Aspetti Genetici & Ambientali, …. Aderenza Alla Terapia

Dott. Prof. Vincenzo PatellaDirector: Division of Allergy and Clinical Immunology, Hospital of Battipaglia,

ASL Salerno, Salerno, Italyinfo@allergiasalerno3.it

Division of Allergy and Clinical Immunology, Hospital of Battipaglia, ASL Salerno, Salerno, Italy

Dal Wheezing prescolare alla Asma dell’Adolescente

Eosinophiliccorticosteroid responsive

Excercise-induced

Allergic

Fixedobstruction

SevereExacerbation-prone

Allergic

Occupational

Non-allergic

Acido acetilsalicilicosensitive

Eosinophilic corticosteroid responsive

PMA

Severe

Early/childhood onset phenotypes

Late/adult onset

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?

GENOTYPE/PHENOTYPE ANALYSIS

ASTHMA & GENESGene Exposure Phenotype Comment Reference

LTC4S Aspirin Asthma 2 444C allele ↑ w/

aspirin induced asthma Sanak et al.

ADRB 2 Cigarette smoke Asthma ↑ risk among smokers w/Arg16 genotype

Wang et al.

ADRB 2 Physical activity Asthma ↑ risk among sedentary women w/Gly16 genotype

Barr et al.

TIM 1 Hep A Atopy HAV protects against atopy

McIntire et al.

TLR 4 Endotoxins Asthma

↑ levels of endotoxins (carriers of Gly299 and Ille399) reduce risk of asthma

Werner et al.

CD 14 Dog ownership Atopic dermatitis (AD)

2 159TT genotype is protective against AD

Gern et al.

GSTM 1 Diesel exhaust IgE / histamine response

↑ response among GSTM 1 – null individuals

Gilliland et al.

GSTP 1 Diesel exhaust IgE / histamine response

↑ response among individuals w/ lle105 allele

Gilliland

NOS 3 Day-care changes in TH2

cytokine response in first yr. of life

↑ T H2 response in children not attending day care

Hofjan et al.

FCERB 1 Day-care IL5 response at 1 year

Gly237 associated w/ ↑ IL5 responsiveness for children not attending day care

Hofjan

IL4RA Day-care IFN-g response at 1 yr. of age

↑ Val50 homozygosity in children not attending day care

Hofjan

HLAG Maternal Bronchial hyperresponsiveness (BHR)

Asthma-BHR in child

964G allele is associated w/asthma is ↑ with mothers w/BHR

Nicolae et al.

• IL-1 (α,β), IL-1RN, TSLP-R, IL-1R1,

• IL-8RA,

• IL-3,4,5,9,10,12,13,

• NAT2, CTLA-4, SPINK5, ,

• V-CAM 1,

• TNF-α,

• ARG1,

• A3AR,

• CHIA, LELP1, TGFβ1,

• SOD-1, EGFR, GPRA, CCR2,

• PHF11,

• ACE, IRAK-3 ,CD69, IL-18,

• MUC-2, eNOS; NOS3, CMA1,

• ADAM33

REGIONS MOST OFTEN REPLICATED ACROSS POPULATIONS

Region Asthma Atopy IgE EOS BHR FEV1

1p31-36 +++++ ++ +++ +

5q31 ++++ ++ ++ +

6p21 ++++ ++ ++++ +++

11q13 + ++ +++ + +

12q21 +++++ + ++ ++

13q12 ++ ++ + + +

Phenotype linked to several regions: polygenic?One region linked to several phenotypes: one pleiotropy gene or several

genes in the same region?

> 20 genome screens conducted to date

Populations: Europeans +++, Australians, North-Americans, Chinese, Japanese

IL MODELLO LINEARE DI MALATTIA

ASTHMA

G0 G1 G2 G3 G4

IgE Atopy EOS BHR FEV1 (SPT/ sIgE)

E1

E0

E2

G5

E3

BIOLOGICAL & PHYSIOLOGICAL « INTERMEDIATE » PHENOTYPES INVOLVED IN THE PATHOLOGICAL PROCESS

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 DEATHSMILD PATIENTS ARE ALSO AT RISK

0

5

10

15

20

25

30

35

40

severe moderate mild

Pati

ents

Dea

ths

(%)

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

Patient Assessment

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

IL FATTORE TEMPO E LE FLUTTUAZIONI DELLA MALATTIA

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.

Floriana 22 anni

Esame citologico dell’espetterotato indotto

Fenotipi infiammatori dell’asma

• Fenotipo eosinofilico

• Fenotipo neutrofilico

• Fenotipo paucigranulocitico

• Fenotipo misto

Pauci-granulocyticMixed

Neutrophilic Eosinophilic

Fenotipo EosinofiloL’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

Floriana 12 anni, Qual’è il suo fenotipo?

NEUTROFILI (PMN)

Esame citologico dell’espetterotato indotto

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

New treatments in Asthma

Cell B

Th1

IFN-gIL-12

Anti-IL-5 MAb Anti-IL-4, Anti-IL-13IL-4R

Eosinophil

Anti-IgEIgE

Immunomodulators

PDE4 Inhibitors Glucocorticoïds

Ciclosporine

Th2

Inflammation & BHR

Apoptosis GCs

Inhibitors p38 MAP

TNF-alpha

• Despite the many recent advances in diagnosis and treatment, asthma-related morbidity and mortality continue to affect both adults and children.

Risk Factors Associated with Higher Mortality in Acute Asthma

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

Breekveldt-Postma et al. Pharmacoepidemiology and Drug Safety 2008

Adults

Children &Adolescents

The prevalence of non adherence in difficult asthma

Gamble et al. Am Rev Resp Crit Care Med, 2009

44%

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

Respiratory Medicine (march 2011)

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)

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

• 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

Centro di Riferimento Aziendale per la Cura delle Malattie Allergiche ed Immunologiche Gravi

ASL SALERNO

Facoltà di Medicina e Chirurgia Università di Napoli Federico II

Ospedale Santa Maria della Speranza, BATTIPAGLIA (SA)(Direttore Sanitario: Rocco Calabrese)

Ringraziamen

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