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Phenotyping the patient with Rhinitis and Asthma
Sergio Bonini Guido RasiProfessor of Medicine Professor of MicrobiologySecond University of Naples University Tor Vergata, RomeIFT-CNR, Rome General Director AIFA
Modena March 1, 2011
From EBM to EBM
Approach Target ProductExperienceBased Empirical Individual TextbooksMedicine
EvidenceBased RCT Population GuidelinesMedicine
Evidence of superiority does not mean it works for all
Drug Comparator
P < 0.05Outcome
Threshold of clinical relevance
Sublingual immunotherapy for hazelnut food allergy: A randomized, double-blind, placebo-controlled study with a standardized hazelnut extract
Enrique E et al. JACI 2005
BEFORE AFTER
SLIT (n= 14) PLACEBO (n= 12)
6
30
24
18
12
BEFORE AFTER
6
30
24
18
12
0.02
0.014NS
Larj, M. J. et al. Chest 2004;126:138S-149S
Distribution of FEV1 response in 895 asthmatic patients aged 15 to 85 years treated with either beclomethasone or
montelukast for 12 weeks
Reasons for different responses to drugs in patients with rhinitis and/or asthma
Different genotypes
• Beta-2 agonists (ADRB2, ARG1)
• Anti-leucotrienies (ALOX5, MRP1, LTC4S,CYSLTR1,2)
• Corticosteroids (CRHHR1, NR3CI, STIP1)
Different phenotypes
• Age, race, gender
• Duration of the disease
• Co-morbidities
Phenotype-targeted therapy (PTT)
An individualized/mass treatment, a compromise between EBM and a more patient-tailored approach, made actual and accepted from the industry by the increasing trend of regulatory bodies to “pay per response”
No. of papers
383
710
120
Accessed, February 2010
Approaches used to define phenotypes
Pre-defined• Resulting from a classificatory dissection of the
disease or from demographic features of patients• Endotypes
Experimental• Resulting from drug response in RCT• Factor analysis • Cluster analysis
Requirements for defining a phenotype
• Well-established genetic, biological, functional or clinical markers
• Epidemiologically defined
Approaches used to define phenotypes
Pre-defined• Resulting from a classificatory dissection of the
disease or from demographic features of patients• Endotypes
Experimental• Resulting from drug response in RCT• Factor analysis • Cluster analysis
Phenotyping of Rhinitis
Infectious Rhinitis
Viral
Bacterial
Parasitic
Non infectiousRhinitis
AllergicIgE-mediated
AllergicNon IgE-mediated
Non allergic
Asthma Phenotypes• Age (adult, children)• Time of onset (early, late)• Triggers (allergic, occupational, ASA, menses, exercise)• Co-morbidities (Obesity, GER)• Pathology (eosinophilic., neutrophilic, pauci-granulocytic)• Severity (exacerbation-prone, with chronic airflow obstruction, severe)
Eosinophilic
corticosteroid responsiveExcercise-induced
Allergic
Fixedobstruction
Severe
Exacerbation-prone
Allergic
Occupat
ional
Non-allergic
Aspirin-sensitive
Eosinophilic corticosteroid responsive
PMA
Severe
Early/childhood onset phenotypes
Late/adult onsetphenotypes
Approaches used to define phenotypes
Pre-defined• Resulting from a classificatory dissection of the
disease or from demographic features of patients• Endotypes
Experimental• Resulting from drug response in RCT• Factor analysis • Cluster analysis
PRACTALL Endotypes
1. Aspirine sensitive asthma
2. Allergic bronchopulmonary mycosis
3. Allergic asthma (adults)
4. Pre-school weezers at high risk for asthma
5. Severe late-onset eosinophilic
6. Asthma in country-skiers
Lotvall J et al. J Allergy Clin Immunol 2011,127:355-360
Hallmarks of allergic diseases
• Specific IgE response
• Allergic inflammation (high total IgE, eosinophils, mast cells and basophils, etc.)
• Hyperreactivity of target organs (lung, nose, skin, eye)
HLA genes and allergen exposure
Genetic and environmental influences on inflammatory genes overexpression
Neural and tissue factor (?)
Cytokines
Enhanced specific IgE response High total IgE Upregulation of inflammatory cells
Increased number Eosinophilic and releasability of NeutrophilicMC and basophils
Tissue hyperreactivity
I II III IV V
Allergic ASA intolerance , Pollutants, Hormones EIA,GER, Stress
Clinical phenotypes
The Spectrum of Allergic DiseaseBonini S, Rasi G et al. Ann Allergy Asthma Immunoll 2001;87 Suppl.3:48-51
INFLAMMATION
How to distinguish differentallergy phenotypes?
• Markers of sensitization
• Markers of inflammation
• Markers of tissue hyperreactivity
• Skin tests, IgE tests
• Total IgE• Eosinophil and eosinophil
products• Th2 profile
• Non specific provocation tests• New markers?
Asthma
Rhinitis
Conjunctivitis
Type I Late-phase IgE Eos/Neutrophilic TargetHypersensitivity dependent inflammation organ
inflammation without sIgE hyperreactivity
Hyposensitisation Topical steroids ß2 agonists Antihistamines Antileukotrienes Anticolinergics
Pollenosis SCUAD EIB , CR
Approaches used to define phenotypes
Pre-defined• Resulting from a classificatory dissection of the
disease or from demographic features of patients• Endotypes
Experimental• Resulting from drug response in RCT• Factor analysis • Cluster analysis
Phenotypes resulting from drug response in RCT
Population Intervention Outcome Analysis
Responders Unselected RCT Phenotyping Non-responders
Sub-group analysis should be defined in advance, and notresulting from the most favorable post-hoc analysis
WHO Classification of severe asthma
• Untreated
• Difficult-to-treat
• Treatment resistant– Uncontrolled (Refractory, Corticoid-resistant)– Controlled with the highest level of treatment
Bousquet J et al. J Allergy Clin Immunol 2010;126:926-938
Approaches used to define phenotypes
Pre-defined• Resulting from a classificatory dissection of the
disease or from demographic features of patients• Endotypes
Experimental• Resulting from drug response in RCT• Factor analysis • Cluster analysis
GAIN PhenotypesFactor analysis
1. FEV1 and FVC
2. SPT sensitization
3. Self-reported allergies
4. Rhinitis symptoms
5. Asthma symptoms
Pillon SG et al. Clin exp Allergy 2008,38:421-429
Approaches used to define phenotypes
Pre-defined• Resulting from a classificatory dissection of the
disease or from demographic features of patients• Endotypes
Experimental• Resulting from drug response in RCT• Factor analysis • Cluster analysis
SARP PhenotypesCluster Analysis
1. Early-onset atopic asthma, mild 15%2. Early-onset atopic asthma, moderate 44%3. Obese women, late-onset, non atopic 8%4. Severe airflow obstruction* 16.5%5. Severe airflow obstruction* 16.5%
* Differing for lung function, age of onset, atopic status, response to steroids
Moore WC et al. AJRCCM 2010,181:315-
323
Summary
INFLAMMATION PREDOMINANT Late onset
Greater proportion of malesFew daily symptoms
Concordant disease
Discordant Inflammation
Discordant Symptoms
OBESE FEMALE NON EOSINOPHILIC
High symptom expression
EARLY SYMPTOM PREDOMINANTNon-eosinophilic
Normal BMIHigh symptom expression
EARLY ONSET ATOPIC
Concordant symptoms, in
flammation & airw
ay dysfunction
BENIGN ASTHMAMixed middle aged cohort
Few symptomsNo airway inflammationLittle airway dysfunction
Primary Care Asthma Refractory AsthmaS
ymp
tom
s
Haldar et al, AJRCCM 2008:178:218
Sym
ptom
s
Eosinophilic Inflammation
From E. Bel Auffray et al. Genome Med 2009;1:2
Patient reported
Clinical
Functional
Cellular
Molecular
Future of phenotyping: ‘Systems Medicine’
The usefulness of phenotyping the patient with asthma and/or rhinitis
Conclusions
• Phenotyping of asthma and rhinitis represents a step forward vs guidelines, since it reduces the heterogeneity of these diseases and the variable response to drugs in individual patients
• Phenotyping of asthma and rhinitis is at present not satisfactory. Phenotyping should be based on well defined clinical criteria and biomarkers relevant to the disease course, severity and response to therapy
• Phenotyping is essential in future clinical trials of existing and new treatments of asthma and rhinitis, in order to document their effectiveness (and not only their efficacy!)