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ASMA GRAVE E ACOS
NEL DOCUMENTO GINA 2014
Pierluigi Paggiaro
GINA International Executive Committee, Chairman GINA ITaly
Cardio-Thoracic and Vascular Department, University of Pisa
Università degli
Studi di Pisa
Azienda
Ospedaliera
Pisana
1° Convegno Pneumologia 2.0
Firenze Villa Castiglione, 8-10 maggio 2014
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Bronchial Asthma heterogeneity in clinical presentation
• Large difference in clinical manifestations, related to:
–Severity of the disease
–Heterogeneity of inducers and/or triggers
– Level of adherence to therapeutical plan
• Existance of different phenotypes
–Clinical and functional
–Biological
• Difference in:
–Strategy of asthma treatment
–Strategy in asthma management
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A new definition of asthma: a heterogeneous disease
GINA 2014, draft
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Main objectives in asthma treatment: control vs future risk
ATS Statement, AJRCCM 2009
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Symptom control vs future risk
GINA 2014, draft
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Bronchial Asthma heterogeneity in clinical presentation
• Large difference in clinical manifestations, related to:
–Severity of the disease
–Heterogeneity of inducers and/or triggers
– Level of adherence to therapeutical plan
• Existance of different phenotypes
–Clinical and functional
–Biological
• Difference in:
–Strategy of asthma treatment
–Strategy in asthma management
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Bronchial Asthma examples of special cases
• According to severity
– Mild-moderate vs severe («difficult to treat»)
– Frequent exacerbators vs chronic airway obstruction
• According to comorbidities or concominat situations:
– Obesity
– Pregnancy
• According to risk factors:
– Smoking habit
– Occupational sensitizers
• According to biological mechanisms:
– Non eosinophilic asthma
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Different asthma phenotypes
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Clinical asthma phenotypes Severity
• Assessment of severity
– Intensity and frequency of symptoms
– Level of treatment needed to control asthma
• Severity (first examination) vs control (under treatment)
– Large variability in moving from different levels of severity or control
• Implication for treatment
– Only for «difficult-to-treat» asthma
– «Steroid-resistant» asthma: biologic basis (?)
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Bousquet et al, JACI 2010
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Asthma control in severe asthmatic patients
68.8% of patients had at least one exacerbation in the last year
Novelli et al, ERS 2013
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Prevalence of comorbidities
Novelli et al, ERS 2013
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Chronic rhinosinusitis with nasal polyps
Nasal polyps
(N=21)
No nasal polyps
(N=43)
Pre-BD FEV1, % 71.0±17.5 * 81.1±17.7
Sputum eosinophils, % 22.3 (0.4-95.6) 10.6 (0-84.1)
Sputum eosinophils ≥3% 89.5 * 63.9
ACT score 21 (10-24) 20 (7-25)
Poorly controlled, % 8 (38.1) 23 (53.5)
Exacerbation in the last year, % 66.7 69.8
AQLQ score 4.63 (2.69-6.56) 4.92 (3.03-6.75)
Novelli et al, ERS 2013
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Obesity
Obese
(N=22)
Normal weight
(N=42)
Pre-BD FEV1, % 77.7±23.5 77.9±14.8
Sputum eosinophils, % 8.3 (0-71.2) 17.4 (0-95.6)
Sputum eosinophils ≥3% 63.2 77.8
ACT 16.5 (7-25) * 21 (12-25)
Poorly controlled, % 72.7 * 35.7
Exacerbation in the last year, % 77.3 64.3
AQLQ score 4.47 (3.03-6.16) 5.31 (2.69-6.75)*
Novelli et al, ERS 2013
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GERD
GERD
(N=25)
No GERD
(N=39)
Pre-BD FEV1, % 77.4±16.5 78.1±19.3
Sputum eosinophils, % 14.9 (0-82.8) 15.8 (0-95.6)
Sputum eosinophils ≥3% 59.1 § 81.8
ACT 19 (7-25) 21 (10-25)
Poorly controlled, % 56.0 43.6
Exacerbation in the last year, % 76.0 64.1
AQLQ score 4.42 (2.69-6.16) * 5.28 (3.19-6.75)
No difference in prevalence of obesity beetween the two groups
Novelli et al, ERS 2013
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Predictors of poor control, lower lung function and eosinophilic phenotype
Poor control Lower lung function
(Post-BD
FEV1<80%)
Eosinophilic
phenotype
OR (CI 95%) OR (CI 95%) OR (CI 95%)
Obesity 5.3 (1.5-18.2) * 1.7 (0.6-5.3) 0.6 (0.2-1.9)
Nasal polyps 0.4 (0.1-1.5) 3.6 (1,2-11.3) * 5.5 (1.1-27.8) *
GERD 1.8 (0.6-5.8) 0.6 (0.2-1.8) 0.4 (0.1-1.5)
Novelli et al, ERS 2013
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Clinical asthma phenotypes Exacerbations vs FEV1 decline vs age of
onset
• Exacerbation-prone phenotype («frequent exacerbators»)
– 50% of severe and 30% of moderate asthmatics (SARP study)
– Related to risk factors
– Different susceptibility to viral infections ?
• Progressive decline in FEV1 («decliners»)
– 25% of mild-moderate asthmatics (CAMP study)
– Persistent airflow limitation in 60% of severe asthmatics (TENOR study)
– Risk factors: male, age, smoking, asthma duration, airway inflammation
– Genetic predisposition (ADAM33) (?)
• Age of onset
– Early-onset asthma: more atopic, lower severity (?)
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Different asthma phenotypes
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Asthma phenotypes according to triggers
• Allergens («allergic asthma»)
– Prevalent in children and in mild-moderate asthmatic adults
– Typical Th2-driven inflammation
– Target for Immunotherapy
• Occupational and environmental factors
– Up to 15% of asthma is related to occupation
– Work-related asthma: occupational asthma + work-aggravated asthma
• Exercise
– In children and elite athletes («exercise-induced bronchospasm»)
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Asthma phenotypes Smoke
• High risk for asthma developing
• Prevalence in asthmatics: 20% smokers
• Characteristics of asthma in smokers – Lower eosinophilic inflammation
– Lower response to ICS
– Greater FEV1 decline over time
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Current smokers with asthma have greater rate of exacerbations, despite
ICS or ICS/LABA treatment
Pedersen et al, JACI 2007
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Different asthma phenotypes
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Asthma phenoypes Eosinophilic vs non-eosinophilic asthma
• Eosinophilic phenotype – Allergen-induced asthma, children asthma
– Severe asthma with frequent exacerbations (CS-dependent asthma)
• Non eosinophilic phenotype – Specific “triggers” (pollutants, endotoxins, chemicals,
viruses)
– In all asthma severity levels
– Stable over time ?
– Lower response to ICS
different therapeutic strategies ?
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Different asthma phenotypes
Haldar et al, AJRCCM 2008
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Vagaggini et al., AJRCCM 2001
Acute ozone exposure in laboratory induces in mild-moderate asthmatics a prominent neutrophilic inflammatory response, which
is blunted by inhaled budesonide
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Asthma inflammatory phenotypes do not correlate with clinical
findings
Simpson et al, Respirology 2006
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Bacci et al, Chest 2006
Absence of sputum eosinophilia in corticosteroid”naive” asthmatics
predicts a poor short-term response to ICS
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Bacci et al, Respirology 2012
Steroid-naif symptomatic noneosinophilic asthma may remain stable over 6 months
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Asthma phenotypes Implications for treatment
• With current available drugs – High dose vs low dose ICS (non eosinophilic, smokers)
– Eosinophil-driven strategies
– LTRA (exercise asthma, aspirin-inuced asthma, asthma + rhinitis)
– Heterogeneity of the response also in unselected asthmatics
• With new therapeutic targets – Anti-IgE, anti-IL5, anti-IL13, …..
– Allergic and eosinophilic allergic asthmatics
• With new treatments (thermoplasty) – Severe uncontrolled patients (which phenotype ?)
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Green et al, Lancet 2002
The control of sputum eosinophilia is associated with a reduction in asthma exacerbations,
but only for eosinophilic exacerbations
Jayaram et al, ERJ 2006
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Italian multicentre observational study in patients under treatment with
Omalizumab
• 24 Italian pulmonary and allergology centres
• More than 300 patients under treatment
• Aims:
• Evaluation of the level of asthma control
(symptoms, pulmonary function, exacerbations)
• Factors related to poor asthma control
• Relationship «duration of treatment / level of
control»
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Control of asthma in severe asthmatics treated with omalizumab
Novelli et al, ERS 2013
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Asthma control in severe asthmatics treated with omalizumab
Poorly controlled Well-partially controlled
Number of patients 75 221
Age, yrs 53,4±13,5 51,5±13,9
Gender, M/F % 34,7/65,3 38/62
Smoke, Y/Ex/No % 4,0/25,3/70,7 3,6/28,1/67,4
Rhinitis, n (%) 51(68,9) 142(65,1)
Chronic rhinosinusitis, n (%) 28(38,4) 70(33)
Nasal polyps, n (%) 20(27,8) 51(23,6)
Aspirin intolerance, n (%) 24(33,8) 39(18,6)*
Obesity, n (%) 25(33,3) 43(19,5)*
Gastro-oesophageal reflux, n(%) 35(47,3) 69(32,5)*
Mental disorders, n (%) 8(11,3) 15(7,1)
Months of OT 29,5(4-96) 33(4-120)
Pre-BD FEV1, % del predetto 64,1±19,8 78,3±19,7* * p<0.05
Novelli et al, ERS 2013
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Exacerbations in severe asthmatics treated with omalizumab
No exacerbations Exacerbations ≥1
Number of patients 167 125
Age, yrs 51,6±13,2 52,5±14,4
Gender, M/F 39,5/60,5 34,4/65,6
Smoke, Y/Ex/No 3,6/28,1/67,1 3,2/25,6/71,2
Rhinitis, % 108(65,9) 80(64,5)
Chronic rhinosinusitis, % 43 (27) 52 (43,3)*
Nasal polyps, % 30 (18,5) 43 (35,2) 3 *
Aspirin intolerance, % 25(15) 35(29,4) 5*
Obesity, % 28(16,9) 38 (30,4)*
Gastro-oesophageal reflux, % 47 (29,4) 55(45,1)*
Mental disorders, % 10(6,3) 11 (9,2)
Months of omalizumab 32 (5-79) 36 (4-120)
Pre-BD FEV1, % del predetto 77,8±18,6 70,6±22,4*
ACT score 22 (10-25) 20 (6-25)*
* p<0.05 Novelli et al, ERS 2013
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Asthma control in patients without comorbidities
Novelli et al, ERS 2013
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Duration of omalizumab treatment may be associated with a better asthma control
*
* p=0.003
Novelli et al, ERS 2013
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Castro et al, AJRCCM 2010
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Asthma-COPD overlap syndrome
GINA 2014, draft
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Prevalence of self-reported physician-diagnosed asthma and COPD
De Marco et al, PlosOne 2013
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GINA 2014, draft
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GINA 2014, draft
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Check different features of asthma and COPD
GINA 2014, draft
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GINA 2014, draft
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Asthma: a heterogeneous disease
• Identification of different phenotypes – According to etiology
– According to pathogenesis
– According to severity
• Implication for treatment – With current drugs
– With biolgoic drugs
– With allergen-immunotherapy
– With thermoplaty
• «tailoring» asthma approach