Stefano Miceli Sopo L utilizzo dei cortisonici inalatori, un dettaglio

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

2 Lo spuntino per il dettaglio La 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 fluticasonenon ha mostrato un rallentamento della crescita dopo i primi tre mesi di trattamento (WardenierNR, et al. ArchDis 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.

3 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 Fluticasoneda 50 mcg4 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.

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

5 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

6 Quali fonti hanno contribuito alla tua conoscenza in merito ai CSI ad intermittenza? Puoi scegliere più opzioni Sondaggio alle liste APAL (77 risposte) ed APEL (35 risposte), fine Luglio 2017 Ricordatevi di questa diapositiva quando citerò le LG BTS 2016

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

8 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

9 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?

10 Le Linee Guida BTS 2016 * 3 righe vs le 5 pagine fitte dell analisi effettuata da Marcello Bergamini 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 ambitodel paragraforecommendations FOR RESEARCH: Is intermittent ICS therapy more, the same, or less effective than daily ICS therapy? RIMANDATO

11 Le Linee Guida GINA 2017 Pag. 76 (Management of exacerbations) : There is emerging evidence in adults and young children that higherics doses might help prevent worsening asthma progressing to a severe exacerbation. (per ibambini citato lo studio di Ducharme et al, NEJM 2009) PROMOSSO? In contraddizione? Non proprio, vedremo Esacerbazione? Attacchi?

12 Definizione di Esacerbazione LG 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

13 Le RS della CochraneLibrary Chong 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 hospitalisationrates in any group.

14 Le RS della CochraneLibrary -A1 Chauhan 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. E le BTS allora? E l apprendimento tramite congressi e Forum? E Bergamini? 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.

15 Le RS della CochraneLibrary -A2 Chauhan 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

16 Le RS della CochraneLibrary -A3 Chauhan 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

17 Insomma Sebbene le LG BTS 2016 apparentemente non vadano proprio in questa direzione (ma le LG GINA 2017 e 2 RS della CL sì) Potremmoimmaginarechel utilizzodeicsi al bisognosiaconsiderabileparia quello dei CSI continui nell ambito della prevenzione del peggioramento delle esacerbazioni Se inveceisintomisonopiùdiscretima piùfrequenti, meglioutilizzareicsi continui Poichèla categoriain cui l asmasiesprimeprevalentementecon esacerbazioniè quella dei prescolari Sunitha ci vienebene adesso

18 La RS di Sunitha -1 Kaiser et al, Pediatrics 2016 The primary objective of this systemic review and metaanalysisis to synthesize the evidence of the effects of daily ICS, intermittent ICS, and montelukastas 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 viraltriggered wheezingand minimal symptoms between exacerbations (EVW or severe intermittent wheezing).

19 La RS di Sunitha -2 Kaiser 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, ; NNT = 11) and daily ICS compared with montelukast(1 study, N = 202; RR 0.59; 95% CI, ). 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, ; 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 viraltriggered wheezing, there is strong evidence to support intermittent ICS for preventing exacerbations.

20 Occhio al Rombo

21 Se persistente vince il persistente Kaiser et al, Pediatrics 2016 Preschoolers with persistent asthma (subgroup analisys)

22 Se intermittente vince l intermittente Kaiser et al, Pediatrics 2016 Preschoolers with intermittent asthma or viral-triggered wheeze (subgroup analisys)

23 L un contro l altro Kaiser et al, Pediatrics 2016 Preschoolers with intermittent asthma or viral-triggered wheeze (subgroup analisys) Uno solo. E nel caso dell asma persistente neanche questo

24 Dov è Papi? Dov è? -1 Kaiser et al, Pediatrics 2016 Preschoolers with with unclear or mixed wheezing phenotypes (subgroup analisys) Papi et al è stato messo qua

25 Dov è Papi? Dov è? -2 Kaiser et al, Pediatrics 2016 Preschoolers with with unclear or mixed wheezing phenotypes (subgroup analisys) E qua

26 Dov è Papi? Dov è? -3 Kaiser et al, Pediatrics 2016 Preschoolers with with unclear or mixed wheezing phenotypes (subgroup analisys) E ancora qua

27 Praticamente l unico - 1 Francine Ducharme et al, NEJM bambini tra 1 e 6 anni di etàfurono 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

28 Praticamente l unico - 2 Francine Ducharme et al, NEJM 2009 L 8%degli episodi di IR dei bambini appartenenti al gruppo fluticasonenecessitò di cortisone per via orale Verso il 16% degli episodi del gruppo placebo OR = 0.49 (IC = ), NNT= 4 bambini e 13 IR I bambini trattati con fluticasoneebbero una più breve durata dei sintomi e dell uso di salbutamolo(10%-15% = 1-2 giorni) I bambini trattati con fluticasonepresentarono una significativamente ridotta velocità di crescitaper 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 fluticasonea 200 mcgal 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

29 Il Dilemma Ducharme et al, NEJM 2009 Un totale di 48/129 bambini (37% dei randomizzati) non sono stati aderenti al protocollo

30 Anche Sunitha Kaiser et al, Pediatrics 2016 Six studies compared intermittent ICS with placebo. 1. BacharierLB, Phillips BR, ZeigerRS, 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 ConnettG, LenneyW. Prevention of viral induced asthma attacks using inhaled budesonide. Arch Dis Child DucharmeFM, Lemire C, NoyaFJD, et al. Preemptive use of high-dose fluticasonefor virus-induced wheezing in young children. N EnglJ Med PapiA, NicoliniG, BaraldiE, BonerAL, CutreraR, Rossi GA, Fabbri LM; Beclomethasone and Salbutamol Treatment (BEST) for Children Study Group. Regular vs prn nebulized treatment in wheeze preschool children. Allergy SvedmyrJ, Nyberg E, ThunqvistP, Asbrink-Nilsson E, HedlinG. Prophylactic intermittent treatment with inhaled corticosteroids of asthma exacerbations due to airway infections in toddlers. Acta Paediatr WilsonNM, Silverman M. Treatment of acute, episodic asthma in preschool children using intermittent high dose inhaled steroids at home. Arch Dis Child The studies used several different delivery systems and types of ICS at high dosages (budesonide mg/day, fluticasone 1.5 mg/day, beclomethasone 2.3 mg/day).

31 a voler fare i pignoli Kaiser 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, ; 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, ). Però di poco

32 La RS di Sunitha -Infine 1 Kaiser 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.

33 La RS di Sunitha -Infine 2 Kaiser 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 ICSstarted at the first sign of a URTI for 7 to 10 days.

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

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

36 Ma l INFANT Studynon è la stessa cosa Fitzpatrick 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 coadministeredwith an open-label short-acting bronchodilator for symptom relief (fluticasone propionate, 2 inhalations, 44 mg each; albuterol sulfate, 2 inhalations, 90 mg each) (non sonoindicate numerodi somministrazionial giorno e numero di giorni di terapia, è proprio al bisogno ) * 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. Manca un gruppo placebo, certamente difficile a realizzarsi visto che si trattava di bambini candidati allo step 2

37 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. Poi venne l INFANT Study-2 Fitzpatrick et al, JACI 2016 No predictor identified a group in which LTRAs or as-needed ICSs were more likely than a daily ICS to yield the best response. 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

38 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»

39 Poi venne l INFANT Study-4 Fitzpatrick 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.

40 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 nelcontrollodeisintomipiùdiscretie frequenti. E quindiper loromeglioi CSI continui. Neibambini con storiadi asmaintermittentela cui storiapèfattadi esacrbazioni, i CSI somministrati per via inalatoria ad intermittenza e ad alte dosi riducono la probabilità di insorgenza di esacerbazioni gravi Insomma, in queibambini per iquali, secondo le correntiindicazioni, non dovremmodaraltrochesalbutamoloal bisognoedeventualmentecortisone per via orale, inveceaggiungeremmoicsi ad altedosifin daiprimisintomidi infezione delle alte vie aeree

41 La domanda ve la faccio io Ne vale la pena?

42 «Gli esseri umani commettono errori» Bruce Willis in Moonrise Kingdom - Una fuga d'amore di Wes Anderson

43 Inoltre Bacharier et al, JACI 2008 Basedon the variabilityin the signsand symptomsof RTI (respiratorytractillness) thatprecede the developmentof significantwheezing, the individualizedtiming for starting study medications was derived according to an educational protocol Parentswereinstructedto begina 7-day courseof the studymedicationatthe onsetof the individualized set of symptoms identified as the child s starting point Parentsreceivedextensiveeducationatallstudyvisitsregardingcloseattentionto the developmentof symptomsthatwerelikelyto representan RTI followedby extension to chest symptoms

44 Il Timing giusto Bacharier et al, JACI 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(respirazionerumorosa) 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