Dal Mito alla Realtà 31 Gennaio – 2 Febbraio 2008 Atahotel Executive Milano Usare i markers della flogosi non migliora molto la terapia dell’asma Renato Cutrera Dir. U.O.C. Broncopneumologia Dipartimento Medicina Pediatrica (Prof. A.G. Ugazio) Ospedale Pediatrico Bambino Gesù IRCCS - Roma R. Cutrera, Milano, 2008

Domande che mi farei? E’ utile misurare l’infiammazione delle vie aeree? E’ utile misurare l’infiammazione delle vie aeree in tutti i bambini con asma? E’ utile misurare l’infiammazione delle vie aeree routinariamente in tutti i bambini con asma? Tutti i pediatri che curano un bambino asmatico dovrebbero possedere la tecnologia per misurare l’infiammazione delle vie aeree? Ogni centro specialistico che segue bambini asmatici dovrebbe possedere la tecnologia per misurare l’infiammazione delle vie aeree? R. Cutrera, Milano, 2008

Asma bronchiale: definizione L’asma è una malattia infiammatoria cronica delle vie aeree caratterizzata da: Episodi ricorrenti di dispnea, respiro sibilante, tosse e senso di costrizione toracica Ostruzione bronchiale (di solito reversibile spontaneamente o dopo trattamento farmacologico) Iperreattività bronchiale Infiltrazione di cellule infiammatorie, rilascio di mediatori e rimodellamento strutturale delle vie aeree R. Cutrera, Milano, 2008

Principali caratteristiche anatomo-patologiche dell’asma bronchiale Quadro anatomo-patologico della morte per asma. In questa via aerea periferica si può notare che il lume è completamente ostruito da muco e detriti cellulari. La parete del bronchiolo presenta un aumento dell’area occupata dal muscolo liscio, ectasia dei vasi ed un marcato infiltrato infiammatorio, costituito prevalentemente da granulociti eosinofili. La biopsia bronchiale con fibroscopio a fibre ottiche è il gold standard per la misurare l’infiammazione delle vie aeree nell’asma ma è: Invasiva Non ripetibile R. Cutrera, Milano, 2008

Altri metodi di analisi Challenge all’istamina o alla metacolina Interpretazione confusa dall’uso di broncodilatatori Difficile da attuare in pazienti gravi e bambini  Metodo dell’espettorato indotto Abbastanza fastidioso Ripetibile non prima di 24 ore R. Cutrera, Milano, 2008

Markers dell’infiammazione nell’aria espirata Metodica non invasiva Facile da misurare Istantanea e ripetibile Attuabile in pazienti gravi e bambini  Supera il concetto di sintomo Utile nella diagnosi differenziale Valuta la gravità della malattia Valuta la risposta al trattamento R. Cutrera, Milano, 2008

Markers dell’infiammazione nell’aria espirata Ossido Nitrico (NO) Monossido di carbonio (CO) Idrocarburi esalati Breath-condensate R. Cutrera, Milano, 2008

Ossido Nitrico (NO) Prodotto da cellule epiteliali In risposta a citochine proinfiammatorie NO  in asma, CF, bronchiolite obliterante R. Cutrera, Milano, 2008

FUNZIONALITA’ RESPIRATORIA Ossido d’Azoto (NO) marcatore di infiammazione FUNZIONALITA’ RESPIRATORIA R. Cutrera, Milano, 2008

Cosa sappiamo del FeNO nell’asma È correlato a infiammazione eosinofilica (Payne, AJRCCM 2001) È elevato nell’asma atopico (Alving, Eur Resp J, 1993) È ridotto da ICS (Kharitonov, Lancet 1994) È utile nel decidere a quali pazienti iniziare ICS (Smith, AJRCCM 2005) È utile nel decidere quando interrompere ICS (Pijnenburg, Thorax 2005) R. Cutrera, Milano, 2008

Taylor, D R et al. Thorax 2006;61:817-827 Exhaled nitric oxide measurements: clinical application and interpretation. Taylor, D R et al. Thorax 2006;61:817-827 R. Cutrera, Milano, 2008

Taylor, D R et al. Thorax 2006;61:817-827 Exhaled nitric oxide measurements: clinical application and interpretation. Taylor, D R et al. Thorax 2006;61:817-827 R. Cutrera, Milano, 2008

Ma abbiamo bisogno del FeNO come un infiammometro? Misurare spesso il FeNO con gli obbiettivi di: Predire e diminuire le riacutizzazioni Ottimizzare (diminuire) la dose di ICS Migliorare il calibro bronchiale? R. Cutrera, Milano, 2008

Use of Exhaled Nitric Oxide Measurements to Guide Treatment in Chronic Asthma Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR- N Engl J Med 2005;352:2163–2173. Single-blind, placebo-controlled trial 97 patients (12-75 yrs) with chronic asthma Primary care setting Regularly receiving treatment with inhaled corticosteroids for 6 months or more Corticosteroid dose adjusted, in a stepwise fashion, on the basis of either FeNO measurements or an algorithm based on conventional guidelines (GINA) Use of long acting beta 2 agonist was discontinued Primary outcome: frequency of asthma exacerbations Secondary outcome: mean daily dose of inhaled steroid. R. Cutrera, Milano, 2008

Use of Exhaled Nitric Oxide Measurements to Guide Treatment in Chronic Asthma Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR- N Engl J Med 2005;352:2163–2173. R. Cutrera, Milano, 2008

Use of Exhaled Nitric Oxide Measurements to Guide Treatment in Chronic Asthma Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR- N Engl J Med 2005;352:2163–2173. R. Cutrera, Milano, 2008

Use of Exhaled Nitric Oxide Measurements to Guide Treatment in Chronic Asthma Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR- N Engl J Med 2005;352:2163–2173. Primary Outcome: Total rate of exacerbations: FeNO group: 0.49 exacerb ppyr Control group 0.90 p=0.27. 45.6 percent reduction Secondary outcomes (1) No significant differences: Nighttime wakening Use of bronchodilators Symptom free days Prednisone courses R. Cutrera, Milano, 2008

Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR- Use of Exhaled Nitric Oxide Measurements to Guide Treatment in Chronic Asthma Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR- N Engl J Med 2005;352:2163–2173. Secondary Outcome (2): The final mean daily doses of fluticasone were: FeNO group 370 μg per day Control group: 641 μg per day difference of 270 μg per day p=0.003 R. Cutrera, Milano, 2008

Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma Pijnenburg MW, Bakker EM, HopWC, De Jongste JC. Am J Respir Crit Care Med 2005;23:23. DBRCT tertiary care setting 85 children (6-18 yrs) with atopic asthma, using inhaled steroids for 3 months or more, were allocated to: FENO group (n 39) in which treatment decisions were made on both FENO and symptoms, Symptom group (n 46) treated on symptoms only. Children were seen every 3 months over a 1-year period. Beta 2 long acting permitted R. Cutrera, Milano, 2008

Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma Pijnenburg MW, Bakker EM, HopWC, De Jongste JC. Am J Respir Crit Care Med 2005;23:23. Primary endpoint: Cumulative steroid dose Secondary endpoints: Mean daily symptom score Bronchodilator use Symptoms free days (last 4 weeks) Oral prednisone courses PD20 at final visit FVC, FEV1, MEF25 at final visit R. Cutrera, Milano, 2008

Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma Pijnenburg MW, Bakker EM, HopWC, De Jongste JC. Am J Respir Crit Care Med 2005;23:23. Primary endpont: Mean (SEM) cumulative ICS doses did not differ between groups: FeNO group: 4,407 (367) g Symptom group 4,332 (383) g (p=0.73). In both groups, mean daily ICS dose increased between Visits 1 and 2: FeNO group: by 169 g (p 0.001) Symptom group: by 172 g (p 0.001) The dose increase between Visits 1 and 5 was not significant within groups and did not differ between groups Closed circles, FENO group; open triangles, symptom group R. Cutrera, Milano, 2008

Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma Pijnenburg MW, Bakker EM, HopWC, De Jongste JC. Am J Respir Crit Care Med 2005;23:23. Miglioramento FEV1 Secondary endponts: No differences in: Mean daily symptom score Bronchodilator use Symptoms free days (last 4 weeks) Oral prednisone courses Significant differences in: PD20 FEV1 FeNO Closed circles, FENO group; open triangles, symptom group R. Cutrera, Milano, 2008

Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma Pijnenburg MW, Bakker EM, HopWC, De Jongste JC. Am J Respir Crit Care Med 2005;23:23. Miglioramento FEV1 Miglioramento FeNO R. Cutrera, Milano, 2008

Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma Pijnenburg MW, Bakker EM, HopWC, De Jongste JC. Am J Respir Crit Care Med 2005;23:23. Conclusions: we have shown that a treatment algorithm using FeNO for ICS dose titration every 3 months for 1 year is superior to conventional treatment guided by symptoms, and leads to similar clinical asthma control and less airway hyperresponsiveness, obstruction, and inflammation with a similar ICS dose. Conclusioni (personali): Il primary endpoint dello studio (diminuzione dello steroide) è negativo I secondary endpoints clinici sono negativi I secondary endpoint funzionali sono significativi Utilizzando il FeNO non diminuiremo lo steroide necessario, i sintomi non miglioreranno, ma avremo meno infiammazione, ostruzione e BHR R. Cutrera, Milano, 2008

SBRCT in tertiary care setting Exhaled Nitric Oxide in the Management of Childhood Asthma: A Prospective 6-Months Study Fritsch M, Uxa S., Horak F Jr, Putschoegl B., Dehlink E., Szepfalusi Z., and Frischer T. Pediatr. Pulmonol.2006;41:855-862 SBRCT in tertiary care setting 47 children (6-18 yrs) mild to moderate atopic asthma: FeNO group (22) Control group (25) Patients performed five visits in 6 weeks intervals. R. Cutrera, Milano, 2008

Exhaled Nitric Oxide in the Management of Childhood Asthma: A Prospective 6-Months Study Fritsch M, Uxa S., Horak F Jr, Putschoegl B., Dehlink E., Szepfalusi Z., and Frischer T. Pediatr. Pulmonol.2006;41:855-862 German asthma guidelines Cut off point for FeNO 20 ppb Beta 2 long acting and montelukast permitted Primary outcome: FEV1 Secondary outcome: Exacerbations, Symptom control, ICS dose, Bronchodilators use MEF50, BHR PD15 R. Cutrera, Milano, 2008

nessuna differenza tra gruppi per outcome primario e secondari Exhaled Nitric Oxide in the Management of Childhood Asthma: A Prospective 6-Months Study Fritsch M, Uxa S., Horak F Jr, Putschoegl B., Dehlink E., Szepfalusi Z., and Frischer T. Pediatr. Pulmonol.2006;41:855-862 Risultati: nessuna differenza tra gruppi per outcome primario e secondari R. Cutrera, Milano, 2008

The Use of Exhaled Nitric Oxide to GuideAsthma Management: A Randomized Controlled Trial Shaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, and Pavord ID Am J Respir Crit Care Med Vol 176. pp 231–237, 2007 118 adults with a primary care diagnosis of asthma were randomized to a SBRCT of corticosteroid therapy based on: FENO measurements (n=58) BTS guidelines (n= 60). Assessed monthly for 4 months then every 2 months for a further 8 months. The primary outcomes: severe asthma exacerbations dosage of ICS (BDP equivalent) R. Cutrera, Milano, 2008

The Use of Exhaled Nitric Oxide to GuideAsthma Management: A Randomized Controlled Trial Shaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, and Pavord ID Am J Respir Crit Care Med Vol 176. pp 231–237, 2007 In the FeNO group, treatment was adjusted following a set protocol according to both the FeNO and Juniper scores. If the FeNO was greater than 26 ppb, inhaled corticosteroid treatment was increased; if the FeNO was less than 16 ppb or less than 26 ppb on two consecutive occasions, treatment was decreased. Asthma control: Juniper asthma control questionnaire (scores asthma control from 0 to 6) score of greater than 1.57 was used to identify poorly controlled asthma. In the control group treatment was doubled if the score was more than 1.57, and treatment was halved if the score was less than 1.57 for 2 consecutive months R. Cutrera, Milano, 2008

The estimated mean (SD) exacerbation frequency was: The Use of Exhaled Nitric Oxide to GuideAsthma Management: A Randomized Controlled Trial Shaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, and Pavord ID Am J Respir Crit Care Med Vol 176. pp 231–237, 2007 Primary outcome: The estimated mean (SD) exacerbation frequency was: FENO group: 0.33 per patient per year (0.69) Control group: 0.42 (0.79) (mean difference, 21%; p= 0.43). Cumulative exacerbations in the control (dotted line) and FENO (solid line) groups. R. Cutrera, Milano, 2008

Overall the FENO group used 11% more inhaled corticosteroid (p= 0.40) The Use of Exhaled Nitric Oxide to GuideAsthma Management: A Randomized Controlled Trial Shaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, and Pavord ID Am J Respir Crit Care Med Vol 176. pp 231–237, 2007 Overall the FENO group used 11% more inhaled corticosteroid (p= 0.40) The final daily dose of inhaled corticosteroid was lower in the FENO group (557 vs. 895 g; mean difference, 338 g; p= 0.028). FENO group, closed circles; control group, open circles. R. Cutrera, Milano, 2008

did not result in a large reduction in asthma exacerbations The Use of Exhaled Nitric Oxide to GuideAsthma Management: A Randomized Controlled Trial Shaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, and Pavord ID Am J Respir Crit Care Med Vol 176. pp 231–237, 2007 Conclusions: An asthma treatment strategy based on the measurement of FeNO did not result in a large reduction in asthma exacerbations or in the total amount of inhaled corticosteroid therapy used over 12 mo, when compared with current asthma guidelines. R. Cutrera, Milano, 2008

Studi esaminati: metodologia Setting Durata ICS FeNO ppb LABA Smith, NEJM 2005 Ad Primary Care 12-24 mesi FP 35 NO Shaw, AJRCCM 2007 Primary Care 12 mesi BDP equival 26 SI Pijnenburg, AJRCCM 2005 Ped Tertiary Care 12 mesi BUD equival 30 Fritsch, PedPulm 2006 6 20 SI + antilk R. Cutrera, Milano, 2008

Studi esaminati: differenze tra gruppo FeNo e Controllo Riacutiz-zazioni Controllo Asma Dose ICS Funzionalità Respiratoria Smith, NEJM 2005 NO SI Shaw, AJRCCM 2007 No cumulat. SI fine studio Pijnenburg, AJRCCM 2005 SI BHR FEV1 FeNO Fritsch, PedPulm 2006 MEF50 R. Cutrera, Milano, 2008

Problemi aperti Differenti fenotipi di asma Algoritmi di trattamento differenti Utilizzo di farmaci concomitanti Valori di normalità del FeNo (età altezza, inquinamento atmosferico) Cut point “patologico” su cui agire Correlazione tra FeNo e eosinofili bronchiali Coesistenza di infiammazione eosinofila e neutrofila nello stesso momento R. Cutrera, Milano, 2008

Risposte che provo a dare E’ utile misurare l’infiammazione delle vie aeree? E’ utile misurare l’infiammazione delle vie aeree in tutti i bambini con asma? E’ utile misurare l’infiammazione delle vie aeree routinariamente in tutti i bambini con asma? Tutti i pediatri che curano un bambino asmatico dovrebbero possedere la tecnologia per misurare l’infiammazione delle vie aeree? Ogni centro specialistico che segue bambini asmatici dovrebbe possedere la tecnologia per misurare l’infiammazione delle vie aeree? Si Si, almeno una volta, e sempre nelle asma che non rispondono alla terapia No allo stato attuale delle conoscenze No Si R. Cutrera, Milano, 2008