Non-Allergic Rhinitis and Asthma

Glenis Scadding

Royal National Throat Nose &Ear Hospital

London

Disclosures

�Research funds:

ALK-Abello, GSK ,

�Advisory Boards:

ALK-Abello, Allergen Therapeutics, GSK, Merck, Uriach, USB

�Speaker/Chair:

ALK-Abello, GSK , Merck, Uriach

Learning Objectives

�Classification & phenotypes NAR

�Co-morbid asthma association- or lack of it

� (Diagnosis and treatment of NAR-see www.bsaci.org)

Causes of rhinitis

Aspirin

Other medications

Viral

Bacterial

Non-allergic rhinitis with

eosinophilia syndrome

Irritants

Food

Emotional

Other infective agents

Atrophic

Gastro-oesophageal refiux

Persistent

Intermittent Intermittent

Persistent

Infectious AllergicOccupational

(allergic/non-allergic)Drug-induced Other Causes Idiopathic

Hormonal

RHINITIS

ALLERGIC INFECTIVE OTHER

?

?

Cumulative incidence rate of asthma

Shaaban R. Et al., The Lancet, 2008

Non-allergic global AW disease

PROBLEMS

heterogeneity of non-allergic rhinitis

rhinitis - rhinosinusitis

NON-ALLERGIC

RHINITIS

ASTHMA

Heterogeneity of non-allergic rhinitis

ALLERGIC

rhinitisundiagnosed

local IgE production

OCCUPATIONAL-

Allergic & non-allergic

HORMONAL

INFECTIOUS

IDIOPATHIC

Inflammatory &

Non-inflammatory

RHINOSINUSITIS

w/wo

nasal polyps

MEDICATION

inducedNON-ALLERGIC

RHINITIS

Heterogeneity of non-allergic rhinitis

ALLERGIC

rhinitisundiagnosed

local IgE production

OCCUPATIONAL-non allergic

HORMONAL

INFECTIOUS

IDIOPATHIC

Non inflammatory

RHINOSINUSITIS

w/wo

nasal polyps

MEDICATION

inducedNON-ALLERGIC

RHINITIS

Potential mechanisms of Idiopathic Rhinitis

NAR Symptoms

Inflammatory Mediator Release

STIMULI

Sensory NerveActivation &

Hyperresponsiveness

Local release of neuropeptides

Recruitment of parasympathetic reflexes, sneeze, itch

Vascular Congestion

Mucus Secretion

Vascular Leakage

Sneeze & Itch

INFLAMMATIONEpithelial Activation

Mast cell activation (non-IgE mediated)

Epithelial Damage

Local IgE response

Sympathetic & Parasympathetic

imbalance

Glandular & vascular hyperresponsiveness

Heterogeneity of non-allergic rhinitis

ALLERGIC

rhinitisundiagnosed

local IgE production

OCCUPATIONAL

HORMONAL

INFECTIOUS

IDIOPATHICRHINOSINUSITIS

w/wo

nasal polyps

MEDICATION

inducedNON-ALLERGIC

RHINITIS

UUU

Physiologiccircumstances

Protection

air filteringair conditioning

air humidification

Physiologiccircumstances

Protection

air filteringair conditioning

air humidification

Nasaldisease

Trigger

TRIGGER SYNERGY IN ASTHMA

• AllergenIncreased BHR-most allergens stay in nose.

• Infection - viral rhinitis causes BHR Rhinovirus present in nose in asthma exacerbations.

• Both - synergy• Lemanske et al J. Clin. Invest.1989;83:1-10• Johnstone Pediatr.Pul Suppl.1991;16:88-9• Johnstone AJRCCM1995;152:S46-52.

Heterogeneity of non-allergic rhinitis

ALLERGIC

rhinitisundiagnosed

local IgE production

OCCUPATIONAL

HORMONAL

INFECTIOUS

IDIOPATHIC

inflammatory

RHINOSINUSITIS

w/wo

nasal polyps

MEDICATION

inducedNON-ALLERGIC

RHINITIS

Global Airway Disease

NON-ALLERGIC RHINITIS WITH EOSINOPHILS

ASTHMA

FACTS

similar pathophysiology

mucosal IgE

risk factor

?progression to AERD

Sinonasal disease in asthma & COPD

7 (29%)9 (29%)4 (11%)2 (8%)2 (6%)Smoking

10 (42%)14 (58%)

27 (87%)4 (13%)

15 (41%)22 (59%)

14 (56%)11 (44%)

14 (41%)20 (59%)

Gender Male Female

61.33 + 2.2565.65 + 1.6847.49 + 2.4954.20 + 2.9642.74 + 2.99Age

2431372534Number

ControlsPatientsControlsNon-allergicpatients

Allergicpatients

COPDASTHMA

Hens G and Hellings P, Allergy, 2008

Sino-nasal VAS scores

Hens G and Hellings P, Allergy, 2008

1.16 + 0.461.78 + 0.450.74 + 0.293.68 + 0.663.65 + 0.58Itchy nose or eyes

1.23 + 0.421.89 + 0.430.87 + 0.213.26 + 0.542.83 + 0.43Sneezing

0.93 + 0.382.00 + 0.520.97 + 0.462.35 + 0.662.32 + 0.46Headache

1.19 + 0.472.09 + 0.490.60 + 0.182.54 + 0.602.23 + 0.36Nasal discharge

0.84 + 0.431.65 + 0.470.52 + 0.253.47 + 0.563.77 + 0.56Nasal obstruction

ControlsPatientsControlsNon-allergicpatients

Allergicpatients

COPDASTHMA

P<0.001

P<0.01

P<0.05

Mean + SEM

Nasal lavage fluid analysis

Hens G and Hellings P, Allergy, 2008

13.08+1.1915.58+1.6013.05+1.4515.36+1.7712.40+0.82VEGF

2.75+0.4011.91+4.983.56+0.6512.29+6.7212.97+3.90G-CSFGrowth factors

3.55+0.855.34+0.942.88+0.594.99+0.864.37+0.78MCP-1

39.59+24.7155.13+24.7310.91+2.1399.14+69.4471.93+33.24MIG

42.55+17.1940.85+11.9027.37+5.7060.73+32.9557.33+13.78IP10

1.56+0.372.85+0.481.11+0.252.33+0.372.09+0.27Eotaxin

79.94+23.92103.0+24.8361.72+9.0883.35+20.7870.58+12.70IL-8Chemokines

Below detection limit in nearly all samplesTNF

1.04+0.401.74+0.760.59+0.083.27+2.461.23+0.34IL-1Pro-inflammatorycytokines

0.17+0.040.38+0.080.10+0.030.21+0.050.25+0.05IFN-Th1

Below detection limit in nearly all samplesIL-5Th2

ControlsPatientsControlsNon-allergicpatients

Allergic patients

COPDASTHMA

γ

β

Heterogeneity of non-allergic rhinitis

ALLERGIC

rhinitisundiagnosed

local IgE production

OCCUPATIONAL

HORMONAL

INFECTIOUS

IDIOPATHICRHINOSINUSITIS

w/wo

nasal polyps

MEDICATION

inducedNON-ALLERGIC

RHINITIS

Heterogeneity of non-allergic rhinitis

ALLERGIC

rhinitisundiagnosed

local IgE production

OCCUPATIONAL-

Allergic & non-allergic

HORMONAL

INFECTIOUS

IDIOPATHIC

Inflammatory &

Non-inflammatory

RHINOSINUSITIS

w/wo

nasal polyps

MEDICATION

inducedNON-ALLERGIC

RHINITIS

ALLERGICRHINITIS

Non-allergicNon-inflammatoryRhinitis (NINAR)

? neurogenic

Non-allergic Rhinitis with Eosinophilia

Syndrome (NARES)

Oral aspirinchallenge

Nasal allergen challenge(s)(according to history)

or nasal aspirin challenge

History + veSPTs – ve

Further SPTs suggested by history

e.g. latex, pet, occupational allergen

ASPIRIN / NSAIDSENSITIVITY

Check for inflammation – nasal smear for eosinophils(↑nNO may be a substitute)

+ ve

– ve

– ve

– ve+ ve+ ve

+ ve

+ ve– ve

– ve

Further investigation of rhinitis

Asthma

Nasal polyps

Aspirin hypersensitivity }First First

described described by Widal by Widal (1922)(1922)

1.AETIOLOGY & PATHOGENESIS

Site of disease onset

Availability for investigation

2. CLINICAL RELEVANCE

Need for treatment

Diagnosis-safest test for

aspirin sensitivity

Specific treatment-” desensitization”

� Persistent rhinitis, onset 29.7+- 12.5 years

then asthma, aspirin intolerance, nasal polyposis

� Earlier and more severe in females

� Atopics (1 in 3 ) earlier rhinitis and asthma

� ? Viral induction of disease

� Szczeklik A et al Eur. Respir. J 2000, 16, 432-6.

AIANE network-data from 500 patients from 16 centres in 10 European countries

Sequential pattern emerged:

Normal population

0.6-2.5%

Perennial Rhinitis 6%

Asthma-21% adult

onset

CRS & Nasal polyps 30-

40%Varga et al ,1994

Nasal polyps and eosinophils: often a systemic inflammation

↑↑↑↑ ECP

↑↑↑↑ ↑↑↑↑ IL-5↑↑↑↑ IL-5

↑↑↑↑ ↑↑↑↑↑↑↑↑ ↑↑↑↑

↑↑↑↑ ↑↑↑↑Migration

Survival

Activation

MaturationDifferentiationRecruitment

IL5 + Eotaxin

Chemotaxis

Asthma

3327

64 67

88

146

28

54

80

0

10

20

30

40

50

60

70

80

90

100

Controls

(n=9)

CRS

(n=22)

NP

(n=53)

NP +

asthma

(n=18)

NP +

ASS

(n=8)

Patients (%)

S. aureuscolonization

SAE-IgE+

*

*

*

*

**

*P<0.05 vs CRS.

T. Van Zele et al.

JACI 2004

Staph. aureus/Enterotoxin in U & L airway epithelium

T

B

TCRVß

Eosinophil: ECP

Plasma cellIgEIgAIgG

T-Cell:IL-5IL-4IL-13

aspirin sensitiveaspirin tolerant

pLTspLTs < PGEPGE22 pLTs pLTs > PGEPGE22

Gosepath et al. ORL 1999

Yamashita et al. Rhinology 1989

Ziroli et al. Otolaryngol H & N Surg 2002

Kowalski et al. AJRCCM 2000Pinto et al. Prost Leuk Ess F A 1987

Membrane Phospholipids

Arachidonic Acid

15S-HETE LX

LTA4 PGG2

LTB4 LTC4

LTD4

LTE4

PGE2PGI2

PGD2

PGF2αααα

Pro-inflammatory Anti-inflammatory

LTC4 synthaseLTA4 hydrolase

Phospholipase A2

CysLT1

receptor antagonists

5-LO/FLAP inhibitors

Aspirin/NSAIDs COX-2 inhibitors

5-LO/FLAP5-LO

COX-1

COX-2

Sun Ying et al AI 2004;53:111

Outline of eicosanoid metabolism

EX

LTC4 synthase

Hens G and Hellings P, Allergy, 2008

13.08+1.1915.58+1.6013.05+1.4515.36+1.7712.40+0.82VEGF

2.75+0.4011.91+4.983.56+0.6512.29+6.7212.97+3.90G-CSFGrowth factors

3.55+0.855.34+0.942.88+0.594.99+0.864.37+0.78MCP-1

39.59+24.7155.13+24.7310.91+2.1399.14+69.4471.93+33.24MIG

42.55+17.1940.85+11.9027.37+5.7060.73+32.9557.33+13.78IP10

1.56+0.372.85+0.481.11+0.252.33+0.372.09+0.27Eotaxin

79.94+23.92103.0+24.8361.72+9.0883.35+20.7870.58+12.70IL-8Chemokines

Below detection limit in nearly all samplesTNF

1.04+0.401.74+0.760.59+0.083.27+2.461.23+0.34IL-1Pro-inflammatorycytokines

0.17+0.040.38+0.080.10+0.030.21+0.050.25+0.05IFN-Th1

Below detection limit in nearly all samplesIL-5Th2

ControlsPatientsControlsNon-allergicpatients

Allergic patients

COPDASTHMA

γ

β

Rhinitis and COPD

Limited information !

Up to 88% of patients with COPD experience nasal symptomsUri N et al., J Laryngol Otol, 2002

Correlation between nasal symptoms and impairment of QOLHurst J et al., Respir Med, 2004

Involvement of upper airways in COPDHens G et al., Allergy, 2008

Hurst, J. R. et al. Chest 2005;127:1219-1226

Relationship between IL-8 concentration in paired nasal wash fluid and sputum samples from 47 patients with COPD (r = 0.30; p = 0.039)

CRS & BronchiectasisCRS & BronchiectasisComorbiditiesComorbidities

BRONCHIECTASISBRONCHIECTASIS(n=85)(n=85)

with NPwith NP

26%26%

without NPwithout NP

55%55%

with CRS

81%

without CRS

19%

Guilemany et al. Guilemany et al. Respir MedRespir Med 20062006

Guilemany et al. Guilemany et al. AllergyAllergy 2008 2008

RHINITIS

allergic vs non-allergic

ASTHMA COPD

RHINOSINUSITIS

with NP / without NP

UPPER LOWER AIRWAYS AIRWAYS

� Allergic rhinitis

� NARES

� CRS &Nasal polyps

� AFS

� CRS

� Rhinitis

� Allergic asthma

� Intrinsic asthma

� Intrinsic Asthma

� ABPA

� ?panbronchiolitis/bronchiectasis

� COPD

IMPLICATIONS

• Whole airway should be considered – even by chest physicians and ENT surgeons

...who might like to work together

• URT is easily available for investigation: challenge, sampling- see soon Diagnostic tools in Rhinology an EAACI Task Force document

...and for therapy INCLUDING ASTHMA PREVENTION

• United pathways /guidelines- a start has been made.....

Children with asthma and rhinitis/ rhinosinusitisRCPCH pathways UK 2010

ACKNOWLEDGEMENTS

Ideas and slides from

Peter Hellings Belgium

Peter Howarth, UK

Claus Bachert,Belgium

Further reading

Further marches: allergic and non-allergic

Scadding GK,CEA 2007.

Airways disease:just nosing around

ScaddingGK & Kariyawasam H Thorax 2009