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

ALLERGICrhinitis

INFECTIOUSrhinitisMIXED

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 RHINITISPHENOTYPES

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)

PhenotypesEndotypesDifferential diagnoseTreatment

Rhinitis Phenotypes

SEVERITY

MILD MODERATESEVERESCUAD

DURATION

PERSISTENTINTERMITTENT

ACUTECHRONIC

TEMPORAL

SEASONALPERENNIALOCCUPATIONAL

SYMPTOMS

“RUNNERS”“BLOCKERS”

CONTROL

CONTROLLEDUNCONTROLLED

TREATMENT

“RESDONDERS”“NON RESPONDERS”

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

Nasal Hyperreactivity

Staevska M, N Baraniuk. Curr Allergy Asthma Rep 2005

Salib RJ, et al. Clin Exp Allergy 2008

• Chemical irritants:

• Physical irritants:

Tobacco smoke Pollutants: smog, diesel, SO2, NO2, CO, CO2Strong smells: perfumes, bleach, solvents

Intense lightCold dry air: VR1 vanilloid receptorHyperosmotic: pollen – osmoreceptorsTemperature and humidity changes

ALLERGICrhinitis

INFECTIOUS rhinitis

MIXEDrhinitis

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 localized allergic 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, 2001Powe DG. Allergy, 2004Rondón C. J Allergy Clin Immunol 2007Rondón C. Allergy 2008

• Nasal production of sIgEHuggins KG. J. Lancet, 1975Rondón C. J Allergy Clin Immunol, 2007Rondón C. Allergy, 2008Fuiano N, et al. Allergol Immunopathol 2012Reisacher WR, et al. Int Forum Allergy Rhinol 2014

• Positive response to NAPTCarney AS. Clin Exp Allergy, 2002Wedbäck A. Rhinology, 2005Rondón C. J Allergy Clin Immunol, 2007Rondón C. Allergy 2008

Rondón C. J Allergy Clin Immunol, 2009López S. Clin Exp Allergy, 2010

Rondón C, AAAAI 2011

Symptoms

Rhinomanometry

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 etiologic treatment

• 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 skin

sensitizations

– 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 etiologic treatment

• 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 skin

sensitizations

– 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 immunologicchanges after preseasonal SCIT- grass pollen

SCIT group (N:10) = SCIT (6 months) + RM springControl 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 antihistaminesIntranasal corticosteroidsOral corticosteroids

PRELIMINARY RESULTS

Subjects, N (%) recruited withdrawncompleted

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

ECRL1 sutdy. NCT02123316

ALL SUBJECTS RECRUITED (N=36)

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

Active Group

Basal 24 months

Nasal allergen provocation test with DP

Negative

ImprovementNegativeIncrease of tolerance

12/18 (67%)9/18 (50%)3/18 (17%)

No ImprovementNo changesDecrease 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

ImprovementNegativeIncrease of tolerance

1/18 (6%)0/18 (0%)1/18 (6%)

No ImprovementNo changesDecrease 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

ECRL1 sutdy. NCT02123316

67 %

6 %

33 %

50 %

94 %

RHINITIS MANAGEMENT

ALLERGICNON ALLERGIC

Patient Education

Avoidance MeasuresSpecific

ImmunotherapyPharmacotherapy

NO

RHINITIS

ALLERGICNON-ALLERGIC

SymptomsSPTsIgEYES NO

NOTSUFFICIENTLAR

• Diagnosis

• Immunologic mechanism

• Clinical and immunological response to AIT

Nasal allergen provocation test in LAR

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;63:842-853

Rondón C. JACI 2009;123:1098-1102

Non infectious, Non-Allergic Rhinitis

Idiopathic rhinitisNARESNon-allergic occupational rhinitisSenile rhinitisDrug-induced rhinitisHormonal rhinitisGustatory rhinitis

InflammatoryNeurologicIdiopathic

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, nociceptiveTRPV1- SP signaling pathway upregulated- Inflammatory: controversial

Idiopathic rhinitisNeurogenic endotye

Mucosal/glandular atrophy and/or MONon-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 corticosteroidsNasal cromones ?

Avoidance

Nasal corticosteroidsNasal 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 JerezSecretary

Luisa GalindoATS

Veronique Godenau Molecular Biology

Technician

Mª Jose TorresClinical coordination

Lina MayorgaResearch

coordination

Miguel BlancaGroup Leader

Mª Isabel MontañezDendrimers

Paloma CampoAsthma and

Rhinitis

Carmen RondonRhinology

Francisca Gomez Food allergy

Inmaculada DoñaDrug allergy

Enrique GomezT cells

Tahia FernandezB cells

Jose A CornejoMolecular Genetics

Pedro AyusoMolecular genetics

Ana ArandaMicroarrays

Adriana ArizaHumoral Allergy

Mª Carmen PlazaMolecular Genetics

Mª Luisa MacíasMicroarrays

Lidia MenendezCytometry Technician

Xavier LeguevelNanoparticles

Allergy Research Group, Regional University Hospital of Malaga

Miguel GonzalezHumoral Allergy

María Salas Drug allergy

!

“Clinical Cases in Allergic Rhinitis and Asthma”

28-31 August, 2014 - Malaga-Spain

HOTEL SOL PRINCIPE

!Dear!colleagues,!!!It!is!our!great!pleasure!to!invite!you!to!the!1st!Symposium!of!Clinical!Cases!in!Allergic!Rhinitis!and!Asthma!in!Malaga,!Spain,!from!28th%to%31st%of%August!2014.!!There!are!so!many!interesting!meetings!in!allergy!and!asthma!field,!which!are!mostly!related!with!immunology!and!basic!research.!But!this!meeting!has!intended!to!have!less!basic!research!but!more!clinical!and!pragmatic!information!in!order!to!participate!interdisciplinary!teamwork!between!ENT,!pulmonology,!allergy!and!family!practitioners!on!allergic!rhinitis,!asthma!and!comorbidities.!!Every!effort!will!be!made!to!set!an!outstanding!meeting!that!will!be!a!truly!integrated!combination!of!real!case!timelines!with!physiologic!and!clinical!comments!and!case!questions!beside!panels!and!free!papers.!

An!exceptional!faculty,!program,!and!conference!venue!waits.!We!look!forward!to!welcoming!you!at!1st!Symposium!of!Clinical!cases!in!allergic!rhinitis!and!asthma!!

CoLChairs:!Carmen!Rondon!L!Cemal!Cingi!!

Preliminary!Speakers!

Cezmi!Akdis!! ! ! ! Switzerland!Peter!Hellings!!! ! ! Belgium!!Cemal!Cingi! ! ! ! Turkey!Philippe!Gevaert!! ! ! Belgium!Ralph!Mösges!! ! ! ! Germany!Nuray!Bayar!Muluk!! ! ! Turkey!Carmen!Rondon!! ! ! Spain!Michael!Rudenko!! ! ! Great!Britain!!!!!!!

www.c2ar.org

Carmen Rondon SpainCemal Cingi TurkeyMichael Rudenko Great BritainMiguel Blanca SpainPaloma Campo SpainPeter Hellings BelgiumPhilippe Gevaert BelgiumPhilippe Rombaux BelgiumRalph 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

Allergic

rhinitisB cells

Plasma

cells

Nasl

mucosa1 / 25 1 / 15

Serum 1/10.000 1/10.000

KleinJan A. Eur.Respir.J. 2000

King CL J.Immunol.Methods 1990