The impact of allergic rhinitis on asthma Gert-Jan Braunstahl Pulmonary medicine, EMCR, Rotterdam.

The impact of allergic rhinitis The impact of allergic rhinitis on asthmaon asthma

Gert-Jan BraunstahlGert-Jan BraunstahlPulmonary medicine, EMCR, RotterdamPulmonary medicine, EMCR, Rotterdam

ARIAARIA

Objectives:Objectives: Update knowledge of ARUpdate knowledge of AR Recognise AR as global Recognise AR as global

health problemhealth problem Asthma and AR commonly Asthma and AR commonly

occur togetheroccur together Evidence-based approach Evidence-based approach

to diagnosis and treatmentto diagnosis and treatment Management of allergic Management of allergic

airways diseaseairways disease

Bousquet et al, J Allergy Clin Immunol 2001

Why do we have a nose?Why do we have a nose?

Functional relationshipFunctional relationship

Macroscopic viewMacroscopic view

Nose

Lung

normal

disease

Rhinitis

Asthma

AsthmaRhinitis

Microscopic viewMicroscopic view

Dendritic cell

Th1-cell Th2-cellIFN-

IL-10

IL-1

Th0-cell

VCAM-1 ICAM-1 E-selectin

IL-4 IL-13

B-cell

IgE

Allergen

Mast cell

histamine

LTs PGs PAF

Eotaxin IL-5 RANTES

Eosinophil

MBP ECP

Systemic circulation

Airway inflammationAirway inflammation

Pathogenesis allergic Pathogenesis allergic airway disease airway disease

Genetic factors

Environmental factors

Atopic sensitization

Structural changes

Mucosal inflammation

Phenotype

Association Association rhinitis/sinusitisrhinitis/sinusitis

and asthmaand asthma

0

2

4

6

8

10

R-S- R+S- R-S+ R+S+

OR

1

*

*

* p < 0.001 Guerra, J Allergy Clin Immunol 2002

80-95% of asthmatic patients have 80-95% of asthmatic patients have rhinitis.rhinitis.

76% asthmatic patients reported 76% asthmatic patients reported presence of rhinitis before onset presence of rhinitis before onset asthma.asthma.

Asthma presence associated with Asthma presence associated with duration and severity of rhinitis.duration and severity of rhinitis.

EpidemiologyEpidemiology

Leynaert, J Allergy Clin Immunol 2004

Causal relationshipCausal relationship

rhinitis

asthma

Dis

ease

sev

erit

y

time

Togias, Allergy 1999

QuestionsQuestions

What is the relationship between What is the relationship between allergic rhinitis and asthma?allergic rhinitis and asthma?

Is there any interaction between upper Is there any interaction between upper and lower airwaysand lower airways??

What are the mechanisms that may What are the mechanisms that may play a role in nasobronchial cross-talk?play a role in nasobronchial cross-talk?

QuestionsQuestions




Australia

asthma 18%

rhinitis 25%

Canada

asthma 13%

rhinitis 25%

Sweden

asthma 8%

rhinitis 15%

China

asthma 5%

rhinitis 10%

Brasil

asthma 10%

rhinitis 22%Kenya

asthma 8%

rhinitis 13%

ISAAC study, Lancet 1998

Worldwide prevalenceWorldwide prevalence

Prevalence asthma and Prevalence asthma and rhinitis in NLrhinitis in NL

Non-allergic

68

Allergic no symptoms

10

Rhinitis12

Asthma + Rhinitis

8

Asthma

2

Nasal inflammation in Nasal inflammation in asthmaasthma

Gaga M. et al, Clin Exp Allergy 2000

16

AR ANR

HC

EG

2+ c

ells

per

field

12

8

4

0p<0.001

p<0.001

Nasal inflammation and Nasal inflammation and BHRBHR

Nasa

l eosi

nophil

num

ber

20

22

absent

3

low

11

moderate

12

high

10

0 PD20 methacholine

Ciprandi G. et al, Int Arch Allergy Immunol 2004

Lower airway involvement Lower airway involvement in in

atopic patientsatopic patients

5

6

7

8

9

10

m RBM

* *

HC NANR RNA A+Rn=16 n=8 n=18 n=19

Braunstahl GJ. et al, Clin Exp Allergy 2003* = p < 0.05 vs controls

cell/mm2Eosinophils

0

20

40

60


*

** **

5

6

7

8

9

10

m RBM

* *


5

6

7

8

9

10

m RBM

* *

5

6

7

8

9

10

m RBM

5

6

7

8

9

10

m RBM

5

6

7

8

9

10

m RBM

* ** ** *

HC NANR RNA A+Rn=16 n=8 n=18 n=19HC NANR RNA A+R

n=16 n=8 n=18 n=19

Braunstahl GJ. et al, Clin Exp Allergy 2003* = p < 0.05 vs controls

cell/mm2Eosinophils

0

20

40

60


*

** **cell/mm2

Eosinophils

0

20

40

60

0

20

40

60

HC NANR RNA A+Rn=16 n=8 n=18 n=19HC NANR RNA A+R

n=16 n=8 n=18 n=19

*

** **

Bronchial remodeling in Bronchial remodeling in asthma and rhinitisasthma and rhinitis

Chakir et al, Lab Invest 1996Chakir et al, Lab Invest 1996

0

5

10

15

20

25

base

men

t m

embr

ane

thic

knes

s (µ

m)

controls rhinitis asthma

type I collagen

0

5

10

15

20

25


type III collagen

0

5

10

15

20

25


fibronectin

Nasal and bronchial mucosa Nasal and bronchial mucosa in asthma and rhinitisin asthma and rhinitis

nosenose bronchusbronchus

EpitheliumEpithelium

sheddingshedding 0 to +0 to + ++++++

metaplasia metaplasia 00 00

Basement membrane Basement membrane

pseudo-thickeningpseudo-thickening 0 to + 0 to + ++ to +++++ to +++

collagen depositioncollagen deposition 0 to +0 to + ++ to +++++ to +++

other proteinsother proteins ?? ++ to +++++ to +++

Fibroblasts sub-mucosaFibroblasts sub-mucosa 0 to + ?0 to + ? ++ to +++++ to +++

Collagen in sub-mucosaCollagen in sub-mucosa ?? + to +++ to ++

Courtesy of Jean Bousquet

SummarySummary

Mucosal inflammation is present in the entire airway of patients with allergic rhinitis and/or asthma.

Upper airway inflammation is associated with bronchial hyperresponsiveness

Lower airway remodeling is present in asthmatic, but also in allergic rhinitis patients.

InflammationInflammationInflammation

QuestionsQuestions




NP in allergic rhinitis NP in allergic rhinitis influence on lower airwaysinfluence on lower airways

T0

blood sample

bronchus biopsy

nose biopsy

hr

= PNIF, PEF, symptom score

T24

9 9

subjects

T0

blood sample

bronchus biopsy

nose biopsy

T0

blood sample

bronchus biopsy

nose biopsy

hrhr

= PNIF, PEF, symptom score

T24

= PNIF, PEF, symptom score= PNIF, PEF, symptom score

T24

9 9

subjects

9 999 99

subjects

Symptoms (VAS)Symptoms (VAS)

RhinitisControls

0 ½ 2 4 6 8 10 12 24 24½ hr

Nose

mm

NP

Braunstahl GJ et al, JACI, 2001

p = 0.0002 (ANOVA)

0 ½ 2 4 6 8 10 12 24 24½ hr

Lung

mm

NP

p = 0.01

RhinitisControls

0 ½ 2 4 6 8 10 12 24 24½ hr

Nose

mm

NP


p = 0.0002 (ANOVA)

RhinitisControlsRhinitisControls

0 ½ 2 4 6 8 10 12 24 24½ hr

Nose

mm

NP


p = 0.0002 (ANOVA)

0 ½ 2 4 6 8 10 12 24 24½ hr

Nose

mm

NP


p = 0.0002 (ANOVA)

0 ½ 2 4 6 8 10 12 24 24½ hr

Lung

mm

NP

p = 0.01

0 ½ 2 4 6 8 10 12 24 24½ hr

Lung

mm

NP

p = 0.01

Airway functionAirway function

RhinitisControls

PNIF

0 ½ 2 4 6 8 10 12 24 24½ hr

L/min

NP


p = 0.0001

0 ½ 2 4 6 8 10 12 24 24½ hr

PEFL/min

NP

p = 0.04

RhinitisControls

PNIF

0 ½ 2 4 6 8 10 12 24 24½ hr

L/min

NP


p = 0.0001

0 ½ 2 4 6 8 10 12 24 24½ hr

PEFL/min

NP

p = 0.04

Baseline

nose

lung

VCAM-1 Eosinophils

Allergic inflammationAllergic inflammation

Bronchial inflammation Bronchial inflammation after NPafter NP

T0 T24

*

0

20

40

60

80

VCAM-1% +vessels

control

rhinitis

* = p < 0.05 vs controls and T0


T0 T24

*

0

40

80

120

160Cell/mm2

Eosinophils

T0T0 T24

*

T24

**

0

20

40

60

80

VCAM-1% +vessels

0

20

40

60

80

VCAM-1% +vessels

0

20

40

60

80

VCAM-1% +vessels

0

20

40

60

80

VCAM-1% +vessels

control

rhinitis

* = p < 0.05 vs controls and T0


T0T0 T24

*

T24

**

0

40

80

120

160Cell/mm2

Eosinophils

0

40

80

120

160Cell/mm2

Eosinophils

0

40

80

120

160

0

40

80

120

160Cell/mm2

Eosinophils

SBP in allergic rhinitisSBP in allergic rhinitis

influence on upper airwaysinfluence on upper airways

8 8

subjects

control

allergic biopsy after (T24)

biopsy before (T0)

+

8 8

subjects

control

allergic

8 888 88

subjects

control

allergic

control

allergic biopsy after (T24)

biopsy before (T0)

++

MethodsMethods

Nasal inflammation after Nasal inflammation after SBPSBP

Before100 x

After

MBP

bronchial challenge


MBP Lamina propria

controls

allergic

before

*

after0

20

40

60

80LungCell/mm2

before

*

after0

10

20

30

40

NoseCell/mm2

Braunstahl GJ et al, AJRCCM, 2000

Chymase (C) and Tryptase (T) 400x


MCTC Lamina propria

MCTMCC

MCTC

before

*

after0

50

100

150

200

Cell/mm2

controls

allergicBraunstahl GJ et al, AJRCCM, 2001

Nose

SummarySummary

The interaction between nose and lung in allergic airways disease is a bi-directional process

QuestionsQuestions




Nasal vs. oral ventilationNasal vs. oral ventilation effect of cold air inhalationeffect of cold air inhalation

McLane, J. Appl. Physiol. 2000

B = baseline

R = frigid air

NHV NHV OHVN

R c

m H

2O

/L/s

ec

FEV

1

P value 0.01

0.27

<0.001B R B R B R

FEV

1

0

5

0

4

0

4

Pulmonary aspiration?Pulmonary aspiration? Radio-active markersRadio-active markers

Bardin et al, JACI, 1990

Maxillary sinusnasopharynx

Oesophagusstomach

Rest of GI tract

99mTc1 hr 6 hr 24

hr

Naso-bronchial reflex?Naso-bronchial reflex?effect of intranasal methacholineeffect of intranasal methacholine

base peak

controls

base peak

asthmatics

LARcmH20/L/sec

5

4

3

2

1

0

*

*

Lidocaine: no blockage

base peak

controls

base peak

asthmatics

NARcmH20/L/sec

20

15

10

5

0

* *

* = p < 0.05 vs baseline

Littell et al, Am Rev Respir Dis, 1990Phenylephrine: blockage

Systemic interaction?Systemic interaction?effect of NP on IL-5 plasmaeffect of NP on IL-5 plasma

Beeh et al, Clin Exp Allergy, 2003

IL-5

(pg/m

L)

Allergenpre post

80

*

Placebopre post

60

40

20

0

* p < 0.001

control

allergic

before

*

after0

10

20

30

40

50 IL-5pg/mL

before

*

after0

100

200

300

400eosinophils

cell x 106

Braunstahl GJ et al, AJRCCM, 2001

Systemic interaction?Systemic interaction?effect of SBP on IL-5 and effect of SBP on IL-5 and

eosinophilseosinophils

SummarySummary

Allergen

Aspiration

Neural reflex

Lymph nodes

Circulation

Ingestion

Nose breathing

Mouthbreathing

Allergen

Aspiration

Neural reflex

Lymph nodes

Circulation

Ingestion

Nose breathing

Mouthbreathing

Take home messagesTake home messages

Allergic rhinitis often precedes asthma.Allergic rhinitis often precedes asthma. Allergic rhinitis and asthma Allergic rhinitis and asthma

characterized by global airway characterized by global airway inflammation.inflammation.

There is a bi-directional influence There is a bi-directional influence between upper and lower airways.between upper and lower airways.

The systemic pathway plays an The systemic pathway plays an important role in the interaction important role in the interaction between nose and lungbetween nose and lung

The impact of allergic rhinitis on asthma Gert-Jan Braunstahl Pulmonary medicine, EMCR, Rotterdam.

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