ASMA GRAVE E ACOS

NEL DOCUMENTO GINA 2014

Azienda
Ospedaliera
Pisana

Universit degli
Studi di Pisa

Pierluigi Paggiaro
GINA International Executive Committee, Chairman GINA ITaly
Cardio-Thoracic and Vascular Department, University of Pisa

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, %

71.017.5 *

81.117.7

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, %

77.723.5

77.914.8

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, %

77.416.5

78.119.3

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 (CSdependent 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

Acute ozone exposure in laboratory induces

in mild-moderate asthmatics a prominent
neutrophilic inflammatory response, which
is blunted by inhaled budesonide

Vagaggini et al., AJRCCM 2001

Asthma inflammatory phenotypes

do not correlate with clinical
findings

Simpson et al, Respirology 2006

Absence of sputum eosinophilia

in corticosteroidnaive asthmatics
predicts a poor short-term response to ICS

Bacci et al, Chest 2006

Steroid-naif symptomatic noneosinophilic asthma

may remain stable over 6 months

Bacci et al, Respirology 2012

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 ?)

The control of sputum eosinophilia is associated

with a reduction in asthma exacerbations,
but only for eosinophilic exacerbations

Green et al, Lancet 2002

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
Number of patients
Age, yrs
Gender, M/F %
Smoke, Y/Ex/No %
Rhinitis, n (%)
Chronic rhinosinusitis, n (%)
Nasal polyps, n (%)
Aspirin intolerance, n (%)
Obesity, n (%)
Gastro-oesophageal reflux, n(%)
Mental disorders, n (%)
Months of OT
Pre-BD FEV1, % del predetto

75
53,413,5
34,7/65,3
4,0/25,3/70,7
51(68,9)
28(38,4)
20(27,8)

Well-partially
controlled
221
51,513,9
38/62
3,6/28,1/67,4
142(65,1)
70(33)
51(23,6)

24(33,8)
25(33,3)
35(47,3)
8(11,3)
29,5(4-96)
64,119,8

39(18,6)*
43(19,5)*
69(32,5)*
15(7,1)
33(4-120)
78,319,7*

* p<0.05

Novelli et al, ERS 2013

Exacerbations in severe asthmatics

treated with omalizumab
Number of patients
Age, yrs
Gender, M/F
Smoke, Y/Ex/No
Rhinitis, %
Chronic rhinosinusitis, %
Nasal polyps, %
Aspirin intolerance, %
Obesity, %
Gastro-oesophageal reflux, %
Mental disorders, %
Months of omalizumab
Pre-BD FEV1, % del predetto
ACT score
* p<0.05

No exacerbations

Exacerbations 1

167
51,613,2
39,5/60,5
3,6/28,1/67,1
108(65,9)
43 (27)
30 (18,5)
25(15)
28(16,9)
47 (29,4)
10(6,3)
32 (5-79)
77,818,6
22 (10-25)

125
52,514,4
34,4/65,6
3,2/25,6/71,2
80(64,5)
52 (43,3)*
43 (35,2) 3 *
35(29,4) 5*
38 (30,4)*
55(45,1)*
11 (9,2)
36 (4-120)
70,622,4*
20 (6-25)*
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 physiciandiagnosed 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