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Allergy Phenotypes - Rhinitis

Carmen Rondón, MD PhDAllergy Unit, Regional University Hospital

Málaga, Spain



Rhinitis a Complex SyndromeMultifactorial Etiology

ENDOTYPES

CLINICAL

PRESENTATION

EVOLUTION

COMORBIDITIES

TREATMENT

PHENOTYPES

GENOTYPE

CLINICAL MANAGEMENT

Rondon C. JIACI 2012



European Academy of Allergy and Clinical Immunology

PRACTALL 2014: Phenotypes and Edotypes of Rhinitis

TASK FORCE (ENT SECTION) 2014: Phenotype of NAR

Under elaboration

Under elaboration



ALLERGIC

rhinitis

INFECTIOUS

rhinitisMIXED

rhinitis

Rhinitis Phenotypes Phenotypes can be dynamic and overlap or may

develop into one another

Different endotype may share a same phenotype

Papadopoulos NG, et al. PRACTALL Phenotypes and Endotypes of rhinitis 2014 (under elaboration)Hellings PW, et al. Non-Allergic Rhintiis: Position paper of the EAACI (under elaboration)



ALLERGIC RHINITIS

PHENOTYPES

Rhinitis Phenotypes Phenotypes can be dynamic and overlap or may

develop into one another

Different endotype may share a same phenotype

Papadopoulos NG, et al. PRACTALL Phenotypes and Endotypes of rhinitis 2014 (under elaboration)Hellings PW, et al. Non-Allergic Rhintiis: Position paper of the EAACI (under elaboration)

Phenotypes

Endotypes

Differential diagnose

Treatment



Rhinitis Phenotypes

SEVERITY

MILD

MODERATE

SEVERE

SCUAD

DURATION

PERSISTENT

INTERMITTENT

ACUTE

CHRONIC

TEMPORAL

SEASONAL

PERENNIAL

OCCUPATIONAL

SYMPTOMS

“RUNNERS”

“BLOCKERS”

CONTROL

CONTROLLED

UNCONTROLLED

TREATMENT

“RESDONDERS”

“NON RESPONDERS”

Papadopoulos NG, et al. PRACTALL Phenotypes and Endotypes of rhinitis 2014 (under elaboration)



Nasal Hyperreactivity

Staevska M, N Baraniuk. C u r r A l l e r g y A s t h m a R ep 2005

Salib RJ, et al. C l i n E x p A l l e r g y 2008

• Chemical irritants:

• Physical irritants:

Tobacco smoke

Pollutants: smog, diesel, SO2, NO2, CO, CO2

Strong smells: perfumes, bleach, solvents

Intense lightCold dry air: VR1 vanilloid receptor

Hyperosmotic: pollen – osmoreceptors

Temperature and humidity changes

ALLERGIC

rhinitis

INFECTIOU

S rhinitisMIXED

rhinitis

NOT EXCLUSIVE ONLY IDIOPATHIC RHINITIS



Infectious rhinitis

• Etiology:

– Viral Rhinitis (Common cold): acute and self-limiting

– Bacterial Rhinosinusitis

– Fungal Rhinosinusitis

• Symptoms: – Discolored rhinorrea

– Crust formation

•Duration of the disease: – Acute (ARS)

• < 12 weeks and Complete resolution

– Chronic (CRS):• ≥ 12 weeks and No complete resolution

Papadopoulos NG, et al. PRACTALL Phenotypes and Endotypes of rhinitis 2014 (under elaboration)



Allergic rhinitis

• Global health problem

•

Affecting 400 million persons• Countries, ethnic groups, ages

• Impairment of quality of life

• Frequent co-morbidities

•

Risk factor for development of asthma



ARIA Classification

Bousquet J, et al. ARIA update 2008. Allergy 2008: 63 (Suppl. 86): 8 –160

Time of exposure

• Seasonal

• Perennial

• Occupational AR

Allergic rhinitis phenotypes



Nasal localizedallergic response

Absence of

Systemic Atopy

Rondón C, et al.J Allergy Clin Immunol. 2012

Clinical symptoms

suggestive of AR



•Th2 helper inflammatory patternPowe DG. Clin Exp Allery, 2001

Powe DG. Allergy, 2004

Rondón C. J Allergy Clin Immunol 2007

Rondón C. Allergy 2008

• Nasal production of sIgEHuggins KG. J. Lancet, 1975

Rondón C. J Allergy Clin Immunol, 2007

Rondón C. Allergy, 2008

Fuiano N, et al. Allergol Immunopathol 2012

Reisacher WR, et al. Int Forum Allergy Rhinol 2014

• Positive response to NAPT

Carney AS. Clin Exp Allergy, 2002Wedbäck A. Rhinology, 2005


Rondón C. Allergy 2008


López S. Clin Exp Allergy, 2010

Rondón C, AAAAI 2011

SymptomsRhinomanometry

Acoustic Rhinometry

Inflammatory Mediators and sIgE

Cytokines (IFN-g, IL-1b, IL-2, IL-4, IL-6,IL-8, IL-12p70)

Immunological characteristics



persistence

91%

9,1

persistent

intermittent

severity

5%

36%

59%

mild

moderate

severe

Local Allergic Rhinitis

Rondón C, et al. Allergy 2012

110 LAR patients



SAR(n=270) LAR(n=110) NAR(n=48)

Age 18 ys 21 ys 36 ys (a,b)

Woman 57.8% 78.2% 52.1% (a,b)

Family history of atopy 37.4% 44.5% 20.8%

Rhinitis

Persistence

Seasonality

Severity

persistent

seasonal/perennial

severe 59%

persistent

perennial

severe 56%

persistent

perennial

moderate 57%

Nasal symptoms

Frequently

Severe

itching, sneezing and

watery rhinorrea

watery rhinorrea

itching, sneezing and

watery rhinorrea

watery rhinorrea

obstruction and

rmucous rhinorrea

obstruction

Triggering factors house dust

pollen

house dust

pollen

chemical irritants

air conditioning

Comorbidities

Asthma

Conjunctivitis

Atopic dermatitis

39%

62%

11%

31%

65%

8%

19%

50%

0%

Onset childhood 38% 36% 9%

(a,b)

Rondón C, et al. Allergy 2012

Demographic-clinical phenotype

a: NAR vs SAR p<0.05; b: NAR vs LAR p<0.05



ARIA Treatment Strategy

Bousquet J, et al. ARIA update 2008. Allergy 2008: 63 (Suppl. 86): 8 –160

ALLERGIC RHINITIS



Allergen Immunotherapy

• Immune-modifying and etiologictreatment

• Safe and effective

• Symptom improvement and/or reduction

of the use of rescues medication• Long-lasting effect once discontinued

• Modify disease evolution

– Prevention of the onset of new skinsensitizations

– Prevention of the onset of asthma (?)

• Improvement of the quality of life

Alvarez-Cuesta E. Clin Exp Allergy 2005Pfaar O. Allergy 2014

Bousquet J. Allergy 1998Walker SM, JACI 2001



Allergen Immunotherapy

• Immune-modifying and etiologictreatment

• Safe and effective

• Symptom improvement and/or reduction

of the use of rescues medication• Long-lasting effect once discontinued

• Modify disease evolution

– Prevention of the onset of new skinsensitizations

– Prevention of the onset of asthma (?)

• Improvement of the quality of life

Alvarez-Cuesta E. Clin Exp Allergy 2005Pfaar O. Allergy 2014

Bousquet J. Allergy 1998Walker SM, JACI 2001

Could LAR patients benefit from specific

Immunotherapy? …?



Study Design: Pilot observational study in real condition

Study Groups:20 adult LAR-grass:

Immunotherapy: Aluminium-adsorbed grass mix pollen extract

Study duration: One year : 6 months of preseasonal SCIT

Rondón C, JACI 2011

LAR: Allergen tolerance and immunologic

changes after preseasonal SCIT- grass pollen

SCIT group (N:10) = SCIT (6 months) + RM spring

Control group (N:10) = RM spring



Rondón C et al., JACI 2011

Immunotherapy in LAR6 month of preseasonal grass-SCIT

Increase of tolerance 100%

NAPT Neativization 30%



DBPC Clinical Trials (Phase 2 )

1. Subcutaneous Immunotherapy with Dermatophagoides Pteronyssinus in

local allergic rhinitis (ECRL1). EucraCT:2008-003680-39.

NCT02123316.Completed 30-04-2014. Under analysis

2. Efficacy of a Depigmented extract of Phleum in local allergic rhinitis

(GRAMAL). EudraCT:2010-020949-26. On going

Efficacy of ITA in LAR



Subcutaneous Immunotherapy with

Dermatophagoides Pteronyssinus in LAR

(ECRL1 Study)

ECRL1 sutdy. NCT02123316

Study Type Interventional

Study Design: Treatment, parallel assignment, randomized, double-

blind, placebo-controled, safety/efficacy study

Enrolment: 36 LAR patients

Duration: 24 months

Arms: Active = Pangramin Plus® D. pteronyssinus 100%

Placebo = Placebo

Rescue medication

(both arms):

Oral antihistamines

Intranasal corticosteroids

Oral corticosteroids



PRELIMINARY RESULTS

Subjects, N (%)

recruited

withdrawn

completed

36 (100%)

8 (22.2%)

28 (77.8%)

Gender, N (%)

menwomen

9 (25)27 (75)

Age, mean (SD) 39 (4.8)

Characteristics of the subjects


ALL SUBJECTS RECRUITED (N=36)



0

0.51

1.52

2.53

3.54

4.55

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Active Group

Basal 24 months

Nasal allergen provocation test with DP

Negative

Improvement

Negative

Increase of tolerance

12/18 (67%)

9/18 (50%)

3/18 (17%)

No ImprovementNo changes

Decrease of tolerance

6/18 (33%)4/18 (22%)

2/18 (11%)

00.5

11.5

22.5

33.5

44.5

5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Placebo Group

Basal 24 months

Negative

Improvement

Negative

Increase of tolerance

1/18 (6%)

0/18 (0%)

1/18 (6%)

No Improvement

No changes

Decrease of tolerance

17/18 (94%)

11/18 (61%)

6/18 (33%)

2 3 6 8 9 11 15 16 19 20 23 24 25 27 29 32 33 35

1 2 4 5 7 10 12 13 14 17 18 21 22 26 28 30 31

34


67 %

6 %

33 %

50 %

94 %



RHINITIS MANAGEMENT

ALLERGICNON ALLERGIC

Patient Education

Avoidance MeasuresSpecific

Immunotherapy

Pharmacotherapy

NO



RHINITIS

ALLERGICNON-ALLERGIC

SymptomsSPT

sIgEYES NO

NOT

SUFFICIENTLAR



• Diagnosis

• Immunologic mechanism

• Clinical and immunological response to AIT

Nasal allergen provocation test in LAR

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Important health problem

Prevalence 23-70% adults – 19 millions USA

– > 200 millions worldwide

Heterogenoeus group: different phenotypes and endotypes

Molgaard E. Allergy 2007; 62:1033-7

GA2LEN Review Allergy 2008;63:842-853Rondón C. JACI 2009;123:1098-1102

Non infectious, Non-Allergic Rhinitis

Idiopathic rhinitis

NARES

Non-allergic occupational rhinitis

Senile rhinitis

Drug-induced rhinitis

Hormonal rhinitis

Gustatory rhinitis

Inflammatory

Neurologic

Idiopathic

ENDOTYPESPHENOTYPES



• It is the most prevalent NAR phenotype (50-70%)

•Unknown aetiology

• Diagnosis by exclusion

• A better definition of endotypes and biomarkers is required

• Endotypes:

- Neurogenic: NANC or peptidergic disorder, nociceptive

TRPV1- SP signaling pathway upregulated

- Inflammatory: controversial

Idiopathic rhinitisNeurogenic endotye



Mucosal/glandular atrophy and/or MO

Non-allergic Senile rhinitis

(>65 y)

Gustatory rhinitis

Non-allergic Occupational

rhinitis

Hormonal-induced rhinitis

Non-allergic Drug-induced

rhinitis

Idiopathic rhinitis

NAR Phenotypes

Pathophysiology

Treatment

Neurogenic inflammation

Neuronal imbalance

Neurogenic inflammation and/or MO

MO = mechanislm unknown

Ipratropium bromide

AvoidanceNasal capsaicin

Avoidance

Nasal corticosteroids

Nasal cromones ?

Avoidance

Nasal corticosteroids

Nasal capsaicin

Neuronal imbalance

Neurogenic inflammation

Hellings PW, et al. Non-Allergic Rhintiis: Position paper of the EAACI (under elaboration)

NAR Treatment strategy



Miriam Osorio

Microarrays

Technician

Raquel Jerez

SecretaryLuisa Galindo

ATS

Veronique Godenau

Molecular Biology

Technician

Mª Jose Torres

Clinical coordination

Lina Mayorga

Research

coordination

Miguel Blanca

Group Leader

Mª Isabel Montañez

Dendrimers

Paloma Campo

Asthma and

Rhinitis

Carmen Rondon

Rhinology

Francisca Gomez

Food allergy

Inmaculada Doña

Drug allergy

Enrique Gomez

T cells

Tahia Fernandez

B cells

Jose A Cornejo

Molecular Genetics

Pedro Ayuso

Molecular genetics

Ana Aranda

Microarrays

Adriana Ariza

Humoral Allergy

Mª Carmen Plaza

Molecular Genetics

Mª Luisa Macías

Microarrays

Lidia Menendez

Cytometry

Technician

Xavier Leguevel

Nanoparticles

Allergy Research Group, Regional University Hospital of Malaga

Miguel Gonzalez

Humoral Allergy

María Salas

Drug allergy



!

“Clinical Cases in Allergic R hinitis and Asthma”

28-31 August, 2014 - Malaga-Spain

HOTEL SOL PRINCIPE

www.c2ar.org

Carmen Rondon Spain

Cemal Cingi Turkey

Michael Rudenko Great BritainMiguel Blanca Spain

Paloma Campo Spain

Peter Hellings Belgium

Philippe Gevaert Belgium

Philippe Rombaux Belgium

Ralph Mösges Germany

Co Chairs: Carmen Rondon - Cemal Cingi

Preliminary Speakers



• Nasal mucosa 1er line of contact Immunological System and Allergens

• IgE medated nasal inflammatory with inflitation of Th2 lymphocytes,

basophils, mast cells, dendritic cells and eosinophils

• Local synthesis of IgE: Higher proportion of B cells and plasma cells in

nasal mucosa than in serum

Allergic response in nasal mucosa

Allergicrhinitis

B cells Plasmacells

Nasl

mucosa1 / 25 1 / 15

Serum 1/10.000 1/10.000

KleinJan A Eur Respir J 2000

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