Fn: PatofisDiag RINAL Exp15 Avt 3 Feb 2001

UNIVERSITAS PADJADJARAN
KAMPUS

IWA KOESOEMA SOEMANTRI

JALAN DIPATI UKUR 35 BANDUNG INDONESIA

Pathophysiology and
Diagnostic Procedure
in Allergic Rhinitis
By :

Iwin Sumarman

Faculty of Medicine Padjadjaran University

Dr. Hasan Sadikin General Hospital
Bandung - Indonesia

Allergic Rhinitis

Chronic ongoing disease

Factors :
Environmental (allergenic and or nonallergenic)

Genetics
Immunity disturbances
Suceptible to secunder infections
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

Distribution of PAR symptoms

in Indonesia
Symptoms

1)

Rhinorhea
Sneezing
N Congestion
N Itching

98,1
97,6
47,4
18,7

2)
55,0
53,3
30,0
26,7

3)
Stage 2+3+4
80,2
87,1
52,3
nd

Stage 3+4
41,8
46,4
15,3
nd

Adapted from:
1) Sumarman et al. Hasan Sadikin Hosp. ENT-OPD patients (Bandung, 1992)
2) Suprihati et al Karyadi Hosp. ENT-OPD patients (Semarang, 1983)
3) Haryanto & Sumarman. (Population of Bandung City, 1999)

Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

DIAGNOSTIC Procedure:
History of Nasal & non nasal symptoms
History of Family Allergy
Nasal & Non nasal clinical signs
Adjunct diagnostic

Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

The potential treatment modalities of

Allergic Rhinitis management:
Three basic approach:
1. Allergen avoidance
2. Pharmacotherapy
3. Immunotherapy
(WHO Initiative ARIA 2000)
Optional therapy:
Pharmacotherapy and/or surgery for complications

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

Either diagnostic or
management of allergic rhinitis,
present or future, needs a good
understanding of allergic rhinitis
phatophysiology

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

Allergic rhinitis inflammatory cells accumulation

Why ?
Normal immune physiology
Antigen
stimmulation
CD4+ T
cell

Th 0

Unrestricted
cytokine profile

Th 2
(CD4+ T)

en

Th 1
(CD4+ T)

Th 0

Th 0

tig
An

Chronic Antigen
stimmulation

Activate M
Inducing CMI

Th 0

Humoral immunity

Normal equilibr. of the immune system

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

Pathophysiology of Allergic Inflammation

Three phases :
Sensitization phase
Early Phase Allergic Reaction
Late Phase Allergic Reaction

Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

Allergic rhinitis phatophysiology

Sensitization phase of allergic rhinitis

How ?
Antigen
stimmulation
CD4+ T
cell

Th 0

Th 0

Th 0

Unrestricted
cytokine profile

Th 2
(CD4+ T)

en

Th 1
(CD4+ T)

tig
An

Chronic Antigen
stimmulation

Activate M
Inducing CMI

Th 0

Humoral immunity
Allergic disease
(IL-4, IL-5, IL-13)

Disequilibr. of the immune sistem

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis 2001

10

CD

4
ce + T
ll

Disequilibrium of the immune

system (phatophysiology)

sti Ant
m ig e
m
ul n
at
io n

Th 0
Th 0

Activate M
Inducing CMI:
IFN-, IL-2, TNF-
IL-2 responsive
IFN- unresponsive
Cell Med Im

en
tig
An

Chronic Antigen
stimmulation

M cell

Th 1

(CD4+ T)

M AutoimmD
M Trans Rejc

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis 2001

Th 2

(CD4+ T)

Humoral immunity
Allergic disease:
IL-4, IL-5,
IL-10, IL-13
IL-12 unresponsive
IFN- responsive

M Hum. Imm
M Allergic Dis.
Virus inf.
Intracell.path-en

11

1. Sensitization & IgE production

Allergic Inflammation
IgE antibody
IgE

IgE

IgE-bearing B-cells
Th2
MH
-C

Fragment

Adapted from Creticos, 1998

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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2. Early Phase Allergic Reaction

(Reaksi alergi fase cepac (RAFC)

Allergic Inflammation
IgE

Mastosit

IgE antibody
IgE

Rhinorea
Sneezing
Congestion

IgE

IgE

IgE-bearing B-cells
Th2
MH
-C

Fragment

Adapted from Creticos, 1998

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

13

3. Late phase Allergic Reaction

Allergic Inflammation
Mastosit

IgE antibody
IgE

Rhinorea
Sneezing
IgE

Congestion

IgE-bearing B-cells
Th2

CHRONIC

MHC

INFLAMMATION

Rhinorea

Fragment

Sneezing
Congestion
Adapted from Creticos, 1998
Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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Proinflammatory cytokines and cells involved in airway

late phase allergic inflammation (Weiss. J Allergy Clin Immunol.2000;105

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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Other important molecular products during

Early- and Late-Phase Allergic Reactions :
Adhesion molecules :
Immunoglobulin gene superfamily :

ICAM-1, ICAM-2, VCAM-1

Selectin gene superfamily
E-selectin, P-selectin, L-selectin
Integrin family:
LFA-1, Mac-1, p150,95, VLA-4, VLA-6, Act-1

Adhesion molecules functions :

VCAM-1 (especially for EOS cells)
ICAM-1 and E-selectin
(for EOS, Baso and Neutro cells)
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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Adhesion molecules functions on

recruitment of inflammatory cells :

1. Rolling

Blood vessel

(Ig superfammily and

integrin)

2. Margination
(Ig superfammily and
integrin)
Eos in air
cavity

Eos
inTissue

Bochner,
1997

3. Diapedesis (L-selectin)
4 and 5. Chemotaxis (Ig superfammily and integrin)
Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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Mast cell T cell interactions. Mast cell as presenting cell for antigen to T-cell.
(Adapted from : Mekori and Metcalfe, J Allergy Clin Immunol 1999;104:519)
Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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 Symptoms:
* Rhinorrhea

* Congestion
1 = trivial ; 2 = mild;

* Sneezing
* Nasal Itchy

3 = moderate; 4 = severe

Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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Sneezing
Predominantly in EPR

(1-2 minutes after allergen exposure)

Is associated with mast

cells degranulation:

Histamine stimmulation on H1 receptor on

C fibre sensory nerve ending

Peptide endotelin-1
Leukotrien
Naclerio, 1999

Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

20

Pruritus
Exclusively in EPR
Nasal itching and Palatal clicking
Histamine stimmulation on H1 receptor on C fibre
sensory nerve ending
Protaglandin may also constribute
Naclerio, 1999

Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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Rhinorrhea
Excessive discharge from nasal mucous. membrane
Begin 3 min., last for approx. 20 to 30 min. after alergen challenge

Rhinorrhea (Histamine release from Mast cells)

Predominantly in EPR, can also in LPR

Effect of :
Histamine on H1 receptor:
Leak of plasma and large molecular-weight of proteins
Glandular stimulation through parasympathetic nerve
Acetylcholine
LTC4, LTD4, and LTE4, Bradikinin, PGD2, neuropeptide (SP, VIP)
Naclerio, 1999
Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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Congestion
Sensation of increase resistance to air flow within the nose

Vascular obstructive event (dilatation) (non fix obstruction):

Histamine-H1-receptor-mediated-vasodilatation
But, Histamine is a minor factor and only during EPR

Mayor factors are:

Naclerio, 1999

PGD2, LTC4, LTD, PAF (vasodilatation mayor factors)

PGD2: 10 X histamine effects

Bradykinin-bradykinin 2 receptor
Neuropeptide (SP, calcitonin-gene related peptide)
Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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DIAGNOSTIC Procedure:

Routine tests:(according to WHO initiative ARIA 2000)

Nasal symptoms:

1. Sneezer and runners 2. Blockers

(Rhinorrhea Sneezing Congestion- Nasal Itchy)

History of non-nasal allergic symptoms
(pharynx, ear, eye, skin, lung)

History of Family Allergy

External Nasal & internal nasal clinical signs
Non nasal clinical allergic signs
Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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Bandung AR classification
Perenial allergic rhinitis
Occupational allergic rhinitis
Seasonal allergic rhinitis

Staging or Allergic Rhinitis

Total nasal symptoms score:
(for rhinorhea, sneezing, congestion, nasal itching)

Stage I (Trivial)

1-3

Stage II (mild)

4-6

Stage III (moderate)

7-9

Stage IV (severe)

10 - 12

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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New Classification of AR:

(according to WHO iitiative ARIA 2000):

Intermitten : the symptoms are present:

< 4 days a week
Or for less than 4 weeks
Persistent : the symptoms are present:
> 4 days a week
And for more than 4 weeks

Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

26

New AR symptoms grading classification

(according to WHO initiative ARIA 2000):

Mild : that none of the following items are present:

Sleep disturbances
Impairment of daily activity, leisure and/or sport
Impairment of school or work
Trouble some symptoms

Moderate Severe :
One or more of the following items are present:
Sleep disturbances
Impairment of daily activity, leisure and/or sport
Impairment of school or work
Trouble some symptoms
27

DIAGNOSTIC Procedure:
Routine tests:(according to WHO initiative ARIA 2000)

Allergy tests
* Skin test and or
* Serum specific IgE)
Endoscopy
* rigid or * flexible

Nasal secretion (cytology)

Nasal challenge ( * allergen * lysin aspirin )
Radiology (plain radiographs and or CT-scan)
Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

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DIAGNOSTIC Procedure:

Optional tests:(according to WHO initiative ARIA 2000)

Nasal biopsy
Nasal swab bacteriology

Radiology MRI
Mucociliary function
Nasal airway assessment
Olfaction tests
Nitric oxide meassurement
Sumarman. Patophysiology and Diagnostic Procedure of Allergic Rhinitis

29

Skin Tests
Scratch test
Patch test
Intracutan test
Skin prick test
Skin endpoint titration (SET)
Each test has own advantages and
disadvantages and specific indication
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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Skin Prick Test

Indonesian : Tes kulit tusuk
(Tes kulit cungkit)
Simple, save, painless, and preferably
Single device (good enough and cheap)
Multiple devices (better but more expensive)
Volar region
The prick be placed > 3 cm apart
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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Skin Prick Test

Standardized extract
The best set: 6 allergen, but can more
No prick bleeding (in appropriate result)
Assesment: diam. wheal and flare (mm)
(0, 1+, 2+, 3+ and 4+)
False negative > positive
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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33

Skin endpoint titration (SET)

Indications:
If SPT negative

ID test

SET

For determinining IT allerg. starting dose

Extract mite 1:100; other 1:20 (Standardized extract)

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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Skin endpoint titration (SET)

Dilution 1 : 5 (Mite #1=1:500; #5=312.500)

(Other Alg: #1=1:100; #5=62.500)

Upper hand region, be placed > 5 cm apart

Assesment: diam. wheal (mm)
wheal 0 = 4mm
wheal 15 < 5 mm (Negative resp)
wheal 15 > 5 mm (Positive resp)
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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SET dilution

36

SET interpretation
The endpoint is the next stronger dilution
with a > 2mm larger wheal positive response

0 minute wheal : 4 mm
15 minutes wheal:
#5
#4
#3
#2

#1

Dilution
Normal response

7
9 mm
Endpoint is # 3

Abnormal response:
Flash response; Plateau response; Hourglass response
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

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Skin endpoint titration (SET)

The ultimate objective of SET are:
1.
2.
3.
4.

Safe initiate dose of immunotherapy (IT)

Decrease of interval of injection of IT
Usefull at prae seasonally or co-seasonally IT
Safe testing and treatment on patient with
severe symptoms

Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

38

The advantages and disadvantages of in vitro test

Imunoglobulin E (IgE)
Does not mediate the allergic alone
sensitized to miscellaneous antigens
(not specific)

IgE RAST (0, 1+, 2+, 3+, 4+)

IgE modified RAST (0, 1+, 2+, 3+, 4+)
Specific to one antigen/allergen
But expensive
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

39

CONCLUSIONS :
1. Allergic rhinitis is IgE mediated hypersensitivity,
starting by sensitization phase, followed by
EPR and LPR
2. During LPR : inflammatory cells accumulation
followed by mediators, cytokines, chemokines
release (including adhesion molecules and
chemotactic factors)
3. Adhesion molecules play an important role on rolling
and margination, diapedesis, and chemotaxis of
inflammatory cells
Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

40

CONCLUSIONS :
4. Well understanding of AR pathophysiology is
important for selecting either rational present
diagnosis or treatment strategies
5. Well understanding of AR pathophysiology is
more important for searching either future
diagnotic or treatment strategies (eg. Recombinant allergens)
6. The WHO initiative ARIA 2000 has lay down
the rational concept of diagnotic strategies: the
routine tests and the optional tests.
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Sumarman. Pathophysiology and Diagnostic Procedure of Allergic Rhinitis

42