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IMPACT OF ASTHMA AND ALLERGIC RHINITIS ON EACH. Arzu Yorgancıoğlu. Epidemiologic Anatomic Physiologic Immunopathologic Therapeutic. EMBRYOLOGIC DEVELOPMENT. Begins during the 4th week of gestation and continues after birth Nasal placode and prominences ; Nose

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slide2
Epidemiologic
  • Anatomic
  • Physiologic
  • Immunopathologic
  • Therapeutic
embryologic development
EMBRYOLOGIC DEVELOPMENT
  • Begins during the 4th week of gestation and continues after birth
  • Nasal placode and prominences ;

Nose

  • Laryngotracheal groove in the ventral wall of primitive pharynx ;

Larynx,trachea and bronchi

anatomy
SIMILARITIES

Chronology in embryology

Respiratory epithelium

DIFFERENCES

Subepithelial capillaries, arterial system, venous,cavernous sinosoids

Cartilage (nasal fossa-bronchi)

No muscle in nasal cavity,

Lower airways

SMOOTH MUSCLE

ANATOMY
slide6

VASCULAR ENGORGEMENT

BRONCHOCONSTRICTION

Bousquet J JACI 2004;113

chronic allergic inflammatory airway syndrome
Chronic Allergic Inflammatory Airway Syndrome

Allergic Rhinitis

Allergic rhinitis + Bronchial Hyperreactivity

Allergic Rhinitis + Asthma

slide9

VERTICAL RELATIONSHIP

Aspiration of Inflammatory Material

Oral breathing

Systemic Propagation of Nasal Inflammation

Nasopharyngo-bronchial reflex

Togias A Allergy 1999;54(suppl 57):94..

aspiration of inflammatory material
ASPIRATION OF INFLAMMATORY MATERIAL
  • First contact for inhaled allergens, contact with nasal secretions, allergenity and biologic activity
  • Insufficient invivo data,rabbit study +
  • No deposition of nasal secretions in lung (Tc99m enj)

Bardin P J Allergy Clin Immunol 1990;86:82

oral breathing
ORAL BREATHING
  • Bypassing the nose
  • Deprivation of lower airways from protective mechanisms (Nasal air conditioning, humidifying, filtering
  • Possible detrimental consequences
healthy ind v dual

NAZOBRONCHIAL REFLEX

Healthy Indıvıdual
  • Nasal provocation with dry cold air bronchoconstruction
  • With oral breathing , warming , local anesthesia or antikcholinergic no response
ar asthma

NAZOBRONCHIAL REFLEX

AR +, Asthma -
  • Provocation with natural or metacholine , histamin BHR +
  • Sensorineural apparatus of the inflamed nose is upregulated nasobronchial reflex is upregulated as well.

Simons Clin Exp All Rev 2003;3

nasal allergen provocation increases bronchial hyperresponsiveness
Nasal allergen provocation increases bronchial hyperresponsiveness

Change in PC20 after nasal provocation

Plasebo (n=10)Allergen (n=10)

3

2

0

Geometricmean PC20(methacholine,mg/ml)

***

**

1600

Postchallenge

Time

0800

Baseline

1200

Postchallenge

Corren J et al J Allergy Clin Immunol 1992;89:611-618.

patients with allergic rhinitis develops bronchial hyperresponsivess in polen season
Patients with allergic rhinitis develops bronchial hyperresponsivess in polen season

Prevalance of Bronchial hyperresponsiveness

60

50

40

30

20

10

0

(n=27)

p<0.02

%

of patients

48

11

Off season

Season

Madonini E et al J Allergy Clin Immunol 1987;79:358-363.

slide16

seasonal

perennial

seasonal

rhinitis

rhinitis

+ perennial

rhinitis

80

Bronchial hyperresponsiveness

- 821 adult

- 20-44 y

- PC20 methacholine ≤4mg

60

40

% subjects

20

0

controls

asthma

non-asthmatic

without wheeze

slide17
Nasal mucosa of rhinitic patients with asthma responds more vigorously to nasal cold dry air than the ones without asthma
  • Nasal response to natural cat allergen exposure is greater with rhinitis and asthma than in patients with rhinitis alone
  • The presence of asthma and rhinitis signifies a higher degree of functional abnormality of the entire airway

Hanes LS Clinical and Experimental Allergy 2006;36:26

Corren J J Allergy Clin Immunol 2005 ;

slide18
BHR Asymptomatic in rhinitic patients

Close connection between BHR and allergen exposure

  • A relationship between the degree of BHR

And FEF 25-75

Ciprandi G Respiratory medicine 2004;98:826

slide19

SYSTEMIC

INFLAMMATION

CLINICAL

DATA

common immunolog cal mechanism
Common Immunologıcal mechanism

Preformed mediators

Histamine

IgE

Mastcell

Acute allergikreaction

Newly synthesized mediatorsCysLT, PG, PAF

Eosinophills

Allergen

T cell

Chronic allergikreaction

Cytokines

Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21

Kay AB N Engl J Med 2001;344

eosinophilic infiltration
Eosinophilic Infiltration

Allergic rhinitis

Astma

Eosinophil infiltration

Bousquet J et al J Allergy Clin Immunol Suppl 2001;108(5):S148-S149.

similarities in early and late response
Similarities in early and late response

100

FEV1(% change)

50

0

0

1

2

3

4

5

6

7

8

9

10

24

Time (h)

AsthmaAllergic rhinitis

Late Phase

Early phase

Symptom score

Antigenprovocation

1

3–4

8–12

24

Time(h)

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.

nasal provocation systemic response
NASAL PROVOCATION SYSTEMIC RESPONSE
  • Nasal allergen provocation peripheric eosinophilia

Togias A J Allergy Clin Immunol 2000:106.

  • Nasal provocation spontaneus cytokine decharge from peripheric leucocysts

Togias A J Allergy Clin Immunol 2002:109.

slide24

NASAL PROVOCATION SYSTEMIC RESPONSE

P=0.004

Eosinophils /mm3

Togias JACI 2000; 106: 247 - 50

increase in eosinophils in bronchial epithelium after allergen provocation
Increase in eosinophils in bronchial epithelium after allergen provocation

1600

1200

800

400

0

**

+cell/mm2

**

BMK13 bronchial subepithelium

*

T0

A

B

C

T24

Braunstahl, Am J Respir Crit Care Med 2000; 161:2051-57.

increase in eosinophils in bronchial epithelium
Increase in Eosinophils in Bronchial Epithelium

Braunstahl, Am J Respir Crit Care Med 2000; 161:2051-57.

slide27

NASAL PROVOCATION SYSTEMIC RESPONSE

  • 9 AR , 9 controls ( nasal provocation)
  • Symptom scores, PFT, Peripheric Blood, nasal and bronchial biopsy
  • ½ ve 12h ; pulmonary and nasal symptom scores, functions
  • 24h;

Peripheric eosinophil and IL-5

Nasal + bronchial eosinophil and IL-5

Endothelial adhesion molecules in

Nasal and bronchial mucosa

Braunstahl GJ J Allergy Clin Immunol 2001:107

systemic inflammatory response to allergen provocation
Systemic Inflammatory Response to Allergen Provocation

ICAM-1/CD31

VCAM-1/CD31

ELAM-1/CD31

%

Braunstahl GJ et al. JACI 2001; 107: 469-76

nasal biopsy icam 1 vcam 1 e selectin cd31
Nasal biopsy(ICAM-1,VCAM-1,E-Selectin,CD31

24s

Braunstahl GJ JACI 2001:107

slide32
Inhalation study with 99mTc
  • No deposition in lung after nasal exposition

Corren J J Allergy Clin Immunol 1992:89.

slide33

BRONCHIAL PROVOCATION SYSTEMIC RESPONSE

  • Segmental bronchial provocation in AR patients
  • Eosinophilia after 24 h
  • Nasal and bronchial mucosa ;

eosinophilia

IL-5

eotaksin + cell

Braunstahl AJRCCM 2000:161.

slide34

BRONCHIAL PROVOCATION SYSTEMIC RESPONSE

  • Segmental bronchial provocation in AR
  • 24 s;

Nasal mucosal mast c.(degranulation) and basophil

Peripheric basophilia (migration)

Lower and upper airways; eosinophil , IL 5 and eotaksin positive cells

Braunstahl AJRCCM 2001:164.

9 atopic asthmatics 9 ar asthma segmental bronchial provocation
9 atopic asthmatics9 AR, Asthma –Segmental bronchial provocation
  • BAL; cell count, histamine, MMP, IL-5, IFN-  , IL-10
  • Cell,mediatör and cytokine profile similar
  • PD causing airway response change 5 times lower in asthmatics
  • Preexisting airway sensitivity, injury, remodeling??

Kelly E J Allergy Clin Immunol 2003;111:79.

nasal mucosal inflammation in asthma in the absence of rhinitis
Nasal mucosal inflammation in Asthma in the absence of rhinitis

(n=9)

(n=8)

(n=10)

18

16

14

12

10

8

6

4

2

0

Eosinophils

p<0.001

p<0.001

Rhinitis

No Rhinitis

Control

Asthma

Gaga M et al Clin Exp Allergy 2000;20:663-669.

eosinophils in asthmatics

Bronchial mucosa

Nasal mucosa

Bousquet J et al. N Engl J Med 1990

Chanez P et al. Am J Respir Crit Care Med 1999

Eosinophils in asthmatics
slide38
Similar airway findings in patients with rhinitis without asthma

Bavbek S, J Invest Allergol Clin Immunol 1996; 6(3): 172-182

result
RESULT
  • AR-Asthma relationship BIDIRECTIONAL
  • Local allergen exposure causes generalized airway inflammation
  • SYSTEMIC RESPONSE due to IL-5
differences
DIFFERENCES
  • Pathogenetic mechanisms and the resultant inflammation ; not different
  • Difference due to TARGET ORGAN characteristics (intrinsic features)
immunopathologic differences between rhinitis and asthma
Immunopathologic Differences between Rhinitis and Asthma
  • Epithelial injury – Specific for asthma
  • Remodelling – Specific for asthma
  • Mechanism in hyprereactivity - ? sensorineural in nose

Multifaceted in lung

slide43

Epithelial Shedding

Nasal patient

Nasal control

Bronchial kcntrol

Bronchial patient

Chanez P AJRCCM 1999;159

epithelial shedding
EPITHELIAL SHEDDING
  • Epithelial sheeding more prominent in bronchus (correlating with disease severity)
  • The less severe eosinophilic inflammation ?
  • A reason other than eosinophils (Episialin ?)

Polosa R J Allergy Clin Immunol 2000;106:1124

Shaida A J Allergy Clin Immunol 2001;108:791

epithelial shedding1
EPITHELIAL SHEDDING
  • The characteristics of nasal mucosa
    • Higher clearance rate
    • More resistance to injury
    • Higher regeneration capacity
    • Protection against MMP
basal membrane in rhinitis
Basal Membrane in Rhinitis
  • Thickness of the nasal epithelium in patients with PAR is greater than that of patients with SAR and controls

Calderon et al. JACI 1994; 93: 635-43

  • Thickness of BM is greater in patients with SAR than controls

Limet al. Am J Respir Crit Care Med 1995; 151: 136-44

slide47

Thickness of Nasal and Bronchial Basal Membrane in Steroid -dependant asthmatics

Control

Asthma

p<0.001

14

12

10

8

6

4

2

0

14

12

10

8

6

4

2

0

Basal membrane Thickness

(mm)

p<0.004

Nose

Bronchus

Nose

Bronchus

Chanez P et al. Am J Respir Cit Care Med 1999; 159: 588-95

slide48
BM thickening more prominent in bronchus
  • Episialine (antiadhesion molecule secreted by epithelium)s ignificantly more in bronchus

Chanez P AJRCCM 1999;159

episialine immunoreactivity
Episialine immunoreactivity

NASAL

BRONCHIAL

Chanez P AJRCCM 1999;159

remodelling
REMODELLING

Bousquet J JACI 2004;113

slide52
Another bronchial factor causing BM thickening???
  • Fibroblast? Myofibroblast?
  • Protease-antiprotease ?
smooth muscle
SMOOTH MUSCLE
  • Basic difference
  • Self interaction with epithelial , and mezenchymal cells
  • Ep. Sheeding and thickening of BM is related with the secretory activity of smooth muscle cell
  • Effected by the cytokines released
slide54
The secretory characteristics of smooth muscle cell
  • Genetic defects in embryologic differentiation

Genes in the embryologic differentiation may direct remodeling ???

Emryologic origins are different

Bousquet J JACI 2004;113

Salib RJ Clin Exp Allergy 2003:33

slide55
RHINITIS

Epithelial-mesenchymal trophic unit

ASTHMA

Epithelial --mesenchymanl-MUSCULAR trophic unit

Bousquet J et al J Allergy Clin Immunol Suppl 2001;108

result1
RESULT
  • Immunopathogenetic processses ; not different
  • Different manifestations of the same pathogenetic process in different parts of the airways
  • The difference in remodeling; due to structural and intinsic characteristics of the Upper ve lower respiratory tracts