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FUNCTIONAL AND CELLULAR EVALUATION
OF ASTHMA
Azienda
Ospedaliera
Pisana
Università degli
Studi di Pisa
Pierluigi Paggiaro
GINA International Executive Committee, Chairman GINA ITaly
Cardio-Thoracic and Vascular Department, University of di Pisa
2011 International Guidelines on Rhinitis, Asthma and COPD
Modena, 1-3 march 2011
Functional and cellular evaluation of
asthma
• Tradictional assessment of asthma
–
–
–
–
Symptoms, rescue medication
Baseline pulmonary function
Variability over time
Rate of exacerbations
• Old and new assessments
– Functional
» Bronchial hyperresponsiveness
» Small airway involvement
» Decline in FEV1 over time
– Cellular (biomarkers)
» Sputum inflammatory cells (eosinophils)
» Exhaled NO
• Are they really useful ?
Bronchial hyperresponsiveness
a multifactorial manifestation
Busse, Chest 2010
Methacholine improvement after ICS
depends from the activity of asthma
Koh et al., Chest 2001
Bronchial reactivity (but not sensitivity)
is related to asthma quality of life
Cisneros et al, Thorax 2010
Small airways involvement
is it relevant for asthma management ?
• Several indices of small airway involvement
–
–
–
–
Expiratory flows at medium-low expiratory volumes
Closing volume, closing capacity, single breath N2 washout slope
Fractional eNO
Alveolar-arterial differences in O2 and CO2
• Related to asthma severity (?)
– Difference between severe and non severe asthmatics
• Target for treatment ?
– Oral route vs small inhaled particles
• May it represent a specific “phenotype” ?
In ‘t Ven et al, AJRCCM 2000
In partly controlled asthmatics, indices of small
airways poorly correlate with traditional clinical,
funtional and biological indices
FEV1%
FEF25-75
Symptom
Score
ΔPEF
Sputum
Eosinophils %
FeNO50
SBNW, slope
R= -0,424
ns
ns
ns
ns
ns
CalvNO
ns
ns
ns
ns
ns
ns
D(A-a)O2
R= -0,494
R= -0,624
ns
ns
ns
ns
D(a-A)CO2
R= -0,662
R= -0,795
ns
ns
ns
ns
Ventilated
Area
ns
ns
ns
ns
ns
ns
Inhomogen.
Index
ns
ns
ns
ns
ns
ns
Malagrinò et al, submitted
Extrafine BDP/FF significantly improves
bronchial hyperresponsiveness
# p<0.001 vs baseline
BDP/FF (400/24µg)
FP/SALM (500/100µg)
Scichilone et al., Allergy 2010
Decline in FEV1
role of airway remodelling
• Occurring in a subpopulation of asthmatics
–
–
–
–
Uncontrolled untreated asthmatics
Related to the rate of exacerbations
Late-onset asthma (?)
Genetic predisposition (?)
• Detection of rapid decliners
– Difference between severe and non severe asthmatics
• Effect of treatment
– On morphologic markers (effect with high ICS doses)
– On indirect functional measurement (no effect)
Models of the longitudinal changes in FEV1
in the natural history of asthma
Relationship between frequent exacerbations
and decline in FEV1
Bai et al, ERJ 2007
O’Byrne et al, AJRCCM 2009
Regular follow-up of severe asthmatics reduces
the rate of severe exacerbations and FEV1 decline
0
Regular FU
Non regular FU
-20
N. exacerb./yr
N. OCS treatments/yr
21 subjects with regular FU
Baseline
FU
1.55 ± 1.91
0.86 ± 1.23
p=0.04
1.45 ± 1.91
0.62 ± 1.12
p=0.06
-40
-60
-80
-100
N. exacerb./yr
N. OCS treatments/yr
12 subjects without regular FU
Baseline
FU
1.25 ± 0.75
1.75 ± 2.30
p=n.s.
1.33 ± 0.98
1.75 ± 2.30
p=n.s.
-120
-140
-160
-180
Dente et al, ERS 2011 (submitted)
-200
p=0.01
Cellular evaluation
role of different biological phenotypes
• Eosinophilic vs neutrophilic vs paucigranulocytic
– Well characterised
» Different pathologic mechanisms and risk factors
– Stable over time
• Different response to treatment
– Corticosteroids
– Other anti-inflammatory drugs (azitromycin, roflumilast, etc)
– New specific targets (anti-IL5, anti-IL13, etc)
• Different strategies for the management
Different asthma phenotypes
Haldar et al, AJRCCM 2008
Asthma inflammatory phenotypes do not
correlate with clinical findings
Simpson et al, Respirology 2006
Pattern of inflammatory cells in sputum is
stable over short-term and long-term period
Simpson et al, Respirology 2006
Noneosinophilic asthma is a fairly stable
feature in a subgroup of asthmatics
ns
ns
50
40
Sputum
Eosinophils, %
30
20
10
0
B
1
3
LABA
6
B
1
3
6
ICS
Bacci et al, JACI in press
Spontaneous changes in sputum eosinophils over
6 months in noneosinophilic asthmatics
4 0
2 0
Sputum
Eosinophils, %
1 0
0
B a s ale
Group B = ICS
1 mese
3 mesi
6 mesi
Group A = LABA
Sputum eosinophila is a stable characteristic
in severe difficult-to-control asthmatics
Sputum Eosin %
100
100.0
30%
100
10
10.0
10
3%
1
0.1
1
1.0
0.1
0.1
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21
Time Course of sputum eosinophils over 3 yrs
Dente et al, ERS 2010
Cellular evaluation
role of different biological phenotypes
• Eosinophilic vs neutrophilic vs paucigranulocytic
– Well characterised
» Different pathologic mechanisms and risk factors
– Stable over time
• Different response to treatment
– Corticosteroids
– Other anti-inflammatory drugs (azitromycin, roflumilast, etc)
– New specific targets (anti-IL5, anti-IL13, etc)
• Different strategies for the management
Absence of sputum eosinophilia
in corticosteroid”naive” asthmatics
predicts a poor short-term response to ICS
Bacci et al, Chest 2006
Asthmatics with eosinophilic inflammation
have a better response to a short period
treatment with ICS
Cowan et al, Thorax 2010
Non-eosinophilic and neutrophilic
asthmatics have a good response to
tiotropium
Iwamoto et al, ERJ 2009
Cellular evaluation
role of different biological phenotypes
• Eosinophilic vs neutrophilic vs paucigranulocytic
– Well characterised
» Different pathologic mechanisms and risk factors
– Stable over time
• Different response to treatment
– Corticosteroids
– Other anti-inflammatory drugs (azitromycin, roflumilast, etc)
– New specific targets (anti-IL5, anti-IL13, etc)
• Different strategies for the management
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
Strategy to reduce sputum eosinophils
in mild-moderate asthmatics does not lead
to improvement in BH
p<0.05
p<0.05
60
50
Spu tum
eos inoph ils ,
%
40
30
20
10
0
B
1
2
3
4
5
6
B
1
2
3
4
5
6
months
p<0.01
p<p<0.o
0.01
10000
1000
PD 20 FEV1 ,
mcg
100
10
Group A
Group b
1
B
1
2
3
4
5
6
B
1
2
3
4
5
6
months
Sputum inflammatory cells
an important marker for prognosis and treatment
• Sputum eosinophilia
– Associated with more severe asthma
– Predictor of future loss of asthma control
» In all subjects ?
– Possible target of the treatment
• Sputum neutrophilia
– In different asthma models
» Smoker asthmatics
» Obese asthmatics
» Asthma due to pollutants and simple chemicals
– Related to chronic asthma (remodelling)
Patients with persistent eosinophilia after 1 month
ICS treatment tend to have greater BH
p=0.08
10000
1000
PD20FEV1,
mcg
100
10
1
Group A
Low
sputum
eosinophils
High
sputum
eosinophils
Group b
Bacci et al, ATS 2011
6 months treatment with ICS leaves some
patients with sputum eosinophilia, without any
relationship with the current asthma control
Eosinophils after ICS
< 2%, n=64
Eosinophils after ICS
≥ 2%, n=58
FEV1, %
92±15
99±15
93±16
98±14
PEF, %
76±18
86±18
76±15
88±20
PD20FEV1, mcg
130
432
98
337
Symptom score
1.0 [0.1-3.1]
0 [0-2.0]
1.5 [0.1-3.6]*
0 [0-3.8]
Rescue
beta2-agonist
0.5 [0.1-3.5]
0 [0-1.6]
0.8 [0.1-5.0]
0 [0-3.0]
p < 0.01 for all pre-post comparisons
*p < 0.05 between baseline values
Bacci et al, ERS 2011 (submitted)
Sputum inflammatory cells
an important marker
• Sputum eosinophilia
– Associated with more severe asthma
– Predictor of future loss of asthma control
» In all subjects ?
– Possible target of the treatment
• Sputum neutrophilia
– In different asthma models
» Smoker asthmatics
» Obese asthmatics
» Asthma due to pollutants and simple chemicals
– Related to chronic asthma (remodelling)
Sputum neutrophilia is related to the decline
in FEV1 and asthma duration
Little et al, AJM 2002
Persistent sputum neutrophilia is
associated with greater remodelling in
severe asthmatics
Gupta et al, Thorax 2010
Severe asthma
usefulness of functional and cellular
characterization
• Large heterogeneity (according to WHO 2010
definition)
–
–
–
–
Severe untreated asthmatics
Difficult to treat asthmatics (comorbididties, compliance)
Treatment resistant asthmatics
Persistent chronic obstruction (?)
• Different response to treatment
– Corticosteroids
– Other anti-inflammatory drugs (azitromycin, roflumilast, etc)
– New specific targets (anti-IL5, anti-IL13, etc)
• Different strategies for the management
Sputum cellular and cytokine pattern
in different phenotypes of severe asthma
Dente et al. AAAI 2006
Functional and cellular evaluation
which usefulness in asthma
• Functional evaluation (BH, FEV1 decline, etc)
– May select distinct asthma populations
» With greater impact on quality of life
» With greater remodelling
– May be used for targeting treatment (QoL, FU, etc)
• Cellular evaluation (sputum inflammatory cells)
– May distinguish inflammatory phenotypes
» With different prognosis and response to treatment
– May suggest different treatment strategies
• More extensive and accurate functional and biological
assessment may be useful in asthma management