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New Invasive and non-Invasive Diagnostic Methods in Paediatric Respiratory Diseases. Andrew Bush MD FRCP FRCPCH Imperial School of Medicine & Royal Brompton Hospital. Email: [email protected]. New Methods In Paediatric Respiratory Diseases. Ethical Issues in using Innovative Methods - PowerPoint PPT Presentation
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New Invasive and non-Invasive Diagnostic
Methods in Paediatric Respiratory Diseases
Andrew Bush MD FRCP FRCPCH
Imperial School of Medicine &Royal Brompton Hospital
Email: [email protected]
New Methods In Paediatric Respiratory Diseases
Ethical Issues in using Innovative Methods
Measuring Inflammation: General Measuring Inflammation: Non-
invasive Measuring Inflammation: Invasive Summary and Conclusions
Paediatric Ethical issues:General Principles
Must do adult studies before children Research in children only if unavoidable Risks are not permitted without benefit Adults cannot consent to risk their children Bribery is not allowed Children can be altruistic, and this should be permitted
Paediatric Ethical issues:General Principles
Testing involves not just the child, but the extended family - consent issues for all
Should a child be tested for carrier status?
Should a child be tested for an incurable condition?
Should DNA from a child be stored?
New Methods In Paediatric Respiratory Diseases
Ethical Issues in using Innovative Methods
Measuring Inflammation: General
Measuring Inflammation: Non-invasive
Measuring Inflammation: Invasive Summary and Conclusions
Lungs
•Airway wall andlumen
•Lung parenchyma
•Intravascularevents
Bone marrow
EBCExhaled breathSputumFOB, BAL, Bx
Adhesion moleculesBone marrow signals
Blood sampleUrine tests
Biopsy
TBB
Tests to Assess Different Aspects of Inflammation
The Perfect “Inflammometer”
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
Facets of Inflammation Cellular mechanisms
Resident cells – epithelial, fibroblasts, myofibroblasts
Invading cells – eosinophil, neutrophil, mixed
Chemical mechanisms Cytokines, chemokines Lipid mediators, e.g.leukotrienes Oxidative stress
Neurogenic mechanisms NANC system
How to Measure Inflammation
Invasive FOB, BAL, Bronchial
biopsy, (TBB)
(Blood tests)
Non-invasive Exhaled breath (eNO)
Induced sputum
Exhaled breath condensate
(BHR)
Mechanisms vs. Individuals
Statistically significant differences between groups
May help predict mechanisms (beware guilt by association)
No use for clinic decisions
New Methods In Paediatric Respiratory Diseases
Ethical Issues in using Innovative Methods
Measuring Inflammation: General Measuring Inflammation: Non-
invasive Measuring Inflammation: Invasive Summary and Conclusions
Measurement of exhaled nitric oxide
Alveolar and Airway NO Measure eNO and hence NO production
at multiple flow rates Slope of line gives airway production Extrapolated intercept gives alveolar
production Still needs to be evaluated in children
JAP 1999; 87: 1532-42BlueJ 2001; 163: 1557-61
eNO – What does it mean? Measurement conditions crucial
Good for looking at group mechanisms
Variable relationship with airway eosinophilia
MAY be useful in monitoring asthma, but at best indirect
Multiple flow rate measurements need further work
Collection of exhaled breath condensate
EBC – What does it Mean? Many molecules can be measured
Assay more important than collection methods
No value monitoring inhaled steroid reduction
Still unclear if any PRACTICAL value
Sputum induction
A dosimeter is usedto administer ameasured quantity ofhypertonic saline
Induced sputum sample – DTT treated
Inflammation in Severe Asthma
Sputum induction (3.5% saline) in 40 children, symptomatic despite > 1 mg FP/day
Two excluded as FEV1 < 65%; all given β-2 agonist prior to procedure
28/38 (74%) sample obtained
Inflammation in Severe Asthma
0
2
4
6
8
10
12
14
16
18
NO+,E+ NO+,E- NO-,E- NO-,E+
Nos.
Conclusion: eosinophilic inflammation overcalled by eNO
Inflammation in Severe Asthma
7/38 symptomatic during induction, only 3 Δ FEV1 > -20%
Only 9/28 had persistent inflammation
6 eosinophilic (eosins > 2.5%) 3 non-eosinophilic (neutrophils > 54%)
Conclusion: inflammation apparently not that common
Can FENO measurements be used to diagnose asthma?
Diagnosing asthma: role of exhaled nitric oxide Smith et al. AJRCCM., 2004
Consecutive patients referred by GP ?asthma
Diagnostic work-up over three study visits: twice-daily peak flow measurements (7days) spirometry bronchodilator response (FEV1) bronchial challenge testing (AHR) induced sputum analysis response (peak flows and FEV1) to pred 30 mg/day
for 2 weeks
Exhaled NO and sputum eosinophil results
Asthma(n=17)
Non-asthma(n=30)
p
FENO (ppb) 52.0(35.3, 68.6)
15.7(10.9, 20.4)
<0.001
Sputum eosinophils (%)
13.8(8.6, 19.1)
1.8(0, 3.7)
<0.001
Conventional testsTest
* Recommended values from current guidelines
Positive tests
Asthma
(n=17)
Non-asthma(n=30)
Sensitivity
(%)
Specificity
(%)
Positive AHR 15 0 - -Positive bronchodilator response
7 0 - -
FEV1 <80% predicted * 5 0 29 100
FEV1/VC ratio <70% * 6 0 35 100
Peak flow variation >20% *
0 0 0 100
15% improvement in PEFR with steroid *
4 0 24 100
15% improvement in FEV1 with steroid *
2 0 12 100
Results:FENO and sputum eosinophils
Test Positive tests
Asthma Non-asthma
Sensitivity
(%)
Specificity
(%)
FENO > 20ppb 14/16 6/28 88 79
Sputum eosinophils > 3%
12/14 3/26 86 89
ROC Curves for eNO As Diagnostic Test: Comparisons Between Studies
Berkman et alMalmberg et al
eNO
eNO
Dupont et al
eNO
eNO
PC20 methacholine
Smith et al
Deykin et al
eNO (42ml/sec) eNO
(500ml/sec)
eNO
Can non-invasive measurements be used to manage asthma?
BlueJ 1999; 159: 1043-51
BlueJ 1999; 159: 1043-51
Managing asthma by normalisingsputum eosinophils in adults
Lancet 2002; 360: 1715-21
Non-invasive Markers to Monitor Steroid Reduction
BlueJ 2005; 171: 1077-82
Non-invasive Markers to Monitor Steroid Reduction
me
an
PD
20
me
tha
cho
line
(u
g)
2000
1000900800700
600
500
400
300
200
100Visit
6543210
ICS
do
se (
mic
rog
ram
s)
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 FENO group: 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 PD20 methacholine Changes in ICS dose (micrograms)
P = 0.04 P = NS
New Methods In Paediatric Respiratory Diseases
Ethical Issues in using Innovative Methods
Measuring Inflammation: General Measuring Inflammation: Non-
invasive Measuring Inflammation:
Invasive Summary and Conclusions
The Difficult Asthma Protocol
Visit two: FOBAssess reversible factorsAssess symptoms, use of rescue medicationSpirometry, PC20, reversibilityInduced sputum, eNOFOB, BAL, biopsy
Visit three: Decision timeAssess symptoms, diary card, and use of rescue medication Spirometry, PC20, reversibilityInduced sputum, eNOSerum cortisol assay
IntramuscularTriamcinolone
4-6 weeks
Visit one: MDT AssessmentDrug delivery deviceHome visit: environmentSchool visit: bullying?Assess compliancePsychological assessment
1-2 months
Endobronchial Biopsy
1 10 1000.1
1.0
10.0
100.0
FENO (ppb)
Eosinophilscore (%)
r = 0.67p = 0.001
Evidence of adherence
Adherence unknown
Correlation between FENO and eosinophils in biopsy
Phenotype Specific Asthma Treatment
Steroid sensitive (eosinophilic) inflammation
Normal lung function
No BHR No inflammation on
visit 2 biopsy
Treatment approach
Wean steroids (Cyclosporin A if
intolerable side-effects)
Phenotype Specific Asthma Treatment
Steroid resistant eosinophilic
inflammation
Symptomatic Eosinophilic biopsy on
visit 2 (steroid receptor
abnormalities) Adherence to oral
steroids
Treatment approach
Cyclosporin A Other steroid
sparing agent
Phenotype Specific Asthma Treatment
Neutrophilic inflammation
Symptomatic Neutrophilic
inflammation on visit 2 biopsy
Treatment approach
Theophyllines (neutrophil apoptosis)
Macrolides (reduced epithelial IL-8)
5-Lipoxygenase inhibitor (LTB4) or LTB4 receptor antagonist
Smoking??
Phenotype Specific Asthma Treatment
BHR, no inflammation
Symptomatic Marked PF
variability and reversibility
No inflammation on visit 2 biopsy
Treatment approach
Subcutaneous terbutaline infusion
(Increase dose of LABs)
Phenotype Specific Asthma Treatment
Fixed airflow obstruction
Symptomatic Obstructive
spirometry, no reversibility
No inflammation on visit 2 biopsy
Treatment approach
Reduce treatment until evidence of reversibility appears
New Methods In Paediatric Respiratory Diseases
Ethical Issues in using Innovative Methods
Measuring Inflammation: General Measuring Inflammation: Non-
invasive Measuring Inflammation: Invasive Summary and Conclusions
Overall Conclusions No one ideal “inflammometer” May be helpful in looking at
mechanisms – individual vs. group differences
May be useful to improve monitoring of asthma
May be useful in planning treatment