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IMPACT OF ASTHMA AND IMPACT OF ASTHMA AND ALLERGIC RHINITIS ON EACHALLERGIC RHINITIS ON EACH
Arzu YorgancıoğluArzu Yorgancıoğlu
EpidemiologicEpidemiologic AnatomicAnatomic PhysiologicPhysiologic ImmunopathologiImmunopathologi
cc TherapeuticTherapeutic
EMBRYOLOGIC DEVELOPMENTEMBRYOLOGIC DEVELOPMENT Begins during the 4th week of gestation Begins during the 4th week of gestation
and continues after birthand continues after birth Nasal placode and prominences ;Nasal placode and prominences ;
NoseNose
Laryngotracheal groove in the ventral wall Laryngotracheal groove in the ventral wall of primitive pharynxof primitive pharynx ;;
Larynx,trachea and bronchi Larynx,trachea and bronchi
Bousquet J JACI 2004;113
ANATOMYANATOMY
SIMILARITIESSIMILARITIES
Chronology in Chronology in embryologyembryology
Respiratory epitheliumRespiratory epithelium
DIFFERENCESDIFFERENCES
Subepithelial capillaries, Subepithelial capillaries, arterial system, arterial system, venous,cavernous venous,cavernous sinosoidssinosoids
Cartilage (nasal fossa-Cartilage (nasal fossa-bronchi)bronchi)
No muscle in nasal No muscle in nasal cavity, cavity,
Lower airways Lower airways
SMOOTH SMOOTH MUSCLEMUSCLE
Bousquet J JACI 2004;113VASCULAR ENGORGEMENT BRONCHOCONSTRICTION
Chronic Allergic Inflammatory Airway Chronic Allergic Inflammatory Airway SyndromeSyndrome
Allergic RhinitisAllergic Rhinitis
Allergic rhinitis + Bronchial Allergic rhinitis + Bronchial HyperreactivityHyperreactivity
Allergic Rhinitis + AsthmaAllergic Rhinitis + Asthma
Vertical and Horizontal Vertical and Horizontal RelationshipRelationship
Togias A JACI 2003;111
Togias A Allergy 1999;54(suppl 57):94..
Aspiration of Inflammatory Material
Oral breathing
Nasopharyngo-bronchial reflex
Systemic Propagation of Nasal Inflammation
VERTICAL RELATIONSHIPVERTICAL RELATIONSHIPVERTICAL RELATIONSHIPVERTICAL RELATIONSHIP
ASPIRATION OF INFLAMMATORY ASPIRATION OF INFLAMMATORY MATERIALMATERIAL
First contact for inhaled allergens, contact First contact for inhaled allergens, contact with nasal secretions, allergenity and with nasal secretions, allergenity and biologic activity biologic activity
Insufficient invivo data,rabbit study + Insufficient invivo data,rabbit study + No deposition of nasal secretions in lung No deposition of nasal secretions in lung
(Tc99m enj)(Tc99m enj)
Bardin P J Allergy Clin Immunol 1990;86:82
ORAL BREATHINGORAL BREATHING
Bypassing the nose Bypassing the nose
Deprivation of lower airways from Deprivation of lower airways from protective mechanisms (Nasal air protective mechanisms (Nasal air conditioning, humidifying, filteringconditioning, humidifying, filtering
Possible detrimental consequences Possible detrimental consequences
Healthy Indıvıdual Healthy Indıvıdual
Nasal provocation with dry cold airNasal provocation with dry cold airbronchoconstructionbronchoconstruction
With oral breathing , warming , local With oral breathing , warming , local anesthesia or antikcholinergicanesthesia or antikcholinergic no no responseresponse
NAZOBRONCHIAL REFLEXNAZOBRONCHIAL REFLEX
AR +, Asthma -AR +, Asthma -
Provocation with natural or metacholine , Provocation with natural or metacholine , histamin histamin BHR +BHR +
Sensorineural apparatus of the inflamed Sensorineural apparatus of the inflamed nose is upregulatednose is upregulated nasobronchial nasobronchial reflex is upregulated as well.reflex is upregulated as well.
Simons Clin Exp All Rev 2003;3
NAZOBRONCHIAL REFLEXNAZOBRONCHIAL REFLEX
Nasal allergen provocation increases bronchial Nasal allergen provocation increases bronchial hyperresponsivenesshyperresponsiveness
Change in Change in PCPC2020 after nasal provocation after nasal provocation
Corren J et al J Allergy Clin Immunol 1992;89:611-618.
0800Baseline
3
2
0
Geometricmean PC20
(methacholine,
mg/ml)
Plasebo (n=10)Allergen (n=10)
1200Postchallenge
1600Postchallenge
**
***
Time
Prevalance of Prevalance of BronBronchial hyperresponsivenesschial hyperresponsiveness
Patients with allergic rhinitis develops bronchial Patients with allergic rhinitis develops bronchial hyperresponsivess in polen seasonhyperresponsivess in polen season
Madonini E et al J Allergy Clin Immunol 1987;79:358-363..
60
50
40
30
20
10
0
% of patients
Off season Season
(n=27)
11
48
p<0.02
BronBronchial hyperresponsivenesschial hyperresponsiveness
0
20
40
60
80
% s
ubje
cts
controlsseasonalrhinitis
perennialrhinitis
seasonal+ perennial
rhinitis
asthma
- 821 adult
- 20-44 y
- PC20 methacholine ≤4mg
non-asthmatic without wheeze
Nasal mucosa of rhinitic patients with Nasal mucosa of rhinitic patients with asthma responds more vigorously to asthma responds more vigorously to nasal cold dry air than the ones nasal cold dry air than the ones without asthmawithout asthma
Nasal response to natural cat Nasal response to natural cat allergen exposure is greater with allergen exposure is greater with rhinitis and asthma than in patients rhinitis and asthma than in patients with rhinitis alonewith rhinitis alone
The presence of asthma and rhinitis The presence of asthma and rhinitis signifies a higher degree of signifies a higher degree of functional abnormality of the entire functional abnormality of the entire airwayairway
Hanes LS Clinical and Experimental Allergy 2006;36:26
Corren J J Allergy Clin Immunol 2005 ;
BHR Asymptomatic in rhinitic BHR Asymptomatic in rhinitic patientspatients
Close connection between BHR and Close connection between BHR and allergen exposure allergen exposure
A relationship between the degree A relationship between the degree of BHRof BHR
And FEF 25-75 And FEF 25-75
Ciprandi G Respiratory medicine 2004;98:826
SYSTEMIC SYSTEMIC INFLAMMATIONINFLAMMATION
CLINICAL CLINICAL
DATADATA
Common Immunologıcal Common Immunologıcal mechanismmechanism
Common Immunologıcal Common Immunologıcal mechanismmechanism
Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21
Kay AB N Engl J Med 2001;344
IgE
Acute allergikreaction
Chronic allergikreaction
Mastcell
T cell
Allergen
Cytokines
Preformed mediatorsHistamine
Newly synthesized mediators
CysLT, PG, PAF
EosinophillsEosinophills
Eosinophilic InfiltrationEosinophilic InfiltrationEosinophilic InfiltrationEosinophilic Infiltration
Bousquet J et al J Allergy Clin Immunol Suppl 2001;108(5):S148-S149.
Eosinophil infiltration
Allergic rhinitis Astma
Similarities in early and late Similarities in early and late responseresponse
Similarities in early and late Similarities in early and late responseresponse
Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford: Blackwell Science, 2000:1172-1185
Togias A. J Allergy Clin Immunol 2000;105(6 pt 2):S599-S604.
AsthmaAllergic rhinitis
Symptom score
Time(h)
1Antigenprovocation
3–4 8–12 24
Early phase Late Phase
FEV1
(% change)
Time (h)
1 10 240 2 3 4 5 6 7 8 9
0
50
100
NASAL PROVOCATION SYSTEMIC RESPONSE
Nasal allergen provocation Nasal allergen provocation peripheric peripheric eosinophiliaeosinophilia
Togias A J Allergy Clin Immunol 2000:106.Togias A J Allergy Clin Immunol 2000:106.
Nasal provocationNasal provocation spontaneus cytokine spontaneus cytokine decharge from peripheric leucocystsdecharge from peripheric leucocysts
Togias A J Allergy Clin Immunol 2002:109.Togias A J Allergy Clin Immunol 2002:109.
0
100
200
300
400
500
600
700
Basal 24h after provocation
Eosi
noph
ils /
mm
3 P=0.004
Togias JACI 2000; 106: 247 - 50
NASAL PROVOCATION SYSTEMIC RESPONSE
Increase in eosinophils in bronchial Increase in eosinophils in bronchial epithelium after allergen provocationepithelium after allergen provocation
Braunstahl, Am J Respir Crit Care Med 2000; 161:2051-57.
****
*
1600
1200
800
400
0
T24
T0 B C
+cell/mm2
BM
K13 b
ron
ch
ial su
bep
ith
eliu
m
A
Increase in Eosinophils in Increase in Eosinophils in Bronchial EpitheliumBronchial Epithelium
Braunstahl, Am J Respir Crit Care Med 2000; 161:2051-57.
9 AR , 9 controls ( nasal provocation)9 AR , 9 controls ( nasal provocation) Symptom scores, PFT, Peripheric Blood, nasal Symptom scores, PFT, Peripheric Blood, nasal
and bronchial biopsy and bronchial biopsy ½ ve 12h ; pulmonary and nasal symptom ½ ve 12h ; pulmonary and nasal symptom
scores, functions scores, functions 24h; 24h;
Peripheric eosinophil and IL-5 Peripheric eosinophil and IL-5
Nasal + bronchial eosinophil and IL-5 Nasal + bronchial eosinophil and IL-5
Endothelial adhesion molecules in Endothelial adhesion molecules in
Nasal and bronchial mucosa Nasal and bronchial mucosa
Braunstahl GJ J Allergy Clin Immunol 2001:107Braunstahl GJ J Allergy Clin Immunol 2001:107
NASAL PROVOCATION SYSTEMIC RESPONSE
Braunstahl GJ JACI 2001:107.Braunstahl GJ JACI 2001:107.
Systemic Inflammatory Response to Systemic Inflammatory Response to Allergen ProvocationAllergen Provocation
Systemic Inflammatory Response to Systemic Inflammatory Response to Allergen ProvocationAllergen Provocation
0
10
20
30
40
50
60
70
80
90
Rinit Kontrol Rhinitis Control Rhinitis control
Basal
24h after allergen
ICAM-1/CD31 VCAM-1/CD31 ELAM-1/CD31
%
Braunstahl GJ et al. JACI 2001; 107: 469-76
Nasal biopsyNasal biopsy(ICAM-1,VCAM-1,E-Selectin,CD31(ICAM-1,VCAM-1,E-Selectin,CD31
Braunstahl GJ JACI 2001:107Braunstahl GJ JACI 2001:107
24s
Bronchial biopsyBronchial biopsy(ICAM-1,VCAM-1,E-Selectin,CD31(ICAM-1,VCAM-1,E-Selectin,CD31
Braunstahl GJ JACI 2001:107Braunstahl GJ JACI 2001:107
24s
Inhalation study with 99mTcInhalation study with 99mTc No deposition in lung after nasal No deposition in lung after nasal
expositionexposition
Corren J J Allergy Clin Immunol 1992:89Corren J J Allergy Clin Immunol 1992:89..
Segmental bronchial provocation in Segmental bronchial provocation in AR patientsAR patients
Eosinophilia after 24 hEosinophilia after 24 h Nasal and bronchial mucosa ; Nasal and bronchial mucosa ;
eosinophiliaeosinophilia
IL-5 IL-5
eotaksin + cell eotaksin + cell Braunstahl AJRCCM 2000:161.Braunstahl AJRCCM 2000:161.
BRONCHIAL PROVOCATION SYSTEMIC RESPONSE
Segmental bronchial provocation in AR Segmental bronchial provocation in AR 24 s; 24 s;
Nasal mucosal mast c.(degranulation) Nasal mucosal mast c.(degranulation) and basophil and basophil
Peripheric basophilia (migration) Peripheric basophilia (migration)
Lower and upper airways; eosinophil , IL Lower and upper airways; eosinophil , IL 5 and eotaksin positive cells5 and eotaksin positive cells
Braunstahl AJRCCM 2001:164.Braunstahl AJRCCM 2001:164.
BRONCHIAL PROVOCATION SYSTEMIC RESPONSE
9 atopic asthmatics9 atopic asthmatics9 AR, Asthma –9 AR, Asthma –
Segmental bronchial provocationSegmental bronchial provocation
BAL; cell count, histamine, MMP, IL-5, BAL; cell count, histamine, MMP, IL-5, IFN- IFN- , IL-10 , IL-10
Cell,mediatör and cytokine profile Cell,mediatör and cytokine profile similarsimilar
PD causing airway response change 5 PD causing airway response change 5 times lower in asthmaticstimes lower in asthmatics
Preexisting airway sensitivity, injury, Preexisting airway sensitivity, injury, remodeling??remodeling??
Kelly E J Allergy Clin Immunol 2003;111:79.
Nasal mucosal inflammation in Nasal mucosal inflammation in Asthma in the absence of Asthma in the absence of
rhinitisrhinitis
Nasal mucosal inflammation in Nasal mucosal inflammation in Asthma in the absence of Asthma in the absence of
rhinitisrhinitis
Gaga M et al Clin Exp Allergy 2000;20:663-669.
18
16
14
12
10
8
6
4
2
0
Eosinophils
Rhinitis No Rhinitis Control
(n=9) (n=8) (n=10)
p<0.001p<0.001
Asthma
Eosinophils in asthmaticsEosinophils in asthmatics
Bousquet J et al. N Engl J Med 1990
Bronchial mucosa
Chanez P et al. Am J Respir Crit Care Med 1999
Nasal mucosa
Similar airway findings in patients Similar airway findings in patients with rhinitis without asthmawith rhinitis without asthma
Bavbek S, J Invest Allergol Clin Immunol 1996; 6(3): 172-182
RESULTRESULT
AR-Asthma relationship AR-Asthma relationship BIDIRECTIONALBIDIRECTIONAL
Local allergen exposure Local allergen exposure causes generalized causes generalized airway inflammationairway inflammation
SYSTEMIC RESPONSE SYSTEMIC RESPONSE due to IL-5 due to IL-5
DIFFERENCESDIFFERENCES
Pathogenetic mechanisms and the Pathogenetic mechanisms and the resultant inflammation ; not differentresultant inflammation ; not different
Difference due to TARGET ORGAN Difference due to TARGET ORGAN characteristics (intrinsic features)characteristics (intrinsic features)
Immunopathologic Immunopathologic Differences between Differences between Rhinitis and AsthmaRhinitis and Asthma
Epithelial injury – Specific for asthmaEpithelial injury – Specific for asthma
Remodelling – Specific for asthmaRemodelling – Specific for asthma
Mechanism in hyprereactivity - ?Mechanism in hyprereactivity - ? sensorineural in nose sensorineural in nose
Multifaceted in lung Multifaceted in lung
Chanez P AJRCCM 1999;159Chanez P AJRCCM 1999;159
Nasal control Nasal patient
Bronchial kcntrol Bronchial patient
Epithelial Shedding
EPITHELIAL SHEDDINGEPITHELIAL SHEDDING
Epithelial sheeding more prominent in Epithelial sheeding more prominent in bronchus (correlating with disease severity) bronchus (correlating with disease severity)
The less severe eosinophilic inflammation ?The less severe eosinophilic inflammation ?A reason other than eosinophils (Episialin ?)A reason other than eosinophils (Episialin ?)
Polosa R J Allergy Clin Immunol 2000;106:1124Shaida A J Allergy Clin Immunol 2001;108:791
EPITHELIAL SHEDDINGEPITHELIAL SHEDDING
The characteristics of nasal mucosa The characteristics of nasal mucosa Higher clearance rateHigher clearance rate More resistance to injuryMore resistance to injury Higher regeneration capacityHigher regeneration capacity Protection against MMP Protection against MMP
Basal Membrane in RhinitisBasal Membrane in Rhinitis Thickness of the nasal epithelium in patients with PAR Thickness of the nasal epithelium in patients with PAR
is greater than that of patients with SAR and controlsis greater than that of patients with SAR and controls
Calderon et al. JACI 1994; 93: 635-43
Thickness of BM is greater in Thickness of BM is greater in patients with SAR than controlspatients with SAR than controls
Lim et al. Am J Respir Crit Care Med 1995; 151: 136-44
Thickness of Nasal and Bronchial Basal Thickness of Nasal and Bronchial Basal Membrane in Steroid -dependant Membrane in Steroid -dependant
asthmaticsasthmatics
Thickness of Nasal and Bronchial Basal Thickness of Nasal and Bronchial Basal Membrane in Steroid -dependant Membrane in Steroid -dependant
asthmaticsasthmatics
Chanez P et al. Am J Respir Cit Care Med 1999; 159: 588-95
Control Asthma
Basal membra
ne Thicknes
s(mm)
Nose Bronchus Nose Bronchus
14
12
10
8
6
4
2
0
14
12
10
8
6
4
2
0
p<0.004
p<0.001
BM thickening more prominent in BM thickening more prominent in bronchusbronchus
Episialine (antiadhesion molecule Episialine (antiadhesion molecule secreted by epithelium)s ignificantly secreted by epithelium)s ignificantly more in bronchusmore in bronchus
Chanez P AJRCCM 1999;159Chanez P AJRCCM 1999;159
Episialine immunoreactivityEpisialine immunoreactivity
Chanez P AJRCCM 1999;159Chanez P AJRCCM 1999;159
NASAL
BRONCHIAL
Upper airway response leads to less Upper airway response leads to less remodeling??remodeling??
REMODELLINGREMODELLINGNasal Nasal mucosamucosa
Bronchial Bronchial mucosamucosa
Epithelial Epithelial sheddingshedding
minimalminimal Often(Sp Often(Sp severe )severe )
BM ThickeningBM Thickening LimitedLimited OftenOften
EosinophilsEosinophils ++++ ++++++
CollagenCollagen (+-)(+-) ++++
FibroblastFibroblast May May invcreaseinvcrease
++++++
MyofibroblastMyofibroblast ?? ++++++
Smooth Smooth MuscleMuscle
-- Metaplasia, Metaplasia, hyperplasiahyperplasia
Bousquet J JACI 2004;113
Another bronchial factor causing BM Another bronchial factor causing BM thickening???thickening???
Fibroblast? Myofibroblast?Fibroblast? Myofibroblast? Protease-antiprotease ?Protease-antiprotease ?
SMOOTH MUSCLESMOOTH MUSCLE
Basic difference Basic difference Self interaction with epithelial , and Self interaction with epithelial , and
mezenchymal cellsmezenchymal cells Ep. Sheeding and thickening of BM is Ep. Sheeding and thickening of BM is
related with the secretory activity of related with the secretory activity of smooth muscle cellsmooth muscle cell
Effected by the cytokines releasedEffected by the cytokines released
1.1. The secretory characteristics of The secretory characteristics of smooth muscle cellsmooth muscle cell
2.2. Genetic defects in embryologic Genetic defects in embryologic differentiation differentiation
Genes in the embryologic Genes in the embryologic differentiation may direct differentiation may direct remodeling ???remodeling ???
Emryologic origins are different Emryologic origins are different Bousquet J JACI 2004;113Salib RJ Clin Exp Allergy 2003:33
RHINITISRHINITIS
Epithelial-Epithelial-mesenchymal mesenchymal trophic unittrophic unit
ASTHMAASTHMA Epithelial --Epithelial --
mesenchymanl-mesenchymanl-MUSCULAR trophic MUSCULAR trophic unitunit
Bousquet J et al J Allergy Clin Immunol Suppl 2001;108
RESULTRESULT
Immunopathogenetic processses ; not Immunopathogenetic processses ; not differentdifferent
Different manifestations of the same Different manifestations of the same pathogenetic process in different parts of pathogenetic process in different parts of the airwaysthe airways
The difference in remodeling; due to The difference in remodeling; due to structural and intinsic characteristics of structural and intinsic characteristics of the Upper ve lower respiratory tracts the Upper ve lower respiratory tracts