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

Department of Medicine, Department of Medicine, Faculty of MedicineFaculty of Medicine

Chulalongkorn UniversityChulalongkorn University

AASTHMASTHMA A A HHIGHLY IGHLY VVARIABLE ARIABLE DDISEASEISEASE

Case Study 1Case Study 1: PM, age 44(cont’d): PM, age 44(cont’d)

250

410

230

400

240

120

410

250

0

100

200

300

400

500

Mar-97

Jun-00

July-00

Aug-00

Nov-00

Jan-01

May-01

Jun-01

Peak

flow

rate

(L/m

in)

PEF

Variation of Clinical symptoms and PEFVariation of Clinical symptoms and PEF

SinusitisSinusitis SinusitisSinusitis SinusitisSinusitisLost FULost FU

LABA/ICSLABA/ICS LABA/ICSLABA/ICS

Case Study 2Case Study 2: VN, Male age 60: VN, Male age 60

370

250300 290

230

370

280240

320

230

300

360

300 320390

230

0

100

200

300

400

500

Jan-9

9

Jan-9

9

Mar

-99

May

-99

Aug-99

Dec-9

9

Feb-0

0

Apr-00

May

-00

Oct-0

0

Nov-00

Dec-0

0

Jan-0

1

Apr-01

Jun-0

1

July-

01

Peak

flow

rate

(L/m

in) PEF

Known of Asthma for 30 years, non-smokerKnown of Asthma for 30 years, non-smokerVariation of Clinical symptoms and PEFVariation of Clinical symptoms and PEF

LABA/ICSLABA/ICS LABA/ICSLABA/ICS

Lost FULost FU Lost FULost FU Non-adherenceNon-adherenceworsening ARworsening AR

Case Study 5Case Study 5: AC, Male age 37: AC, Male age 37

540

320

480 480

550

460

540540

550

510

300350

0100200300400500600

Jul-1

996

Nov-199

7

Jan-1

998

Feb-1

998

Mar

-199

8

Apr-199

8

Jun-1

998

Jul-1

999

Aug-199

9

Oct-1

999

Jan-2

000

Jul-2

001

Peak

flow

rate

(L/m

in)

Asthma and AR since childhood, non-smokerAsthma and AR since childhood, non-smoker

ICSICS

ICS/LABAICS/LABAINCS/H1 inhINCS/H1 inh

URIURI Cigarette smokeCigarette smoke

ICSICS

Asthma: CharacteristicsKey characteristicsKey characteristics• Reversible airway obstructionReversible airway obstruction• Chronic eosinophilic airway inflammationChronic eosinophilic airway inflammation• Airway hyperresponsivenessAirway hyperresponsiveness

Clinical featuresClinical features• episodic cough and dyspnea, wheezingepisodic cough and dyspnea, wheezing• Variation of PEF or FEV1 >15-20% with/without brVariation of PEF or FEV1 >15-20% with/without br

onchodilatorsonchodilators

Asthma: Risk Factors

Environmental Genetic

~5 % in Adults13 % in Children

Clinical Asthma

AeroallergensPollutantsTriggers

ThailandThailand

~19 genes

5q: IL4, CD14, B2ADR

6p: DRB1, TNF

11q: FCERB1, CC16

16p: IL4RA

AllergyChula

Immediate and Late Phase Asthmatic Reactions (IPAR and LPAR)

mins 1 2 3 4 5 6 7 8 9 10 -hrs//-------- days

Time after Allergen ChallengeTime after Allergen Challenge

FEV1

BHRBHR

AllergyChulaAllergyChula

Allergen

IPARIPAR

LPARLPAR

Asthma 2001

Airway Airway InflammationInflammation

Smooth Smooth MuscleMuscle

DysfunctionDysfunction

Airway Airway RemodelingRemodeling

Barnes P 2001

Fatal AsthmaFatal Asthma

Normal subject (postmortem)

Living severe asthma (opened lung biopsy): markedly folded bronchial epithelia and mucosa, thickened airway wall, and epithelial cell aggregate in the airway lumen.

Fatal asthma (autopsy): goblet cell hyperplasia and eosinophilic inflammation. The airway lumen is occupied with a mucus plug.

Busse W JACI 2000

Reliable markers for predicting of severe and fatal prone asthma is needed

AllergyChula

Smooth Muscle Dysfunction in Asthma

Increase contractionIncrease contraction Increase smooth muscle mass, Increase smooth muscle mass,

hyperplasiahyperplasia Increase release of inflammatory Increase release of inflammatory

mediatorsmediators

AllergyChula

Airway Remodeling in Asthma

Cells proliferation: smooth muscle cells, mucous glands

Increase matrix protein deposition Reticular basement membrane

thickening Angiogenesis

AllergyChula

Cells Involved in AsthmaCells Involved in Asthma

AllergyChula

Cells, cytokines and molecules in Asthma

IL-1IL-1

IL-12IL-12

AntigenAntigenpresentationpresentation

CD4CD4ICAM-3ICAM-3

ICAM-1ICAM-1CD8CD8

Johnson M et al 2000 and Vignola M Nice 2001 AllergyChula

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

SCFSCF

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-2IL-2

IL-8IL-8

MIP-1MIP-1

PDGFPDGF

L-selectinL-selectin

MCP-1MCP-1

15-HETE15-HETE

RANTESRANTES

ICAM-1ICAM-1

TXB2TXB2

IFN-IFN-

CR3CR3

EDPEDP

MBPMBP

LTB4LTB4

TGFTGF

HB-EGFHB-EGF

OO22

--

MAC-1MAC-1

PAFPAF

LTC4LTC4

ECPECP

EPOEPO

EDNEDN

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-8IL-8

MIP-1MIP-1 MCP-3MCP-3RANTESRANTES

IFN-IFN-

LTB4LTB4

LTD4LTD4

LTE4LTE4

SCFSCF

eotaxineotaxin

histaminehistamine

PGD2PGD2

IL-14IL-14

NCFNCF

TryptaseTryptase

LTC4LTC4

PAFPAF

IL-6IL-6

IL-8IL-8GM-CSFGM-CSF

TNFTNF

SCFSCFPGEPGE22

RANTESRANTES

eotaxineotaxin

MCP-1MCP-1

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-11IL-11

IL-17IL-17

IL-1IL-1

IL-8IL-8

IL-16IL-16

PGF2PGF2PGE2PGE2

IGF-1IGF-1

CGRPCGRP

FGFFGF

cPLA2cPLA2

NONO

SLPISLPI

NEPNEP

COX2COX2

iNOSiNOS

15-LO15-LO

MIP-1MIP-1

VIPVIP

PDGFPDGF

E-selectinE-selectin

eotaxineotaxin

MCP-1MCP-1

ET-1ET-1

MCP-4MCP-415-HETE15-HETE

RANTESRANTES

MCP-2MCP-2

MMP-9MMP-9

GRO-BGRO-B

ICAM-1ICAM-1

Comparable Asthma Severity in the Two Study Populations

Europe

Mild 19%

43%

19%

Severe

19%

US

Severe19%

19%

Mild 22%

40%

Severity classified by NIH Symptom Severity Index

ModerateModerate

AllergyChula

AIRE AIA

Intermittent Intermittent

AdrenalineAdrenaline

IsoprenalineIsoprenaline

Salbutamol, terbutalineSalbutamol, terbutaline

Salmeterol, FomoterolSalmeterol, Fomoterol

Synergy of CS and LABAAdrenal extract

CortisolCortisol

BDP, BudBDP, Bud

FPFP

CombinationCombinationCS+LABACS+LABA

19001900

19991999P Barnes Berlin 1999

Synergy of ICS and LABA

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-2IL-2

IL-8IL-8

MIP-1MIP-1

PDGFPDGF

L-selectinL-selectin

MCP-1MCP-1

15-HETE15-HETE

RANTESRANTES

ICAM-1ICAM-1

TXB2TXB2

IFN-IFN-

CR3CR3

EDPEDP

MBPMBP

LTB4LTB4

TGFTGF

HB-EGFHB-EGF

OO22--

MAC-1MAC-1

PAFPAF

LTC4LTC4

ECPECP

EPOEPO

EDNEDN

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

SCSCFF

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-8IL-8

MIP-1MIP-1 MCP-3MCP-3

RANTESRANTES

IFN-IFN-

LTB4LTB4

LTD4LTD4

LTE4LTE4

SCFSCF

eotaxineotaxin

histaminehistamine

PGD2PGD2

IL-14IL-14

NCFNCF

TryptaseTryptase

LTC4LTC4

PAFPAF

IL-6IL-6

IL-8IL-8GM-CSFGM-CSF

TNFTNF

SCFSCFPGEPGE22

RANTESRANTES

eotaxineotaxin

MCP-1MCP-1

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-11IL-11

IL-17IL-17

IL-1IL-1

IL-8IL-8

IL-16IL-16

PGF2PGF2PGE2PGE2

IGF-1IGF-1

CGRPCGRP

FGFFGF

cPLA2cPLA2

NONO

SLPISLPI

NEPNEP

COX2COX2

iNOSiNOS

15-LO15-LO

MIP-1MIP-1

VIPVIP

PDGFPDGF

E-selectinE-selectin

eotaxineotaxin

MCP-1MCP-1

ET-1ET-1

MCP-4MCP-415-HETE15-HETE

RANTESRANTES

MCP-2MCP-2

MMP-9MMP-9

GRO-BGRO-B

ICAM-1ICAM-1

15-LTs15-LTs

Johnson M et al 2000 and Vignola M Nice 2001

Synergistic Effects of ICS+LABA on Eosinophil

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-2IL-2

IL-8IL-8

MIP-1MIP-1

PDGFPDGF

L-selectinL-selectin

MCP-1MCP-1

15-HETE15-HETE

RANTESRANTES

ICAM-1ICAM-1

TXB2TXB2

IFN-IFN-

CR3CR3

EDPEDP

MBPMBP

LTB4LTB4

TGFTGF

HB-EGFHB-EGF

OO22--

MAC-1MAC-1

PAFPAF

LTC4LTC4

ECPECP

EPOEPO

EDNEDN

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-2IL-2

IL-8IL-8

MIP-1MIP-1

PDGFPDGF

L-selectinL-selectin

MCP-1MCP-1

15-HETE15-HETE

RANTESRANTES

ICAM-1ICAM-1

TXB2TXB2

IFN-IFN-

CR3CR3

EDPEDP

MBPMBP

LTB4LTB4

TGFTGF

HB-EGFHB-EGF

OO22--

MAC-1MAC-1

PAFPAF

LTC4LTC4

ECPECP

EPOEPO

EDNEDN

Synergistic Effects of ICS+LABA on Mast Cells

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-8IL-8

MIP-1MIP-1 MCP-3MCP-3RANTESRANTES

IFN-IFN-

LTB4LTB4

LTD4LTD4

LTE4LTE4

SCFSCF

eotaxineotaxin

histaminehistamine

PGD2PGD2

IL-14IL-14

NCFNCF

TryptaseTryptase

LTC4LTC4

PAFPAF

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-8IL-8

MIP-1MIP-1 MCP-3MCP-3RANTESRANTES

IFN-IFN-

LTB4LTB4

LTD4LTD4

LTE4LTE4

SCFSCF

eotaxineotaxin

histaminehistamine

PGD2PGD2

IL-14IL-14

NCFNCF

TryptaseTryptase

LTC4LTC4

PAFPAF

Synergy of CS and LABA on Epithelial Cells in Asthma

IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-11IL-11

IL-17IL-17

IL-1IL-1

IL-8IL-8

IL-16IL-16

PGF2PGF2PGE2PGE2

IGF-1IGF-1

CGRPCGRP

FGFFGF

cPLA2cPLA2

NONO

SLPISLPI

NEPNEP

COX2COX2

iNOSiNOS

15-LO15-LO

MIP-1MIP-1

VIPVIP

PDGFPDGF

E-selectinE-selectin

eotaxineotaxin

MCP-1MCP-1

ET-1ET-1

MCP-4MCP-415-HETE15-HETE

RANTESRANTES

MCP-2MCP-2

MMP-9MMP-9

GRO-BGRO-B

ICAM-1ICAM-1 IL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

IL-13IL-13

IL-1IL-1

GM-CSFGM-CSF

TNFTNF

IL-11IL-11

IL-17IL-17

IL-1IL-1

IL-8IL-8

IL-16IL-16

PGF2PGF2PGE2PGE2

IGF-1IGF-1

CGRPCGRP

FGFFGF

cPLA2cPLA2

NONO

SLPISLPI

NEPNEP

COX2COX2

iNOSiNOS

15-LO15-LO

MIP-1MIP-1

VIPVIP

PDGFPDGF

E-selectinE-selectin

eotaxineotaxin

MCP-1MCP-1

ET-1ET-1

MCP-4MCP-415-HETE15-HETE

RANTESRANTES

MCP-2MCP-2

MMP-9MMP-9

GRO-BGRO-B

ICAM-1ICAM-1

15-LTs15-LTs

Synergy of CS and LABA on Smooth muscle cell in Asthma

IL-6IL-6

IL-8IL-8GM-CSFGM-CSF

TNFTNF

SCFSCFPGEPGE22

RANTESRANTES

eotaxineotaxin

MCP-1MCP-1

IL-6IL-6

IL-8IL-8GM-CSFGM-CSF

TNFTNF

SCFSCFPGEPGE22

RANTESRANTES

eotaxineotaxin

MCP-1MCP-1

Asthma: A Highly Variable DiseaseAsthma: A Highly Variable Disease

Airway Airway InflammationInflammation

Smooth Smooth MuscleMuscle

DysfunctionDysfunction

Airway Airway RemodelingRemodeling

Infection

AllergensAllergens

ARAR

PollutantsPollutants

SinusitisSinusitis

Cold airCold air

ExcerciseExcercise

DrugsDrugs

ASA/NSAIDSASA/NSAIDSPsychologicalPsychological

Variable AsthmaticVariable AsthmaticSymptomsSymptoms

• IntermittentIntermittent• PersistentPersistent

• MildMild• ModerateModerate• SevereSevere

• IrreversibilityIrreversibility

TreatmentTreatment

AdherenceAdherence

AvoidanceAvoidance

GeneticsGenetics

AHRAHR

ReversibleReversibleAirwayAirway

ObstructionObstruction

Treating Asthma: Individualized and Dynamics ApproachTreating Asthma: Individualized and Dynamics Approach

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 Asthma

PlaceboPlacebo

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

Mean Changes in PEFR (L/min)in Treated AR with Mild Asthma

05

1015202530

Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6

Placebo Loratadine/Pseudoephredine

05

1015202530

Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6

Placebo Loratadine/Pseudoephredine

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) Evening (PM)

*

****

******

* *<0.05

P=0.002

SINUSITISSINUSITIS

A Thai Cohort of NSAIDs/Analgesic Sensitivity

MeanMean (range) (range) Age at visit: Age at visit: 37 (14-64) 37 (14-64) Age of first episodeAge of first episode: 25 (10-37): 25 (10-37)

N=31

Ruxrungtham K. 2001

AllergyChula

Male23%

Female77%

GenderFemale: Male 3:1

Clinical Features of NSAIDs/Analgesic Sensitivity

A Thai Cohort (N=31)

3% 3%

10%

10%

17%

13% 44%

Angioedema

Anaphylactoid

Urticaria/angioedema

Asthma with others

Naso-ocular withangioedemaUrticaria

Rash

AngioedemaAngioedema

AnaphylactoidAnaphylactoid

2 Aspirin disease (ASA Triad)2 Aspirin disease (ASA Triad)

Asthma+

Urticaria+angioedema

Nasoocular+angioedema

Ruxrungtham K. 2001

AllergyChula

NSAIDs/Analgesic SensitivityA Thai Cohort

Mixed32%

Dipyrone7%

Paracetamol21%

NSAIDs14%

ASA26%

ASA

NSAIDs

Dipyrone

Paracetamol

Mixed

Ruxrungtham K. 2001

AllergyChula

Type of Agents N=31

NSAIDs/Analgesic SensitivityA Thai Cohort

Cross-reaction with paracetamol

Yes40%No

56%

4% Yes

No

Notknown

N=25

Ruxrungtham K. 2001

AllergyChula

Case study: Diagnosis

Aspirin TriadAspirin Triad Rhinosinusitis witRhinosinusitis wit

h nasal polypsh nasal polyps Chronic asthmaChronic asthma ASA sensitivity ASA sensitivity

AllergyChula

More specific diagnosisMore specific diagnosis: : Aspirin DiseaseAspirin Disease

AIRE Survey FindingsAIRE Survey Findings

23 26 2630

63

7681

75

0

20

40

60

80

100

AIRE Total SeverePersistent

ModeratePersistent

MildPersistent

% o

f Pat

ient

s

N=2803 in 7 European Countries

AllergyChula

AIRE Survey FindingsAIRE Survey Findings

63 %

17 %

43 %

30 %

30 %

46 %

0 20 40 60 80 100

Daytime symptoms

Sleep disturbance (1/wk)

Emergency visits

Activity limited

Missed work

Missed school

AIRE Survey Findings (%)

N=2803 in 7 European Countries

AllergyChula

Asthma: A Highly Variable DiseaseAsthma: A Highly Variable Disease

Airway Airway InflammationInflammation

Smooth Smooth MuscleMuscle

DysfunctionDysfunction

Airway Airway RemodelingRemodeling

Infection

AllergensAllergens

ARAR

PollutantsPollutants

SinusitisSinusitis

Cold airCold air

ExcerciseExcercise

DrugsDrugs

ASA/NSAIDSASA/NSAIDSPsychologicalPsychological

Variable AsthmaticVariable AsthmaticSymptomsSymptoms

• IntermittentIntermittent• PersistentPersistent

• MildMild• ModerateModerate• SevereSevere

• IrreversibilityIrreversibility

TreatmentTreatment

AdherenceAdherence

AvoidanceAvoidance

GeneticsGenetics

AHRAHR

ReversibleReversibleAirwayAirway

ObstructionObstruction

Treating Asthma: Individualized and Dynamics ApproachTreating Asthma: Individualized and Dynamics Approach