Wheezing nel bambino. Incidenza, pattern longitudinale e fattori che predicono la persistenza. Luciana Indinnimeo Dipartimento di Pediatria e NPI

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1 Wheezing nel bambino. Incidenza, pattern longitudinale e fattori che predicono la persistenza Luciana Indinnimeo Dipartimento di Pediatria e NPI

2 Il bambino con wheezing La prevalenza di wheezing può raggiungere il 32% ISAAC 2003 Fino al 50% di tutti i bambini < 3 anni hanno avuto almeno un episodio di wheezing Martinez FD N Engl J Med 1995 Nel periodo invernale, nei bambini < 5 anni, il wheezing è responsabile del 50% dei ricoveri in ospedale

3 Does preschool wheeze lead to asthma?

4 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,

5 FEV1 percent predicted at ages 7, 10, 14, 21, 28, 35, and 42 years in subjects in their recruitment groups. C, Control; MWB, mild wheezy bronchitis; WB, wheezy bronchitis; A, asthma; SA, severe asthma. Peter D. Phelan, et al. The Melbourne Asthma Study: Journal of Allergy and Clinical Immunology, Volume 109, Issue 2, 2002,

6 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 Sears MR et al. N Engl J Med 2003;349:

7 Mean (±SE) FEV 1 :FVC Ratios Measured at 9, 11, 13, 15, 18, 21, and 26 Years in Male (Panel A) and Female (Panel B) Study Members, According to the Pattern of Wheezing. 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:

8 Fenotipi di Sibilo (in 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:

9 I fenotipi del wheezing? Martinez FD 1995

10 Transient early wheezers Ridotto diametro delle vie aeree prima del primo episodio di wheezing Martinez FD. N Engl J Med 1988; Tager IB. Am Rev Respir Dis 1993; Young S. Arch Dis Child Aumento della compliance delle vie aeree (aumentata collassabilità) Frey U. AJRCCM 2000 Mancanza della ventilazione collaterale Aumento della muscolatura liscia bronchiale (soprattutto nel prematuro) Landau LI. Thorax 2008

11 Fattori di rischio: - prematurità Speer CP Eur Respir J presenza di fratelli e frequenza in asilo Ball TM N Engl J Med 2000 Transient early wheezers - fumo materno durante la gravidanza ed - esposizione al fumo di tabacco dopo la nascita Stein RT Am J Epidemiol 1999

12 Maximal Expiratory Flow at Functional Residual Capacity (Vsub maxfrc) during the First Year of Life and at Six Years of Age, According to History of Wheezing Martinez F et al. N Engl J Med 1995;332:

13 Forced Expiratory Flows from Age 6 to 16 Yr for the Preschool Wheeze Phenotypes Conclusion: Patterns of wheezing prevalence and levels of lung function are established by age 6 yr and do not appear to change significantly by age 16 yr in children who start having asthma like symptoms during the preschool years. Morgan WJ. Am J Respir Crit Care Med *p < p = 0.03 p = δ p = 0.02 compared with never wheeze

14 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.)

15 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.

16 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

17 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:

18 The present authors hypothesised that atopy and other risk factors may have a different impact on the natural history of wheezing disorders in children according to their propensity to wheeze. The aim of the present study was to investigate the incidence and natural course of wheeze over the first 13 yrs of life and analyse the risk factors predicting wheeze at yrs of age. The major question of the present study was how to identify, at 3 yrs of age, among early wheezers, those at risk for long-term persistent wheezing.

19 Incidence of wheezing up to the age of 13 yrs Incidence of wheezing declined with age. 126 (29%) out of 441 of the children started wheezing in their first 3 yrs of life (early wheezers), 40 (9%) started wheezing between 3 and 6 yrs of age (late wheezers) and 42 (9%) started wheezing after 6 yrs of age (very late wheezers).

20 Parental atopy, sex and atopy in children with different longitudinal patterns of wheezing from birth to age 13 yrs Among very late onset wheezers, the prevalence of sensitisation at 10 yrs of age was three times higher than in the first 3 yrs of life, suggesting that this wheezing pattern was associated with later development of sensitisation.

21 Risk factors for wheezing at age yrs by age at onset A strong predisposition to atopy (a positive family history or early IgE sensitisation) is the strongest factor predicting whether children wheezing early in life will keep on wheezing until puberty

22 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

23 Rapporti tra infezioni virali precoci e comparsa di wheezing Metapneumovirus M. pneum. 9% H. infl./strept. Pneum. 4% Para 2% Adeno 2% Infl. A 3% 7% Il VRS rappresenta: 90% delle infezioni durante il picco stagionale Oltre il 50% delle infezioni respiratorie durante l intera stagione epidemica Rhinovirus 18% VRS 55%

24 % of group Rischio per Asma e per Allergia all età di 7 anni dopo Bronchiolite da RSV 47 bambini ricoverati per RSV LRTI nel primo anno di vita 93 control senza RSV LRTI 45% 40% 35% 30% 25% * ** *** ** ** Age 1 Age 3 Age 7 Rischio di wheezing ancora significativamente aumentato a 7 anni (p<0.0001) 20% 15% 10% 5% 0% RSV Controls RSV Controls Any Wheezing Asthma *p = **p < ***p < p = Sigurs N, et al. Am J Crit Care Med. 2000;161:1501-7

25 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

26 Proportion (%) with current asthma/recurrent wheeze Nele Sigurs Thorax 2010;65:1045e1052

27 Odds Ratios (95% CI) The Tucson Children s Respiratory Study 207 children with mild RSV LRTI not hospitalized Controls had no LRTI in the first 3 years of life Risk for frequent wheeze was still significantly increased at 11 years (p 0.01) *** Frequent wheeze Infrequent wheeze *** *** ** * NS 6 years 8 years 11 years 13 years *p 0.05 **p 0.01 ***p Stein RT, et al. Lancet. 1999;354:541-5

28 Editorial C.E. Kuehni, B.D. Spycher, M.Silverman, Am J Respir Crit Care Med does RSV infection confer a long-term change in the host, which increases the risk of subsequent asthma? Or is a hospitalization with RSV bronchiolitis simply an early marker of an underlying predisposition for reversible airway disease (i.e., asthma)?

29 Is it asthma?

30 E presente il remodeling delle vie aeree, anche se il wheezing si verifica nei primi 3 anni di vita. Morgan WJ. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescenceam J Respir Crit Care Med Phelan PD. The Melbourne Asthma Study: J Allergy Clin Immunol Sears MR. A longitudinal,population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003 Saglani S. Am J Respir Crit Care Med Vol 176. pp , 2007

31 Preschool children with confirmed wheeze between the ages of 1 and 3 years Increased reticular basement membrane (RBM) thickness EG2 cells in an endobronchial biopsy Sejal Saglani Am J Respir Crit Care Med Vol 176. pp , 2007

32 Am J Respir Crit Care Med Vol, 2008 Both nonatopic and atopic wheezing children had increased thickened basement membrane as compared with control subjects

33 Both non atopic and atopic wheezing children had increased numbers of eosinophils compared with control subjects.

34 Does preschool wheeze lead to asthma?

35 Criteri di Rischio per Asma (2-4 anni) > 4 episodi di wheezing nell anno precedente Un Criterio Maggiore 1. Asma nei genitori 2. Dermatite atopica 3. Sensibilizzazione ad >1 inalanti PIU O Due Criteri Minori 1. Sensibilizzazione ad alimenti 2. Wheezing anche senza infezioni 3. Eosinofilia (>4%) Asma nel 65% a 6 anni F.D. Martinez, JACI 2004

36 Distribution of severity score in children with recurrent bronchial obstruction at the age of 2 years (n=233). Compared with 216 subjects (2 year)without bronchial obstruction, OR (95% CI) of current asthma among recurrent bronchial obstruction (n=233) was 7.9 (4.1, 15.3), among recurrent bronchial obstruction with a severity score of >5 was 20.2 (9.9, 41.3) CS Devulapalli Thorax 2008;63:8 13.

37 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.

38

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