4

PC

20 M

eth

ach

oli

ne

(mg

/mL

)

Baseline Intranasal BDP Placebo

At 4 Weeks of Treatment

Baseline Intranasal BDP Placebo

P =0.04

Watson WTA et al J Allergy Clin Immunol 1993; 91:97-101 AllergyChula

Mean Changes in FEV1 (Litre)Mean Changes in FEV1 (Litre)in Treated AR with Mild Asthmain Treated AR with Mild Asthma

0

0.05

0.1

0.15

0.2

0.25

Wk 1 Wk 2 Wk 4 Wk 6

Loratadine/Pseudoephredine Placebo

Corren J, et al J Allergy Clin Immuno 1997; Corren J, et al J Allergy Clin Immuno 1997; 100:781-788100:781-788

Morning (AM)

*

*

* P=0.01

***<0.05

Ideal AntihistaminesIdeal AntihistaminesSafety No CNS toxicity No cardiotoxicity

Pharmacology• Specific H1 receptor blockade• Additional potent anti-allergic/anti-

inflammatory effects• Rapid onset of action• Long-acting• No-tachyphylaxis• No drug interaction• No dose-adjustment required in

special-risk groups

Simons FE EAACI 1998 AllergyChula

PK and PD : Second-Third generation AntihistaminesPK and PD : Second-Third generation Antihistamines

Drug Metabolism T1/2 (h)* Onset Peak Duration

Terfenadine Liver 16-24 1-2 h 3-4 h 8-12 h

Astemizole Liver 9.5 days 2 day 9-12d weeks

Loratadine Liver 17-24 >1 h 4-8 h 24 h

Cetirizine no (Kidney) 25 1 h 4-8 h 24 h

Fexofenadine minimal 14.4 1 h 2-3 h 24 h

-Inhibition of Histamine wheal/flare -Inhibition of Histamine wheal/flare

Kaliner M. Clin Geriatrics 1997; Simons FE, NEJM 1994Kaliner M. Clin Geriatrics 1997; Simons FE, NEJM 1994AllergyChulaAllergyChula

H1-Antagonists and Drug Interaction

First-generation H1-AntagonistsFirst-generation H1-Antagonists Potentiation of SedationPotentiation of Sedation : : Alcohol, sedative agents, hypnotics, antidepr Alcohol, sedative agents, hypnotics, antidepr

essantsessants Potentiation of anticholinergicPotentiation of anticholinergic effect:effect: Antidepressants Antidepressants

Second-generation H1-AntagonistsSecond-generation H1-Antagonists

(Terfenadine, astemizole, ebastine-animal model , but not loratadine)(Terfenadine, astemizole, ebastine-animal model , but not loratadine)

Decrease hepatic metabolism and increase risk of cardiotoxicity:Decrease hepatic metabolism and increase risk of cardiotoxicity:

Drugs that inhibit cytochrome p450 : Ketoconazole, macrolides-erythromyDrugs that inhibit cytochrome p450 : Ketoconazole, macrolides-erythromycin, other azoles- itraconazolecin, other azoles- itraconazole

Drugs that prolong QTDrugs that prolong QT : quinidine : quinidine

Third-generation H1-AntagonistsThird-generation H1-Antagonists (Cetirizine, Fexofenadine)(Cetirizine, Fexofenadine) No clinical significant in drug interaction No clinical significant in drug interaction

AllergyChula

Antihistamines in Elderly

• Drawsiness, fatigue and may increase risk falling or accident

• The first-generation H1 antagonist should be avoided in patient with glaucoma

• The first-generation H1 antagonist should also be avoided in patient with prostrate hypertrophy

• Be aware of cardiotoxic risk; terfenadine, astemizole should be used with caution

AllergyChula

Treatment of Allergic Rhinitis in AdultsTreatment of Allergic Rhinitis in Adults

Allergy Immunol Clinic 2000

Drug Itch/sneezing

Rhinorrhea Blockage Anosmia

Antihistamines +++ ++ + -Topical CS +++ +++ ++/+++ +/++

Oral CS +++ +++ +++ ++/+++

Topicaldecongestants

- - +++ -

Ipratropiumbromide

- +++ - -

Sodiumcromoclycate

+ + + -

เย� อจมิ�กบวมิในั โรคภู�มิ�แพ้ เย� อจมิ�กบวมิในั โรคภู�มิ�แพ้ที่างจมิ�กที่างจมิ�ก

Allergy Chula 1999

Characteristics of Antihistamines

AllergyChula

H1 Antagonist H1 Antagonist +++ +++ ++++++

Anticholinergic Anticholinergic +++ +++ -- ((Cetirizine -dry mouth)Cetirizine -dry mouth)

Sedation Sedation ++/+++ ++/+++ -- (Cetirizine +/-)(Cetirizine +/-)

Duration of Action Duration of Action +/++ +/++ ++/+++++/+++ (Astemizole-longest)(Astemizole-longest)

Antiallergic Antiallergic -/+ -/+ -/++-/++ (Azelastine)(Azelastine)

AntiinflammatoryAntiinflammatory - - -/+-/+ (Clinical ?)(Clinical ?) (Citirizine, Loratadine(Citirizine, Loratadine

Fexofenadine)Fexofenadine)

CharacteristicsCharacteristics First First Second/Third Generation Second/Third Generation

Adverse Effects of H1-Antagonists

Adverse Effects CPM HZ TF ASZ LD CZ FX

Sedation + ++ - - - -/+ -

Appetite stim. - -/+ - -/++ - -/+ -

Weight gain - -/+ - -/++ - -/+ -

Dry mouth ++ + - - - -/+ -

Prolong QTc -/ ? -/ ? +* +* - - -

Torsade de Points - - +* +* - - -

AllergyChula

Effects of fexofenadine, diphenhydramine, and alcohol on Effects of fexofenadine, diphenhydramine, and alcohol on driving performance: in the Iowa driving simulatordriving performance: in the Iowa driving simulator

Overall driving performance• Fexofenadine = placebo• Alcohol >placebo• Diphenhydramine > alcohol• Drowsiness ratings were not a good predictor of impair

ment• suggesting: drivers cannot use drowsiness to indicate

when they should not drive.

Weiler JM et al. Ann Intern Med 2000 Mar 7;132(5):354-63

AllergyChula

Sedation with "non-sedating” antihistamines: four prescription-event monitoring studies in general practice

N= a total of 43 363 patients: Drowsiness The Odd Ratio P value(versus Loratadine)

Fexofenadine 0.63 (0.36-1.11) 0.1

Acrivastine 2.79 (1.69-4.58) <0.0001

Cetirizine 3.53 (2.07-5.42) <0.0001

No increased risk of accident or injury was evident with any of the four drugs.

Mann RD, et al. BMJ 2000 Apr 29;320(7243):1184-1187

Antihistamines in Elderly

• Drawsiness, fatigue and may increase risk falling or accident

• The first-generation H1 antagonist should be avoided in patient with glaucoma

• The first-generation H1 antagonist should also be avoided in patient with prostrate hypertrophy

• Be aware of cardiotoxic risk; terfenadine, astemizole should be used with caution

AllergyChula

Anti-H1 and Anti-inflammation

Antihistamine Evidence-based In Vitro In Vivo (DPCT)

(positive results/total)

Loratadine yes 1/3

Cetirizine yes 3/5

Terfenadine yes 1/1

Fexofenadine yes nd

AllergyChula

GINA guidelines 1998Focus on ICS and ß2-agonists

Short-acting ßShort-acting ß2 2 prnprn

Inhaled corticosteroidsInhaled corticosteroids

Long-acting ßLong-acting ß22

J Bousquet Berlin 1999

IntermittentMild

persistent

Moderate persistent

Severepersistent

Theophylline: Plasma concentrations

Clinical Efficacy in Chronic Asthma as a monClinical Efficacy in Chronic Asthma as a monotherapy : otherapy : – 10-20 10-20 g/mlg/ml

Anti-inflammatory, Immunomodulatory : Anti-inflammatory, Immunomodulatory : – >5-10 >5-10 g/mlg/ml

Food and Drug InteractionFood and Drug Interaction• Increase clearance: Increase clearance: anticonvalsants (phenobarbitanticonvalsants (phenobarbit

al, phynytoin,carbamazepine), rifampicinal, phynytoin,carbamazepine), rifampicin

• Decrease clearnace: Decrease clearnace: alcohol, antibiotics (erythroalcohol, antibiotics (erythromycin, clarithromycin, ciprofloxacin), cimetidinemycin, clarithromycin, ciprofloxacin), cimetidine

AllergyChula

Theophylline as an Add On Regimen (1)

412

402

360

380

400

420

440

Week 0 Week 3 Week 6 Week 9 Week 12

Mea

n M

orn

ing

PE

F (

L/m

in)

Low dose Bud + Theo Low dose High dose + Placebo

Evans DJ, et al N Engl J Med 1997; 13:1412-8

NS

N=31 per group

Budesonide: Low dose =400, High dose=800 BID** (**Decreased cortisol level)Theophylline: Low dose =250 mg BID (BW<80 kg) or =375 mg BID (BW>80)

*Median serum Theophylline =8.7 mg/ml

Theophylline as an Add On Regimen Theophylline as an Add On Regimen (2)(2)

0

100

200

300

400

500

Mea

n A

M P

EF

(L

/min

)

Beclo 200 bid +Theophylline

Beclo 400 bid +Placebo

Week 0 Week 6

Ukena et al Eur Respir J 19971997; 10:2754-60

P<0.01P<0.01P=ns

N= 69 N= 64

Pathogenesis of Allergy and Asthma and Potential Novel Therapy

LeukotrienesPGD2

Histamine

TryptasePAF

Bronchoconstrictionand Mucus Secretion

Chemotaxis

EotaxinRANTES

MCP4Airway HyperreactivityAirway Hyperreactivity

T-Helper CellsT-Helper CellsTh2Th2

IL-5

IL-4B CellsB Cells

IgE

Eosinophil Recruitment and Production

Anti--IL-4 AbAnti--IL-4 AbIFNIFN (Th1) (Th1)

Anti--IL-5 AbAnti--IL-5 Ab

Anti--leukotrienes Anti--leukotrienes ZileutonZileuton ZafirlukastZafirlukast MontelukastMontelukast

Mast cell

Tryptase inhibitorTryptase inhibitorAnti-PAFAnti-PAF

IFNIFN (Th1 switch) (Th1 switch)

Eosinophil

InflammationInflammation

Future OptionsFuture OptionsPhosphodiesterase 4 (PDE-4) inhibitorsPhosphodiesterase 4 (PDE-4) inhibitors• TheophyllineTheophylline is a non-selective PDE-4 inhibiis a non-selective PDE-4 inhibi

tortor

• Selective inhibitorsSelective inhibitors:: CDP840, KF 19514, CDP840, KF 19514, CP80, 633CP80, 633– Increase intracellular c-AMPIncrease intracellular c-AMP– Decreased eosinophil survival (IL-5 induced)Decreased eosinophil survival (IL-5 induced)– Decreeased IL-4, IL-13 production Decreeased IL-4, IL-13 production

Momose T 1998, Faissier L 1996, Shichijo M 1997

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คว�นับ%หืร� คว�นัธู�ป

Principles of Allergen ImmunotherapyPrinciples of Allergen Immunotherapy

AllergyChula

Induction Maintenance Phase

Allergen IT: LiteratureSearched

31by Tittle Words in IGM ( Oct1998

407

143

64

4

21

16

3

1

1

0 100 200 300 400

Venom

Pollen

Ragweed

HDM

Cat

Dog

Mold

Cock

Food

AllergyChula

Efficacy of Venom Immunotherapy (VIT)Efficacy of Venom Immunotherapy (VIT)(Protection from systemic reaction to the insect stings)(Protection from systemic reaction to the insect stings)

0 25 50 75 100

Hunt 1978

Gillman1980

Golden 1981

Reisman 1986

Mosbach 1986

Muller 1992(Bee)

Muller 1992(wasp)

% Efficcacy% EfficcacyAllergyChula

Clinical Efficacy of AIT in Allergic Rhinitis

(41 DBPC trials as by October 1998)

17

2

12

23

13

1

0

5

10

15

20

No

. o

f st

ud

y

GrassPollen

Ragweed Tree HDM

Yes No

AllergyChula

Indications of Allergen Immunotherapy

• Insect sting allergyInsect sting allergy Systemic reaction (absolute indication)Systemic reaction (absolute indication)

• Allergic rhinitis*Allergic rhinitis*

• Allergic asthma*Allergic asthma* (PFT >70% pred. value)(PFT >70% pred. value)

AllergyChula

**Dissatisfactory with avoidance + pharmacotherapyDissatisfactory with avoidance + pharmacotherapy

Allergen Immunotherapy not proven effective in:

• Atopic DermatitisAtopic Dermatitis

• Food AllergyFood Allergy

• Chronic UrticariaChronic Urticaria

AllergyChula

Pathogenesis of Allergy and Asthma and Potential Novel Therapy

LeukotrienesPGD2

Histamine

TryptasePAF

Bronchoconstrictionand Mucus Secretion

Chemotaxis

EotaxinRANTES

MCP4Airway HyperreactivityAirway Hyperreactivity

T-Helper CellsT-Helper CellsTh2Th2

IL-5

IL-4B CellsB Cells

IgE

Eosinophil Recruitment and Production

Anti--IL-4 AbAnti--IL-4 AbIFNIFN (Th1) (Th1)

Anti--IL-5 AbAnti--IL-5 Ab

Anti--leukotrienes Anti--leukotrienes ZileutonZileuton ZafirlukastZafirlukast MontelukastMontelukast

Mast cell

Tryptase inhibitorTryptase inhibitorAnti-PAFAnti-PAF

IFNIFN (Th1 switch) (Th1 switch)

Eosinophil

InflammationInflammation

Factors Affecting Clinical OutcomesFactors Affecting Clinical Outcomes of Allergic Diseases of Allergic Diseases

AllergyChula

Enivronmental• Allergens• Irritants• Westernization

Infection• Viral• Bacterial

Treatment• Anti-inflammatory• Anti-allergic• Relievers

Compliance• Avoidance• Medication uses

Allergic DiseasesAllergic Diseases

Remission ModerateMild Severe

Allergen Immunotherapy

Genetic Degree of atopy

Future Therapy