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