Transcript No Slide Title

Clinical Conference on
Allergic Disease
Adrian Casillas, MD
Division of Clinical Immunology and
Allergy
UCLA School of Medicine
ALLERGIC RHINITIS
• Affects 20-40 million Americans (15-20% of the
Population)
- Predominantly Older Adolescents and Young Adults
• 5th Most Common Chronic Illness
• Significant Impact on Quality of Life, Productivity,
Healthcare Costs
• Prevalence is Increasing
IMPACT OF ALLERGIC RHINITIS
• 28 Million Restricted Activity Days Each Year
• 6 Million Bedridden Days Each Year
• 2 Million Lost School Days Each Year
• 3.5 Million Lost Work Days Each Year
• Can Be a Factor in Other Illnesses
(Asthma, Chronic Sinusitis, Otitis Media with Effusion,
Nasal Polyposis, Upper Respiratory Infections)
Hypersensitivity States
The Allergic Response
• Susceptibility (approximately 25-30% of
population)
• Allergen exposure
• IgE induction
• Effector cells of allergic inflammation:
Mast cells, Basophils, and Eosinophils
Allergic Sensitization
Presentation of
Allergic Rhinitis: Clues
Nasal
itching
Mouth
breathing
Reprinted from:
Skoner et al. In: Zitelli et al. Atlas of Pediatric Physical Diagnosis. 1997.
By permission of the publisher Mosby-Wolfe.
Repeated
nose
rubbing
(“allergic
salute”)
Allergic
shiners
Classification of Rhinitis
• Allergic rhinitis
– Seasonal
– Perennial
– Both
• Nonallergic rhinitis
– Perennial nonallergic rhinitis
(idiopathic/vasomotor)
– Infectious
– Rhinitis medicamentosa
– Hormonal
– Anatomical
American Academy of Allergy, Asthma and Immunology. The Allergy Report. http://www.aaaai.org/. Accessed: April 13, 2000.
Prevalence of Allergic Rhinitis
by Age Group
In Chronic Rhinitis, Nonallergic Rhinitis Is a
Major Causative Factor
National Rhinitis Classification Task Force Survey Results
Pure Nonallergic Rhinitis
23%
Mixture of Both Allergic and
Nonallergic Rhinitis
34%
Settipane et al. In: Kaliner, ed. Current Review of Allergic Diseases. 2000.
Pure Allergic Rhinitis
43%
Mast Cells and Basophils
Characteristic
Mast Cells
Basophils
Origin
CD34+
progenitors
Connective tissue
No
Stem Cell Factor
CD34+
progenitors
Bone Marrow
Yes
IL3
Maturation
Circulation
Major
Developmental.
Factor
Life Span
FcRI
Weeks to months Days
High
High
Eosinophils
Characteristic Eosinophils
Origin
CD34+ progentor
Maturation
Bone marrow
Circulation
Yes
Major
Developmental
Factor
Life span
IL5
FcRI
Low levels
Days to weeks
IgE-Dependent Mast Cell
Activation
LTs
PGs
Preformed Mediators
Ag
Ca++
Phosphodiesterase
Ca++
cAMP
AA
Direct Activation of Mast Cells
and Basophils (not dependent on
IgE)
•
•
•
•
•
•
Complement:C3a, C5a
Neuropeptides
Opiates:Morphine, codeine
Radiocontrast dyes (ionic)
Muscle relaxants
Physical stimuli: vibration, light,
temperature changes.
Major Biological Effects of
Leukotrienes
LTC4, LTD4 and LTE4
• contraction of smooth muscle,bronchioles and coronary arteries
• vasoconstriction with leakage from postcapillary venules and
edema formation
• phospholipase A2 stimulation with subsequent prostaglandin and
thromboxane release
• secretion of mucus in the respiratory tract
LTB4
• potent chemotactic mediator that regulates leukocyte function
• increases vascular permeability with exudation of plasma
• induces lymphocyte transformation into suppressor or cytotoxic T
cells
Larsen,JS;Acosta,EP. Ann Pharmacol
July/Aug 1993
Mediators Mast Cells
Basophils
Preformed
Histamine, Chondroitin
SO4, Neutral
Proteases, Major basic
protein,
lysophospholipase
Lipid mediators
(newly formed)
Cytokines
Histamine,
heparin, neutral
proteases
(Tryptase+/Chymase), acid
hydrolases, etc
PGD2, LTC4,
PAF
LTC4
IL4, IL5, IL6,
IL4, IL13
IL8, IL13, TNFa,
MIP-1a, bFGF
Mediators
Eosinophils
Preformed
Major basic protein, ECP,
neurotoxin, EPO,
lysophospholipase
LTC4
Lipid mediators (newly
formed)
Cytokines
IL1a, IL2, IL3, IL4, IL5,
IL6, IL8, IL10, GMCSF,
TNFa, RANTES, MIP1a,
etc
Allergic Mechanisms in Health
and Disease
• Immediate hypersensitivity
• Late phase reactions-follows immediate reaction
by about 4 to 8 hours and is characterized by
swelling and leukocyte infiltration
• Parasitic diseases-Trichinella spiralis and
Strongyloides ratti infections are longer in mast
cell deficient mice. Resolution of ectoparasite
(i.e. ticks) infections also depend on
basophil/mast cell activation
Induction of Allergic Sensitization
IL-12, IFN-
IFN-
T-1
APC
T
naive
APC
IL-5
T-2
IL-4
IL4, IL10
IL-4
B
IL-4
Allergen
Mast
IgE
Eos
Mediators of
allergic response
Role of IgE in Atopic Disease
Allergen
Second
allergen
encounter
First exposure
to antigen
Mast cell
IgE
B-cell
Granules
IgE
PRODUCTION
MAST CELL
SENSITIZATION
DEGRANULATION
REACTION
Chemical mediators
induce hay fever,
eczema, asthma
Adapted from Cochrane GM, Jackson WF, Rees PJ.
Asthma
Diagnosis of Allergic Rhinitis: History
 Family history of atopy
 Personal history of other allergenic conditions
– Asthma
– Atopic dermatitis
– Food hypersensitivity
 Personal history of
– Long-lasting or recurrent colds
– Chronic sinusitis
– Frequent ear infections
– Chest symptoms (e.g., pain or wheezing)
Allergic Rhinitis: Physical Examination
 Allergic facies (e.g., shiners, transnasal crease)
 Pale, edematous nasal mucous membranes;

clear, watery nasal discharge
 Watery, swollen, red eyes
 Wheezing, noticeable cough
 Middle ear fluid, eustachian tube dysfunction
 Tenderness over the sinuses
 Eczema
Environment and Genetics in
Allergic Disease
Genetic Factors
• Monozygous twins show a 70% concordance rate for an IgE
response to any common allergen.
•Statistically significant genetic linkages identified for a number
of genes, for example:
• IL-4 gene cluster (chr. 5) polymorphism related to high
IgE production and asthma
•Variants of the high affinity IgE receptor (chr. 11) on
mast cells and basophils
Why the increased
prevalence?
Evidence for environmental
effects on atopic disease
Other theories for increase in atopic disease prevalence
• Increase in levels of indoor allergen loads--”tighter” homes
• Dietary changes--too much controversy to accept
• Microbial exposure
Relationship between atopic state and
1. Lack of immunity to HAV
2. Vaccination to measles
3. Negative DTH reaction to TB
(these are all intracellular diseases which would stimulate a
Th1 response and downregulate a Th2 (favoring atopy)
response)
Diagnostic Tests for Allergic
Disease
Allergic Rhinitis: Diagnostic Testing
 Skin tests for specific IgE antibodies
– Confirm allergens suspected by history
 Serum-specific IgE tests
– Correlate well with skin tests
– Not as sensitive as skin tests
 Nasal cytology
– Eosinophils, basophils imply allergy or
NARES syndrome*
– Neutrophils suggest bacterial infection
*Nonallergenic rhinitis with eosinophilia syndrome.
RAST or ELISA Tests
•Rast Testing--detects the presence of preformed IgE
in a patient’s serum
•Less sensitive than skin tests
•May take several days to get results
Rast Testing
• Use when it is not possible to skin test
+
Immobilized Ag + Patient’s
serum
Tagged antihuman IgE
Colorimetric
assay
-
RAST HONEY BEE VENOM IGE
RAST PAPER WASP VENOM IGE ALL
RAST WHITE-FACE HORNET VENOM
RAST YELLOW HORNET VENOM IGE
RAST YELLOW JACKET VENOM IGE
Allergen Interpretation Range
IgE counts
0-500
501-750
751-1600
1601-3600
3601-8000
8001-18000
18000-40000
40000+
144 count
@ 808 count
220 count
212 count
@ 2739 count
Score Interpretation
0 No antibodies detected
0-1 Low equivocal
1 Equivocal
2
3 Scores 2-6 indicate
4 increasing levels
5 of antibody
6
0-500
0-500
0-500
0-500
0-500
Skin testing
• Quicker and cheaper that RAST
• A physiological test that detects the
presence of sensitized mast cells within in a
patient’s dermis
• Refer to experienced allergist
• Prick vs Intradermal--start with prick
although less sensitive, it is safer since
intradermal introduces 103 to 104 more
antigen to the patient
Skin Testing
Photographs courtesy of Dr. Ed Philpot.
Treatment
I. Avoidance
II. Pharmacotherapy
III. Immunotherapy
IV. Psychotherapy
I. AVOIDANCE
Environmental Control Measures
• Keep windows/doors closed during the
allergy season
• Reduce outdoor activity during high pollen
days
• Maintain a dust/allergen-free environment
• Keep pets outdoors
• Avoid smoke and strong odors
• Use air conditioning and/or air filters
Druce. In: Middleton et al, eds. Allergy Principles & Practice. 1998.
Potentially Avoidable Environmental
Allergens
– Molds
– Cockroaches
– Dust mites
– Pet dander
Dust Mites
Dust mites
• Dust mite covers
• Wash
sheets/covers in
HOT water
• Diminish humidity
• Vacuum with
HEPA filter
• Move to Taos, NM
Cats
• Keep out of
bedroom
• Wash
frequently
• Wash once
(permanently
)
Cat allergen--Fel D1saliva and skin, not hair
Compliance With Environmental
Control Measures
•Response
%
Dust my house frequently
34.1
Do not have pets inside my house
20.8
Avoid outdoor activities
18.7
Wash bedding in hot water
15.0
Wrap mattresses in plastic cover
6.0
Do not have carpeting (or rugs) in my house
2.1
No measures
25.4
II. PHARMACOTHERAPY
Allergic Rhinitis: Pharmacotherapy
This table lists the various classes of pharmacotherapy
available to treat allergic rhinitis.
OTC treatments
•
•
•
•
•
Intranasal cromolyn sodium
Intranasal decongestants
Intranasal saline
Oral antihistamines
Oral decongestants
Rx treatments
• Antihistamines
– Intranasal
– Systemic
• Decongestants
– Systemic
• Corticosteroids
– Intranasal
– Systemic
• Anticholinergics
– Intranasal
• LT receptor antagonists
American Academy of Allergy, Asthma and Immunology. The Allergy Report. http://www.aaaai.org/. Accessed: April 13, 2000.
First-generation Antihistamines
H1
Blockade
Sedative
Effects
Ethylenediamines
(tripelennamine)
+++
++
++
++
Ethanolamines
(diphenhydramine)
+++
+++
+++
+
Alkylamines
(chlorpheniramine)
+++
+
++
+
Piperazines
(hydroxyzine)
+++
++
++
+
Piperidines
(azatadine)
+++
++
++
+
++++ Strongly positive effects
Anticholinergic
GI
Effects
Effects
Second-generation
Antihistamines
H1
Blockade
Sedative
Effects
Anticholinergic
Effects
Fexofenadine
(60 mg bid)
+++
–
–
–
Astemizole
(10 mg qd)
++++
–
–
–
Loratadine
(10 mg qd)
+++
–
–
–
Cetirizine
(10 mg qd)
+++
+
–
–
– Negative effect
++++ Strongly positive effect
GI
Effects
Advantages of Second-generation
Nonsedating Antihistamines
• Bind strongly to histamine (H1) receptors
• negligible affinity for nonhistamine receptors
• no anticholinergic effects
• Do not cross the blood-brain barrier
• do not affect cognitive functions
or psychomotor performance
• do not potentiate impairment caused by alcohol
or benzodiazepines
• do not impair driving skills
Decongestants
• Actions
– Constrict mucous membranes: shrinkage promotes drainage,
improves ventilation, relieves nasal stuffiness
• Routes of administration
– Systemic, topical
• Indications
– Allergic rhinitis, vasomotor rhinitis, sinusitis, eustachian tube
congestion
• Side effects
– Systemic: stimulation (CNS, cardiovascular)
– Topical: rhinitis medicamentosa, CNS stimulation, local irritation
Intranasal Corticosteroid Use Is
Increasing
% incr vs
previous yr
% of Use
Prescription
Intranasal
Intranasal
Antihistamines Corticosteroids Corticosteroids
Primary Care
(including Internal Medicine) 72.2%
27.8%
10.8%
ENT
50.7%
49.3%
4.2%
Allergist
63.5%
36.5%
4.9%
Pediatrician
72.4%
27.6%
14.3%
All Others
73.9%
26.1%
9.8%
Source: SourceTM Prescription Audit (SPA). MAT August 2000. Scott-Levin, Inc.
Reduction in the Infiltration of
Mast Cells
Before Treatment
After 52 weeks
of Treatment
Absence of redstained cells is
evidence of a
reduction in
mast-cell
infiltration after
1 year of therapy
with fluticasone.
[Magnification: x100]
The direct relationship of these findings to long-term symptom relief is unknown.
The Fate of Intranasal Steroids
Adapted from: Allen. J Allergy Clin Immunol. 2000.
Fate of Intranasal Steroids
• Majority of nasal steroid administered is
swallowed
• Systemic bioavailability is determined primarily
by the amount of swallowed drug — not
inactivated by first-pass hepatic inactivation —
that subsequently reaches the circulation
• Factors such as lipophilicity affect the amount of
drug that is absorbed across the nasal mucosa
– Drugs with higher lipophilicity have lower absorption
Allen. J Allergy Clin Immunol. 2000.
The esterified
carbothioate
molecule
fluticasone
propionate
The major metabolite of fluticasone
propionate, 17ß-carboxylic acid, wich is
devoid of glucocorticoid activity because
of the loss of ester at C17ß.
Fluticasone propionate undergoes firstpass metabolism in the liver, being rapidly
hydrolysed to the corresponding 17ßcarboxylic acid (GR36264).
III. IMMUNOTHERAPY
HISTORY OF ALLERGEN IMMUNOTHERAPY
1819: Bostock described his personal experience of having hayfever.
1889: Seventy years later, Wyman identified pollen as a cause of fall
hayfever.
1890: Blackley identified grass pollen as the cause of his seasonal
rhinitis.
1900: Curtis reported beneficial effects from the injection of aqueous
pollen extracts for rhinitis and asthma.
1911: Freeman published data suggesting decreased symptoms in
patients with allergic rhinitis treated with grass extract-“desensitization.”
Immunological Changes in
Allergen Immunotherapytherapy
• Diminished leukocyte histamine release
sensitivity with allergen challenge
• Diminished lymphoproliferative response to
allergen
• Stimulation of Allergen specific CD8+
lymphocytes
• Decreased tissue CD4+ lymphocytes
Immunological Changes (cont)
• Blunted IL2 production to antigen
• Increased IFN g production
• Down regulation of the low affinity IgE
receptor
• Decreased recruitment and activation of
tissue eosinophils
DISEASES IN WHICH
IMMUNOTHERAPY IS EFFECTIVE
1. Allergic Rhino-Conjunctivitis
2. Allergic Asthma
3. Hymenoptera Hypersensitivity
IV. PSYCHOTHERAPY
Some patients have unrealistic expectations from treatment.
Key Points
• Allergic (atopic) disease is one type of
hypersensitivity state that depends on IgE
production
• AR and asthma are characterized by early and late
phase reactions due to rapidly released medators
and newly formed AA metabolites.
• Th cell differentiation along a Th2 pathway favors
allergic disease development
Key Points
(cont.)
• Diagnostic tests for atopic deseases can be
physiologic or simply measure preformed IgE
• IT is effective in part due to alterations in allergen
specific antibody formation
Cortisol Levels Comparable to Vehicle Placebo
After Treatment With Futicasone
Mean Plasma Cortisol
(mcg/dl)
40
Stimulation Challenge
After 4 Weeks of Therapy
30
*
20
*
*
10
*
*
*
*
0
Pre-Infusion 2
4
6 Post-Infusion
Cosyntropin Infusion Time (hr)
Placebo
Fluticasone 200 mcg QD
Prednisone 7.5 mg QD
Fluticasone 400 mcg BID
Prednisone 15 mg QD
*P < 0.01 for prednisone vs placebo, FP ANS 200 mcg QD, and FP ANS 400 mcg QD
Vargas et al. J Allergy Clin Immunol. 1998.