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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