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Division of Allergy and Clinical Immunology, Hospital
of Battipaglia, ASL Salerno, Salerno, Italy
Dal Wheezing prescolare alla Asma
dell’Adolescente
Aspetti Genetici & Ambientali,
…. Aderenza Alla Terapia
Dott. Prof. Vincenzo Patella
Director: Division of Allergy and Clinical Immunology, Hospital of Battipaglia,
ASL Salerno, Salerno, Italy
[email protected]
Fixed
obstruction
Exacerbation-prone
SevereEosinophilic
corticosteroid responsive
Excercise-induced
Early/childhood
onset phenotypes
Allergic
PMA
Allergic
Non-allergic
Late/adult onset
GENOTYPE/PHENOTYPE ANALYSIS
DISCOVER NEW GENES AND PATHWAYS
 REFINING PHENOTYPES CAN HELP IN GENE IDENTIFICATION
PHENOTYPES
GENES
IDENTIFICATION OF GENES MAY HELP IN ISOLATING PHENOTYPIC ENTITIES
 PHARMACOGENETICS
TO IMPROVE THE ADAPTATION OF THE TREATMENT TO THE INDIVIDUALIZED PATIENT
 PREDICTIVE MEDICINE?
ASTHMA & GENES
Phenotype
Comment
Reference
• IL-1 (α,β), IL-1RN, TSLP-R, IL-1R1,
LTC4S
Aspirin
Asthma
ADRB 2
Cigarette smoke
Asthma
Sanak et
al.
Wang et
al.
• IL-8RA,
ADRB 2
Physical activity
Asthma
2 444C allele ↑ w/
aspirin induced asthma
↑ risk among smokers
w/Arg16 genotype
↑ risk among sedentary
women w/Gly16
genotype
HAV protects against
atopy
↑ levels of endotoxins
(carriers of Gly299
and Ille399) reduce
risk of asthma
2 159TT genotype is
protective against AD
Barr et al.
McIntire
et al.
• NAT2, CTLA-4, SPINK5, ,
Gene
Exposure
TIM 1
Hep A
Atopy
TLR 4
Endotoxins
Asthma
CD 14
GSTM 1
GSTP 1
NOS 3
Dog ownership
Diesel exhaust
Diesel exhaust
Day-care
FCERB 1
Day-care
IL4RA
Day-care
HLAG
Maternal Bronchial
hyperresponsiveness
(BHR)
Atopic
dermatitis
(AD)
IgE /
histamine
response
IgE /
histamine
response
changes in
T H2
cytokine
response in
first yr. of
life
IL5 response
at 1 year
IFN-g
response at 1
yr. of age
AsthmaBHR in child
Werner et
al.
• IL-3,4,5,9,10,12,13,
• V-CAM 1,
• TNF-α,
Gern et al.
↑ response among
GSTM 1 – null
individuals
↑ response among
individuals w/ lle105
allele
↑ TH2 response in
children not attending
day care
Gilliland
et al.
• A3AR,
Gilliland
• CHIA, LELP1, TGFβ1,
Hofjan et
al.
Gly237 associated w/
↑ IL5 responsiveness
for children not
attending day care
↑ Val50 homozygosity
in children not
attending day care
964G allele is
associated w/asthma is
↑ with mothers w/BHR
• ARG1,
• SOD-1, EGFR, GPRA, CCR2,
•
PHF11,
Hofjan
• ACE, IRAK-3 ,CD69, IL-18,
Hofjan
• MUC-2, eNOS; NOS3, CMA1,
Nicolae et
al.
• ADAM33
> 20 genome screens conducted to date
Populations:
Europeans +++, Australians, North-Americans, Chinese,
Japanese
REGIONS MOST OFTEN REPLICATED ACROSS POPULATIONS
Region
Asthma
Atopy
IgE
EOS
1p31-36
+++++
++
+++
+
5q31
++++
6p21
++++
++
++++
+++
11q13
+
++
+++
+
12q21
+++++
+
++
++
13q12
++
++
+
+
++
BHR
FEV1
++
+
+
+
Phenotype linked to several regions: polygenic?
One region linked to several phenotypes: one pleiotropy gene or several
genes in the same region?
IL MODELLO LINEARE DI MALATTIA
BIOLOGICAL & PHYSIOLOGICAL « INTERMEDIATE » PHENOTYPES
INVOLVED IN THE PATHOLOGICAL PROCESS
G0
E0
G1
G2
IgE
G3
Atopy
G4
EOS BHR
(SPT/ sIgE)
E2
E1
E3
ASTHMA
G5
FEV1
Achievements in asthma genetics appear
both impressive and confusing.
• Many susceptibility genes are robust
candidates, new genes have been
discovered leading to new hypothesis
(functional role?)
• Replication of previous results of linkage
and associations has been generally poor.
• Asthma is a complex disease, with
implication of multiple genes of small
effects with modulation of expression
(gene and/or environment interactions).
importance of careful definition of
phenotypes and environmental exposures
• Studies are expensive
Achievements in asthma genetics appear
both impressive and confusing
• Due to strong gene/environment
interactions, careful assessments of
environmental factors are necessary.
• Link all the available data from
geneticists, biologists, clinicians,
epidemiologists
• Necessity of analysis taking into account
the whole system biology: genome, but
also transcriptome and proteome
MEDICINA OMICA
Key points
 Il controllo dell’asma non è soddisfacente in Europa
come in Italia nella popolazione infantile e negli adulti il
30% degli asmatici lievi non sono controllati nel contesto
della MG e PLS
La mancanza di controllo anche nell’asma lieve è
responsabile di riacutizzazioni, ospedalizzazioni,
deterioramento funzionale
L’eccessivo uso di SABA è il marker di scarso controllo
PEDIATRIC ASTHMA DEATHS
MILD PATIENTS ARE ALSO AT RISK
40
Patients Deaths (%)
35
SAA may occur in asthmatics
classified as mild, moderate or
severe

Some patients (or family members)
may report excessive allergen exposure,
or be unware of such an exposure even
if such an exposure seemed to play
an important role in the fatal attack

30
25
20
15
10
5
0
severe
moderate
mild
Patient Assessment
Finding from a cohort study reviewing all pediatric asthma-related deaths in the
Australian state of Victoria
Robertson C. et al. Pediatric Pulmology, 1992; 13: 95-100
IL FATTORE TEMPO E LE
FLUTTUAZIONI DELLA MALATTIA
Floriana 22 anni
 Familiarità per atopia
 Svezzamento precoce con nell’introduzione dell’uovo
successivamente tollerato
 A due anni dermatite atopica
 A cinque anni prove allergiche diagnosi di rinite e
asma lieve per diversi anni cicli di anti h1 e Ventolin al
bisogno
 A 12 anni asma e rinite curate con terapie a base di
ICS con diversi episodi di riacutizzazione e uso di
cortisone sistemico
 Assenza di altre malattie degne di nota
 Assenza di malattia per circa 10 anni rare volte ha
usato il Ventolin
• All’improvviso episodio acuto di asma preceduto da tosse
stizzosa per 2-3 giorni e ricovero di urgenza in P.S.
Esame citologico
dell’espetterotato indotto
Fenotipi infiammatori dell’asma
•
Fenotipo eosinofilico
•
Fenotipo neutrofilico
•
Fenotipo paucigranulocitico
•
Fenotipo misto
Pauci-granulocytic
Neutrophilic
Mixed
Eosinophilic
Floriana 12 anni, Qual’è il suo fenotipo?
Fenotipo Eosinofilo
L’eosinofilia nell’espettorato permette
 di valutare il controllo dell’infiammazione bronchiale
nell’asma (Gibson, 2003; Deykin,)
 di predire la perdita di controllo dell’asma (Jatakanon, 2000)
 di predire la risposta a breve termine alla terapia con CS
inalatori (Pavord, 1999; Bacci, 2006; Berry, 2007)
Fenotipo Neutrofilo
La neutrofilia nell’espettorato può essere osservata in alcuni
particolari condizioni
 riacutizzazioni asmatiche (specie quelle a rapida insorgenza)
 asma grave
 esposizione a endotossine, inquinanti atmosferici, agenti
professionali
Esame citologico dell’espetterotato
indotto
NEUTROFILI (PMN)
Risk Factors Associated with Higher Mortality in Acute
Asthma
• Previous severe exacerbation (e.g., ICU admission).
• Two or more hospitalizations for asthma.
• Three or more ED visits for asthma in the past year.
• Using >2 canisters of SABA per month.
• Difficulty perceiving asthma symptoms or severity of exacerbations.
• Other risk factors:
•
•
•
•
sensitivity to Alternaria
low socioeconomic status or inner-city residence
illicit drug use
major psychosocial problems
• comorbidities like cardiovascular disease, etc.
Ann Allergy Asthma Immunol. 2008
Risk Factors Associated with Higher Mortality in
Acute Asthma
•
Despite the many recent
advances in diagnosis and
treatment, asthma-related
morbidity and mortality
continue to affect both
adults and children.
Th1
IFN-g
IL-12
Immunomodulators
Th2
PDE4 Inhibitors
 Glucocorticoïds
 Ciclosporine

Anti-IL-4, Anti-IL-13
IL-4R
Anti-IL-5 MAb
TNF-alpha
Cell B
Eosinophil

Apoptosis
Inflammation
 GCs
& BHR
Inhibitors p38 MAP
Anti-IgE
IgE
Bronchial Thermoplasty
Am J Respir Crit Care Med. 2012 Apr 1;185(7):709-14.
Am J Respir Crit Care Med. 2010 Jan 15;181(2):116-24.
Drugs don’t work in patients
who don’t take them
- C. Everett Koop MD
ADHERENCE TO ASTHMA TREATMENT
Adults
Breekveldt-Postma et al.
Pharmacoepidemiology and
Drug Safety 2008
Children &
Adolescents
The prevalence of non adherence in difficult
asthma
44%
Gamble et al. Am Rev Resp Crit Care Med, 2009
J Investig Allergol Clin
Immunol 2006; 16(4):
218-223
Self-management of asthma in daily life presents some critical
aspects: patients report being unable to take medicines
correctly (25.4%), an inability to identify worsening signs
(19%) and monitor clinical parameters (57.1%)
Monitoring the adherence to beclomethasone in asthmatic
children and adolescents through four different methods
Jentzsch et al. Allergy 2009
Adherence rate to inhaled corticosteroids and their impact
on asthma control
Lasmar et al. Allergy 2009
Lasmar et al. Allergy 2009
Critical mistakes:
• 12% for MDIs
• 35% for Diskus
• 35% for HandiHaler
• 44% for Turbuhaler.
Strongest association between inhaler misuse and:
• older age (p = 0.008)
• lower schooling (p = 0.001)
• lack of instruction received for inhaler technique by health caregivers (p < 0.001).
Inhaler misuse was associated with:
• increased risk of hospitalization (p = 0.001)
• emergency room visits (p < 0.001)
• courses of oral steroids (p < 0.001) and antimicrobials (p < 0.001)
• poor disease control evaluated as an ACT score (p < 0.0001)
Respiratory Medicine (march 2011)
TAKE HOME MESSAGES
• Il controllo dell’asma è ancora lungi dall’essere
raggiunto rimanendo una rilevante criticità clinica
• La possibilità di individuare un Fenotipo stabile
dalle indagini genetiche attualmente è ancora
remota
• Il controllo dell’asma è un indice composito e non
può basarsi sul solo sui sintomi riferiti dal paziente.
• Altri parametri devono essere ad esso associati
come l’educazione del paziente al corretto utilizzo
del device.
• Il ruolo dei singoli parametri non è chiaro e
verosimilmente è variabile nei diversi fenotipi.
• L’aderenza al trattamento e il momento educativo
appaiono le criticità gestionali essenziali
nell’ottenimento del controllo dell’asma
Facoltà di Medicina e Chirurgia
Università di Napoli Federico II
Ospedale Santa Maria della Speranza, BATTIPAGLIA (SA)
(Direttore Sanitario: Rocco Calabrese)
Centro di Riferimento Aziendale per la Cura delle Malattie
Allergiche ed Immunologiche Gravi
ASL SALERNO
• Giovanni Florio, Roberta Pio, Agostino Rubano, Francesca Scotese,
Anna Strollo, Division of Allergy and Clinical Immunology, Hospital of
Battipaglia, ASL Salerno, Salerno, Italy
• Cristoforo Incorvaia, MD, Allergy/Pulmonary rehabilitation, ICP Hospital,
Milan, Italy
• Sebastiano Gangemi MD School and Division of Allergy and Clinical
Immunology, Department of Clinical and Experimental Medicine, University of
Messina, Messina, Italy and Institute of Clinical Physiology, IFC CNR, Messina
Unit, Italy
• Antonella Saija, MD, Farmaco-Biologico Department, School of Pharmacy,
University of Messina, Messina, Italy