Il respiro sibilante che resta
Luciana Indinnimeo Dipartimento Integrato di Pediatria e NPI
Il Respiro sibilante in età Pediatrica
Atopia - Gravità del wheezing
Genetica - Virus
Terapia
Il respiro sibilante che resta
Atopia - Gravità del wheezing
Genetica - Virus
Terapia
Il respiro sibilante che resta
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.
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
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 house-
dust 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).
Martinez FD et al. N Engl J Med 1995;332:133-138
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 %
Fenotipi di Wheezing (826 Bambini seguiti dalla nascita)
Stein RT et al. Thorax 1997;52:946-952
0
10
20
30
40
50
60
70
Serum IgE
(IU/ml)
Positive skin
test (%)
No wheezing
Transient early
wheezing
Late onset
wheezing
Persistent wheezing
Livelli di IgE seriche e prevalenza di positività cutanea ad allergeni inalanti in relazione al tipo di wheezing.
* p
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;156:1863–1869
Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood.
Henderson J, Thorax. 2008 Nov;63(11):974-80
5.760 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 )
Estimated prevalence of wheeze at each time point from birth to age 8 years for each wheezing phenotype in PIAMA optimal 5-class model
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, 1505 - 1512.e14
The wheezing phenotypes most strongly associated with atopy and airway responsiveness were PW, IOW, LOW
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
The German Multicentre Allergy Study followed 1314 children
Risk factors for wheezing at age 11–13 yrs by age at onset
[Matricardi PM, et al. Eur Respir J 2008; 32: 585–592]
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;349:1414-1422.
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).
• Protection against Allergy—Study in Rural Environments (PASTURE). • Prospective birth cohort, 1.133 enrolled children in Austria, Finland, France, Germany, Switzerland. • Yearly questions about current wheeze until age 6 years.
Am J Respir Crit Care Med Vol 189, pp 129–138, Jan 15, 2014
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.
Journal of Allergy and Clinical Immunology, Volume 109, Issue 2, 2002, 189 - 194
Peter D. Phelan, et al. The Melbourne Asthma Study: 1964-1999
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)
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:
2177–2181.
Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 1964–1999. J Allergy
Clin Immunol 2002; 109: 189–194.
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: 1414–1422.
Toelle BG, Xuan W, Peat JK, et al. Childhood factors that predict asthma in young
adulthood. Eur Respir J 2004; 23: 66–70.
Atopia - Gravità del wheezing
Genetica - Virus
Terapia
Il respiro sibilante che resta
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
Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses. Childhood Origins of Asthma (COAST) Cohort.
P = 0.004 for the interaction between the rs7216389 SNP and HRV wheezing illness with respect to the development of asthma.
Minal Çalışkan, et al. N Engl J Med 2013;368:1398-407
The Tucson Children’s Respiratory Study Risk of Subsequent Wheezing After RSV
Generalized
estimation equation
odds ratios
(longitudinal analysis)
Multiple logistic
regression odds ratios
Age (Years)
6
5
4
3
2
1
0
5 6 7 8 9 10 11 12 13 14
p
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
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
A hypothetical schema for the cause of childhood asthma
Holt, Upham, and Sly, 2005
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.
L’aumentata suscettibilità ai
virus potrebbe essere
causata da un difetto
primitivo nell’immunità
innata antivirale, con scarsa
produzione di TLR7 o
dell’interferon di tipo I (IFN-
α and IFN-β) e di tipo III (IFN-
λ), oppure da un probabile
effetto soppressivo degli
eosinofili e/o dei macrofagi
attivati.
Bart E Lambrecht, Nature Immunology 2015
, TLR7
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.
Atopia - Gravità del wheezing
Genetica - Virus
Terapia
Il respiro sibilante che resta
© Global Initiative for Asthma
Altre opzioni
di controllo
FARMACI AL BISOGNO
STEP 1 STEP 2
STEP 3
STEP 4
STEP 5
Bassa dose di ICS
Considerare bassa dose di
ICS
Antagonista del recettore dei leucotrieni (LTA)
Bassa dose di teofillina
Dose medio-alta di ICS Bassa dose di ICS+LTRA (o + teofillina)
SABA secondo necessità SABA secondo necessità o bassa dose di ICS/Formoterolo**
Bassa dose
ICS/LABA
Dose
medio/alta
ICS/LABA
Ricorrere ad un trattame
nto aggiunti
vo per es: anti-IgE
FARMACI DI CONTROLLO
DI PRIMA SCELTA
Aggiungere Alta dose di ICS + LTRA (o + teofillina)
Aggiungere bassa dose di OCS
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
Basse, medie e alte dosi di corticosteroidi inalatori
Bambini 6–11 anni
Corticosteroidi inalatori Dose giornaliera totale (mcg)
Bassa Media Alta
Beclometasone dipropionato (CFC) 100–200 >200–400 >400
Beclometasone dipropionato (HFA) 50–100 >100–200 >200
Budesonide (DPI) 100–200 >200–400 >400
Budesonide (nebules) 250–500 >500–1000 >1000
Ciclesonide (HFA) 80 >80–160 >160
Fluticasone propionato (DPI) 100–200 >200–400 >400
Fluticasone propionato (HFA) 100–200 >200–500 >500
Mometasone furoato 110 ≥220–800–1200 >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
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 • www.ginasma.it 31
Corticosteroidi inalatori
..... 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