. Ομάδα Άσθματος 2010 Μη επεμβατικοί δείκτες φλεγμονής αεραγωγών στην κλινική πράξη: Πότε, σε ποιον, με τι κόστος και με ποιο όφελος; Κωνσταντίνος Θ. Κωστίκας Πνευμονολόγος
Η ιστορία της Τζούλια ή μια ευαίσθητη ιστορία προσωπικών δεδομένων
Exhaled breath analysis: current state of standardization, research, and clinical use Kharitonov SA & Barnes PJ, Chest 2006
PubMed 21.03.2010 exhaled nitric oxide asthma: 1235 induced sputum asthma: 1106 sputum eosinophils asthma: 1005 exhaled breath condensate asthma: 260
FeNO and Sputum Eosinophils Whole population (n=566) R 2 =0.26 (p<0.001) Non-smokers R 2 =0.28 (p<0.001) Berry MA, Clin Exp All 2005
Diagnosing Asthma with FeNO: Comparison with Conventional Tests PEF variation PEF steroid response FEV 1, FEV 1 /VC, FEV 1 steroid response 47 pts. with symptoms suggestive of asthma FeNO 50 >20 ppb AUC 0.864 Sens. 88% Spec. 79% PPV 70% NPV 92% Sputum eosinophils FeNO 50 Smith AD, AJRCCM 2004
FeNO and ICS Response 52 patients with undiagnosed respiratory symptoms Parameters: FeNO FEV 1 % pred. FEV 1 bronchodilator response PD 20 metacholine PEFR variation FP and Placebo (4w + 4w) FeNO >47 ppb "best predictor" of steroid response Smith AD, AJRCCM 2005
Prediction of failure after reduction of ICS: BHR, sputum eosinophils, FeNO Sens. Spec. PPV NPV n = 40 children ICS dose: 200-500 μg/day 50% dose reduction every 8 weeks 30% discontinued ICS 38% lost control BHR fall >15% 63.6 59.5 31.8 84.6 Eosinophils >0% 100 51.0 41.0 100 >3% 54.5 84.8 46.1 78.7 F E NO >22ppb 78.6 68.6 44.0 92.5 >35ppb 71.4 82.4 52.6 91.3 Zacharasiewicz A, AJRCCM 2005
Sputum Eosinophils and Asthma Management SYMPTOMS CONTROLLED anti-inflammatory Rx bronchodilator Rx Sputum guidelines group Sputum eosinophils <1% SYMPTOMS NOT CONTROLLED anti-inflammatory Rx bronchodilator Rx No change in anti-inflammatory Rx bronchodilator Rx Sputum eosinophils 1-3% No change in anti-inflammatory Rx bronchodilator Rx anti-inflammatory Rx bronchodilator Rx Sputum eosinophils >3% anti-inflammatory Rx bronchodilator Rx if on maximum anti-inflammatory Rx Green RΗ, Lancet 2002
Σοβαρές παροξύνσεις Sputum Eosinophils and Asthma Management 120 Θεραπεία με βάση συμπτώματα και λειτουργικό έλεγχο Θεραπεία με βάση τα ηωσινόφιλα των πτυέλων 100 80 60 63% μείωση παροξύνσεων *p = 0.01 40 20 0 Χωρίς αύξηση κορτικοστεροειδών 0 1 2 3 4 5 6 7 8 9 10 11 12 Μήνες Green RΗ, Lancet 2002
Sputum Eosinophils and Asthma Management 49% μείωση παροξύνσεων Ηωσινοφιλικές Μη ηωσινοφιλικές Χωρίς αύξηση κορτικοστεροειδών Jarayam L, Eur Respir J 2006
FeNO to Guide Treatment in Chronic Asthma 45.6% reduction in exacerbation rate (p=0.27) 40% ICS reduction (270 μg/day) (p=0.008) Smith AD, NEJM 2005
The Use of FeNO to Guide Asthma Management 118 pts. mild-moderate asthma FeNO-guided vs. BTS management Exacerbation frequency: 0.33 (0.69) vs. 0.42 (0.79) p=0.43 The FENO group used 11% more ICS (p=0.40) The final daily dose of ICS was lower in the FENO group (557 vs. 895 μg, p=0.028) Shaw DE, AJRCCM 2007
FeNO for Asthma Management: 46 weeks RCT FeNO Management resulted in higher doses of ICS, without clinically important improvements in symptomatic asthma control BUT included pts. with low FeNO AND Was more efficient in pts with: BMI >30 kg/m 2 high blood eosinophils atopy high total IgE Szefler SJ, Lancet 2008
FeNO to Guide Treatment in Chronic Asthma Gibson PG, Clin Exp All 2009
FeNO: Normal Values? Contradictory results In a large population-based study (n=2,200), age, height and atopy (but not gender) were predictors of FeNO. Smoking was negatively associated with FeNO 1 In another study (n=895), FeNO was found to be: 2 25% lower in females (gender) 50% lower in smokers (especially if smoked the same day) 60% higher in the presence of atopy In our study, the only independent predictors of FeNO were asthma, allergic rhinitis and current smoking 3 1 Olin AC, Chest 2006; 2 Taylor DR, Respir Res 2007; 3 Kostikas K, Chest 2008
FeNO: Personal Best vs. Predicted Values 1 Olin AC, Chest 2007; 2 Travers J, AJRCCM 2007 3 Dressler H, Respir Med 2008; 4 Smith AD, JACI 2009
Parameters Related to Asthma in an Unselected Birth Cohort Study Isle of Wight birth cohort (n=1456) reassessed at 18 years of age Scott M, Thorax 2010
Increased FeNO Predicts New-Onset Wheeze n=2,200 from a general population-based study All subjects reporting wheeze, asthma, or asthma symptoms at baseline were excluded resulting in a study population of 1,506 subjects Olin A-C, AJRCCM 2010
Portable FeNO as a Screening Tool for Asthma in Young Adults During Pollen Season p<0.0001 120 100 p<0.0001 p<0.0001 p=ns p<0.0001 NO (ppb) F E 80 60 40 20 0 F E NO (ppb) 10.5 (7.0, 13.0) Controls Asthma Allergic Rhinitis 20.0 (14.0, 31.0) 17.0 (12.5, 23.0) Non-specific symptoms 11.0 (8.5, 12.5) Data are presented as median (interquartile ranges) Kostikas K, Chest 2008
Portable FeNO as a Screening Tool for Asthma in Young Adults During Pollen Season Non-Smokers Smokers Cut-off points Sensitivity Specificity Sensitivity Specificity >30 ppb 41.0 94.3 4.8 96.0 >25 ppb 46.2 91.5 6.2 92.0 >20 ppb 64.1 84.9 25.0 86.0 >15 ppb 79.5 65.1 50.0 68.0 >10 ppb 94.9 30.2 70.8 44.0 Kostikas K, Chest 2008
Effects of ICS on Inflammatory Cell Subtypes n=94 Eosinophilic (EA) vs. Non-Eosinophilic Asthma (NEA) Treatment response greater in EA: symptoms (p<0.001), QoL (p=0.012), AHR (p=0.036), FeNO (p=0.007) Lesser but significant changes occurred in NEA FeNO best predictor of steroid response in NEA (AUC 0.810, optimum cut-point of 33ppb) Cowan DC, Thorax 2010 (in press)
FeNO Predicts Control in DTT of Asthma 102 consecutive patients with suboptimal asthma control received SFC 50/500 for 1 month - then, those who remained uncontrolled received oral CS for 1 month 53 patients (52%) gained control Those who achieved control were more likely to have positive skin results (60.4 % vs. 34 %; p = 0.01) positive bronchodilator test (57.1 % vs. 35.8 %; p = 0.02) PEFR variability 20% (71.1 % vs. 49.1 %; p = 0.04) FeNO 30 ppb demonstrated a sensitivity of 87.5% and a specificity of 90.6% for the identification of responsive asthmatics (AUC=0.925) Pérez de Llano LA, ERJ 2010 (in press)
Μεταβολή FeNO και έλεγχος άσθματος Μείωση του FeNO κατά 40% σχετιζόταν με βελτίωση του άσθματος (ΝPV 79%) Αύξηση του FeNO κατά 30% σχετιζόταν με επιδείνωση του άσθματος (NPV 82%) Michils Α, ERJ 2008
Μεταβολή FeNO και έλεγχος άσθματος: Καπνιστές Ελάττωση του FeNO κατά 20% υποδηλώνει βελτίωση του άσθματος τόσο σε μη καπνιστές (NPV 78%) όσο και σε καπνιστές (NPV 72%) Αύξηση του FeNO κατά 30% σχετίζεται με επιδείνωση του άσθματος και στις δύο ομάδες ασθενών (NPV 86% και 84% αντίστοιχα σε μη καπνιστές και καπνιστές) Michils Α, ERJ 2009
Μεταβολή FeNO και Έλεγχος Άσθματος: Αλλεργική Ρινίτιδα Papaioannou AI, ERJ 2009
FeNO and Lung Function Decline in Difficult to Treat Asthma Van Veen IH, ERJ 2008
Eosinophilic Inflammation Predicts Lung Function Decline in Asthma with Fixed Airflow Obstruction 5-year follow up of patients with Asthma and COPD with fixed airflow obstruction Contoli M, J All Clin Immunol 2010 (in press)
FeNO and persistent eosinophilic phenotype in Severe Refractory Asthma 17 controls 15 pts. mild-moderate asthma 24 pts. severe refractory asthma (SRA) Correlation of FeNO with tissue eosinophils only in pts with SRA r s = 0.54, p = 0.007 FeNO values >72.9 ppb predict the presence of tissue eosinophilia Sensitivity 0.56 - Specificity 1.0 (AUC=0.83) Silkoff PE, J All Clin Immunol 2005
Sensitivity Sensitivity FeNO in SRA: Prediction of Sputum Cell Counts 100 FeNO-SRA 100 FeNO-SRA 80 80 60 60 40 40 20 20 0 0 20 40 60 80 100 100-Specificity 0 0 20 40 60 80 100 100-Specificity Sputum Eosinophilia FeNO level > 19ppb Sensitivity 0.78 - Specificity 0.73 AUC of 0.8 (95% CI 0.6-0.9, p=0.0001) Sputum Neutrophilia FeNO level <19 ppb Sensitivity 0.63 - Specificity 0.9 AUC 0.79 (95% CI 0.6-0.9, p=0.0009) Tseliou E, Chest 2010 (in press)
Asthma Phenotypes Cluster Analysis (SARP) Moore W, AJRCCM 2010
FeNO Identifies a Reactive At Risk Asthma Phenotype (NHLBI SARP) 446 pts w. asthma (175 severe, 271 non-severe) and 49 healthy FeNO similar among severe and non-severe asthma patients The proportion of individuals with high FENO levels (> 35 ppb) was the same (40%) among groups (despite more CS in severe asthma) Asthmatics with high FENO had more airway reactivity (B/D response and by methacholine AHR) more evidence of allergic airway inflammation (sputum eosinophils) more evidence for atopy (skin tests, serum IgE and blood eosinophils) more hyperinflation decreased awareness of their symptoms High FENO identified those severe asthma patients characterized by the greatest airflow obstruction and hyperinflation and most frequent utilization of emergency care in the previous year Dweik RA, AJRCCM 2010 (in press)
Clinical Asthma Phenotype and Management of Eosinophilic inflammation Haldar P, AJRCCM 2008
The greater our knowledge increases, the greater our ignorance unfolds John F. Kennedy
Always look on the bright side of life
Algorithm for Assessment of Airways Disease Pavord ID, Shaw DE, Gibson PG, Taylor DR; Lancet 2008
Omalizumab (Xolair ) and Eosinophils Djucanovic R, AJRCCM 2004
Omalizumab (Xolair ) and FeNO Steroid Stable Phase Steroid Reduction Phase Open-Label Silkoff P, Pediatrics 2004
Mepolizumab (anti-il-5) in Severe Refractory Eosinophilic Asthma 2.0 vs. 3.4 Haldar P et al. N Engl J Med 2009;360:973-984
Mepolizumab (anti-il-5) in Severe Refractory Eosinophilic Asthma Haldar P et al. N Engl J Med 2009;360:973-984
Asthma Management by Monitoring Sputum Neutrophil Counts A Light at the End of the Tunnel of Inflammation in Obstructive Airway Diseases? Gibson PG, Chest 2008 (EDITORIAL) Pallan S, Chest 2008
Macrolides in Severe Refractory Asthma Simpson JL, AJRCCM 2007
And a few numbers In both treated and untreated asthmatic patients: Sputum eosinophilia >3% Sputum neutrophilia >60% (>40%) In untreated subjects with respiratory symptoms FeNO <25 ppb "normal" FeNO 25-50 ppb "present, but mild" FeNO >50 ppb "significant" In treated asthmatics increase ICS if FeNO >35 ppb (>50 ppb) or increase >30-40%
Factors Affecting FeNO Measurements Aerocrine, Sweden
Caffeine and FeNO Taylor ES, AJRCCM 2004; Welsh EJ Cochrane 2010
Viagra does not increase FeNO (!) Rothe T, Respir Med 2010
Η ιστορία της Τζούλια ή μια ευαίσθητη ιστορία προσωπικών δεδομένων
Η ιστορία της Τζούλια Έγκυος 42 ετών (28η εβδομάδα κύησης) με επαπειλούμενη εγκυμοσύνη προσέρχεται λόγω βήχα και δύσπνοιας Λαμβάνει από εβδομάδος αμοξυκιλλίνη και FORM/BDP 6/100 1x2 χωρίς βελτίωση Κλινικώς: παράταση εκπνοής, ρινική συμφόρηση και οπισθορρινική έκκριση FeNO 52 ppb
Η ιστορία της Τζούλια Τίθεται σε BUD 400 μg x 2 και nasal BUD 64 μg 2x2 και σετιριζίνη PO Εμφανίζει βελτίωση της κλινικής της εικόνας, με ύφεση του βήχα και της ρινικής συμφόρησης και σε 2 εβδομάδες εμφανίζει FeNO 32 ppb Διατηρείται η αγωγή της και της ορίζεται ραντεβού σε 4 εβδομάδες
Η ιστορία της Τζούλια 4 εβδομάδες αργότερα εμφανίζει δύσπνοια με συρίττουσα αναπνοή, συχνή ανάγκη για λήψη SABA και νυκτερινές αφυπνίσεις. Τίθεται επιπλέον σε FORM 12 μg x 2, αλλά μετά τις 2 πρώτες δόσεις εμφανίζει τρόμο και ανησυχία. Σε επανεκτίμηση, η συρίττουσα αναπνοή επιμένει και εμφανίζει FeNO 56 ppb Τίθεται σε BUD 800 μg x 2 και σε 4 εβδομάδες δεν εμφανίζει νυκτερινές αφυπνίσεις και δεν λαμβάνει SABA. Σε νέα μέτρηση FeNO 18 ppb
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