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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)

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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 aereeroutinariamente 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

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 bronchiale

  • 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

R. Cutrera, Milano, 2008


Markers dell’infiammazione bronchiale

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 bronchiale

nell’aria espirata

  • Ossido Nitrico (NO)

  • Monossido di carbonio (CO)

  • Idrocarburi esalati

  • Breath-condensate

R. Cutrera, Milano, 2008


Ossido nitrico no
Ossido Nitrico (NO) bronchiale

  • Prodotto da cellule epiteliali

  • In risposta a citochine proinfiammatorie

  • NO  in asma, CF, bronchiolite obliterante

R. Cutrera, Milano, 2008


FUNZIONALITA’ RESPIRATORIA

R. Cutrera, Milano, 2008


Cosa sappiamo del feno nell asma
Cosa sappiamo del FeNO nell’asma bronchiale

  • 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


Exhaled nitric oxide measurements: clinical application and interpretation.

Taylor, D R et al. Thorax 2006;61:817-827

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 feno come un infiammometro
Ma abbiamo bisogno del FeNO interpretation. 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


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 Chronic Asthma

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 Chronic Asthma

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 Chronic Asthma

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 Chronic Asthma

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 Chronic Asthma

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 Chronic Asthma

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


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


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 Prospective 6-Months StudyA 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 Prospective 6-Months StudyA 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

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 Use of Exhaled Nitric Oxide to GuideAsthma Management: A Prospective 6-Months StudyA 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 Prospective 6-Months StudyA 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 Prospective 6-Months StudyA 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
Studi esaminati: metodologia A Prospective 6-Months Study

R. Cutrera, Milano, 2008


Studi esaminati: differenze A Prospective 6-Months Studytra gruppo FeNo e Controllo

R. Cutrera, Milano, 2008


Problemi aperti
Problemi aperti A Prospective 6-Months Study

  • 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 A Prospective 6-Months Study

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


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