I fenotipi dell’asma
Maria Caruso
Il riscontro di sibili è un sintomo frequente nei
primi anni di vita
nel bambino molto piccolo troviamo cause diverse
dall’asma ( fibrosi cistica, inalazione di latte,
discinesia ciliare primitiva, immunodeficienze
primitive, cardiopatie congenite, malformazioni
congenite, aspirazione di corpo estraneo, ecc)
FENOTIPI DEL BAMBINO CON RESPIRO
SIBILANTE
PEDIATRICS Vol. 109 No. 2 February 2002,
pp. 362-367
Development of Wheezing Disorders
and Asthma in Preschool Children
Fernando D. Martinez, MD
From the University of Arizona, Tucson,
Arizona
TABLE 1. Distribution of Asthma in 401 Subjects Aged 35 According to Whether They Had
Bronchitis or Asthma as Children
Asthma at Age 35* N(%)
At Age 7*
No Recent Asthma
Infrequent
Frequent
Persistent
Total
Mild wheezy bronchitis
42 (65)
8 (12)
10 (15)
5 (8)
65
Wheezy bronchitis
54 (63)
10 (12)
9 (10)
13 (15)
86
Asthma
29 (30)
20 (20)
18 (18)
31 (32)
98
7 (10)
10 (15)
8 (12)
42 (63)
67
132
48
45
91
401
Severe asthma
Total
*
Values are numbers (percentages) of participants. Eighty-five controls are excluded.
Patients entered study at age 10.
Adapted from Oswald et al.7
Tucson children's respiratory study: 1980 to present*1
Lynn M. Taussig MDa, Anne L. Wright PhDb, Catharine J. Holberg PhDb,
Marilyn Halonen PhDb, Wayne J. Morgan MDb and Fernando D. Martinez
MDb Volume 111,number 4 APRIL 2003
Table I. Potential risk factors evaluated for possible
relationships with acute LRI or chronic lung disease (asthma)
Sex, ethnicity
Birth weight
Parents' education, income, age
Respiratory symptoms and illnesses in other household members
Genetic determinants
Number and order of siblings
Bottle/breast-feeding
Day care
Type of home heating, cooking, and cooling
Number and type of pets
Indoor air pollution
Passive/active smoking
Atopy
Immune function
Lung function
Airway reactivity
Tucson children's respiratory study: 1980 to present*1
Lynn M. Taussig MDa, Anne L. Wright PhDb, Catharine J. Holberg
PhDb, Marilyn Halonen PhDb, Wayne J. Morgan MDb and
Fernando D. Martinez MDb Volume 111,number 4 APRIL 2003
Table II. Data collection
Enrollment (birth)
Questionnaire (family) data
Maternal pregnancy history
Cord blood (IgE, immune studies)
CBC/differential
Periodic data
Well-baby visit forms
Periodic questionnaires on all household members
2 to 3 months of age
Pulmonary function tests
9 to 15 months of age
IgE, CBC and differential, immune studies
LRIs in first 3 years of life
Sign/symptom and history forms
Cultures, serologies, CBC and differential, IgE
Convalescence (3-5 wk post LRI) serologies, IgE, CBC and
differential
CBC, Complete blood count.
Table III. Number of index subjects in the CRS with data at each
evaluation
Early years of In-depth
life
I
In-depth II
Age of index subjects
In-depth III
Birth to 3 y
6y
11 y
16 y
1055 (age 2 y)
1025
955
509†
888
—
—
—
—
762
689
397†
Serum IgE
1120 (at birth)
550
633
357†
Peripheral blood
eosinophils
880 (at 9 mo)
550
633
357†
Pulmonary function
studies
176 (at 4 mo)
676
595
376†
Airway challenge studies
—
368
396
303†
Peak flow variability
—
—
600
383†
Respiratory
questionnaires*
LRI evaluations through
age 3 y
Skin prick tests
*Respiratory questionnaires were also obtained on the enrolled child at age 3
(n = 940), 8 (n = 841), and 13 (n = 714) years. Questionnaires are also being
obtained at age 18, but this is still in progress.
†Data collection is still in progress.
Table IV. Evaluation of family members at in-depth I
Mothers
Fathers
Siblings
Questionnaire
1008
908
1150
Pulmonary
function tests
840
671
625
Blood sample
806
635
540
Allergy skin
tests
813
664
847
Methacholine
studies
319
272
51
Hypothetical yearly peak prevalence of wheezing according to phenotype in
childhood
Martinez, F. D. Pediatrics 2002;109:362-367
Copyright ©2002 American Academy of Pediatrics
Am. J. Respir. Crit. Care Med., Volume 162, Number 4, October
2000, 1403-1406
A Clinical Index to Define Risk of Asthma in Young
Children with Recurrent Wheezing
JOSÉ A. CASTRO-RODRÍGUEZ, CATHARINE J. HOLBERG, ANNE L.
WRIGHT, and FERNANDO D. MARTINEZ
Respiratory Sciences Center, University of Arizona, College of Medicine,
TABLE 1
Tucson, Arizona
A CLINICAL INDEX TO DEFINE ASTHMA RISK*
Major Criteria
1. Parental MD asthma
2. MD eczema
Minor Criteria
1. MD allergic rhinitis§
2. Wheezing apart from colds
3. Eosinophilia ( 4%)
*
Loose index for the prediction of asthma: Early wheezer plus at least one of two major criteria or two
of three minor criteria. Stringent index for the predication of asthma: Early frequent wheezer plus at
least one of two major criteria or two of three minor criteria.
History of a physician diagnosis of asthma.
Physician diagnosis of atopic dermatitis as reported in questionnaires at ages 2 or 3.
§
Physician diagnosis of allergic rhinitis as reported in questionnaires at ages 2 or 3.
Criteri di Rischio per Asma nell’Early Wheezing
(Castro-Rodriguez, AJRCCM 2000;162:1403)
Criteri Maggiori
Criteri Mino
1. Asma nei genitori
1. Rinite allergica
2. Dermatite atopica
2. Wheezing anche senza
raffreddore
3. Eosinofilia (> 4%)
1 criterio maggiore oppure 2 criteri minori
+
Wheezing precoce
Asma nel 59%
Wheezing precoce
frequente
Asma nel 76 %
Criteri di Rischio per Asma nell’Early Wheezing
(Castro-Rodriguez, AJRCCM 2000;162:1403)
Criteri Maggiori
Criteri Mino
1. Asma nei genitori
1. Rinite allergica
2. Dermatite atopica
2. Wheezing anche senza
raffreddore
3. Eosinofilia (> 4%)
1 criterio maggiore oppure 2 criteri minori
Wheezing precoce
No asma nel 73 %
Wheezing precoce
frequente
No asma nel 68 %
December 2004 • Volume 114 • Number 6
Atopic characteristics of children with recurrent
wheezing at high risk for the development of
childhood asthma
Theresa W. Guilbert, Wayne J. Morgan, Robert S. Zeiger,
Leonard B. Bacharier, Susan J. Boehmer, Marzena
Krawiec, Gary Larsen, Robert F. Lemanske, Andrew Liu,
David T. Mauger, Chris Sorkness, Stanley J. Szefler,
Robert C. Strunk, Lynn M. Taussig, Fernando D. Martinez
1
2
8
2
mAPI versus original API
( Castro-Rodriguez et al)
Il bambino deve avere una storia di 4 o più episodi di
wheezing con almeno una diagnosi da parte del
medico
Criteri maggiori:
• Asma in un genitore
• Dermatite atopica diagnosticata da un medico
• Sensibilizzazione ad 1 o più aeroallergeni
Criteri minori:
• Sensibilizzazione ad allergeni alimentari ( latte,
uova, arachidi)
• Wheezing non correlato a raffreddamento
• Eosinofilia ematica ≥ 4%
Asma Predictive Index
Castro-Rodriguez , Martinez. Am J respir Crit Care Med,
2000; 162: 1403-6
• L’individuazione precoce del fenotipo del
bambino che “ fischia” nei primi anni di
vita è importante per distinguere quei
bambini che hanno broncospasmo ma non
saranno destinati a presentare un quadro
cronico, più persistente di asma.
• Il 70-80%dei bambini con indice positivo
continueranno ad avere asma fra i 6-13
anni, mentre il 68% di quelli con indice
negativo non hanno più asma nel periodo
scolastico
Bambino con respiro sibilante transitorio
•L’80%dei bambini che “fischia” nel primo anno di vita
rientra in questa categoria; nel 2° anno rientrano in tale
categoria il 60% e nel 3° anno il 30- 40%
•Non hanno una maggiore prevalenza di familiarità per
atopia, dermatite atopica, eosinofilia o IgE elevate o altri
markers di diatesi allergica
•Condizione transitoria, priva di conseguenze a lungo
termine, soprattutto nel bambino non allergico, che si
risolve abitualmente entro i 3 anni
•Il fattore di rischio principale è una riduzione della
funzione polmonare , che persiste diminuita anche
all’età di 6 anni.
…….Bambino con respiro sibilante
transitorio
•Non presenta una iperreattività bronchiale.
•Altri fattori di rischio sono la prematurità e il
contatto con altri bambini nei primi anni di vita (
frequenza di comunità o presenza di altri fratelli)
•Nell’età adulta è possibile che abbiano un
aumentato rischio di BPCO, soprattutto se
fumatori,a causa della loro congenita ristrettezza
delle vie respiratorie
Bambini non atopici
Rientrano nella categoria precedentemente
classificata come “persistent wheezer” , con sintomi
ancora presenti all’età di 3 anni, e della quale i non
atopici rappresentano il 40% mentre il 60%
diventano atopici all’età di 6 anni
possono presentare sibili associati ad infezioni
respiratorie virali acute, molto frequentemente
determinate da infezione da RSV ( in tali casi è
aumentato il rischio di wheezing nei primi 10 anni e
poi decresce e non è più significativa a 13 anni. Non
è descritta correlazione fra infezione da RSV e
sensibilizzazione allergica).
……Bambini non atopici
•I sintomi per lo più scompaiono nel corso degli anni
prescolari; possono residuare alterazioni minori della
funzionalità respiratoria e una iperresponsività delle
vie aeree.
•All’età di 11 anni il test di broncodilatazione con
salbutamolo riporta a valori di normalità il FEV1,
dimostrando una completa reversibilità delle
alterazioni minori della funzionalità respiratoria
•Questo indicherebbe che i “ non atopic wheezers”
rispondono con broncoostruzione a stimoli virali per
un alterato controllo del tono bronchiale. Non è
conosciuto se questa alterazione sia primitiva a
secondaria ad infezione virale.
Bambini atopici, con storia familiare di asma
 verso i 2-3 anni possono sviluppare sintomi di
asma che persistono nel corso degli anni futuri.
La comparsa di asma nei primi 3 anni di vita è
associata a maggiore gravità.
L’asma precoce è frequentemente associata ad
atopia
Una sensibilizzazione precoce gioca un
importante ruolo nella persistenza dell’asma
In essi prevale l’infiammazione eosinofila dei
bronchi
Allergy
Volume 63 Issue 1 Page 5-34, January 2008
Diagnosis and treatment of asthma in childhood: a PRACTALL
consensus report
L. B. Bacharier11Department of Pediatrics, Washington University, St Louis, MO, USA,
A. Boner22Department of Pediatrics, University of Verona, Verona, Italy,
K.-H. Carlsen33Department of Pediatrics, University of Oslo, Oslo, Norway,
P. A. Eigenmann44Pediatric Allergy, University Children’s Hospital of Geneva, Geneva,
Switzerland,
T. Frischer55University Children’s Hospital Vienna, Vienna, Austria,
M. Götz66Department of Paediatrics & Adolescent Medicine, Medical University of Vienna,
Vienna, Austria,
P. J. Helms77Department of Child Health, University of Aberdeen, Aberdeen, Scotland,
J. Hunt88Department of Pediatrics, University of Virginia, Charlottesville, VA, USA,
A. Liu99Department of Pediatrics, National Jewish Medical and Research Center, University of
Colorado School of Medicine, Denver, CO, USA,
N
The European Pediatric Asthma Group* (2008)
Diagnosis and treatment of asthma in childhood: a
PRACTALL consensus report
Allergy 63 (1), 5–34.
Asthma in children can be described as ‘repeated attacks of
airway obstruction and intermittent symptoms of increased
airway responsiveness to triggering factors, such as exercise,
allergen exposure and viral infections’ . However, the
definition becomes more difficult to apply confidently in
infants and preschool age children who present with recurrent
episodes of coughing and/or wheezing. Although these
symptoms are common in the preschool years, they are
frequently transient, and 60% of children with infantile
wheeze will be healthy at school age .
Physicians should manage and exclude diagnoses other than
asthma, and be aware of the variable natural history patterns
of recurrent wheezing in early childhood.
Bacharier, L. B., Boner, A., Carlsen, K.-H., Eigenmann, P. A., Frischer, T., Götz, M.,
Helms, P. J., Hunt, J., Liu, A., Papadopoulos, N., Platts-Mills, T., Pohunek, P.,
Simons, F. E. R., Valovirta, E., Wahn, U. & Wildhaber, J.
The European Pediatric Asthma Group* (2008)
Diagnosis and treatment of asthma in childhood: a
PRACTALL consensus report.
Allergy 63 (1), 5-34.
Asthma phenotypes
In asthma, age and triggers can be used to define
different phenotypes of disease. These phenotypes are
likely to be useful because they recognize the
heterogeneity of childhood asthma. They do not
represent separate diseases, but are part of the
‘asthma syndrome’. Guidelines that recognize different
phenotypes should provide better direction for
prognosis and therapeutic strategies.
The European Pediatric Asthma Group* (2008)
Diagnosis and treatment of asthma in childhood: a
PRACTALL consensus report
Allergy 63 (1), 5–34.
Three different patterns of recurrent
wheeze in pediatric patients have been
proposed , and a fourth was recently
described . However, it should be noted
that patterns 1 and 2 (listed below) can
only be discriminated retrospectively and
are not suitable for use when treating the
child.
1.Transient wheezing: Children who wheeze during
the first 2–3 years of life, but do not wheeze after
the age of 3 years
2. Nonatopic wheezing: Mainly triggered by viral
infection and tends to remit later in childhood
3. Persistent asthma: Wheezing associated with the
following: • Clinical manifestations of atopy
(eczema, allergic rhinitis and conjunctivitis, food
allergy), blood eosinophilia, and/or elevated total
immunoglobulin E (IgE) • Specific IgE-mediated
sensitization to foods in infancy and early childhood,
and subsequently to common inhaled
allergens • Inhalant allergen sensitization prior to
3 years of age, especially with sensitization and high
levels of exposure to specific perennial allergens in
the home • A parental history of asthma
4. Severe intermittent wheezing : Infrequent acute
wheezing episodes associated with the
following: • Minimal morbidity outside of time of
respiratory tract illness • Atopic characteristics,
including eczema, allergic sensitization and
peripheral blood eosinophilia
The highest incidence of recurrent wheezing is found
in the first year of life.
According to long-term population-related prospective
birth cohort studies, up to 50% of all infants and
children below the age of 3 years will have at least
one episode of wheezing .
Infants with recurrent wheezing have a higher risk of
developing persistent asthma by the time they reach
adolescence, and atopic children in particular are
more likely to continue wheezing (Fig. 1) .
In addition, the severity of asthma symptoms during
the first two years of life is strongly related to later
prognosis .
However, both the incidence and period prevalence of
wheezing decrease significantly with increasing age .
Diagnosis and treatment of asthma in childhood: a
PRACTALL consensus report.
Allergy 63 (1), 5-34.
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 (10).
Age is one of the strongest determinants of asthma
phenotype in childhood, and involves pathophysiological
events, exposure and natural history determinants.
Because of differences in disease presentation between
the age groups, it is important to design diagnostic and
management strategies based on age.
Practical age groupings for these purposes are:
• Infants (0–2 years old)
• Preschool children (3–5 years old)
•School children (6–12 years old)
• Adolescents.
Infants (0–2 years old).
In infants, persistence of symptoms is a major
indicator of severity. Therefore, it should be
established whether the child has wheezed on
most days of the week during the last 3 months.
If so, these children should be diagnosed with
persistent infantile wheeze, after careful exclusion
of other causes.
Children with intermittent disease (recurrent
episodes) can be classified as having either
severe or mild disease, depending upon the need
for medical resources (systemic steroids,
hospitalization).
Preschool children (3–5 years old). In preschool
children, the key differentiator of asthma phenotype
is persistence during the last year (Fig. 2). If
symptoms disappear completely between episodes,
and usually follow a cold, viral-induced asthma is
the most appropriate diagnosis. Viruses are the
most common trigger in this age group. Exerciseinduced asthma can also be a unique phenotype in
this age group.
Skin prick tests or in vitro tests for the presence of
specific IgE antibodies should be performed along with
efforts to ascertain whether there is a clinically relevant
association between exposure and symptom occurrence. If
so, the phenotype is allergen-induced asthma. It should be
emphasized that atopy is a risk factor for asthma
persistence irrespective of whether or not allergens are
obvious triggers of disease activity. If no specific allergic
trigger can be identified, the phenotype can be
characterized as nonallergic asthma with some
caution. However, this may still mean that the specific
allergic trigger was not detected.
School-age children (6–12 years old).
The differentiators in school-age children are the same
as those in preschool children (Fig. 2).
However, allergen-induced cases are more common
and visible and seasonality may become evident.
Virus-induced asthma is still common in this age group.
Severity may become an important issue in the
treatment of allergen-induced asthma.
Adolescents.
Atopic asthma can have its onset during adolescence
and there are more new cases than remissions .
Nonatopic asthma can also start during adolescence .
There are additional problems associated with
managing and classifying asthma in adolescent
patients.
Many adolescents are reluctant to use regular daily
medications and do not like having any restrictions
placed on their lives.
Smoking may also become an issue.
Also, there may be a difficult transition period when
patients stop seeing a pediatrician and start seeing
another physician.
Pathologically, severe asthma in both adults (76) and
children has particular characteristics suggesting that it
could be considered as a unique phenotype.
Severity is associated with persistence and
unresponsiveness to therapy.
Although it can be useful as an additional parameter in
defining phenotypes, severity levels tend to be
arbitrary. Severity also depends on age.
In infants, persistent disease should be considered
severe; in older children, severe exacerbations are
those with respiratory distress who require oxygen and
hospitalization; these may occur independently of the
usual measures of severity, i.e. frequency of symptoms,
or lung function.
Figure 2. Asthma phenotypes in children aged >2 years of age. Note that
phenotypes are a useful guide to the predominant problem and overlap between
phenotypes is frequently present.
Interactions between respiratory tract
infections and atopy in the aetiology of
asthma
Holt. ERJ 2002; 19: 538
…il danno determinato dagli episodi di
wheezing virus indotti sulle basse
vie aeree interagisce con le
manifestazione allergiche
respiratorie, incrementando il rischio
di sviluppo di asma persistente.
Le infezioni virali sono implicate sia nella
patogenesi che nelle riacutizzazioni dell’ asma
Primi anni di vita: RSV, virus parainfluenzale,
adenovirus
Nelle età successive: rinovirus e virus influenzali
Il trattamento solo sintomatico degli
episodi di wheezing determina un
quadro infiammatorio che interferisce
con lo sviluppo e la differenziazione
del polmone e progressione verso una
forma di asma cronica
“Progression of intermittent infant wheezing to persistent
asthma in early childhood”
Holt, Nature Immunology 2004;5:695
Gli episodi di wheezing del bambino in età
prescolare sono associati ad una infiammazione
neutrofila sistemica e si ritiene che i bambini che
sviluppano wheezing in corso di infezione virale
abbiamo la propensione a reclutare maggiore
quantità di neutrofili nelle loro vie aeree e che
mediatori di derivazione neutrofila possano
attivare altre cellule infiammatorie, quali i
mastociti.
“Sistemic neutrophil activation in acute preschool viral wheeze”.
Oommen A.et all. Arch Dis Child 2003; 88: 529-531
Molti meccanismi sono stati ipotizzati per spiegare
come i rinovirus inducano asma, comprendendo
l’infiammazione diretta del tratto respiratorio,
riduzione della funzione polmonare, incremento
della reattività bronchiale ed una up-regolazione
delle molecole di adesione ( ICAM-1)sulla
membrana cellulare dell’epitelio delle vie aeree.
“Allergy and infection: understanding their relationship”.
Custovic A.et all. Allergy 2005; 60 (suppl.79): 10-13
L’infanzia è caratterizzata da una maggiore
suscettibilità ad infezioni virali e questo stadio è
anche caratterizzato da una moltiplicazione degli
alveoli polmonari e da un remodeling delle vie aeree
per accompagnare la crescita. Queste coincidenze
suggeriscono che le infezioni virali possono agire in
modo negativo sullo sviluppo del polmone.
“Effect of viral respiratory infections on lung development
and childhood asthma”
Gern Je et all. J Allergy Clin Immunol 2005 Apr; 115 (4):
668-74
GRAZIE
PER
L’ATTENZIONE