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Stefano Miceli Sopo L’ utilizzo dei cortisonici inalatori, un dettaglio

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Page 1: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

Stefano Miceli Sopo

L’ utilizzo dei cortisonici inalatori, un dettaglio

Page 2: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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.

Page 3: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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.

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Sapevi dell' utilizzo dei CSI ad intermittenza nell' asma pediatrico?Sondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017

Page 5: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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

Page 6: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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

Page 7: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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Utilizzi i CSI ad intermittenza nell' asma?Sondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017

Page 8: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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

Page 9: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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?

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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

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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?

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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

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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.

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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?

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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

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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

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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

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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).

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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.

Page 20: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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Occhio al Rombo

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Se persistente vince il persistenteKaiser et al, Pediatrics 2016

• Preschoolers with persistent asthma (subgroup analisys)

Page 22: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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Se intermittente vince l’ intermittenteKaiser et al, Pediatrics 2016

• Preschoolers with intermittent asthma or viral-triggered wheeze (subgroup analisys)

Page 23: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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

Page 24: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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

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Dov’è Papi? Dov’è? - 2Kaiser et al, Pediatrics 2016

• Preschoolers with with unclear or mixed wheezing phenotypes (subgroup analisys)

E qua

Page 26: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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Dov’è Papi? Dov’è? - 3Kaiser et al, Pediatrics 2016

• Preschoolers with with unclear or mixed wheezing phenotypes (subgroup analisys)

E ancora qua

Page 27: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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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

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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

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Il DilemmaDucharme et al, NEJM 2009

Un totale di 48/129

bambini (37% dei

randomizzati) non

sono stati aderenti al protocollo

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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).

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… 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

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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.

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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.

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Poi venne l’ INFANT Study - 0Fitzpatrick et al, JACI 2016

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Poi venne l’ INFANT Study - 1Fitzpatrick et al, JACI 2016

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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.

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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.

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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»

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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.

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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

Page 41: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

SMS

La domanda ve la faccio io

Ne vale la pena?

Page 42: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

SMS

«Gli esseri umani commettono errori»

Bruce Willis in

Moonrise Kingdom - Una fuga d'amore

di Wes Anderson

Page 43: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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

Page 44: Stefano Miceli Sopo SOPO STEFANO.pdf•Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual status or, in some cases, the

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