Download M201_Asthma_03

UPDATE on ASTHMA:
INFLAMMATION, ENVIRONMENT,
and THERAPY
Adrian M. Casillas, MD
UCLA School of Medicine
Division of Clinical Immunology and Allergy
ASTHMA DEFINED
1952: “The presence of widespread narrowing of
the airways which alters in severity either
spontaneously or as a result of treatment”
1962: Presence of bronchial hyperesponsiveness
added
1970’s: Autopsy studies revealed inflammation
1980’s: Bronchoscopic evidence of inflammation in
vivo
WHAT IS ASTHMA?
1995 Definition:
• Chronic inflammatory disorder of the
airways
- Mast cells, eosinophils, T lymphocytes
• Inflammation associated with:
- Airways hyperresponsiveness
- Airflow limitation (at least partially
reversible)
- Respiratory symptoms: wheezing,
breathlessness, cough, chest tightness
1995 NHLBI/WHO Workshop Report
Cardinal Features of Asthma
• Hyper-reactive airways
• Late phase reaction
• Multicellular infiltrate
Provocative Inhalation Challenge in
Asthmatics
50
40
30
SEVERE
20
MODERATE
MILD
SLIGHT
10
Normal
0
0.01
0.1 Dose (mol)
1
10
% Fall in Baseline FEV1
Mediators in Early and Late Phase Responses
10
EPR
0
LPR
-10
-20
LTB4, LTC4
PGE2 , PGD2
Histamine
GM-CSF, IL-5
LTB4 LTB4 LTB4
PGD2 TX
Histamine
Tryptase
LTC4
-30
-40
-50
0
1
2
3
4
5
6
Hours After Allergen Challenge
7
8
9
10
Busse WW and Lemanske RF. Asthma.
NEJM. 2001. 344;350-362
Normal
Asthma
Inflammatory Cells in Bronchial Epithelium
of Newly Diagnosed Asthmatics
**
120
Cells/mm2
**
Controls
Asthmatics
612
**
80
40
*
0
N
E
M
MC
L
* p<0.05
** p<0.001
Laitinen et al, ARRD 1993;147:697
Asthma
Pathological Changes in the Airways of Asthmatics
Vasodilatation
Plasma leakage
New vessels
Plasma
exudation
Desquamation
of epithelium
Goblet cell
hyperplasia
Mucus
plug
Air
passage
Hyperplasia
of mucus
glands
Edema
Smooth muscle hypertrophy
and contraction
Basement
membrane
thickening
Subepithelial
fibrosis
Neutrophil and
eosinophil infiltration
Chronic changes are identified in italics, the remainder are acute changes.
Adapted from Cochrane GM, Jackson WF, Rees PJ.
Asthma
Mechanisms Underlying the
Definitions of Asthma
Environmental risk factors (causes)
INFLAMMATION
Airway
hyperresponsiveness
Airflow
limitation
Triggers
Symptoms
Adapted with permission from Stephen T. Holgate, M.D., D.Sc.
Asthma
IS THE PREVALENCE OF ASTHMA
INCREASING?
per 1000 population
TRENDS
IN ASTHMA
PREVALENCE
IN THE
Trends
in Asthma
Prevalence
UNITED STATES
80
70
60
50
40
30
20
10
0
all ages
0 to 4
5 to 14
15 to 34
35 to 64
65 +
1980
81 - 93 84 - 86 87 - 89 90 - 92 93 - 94
Years
Source: MMWR 1998; 47:1-27
Per 100k population
TRENDS IN U.S. ASTHMA MORTALITY RATES
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
AfricanAmerican
Caucasian
All persons
79 81 83 85 87 89 91 93 95
Year
ASTHMA MORTALITY RATES (per 100k)
COUNTRY
1975-77
1985-87
% INCREASE
AUSTRALIA
0.86
1.42
65
CANADA
0.33
0.47
42
ENGLAND & WALES
0.57
0.90
58
FRANCE
0.24
0.51
113
JAPAN
0.44
0.59
34
SINGAPORE
0.75
0.88
17
SWEDEN
0.37
0.54
46
SWITZERLAND
0.31
0.45
45
UNITED STATES
0.19
0.40
111
WEST GERMANY
0.59
0.78
32
Beasley, et al. Ciba Symposium 206; 1997
RISK FACTORS for DEVELOPMENT of ASTHMA
• GENDER
• ATOPIC
STATUS
Lung and Immune system
development
Induction of atopy:
Th1/Th2
• GENETIC
FACTORS
Susceptibility genes
• RESPIRATORY
INFECTIONS
Viral respiratory disease
(RSV)
• ENVIRONMENT
Pollution (DEP)
IMMUNOLOGICAL DEVELOPMENT
AND ATOPIC STATUS
THE Th1/Th2 CELL PARADIGM
Kay AB. Allergy and Allergic diseases. NEJM. 2001. 344;30-37
Busse WW and Lemanske RF. Asthma. NEJM. 2001. 344;350-362
TH1/TH2 PARADIGM
PARADIGM
TH1/TH2
TH1
TH2
IL-2
INF-
IL-3
GM-CSF
TNF-
IL-4 (IL-13)
IL-5
IL-3
GM-CSF
TNF-
DELAYED
HYPERSENSITIVITY
ALLERGIC
INFLAMMATION
Need a balance of TH1 and TH2; with asthma, a more “TH2-like”
phenomenon is seen.
Tang et al. Lancet 1994;344(8928):983-5; *Prescott S. et al. Lancet 1999;16;353(9148):196-200
THE ROLE OF IgE
Busse WW and Lemanske RF. Asthma. NEJM. 2001.
344;350-362
IgE and ASTHMA
Prevalence of Asthma (%)
40
Age 6 to < 35
Age 35 to < 55
Age 55 +
30
20
10
0
<-1.5
-1.5 to < -0.5
-0.5 to < 0.5 0.5 to < 1.5
Ranges of Serum IgE Z Score
Prevalence of Asthma in Relation to IgE Z Scores
standardized for Age and Sex.
Burrows et al.NEJM 1989;320(5):271-7
1.5+
EXOGENOUS FACTORS:
INFECTION AND ENVIRONMENT
VIRAL RESPIRATORY ILLNESS:
THE ROLE OF RSV
RSV IN EARLY LIFE and RISK of WHEEZE and
ALLERGY by AGE 13 YEARS
Relative Risk
5
Infrequent
wheeze
4
3
Frequent wheeze
2
Decreased FEV
1
0
5 yrs
6 yrs
11 yrs
13 yrs
Atopic status
Age
RSV is a risk-factor early on, but there is a change in the asthma phenotype over time.
Adapted from Stein RT, et al. Lancet 1999;354;9178
Why has there been such a remarkable change in the
level of allergic airway disease the last two centuries?
This is a complex problem
• Industrialization
• Change in antigens
• Changes in childhood infections
• Change in activities
- Indoors
- Inactivity
•Smoking by infants care givers
For every complex problem, there is a simple solution which is WRONG! H.L. Mencken
ENVIRONMENTAL ISSUES:
POLLUTION
EXPERIMENTAL RESEARCHERS
OF THE
CAUSES AND NATURE
OF
CATARRHUS AESTIVUS
(HAY-FEVER OR HAY-ASTHMA)
BY
CHARLES H. BLACKLEY, M.R.C.S.ENG
LONDON
DAWSON’S OF PALL MALL
1873
CHAPTER V
ON THE GREATER PREVALANCE OF HAY-FEVER AND ON
THE INCREASE OF ITS PREDISPOSING AND EXCITING
CAUSES
162
Experimental Researchers on Hay-Fever
and I have shown that large numbers of the people have been
transferred from the country to the workshops and mills of the
towns, and have thus been placed in circumstances where the
predisposition to hay-fever would be most rapidly developed in
those who rise to a place amongst the educated class. And lately,
I have shown that the production of the exciting cause has of late
years been largely increased.
Taking all these circumstances into account it is a highly
probable that hay-fever was at one time altogether unknown,
and it is tolerably certain that it has not only been much more
frequent of late, but that, as population increases and as
civilization and education advance, the disorder will become
more common than it is at the present time.
PREVALENCE of ATOPIC DISEASE
SINCE the INDUSTRIAL REVOLUTION
30
% GENETIC PREVALENCE LIMIT FOR ALLERGIC RHINITIS
20
%
Airborne Allergen load
10
%
Bostock Bostock
1 case 28 cases
1828
1819
Lloyd
Common
1907
0
1800
1850
1900
1950
2000
DEP are made up of a carbonaceous core
containing unburnt chemicals
DEP + RW INDUCE a
TH2-TYPE CYTOKINE PATTERN
mRNA level
(Units)
20
15
Pre-Challenge
Post RW
Post RW + DEP
10
5
0
IL-4
IL-5
IL-6
IFN-
IL-2
Exacerbation of allergic response
• Allergic subjects
challenged nasally with
pollen ± 0.3 mg DEP
• Allergic antibody
production is up to 50
times greater if DEP
present
Diaz-Sanchez et al., J Immunol. 1997;
158:2406-13.
Secondhand smoke augments
allergen-induced Th2 responses
Secondhand smoke exposure
exacerbates IgE responses
Pharmacological Therapy of Asthma
• Quick-relief medications
– Short-acting inhaled ß2-agonists
– Inhaled anticholinergics
• Long-term control medications
–
–
–
–
–
–
Antihistamines
Corticosteroids
Cromolyn sodium, nedocromil
Long-acting inhaled ß2-agonists
Methylxanthines
Leukotriene modifiers
Mechanism of Glucocorticoid Action
Protein
enzyme
receptor
cytokine
Cytokine
e.g. TNF-a
GCS
CyR
Cell Membrane
+
+
NF-kB
GR
Direct interaction
mRNA
AP-1
(Fos + Jun)
Nucleus
Target gene
TRE
kB
GRE
Cellular Effect of Glucocorticoids
Inflammatory Cells
Structural Cells
Eosinophil
Epithelial cells
Numbers
(apoptosis)
Cytokines
Mediators
T-lymphocyte
Cytokines
Endothelial cell
Mast Cell
Glucocorticoids
Leak
Numbers
Macrophage
Airway smooth muscle
Cytokines
B2-recep.
Dendritic cell
Mucus gland
Numbers
Mucus
secretion
Summary
• Asthma is a CHRONIC INFLAMMATORY disorder of
the airways caused by immune cell activation
– Hyper-reactivity, late phase response, multicellular infiltrate
• Prevalence is increasing globally
• Risk factors include gender, atopic status, genetics,
respiratory infections, environmental effects
• Anti-Inflammatory agents should be considered in
treatment regimens where asthma is persistent
• Among newer therapeutic agents currently available,
steroids and anti-leukotrienes offer specific benefits