PREVENZIONE DEL PREVENZIONE DEL
WHEEZING WHEEZING RICORRENTE RICORRENTE
Michele Miraglia del Giudice
Servizio Asma e Fisiopatologia Respiratoria Infantile
“MAURIZIO MIRAGLIA del GIUDICE”
Dipartimento di Pediatria Seconda Università di Napoli
PREVENZIONE DEL PREVENZIONE DEL
WHEEZING WHEEZING RICORRENTE RICORRENTE
Chi è il bambino con wheezing ricorrente?
Che cosa è il
Che cosa è il wheezing wheezing ? ?
Il wheezing è il “sibilo”prodotto dalle turbolenze dell’aria che passa attraverso vie aeree ristrette.
. . . . è è anatomicamente anatomicamente favorito nel bambino favorito nel bambino
dal ridotto calibro dal ridotto calibro
delle vie aeree e dalla delle vie aeree e dalla
maggiore
maggiore collassabilit collassabilit à à delle pareti bronchiali delle pareti bronchiali
durante la fase durante la fase
espiratoria..
espiratoria..
Rational approach to the wheezy infant
Nemr S. Eid- Paediatric Respiratory Reviews 2004; 5: S77–S79
Cause di wheezing durante l’infanzia
INFIAMMAZIONI (asma, fibrosi cistica, displasia broncopolmonare)
INFEZIONI (bronchiolite, pertosse, chlamydia),
MALFORMAZIONI (anello vascolare, anomalie delle vie aeree, cisti broncogeniche)
COMPRESSIONI ESTRINSECHE O INTRINSECHE (corpo estraneo, linfoadenopatia)
REFLUSSO GASTROESOFAGEO
PATOLOGIE EXTRATORACICHE
dal punto di vista clinico...
dal punto di vista clinico...
Annals of Allergy. 1987;59: 334
Annals of Allergy. 1987;59: 334-335 e 373-335 e 373--375375 Stridore inspiratorio
Si
No Wheezing Espiratorio
1)Anello vascolare 2)Tracheomalacia 3)Anomalie laringee
o tracheali
Vomito
GER
1)Fibrosi cistica 2)Asma
3)BPD
4)Anomalie cardiovascolari o bronchiali
Infezioni ricorrenti:
1) Immunodeficit 2) Sindrome
delle ciglia immobili
+ + + +
+ +
Wheezing e
Wheezing e asma asma nell’infanzia nell’infanzia
Percentualedi pazienti
60 - 50 - 40 - 30 - 20 - 10 -
0
51.5 %
Assenza di respiro sibilante
15 %
Respirosibilantead insorgenza tardiva:
3-6 anni
13.7 %
*
Respirosibilante persistente: 1-6 anni
19.8 %
Respirosibilante transitorio: 0-3 anni
*
1246 neonati sono stati seguiti per 6 anni in uno
studio prospettico.
Martinez NEJM 1995; 332:133Development of wheezing disorders and asthma in preschool children
Martinez F. Pediatrics 2002; 109: 362-367
1246
1246 neonati neonati seguiti seguiti per 11 per 11 anni anni in in uno uno studio studio prospettico prospettico
Lung function (V´maxFRC) at infancy and 6 years of age expressed in Z-scores by wheezing group:
znever wheeze;
Stransient early wheeze;
late onset wheeze;
Tpersistent wheeze
Development of wheezing disorders and asthma in preschool children
Martinez F. Pediatrics 2002; 109: 362-367
FATTORI DI RISCHIO:
Vie aeree ristrette Prematurità
Fumo materno durante la gravidanza e
esposizione postnatale al fumo passivo
materno
Scolarizzazione precoce
Increased incidence of asthma in children of smoking mothers
Martinez F. Pediatrics 2002; 89: 21-26*P<0.01
*P<0.01
I nati da madri che hanno fumato in gravidanza almeno 10 sigarette al giorno sviluppano asma in modo significativamente maggiore rispetto ai figli di madri che hanno fumato meno o per nulla.
Il fumo paterno è ininfluente.
The effect The effect of of maternal maternal smoking on the incidence smoking on the incidence of of asthma asthma or or wheezing wheezing
Strachan
Strachan D. etD. et Al.Al.
Thorax
Thorax 1998, 53, 742 1998, 53, 742
Exposure
Exposure to to siblings siblings and day care and day care during during infancy infancy and and subsequent
subsequent development development of of asthma asthma and and frequent frequent wheeze wheeze . .
Ball TM. N
Ball TM. N EnglEngl J MedJ Med 2000;343:538-2000;343:538-4343
Tucson Children’s Respiratory Study: 1980 to present
M.Taussig. J Allergy Clin Immunol 2003;111:661-75 infezioni respiratorie
virali (RSV),chlamydia
Vie aeree ristrette
Prematurità , Scolarizzazione Fumo materno
Hypothetical
Hypothetical peak peak prevalenceprevalencebyby ageage forforthe 3 differentthe 3 different wheezingwheezing phenotypesphenotypes
. .
Kneyber MCJ et al. – Acta Paediatr., 2000, 89,654
RSV bronchiolitis and recurrent wheezing
Neuro inflammatory interactions and neural
remodelling in RSV-infected airway da Piedimonte G. 2002
Neuro
Neuro inflammatory interactions and neural inflammatory interactions and neural remodelling
remodelling in RSV in RSV - - infected airway infected airway da da Piedimonte Piedimonte G. 2002 G. 2002
RSV RSV EPITELIUM EPITELIUM
N N
eurotrophineurotrophin nervenerveG G
rowthrowthF F
actoractorNK 1 receptors NK 1 receptors
T cells
T cells PMNs PMNs Vessels Vessels Mast cells Mast cells Cytokines
Cytokines Chemotaxis Chemotaxis Edema Edema LTs LTs IRRITANT IRRITANT ALLERGENS ALLERGENS MEDIATORS MEDIATORS
SUBSTANCE P SUBSTANCE P SENSORY NERVES SENSORY NERVES
inflammation
The risk of frequent and infrequent wheeze in children who had mild-moderate RSV LRTI
The risk of frequent and infrequent wheeze in children who had mild-moderate RSV LRTI
Stein LT. Lancet 1999 Age 6 Age 8 Age 11 Age 13
4 3 2 1 0
infrequent wheeze frequent wheeze
***
***
*** **
* NS
*** p < 0,001 ** p < 0,01 * p < 0,05
Odds Rations (95% CI)
Children with a history of RSV infection had significantly lower FEV 1 , partly reversible by bronchodilator administration, at age 11
years.
Differences in total serum IgE (A) and peripheral blood (PB)
eosinophil levels (B) during and after the first LRI for children grouped as to their subsequent age 6 wheezing patterns
.These
These data data support support the possibility the possibility that that children children destined
destined to to develop develop persistent persistent wheezing wheezing are are already
already “ “ programmed programmed ” ” immunologically immunologically before before the first LRI
the first LRI to to respond respond differently differently to to a a respiratory respiratory viral
viral infection infection . .
Sustained increases in numbers of pulmonary dendritic cells after respiratory syncytial virus infection
Marc Beyer-J Allergy Clin Immunol 2004;113:127-33
RSV infection results in
sustained increases in numbers of mature dendritic cells in the lung.
These might well contribute to the development of intense
airway inflammation and airway hyperresponsiveness after RSV Infection and to enhancement of subsequent responses to
allergen exposure.
In contrast, in influenza A virus infection
numbers of pulmonary DCs were elevated during the acute phase of infection only,and sensitization and airway inflammation were induced exclusively if
allergen was administered during this phase.
VIRUS INFECTIONS, WHEEZE AND ASTHMA VIRUS INFECTIONS, WHEEZE AND ASTHMA
PAEDIATRIC RESPIRATORY REVIEWS (2003) 4, 184
PAEDIATRIC RESPIRATORY REVIEWS (2003) 4, 184––192192
Tucson Children’s Respiratory Study: 1980 to present
M.Taussig. J Allergy Clin Immunol 2003;111:661-75 fumo in gravidanza,
vie aeree più ristrette infezione respirat da RSV
Hypothetical
Hypothetical peak peak prevalenceprevalencebyby ageage forforthe 3 differentthe 3 different wheezingwheezing phenotypesphenotypes
. .
Lung function (V´maxFRC) at infancy and 6 years of age expressed in Z-scores by wheezing group:
znever wheeze;
Stransient early wheeze;
late onset wheeze;
Tpersistent wheeze
Tucson Children’s Respiratory Study: 1980 to present
M.Taussig. J Allergy Clin Immunol 2003;111:661-75 fumo in gravidanza,
vie aeree più ristrette infezione respirat
da RSV presenza di
atopia
Hypothetical
Hypothetical peak peak prevalenceprevalencebyby ageage forforthe 3 differentthe 3 different wheezingwheezing phenotypesphenotypes
. .
C RITERI Minor
1) Rinite allergica 2) Respiro sibilante
(in assenza di infezioni respiratorie)
3) Eosinofilia (> 4%)
59% rischio di asma 76% sviluppo di asma
DUE
Major
1) Asma familiare 2) Eczema
3) Atopia
+
oppure
ALMENO UNO
•
respiro sibilante precoce
•
respiro sibilante precoce frequente
(>3 episodi nell’anno precedente)
CRITERI DI RISCHIO DI ASMA
Castro-Rodriguez et al., AJRCCM 2000CRITERI DI
CRITERI DI RISCHIO DI ASMA RISCHIO DI ASMA
Castro-Castro-Rodriguez et al., AJRCCM 2000Rodriguez et al., AJRCCM 2000PREVENZIONE DEL PREVENZIONE DEL
WHEEZING WHEEZING RICORRENTE RICORRENTE
Chi è il b. con wheezing ricorrente?
La prevenzione non
La prevenzione non farmacologica farmacologica
STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN.
Wickman Allergy 2003;58:742STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN.
Wickman Allergy 2003;58:742RECURRENT WHEEZING AT 2 YRS RECURRENT WHEEZING AT 2 YRS
living according to guidelines
YES NO*
30-
20-
10-
0
12,6%
24,1%
• Birth cohort 4089 ch
• Families who lived according the Swedish primary prevention
guidelines:
1.breastfeeding
2.no tabacco smoke 3.good ventilation &
reduced dampness
*NO=exposed to
>2 risk factors
STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN.
Wickman Allergy 2003;58:742STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN.
Wickman Allergy 2003;58:742YES NO*
20-
10-
0 6,8%
17,9%
ASTHMA AT AGE 2 ASTHMA AT AGE 2
living according to guidelines
• Birth cohort 4089 ch
• Families who lived according the Swedish primary prevention
guidelines:
1.breastfeeding
2.no tabacco smoke 3.good ventilation &
reduced dampness
*NO=exposed to
>2 risk factors
STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN.
Wickman Allergy 2003;58:742STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN.
Wickman Allergy 2003;58:742REDUCTION OF ASTHMA AT 2 YRS
living according to guidelines
YES NO
*
30-
20-
10-
0
5,3%10,5%
9,1%27,3%
YES NO
*
HEREDITY FOR ALLERGIC DISEASES HEREDITY FOR ALLERGIC DISEASES
negative positive negative positive
• Birth cohort 4089 ch
• Families who lived according the Swedish primary prevention
guidelines:
1.breastfeeding
2.no tabacco smoke 3.good ventilation &
reduced dampness
*NO=exposed to
>2 risk factors
Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma
Prevention Study (CAPS)
Mihrshahi JACI 2003;111:162Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma
Prevention Study (CAPS)
Mihrshahi JACI 2003;111:162•
616 pregnant women were randomized to an HDM avoidance intervention, comprising the use ofimpermeable mattress covers and an acaricide or control and the use of an oil supplement, margarines, and cooking oils containing high levels of
omega-3 fatty acids or control.
•
Atopic status was measured by skin prick testing. Symptoms, diagnoses, and medicationhistories were elicited by means of parental interviews.
•
Outcomes were assessed at 18 months.• •
616 pregnant women were 616 pregnant women randomized to an HDM avoidance intervention, comprising the use ofimpermeable mattress covers and an acaricide or control and the use of an oil supplement, margarines, and cooking oils containing high levels of
omega-3 fatty acids or control.
• •
AtopicAtopic status was measured by status skin prick testing. Symptoms, diagnoses, and medicationhistories were elicited by means of parental interviews.
• •
Outcomes were assessed at 18 Outcomes were assessed at 18 months.months.
% REDUCTION OF ANY WHEEZE IN OIL SUPPLEMENTED OIL SUPPLEMENTED
0 –
10-
-9.8
P =0.02
PREVENZIONE DEL PREVENZIONE DEL
WHEEZING WHEEZING RICORRENTE RICORRENTE
Chi è il b. con wheezing ricorrente?
La prevenzione non farmacologica La prevenzione
La prevenzione farmacologica farmacologica
! ! antistaminici antistaminici
CETIRIZINE IN THE PREVENTION OF ASTHMA IN
CHILDREN WITH ATOPIC DERMATITIS
Warner JO JACI 2001; 108: 929CETIRIZINE IN THE PREVENTION OF ASTHMA IN
CHILDREN WITH ATOPIC DERMATITIS
Warner JO JACI 2001; 108: 929. placebo . cetirizine
1.0 - 0.9 - 0.8 - 0.7 - 0.6 - 0.5 - 0.4 - 0.3 - 0.2 - 0.1 -
Probability for d eveloping
6 12 18 24 30 36
treatment mo
. . . . . . . . . . . .
follow up mo
p=0.008Risk of developing asthma in children with AD and ↑ IgE for grass pollen
(0.25 mg/Kg x2)
1.0 - 0.9 - 0.8 - 0.7 - 0.6 - 0.5 - 0.4 - 0.3 - 0.2 - 0.1 -
Probability for d eveloping
6 12 18 24 30 36
. . . . . .
. . . . . .
p=0.04
Risk of developing asthma in children with AD and ↑ IgE for mites
. placebo . cetirizine (0.25 mg/Kg x2)
treatment mo follow up mo
CETIRIZINE IN THE PREVENTION OF ASTHMA IN
CHILDREN WITH ATOPIC DERMATITIS
Warner JO JACI 2001; 108: 929CETIRIZINE IN THE PREVENTION OF ASTHMA IN
CHILDREN WITH ATOPIC DERMATITIS
Warner JO JACI 2001; 108: 929Prevention of asthma with ketotifen in preasthmatic children: a three-year follow-up study.
Bustos GJ. Clin Exp Allergy. 1995;25:568-73Prevention of asthma with ketotifen in preasthmatic children: a three-year follow-up study.
Bustos GJ. Clin Exp Allergy. 1995;25:568-7340 40 - -
30 30 - -
20 20 - -
10 10 - -
0 0 - -
4/45 4/45
14/40 14/40 9% 9%
35% 35%
Ketotifen
Ketotifen Placebo Placebo P=0,003
P=0,003
% % of of Ch. WITH ASTHMA Ch . WITH ASTHMA
In this double-blind,
placebo-controlled, parallel study, 100 infants with a
family history of major
allergy and elevated serum IgE levels, but with no
history of bronchial
obstruction, were treated
with either ketotifen (n =
50) or placebo (n = 50)
over a 3-year period.
PREVENZIONE DEL PREVENZIONE DEL
WHEEZING WHEEZING RICORRENTE RICORRENTE
Chi è il b. con wheezing ricorrente?
Quando iniziare la prevenzione?
La prevenzione non farmacologica La prevenzione
La prevenzione farmacologica farmacologica
! antistaminici
! ! corticosteroidi corticosteroidi
Effectiveness of prophylactic inhaled steroids in
childhood asthma: A systemic review of the literature
Calpin JACI 1997; 100: 452
Effectiveness of prophylactic inhaled steroids in Effectiveness of prophylactic inhaled steroids in
childhood asthma: A systemic review of the literature childhood asthma: A systemic review of the literature
Calpin
Calpin JACI 1997; 100: 452 JACI 1997; 100: 452
0 -10 - -20 - -30 - -40 - -50 - -60 - -70 -
40 - 30 - 20 - 10 -
0
From 1966 to 1996
94 studies on ICS vs placebo
- 50 %
- 37 %
- 68 %
Systemic steroids Symptoms
β2use
Mean increase in PEFR (L)
38 (L)
Persistent wheezing in infants with an
Persistent wheezing in infants with an atopic atopic tendency tendency responds to inhaled
responds to inhaled fluticasone fluticasone . .
ChavasseChavasse Arch DisArch Dis Child. 2001;85:143-Child. 2001;85:143-8.8.Bronchoalveolar
Bronchoalveolar lavage lavage findings suggest two different forms of findings suggest two different forms of childhood asthma.
childhood asthma.
Stevenson EC. Stevenson EC. ClinClin ExpExp AllergyAllergy 1997;27:10271997;27:1027-35-35This study has investigated
the cellular constituents of BAL fluid in 95 children with a history of atopic asthma, non- asthmatic atopic children or viral associated wheeze.
RESULTS: during relatively asymptomatic periods there is on-going airways
inflammation, as
demonstrated by eosinophil and mast cell recruitment, in children with asthma and
atopy but not in children with viral associated wheeze or atopy alone.
This study has investigated This study has investigated the cellular constituents of the cellular constituents of BAL fluid in 95 children with a BAL fluid in 95 children with a history of
history of atopic atopic asthma, non- asthma, non - asthmatic
asthmatic atopic atopic children or children or viral associated wheeze.
viral associated wheeze.
RESULTS
RESULTS: during relatively : during relatively asymptomatic periods there asymptomatic periods there is on
is on- -going airways going airways inflammation, as inflammation, as demonstrated by
demonstrated by eosinophil eosinophil and mast cell recruitment, in and mast cell recruitment, in children with asthma and children with asthma and atopy
atopy but not in children with but not in children with viral associated wheeze or viral associated wheeze or atopy
atopy alone. alone.
Eosinophil (P < or = 0.005) and mast cell (P < or = 0.05) numbers were significantly elevated in the group with atopic asthmaInhaled steroids for
Inhaled steroids for epidosodic epidosodic viral wheeze of childhood
viral wheeze of childhood
McKean The Cochrane Library, Issue 1, 2001
Dati Dati di 5 trials di 5 trials clinici clinici in in età età pediatrica pediatrica
O O R R
AlteAlte dosidosi
al bisognoal bisogno di CSI di CSI (1.6
(1.6 --2.25 mg/die) 2.25 mg/die)
1 1
0.53 0.53
0.82 0.82
Basse
Basse dosidosi di di mantenimento
mantenimento di CSI di CSI (400 µg/die)
(400 µg/die)
• Alte dosi al bisogno di CSI rappresentano una strategia parzialmente efficace per la
terapia del wheezing virale di tipo episodico-lieve
• Non c’è alcuna
dimostrazione di efficacia
della terapia di mantenimento con CSI a basse dosi
Richiesta di steroidi per os
Ipotetica efficacia dei CSI nei 3 fenotipi di
Ipotetica efficacia dei CSI nei 3 fenotipi di wheezing wheezing
fumo in gravidanza,
vie aeree più ristrette infezione respirat
da RSV presenza di
atopia
Si Si
Si Si
Si Si
Si Si
Si Si Si Si Si Si Si Si Si Si No No
No No No No
Ni Ni Ni Ni
Ni Ni Ni Ni Ni Ni
Hypothetical
Hypothetical peak peak prevalenceprevalencebyby ageage forforthe 3 differentthe 3 different wheezingwheezing phenotypesphenotypes
. .
PREVENZIONE DEL PREVENZIONE DEL
WHEEZING WHEEZING RICORRENTE RICORRENTE
Chi è il b. con wheezing ricorrente?
Quando iniziare la prevenzione?
La prevenzione non farmacologica La prevenzione
La prevenzione farmacologica farmacologica
! Antistaminici
! ! Corticosteroidi Corticosteroidi
! ! Antileucotrieni Antileucotrieni
Increased
Increased production of IFN production of IFN - - γ γ and and cysteinyl cysteinyl leukotrienes
leukotrienes in in virus virus - - induced induced wheezing wheezing
Schaik
Schaik etet al J ALLERGY CLIN IMMUNOL 2000; 103:630al J ALLERGY CLIN IMMUNOL 2000; 103:630-6-6
• Concentrazione dei cisteinil leucotrieni nelle secrezioni respiratorie di soggetti con wheezing virus indotto e nei soggetti controllo
• Le colonne rappresentano il valore medio della
concentrazione dei leucotrieni in soggetti con infezioni delle vie aeree superiori , un episodio primario di bronchiolite o
wheezing ricorrente
Increased
Increased production of IFN production of IFN - - γ γ and and cysteinyl cysteinyl leukotrienes
leukotrienes in in virus virus - - induced induced wheezing wheezing
Schaik
Schaik etet al al -- J ALLERGY CLIN IMMUNOL 2000; 103:630-J ALLERGY CLIN IMMUNOL 2000; 103:630-66
• Correlazione tra la
concentrazione di IFN-γ e cisteinil LT nelle secrezioni respiratorie di soggetti con wheezing virus indotto
• La concentrazione di IFN- γ può aumentare il rilascio di cisteinil LT
• l’ IFN- γ attiva e prolunga
la sopravvivenza degli eosinofili e aumenta il rilascio di LT da
queste cellule
Montelukast nella Prevenzione degli Episodi di Riacutizzazione Asmatica in Bambini dai 2 ai 5 Anni
Valutare l’effetto del trattamento per 12 mesi con Montelukast, rispetto al placebo, sulla
frequenza degli episodi di riacutizzazione in bambini asmatici di età compresa tra 2 e 5 anni
Bisgaard H. et al. Montelukast reduces asthma exacerbations in 2- to 5- year-old children with intermittent asthma.
Am J Respir Crit Care Med, 2005; 171: 315-22.
Episodio di Riacutizzazione Asmatica
Definito come:
• 3 giorni consecutivi con:
- Sintomi diurni (punteggio medio delle risposte a 4 domande giornaliere sui sintomi diurni ≥1 ogni
giorno) e
- ≥ 2 trattamenti con beta-agonisti ogni giorno oppure
• Ricorso ai corticosteroidi per via inalatoria (≥3 giorni consecutivi) o ai corticosteroidi per via orale (≥1
giorno) oppure
• Ospedalizzazione per asma
Bisgaard H. et al. Montelukast reduces asthma exacerbations in 2- to 5- year-old children with intermittent asthma.
Am J Respir Crit Care Med, 2005; 171: 315-22.
Criteri di Inclusione
• Età 2–5 anni
• Prestudio
– Asma intermittente scatenato da infezione delle vie aeree superiori (anche raffreddore comune)
– Assenza di sintomi e di utilizzo di beta agonisti nei periodi intercorrenti
Bisgaard H. et al. Montelukast reduces asthma exacerbations in 2- to 5- year-old children with intermittent asthma.
Am J Respir Crit Care Med, 2005; 171: 315-22.
Disegno dello Studio
Bisgaard H. et al. Montelukast reduces asthma exacerbations in 2- to 5- year-old children with intermittent asthma.
Am J Respir Crit Care Med, 2005; 171:315-22.
Periodo I Periodo II
Placebo (run-in)
Placebo
Montelukast 4 mg (o 5 mg a seconda dell’età)*
Settimana 48
Visita 7 8
36
1 2 3 4 5 6
24 16
8 0
-3 -2
*Se i pazienti compivano il 6° anno di età durante lo studio veniva loro somministrato Montelukast 5 mg (compresse masticabili)
Frequenza delle Riacutizzazioni
Bisgaard H. et al. Montelukast reduces asthma exacerbations in 2- to 5- year-old children with intermittent asthma.
Am J Respir Crit Care Med, 2005; 171:315-22.
p≤0.001 3
2.34
1.60
32%
Frequenza di 2 riacutizzazioni (numero/anno)
1
0
Montelukast 4 mg (n=265)
Placebo (n=257)
Tempo di Comparsa della Prima Riacutizzazione
Bisgaard H. et al. Montelukast reduces asthma exacerbations in 2- to 5- year-old children with intermittent asthma.
Am J Respir Crit Care Med, 2005; 171:315-22.
• Tempo medio alla prima riacutizzazione:
206 giorni con Montelukast, 147 giorni con il placebo
0 2 4 6 8 10 12
0 20 40 60 80 100
12
Montelukast (n=265) Placebo (n=257)
p=0.024
Percentuale di pazienti senza
riacutizzazioni
Mesi
Stima di Kaplan-Meier. Analisi Intention-to-Treat
Ricorso ai Corticosteroidi (Inalatori+Orali)
Bisgaard H. et al. Montelukast reduces asthma exacerbations in 2- to 5- year-old children with intermittent asthma.
Am J Respir Crit Care Med, 2005; 171:315-22.
1.19
0.66 0.53
1.74
1.10
0.64
0.0 0.5 1.0 1.5 2.0
2.5 Montelukast 4 mg (n=265)
Placebo (n=257) p=0.024
32% p=0.027
Cicli
di trattamento con
corticosteroidi
40%
p=0.368
Totali
(via inalatoria e via orale)
Via Inalatoria Via Orale
Stagionalità delle Riacutizzazioni
% Pazienti con riacutizzazione
Inverno Primavera Estate Autunno Montelukast 4 mg Placebo
Mesi (Emisfero Nord)
GEN FEB MAR APR MAG GIU LUG AGO SET OTT NOV DIC
5 10
0 15
Bisgaard H. et al. Montelukast reduces asthma exacerbations in 2- to 5- year-old children with intermittent asthma.
Am J Respir Crit Care Med, 2005; 171:315-22.
A Randomized Trial of Montelukast in
Respiratory Syncytial Virus Postbronchiolitis
Bisgaard
Bisgaard -- AmAm J RespirJ Respir CritCrit Care MedCare Med Vol 2003;167: 379–Vol 2003;167: 379–383383
• • I bambini spesso sviluppano I bambini spesso sviluppano iperreattività iperreattività delle vie aeree dopo bronchiolite da virus delle vie aeree dopo bronchiolite da virus
respiratorio
respiratorio sinciziale sinciziale (RSV) (RSV)
• • I Cysteinyl I Cysteinyl - - leukotrieni (cys leukotrieni (cys - - LT) sono LT) sono
rilasciati durante l’infezione da RSV e
rilasciati durante l’infezione da RSV e
possono contribuire all’infiammazione
possono contribuire all’infiammazione
A Randomized Trial of Montelukast in
Respiratory Syncytial Virus Postbronchiolitis
Bisgaard
Bisgaard -- AmAm J RespirJ Respir CritCrit Care MedCare Med Vol 2003;167: 379–Vol 2003;167: 379–383383
• 130 bambini tra 3 e 36 mesi ospedalizzati con bronchiolite acuta da RSV sono stati
randomizzati in uno studio in doppio cieco
• 2 gruppi in terapia per 28 giorni entro una settimana dalla scomparsa dei
sintomi:
- montelukast 5mg - placebo
Il trattamento con
Il trattamento con montelukast montelukast riduce i sintomi polmonari dovuti riduce i sintomi polmonari dovuti
alla
alla bronchiolite bronchiolite da RSV da RSV
MONTELUKAST
Riduzione degli eosinofili nell’espettorato indotto
Variazione % degli eosinofili nell’espettorato indotto
-50 -40 -30 -20 -10 0 10 20 30
Placebo
Montelukast
*
% variazione dal
basale
*
p=0.026, basato sul modello ANCOVA, confrontato con il placebo Pizzichini et al. Eur Resp Journal 1999;14:12-18PREVENZIONE DEL PREVENZIONE DEL
WHEEZING WHEEZING RICORRENTE RICORRENTE
Chi è il b. con wheezing ricorrente?
Quando iniziare la prevenzione?
La prevenzione non farmacologica La prevenzione farmacologica
! Antistaminici
!Corticosteroidi
!Antileucotrieni La prevenzione del
La prevenzione del wheezing wheezing : quando iniziare? : quando iniziare?
100 – 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 –
0
% dei soggetti all’età di 26 anni
A LONGITUDINAL, POPULATION-BASED, COHORT STUDY OF CHILDHOOD ASTHMA FOLLOWED TO ADULTHOOD. Sears NEJM 2003;349:1414
1139 newborn (April 1972-March 1973);
Assessed at 3 yrs, every 2 yrs up to 15 yrs than at 18, 21, amd 26 yrs of age;
Questionnaire;
Lung function;
SPT, sIgE;
Methacholine ch.
WHEEZING:
72.6 51.4
26.9
Almeno 1 volta
Più di
1 volta persistente
30 –
20 –
10 –
0
A LONGITUDINAL, POPULATION-BASED, COHORT STUDY OF CHILDHOOD ASTHMA FOLLOWED TO ADULTHOOD. Sears NEJM 2003;349:1414
1139 newborn (April 1972-March 1973);
Assessed at 3 yrs, every 2 yrs up to 15 yrs than at 18, 21, amd 26 yrs of age;
Questionnaire;
Lung function;
SPT, sIgE;
Methacholine ch.
del 26.9% con wheezing persistente
12.5% HAD
14.5
REMISSION FOLLOWED BY RELAPSE
BY AGE 26
% dei soggetti all’età di 26 anni
A LONGITUDINAL, POPULATION-BASED COHORT STUDY OF CHILDHOOD ASTHMA FOLLOWED TO ADULTHOOD
Sears NEJM 2003; 349: 1414
Age at assessment (yr)
9 11 13 15 18 21 26
Classification
Persistent wheezing from 9 yrs of age Persistent wheezing from onset
Remission Relapse
Intermittent wheezing Transient wheezing
No wheezing ever
Patterns of wheezing (shaded bars) in childhood reported by study members or their parents, illustrating definitions of persistent wheezing, remission, relapse, intermittent wheezing, transient wheezing, and no wheezing ever.
A LONGITUDINAL, POPULATION-BASED COHORT STUDY OF CHILDHOOD ASTHMA FOLLOWED TO ADULTHOOD
Sears NEJM 2003; 349: 1414
A) Male study members B) Female study members
