stefano miceli sopo sopo stefano.pdf•exacerbations represent an acute or sub-acute worsening in...
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Stefano Miceli Sopo
L’ utilizzo dei cortisonici inalatori, un dettaglio
SMS
Lo spuntino per il dettaglioLa Pagina Gialla, Medico e Bambino 6/2016
• Uno studio su 99 bambini (2-13 anni) con asma medio-severo trattati per
almeno un anno con fluticasone non ha mostrato un rallentamento della
crescita dopo i primi tre mesi di trattamento (Wardenier NR, et al. Arch Dis
Child 2016;101(7):637-9).
• Del perché l’effetto negativo della terapia corticosteroidea inalatoria cessi nel
tempo non c’è ancora spiegazione e, secondo gli Autori, la terapia può essere
tranquillamente data almeno per un anno.
• Chi siano tutti questi bambini che debbano essere trattati in maniera
continuativa anziché in maniera intermittente (al bisogno), come da tempo la
letteratura ci suggerisce di fare senza rischio di peggiorare il controllo della
malattia, ci rimane meno chiaro.
SMS
In effetti …DH di allergologia pediatrica, 21 Luglio 2017
• Antonio, svedo-calabrese di anni 9, abita a Stoccolma, in vacanza viene a farsi i
TPO con amoxicillina-clavulanato al Gemelli
• Ci racconta che, quando era piccolo, il suo pediatra di Stoccolma, vista la sua
iper-reattività bronchiale, ad ogni inizio di tosse e raffreddore, gli faceva
assumere due spruzzi di Fluticasone da 50 mcg 4 volte al giorno (400 mcg) più
due spruzzi di Salbutamolo 4 volte al giorno per i primi due giorni; poi
dimezzava le dosi per altri 8 giorni. E stava bene.
• E in Italia? Questa è, all’ incirca, la durata
della modalità intermittente, o al
bisogno. Almeno secondo la
letteratura scientifica.
SMS
Sapevi dell' utilizzo dei CSI ad intermittenza nell' asma pediatrico?Sondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017
SMS
Condividi la posizione espressa nella Pagina Gialla suddetta secondo
la quale la maggioranza dei bambini con asma possono essere
trattati con i CSI ad intermittenza invece che continuativa?Sondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017
SMS
Quali fonti hanno contribuito alla tua conoscenza in merito ai CSI ad
intermittenza? Puoi scegliere più opzioniSondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017
Ricordatevi
di questa
diapositiva
quando
citerò le LG
BTS 2016
SMS
Utilizzi i CSI ad intermittenza nell' asma?Sondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017
SMS
Se sì, che caratteristiche devono avere i bambini asmatici per essere
trattati da te con i CSI ad intermittenza?Sondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017
SMS
Quali dosaggi adoperi quando utilizzi i CSI ad intermittenza?Sondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017
Che diranno le LG su
questo dettagliuzzo?
SMS
Le Linee Guida BTS 2016
• Pag. 66: “An RCT comparing daily ICS with intermittent (rescue) ICS in children aged 6 -
18 years with mild persistent asthma suggests that daily ICS are more effective at
preventing asthma attacks. (Martinez et al, Lancet 2011 [Studio TREXA])” *
• Pag. 108: “There is insufficient evidence to support the use of ICS as alternative or
additional treatment to steroid tablets for children with acute asthma. Do not use
inhaled corticosteroids in place of oral steroids to treat children with an acute asthma
attack (raccomandazione di grado A).”
• Pag. 147 nell’ ambito del paragrafo RECOMMENDATIONS FOR RESEARCH: “Is
intermittent ICS therapy more, the same, or less effective than daily ICS therapy?”
RIMANDATO
* 3 righe vs le 5
pagine fitte dell’
analisi effettuata da
Marcello Bergamini
SMS
Le Linee Guida GINA 2017
• Pag. 76 (Management of exacerbations) : “There is emerging evidence in adults and
young children that higher ICS doses might help prevent worsening asthma
progressing to a severe exacerbation.” (per i bambini citato lo studio di Ducharme et al,
NEJM 2009)”
PROMOSSO?
In contraddizione?
Non proprio, vedremo
Esacerbazione? Attacchi?
SMS
Definizione di EsacerbazioneLG GINA 2017
• Exacerbations represent an acute or sub-acute
worsening in symptoms and lung function from
the patient’s usual status or, in some cases, the
initial presentation of asthma.
• The term “episodes”, “attacks”, and “acute
severe asthma” are also often used.
Dalle LG passiamo alle RS
SMS
Le RS della Cochrane LibraryChong et al, 2015 (intermittent vs placebo)
• In children and adults with mild persistent asthma, two studies have shown that the
use of intermittent ICS at the time of exacerbation reduced the chances of needing
oral corticosteroids by half.
• The paucity of published evidence limits our conclusions towards the ’as-needed’ use of
this medication.
• The small number of studies and participants were the major reasons for downgrading
the overall quality of the findings.
• A corresponding result was found in preschool children with wheeze.
• There was no statistical difference in hospitalisation rates in any group.
SMS
Le RS della Cochrane Library - A1Chauhan et al, 2013 (intermittent vs daily)
• In children and adults with persistent asthma and in preschool children suspected of
persistent asthma, there was low quality evidence that intermittent and daily ICS
strategies were similarly effective in the use of rescue oral corticosteroids and the rate
of severe adverse health events. The strength of the evidence means that we cannot
currently assume equivalence between the two options.
• Daily ICS was superior to intermittent ICS in several indicators of lung function, airway
inflammation, asthma control and reliever use.
• Both treatments appeared safe, but a modest growth suppression was associated with
daily, compared to intermittent, inhaled budesonide and beclomethasone.
• Clinicians should carefully weigh the potential benefits and harm of each treatment
option, taking into account the unknown long-term (> one year) impact of intermittent
therapy on lung growth and lung function decline.
E le BTS allora? E l’
apprendimento tramite congressi e
Forum? E Bergamini?
SMS
Le RS della Cochrane Library - A2Chauhan et al, 2013 (intermittent vs daily)
Exacerbations
• There was no statistically significant
group difference in:
• the number of patients with
exacerbation requiring emergency
department visits
• the number of patients
experiencing at least one
exacerbation requiring hospital
admission
• the number of exacerbations
(event rate) requiring emergency
department visits
• and the time to first exacerbation
requiring oral corticosteroids
SMS
Le RS della Cochrane Library - A3Chauhan et al, 2013 (intermittent vs daily)
Asthma control
• There was a statistically significant group difference in disfavor of intermittent
ICS compared to daily ICS in:
• the change from baseline in asthma control days
• the proportion of asthma control days
• the change from baseline in the mean daily use of beta2-agonists
• cumulative dose of rescue albuterol over the period
• and the change in the proportion of symptom-free days.
• No statistically significant group difference was observed in:
• the change from baseline in daytime symptoms scores
• the change from baseline in night-time awakenings and quality of life
SMS
Insomma …
• Sebbene le LG BTS 2016 apparentemente non vadano proprio in questa direzione
(ma le LG GINA 2017 e 2 RS della CL sì)
• Potremmo immaginare che l’ utilizzo dei CSI al bisogno sia considerabile pari a
quello dei CSI continui nell’ ambito della prevenzione del peggioramento delle
esacerbazioni
• Se invece i sintomi sono più discreti ma più frequenti, meglio utilizzare i CSI continui
• Poichè la categoria in cui l’ asma si esprime prevalentemente con esacerbazioni è
quella dei prescolari
• Sunitha ci viene bene adesso
SMS
La RS di Sunitha - 1Kaiser et al, Pediatrics 2016
• The primary objective of this systemic review and metaanalysis is to synthesize the
evidence of the effects of daily ICS, intermittent ICS, and montelukast as strategies
for preventing severe exacerbations in preschool children with recurrent wheeze.
• We performed 1 subgroup analysis restricted to studies that described inclusion
only of children with persistent asthma (symptoms >2 days/week, nighttime
awakenings 1–2/month, short acting β-agonist use >2 days/week, or minor
limitation with normal activity).
• We performed another subgroup analysis that described inclusion only of children
with intermittent asthma (symptoms ≤2 days/week, no nighttime awakenings, short
acting β-agonist use ≤2 days/week, and no limitation with normal activity) or viral-
triggered wheezing and minimal symptoms between exacerbations (EVW or severe
intermittent wheezing).
SMS
La RS di Sunitha - 2Kaiser et al, Pediatrics 2016
• Subgroup analysis of children with persistent asthma showed reduced exacerbations
with daily ICS compared with placebo (8 studies, N = 2505; RR 0.56; 95% CI, 0.46–0.70;
NNT = 11) and daily ICS compared with montelukast (1 study, N = 202; RR 0.59; 95% CI,
0.38–0.92).
• Subgroup analysis of children with intermittent asthma or viral-triggered wheezing
showed reduced exacerbations with preemptive high-dose intermittent ICS compared
with placebo (5 studies, N = 422; RR 0.65; 95% CI, 0.51–0.81; NNT = 6).
• CONCLUSIONS: There is strong evidence to support daily ICS for preventing
exacerbations in preschool children with recurrent wheeze, specifically in children
with persistent asthma. For preschool children with intermittent asthma or viral-
triggered wheezing, there is strong evidence to support intermittent ICS for
preventing exacerbations.
SMS
Occhio al Rombo
SMS
Se persistente vince il persistenteKaiser et al, Pediatrics 2016
• Preschoolers with persistent asthma (subgroup analisys)
SMS
Se intermittente vince l’ intermittenteKaiser et al, Pediatrics 2016
• Preschoolers with intermittent asthma or viral-triggered wheeze (subgroup analisys)
SMS
L’ un contro l’ altroKaiser et al, Pediatrics 2016
• Preschoolers with intermittent asthma or viral-triggered wheeze (subgroup analisys)
Uno solo.
E nel caso dell’ asma persistente neanche questo
SMS
Dov’è Papi? Dov’è? - 1Kaiser et al, Pediatrics 2016
• Preschoolers with with unclear or mixed wheezing phenotypes (subgroup analisys)
Papi et al è stato
messo qua
SMS
Dov’è Papi? Dov’è? - 2Kaiser et al, Pediatrics 2016
• Preschoolers with with unclear or mixed wheezing phenotypes (subgroup analisys)
E qua
SMS
Dov’è Papi? Dov’è? - 3Kaiser et al, Pediatrics 2016
• Preschoolers with with unclear or mixed wheezing phenotypes (subgroup analisys)
E ancora qua
SMS
Praticamente l’ unico - 1Francine Ducharme et al, NEJM 2009
• 129 bambini tra 1 e 6 anni di età furono randomizzati a ricevere, in 3 somministrazioni, 750 mcg di fluticasone (non proprio bruscolini) o placebo due volte al giorno
• All’ inizio di un episodio di infezione delle vie respiratorie (IR), ai primi sintomi (rinorrea, congestione nasale, faringodinia, otalgia)
• E fino a 48 ore dopo la risoluzione dei sintomi, massimo per 10 giorni
• Per essere giudicati eleggibili i bambini dovevano
• Aver avuto almeno 3 episodi di wheezing virus-indotto nei precedenti 12 mesi
• Aver ricevuto almeno una volta il cortisone per via orale
• Non avere sintomi asmatici negli intervalli tra gli episodi
• Avere test allergometrici per aeroallergeni negativi
• Solamente il 17% dei bambini screenati aveva le suddette caratteristiche
• L’ obiettivo primario è stato la valutazione della percentuale di episodi che hanno necessitato della somministrazione di cortisone per via orale
• Lo studio è durato un anno
SMS
Praticamente l’ unico - 2Francine Ducharme et al, NEJM 2009
• L’ 8% degli episodi di IR dei bambini appartenenti al gruppo fluticasone necessitò di cortisone per via orale
• Verso il 16% degli episodi del gruppo placebo
• OR = 0.49 (IC = 0.30-0.83), NNT = 4 bambini e 13 IR
• I bambini trattati con fluticasone ebbero una più breve durata dei sintomi e dell’ uso di salbutamolo (10%-15% = 1-2 giorni)
• I bambini trattati con fluticasone presentarono una significativamente ridotta velocità di crescita per quanto riguarda sia la statura (6.23 cm vs 6.56 cm) che il peso (1.53 kg vs 2.17 kg)
• L’ effetto è simile a quello di un trattamento con fluticasone a 200 mcg al giorno per un anno
• Nessuna differenza per quanto riguarda la cortisolemia basale e a 12 mesi
• A causa del potenziale sovrautilizzo, tale approccio non dovrà essere introdotto nella pratica clinica fino a quando non saranno chiariti i possibili effetti avversi a lungo termine
SMS
Il DilemmaDucharme et al, NEJM 2009
Un totale di 48/129
bambini (37% dei
randomizzati) non
sono stati aderenti al protocollo
SMS
Anche Sunitha …Kaiser et al, Pediatrics 2016
• Six studies compared intermittent ICS with placebo.
1. Bacharier LB, Phillips BR, Zeiger RS, et al; CARE Network. Episodic use of an inhaled corticosteroid or
leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J
Allergy Clin Immunol. 2008
2. Connett G, Lenney W. Prevention of viral induced asthma attacks using inhaled budesonide. Arch Dis
Child. 1993
3. Ducharme FM, Lemire C, Noya FJD, et al. Preemptive use of high-dose fl uticasone for virus-induced
wheezing in young children. N Engl J Med. 2009
4. Papi A, Nicolini G, Baraldi E, Boner AL, Cutrera R, Rossi GA, Fabbri LM; Beclomethasone and Salbutamol
Treatment (BEST) for Children Study Group. Regular vs prn nebulized treatment in wheeze preschool
children. Allergy. 2009
5. Svedmyr J, Nyberg E, Thunqvist P, Asbrink-Nilsson E, Hedlin G. Prophylactic intermittent treatment with
inhaled corticosteroids of asthma exacerbations due to airway infections in toddlers. Acta Paediatr. 1999
6. Wilson NM, Silverman M. Treatment of acute, episodic asthma in preschool children using intermittent
high dose inhaled steroids at home. Arch Dis Child. 1990
• The studies used several different delivery systems and types of ICS at high dosages
(budesonide 1.6 - 2 mg/day, fluticasone 1.5 mg/day, beclomethasone 2.3 mg/day).
SMS
… a voler fare i pignoliKaiser et al, Pediatrics 2016
• Data from these 5 studies showed significant reduction in rates of severe
exacerbations with intermittent ICS (33.9% vs 51.3%, respectively; RR 0.65; 95% CI,
0.51 - 0.81; P = .0002; I2 = 0%). Treatment of 6 children prevented 1 child from
experiencing an exacerbation (NNT = 6; 95% CI, 4–12).
• We performed sensitivity analyses excluding studies with high risk of bias in ≥1
domain.
• With the exclusion of 3 out of 6 studies comparing intermittent ICS with placebo, the
benefit of intermittent ICS was no longer statistically significant (RR 0.61; 95% CI,
0.35–1.07). Però di poco
SMS
La RS di Sunitha - Infine 1Kaiser et al, Pediatrics 2016
• Our subgroup analyses by wheezing phenotype showed that most studies of daily ICS in
preschool children have focused on children with persistent asthma.
• For these children, we found strong evidence to support daily ICS, with data from >1600
children demonstrating 44% reduced risk of severe exacerbations (NNT = 11). In
addition, most studies that reported on symptom-free days found significant
improvements with daily ICS compared with placebo.
• We also found that daily ICS reduced risk of exacerbations more than montelukast, but
these data were limited to a single study.
• These findings support current national and international guidelines, which
recommend daily ICS as first-line therapy for preschool children with persistent
asthma.
SMS
La RS di Sunitha - Infine 2Kaiser et al, Pediatrics 2016
• We also performed a subgroup analysis of preschool children with intermittent asthma
or viral-triggered wheeze, because this is the most common wheezing pattern in this
age group.
• Most studies evaluated intermittent ICS. We found strong evidence to support
intermittent ICS, with a 35% risk reduction in severe exacerbations (NNT = 6).
• In these studies, children generally received high-dose ICS started at the first sign of a
URTI for 7 to 10 days.
SMS
Poi venne l’ INFANT Study - 0Fitzpatrick et al, JACI 2016
SMS
Poi venne l’ INFANT Study - 1Fitzpatrick et al, JACI 2016
SMS
Ma l’ INFANT Study non è la stessa cosaFitzpatrick et al, JACI 2016
• Children were eligible for study entry if they met guideline-based criteria for
daily asthma controller medication * (ie, Step 2 treatment)
• … randomized crossover of three 16-week treatment periods with
• daily ICS (fluticasone propionate, 2 inhalations, 44 mg each, twice daily)
• daily leukotriene receptor antagonist (LTRA) (montelukast, 4 mg, once daily at
bedtime)
• and as-needed ICSs coadministered with an open-label short-acting bronchodilator
for symptom relief (fluticasone propionate, 2 inhalations, 44 mg each; albuterol
sulfate, 2 inhalations, 90 mg each) (non sono indicate numero di somministrazioni al
giorno e numero di giorni di terapia, è proprio “al bisogno”)
Manca un gruppo
placebo, certamente
difficile a realizzarsi
visto che si trattava di
bambini candidati allo
step 2
*• daytime asthma
symptoms more than 2
days per week (averaged
over the preceding
4weeks),
• nighttime awakening
from asthma at least
once over the previous 4
weeks,
• or 4 or more wheezing
episodes, each lasting
24 or more hours, in the
preceding 12 months.
SMS
Poi venne l’ INFANT Study - 2Fitzpatrick et al, JACI 2016
• Seventy-four percent (170/230 *) of children with analyzable data had a differential
response to the 3 treatment strategies.
• Within differential responders, the probability of best response was highest for a daily
ICS and was predicted by aeroallergen sensitization but not exacerbation history or
sex.
• The probability of best response to daily ICS was further increased in children with both
aeroallergen sensitization and blood eosinophil counts of 300/mL or greater.
• In these children daily ICS use was associated with more asthma control days and
fewer exacerbations compared with the other treatments.
* I randomizzati erano 300, quindi il 23% di essi non
è stato incluso nell’ analisi finale, forse un po’ troppo
No predictor identified a group
in which LTRAs or as-needed ICSs
were more likely than a daily
ICS to yield the best response.
The average weekly ICS dose was
approximately 1200 mg of
fluticasone in the daily ICS group
versus 270 mg of fluticasone
in the as-needed ICS group.
SMS
Poi venne l’ INFANT Study – 3
Fitzpatrick et al, JACI 2016
Come posso essere sicuro che nei
«non-differential responders» non si
sia verificato un miglioramento
spontaneo? Hanno performances
«splendide»
SMS
Poi venne l’ INFANT Study - 4Fitzpatrick et al, JACI 2016
• Tra coloro che hanno mostrato una
risposta differenziata, anche coloro senza
sensibilizzazioni ad aeroallergeni
rispondevano meglio, seppur di poco, ai
CSI continui
• Quindi, in un prescolare con asma
persistenze e sensibilizzazioni, la prima
scelta sono i CSI continui
• E negli altri pure
• Diversamente, secondo quali criteri si
sceglierebbe altrimenti?
The overall probability of a best response to ICS was only 0.40 when nondifferential responders are
considered, highlighting the need for personalized medicine with the right therapies for the right
patients. Indeed, many participants had a best response to a daily LTRA or as-needed ICS. Although
we were unable to identify clear predictors of best response to these therapies, further study is
warranted because these therapies are useful for many children.
SMS
Alessandro aveva ragione?Pagina Gialla, Medico e Bambino 6/2016
• Insomma
• Nei bambini con asma persistente, i CSI ad intermittenza funzionano tanto
quanto i CSI continui nella prevenzione delle esacerbazioni gravi
• Ma non nel controllo dei sintomi più discreti e frequenti.
• E quindi per loro meglio I CSI continui.
• Nei bambini con storia di asma intermittente la cui storia pè fatta di
esacrbazioni, i CSI somministrati per via inalatoria ad intermittenza e ad alte
dosi riducono la probabilità di insorgenza di esacerbazioni gravi
� Insomma, in quei bambini per i quali, secondo le correnti indicazioni, non
dovremmo dar altro che salbutamolo al bisogno ed eventualmente cortisone per
via orale, invece aggiungeremmo i CSI ad alte dosi fin dai primi sintomi di
infezione delle alte vie aeree
SMS
La domanda ve la faccio io
Ne vale la pena?
SMS
«Gli esseri umani commettono errori»
Bruce Willis in
Moonrise Kingdom - Una fuga d'amore
di Wes Anderson
SMS
InoltreBacharier et al, JACI 2008
• Based on the variability in the signs and symptoms of RTI (respiratory tract illness)
that precede the development of significant wheezing, the individualized timing
for starting study medications was derived according to an educational protocol
• Parents were instructed to begin a 7-day course of the study medication at the onset of
the individualized set of symptoms identified as the child’s starting point
• Parents received extensive education at all study visits regarding close attention to
the development of symptoms that were likely to represent an RTI followed by
extension to chest symptoms
SMS
Il Timing giustoBacharier et al, JACI 2008
• …. if parents were able to identify a common set of signs and symptoms that precedes and signals the development of severe wheezing during a RTI in young children
Cough, breathing problem, or noisy chest (respirazione rumorosa) were the first (82%) or second (93%) symptoms that led to use of inhaled
beta-agonists
• Overall, parents were confident in their ability to predict symptom progression for their child, and reported that this progression was typical
• While most symptoms were chest-related, there were no individual symptoms that occurred in the majority of children