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Common Pitfalls
in Allergy
Prof. Kiat Ruxrungtham, M.D.
Head, Division of Allergy and Clinical Immunology
Department of Medicine
Faculty of Medicine
Chulalongkorn University
Epidemiology of Allergic Diseases
Prevalence (%)
in Thai Children
45
40
35
30
25
20
15
10
5
0
1990
1995
40
17.9
13
13
4.2
Atopic
Dermatitis
Allergic
Rhinitis
Asthma
AllergyChula
Epidemiology of Allergic Rhinitis
in Thai Adults
25
23
22
Prevalence (%)
20
20
15
10
5
0
1975
Tuchinda
1983
Debhakam
1995
Bunnag
AllergyChula
Allergic Rhinitis:
The General Perception
• Common disease
• Easy to Diagnose
• Easy to treat
“This is partially true”
Common Pitfalls in
Managing Allergic Rhinitis
• Underdiagnosis
• Undertreatment
PAR versus SAR
Characteristic
Secretion
Seasonal
+++ (watery)
Perennial
+ /++ Seromucous,
Post nasal drip
Sneezing
+++
+ /++
Obstruction
+ /++
+++
Anosmia
0 /+
+/ ++
Eye symptoms
+++
0/+
Asthma
0/++
++
Sinusitis
+
++
predominant
Van Cauwenberge P et al Allergy 2000
AllergyChula
Clinical Patterns of PAR




Classic Type: Runner/Sneezer
Blocker Type
Combined Type
Under diagnosed Type:
<10%
30 %
50 %
~20 %
Chronic cough
Post-nasal drip, throat clearing symptoms
Chronic headache
Shortness of breath or mouth breathing
Vertigo, Epistaxis
Problems in sleep, sleepiness during the day
Snoring
Hyperventilation syndrome
AllergyChula
Nasal Blockage
Allergy Chula 1999
Symptoms of Unrecognized
Chronic Nasal Blockage
Chronic Cough
Postnasal drip, +/- BHR
Chronic Headache
Throat clearing S/S
Unregnized
Nasal
Blockage
Paranasal sinsuses
obstruction
Postnasal drip
Severe obstruction
Difficulty in Breathing Mouth breathing
Dry mouth, stomatitis
Aggravating asthma
Vertigo
ET dysfucntion
Snoring or problem in sleeping
AllergyChula
Functions of the Nose
FUNCTION
 Airway: upper
airway
 Olfaction
 Filtration
 Mucociliary
transport
 Airconditioning
 Control of middlle
ear pressure
DYSFUNCTION
• Blockage, mouth
breathing
• Anosmia
• Cough, infection
• Cough, infection
• Headache, Sinusitis
• Eustachian tube
dysfunction, vertigo
AllergyChula
The link :
Noses, Eyes, Ears, and Sinuses
Common Pitfalls in Diagnosis of Rhinitis
Commonly Unrecognised Symptoms
Chronic cough (including nocturnal cough)
The most common cause is rhinitis, not bronchitis
Mechanisms: post-nasal drip (PNDS), rhinitis with
BHR
Shortness of Breath (requires mouth breathing)
“Inadequate air”, relieve by mouthing breathing, some
may have “carpo-pedal spasm” due to hyperventilation
~ can be miss-Dx as anxeity neurosis . Mechanism:
Severe nasal obstruction
Chronic headache (frontal, periorbital, paranasal)
 Rhinitis +/- sinusitis is also a common cause of headache
Mechanisms: severe nasal congestion, sinus
congestion, sinusitis
Vertigo/dizziness (Eustachian tube dysfunction)
Post-nasal drip Throat clearing, hoarseness of voice
AllergyChula
Infra-orbital Edema and Discoloration
Allergic Shiner
Ocular pruritus
Increased lacrimation
Mouth Breathing
Will lead to
• Dry mouth
• Stomatitis
• Dental malocclusion
Indicating Severe Nasal Obstruction
Phenomenon After Allergen Exposure:
Immediate, Late Phase Allergic Reactions and
Hyperreactivity
Nasal Symptoms
Immediate
phase
Late
phase
Nasal
Hyperresponsiveness
Antigen
minutes
1
2
3 4 5 6 7 8 9 10 -hrs//------days
Time after Allergen Challenge
Treatment of allergic rhinitis (ARIA)
Allergic rhinitis and its impact on asthma
>4 days /wk
<4 days /wk
>4 wk/yr
Moderate
<4 wk /yr
severe
Mild
intermittent
Moderate
severe
intermittent
Mild
persistent
persistent
Impaired
QOL
Intra-nasal steroid
local cromone
Antihistamines : oral or local non-sedative H1-blocker
Intra-nasal decongestant (<10 days) or oral decongestant
Allergen and irritant avoidance
immunotherapy
Treatment of Allergic Rhinitis in Adults
Drug
Itch/
sneezing
Rhinorrhea Blockage
Anosmia
Antihistamines
Nasal CS
+++
+++
++
+++
+
++/+++
+/++
Oral CS
+++
+++
+++
++/+++
Nasal
decongestants
-
-
+++
-
Ipratropium
bromide
-
+++
-
-
Sodium
cromoclycate
+
+
+
-
Van Cauwenberge P et al Allergy 2000
Sites of Action of Corticosteroids
Scadding GK. Allergy 2000
Corrigan CJ. 1999
Epithelium
ICAM-1
PGE2, PGF2a
endothelin, NO
Fibroblast
Mo, DC
TNFa, IL-1
T cell
Th2
GM-CSF, G-CSF
IL-6, RANTES,
Eotaxin, etc
SCF
Mast cell
IL-2
IL-3
Myeloid
precursor
B Cell
IL-5
IL-4
Th2
IL-5
Endothelium
VCAM-1
permeability
IL-3, 5
Basophil
Eosinophil
LTC4, histamine
AllergyChula
Meta-analysis of Intranasal Steroids
Favors Steroid
AllergyChula
Pitfalls in prescribing of
the 1st, 2nd and 3rd generation
antihistamines
First Generation antihistamines
and CNS Side Effects
Impact of Sedating Antihistamines
on Safety and Productivity
Kay GG, Quig ME. Allergy Asthma Proc 2001
• Sedating antihistamines remains commonly
use
• Patients taking these agents frequently don’t
feel sleepy, but their brain function impaired
• Frequently found to be a causal factor in:
– Work-related injuries
– fatal traffic accidents
– aviation fatalities
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
Common Cold: Antihistamines ?
• Only 1st generation but not the 2nd
generation antihistamines is effective on
treating clinical symptoms and signs of
“COMMON COLD”
• Confirmed both in the natural or
experimental “COLDs”
Muether PS Clin Infect Dis 2001 Nov; 33:1483-8
AllergyChula
Clinical Uses of H1 Antagonists
Clinical
Generation of Antihistamines
First
Second and Third
Allergic Rhinitis
++
++ (better compliance)
Urticaria
++
Atopic dermatitis ++/+++
Asthma
NS)URI/NAR
++
Itching dermatosis ++/+++
Anti-motion sickness
++
Antiemetic
++
Appetite stimulation
++
Insomnia
++
++ (better compliance)
++ (better compliance)
-/++ (Meta-analysis=
++
- (+ for astemizole)
AllergyChula
Underdiagnosis and treatment
in Rhinosinusitis
PAR and Rhinosinusitis
Concordance of
Allergy and Sinusitis
25-70 %
Rachelefsky GS et al JACI 1978
Shapiro GG Ped Infect Dis J 1985
The Respiratory Tract
Upper Respiratory Tract


Structures
- Nose —> trachea
- Sinuses, eustachian tubes
- Ciliated mucosal lining
Functions
- Conditioning the air
- Defense
Filtration
Inflammatory reaction
Immune reaction
- Smell
- Voice
The Link
Lower Respiratory Tract


Structures
- Trachea —> alveoli
Functions
- Inhalation-exhalation
- Gas exchange
- Acid-base balance
How to Avoid
• Underdiagnosis of AR
– Be aware of non-nasal symptoms or the
underrecognized symptoms
• Undertreatment of AR
– Chronic moderate/severe cases required
nasal steroid therapy not antihistamines
PAR is easy to diagnose and easy to treat,
if we really know about it
ASTHMA
Common Pitfalls
Asthma: Risk Factors
5q: IL4, CD14,
B2ADR
Environmental Genetic
Aeroallergens
Pollutants
Triggers
~19 genes
6p: DRB1, TNF
11q: FCERB1,
CC16
16p: IL4RA
Clinical Asthma
Thailand ~5 % in Adults
13 % in Children
AllergyChula
Asthma 2002
Airway
Inflammation
Smooth
Muscle
Dysfunction
Airway
Remodeling
Normal
Barnes PJ 1999
Asthma
Early and Late Phase Allergic Reactions
(EPAR and LPAR)
FEV1
BHR
mins 1 2 3 4 5 6 7 8 9 10 -hrs//------days
Antigen
Time after Allergen Challenge
AllergyChula
Pitfalls in Asthma Diagnosis
• Over diagnosis
– Shortness of breath is not always
caused by asthma
– diagnose COPD as asthma
• Under diagnosis
–mild asthma
–nocturnal asthma
Classification of Severity
CLASSIFY SEVERITY
Clinical Features Before Treatment
Symptoms
Nocturnal
Symptoms
STEP 4
Severe
Persistent
Continuous
Limited physical
activity
Frequent
STEP 3
Moderate
Persistent
Daily
Attacks affect activity
> 1 time week
STEP 2
Mild
Persistent
> 1 time a week
but < 1 time a day
STEP 1
Intermittent
< 60% predicted
Variability > 30%
60 - 80% predicted
> 2 times a month
Variability > 30%
> 80% predicted
Variability 20 - 30%
< 1 time a week
Asymptomatic
and normal PEF
between attacks
FEV1 or PEF
> 2 times a month
> 80% predicted
Variability < 20%
The presence of one feature of severity is sufficient to place patient in that category.
Part 4: Long-term Asthma Management : GINA 2002
Stepwise Approach to Asthma
Therapy - Adults
Outcome: Best
Possible Results
Outcome: Asthma Control
Controller:

Controller:
Controller:
None
Controller:
Daily inhaled
corticosteroid



Daily inhaled
corticosteroid
Daily longacting inhaled
β2-agonist


Daily inhaled
corticosteroid
Daily long –
acting inhaled
β2-agonist
plus (if needed)
-Theophylline-SR
-Leukotriene
-Long-acting inhaled
β2- agonist
-Oral corticosteroid
Reliever: Rapid-acting inhaled β2-agonist prn
STEP 2:
STEP 3:
STEP 4:
STEP 1:
Moderate
Severe
Mild
Intermittent
Persistent
Persistent
Persistent

When
asthma is
controlled,
reduce
therapy

Monitor
STEP
Down
Alternative controller and reliever medications may be considered (see text).
The Guidelines : not well implemented
48 yo female, with chronic persistent
asthma for 3 years
• Recently, she has asthmatic attack everyday
including at night for 6 months.
• She has been seeking treatment from at least 2
hospitals. The main prescriptions included
slow-released theophylline and inhaled b-2
agonist as needed.
• The severity of her asthma became more and so
severe that she had to miss several working
days a week.
• She was eventually forced to leave the job.
A Case Study (2)
• Baseline PEFR=150 and 180 L/min, pre and post
b-2 agonist, respectively.
• After 2 weeks of a short course prednisolone
followed by inhaled corticosteroids plus inhaled
long-acting b-2 agonist
PEFR = 360 L/min.
• Her QOL has returned to normal.
• Unfortunately, however, she has lost her job.
AllergyChula
Asthma: A Highly Variable Disease
Infection
AR
Avoidance
Sinusitis
Allergens
Treatment
Airway
Inflammation
Pollutants
Adherence
AHR
Variable Asthmatic
Symptoms
Genetics
Smooth
Muscle
Dysfunction
Airway
Remodeling
Reversible
Airway
Obstruction
Drugs
Psychological
ASA/NSAIDS
• Intermittent
• Persistent
• Mild
• Moderate
• Severe
• Irreversibility
Cold air
Excercise
Treating Asthma: Individualized and Dynamics Approach
Peak Flow Meter
Male :
>500 L/min
Female : >400 L/min
Case Study 1: PM, age 44(cont’d)
Variation of Clinical symptoms and PEF
Peak flow rate (L/min)
500
LABA/ICS
400
300
200
100
LABA/ICS
410
400
410
250
250
Lost FU
230
PEF
240
120
Sinusitis
Sinusitis
Sinusitis
0
Mar- Jun- July- Aug- Nov- Jan- May- Jun97
00
00
00
00
01
01
01
Case Study 2: VN, Male age 60
Known of Asthma for 30 years, non-smoker
Variation of Clinical symptoms and PEF
LABA/ICS
400
200
100
PEF
LABA/ICS
370
370
390
300
300
250
290
280
230
360
320
240
300
300
230
230
Lost FU
Lost FU
Non-adherence
worsening AR
n9
Ja 9
n9
M 9
ar
-9
M 9
ay
A 99
ug
-9
D 9
ec
-9
Fe 9
b0
A 0
pr
-0
M 0
ay
-0
O 0
ct
-0
No 0
v0
D 0
ec
-0
Ja 0
n0
A 1
pr
-0
Ju 1
nJu 01
ly
-0
1
0
Ja
Peak flow rate (L/min)
500
320
Case Study 3: PK, male age 35
Peak flow rate (L/min)
Known of Mild Persistent Asthma and AR since 17 y-o
Variation of Clinical symptoms and PEF
800
600
400
200
PEF
730
Treated Asthma
ICS
450
350
620
690
710
650
720
690
680
Started Treating
AR only
0
7
8
0
1
5
6
7
8
9
0
1
8
8
9
9
9
9
9
9
9
0
0
19
19
19
19
19
19
19
19
19
20
20
650
Pitfalls in Asthma management
Undertreatment with inhaled
corticosteroids even in
developed countries
Comparable Asthma Severity
in the Study Populations
Europe AIRE
US AIA
Mild
22%
Mild
19%
Moderate
19%
Moderate
19%
Intermittent
43%
Intermittent
Severe
19%
40%
Severe
19%
Severity classified by NIH Symptom Severity Index
AllergyChula
AIRE : Anti-inflammatory uses
N=2803 in 7 European Countries
% of Patients
100
Anti-inflammatory
Reliever
81
76
80
75
63
60
40
23
26
26
30
20
0
AIRE Total
Severe
Persistent
Moderate
Persistent
Mild
Persistent
AllergyChula
American: AIA Study
Patients and Inhaled Corticosteroids
Medicines Used to Treat Asthma by NIH Severity Index:
Inhaled Corticosteroids vs Quick-Relief Medications
% of Patients
Inhaled CS
80
70
60
50
40
30
20
10
0
Reliever
80
78
70
61
40
20
15
18
16
10
Total
Severe
Persistent
Base: All patients (unweighted N=2509).
Moderate
Persistent
Mild
Persistent
Mild
Intermittent
AllergyChula
Asian-Pacifc: AIRIAP 2001
Prevention treatment vs. Quick
Relief Bronchodilators
Preventative Treatment
60%
50%
Quick Relief Bronchodilators
51%
41%
45%
39%
40%
38%
30%
20%
13%
15%
18%
11%
11%
10%
0%
AIRIAP Total
Severe
Persistent
Moderate
Persistent
Mild
Persistent
Mild
Intermittent
AllergyChula
Comparison of AIRE, AIA and AIRIAP
AIRE : N=2803 in 7 European Countries
AIA :
N= 2509 in USA
AIRIAP: N=3206 in 8 Asian-Pacific countries
19
Emergency
room visit
1-2 in 10
23
AIRIAP
10
AIA
15
Hospitalized
1 in 10
9
AIRE
7
30
29
25
Emergent visit
0
20
3 in 10
40
60
80
100
Survey Findings (%)
AllergyChula
Comparison of AIRE, AIA and AIRIAP
AIRE :
AIA :
AIRIAP:
N=2803 in 7 European Countries
N= 2509 in USA
N=3206 in 8 Asian-Pacific countries
36
Missed school
AIRIAP
49
43
AIA
26
25
Missed work
AIRE
17
52
Activity limited
64
63
0
20
40
60
80
100
Survey Findings (%)
AllergyChula
Chronic asthmatics and long term
outcomes in lung function
Poorly controlled will lead to
irreversible air way obstruction
Height-adjusted FEV1 (litres)
Increased loss of FEV1 in asthma
Male non-smokers
P <0.001
No asthma (n= 5480)
Asthma (n= 314)
Age (years)
Lange P et al, NEJM 1998
Airway Remodeling
in Asthma




Cells proliferation: smooth muscle
cells, mucous glands
Increase matrix protein deposition
Reticular basement membrane
thickening
Angiogenesis
AllergyChula
Pathology of Asthma
Asthma
Normal
Mild Asthma
Heavy smoker
metaplasia
Busse W, NEJM 2001
Jeffery , Chest 2000
Ignorance the link of upper
and lower airway
The United Airway
Diseases
ARIA Guidelines recommendations
• Patients with persistent allergic rhinitis should
be evaluated for asthma by history, chest
examination and, if possible and when necessary,
assessment of airflow obstruction before and
after bronchodilator
• History and examination of the upper respiratory
tract for allergic rhinitis should
be performed in patients with asthma
• A strategy should combine the treatment of both
the upper and lower airway disease in terms of
efficacy and safety
Co-existence of Asthma and AR
23-Years Follow-up Study of
Former Brown University Students (N=738)
21 %
Asthma
79 % no
306 former students
with Allergic Rhinitis
no
86 % AR
84 former students
with Asthma
Greisner WA et al Allergy Asthma Proc 1998; 19:185-8
Ragweed Hay Fever with Seasonal Asthma
Upper-Lower Airway Linked
Placebo
Welsh et al. Mayo Clin Proc 1987;62:125-34
Mean Changes in FEV1 (Litre)
in Treated AR with Mild Asthma
Morning (AM)
Loratadine/Pseudoephredine
0.25
Placebo
* P=0.01
0.2
*
0.15
*
*<0.05
*
0.1*
0.05
0
Wk 1
Wk 2
Wk 4
Wk 6
Corren J, et al J Allergy Clin Immuno 1997; 100:781-788
Ignorance in
Environmental Factors
Environment and Allergy
ฝุ่ นบ้ าน
ฝุ่ นบี่นอน
เกสร
ตัวไร่ ฝุ่น
สั ตว์ เลีย้ ง
เชื้อรา
ทีก่ กั ฝุ่ น
อาหาร
สิ่ งเหล่านี้มีอยูร่ อบตัวเรา มีท้ งั ในบ้านและนอกบ้าน
แต่มีหลายอย่างที่เราหลีกเลี่ยงได้ หากเรารู ้วิธีที่ถูกต้อง
Indoor Irritants
Patient Education
for
Environmental
Control
Pitfalls in Drug Allergy and
Drug Sensitivity
Highlight on 3 issues
• Penicillin Skin Testing
• Aspirin and NSAIDs sensitivity
• Cross sensitivity with paracetamol
Penicillin Skin testing
• Gold standard testing: (sensitivity
>90%)
– Major determinant: Pre-Pen (Penicilloyl
polylysine)
– Minor determinant (MDM)
– Penicillin G
• In Thailand: only penicillin G being
used for testing (sensitivity <50%)
Aspirin/NSAIDs sensitivity
Underestimated and
management
Case study: Diagnosis
Aspirin Triad
Rhinosinusitis
with nasal polyps
 Chronic asthma
 ASA sensitivity

More specific diagnosis: Aspirin
Disease
AllergyChula
Clinical Features of
NSAIDs/Analgesic Sensitivity
A Thai Cohort (N=31)
Angioedema
3% 3%
Nasoocular+
angioedema
10%
Asthma+
Anaphylactoid
Angioedema
44%
13%
10%
Urticaria+
angioedema
17%
Anaphylactoid
2 Aspirin disease (ASA Triad)
Ruxrungtham K. 2001
Urticaria/angioedema
Asthma with others
Naso-ocular with
angioedema
Urticaria
Rash
AllergyChula
NSAIDs/Analgesic Sensitivity
A Thai Cohort
Type of Agents
N=31
Mixed
32%
Paracetamol
21%
ASA
26%
NSAIDs
14%
Dipyrone
7%
ASA
NSAIDs
Dipyrone
Paracetamol
Mixed
Ruxrungtham K. 2001
AllergyChula
NSAIDs/Analgesic Sensitivity
A Thai Cohort
Cross-reaction with paracetamol
N=25
Yes
4%
No
56%
Ruxrungtham K. 2001
Yes
40%
No
Not
known
AllergyChula
A Thai Cohort of
NSAIDs/Analgesic Sensitivity
Hospitalization
 6/27 (22 %)
Ruxrungtham K. 2001
AllergyChula
A Thai Cohort of
NSAIDs/Analgesic Sensitivity
Onset and Duration of Reactions
Median (Range)
Onset:
20 min (5-360 min)
 Duration:
48 hrs (0.5-168 hrs)
 Episodes of event:
3 (1-17 times)

Ruxrungtham K. 2001
AllergyChula
Responses to Standard Treatment
(Adrenaline, antihistamines, steroids)
in patients with angioedema or anaphylactoid reaction
Total N=14
 <30 min :
7 % (n=1)
 30-60 min :
21 % (n=3)
 Not response : 71 % (n=10)
Ruxrungtham K. 2001
AllergyChula
Pitfalls in Urticaria
Over treat chronic urticaria
with systemic corticosteroids
• Problem of rebound
• Systemic side effects of CS
AllergyChula
CHRONIC IDIOPATHIC URTICARIA
TREATMENT
• Antihistamines for Chronic Idiopathic
urticaria
- Non-sedating
- Sedating
CHRONIC IDIOPATHIC URTICARIA
TREATMENT Options: If single drug
therapy ineffective
Combinations
- First + second-generation antihistamines
- H1 antihistamine + H2-blocking agent
Pitfalls in Anaphylaxis
Mediators of Mast Cells and Basophils
Primary Mediators
Histamine
Tryptase
Chymotryptase
Heparin/Chondroitin
Kininogenase
Chemotactic Factors
Sim TC, Grant JA 1996
Secondary Mediators
Prostaglandins
Leukotrienes
PAF
Histamine RFs
IL-3, 4, 5, 6, 7, 8
GM-CSF, TNFa
Chemokines MCP1, MIP1
Oxygen radicals
AllergyChula
Improper treatment
• Use antihistamines and/or dexmethasone
as first choice but not adrenaline
• Standard of care:
– Adrenaline, Adrenaline, Adrenaline IM !!!!
Plus:
– Antihistamines
– Dexamethasone
– H2 blocker, etc
AllergyChula
Thank You