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7/26/2019 2_Rhinitis - Carmen Rondon
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Allergy Phenotypes - Rhinitis
Carmen Rondón, MD PhDAllergy Unit, Regional University Hospital
Málaga, Spain
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Rhinitis a Complex SyndromeMultifactorial Etiology
ENDOTYPES
CLINICAL
PRESENTATION
EVOLUTION
COMORBIDITIES
TREATMENT
PHENOTYPES
GENOTYPE
CLINICAL MANAGEMENT
Rondon C. JIACI 2012
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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
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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)
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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
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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)
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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
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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)
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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
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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
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Nasal localizedallergic response
Absence of
Systemic Atopy
Rondón C, et al.J Allergy Clin Immunol. 2012
Clinical symptoms
suggestive of AR
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•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. J Allergy Clin Immunol, 2007
Rondón C. Allergy 2008
Rondón C. J Allergy Clin Immunol, 2009
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
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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
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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
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ARIA Treatment Strategy
Bousquet J, et al. ARIA update 2008. Allergy 2008: 63 (Suppl. 86): 8 –160
ALLERGIC RHINITIS
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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
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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? …?
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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
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Rondón C et al., JACI 2011
Immunotherapy in LAR6 month of preseasonal grass-SCIT
Increase of tolerance 100%
NAPT Neativization 30%
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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
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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
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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
ECRL1 sutdy. NCT02123316
ALL SUBJECTS RECRUITED (N=36)
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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
ECRL1 sutdy. NCT02123316
67 %
6 %
33 %
50 %
94 %
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RHINITIS MANAGEMENT
ALLERGICNON ALLERGIC
Patient Education
Avoidance MeasuresSpecific
Immunotherapy
Pharmacotherapy
NO
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RHINITIS
ALLERGICNON-ALLERGIC
SymptomsSPT
sIgEYES NO
NOT
SUFFICIENTLAR
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• 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
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• 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
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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
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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
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!
“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
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• 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