r. cutrera, milano, 2008 renato cutrera dir. u.o.c. broncopneumologia dipartimento medicina...
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R. Cutrera, Milano, 2008
Renato CutreraDir. U.O.C. Broncopneumologia
Dipartimento Medicina Pediatrica (Prof. A.G. Ugazio)Ospedale Pediatrico Bambino Gesù IRCCS - Roma
Usare i markers della flogosi non migliora molto la terapia
dell’asma
Dal Mito alla Realtà31 Gennaio – 2 Febbraio 2008
Atahotel Executive Milano
R. Cutrera, Milano, 2008
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?
Domande che mi farei?
R. Cutrera, Milano, 2008
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
Asma bronchiale: definizione
R. Cutrera, Milano, 2008
Principali caratteristiche anatomo-patologiche dell’asma bronchiale
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
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 Difficile da attuare in pazienti gravi e bambini Ripetibile non prima di 24 ore
Altri metodi di analisiAltri metodi di analisi
R. Cutrera, Milano, 2008
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
Markers dell’infiammazioneMarkers dell’infiammazionenell’aria espiratanell’aria espirata
R. Cutrera, Milano, 2008
Ossido Nitrico (NO) Monossido di carbonio (CO) Idrocarburi esalati Breath-condensate
Markers dell’infiammazioneMarkers dell’infiammazionenell’aria espiratanell’aria espirata
R. Cutrera, Milano, 2008
Ossido Nitrico (NO)Ossido Nitrico (NO)
Prodotto da cellule epiteliali
In risposta a citochine proinfiammatorie
NO in asma, CF, bronchiolite obliterante
R. Cutrera, Milano, 2008
Ossido d’Azoto (NO) marcatore di infiammazione
FU
NZ
ION
ALIT
A’
RES
PIR
ATO
RIA
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.
R. Cutrera, Milano, 2008
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 FeNOcome 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 AsthmaSmith 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 AsthmaSmith 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 AsthmaSmith 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 AsthmaSmith 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 reductionSecondary outcomes (1) No significant differences:
Nighttime wakening
Use of bronchodilators
Symptom free days
Prednisone courses
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.
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 AsthmaPijnenburg 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 AsthmaPijnenburg 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 AsthmaPijnenburg 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 AsthmaPijnenburg MW, Bakker EM, HopWC, De Jongste JC. Am J Respir Crit Care Med 2005;23:23.
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
Miglioramento FEV1
R. Cutrera, Milano, 2008
Titrating Steroids on Exhaled Nitric Oxide
in Children with AsthmaPijnenburg 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 AsthmaPijnenburg 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
Exhaled Nitric Oxide in the Management of Childhood Asthma: A Prospective 6-Months StudyFritsch 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 setting47 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 StudyFritsch 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
Exhaled Nitric Oxide in the Management of Childhood Asthma: A Prospective 6-Months StudyFritsch 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 TrialShaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ,
and Pavord IDAm 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 TrialShaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ,
and Pavord IDAm J Respir Crit Care Med Vol 176. pp 231–237, 2007
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
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.
R. Cutrera, Milano, 2008
The Use of Exhaled Nitric Oxide to GuideAsthma Management: A Randomized
Controlled TrialShaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ,
and Pavord IDAm 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
The Use of Exhaled Nitric Oxide to GuideAsthma Management: A Randomized
Controlled TrialShaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ,
and Pavord IDAm 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
The Use of Exhaled Nitric Oxide to GuideAsthma Management: A Randomized
Controlled TrialShaw DE,. Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ,
and Pavord IDAm 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
Età Setting Durata ICS FeNO
ppb
LABA
Smith, NEJM 2005
Ad Primary
Care
12-24 mesi
FP 35 NO
Shaw, AJRCCM 2007
Ad Primary Care
12 mesi
BDP equival
26 SI
Pijnenburg, AJRCCM 2005
Ped Tertiary Care
12
mesi
BUD equival
30 SI
Fritsch, PedPulm 2006
Ped Tertiary Care
6
mesi
BUD equival
20 SI + antilk
R. Cutrera, Milano, 2008
Riacutiz-zazioni
Controllo Asma
Dose
ICS
Funzionalità Respiratoria
Smith, NEJM 2005
NO NO SI NO
Shaw, AJRCCM 2007
NO NO No cumulat.
SI fine studio
NO
Pijnenburg, AJRCCM 2005
NO NO NO SI BHR FEV1 FeNO
Fritsch, PedPulm 2006
NO NO NO MEF50
Studi esaminati: differenze
tra gruppo FeNo e Controllo
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
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?
Risposte che provo a dare
Si
Si, almeno una volta, e sempre nelle asma che non rispondono alla terapia
No allo stato attuale delle conoscenze
No
Si
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