Non invasive monitoring of inflammation in asthma 차의과학대학교 분당차병원 소아과학교실 한 만 용

Asthma is a Chronic Inflammatory Disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation causes an associated increase in Airway Hyperresponsiveness that leads to recurrent episodes of Wheezing, Breathlessness, Chest Tightness, and Coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable Airflow Obstruction that is often reversible either spontaneously or with treatment. Global Strategy for Asthma Management and Prevention, 2008

Asthma is Symptoms Variable airway obstruction Airway hyperresponsiveness (AHR) Airway inflammation Reddel HK, et al. Am J Respir Crit Care Med 2009;180:59-99.

Airway inflammation Invasive –Bronchial biopsy –Bronchoalveolar lavage Non invasive –Induced sputum –FeNO –Exhaled Breath Condensate –Serum ECP –On going…. Reddel HK, et al. Am J Respir Crit Care Med 2009;180:59-99.

Exhaled breath Catching your breath.

Exhaled breath analysis :current state Kharitonov SA. Chest 2006;130: FeNOEBC Other

Fraction of Nitric Oxide (FeNO)

Background Lim KG, et al. Chest 2008;133: ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993;6: Levels Increased Decreased

Introduction Silkoff PE, et al. JACI 2000;105:

Material NIOX MINO (Aerocrine AB) CLD 88 Series (Eco Medics) Nitric Oxide Analyzers 208i (Sievers)

Methods : ATS/ERS recommendations 50 mL/sec Plateau ≥ 3 sec during an exhalation of ≥ 6 sec less than 10% A B Flow mL·s˙ NO ppb

Results - Utility of FeNO Raised in asthma Rises on stopping medication Correlates with eosinophilic and other inflammation Fall after steroids, LT antagonist, anti-IgE Rises with exacerbation Predicts exacerbation Predicts lung function decline ATS Workshop. Proc Am Thorac Soc 2006;3:

Discussion – Point I Reddel HK, et al. Am J Respir Crit Care Med 2009;180: Cut off Value

Discussion – Point I Reddel HK, et al. Am J Respir Crit Care Med 2009;180: ppb

Discussion – Point I Reddel HK, et al. Am J Respir Crit Care Med 2009;180: ppb 20 ppb 50 ppb In children In Infant 35 ppb

Reference ranges 90% CI, 8-41 ppb, yrs Adult Travers J, ea al. Am J Respir Crit Care Med 2007;176: % UL, ppb depending Ht and Age Olin AC, et al. Chest 2007;131: From 15 ppb at 4 yrs to 25 ppb in adolescence Buchvald F, et al. J Allergy Clin Immunol 2005;115:1130-6

Normal - Abnormal Reference CaucasianOriental ControlAsthmaControlAsthma Kaiser G 1) 5-25 ppb>35 ppb Wong GWK 2) 14.9 ppb25.3 ppb Kovesi T 3) 12.7 ppb22.8 ppb Saito J 4) 25.2 ppb60.3 ppb 김상헌 5) 28.6 ppb 나규민 6) 4.5 ppb21.6 ppb 최봉석 7) 20.0 ppb28.3 ppb 1) Chest 2008 (ATS/ERS study) 2) Clin Exp Allergy 2005 (Male, Chineses) 3) Chest 2008 (Asian-Canadian) 4) JACI 2004 (Japanese children) 5) Korean J Med 2008 (Healthy Korean Adult) 6) Korean J Pediatr 2004 (Korean Children) 7) Pediatr Allergy Respir Dis (Korea) 2009 (Korean Children)

Cutoff values in Korea (Children, Adult) 3σ 2σ 1σ µ 2σ 3σ

Discussion - Point II Expert Panel Report Monitoring

Discussion - Point II Written asthma action plan based on signs and symptoms Peak flow monitoring Spirometry Use of minimally invasive markers ; they require further evaluation Expert Panel Report

Discussion - Point II Time FeNO GINA NAEPP

Treatment algorithm I Smith AD, et al. New Engl J Med 2005;352: Patients 48 In FENO group 49 In control group Randomization Study Completion 46 In FENO group 48 In control group 44 In FENO group 45 In control group Optimal Dose Achieved 3-12 mo 12 mo

Cumulative exacerbations I Smith AD, et al. New Engl J Med 2005;352:

Treatment algorithm II In 85 Children with atopic asthma (30 ppb) Pijnenburg MW, et al. Am J Respir Crit Care Med 2005;22:23. In 118 Adults (15~25 ppb) Shaw DE, et al. Am J Respir Crit Care Med 2007;176: In 546 Adolescents with persistent asthma (20 ppb) Szefler SJ, et al. Lancet 2008;372: In 151 Children, Daily telemonitoring (20~25ppb) De Jongste JC, et al. Am J Respir Crit Care Med 2009;179:93-7. Review (6 study, 1,053 participants) Petsky HL, et al. Cochrane Database Syst Rev 2009;7:CD006340

No More Dogma ! –No more Inflammometer –Is Atopometer Stick S. Am J Respir Crit Care Med 2009;179:87-92.

The Cup is half empty ! –Subphenotype Atopic : Non-atopic Eosinophilic : Neutrophilic High BMI : Low BMI Transient : Persistent wheezing Mild : Severe High FeNO : Low FeNO Taylor DR. Am J Respir Crit Care Med 2009;179:88-9. Individual FeNO –Personal Best –Predictive Value

Discussion - Point III Children

For children ≤ 12 years old 50 mL/sec Plateau ≥ 2 sec during an exhalation of ≥ 4 sec less than 10% A B Flow mL·s˙ NO ppb

For preschool children Breathes slowly and regularly ≥ 1 sec within target flow of 50 mL/sec Flow mL·s˙ Pressure cmH2O Time

Infant FeNO Roiha HL, et al. Eur Respir J 2007;29:251-8.

Children – on-line Age yrsSingle-breathFlow controlled during spontaneous breathing Uncontrolled flow < 2+

Conclusion I Airway inflammation – FeNO Point I : Cut off value Ponit II : Monitoring Point III : Children

Limitation and Future Nasal NO Off-line Measurement Alveolar-Airway FeNO Mechanical Ventilated Patients Preschool/Infant FeNO Targeting therapy to inhibit FeNO

Exhaled breath condensate (EBC)

Background/Introduction EBC contains several components. –The principal component is condensed water vapour (>99%). –Only a small fraction is derived from respiratory droplets containing nonvolatile molecules. Small fraction –H 2 O 2, NOx, Adenosine, Arachidonic acid metabolites, 8-isoprostane, Markers of oxidative stress, pH, Ammonia, Cytokine, Chemokine, Other molecule…

Material and Methods EcoScreen® system (Erich Jaeger GmbH, Hochberg, Germany) RTube® (Respiratory Research Inc., Charlottesville, VA, USA)

Results-PubMed (Asthma & EBC)

Results Problematic Well-controlled Asthma 8-isoprostane (pg/ml) Carraro S, et al. Eur Respir J 2009.

Discussion Limitation –On-line –Standardization Future –Metabonomic –Proteomic

Electric Nose

Background/Introduction

Material and Methods Electric nose and Bio nose Cyranose 320 Sniffer Dog nose McCulloch M, et al. Integ Canc Ther 2006;5:

Results - Discrimination of Asthma and COPD Dragonieri S. JACI 2007;120: Fens N. Am J Respir Crit Care Med 2009.

Discussion Limitation –Not chemical identify and separate VOCs –32 organic polymer sensors : 3,000 different VOCs (GC-MS) Future –Complementary to GC-MS –Handheld, Non-invasive, Rapid –Upper airway infection : Lower airway disease

Conclusion Symptoms Variable airway obstruction Airway hyperresponsiveness (AHR) Airway inflammation –Induced sputum –FeNO Cut off Value, Monitoring, Children –Exhaled breath condensate –Electric nose