Il Respiro sibilante in età Pediatrica

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1 Il Respiro sibilante in età Pediatrica Il respiro sibilante che resta Luciana Indinnimeo Dipartimento Integrato di Pediatria e NPI

2 Il respiro sibilante che resta Atopia - Gravità del wheezing Genetica - Virus Terapia

3 Il respiro sibilante che resta Atopia - Gravità del wheezing Genetica - Virus Terapia

4 Dati epidemiologici 80% delle manifestazioni asmatiche nel bambino è di origine allergica; il 40% di bambini con asma allergico ha presentato eczema nel primo anno di vita; i bambini piccoli con allergie multiple più facilmente sviluppano asma; fino all 80% dei soggetti con asma allergico hanno anche rinite allergica.

5 In 6394 bambini tra 8 e 11 anni, tra il 1982 e il 1992, si è passati dal: 34% al 47% di casi di atopia, 17% al 27% di wheezing, 14% al 21% di iperreattività bronchiale, 6% al 10% di asma. The prevalence of current asthma in children living where sensitisation to housedust mites and to alternaria was high, was 12%-13%, which was significantly higher than the prevalence of 7%-10% in children living in regions where sensitisation to these allergens was lower. (P < 0.01). Peat JK,et al. Prevalence and severity of childhood asthma and allergic sensitisation in seven climatic regions of New South Wales. Med J Aust 1995;163(1):22-6

6 Fenotipi di Wheezing (826 Bambini seguiti dalla nascita) Never wheezers mai sibilo Transient early wheezers sibilo nei primi 3 anni, no a 6 Late wheezers no sibilo nei primi 3 anni, sì a 6 Persistent wheezers sibilo 0-6 anni 51.5 % 19.8 % 15.0 % 13.7 % Martinez FD et al. N Engl J Med 1995;332: Stein RT et al. Thorax 1997;52:

7 Livelli di IgE seriche e prevalenza di positività cutanea ad allergeni inalanti in relazione al tipo di wheezing. 70 * ** *** No wheezing Transient early wheezing Late onset wheezing Persistent wheezing 0 Serum IgE (IU/ml) Positive skin test (%) * p <0.01 ** p <0.001 *** p = Asthma and Wheezing in the First Six Years of Life Fernando D. Martinez, et al. (N Engl J Med. 1995;332:133-8.)

8 Atopy and current mild wheezing at age 6 were the only significant and independent predictors of subsequent asthma Lombardi E. Cold air challenge at age 6 and subsequent incidence of asthma. A Longitudinal Study. Am J Respir Crit Care Med 1997;156:

9 Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Henderson J, Thorax Nov;63(11): children in a longitudinal birth cohort (the ALSPAC study) were analysed. Measures of atopy, airway function and bronchial responsiveness were made at 7 9 years of age. Conclusion The wheezing phenotypes most strongly associated with atopy and airway responsiveness were characterised by onset after age 18 months (Persistent, Intermediate, Late )

10 Estimated prevalence of wheeze at each time point from birth to age 8 years for each wheezing phenotype in PIAMA optimal 5-class model The wheezing phenotypes most strongly associated with atopy and airway responsiveness were PW, IOW, LOW Olga E. Savenije, et al. Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. Journal of Allergy and Clinical Immunology, Volume 127, Issue 6, 2011, e14

11 The German Multicentre Allergy Study followed 1314 children Prevalence of current wheeze from birth to age 13 years in children with any wheezing episode at school age (5 7 years), stratified for atopy at school age. Illi S, von Mutius E,et al. Multicentre Allergy Study (MAS) group. Lancet, 2006, Sep30;368:1154

12 Risk factors for wheezing at age yrs by age at onset [Matricardi PM, et al. Eur Respir J 2008; 32: ]

13 Patterns of Wheezing (Shaded Bars) in Childhood Reported by Study Members or Their Parents, Persistent Wheezing, Remission, Relapse, Intermittent Wheezing, Transient Wheezing, and No Wheezing Ever Sensitization to house dust mites predicted the persistence of wheezing (odds ratio,n2.41; P=0.001) and relapse (odds ratio, 2.18; P=0.01). Sears MR et al. N Engl J Med 2003;349:

14 Am J Respir Crit Care Med Vol 189, pp , Jan 15, 2014 Protection against Allergy Study in Rural Environments (PASTURE). Prospective birth cohort, enrolled children in Austria, Finland, France, Germany, Switzerland. Yearly questions about current wheeze until age 6 years.

15 Histogram showing pattern of asthma at age 42 years in subjects from original recruitment groups. MWB: Mild wheezy bronchitis; WB : wheezy bronchitis; A: asthma; SA: severe asthma; NRA: no recent asthma; IA: infrequent asthma; FA: frequent asthma; PA: persistent asthma. Peter D. Phelan, et al. The Melbourne Asthma Study: Journal of Allergy and Clinical Immunology, Volume 109, Issue 2, 2002,

16 Thorax 2008;63:8 13 Compared with 216 subjects (2 years)without bronchial obstruction, OR (95% CI) of current asthma among recurrent bronchial obstruction was 7.9 (4.1, 15.3), among recurrent bronchial obstruction with a severity score of >5 was 20.2 (9.9, 41.3) (n=233)

17 Fattori prognostici per asma grave persistente in età adulta: asma grave, età di esordio dell asma, atopia quadro spirometrico ostruttivo. Wolfe R, Carlin JB, et al. Association between allergy and asthma from childhood to middle adulthood in an Australian cohort study. Am J Respir Crit Care Med 2000; 162: Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: J Allergy Clin Immunol 2002; 109: Sears MR, Greene JM, Willan AR, et al. A longitudinal, populationbased,cohort study of childhood asthma followed to adulthood. N Engl J Med 2003; 349: Toelle BG, Xuan W, Peat JK, et al. Childhood factors that predict asthma in young adulthood. Eur Respir J 2004; 23:

18 Il respiro sibilante che resta Atopia - Gravità del wheezing Genetica - Virus Terapia

19 Fattori genetici che possono influenzare molto aspetti della patogenesi dell asma JW Holloway, IA Yang and ST Holgate. J Allergy Clin Immunol 2008;121:573-9

20 Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses. Childhood Origins of Asthma (COAST) Cohort. Minal Çalışkan, et al. N Engl J Med 2013;368: P = for the interaction between the rs SNP and HRV wheezing illness with respect to the development of asthma.

21 Frequent Wheeze Infrequent Wheeze The Tucson Children s Respiratory Study Risk of Subsequent Wheezing After RSV 6 5 p= Generalized estimation equation odds ratios (longitudinal analysis) Age (Years) Multiple logistic regression odds ratios 6 5 p<0.001 p< Stein RT, et al. Lancet. 1999;354:541-5 Age (Years)

22 Thorax 2010;65:1045e1052 Proportion (%) of subjects in the respiratory syncytial virus and control cohorts who never had an asthma diagnosis at follow-up at ages 3, 7, 13 and 18 years (log rank (Mantel-Cox) c2 21.0; df 1; p<0.001

23 Risk of asthma at age 6 years in children who wheezed during the first 3 years of life with rhinovirus (RV), respiratory syncytial virus (RSV), or both. *P <0.05 vs. Neither; +P <0.05 vs. RSV only DJ Jackson, et al.ajrccm Vol , 2008

24 A hypothetical schema for the cause of childhood asthma Holt, Upham, and Sly, 2005

25 The march from early life wheezing into adult asthma stands on two legs: atopy and viral infection A significant proportion of school-children and adults with asthma show abnormal acute responses to rhinoviruses, and careful follow-up studies suggest that these abnormal responses were already present in these same subjects when they were infants or young children. One potential link between early viral wheezing and subsequent asthma is that abnormalities in immune responses that are first expressed in the toddler persist into the school years creating susceptibility to infection.

26 L aumentata suscettibilità ai virus potrebbe essere causata da un difetto, TLR7 primitivo nell immunità innata antivirale, con scarsa produzione di TLR7 o dell interferon di tipo I (IFNα and IFN-β) e di tipo III (IFNλ), oppure da un probabile effetto soppressivo degli eosinofili e/o dei macrofagi attivati. Bart E Lambrecht, Nature Immunology 2015

27 L alto carico virale danneggia l epitelio, determinando l attivazione delle *CD11b+cDC presenti che polarizzano verso i fenotipi TH2 o TH17 con conseguente infiammazione eosinofila e neutrofila delle vie aeree. Bart E Lambrecht, Nature Immunology 2015 *Le CD11b+ cdcs sono necessarie e sufficienti ad indurre sensibilizzazione allergica.

28 Il respiro sibilante che resta Atopia - Gravità del wheezing Genetica - Virus Terapia

29 STEP 5 FARMACI DI CONTROLLO DI PRIMA SCELTA STEP 1 STEP 2 Bassa dose di ICS STEP 3 Bassa dose ICS/LABA STEP 4 Dose medio/alta ICS/LABA Ricorrer e ad un trattame nto aggiunti vo per es: anti-ige Altre opzioni di controllo FARMACI AL BISOGNO Consider are bassa dose di ICS Antagonista del recettore dei leucotrieni (LTA) Bassa dose di teofillina SABA secondo necessità Dose medio-alta di ICS Bassa dose di ICS+LTRA (o + teofillina) Aggiungere Alta dose di ICS + LTRA (o + teofillina) Aggiungere bassa dose di OCS SABA secondo necessità o bassa dose di ICS/Formoterolo** For children 6-11 years, theophylline is not recommended and preferred Step 3 is medium dose ICS or add LABA (similar effect as increasing ICS) Global Initiative for Asthma

30 Basse, medie e alte dosi di corticosteroidi inalatori Bambini 6 11 anni Corticosteroidi inalatori Dose giornaliera totale (mcg) Bassa Media Alta Beclometasone dipropionato (CFC) > >400 Beclometasone dipropionato (HFA) > >200 Budesonide (DPI) > >400 Budesonide (nebules) > >1000 Ciclesonide (HFA) 80 > >160 Fluticasone propionato (DPI) > >400 Fluticasone propionato (HFA) > >500 Mometasone furoato < Triamcinolone acetonide > >1200 Non è una tabella di equivalenza,ma una comparazione clinica stimata La maggior parte dei benefice clinici da ICS è evidenziabile a base dosi Le alte dosi sono arbitrarie, ma nella maggior parte di ICS l'uso prolungato è associato ad un aumentato del rischio di effetti avversi sistemici Global Initiative for Asthma

31 Corticosteroidi inalatori Riducono la mortalità per asma Prevengono le riacutizzazioni Controllano i sintomi e l uso addizionale di farmaco d emergenza Migliorano la funzione polmonare Riducono l infiammazione bronchiale, anche se non ci sono evidenze che modifichino la storia naturale dell asma 2011 PROGETTO LIBRA 31

32 ... What is needed is the elucidation of biologic and/or genetic markers that can be used to identify children at an early stage of their disease process who will be one of the unfortunate individuals whose disease progresses in severity over time. Robert F. Lemanske, 2016

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