1

1

I Fenotipi del Wheezing in Età Prescolare

Enrico Lombardi SODs Broncopneumologia

Azienda Ospedaliero-Universitaria

“Anna Meyer” Ospedale Pediatrico

Firenze

2

I Fenotipi di Wheezing In Pediatria

L’asma non è un’unica malattia, ma

un insieme di malattie eterogenee

con sintomi in comune

Una delle maggiori sfide nel

trattamento dell’asma è la

comprensione dei diversi fenotipi

e dei meccanismi biologici sottostanti

L’identificazione di questi meccanismi ha

l’obiettivo finale di migliorare l’efficacia

dei trattamenti e delle strategie

Belgrave DCM et al. Expert Rev Clin Immunol 2013;9:921-936

3

Wheezing

in the first 6 years of life

The SIDRIA Study

Gruppo Collaborativo SIDRIA-2a fase

24.628

7.8 8.6

0

5

10

15

20

25

30

35

40

Wheezing ever Current wheezing

2002

1995

p<0.001

OR

(95% CI)

p=0.041

SIDRIA-1 1994/1995

18837 6-7 yo children

SIDRIA-2 2002

20016 6-7 yo children

4

Non tutto è

asma quel che

fischia

5

Cause di Respiro Sibilante

in Lattanti e Bambini Piccoli

COMUNI MENO COMUNI RARE

Wheezing

transitorio

Asma

Aspirazione (RGE o

disfunz. deglutizione)

Infezioni (pertosse,

micoplasma, clamidia,

tubercolosi)

BPD

Corpo estraneo

Anafilassi

Fibrosi cistica

Anomalie vascolari

Anomalie tracheo-

bronchiali

Masse mediastiniche

Bronchiolite

obliterante

Immunodeficienza

Discinesia ciliare

Insuff. cardiaca

Avila PC. Lippincott’s Prim Care Pract 1998;2:559-77

6 Belgrave DCM et al. Expert Rev Clin Immunol 2013;9:921-936

7

8

Fenotipi di Sibilo

nei primi 6 anni di vita

Stein RT et al. Thorax 1997;52:946-952

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 %

9 Belgrave DCM et al. Expert Rev Clin Immunol 2013;9:921-936

Wheezing Phenotypes

10

Wheezing Ricorrente

Prognosi

40% a 10 anni – Isle of Whight Study

37% a 13 anni – German Multicenter Allergy Study (MAS)

30% a 16 anni – Tucson Children’s Respiratory Study (CRS)

11

1. Sibilo transitorio

Sibilo soltanto durante

i primi 2-3 anni di vita

2. Sibilo non atopico

Principalmente scatenato da

infezioni virali e tende a sparire

3. Asma persistente

Sibilo associato a:

Manifestazioni cliniche di atopia,

eosinofilia e/o IgE totali elevate

Sensibilizzazione IgE-mediata ad alimenti nei primi anni di vita

e, successivamente, ai comuni inalanti

Sensibilizzazione ad inalanti prima dei 3 anni di età

Genitore/i con asma

Fenotipi di Sibilo

in età pediatrica

PRACTALL consensus report. Allergy 2008;63:5-34

4. Sibilo grave intermittente

Episodi di sibilo acuti ma non frequenti associati a:

Morbidità minima al di fuori dei periodi di infezione respiratoria

Caratteristiche di atopia

12

Fenotipi di Sibilo

in età pediatrica

Illi S, et al. Lancet 2006;368:763-70

PRACTALL consensus report. Allergy 2008;63:5-34

13

Castro-Rodríguez JA, et al. Am J Respir Crit Care Med 2000;162:1403-6

Guilbert TW, et al. JACI 2004;114:1282-7

Asthma Prediction Index

Asma diagnosticato da un

medico in uno o entrambi i

genitori

Dermatite atopica diagnosticata

da un medico nei primi 3 anni di

vita

Sensibilizzazione verso >1

allergene inalante

CRITERI MAGGIORI

Sensibilizzazione a latte, uovo o

arachidi

Sibilo non associato ad episodi

infettivi

Eosinofilia (> 4%)

CRITERI MINORI

Asma attivo a 6-13 anni

1 criterio maggiore

o

2 criteri minori

59 %

77 %

Sibilo nei primi 3 anni

> 1 episodio

> 3 episodi

14

Asthma Prediction Index

The PIAMA study suggests 8 clinical parameters for the risk

score

male sex

post-term delivery

parental education

Inhaled medicatiom

Wheezing frequency

Wheeze/dyspnea apart from colds

Respiratory infections

Eczema

Caudri D, et al. JACI 2009;124:903-10

API has been proposed has the best, most practical strategy

for predicting children who will develop persistent wheezing

Matricardi PM, et al. ERJ 2010;35:701-3

Belgrave DCM, et al. Expert Rev Clin Immunol 2013;9:921-6

15

There is increasing evidence that obesity affects

childhood asthma and its severity

Papoutsakis C, et al. J Acad Nutr Diet 2013;113:77-105

The nature of the association between obesity

and asthma remains obscure in children and appears to be stronger for

non-atopic asthma.

Longitudinal studies suggest that high body weight precedes asthma

symptoms

However, it is not clear how body mass may influence primary acquisition of

persistent wheeze

It is also of interest that body mass can exert cross generational epigenetic

effects so it is possible that parental obesity may affect their offspring.

Obesity

Walker ML, et al. Front Immunol 2014;5:447

16

Age 22 Age 16 Age 11

PEF

BMI

SPTs

Questionnaires

BMI

SPTs

Questionnaires

BMI

SPTs

Questionnaires

Age 26

BMI

SPTs

Questionnaires

Tucson Children’s Respiratory Study 2

02

53

0

BM

I (K

g/m

2)

10.9 16.6 22.1 26.5Age (years)

Normal PFvar at Yr11

High PFvar at Yr11

p = 0.268

p = 0.013

p < 0.001

p < 0.001

20

25

30

BM

I (K

g/m

2)

10.9 16.6 22.1 26.5Age (years)

Normal PFvar at Yr11

High PFvar at Yr11

Females Males

17

6265 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

The wheezing

phenotypes most

strongly associated

with atopy and airway

responsiveness were

characterised by

onset after age 18

months

18

Wheezing Phenotypes

Belgrave DCM et al. Expert Rev Clin Immunol 2013;9:921-936

19

JACI 2011;127:355-60

20

Lotvall J, et al. JACI 2011;127:355-60

21

22

L’Evoluzione a Lungo Termine

del Wheezing in Età Prescolare

23

Fenotipi di Sibilo

nei primi 6 anni di vita

Morgan WJ et al. Am J Respir Crit Care Med 2005;172:1253-8

24

25

Children with severe asthma are at

increased risk of developing adult

COPD

Children with intermittent asthma

are not at increased risk of

developing adult COPD

Tai A, et al. Thorax 2014;69:805-10

26

Outcomes of childhood asthma and wheezy

bronchitis - a 50-year cohort study

A cohort of children recruited in 1964 at age 10-15years, followed-up in

1989, 1995, and 2001 was followed-up in 2014 at age 60-65 years

330 subjects, mean age 61 years, were followed-up, 38 with childhood

asthma, 53 with childhood wheezy bronchitis, and 239 controls

In adjusted multivariate analyses childhood asthma was associated with

an increased risk of COPD odds ratio (95% confidence interval) 6.37

(3.73-10.94), as was childhood wheezy bronchitis 1.81 (1.12-2.91)

The COPD risk increased with childhood asthma and wheezy bronchitis

was associated with reduced FEV1 evident by the fifth decade and not

accelerated rate of FEV1 decline

Tagiyeva N, et al. Am J Respir Crit Care Med, 2015 Sep 9.

27

Associations of some early childhood factors with adult obstructive

airways disease, such as low birth weight and early childhood

infections, have been recognised for a considerable time

The challenge is to understand the mechanisms by which exposures

in early life, including pregnancy, influence lung growth and

development and to develop interventions to rectify the effects of

adverse influences during these critical years.

28

La Terapia a Lungo Termine

del Wheezing in Età Prescolare

29

30 Castro-Rodriguez JA et al. Pediatrics 2009;123:e519-e525

This effect was higher in those with a diagnosis of asthma than

wheeze

31

ERS Task Force

Definition, assessment and

treatment of wheezing

disorders in preschool children:

an evidence-based approach

Eur Respir J 2008;32:1096-1110

Terapia Farmacologica di Mantenimento

per il Respiro Sibilante in Età Prescolare

Multiple-trigger wheeze

ICSs at a daily dose of up to 400 mg/day

beclometasone equivalent should be given

When the response to this treatment is

poor, patients should not be treated with

higher doses but should probably be

referred to a specialist for further

evaluation and investigations

A trial of montelukast may be considered

Episodic (viral) wheeze

Montelukast 4 mg once daily should

probably be given

A trial of inhaled corticosteroids

may be considered, in particular

when episodes occur frequently or if

the family history of asthma is

positive

32 Acta Paediatrica 2010;99:56-60

33

34

Wheeze patterns in young children vary over time and with treatment, rendering

the distinction between episodic viral wheeze and multiple-trigger wheeze

unclear in many patients

Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze,

but may also be considered in patients with episodic viral wheeze with frequent

or severe episodes, or when the clinician suspects that interval symptoms are

being under reported

Any controller therapy should be viewed as a treatment trial, with scheduled

close followup to monitor treatment effect

The group recommends discontinuing treatment if there is no benefit and taking

favourable natural history into account when making decisions about long-term

therapy

35

Conclusioni

I Fenotipi di Wheezing in Pediatria

L’asma non è un’unica malattia, ma

un insieme di malattie eterogenee

con sintomi in comune

Una delle maggiori sfide nel

trattamento dell’asma è la

comprensione dei diversi fenotipi

e dei meccanismi biologici sottostanti

L’identificazione di questi meccanismi ha

l’obiettivo finale di migliorare l’efficacia

dei trattamenti e delle strategie

Belgrave DCM et al. Expert Rev Clin Immunol 2013;9:921-936

36