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 anatomopatologiche 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
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
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
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
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?
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 DRN 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
R. Cutrera, Milano, 2008
Closed circles, FENO group;
open triangles, symptom group
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
Closed circles, FENO group;
FeNO
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
R. Cutrera, Milano, 2008
Miglioramento FeNO
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
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 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
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 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
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
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
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
Studi esaminati: differenze
tra gruppo FeNo e Controllo
Riacutizzazioni
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
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
Si
vie aeree?
E’ utile misurare l’infiammazione delle
vie aeree in tutti i bambini con asma?
Si, almeno una volta,
e sempre nelle asma che non rispondono alla terapia
E’ utile misurare l’infiammazione delle
vie aeree routinariamente in tutti i
bambini con asma? No allo stato attuale delle conoscenze
Tutti i pediatri che curano un bambino
asmatico dovrebbero possedere la
tecnologia per misurare l’infiammazione
delle vie aeree? No
Ogni centro specialistico che segue
bambini asmatici dovrebbe possedere la
tecnologia per misurare l’infiammazione
delle vie aeree? Si
R. Cutrera, Milano, 2008