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New Invasive and non-Invasive Diagnostic Methods in Paediatric Respiratory Diseases

New Invasive and non-Invasive Diagnostic Methods in Paediatric Respiratory Diseases. Andrew Bush MD FRCP FRCPCH Imperial School of Medicine & Royal Brompton Hospital. Email: a.bush@rbht.nhs.uk. New Methods In Paediatric Respiratory Diseases. Ethical Issues in using Innovative Methods

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New Invasive and non-Invasive Diagnostic Methods in Paediatric Respiratory Diseases

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  1. New Invasive and non-Invasive Diagnostic Methods in Paediatric Respiratory Diseases Andrew Bush MD FRCP FRCPCH Imperial School of Medicine & Royal Brompton Hospital Email: a.bush@rbht.nhs.uk

  2. 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

  3. 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

  4. 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?

  5. 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

  6. Biopsy • Lungs • Airway wall and • lumen • Lung • parenchyma • Intravascular • events EBC Exhaled breath Sputum FOB, BAL, Bx Bone marrow TBB Adhesion molecules Bone marrow signals Blood sample Urine tests Tests to Assess Different Aspects of Inflammation

  7. 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

  8. 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

  9. Invasive FOB, BAL, Bronchial biopsy, (TBB) (Blood tests) Non-invasive Exhaled breath (eNO) Induced sputum Exhaled breath condensate (BHR) How to Measure Inflammation

  10. Mechanisms vs. Individuals • Statistically significant differences between groups • May help predict mechanisms (beware guilt by association) • No use for clinic decisions

  11. 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

  12. Measurement of exhaled nitric oxide

  13. 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: 1532-42 BlueJ 2001; 163: 1557-61

  14. 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

  15. Collection of exhaled breath condensate

  16. 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

  17. Sputum induction A dosimeter is used to administer a measured quantity of hypertonic saline

  18. Induced sputum sample – DTT treated

  19. 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

  20. Inflammation in Severe Asthma Conclusion: eosinophilic inflammation overcalled by eNO

  21. 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

  22. Can FENO measurements be used to diagnose asthma?

  23. Diagnosing asthma: role of exhaled nitric oxideSmith 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

  24. Exhaled NO and sputum eosinophil results

  25. Conventional tests

  26. Results:FENO and sputum eosinophils

  27. Malmberget al eNO eNO Smithet al Deykinet al PC20 methacholine eNO (42ml/sec) eNO (500ml/sec) ROC Curves for eNO As Diagnostic Test: Comparisons Between Studies Berkmanet al eNO Dupontet al eNO eNO

  28. Can non-invasive measurements be used to manage asthma?

  29. BlueJ 1999; 159: 1043-51

  30. BlueJ 1999; 159: 1043-51

  31. Managing asthma by normalising sputum eosinophils in adults Lancet 2002; 360: 1715-21

  32. Non-invasive Markers to Monitor Steroid Reduction

  33. Non-invasive Markers to Monitor Steroid Reduction BlueJ 2005; 171: 1077-82

  34. 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. P = 0.04 P = NS FENO Symptoms A a a a Symptoms FENO Changes in PD20 methacholine Changes in ICS dose (micrograms)

  35. 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

  36. Visit two: FOB • Assess reversible factors • Assess symptoms, use of rescue medication • Spirometry, PC20, reversibility • Induced sputum, eNO • FOB, BAL, biopsy Intramuscular Triamcinolone The Difficult Asthma Protocol Visit one: MDT Assessment • Drug delivery device • Home visit: environment • School visit: bullying? • Assess compliance • Psychological assessment 1-2 months 4-6 weeks Visit three: Decision time • Assess symptoms, diary card, and use of rescue medication • Spirometry, PC20, reversibility • Induced sputum, eNO • Serum cortisol assay

  37. Endobronchial Biopsy

  38. r = 0.67 p = 0.001 100.0 10.0 Eosinophil score (%) 1.0 Evidence of adherence Adherence unknown 0.1 1 10 100 FENO (ppb) Correlation between FENO and eosinophils in biopsy

  39. 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

  40. 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

  41. 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

  42. 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

  43. Fixed airflow obstruction Symptomatic Obstructive spirometry, no reversibility No inflammation on visit 2 biopsy Treatment approach Reduce treatment until evidence of reversibility appears Phenotype Specific Asthma Treatment

  44. 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

  45. 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

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