Assoc. Prof. Bülent Karadağ MD Marmara University, Div. of...
Transcript of Assoc. Prof. Bülent Karadağ MD Marmara University, Div. of...
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Assessment of AirwayInflammation
Assoc. Prof. Bülent Karadağ, MD
Marmara University, Div. of Pediatric Pulmonology
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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.
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Before 10 min afterallergen
challenge
Bronchoconstruction
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AirwayInflammation
AirwayHyperresponsiveness Airflow
limitation
AsthmaSymptoms
GeneticPredisposition
Environmentalexposures
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Asthma:Inflammatory disease
Anti inflammatory treatment
Monitoring of inflammation
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Asthma:Inflammatory disease
Obstructive disease
Anti inflammatory treatment
Monitoring of inflammation
bronchodilators
Monitoringlung function
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Asthma
Asthma treatment is based on:
Symptoms,Pulmonary function
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Assessment of Inflammationin Asthma
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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
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Assessing AirwayInflammation
Mostly difficult-to-perform tests inchildhood asthma.
• Mucosal biopsy, • BAL, • Measurement of inflammatory
mediators in; induced sputum, exhaled breath, urine and serum
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Assessment of AirwayInflammation
Invasive methods: • Mucosal biopsy• BAL • Difficult toperform widely
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Mucosal Biopsy
• Gold standard• Invasive• Unable todistinguish differentwheezingphenotypes
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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
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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
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Induced SputumEosinophil, LXA4, elastaseAdvantages; • Easy to monitor,• Measurement of cells and soluble
mediators, • Correlation with inflammation,• Easy to perform
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Induced Sputum
Disadvantages: • Unable to get sample, • Standardisation problems
• Can be an appropriate method formonitoring airway remodeling
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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.
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1
10
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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
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Gibson, P G et al. Thorax 2003
Sputum eosinophils (%) and clinical asthmapattern
*p<0.05 v persistent
n=143
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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
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Sputum eosinophils 2 and 4 wk after treatment
Beclomethasone1.0mg/d Salmeterol
Bacci et al. ERJ 2002
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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
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.
free
elas
tase
(µg/
ml)
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control asthma CB
0
10
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tota
lelast
ase(µ
g/ml)
control asthma CB
Elastase in sputumVignola et al,Am JRespir CritCare Med 1998
** **** **
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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??
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0
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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
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Exhaled Nitric Oxide (ENO) Measurement
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Exhaled Nitric Oxide(ENO) Measurement
• Can also be used in monitoringthe patient,
• Patients having exacerbationshave high ENO levels.
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Kharitonov A et al Am J Respir Crit Care Med 1996
Raised exhaled NO in asthma
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Exhaled NOKharitonov et al, Lancet 1994
800
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Control AsthmaticsSubjects without with ICS
Peak
eNO
(ppb
)
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Non-invasive measurements eNO
Avital Pediatr Pulmonol 2001;32:308-132-7 yrs 3-7 yrs 2-7yrs 4-6yrs
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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
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Exhaled Nitric Oxide(ENO)
Baraldi et al. J Pediatr 1997.
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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
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Exhaled Nitric Oxide(ENO) Measurement
Advantages: • Non-invasive• Correlation witheosinophilicinflammation,• standardised
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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.
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Titrating steroids on FENO
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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.
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Monitoring Exhaled NOSmith et al N Engl J Med 2005
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Monitoring Exhaled NOSmith et al N Engl J Med 2005
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V 1 V 2 V 3 V 4 V 1 V 2 V 3 V 4
0
50
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250 exacerbationduring ICSreduction
stableduring ICSreduction
**
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eNO
(ppb
)
**
FeNO during stepwise ICS reduction in exacerbated and stable children
Zacharasiewicz et al. Am J Respir Crit Care Med 2005
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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?
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mea
n PD
20 m
etha
chol
ine
(ug)
2000
1000900800700600
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Visit
6543210
ICS
dose
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rogr
ams)
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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
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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?
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Inflammatory Markers in Serum
Oldest methodsSerum eosinophil count, ECP, Total ve Specific IgE levels
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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
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Serum markers
Reichenbach et al Ann Allergy Asthma Immunol 2002:89:498-502
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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
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Exhaled BreathCondensate
• CO andhydrocarbons in exhaled breathcan also be measured.
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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
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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
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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
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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
?
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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
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Future vision of asthma management
• NO levels• Symptoms• Treatment Days
NO Asthma worsenedTreatment adjusted
Stable
Home
Stored (asthma/treatment history)
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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
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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
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Exhaled NO Where to use ?:• Predicting exacerbations• Monitoring adherence• Asthma screening• Diagnosis
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