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

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

A new definition of asthma: a heterogeneous disease

GINA 2014, draft

Main objectives in asthma treatment: control vs future risk

ATS Statement, AJRCCM 2009

Symptom control vs future risk

GINA 2014, draft

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

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

Different asthma phenotypes

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 (?)

Bousquet et al, JACI 2010

Asthma control in severe asthmatic patients

68.8% of patients had at least one exacerbation in the last year

Novelli et al, ERS 2013

Prevalence of comorbidities

Novelli et al, ERS 2013

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

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

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

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

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 (?)

Different asthma phenotypes

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»)

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

Current smokers with asthma have greater rate of exacerbations, despite

ICS or ICS/LABA treatment

Pedersen et al, JACI 2007

Different asthma phenotypes

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 ?

Different asthma phenotypes

Haldar et al, AJRCCM 2008

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

Asthma inflammatory phenotypes do not correlate with clinical

findings

Simpson et al, Respirology 2006

Bacci et al, Chest 2006

Absence of sputum eosinophilia in corticosteroid”naive” asthmatics

predicts a poor short-term response to ICS

Bacci et al, Respirology 2012

Steroid-naif symptomatic noneosinophilic asthma may remain stable over 6 months

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 ?)

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

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»

Control of asthma in severe asthmatics treated with omalizumab

Novelli et al, ERS 2013

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

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

Asthma control in patients without comorbidities

Novelli et al, ERS 2013

Duration of omalizumab treatment may be associated with a better asthma control

*

* p=0.003

Novelli et al, ERS 2013

Castro et al, AJRCCM 2010

Asthma-COPD overlap syndrome

GINA 2014, draft

Prevalence of self-reported physician-diagnosed asthma and COPD

De Marco et al, PlosOne 2013

GINA 2014, draft

GINA 2014, draft

Check different features of asthma and COPD

GINA 2014, draft

GINA 2014, draft

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