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Assessment of AirwayInflammation
Assoc. Prof. Bülent Karadağ, MD
Marmara University, Div. of Pediatric Pulmonology
Asthma• Asthma is a chronic disease
characterized by recurrent episodes of:–wheezing, –shortness of breath, and –cough 2° to reversible airflow
obstruction• Bronchial hyperresponsiveness &• Airway inflammation are hallmarks of
asthma.
Before 10 min afterallergen
challenge
Bronchoconstruction
AirwayInflammation
AirwayHyperresponsiveness Airflow
limitation
AsthmaSymptoms
GeneticPredisposition
Environmentalexposures
Asthma:Inflammatory disease
Anti inflammatory treatment
Monitoring of inflammation
Asthma:Inflammatory disease
Obstructive disease
Anti inflammatory treatment
Monitoring of inflammation
bronchodilators
Monitoringlung function
Asthma
Asthma treatment is based on:
Symptoms,Pulmonary function
Assessment of Inflammationin Asthma
Asthma
The problem with symptoms is:• Weak correlation with airway
inflammation• Poor perception• Symptoms in children
underestimatedContinuing inflammation leads to:
Permanent airway changes,
Airway remodeling
Assessing AirwayInflammation
Mostly difficult-to-perform tests inchildhood asthma.
• Mucosal biopsy, • BAL, • Measurement of inflammatory
mediators in; induced sputum, exhaled breath, urine and serum
Assessment of AirwayInflammation
Invasive methods: • Mucosal biopsy• BAL • Difficult toperform widely
Mucosal Biopsy
• Gold standard• Invasive• Unable todistinguish differentwheezingphenotypes
Bronchoalveolar Lavage
• Alternative to biopsy• Cell distribution, eosinophils, ECP, Leukotriene B4, E4, PGE2, IL 8,tryptase• Able to distinguish children with atopic
asthma and viral wheezing• Overlap
BAL ECP and IL 8
Kim Clin Exp Allergy 2005;35:591-7
n=16 n=18 n=143.3 yrs 1.3 yrs 3.7 yrsrec wheezeß2 agonist responseatopic
Induced SputumEosinophil, LXA4, elastaseAdvantages; • Easy to monitor,• Measurement of cells and soluble
mediators, • Correlation with inflammation,• Easy to perform
Induced Sputum
Disadvantages: • Unable to get sample, • Standardisation problems
• Can be an appropriate method formonitoring airway remodeling
Induced SputumEosinophil counts can be used in:• Diagnosis of asthma and monitoring
the treatment.• Patients having eosinophilia in induced
sputum give better response to ICS treatment and eosinophil ratesdecrease after treatment.
• The presence of eosinophilia in inducedsputum indicates an increase in ICS dosage or LTRA supplementation.
1
10
100
1000
10000
Eosi
noph
ils (X
103 /g
)
p<0.05
p<0.001
p<0.01
Controlgroup
Intermittentasthma
Mild to moderateasthma
Severeasthma
p<0.001
Sputum eosinophil counts in asthma
Louis R et al Am J Respir Crit Care Med 2000
Gibson, P G et al. Thorax 2003
Sputum eosinophils (%) and clinical asthmapattern
*p<0.05 v persistent
n=143
Eos <3% Eos >3%
Number 9 14 Age 53 45 Male 5 11 Atopy 2 8 Current smoker 3 1 Δ FEV1 (ml) 100 [-193, 394] 142 [-5, 289] Δ Symptom VAS (mm) -0.7 [15.4, -16.8] -24.4 [-12.5, -36.3]Δ PEF amplitude % mean -3.2 [4.3, -10.7] -7.0 [-2.5, -11.6] Δ PC20 (doubling doses) 0 [-1.2, 1.2] 2.1 [1.3, 3.0] Decrease sputum eos (fold) 1.6 [0.98, 2.7] 7.1 [3.7, 13.5]
Pavord et al. Lancet 1999;353:2213-4
Sputum eosinophilia and the response to budesonide
Sputum eosinophils 2 and 4 wk after treatment
Beclomethasone1.0mg/d Salmeterol
Bacci et al. ERJ 2002
Sputum eosinophils during stepwise steroid reduction
V 1 V 2 V 3 V 4 V 1 V 2 V 3 V 4
0
10
20
30
**
**
*
*
*
exacerbationduring ICSreduction
% e
osin
ophi
lsstableduring ICSreduction
Zacharasiewicz et al. Am J Respir Crit Care Med 2005
.
free
elas
tase
(µg/
ml)
0
10
20
30
40
50
60
control asthma CB
0
10
20
30
40
50
60
tota
lelast
ase(µ
g/ml)
control asthma CB
Elastase in sputumVignola et al,Am JRespir CritCare Med 1998
** **** **
Induced sputum
Inflammationabsent
No symptoms: Consider: decrease ICS
Plus symptoms: Consider: LABPlus symptoms +no variable airway obstruction: Decrease ICS??
Present
Eosinophilic: Consider: increase ICS, LTRA
Neutrophilic: Consider:other treatments:Macrolides, theophyllineDecrease ICS??
0
20
40
60
80
100
120
1 2 3 4 5 6 7 8 9 10 11 12
Severeexacerbations
Time (months)
BTSmanagement
Sputummanagement
Asthma management based on normalisation of sputum eosinophils
Green RH et al. Lancet 2002
Exhaled Nitric Oxide (ENO) Measurement
Exhaled Nitric Oxide(ENO) Measurement
• Can also be used in monitoringthe patient,
• Patients having exacerbationshave high ENO levels.
Kharitonov A et al Am J Respir Crit Care Med 1996
Raised exhaled NO in asthma
Exhaled NOKharitonov et al, Lancet 1994
800
700
600
500
400
300
200
100
0
Control AsthmaticsSubjects without with ICS
Peak
eNO
(ppb
)
Non-invasive measurements eNO
Avital Pediatr Pulmonol 2001;32:308-132-7 yrs 3-7 yrs 2-7yrs 4-6yrs
Diagnostic value of FeNO
• healthy (n = 34) • asthma (n = 28) • FeNO fall with
increasing flow rate
• FeNO was higherin asthma(p < 0.001)
At each rateboth collection techniques
Deykin A et al. Am J Respir Crit Care Med 2002
Exhaled Nitric Oxide(ENO)
Baraldi et al. J Pediatr 1997.
Exhaled nitric oxide• FENO correlates with eosinophilic airway
inflammation
0,0001
0,001
0,01
0,1
1
1 10 100 1000
Exhaled NO
MB
P de
nsity
epi
thel
ium r=0.40
p=0.022
Van den Toorn et al. AJRCCM 2001
0 Asthma
• remission
Exhaled Nitric Oxide(ENO) Measurement
Advantages: • Non-invasive• Correlation witheosinophilicinflammation,• standardised
Exhaled Nitric Oxide(ENO) Measurement
• Can be performed by 4 years old. Limitations:–Corticosteroids sensitive; time
scale of change?–Costs, expensive equipments–Role to assess remodelling?
But devices are getting cheaperand simple.
Titrating steroids on FENO
0
10
20
30
40
50
0 100 250 500 750 10000
10
20
30
40
50
0 100 250 500 750 1000
FENO group GINA group% patients
Fluticasone µg/day Fluticasone µg/day
Median: 100µg/day
Mean: 370µg/day
Median: 750µg/day
Mean: 641µg/day
% patients
p = 0.008 for between group comparisons
Smith et al. NEJM 2005; 352: 2163-73.
Monitoring Exhaled NOSmith et al N Engl J Med 2005
Monitoring Exhaled NOSmith et al N Engl J Med 2005
V 1 V 2 V 3 V 4 V 1 V 2 V 3 V 4
0
50
100
150
200
250 exacerbationduring ICSreduction
stableduring ICSreduction
**
***
***
eNO
(ppb
)
**
FeNO during stepwise ICS reduction in exacerbated and stable children
Zacharasiewicz et al. Am J Respir Crit Care Med 2005
Exhaled Nitric Oxide• Titrating ICS on FENO and symptoms
results in:1. Less bronchial hyperresponsiveness 2. With the same dose of ICS3. More inflammation in symptom
group?• ENO high plus symptoms; increase
ICS. • ENO low plus symptoms differential
diagnosis?
mea
n PD
20 m
etha
chol
ine
(ug)
2000
1000900800700600
500
400
300
200
100
Visit
6543210
ICS
dose
(mic
rogr
ams)
1050
950
850
750
650
GROUP
2,00
1,00
Titrating Steroids on Exhaled Nitric Oxide in Asthmatic Children: a Randomized Controlled Trial.Pijnenburg et al. AJRCCM, 2005.
85 atopic asthmatic children. ICS dose in FENOgroup: increase if >30ppb; no change if <30ppb and symptoms still present; decrease if <30ppb and reduced symptoms.
A a a a
FENO
FENO
Symptoms
Symptoms
Changes in ICS dose (micrograms) Changes in PD20 methacholine
P = 0.04 P = NS
FeNOlow
No symptoms: Consider: decrease ICS
+ Symptoms: Consider + LABPlus Symptoms+ no variable obstruction:Consider alternative diagnosis:Postviral BHR, VCD, CF,PCD,Gastroesophageal reflux etcConsider reducing treatment ?
high
+Symptoms: Consider: high allergen load
non complianceinhalation technique
Consider: increase ICS
No symptoms:Consider: No change?
Inflammatory Markers in Serum
Oldest methodsSerum eosinophil count, ECP, Total ve Specific IgE levels
Inflammatory Markers in Serum
Serum eosinofil count:• Weakly correlated with the eosinophil
count in biopsy• Not specific for asthmaECP levels:• Correlation with biopsy is NOT clear• Sensitivity is more than blood
eosinophil count but less thaneosinophils in sputum
Serum markers
Reichenbach et al Ann Allergy Asthma Immunol 2002:89:498-502
Inflammatory Markers in Urine
Eosinophil peroxidase (EPX):Less invasive than serum ECP, Alternativeİdrarda LTE4: Requires experienceNot specific for asthmaMore studies are required to confirmthe correlation of urine measurementswith inflammation
Exhaled BreathCondensate
• CO andhydrocarbons in exhaled breathcan also be measured.
Exhaled Breath Condensate• Collection of exhaled air by
condensation • Patient breathes into condenser for
10 min condensed water, volatile compounds and particles present in the airway lining fluid )
• Not standardised
Exhaled Breath Condensate8-isoprostane, H2O2, leukotrienes (LTC4,
LTB4), airway pH etc.Correlation with eosinophils and
symptoms is highly variableEarly to recommend in daily practice
Because of these limitations, newstrategies for monitoring airwayinflammation are under investigation
Monitoring AirwayInflammation
Ideal “Inflammometry”:• Cheap• Easy to maintain and calibrate• Completely non-invasive• Easy to use, no co-operation needed• Direct measurement of all relevant
aspects of inflammation• Rapid availability of answers• Evidence of beneficial clinical
outcomes
Comparison of methods
Time forpatient
Time to result
comfort value
Induced Sputum
30 min ~2 h +? +/ -
+ + +
+ +
good
FeNO 5 min instant good
Exhaled Breath Condensate
10 min ~ 3h orinstant
?
Why Measure Inflammation?
• Mechanisms of DiseaseOverlap between groups unimportantCross-sectional studies informative
• Delineate Asthma PhenotypesOverlap importantMay need longitudinal and cross-sectional work
• Monitor Asthma Control and TherapyLongitudinal data essentialClear differentiation between groupsClinically relevant outcomes
Future vision of asthma management
• NO levels• Symptoms• Treatment Days
NO Asthma worsenedTreatment adjusted
Stable
Home
Stored (asthma/treatment history)
Eosinophilicinflammation interpretation
unlikely
might be
very likely
Further investigations: PCD, CF
Steroid naive: unlikely to respond to ICS, consider alternative diagnosis
Steroid treated: taper ICS; if symptomatic: consider alternative diagnosis
Symptomatic: consider other treatments (LABA, LTRA), consider infection
Asymptomatic: baseline?
Steroid naive: response to steroids likely
Steroid treated: consider compliance, inhalation technique, allergen exposure, steroid dose, loss of control, resistance
FENO (ppb)
5
25
35
Exhaled NO • Probably the best of the
available methods• Where to use ?: • After remission• Titrating ICS dosage• Predicting the response to ICS• Choosing the type of additional
treatment
Exhaled NO Where to use ?:• Predicting exacerbations• Monitoring adherence• Asthma screening• Diagnosis