censimento delle emoglobinopatie nella regione piemonte · prevalenza 1991: 0,008/1000 prevalenza...

AGGIORNAMENTI

Censimento delle emoglobinopatie nella regione Piemonte

Simona Roggero

S.C.D.U. di Pediatria – Centro Microcitemie

A.O.U. S. Luigi Gonzaga, Orbassano Dipartimento di Scienze Cliniche e Biologiche,

Facoltà di Medicina e Chirurgia San Luigi Gonzaga, Università di Torino Email: [email protected]

PREVALENZA 1991: 0,008/1000 PREVALENZA 2011: 0,022/1000

Prevalenza SCD casi/anno

165 (F/M =84/81)

Thalassemia Centre University of Torino

Kaplan-Meier analysis of survival in 168 consecutive SCD patients (2002-2012)

0 10 20 30 40 50 60

Years

70%

72%

74%

76%

78%

80%

82%

84%

86%

88%

90%

92%

94%

96%

98%

100%

Surv

ival

(%)


Orientamenti terapeutici Strumenti di prevenzione Aderenza a presa in cura e follow-up

SINDROMI DREPANOCITICHE IN PIEMONTE

Severe

Hydroxyurea

Chronic transfusion

Bone marrow transplantation

Severity of SCD varies widely between patients

Asymptomatic Moderate

Penicillin, folic acid, hydration

Mariane de Montalembert – TIF - 2008

Pain Acute Chest Syndrome

Cerebrovascular Accident

AIMS OF THIS MANAGEMENT

To suppress mortality

To prepare children to be adults with a good quality of life

Lanzkron S*, et al. ASH 2010, abstract 736

* Department of Medicine, Division of Hematology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA

Severe

Hydroxyurea

Chronic transfusion

Bone marrow transplantation ACS = acute chest syndrome; CVA = cerebrovascular accident.


Penicillin, folic acid, hydration

The Clinical Problems of SCD by Age

Priapism

Upper airway obstruction

Stroke

Subarachnoid Hemorrhage

Retinopathy

Gallstones

Avascular Necrosis

Hyposthuria

Delayed Growth and Development

Age in years 0 5 10 15

Modified from Davis SC, Wonke B. p.361. Bailleire’s Clinical Hematology, Bailliere Tindall, London 1991

Severe

ACS = acute chest syndrome; CVA = cerebrovascular accident.

Severity of SCD varies widely between patients


Hydroxyurea

Chronic transfusion

Bone marrow transplantation

trasfusioneregolareHU

follow-up

tmo

Terapia popolazione SCD età pediatrica (età < 14 anni) – gennaio 2013 71 soggetti, età media 6,2 anni (range 0,2-14 anni)

Prevenzione stroke CRISI VASOCCLUSIVE OSSEE/ADDOMINALI RICORRENTI Sindrome toracica Sequestri splenici ricorrenti ANEMIA


85%

Two major Phenotypes of Sickle Cell Disease....prospettive terapeutiche future

Haemolytic Endothelial Dysfunction • Pulmonary hypertension • Leg ulcers • Priapism • Renal Insufficiency • Stroke

Viscocity-Vasocclusion Erythrocyte Sickling • Vaso-occlusive crisis • Acute chest syndrome • Avascular necrosis

Chronic progressive organ damage

5 years 10 years 20 years 30 years Adapted from Driscoll,2007



PREVENZIONE PRIMARIA STROKE PROFILASSI FATTI INFETTIVI PREVENZIONE-GESTIONE CRISI ACUTE

Mild narrowing of vessel lumen

Stenosis occlusio

n

Velocity > 2 m/s ± Overt stroke

Moya-moya aneurysm

± Cerebral haemorhage

CEREBRAL VASCULOPATHY

0,4

0,5

0,6

0,7

0,8

0,9

1

0 5 10 15 20 25 30 35Time (months)

Prob

abili

ty o

f rem

aini

ng s

trok

e-fr

ee

< 170 cm/s 170–199 cm/s ≥ 200 cm/s

p = 0.0001

STOP I

STROKE RISK INCREASES WITH TCD FLOW RATE

Adams RJ. Control Clin Trials. 1998;19:110-29. Neurologia - Ospedale Gradenigo settembre 2007


0,4

0,5

0,6

0,7

0,8

0,9

1

0 5 10 15 20 25 30 35Time (months)

Prob

abili

ty o

f rem

aini

ng s

trok

e-fr

ee

< 170 cm/s 170–199 cm/s ≥ 200 cm/s

p = 0.0001

STOP I

STROKE RISK INCREASES WITH TCD FLOW RATE

3/78 (3,8%)


Fullerton HJ, et al. Blood. 2004;104:336-9.

Années

Inci

denc

e d’

un p

rem

ier A

VC

(pou

r 100

pt-a

nnée

s)

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Inci

denc

e d’

un p

rem

ier A

VC

(pou

r 100

pt-a

nnée

s)

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Tronco Basilare

Arteria Cerebrale Anteriore

CI 1-2-3

Arteria Cerebrale

Media Arteria Cranica

Posteriore

Neurologia ospedale Gradenigo settembre 2012


Year (range)

Country Incidence Causes

Gill 1978–98 USA 1.1/100 pt-yr 11 sepsis (9 S.pn), 2 ASS, 1 CVA

Thomas 1985–92 France (Paris)

0.29%/yr 15 sepsis (8 S.pn), 3 ASS, 3 CVA

Quinn 1983–04 USA (Texas)

0.59/100 pt-yr 5 sepsis (4 S.pn), 3 ACS, 2 multi-organ failure,

1 CVA, 1 myocardial infarct

Quinn 1983–05 USA (Texas) 0.52/100 pt-yr 5 ACS, 4 multi-organ failure, 4 S.pn sepsis

CVA = cerebrovascular accident; pt-yr = patient years; S.pn = Streptococcus pneumoniae.

Gill FM, et al. Blood. 1995;86:776-83. Thomas C, et al. Arch Pediatr. 1996;3:445-51.

Quinn CT, et al. Blood. 2004;103:4023-7. Quinn CT, et al. Blood. [Epub ahead of print 2010 Mar 1].

CAUSES OF DEATH IN CHILDREN WITH SCD

PROPHYLAXIS WITH ORAL PENICILLIN REDUCES THE MORBIDITY AND MORTALITY OF PNEUMOCCOCAL INFECTIONS

125 SCD children aged 3 to 36 months Randomly assigned to receive either 125 mg oral penicillin or

placebo

Placebo group Peni group p S.pn infections 13 2 0.0025 Death (S.pn) 3 0 0.003 Incidence S.pn 0.09 0.02 <0.05 septicemia (Gaston, et al, NEJM 1986; 314: 1593-9)

NEED FOR PNEUMOCOCCAL VACCINATION IN ADDITION TO DAILY PENICILLIN PROPHYLAXIS IN SCD CHILDREN

Uncomplete level of adherence to penicillin prescription

in a Tennessee study, 25-30% of Medicaid program enrolles were likely to receive penicillin for > 270 days per year, (Halasa et al, CID 2007; 44: 1428-33)

Increase in % of penicillin-resistant strain

invasive pneumococcal infections in SCD children Adamkiewicz et al; J Pediatr 2003;143:438-44

• 36.5 infections /1000 pt-yrs in SCD children 1 to 2 yrs, 20% meningitis, 15% deaths

• 23-valent pneumococcal polysaccharide (PVC) efficacy: 80.4% (95%CI: 39.7-93.6)

• 71% of serotyped isolates PVC serotypes • 71% of nonvaccine serotypes penicillin-sensitive

SCD infections care

SCD infections care DAL 2007- 2012 Decessi per sepsi: 0 Sepsi da pneumococco: 0 Sepsi da salmonella : 1

SCD infections care

Centro regionale

Pediatria territoriale

Medico curante

Servizi vaccinali

Sperimentazione clinica PVN 13

DAL 2007- 2012 Decessi per sepsi: 0 Sepsi da pneumococco: 0 Sepsi da salmonella : 1


N° totale casi 175

Età media casi (range)

19 anni (1 mese- 62 anni)

Sindrome drepanocitica

SS SβThal SC SOarab SHPHF

- 70% - 19% - 9% - 1% - 1%

Origini etniche Italia Non Italia

- 15% - 85%

81%

15% 4%

Profilo dei pz con SCD nota in Piemonte (31/12/2012)

% SCD casi distribuzione per provincia di residenza


aderenza alla presa in cura: punti di debolezza



ETA’ alla diagnosi 6,2 vs 1,6 aa p<0,05


6,2 vs 1,6 aa p<0,05

SCD sintomi Familiarità

Coppie a rischio – follow-up di nati da coppie a rischio

Programmi di screening


MOTIVI DI DIAGNOSI 2010-2012.......

Lieberman L, 2009



ETA’ alla diagnosi 6,2 vs 1,6 aa p<0,05

Raccolta cordone ombelicale



PROPOSTE.......

- Diagnosi precoce

- “nuovi genotipi” (SC…)

- portatori sani di HbS

- RETE ASSISTENZIALE

Profilo delle emoglobinopatie in Piemonte…. 2010 NECESSITA’ di PREVENZIONE

PRENATAL SCREENING

INDAGINI HPLC- IEF – BIOLOGIA MOLECOLARE -

SEQUENZIAMENTO

NEWBORN SCREENING

POCHE coppie “a rischio” di SCD scelgono di ricorrere alla DPN Greenscross P, , J Med Screen 2006

PROPOSTE.......

- Diagnosi precoce

- “nuovi genotipi” (SC…)

- portatori sani di HbS

- RETE ASSISTENZIALE

Medico/Pediatra di famiglia “ESPERTO””

Medicina/Pediatria di TERRITORIO

“PRESA IN CURA”

da RETE ASSISTENZIALE

Centro regionale di riferimento per le emoglobinopatie

S.C.D.U. MICROCITEMIA-PEDIATRIA

A.O.U. SAN LUIGI GONZAGA DI ORBASSANO

Counselling delle emoglobinopatie in Piemonte….: PROSPETTIVE: RETE ASSISTENZIALE

GPs

Who does what?

Local hospital

SCD centre

To establish for each patient a network of 3 physicians working in close collaboration: A general practitioner trained in SCD

management; A local hospital; An SCD centre.

To ensure multidisciplinary management (nurse, psychologist, social workers,…)

To facilitate access to primary care

To coordinate care and to set up an alert procedure for patients lost to follow-up

To increase knowledge among healthcare professionals patients and families

Rete assistenziale SCD …the aims

GPs

Local hospital

SCD centre

Rete assistenziale SCD …PROPOSTA: CENTRO SPECIALISTICO ITINERANTE

Not telling about what we do, but about what we do not do

It is necessary to look at the problems not solved , from a different perspective

Les infections 1ère cause de décès car asplénie fonctionnelle (par micro-thrombose des vaisseaux). Risque d’infections fulminantes : • Chez le petit enfant : à pneumocoque • Chez l’enfant plus grand : à salmonelles => Éducation +++ des médecins de ville et des

familles sur CAT en cas de fièvre car risque vital !

PROPHYLAXIS WITH ORAL PENICILLIN REDUCES THE MORBIDITY AND MORTALITY OF PNEUMOCCOCAL INFECTIONS (GASTON, ET AL, NEJM 1986; 314: 1593-9)

125 SCD children aged 3 to 36 months Randomly assigned to receive either 125 mg oral penicillin or

placebo

Placebo group Peni group p S.pn infections 13 2 0.0025 Death (S.pn) 3 0 0.003 Incidence S.pn 0.09 0.02 <0.05 septicemia

Copyright ©2008 American Academy of Pediatrics

Adamkiewicz, T. V. et al. Pediatrics 2008;121:562-569

FIGURE 4 Kaplan-Meier curve of IPD in children with SCD according to PCV vaccination status from January 1, 2000, through January 1, 2003 for PCV serotypes (4,

6B, 9V, 14, 18C, 19F, and23F) and untyped isolates only

NEONATAL SCD SCREENING

The effectiveness of neonatal screening programs, when integrated into comprehensive follow-up services and coupled with parental education and support, has been clearly demonstrated in the US.

Frempong T. Conn Med. 2007;71:9-12.

• Prevenzione infezioni batteri capsulati PROFILASSI VACCINALE PROFILASSI CON FENOSSIMETILPENICILLINA

• Follow-up regolare per la prevenzione del danno d’organo Prevenzione primaria dello stroke cerebrale mediante doppler transcranico (TCD)

APPLICAZIONE PRECOCE del PREVENTIVE care

Patient CARE

PREVENTION

• CON QUALI OBIETTIVI? -> INFORMARE/COMUNICARE

-> SCELTE CONSAPEVOLI E INFORMATE

EMOGLOBINOPATIE: QUALE COUNSELLING?

Pain Dactylitis

Long Bones

Trunk Sequestrastion

Splenic

Hepatic

Chest syndrome

Girdle syndrome Infection

Pneumococcal

Parvovirus

Salmonella


THE CLINICAL PROBLEMS OF SICKLE CELL DISEASE BY AGE


Therapeutic decision for a severe form of SCD is based on:

1.Assessment of the severity of the disease : objective and subjective (disease burden) 2. Therapeutics available in the country: blood supplies, iron chelation, bone marrow transplantation 3. Nature of the complications: a neurological complication requires at best BMT or regular transfusion 4. Recorded and feared complications of the therapeutics: subsequent fertility…

IN ALL CASES,

- Chronic treatments generate a burden for the patient and family, and they fail to completely eliminate the risk of complications such as recurrent stroke or painful events

- In addition to the need for daily treatment and fear of uncontrolled complications, SCD usually generates a feeling of being different, misunderstood, and inadequate. Families and patients may experience posttraumatic stress disorder, whose rate of occurrence is not correlated with disease severity.

- Thus, the disease itself, independently from the number of hospitalisations and complications, adversely affects the quality of life of the patients and their families. This quality-of-life burden is being increasingly recognized by physicians and families as a key component in the risk/benefit ratio of treatments for SCD

- Social and psychological support are in almost in all cases highly needed - Therapeutic education is in all cases indispensable

Prevention of strokes in children with abnormal TCD or a past history of stroke

Changes in neuro-imaging findings in 29 patients receiving chronic transfusion

for primary or secondary stroke prevention over a mean follow-up of 3.5±3.0 years (range, 0.5-12 years)

Mirre E, et al. Eur J Haematol 2010; 84: 259-65

• chronic transfusion may protect most patients from clinically overt stroke but not from progression of the vascular disease • Proportion of improvement higher in the group transfused for abnormal TCD than in the group transfused after a stroke.

- DIAGNOSI: SINDROME DREPANOCITICA - ETÀ: < 1 ANNO E > 18 ANNI - NON PREGRESSO STROKE ISCHEMICO

TCD (febbraio 2008 -novembre 2008)

Pazienti e metodi

VM (cm/sec)

tecnica doppler sonda per TCD 2 MHz personale “esperto” non attendibilità:

febbre/crisi vasococclusive nella settimana precedente pianto inconsolabile non sufficiente stato di

veglia 2 TCD ( doppio cieco da due operatori )

Criteri di inclusione:


Profilo delle emoglobinopatie:

• Ereditarietà…prevenzione possibile • Cronicità…cura possibile • Eterogeneità

Talassemie Varianti emoglobiniche

Patient CARE

PREVENTION


• CON QUALI OBIETTIVI? Comunicare:



Motivo dell’indagine:

- Sospetto diagnostico

- Screening (familiarità/etnia)


COUNSELLING


Risultato dell’indagine




A.R., 27 anni, 17 w di gestazione

Hb 10.3 12-16 g/L MCV 74.2 80-96 fL MCH 27.7 27-34 pg

Serum Iron 104 40-150 µg/dL

Serum Transferrin 239 200-330 mg/dL Transferrin Saturation 34 15-45 %

Hb F 3 0.0-2.0 %

Hb A2 4.5 2.0-3.2 % Hb S 24 0 %


A.R., 27 anni, 17 w di gestazione

Hb 10.3 12-16 g/L MCV 74.2 80-96 fL MCH 27.7 27-34 pg

Serum Iron 104 40-150 µg/dL

Serum Transferrin 239 200-330 mg/dL Transferrin Saturation 34 15-45 %

Hb F 3 0.0-2.0 %

Hb A2 4.5 2.0-3.2 % Hb S 24 0 %


-> counselling 2012 ….2010

? Nigeria

S.F., 18 MESI HB 5.5 g/dl Mcv 80 fL Hb S 80% HbS/HbS

ITALIA

Nigeria


? Nigeria

S.F., 18 MESI HB 5.2 g/dl Mcv 80 fL Hb S 80% HbS/HbS

ITALIA

Nigeria


Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003859.

http://www.ncbi.nlm.nih.gov/pubmed/15495068






Centro Microcitemie

Università di Torino

DIAGNOSI SEMPLICE, MA NON DIMENTICHIAMO LA COMUNICAZIONE!!!!

CLINICAL OUTCOMES IN CHILDREN WITH SICKLE CELL DISEASE LIVING IN ENGLAND: A NEONATAL COHORT IN EAST LONDON

252 children identified during 1983-2005 by universal birth screening in East London

Followed in a hospital and community-based program

Estimated survival of SS children at 16 years 99.0% (95% CI: 93.2-99.9%)

Pneumoccal sepsis rate: 0.3(95%CI: 0.1-0.8) episodes/100 pts-yrs

Risk of overt stroke: 4.3% (95%CI: 1.5-11.4%)

Piero C. Giordano Clinical Biochemistry 42 (2009) 1757–1766

DIAGNOSI SEMPLICE, MA NON DIMENTICHIAMO LA COMUNICAZIONE!!!!

NON MALATTIA….MA UN GENE ALTERATO…

Piero C. Giordano Clinical Biochemistry 42 (2009) 1757–1766


Nato in Piemonte Variante 30% ->HbC

Dal CARRIER…… alla FAMIGLIA

Tunisia Tunisia

Nato in Piemonte Variante 30% ->HbC

Dal CARRIER…… alla FAMIGLIA

Tunisia

Mcv 55 fL HBC 80% HbC/CD39 -Colelitiasi -Splenomegalia -Retinopatia

MA…. se compaiono sintomi?

R.L.,2 years

Spleen enlargement -

Liver enlargement -

Thalassemia-like bone modifications

-

Hb 9.5 g/dl

MCV 55 fL

HbA2 4.5%

HbF 3%

Reticulocytes

LDH

Erytrhoblasts count/ Growth Differentiation Factor 15/EPO

Iron overload -

Microcitosi in accertamenti

preoperaratori CD39/N

Italia Italia

2 years 3 years 5 years

Spleen enlargement - + ++

Liver enlargement - +/- +


- + ++

Hb 9.5 g/dl 9 g/dl 8,8 g/dl

MCV 55 fL 58 fL 58 fL

HbA2 4.5% 4.5% 4.5%

HbF 3% 3% 3%

Reticulocytes + ++

LDH + ++


+ ++

Iron overload - +/- +

MA…. se compaiono sintomi? RIVALUTARE ILCASO!!!

2 years 3 years 5 years

Spleen enlargement - + ++

Liver enlargement - +/- +


- + ++

Hb 9.5 g/dl 9 g/dl 8,8 g/dl

MCV 55 fL 58 fL 58 fL

HbA2 4.5% 4.5% 4.5%

HbF 3% 3% 3%

Reticulocytes + ++

LDH + ++


+ ++

Iron overload - +/- +

CD39/N αααα/αα

MA…. se compaiono sintomi? RIVALUTARE ILCASO!!!

Counselling di coppia delle emoglobinopatie

PRENATAL SCREENING

’75 Modell (Londra) I DPN per β talassemia


SEQUENZIAMENTO


’75 Modell (Londra) I DPN per β talassemia

PRENATAL SCREENING

In areas where haemoglobinopathies are common, dedicated centres are required in order to ensure adequate services for prevention and treatment. WHO, 2006



Age distribution of thalassemia patients

AGE (years)

num

ber

0

2

4

6

8

10

12

14

16

18

20

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

19871997

1977

Carrier of:

α + thal

αothal

HbS

β thal

δβthal

HbLepore

HbE

HbO

Arab

HbC

HbD

Punjab

HPFH

Nota carrier

α+ thal

αo thal

Hb S

β thal

δβ thal

Hb Lepore

Hb E

Hb O Arab

Hb C

Hb D Punjab

HPFH

Not a carrier

Key:Serious risk

Less serious risk

Possible hidden risk of a0

No risk

Old JM, 2007

MADRE PA

DRE

Rischio di EMOGLOBINOPATIA MAGGIORE…. eterogeneità

Carrier of:

α + thal

αothal

HbS

β thal

δβthal

HbLepore

HbE

HbO

Arab

HbC

HbD

Punjab

HPFH

Nota carrier

α+ thal

αo thal

Hb S

β thal

δβ thal

Hb Lepore

Hb E

Hb O Arab

Hb C

Hb D Punjab

HPFH

Not a carrier

Key:Serious risk

Less serious risk


No risk

Old JM, 2007

Β tal major

Carrier of:

α + thal

αothal

HbS

β thal

δβthal

HbLepore

HbE

HbO

Arab

HbC

HbD

Punjab

HPFH

Nota carrier

α+ thal

αo thal

Hb S

β thal

δβ thal

Hb Lepore

Hb E

Hb O Arab

Hb C

Hb D Punjab

HPFH

Not a carrier

Key:Serious risk

Less serious risk


No risk

Old JM, 2007

Hb SS

MO

RB

IDIT

A’ /

MO

RTA

LITA

’

LIEVE MODERATO SEVERO

FENOTIPO

Adattato da De Montalembert, BJM, 2008

10-15%

65-75%

15-20%

… eterogeneità ….markers predittivi di fenotipo?

Counselling coppie in Piemonte oggi….

PRENATAL SCREENING NEWBORN SCREENING



DIAGNOSI

PROGNOSI





PROFILO DELLE EMOGLOBINOPATIE

• Malato ridotta aspettativa di vita in assenza di cure

esordio in eta’ infantile prevenzione secondaria decisiva per prognosi e

qualità di vita eterogenità fenotipica


• Malato ridotta aspettativa di vita in assenza di

cure…CURA E’ possibile esordio in eta’ infantile prevenzione secondaria decisiva per prognosi e

qualità di vita

eterogenità fenotipica

Adapted from B. Modell and V. Berdoukas, 1984

THALASSEMIA MAJOR - SURVIVAL

Thalassemia survival: IMPROVING IN MANAGEMENT


Transfusion+iron chelation

Age distribution of thalassemia patients

AGE (years)

num

ber

0

2

4

6

8

10

12

14

16

18

20

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

19871997

1977



cure…curare è possibile esordio in eta’ infantile: DIAGNOSI PRECOCE!!! prevenzione secondaria decisiva per prognosi e

qualità di vita


Vichinsky E, et al. Pediatrics. 1988;81:749-55.

100

98

96

94

92

90

88

86 0 10 20 30 40 10

Years Months

Surv

ival

(%)

HbSS diagnosed in newborn period

HbSS diagnosed after newborn period

HbSS = haemoglobin SS.

Earlier diagnosis positively impacts survival

APPLICAZIONE PRECOCE del PREVENTIVE care EARLY DIAGNOSIS



PRESA IN CURA

TEMPO 0

NEONATAL SCD SCREENING



• Prevenzione infezioni batteri capsulati PROFILASSI VACCINALE PROFILASSI CON FENOSSIMETILPENICILLINA

• Follow-up regolare per la prevenzione del danno d’organo Prevenzione primaria dello stroke cerebrale mediante doppler transcranico (TCD)

APPLICAZIONE PRECOCE del PREVENTIVE care

Les signes :

• Paumes des mains • Plantes des pieds • Conjonctives

- Fatigue - Refus alimentaire - Essoufflement anormal - Pâleur :

= URGENCE HOSPITALIERE

Les signes :

= URGENCE HOSPITALIERE

What to do in case of pain?

+

or or => If :

Prévention de la douleur

Eviter les variations brusques de température : froid/ chaud et chaud/froid. Pas de baignade si l’eau est < à 25°. Jamais de vessie de glace ni de froid.

Prévention des infections : vaccins, ATB, mesures d’hygiène.

http://images.google.fr/imgres?imgurl=http://www.sante-abitibi-temiscamingue.gouv.qc.ca/images/clip_image001_001.gif&imgrefurl=http://www.sante-abitibi-temiscamingue.gouv.qc.ca/Pandemieinfluenza.html&h=91&w=135&sz=4&hl=fr&start=0&tbnid=JBaWrOVA-8SvPM:&tbnh=62&tbnw=92&prev=/images?q=laver+mains&gbv=2&svnum=10&hl=fr




qualità di vita


THE CLINICAL PROBLEMS OF SCD BY AGE

Priapism

Upper airway obstruction

Stroke

Subarachnoid Hemorrhage

Retinopathy

Gallstones

Avascular Necrosis

Hyposthuria

Delayed Growth and Development



Masses of Extramedullary Erythropoiesis in Thalassemia Intermedia





qualità di vita


PRESA IN CURA

Andrea C., Thalassemia intermedia (β CD39/βIVSI-6) Diagnosis at 1.5 yrs of life

Role of Blood Transfusion in Preventing or Treating Thalassemia Intermedia Complications

At 3½ - no transfusion and Hb around 7,5


At 5 - after 2 yrs of regular transfusions

Formes sévères Patients asymptomatiques

Formes modérées

La sévérité de la drépanocytose est très variable selon les patients

Penicilline, acide folique, hydratation

Hydroxyurée

Transfusion chronique

GMO

Douleur STA AVC

EMOGLOBINOPATIE: QUALE COUNSELLING...IN PIEMONTE?

Counselling delle emoglobinopatie in Piemonte….: PROSPETTIVE: COMUNICAZIONE E STRATEGIE DI PROPOSTA

Counselling delle emoglobinopatie in Piemonte…. PROSPETTIVE: PREVENZIONE

PRENATAL SCREENING


SEQUENZIAMENTO

NEWBORN SCREENING


GENETIC DISORDERS


Centro Microcitemie

Università di Torino

Diagnosi semplice e importante,ma…..

0

20

40

60

80

100

120

1 3 5 7 9 11 13 15 17 19

Age (years)

Iron

(g)

Hepatic Fibrosis --> Cirrhosis

Cardiac arrhythmia

Hypogonadism

Diabetes

Hypothyroidism

Hypoparathyroidism

Cardiac Failure

Transfusional Iron Overload in Thalassemia

Thalassemia Centre, Dept. of Pediatrics University of Turin, Italy

Death

SURVIVALKAPLAN MEIER ANALYSIS ON 257 CONSECUTIVE

TRANSFUSION-DEPENDENT BETA THALASSEMIC PATIENTS IN TORINO

years

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.00.10.20.30.40.50.60.70.80.91.0

0 5 10 15 20 25 30 35 40 45

High chelation = 15Low chelation = 104

Cox's F test=23.6 p<0.00

Piga A, 1993

Thalassemia minor ASYMPTOMATIC

Thalassemia intermedia INTERMEDIATE

Thalassemia major TRANSFUSION-DEPENDENT

CLINICAL FORMS OF THALASSEMIA


Diagnosis and screening of hemoglobinopathies

CARE

NO CARE AND PREVENTION:

HOW MUCH DOES IT COST?

BETA/S

Barbuti-Ginevra

Caso X-Y

Lei Lui

Nato il 15/12/1976 12/12/1978

Origine P-M NA/NA CZ/CZ

Laboratorio Esterno OIRM Esterno OIRM data 03/10/02 01/02/03 14/11/99 01/02/03 Hb 12,2 11,3 12,6 13

MCV 81,9 78,1 64,9 63,8 MCH 27,9 27,8 21,6 20,8

Sideremia 63 38 166 Transferrina 277 353 266

Ferritina HbA2 (%) 2,8 5,3 5,6 HbF (%) 0,5 <1 0,8 Altro (%) HbS = 39% DNA α/β β6Glu->Val/N IVSI:110/N

Note Grav. 8w Grav. 26w Diagnosi βS / N βthal / N

•Genetic aspects •Diagnosis

•Couple at risk

•Genetic counseling

•Prenatal diagnosis

•Clinic aspects •Anemia

•Folate deficiency

•Iron deficiency/overload

•Others

THE CARRIER OF THALASSEMIA AND PREGNANCY

Β-THALASSEMIA CLINICAL PHENOTYPES

• Carrier with normal phenotype • Requires DNA testing for detection

• Slight anemia with low MCV

• Late onset: > 2 years of age • Moderate anemia: Hb > 7-10 g/dL • Minimal or sporadic transfusions

• Diagnosis in first 2 years

• Severe anemia: Hb < 7 g/dL • Lifelong transfusions

MAJOR

INTERMEDIA

TRAIT

SILENT

Emoglobinopatie: quale counselling nel 2012?

ANTENATAL /PRENATAL SCREENING

INFORMED CHOICE

NEWBORN SCREENING

CARRIER DETECTION

- ESTABLISHING A SCREENING STRATEGY - GENE FREQUENCY

EARLY DIAGNOSIS AND EARLY CARE

COMMUNITY INFORMATION

Patient CARE

PREVENTION

PROFILE OF HAEMOGLOBINOPATHIES

• Hemolytic anemia • Multi-system disease with chronic

progressive organ damage Children • Life expectancy shortened • Remarkable clinical diversity

Equity in medical services requires facilities for crossing social, educational, language, and cultural barriers.

Profilo delle emoglobinopatie in Piemonte…. anni ’70- ’80 SCREENING PRENATALE

PRENATAL SCREENING

’74 Modell (Londra) I prenatal diagnosis of hemoglobin disorders -

identificare portatore sano studio del partner identificazione di coppie a rischio

The objective of carrier screening is informed choice. all couples have a right to be informed and to choose for or against prenatal diagnosis When a carrier is identified her partner is offered testing. Carrier couples are referred for expert risk assessment and counselling, including the offer of prenatal diagnosis

“Hemoglobinopathies are often the first condition requiring set up of PND service” Model, Nature genetics, 2003

routine antenatal screening for carriers was started in north London in 1977

• Genetic disorders • Hemolytic anemia • Children …. if left untreated, result in death in the first few years of life

• Globally widespread

Profile of haemoglobinopathies -3

Vichinsky et al. Pediatrics 2001

Prevalenza SCD casi/anno regione Piemonte

1970s 1990s 2000s

OTHER HEMOGLOBINOPATHIES…..

PROFILE OF HAEMOGLOBINOPATHIES

• Hemolytic anemia • Multi-system disease with chronic

progressive organ damage Children • Life expectancy shortened • Remarkable clinical diversity


Silent • Carrier with normal phenotype • Requires DNA testing for detection

Trait • Slight anemia with low MCV

Intermedia

• Late onset: > 2 years of age • Moderate anemia: Hb > 7-10 g/dL

• Minimal or sporadic transfusions

Major • Diagnosis in first 2 years • Severe anemia: Hb < 7 g/dL • Lifelong transfusions

o Thal. minor

o Thal. intermedia “mild”

o Thal. intermedia “severe”

o Thal. major

DEGREE OF ANEMIA

ASYMPTOMATIC

MILD

MODERATE

SEVERE

TRANSFUSION-DEPENDENT

NO TRANSFUSION

TRANSFUSION

THALASSEMIA PHENOTYPES AND TRANSFUSION



• Carrier with normal phenotype • Requires DNA testing for detection

• Slight anemia with low MCV

• Late onset: > 2 years of age • Moderate anemia: Hb > 7-10 g/dL • Minimal or sporadic transfusions

• Diagnosis in first 2 years

• Severe anemia: Hb < 7 g/dL • Lifelong transfusions

MAJOR

INTERMEDIA

TRAIT

SILENT


THALASSEMIA MAJOR - SURVIVAL

α globin

b + g globin

Imbalance Of Globin Chain Synthesis In Beta Thalassemia

Severity Of Clinical Phenotype

Global distribution of haemoglobin disorders

Births per 1000 infants with a major haemoglobinopathy

300.000/400.000 annual births

7% healthy carriers

Commonest genetic disorder

Global distribution of haemoglobin disorders

Births per 1000 infants with a major haemoglobinopathy

Commonest genetic disorder

…. if left untreated, result in death in the first few years of life

TALASSEMIA

ANEMIA MEDITERRANEA

DREPANOCITOSI

ANEMIA FALCIFORME

Profile of haemoglobinopathies…extremely heterogenous

RIDOTTA SINTESI !!!!

TALASSEMIA

ANEMIA MEDITERRANEA

ANEMIA

RIDOTTA SINTESI !!!!

TALASSEMIA

ANEMIA MEDITERRANEA

ERITROPOIESI INEFFICACE

ANEMIA

DREPANOCITOSI

ANEMIA FALCIFORME

Profile of haemoglobinopathies

STRUTTURA ALTERATA !!!!

TALASSEMIA

ANEMIA MEDITERRANEA

(HbS, β codon 6 Glu→Val)

NORMALE

Profile of haemoglobinopathies: inherited disorders

MALATO

NORMALE


PORTATORE SANO MALATO

NORMALE


Centro Microcitemie Università di Torino


Centro Microcitemie Università di Torino

…. impact of the diagnosis and treatment on family stability and family dynamics


World distribution of THALASSEMIA

Haemoglobin disorders and…

Haemoglobin disorders and…

World distribution of MALARIA The figure outlines the distribution of malaria before

control programmes were established


Haemoglobin disorders and MALARIA

World distribution of MALARIA The figure outlines the distribution of malaria before

control programmes were established


Haemoglobin disorders: CARE

PREVENTION “ACTIVE” CLINICAL

CARE

PROFILE OF HAEMOGLOBINOPATHIES: ACTIVAL CLINICAL CARE

• Chronic condition • No definitive cure * • Without therapy -> death usually in the

first decade of life

* Bone marrow transplantation, - expensive - only available for the limited number of patients with compatible sibling donors

S.F., 18 MESI, nata in Italia

HB 5.2 g/dl Mcv 80 fL Hb S 80%

HbS/HbS

Profilo delle sindromi drepanocitiche in Piemonte

PRENATAL SCREENING

HPLC- IEF – Mutations screening –

DNA sequencing

NEWBORN SCREENING

ANTENATAL SCREENING

PRENATAL SCREENING


Diagnosis and screening of hemoglobinopathies

Need of prevention

ASSESSMENT OF THE COMPLIANCE TO TREATMENT IN A POPULATION OF 31 SCD CHILDREN FOLLOWED-UP IN NECKER HOSPITAL (AGNÈS LAINÉ, WORK SUPPORTED BY THE GROUPAMA FONDATION, 2007)

84% parents are African first generation migrants (Ivory Coast, Congo, Cameroon, Senegal, Mali)(median stay in France for fathers: 7 yrs, for mothers: 8 yrs)

25% mothers are isolated, and have 1 to 6 children (median 2.3)

Level of mothers’ French speaking: excellent 19.3%, good: 54.8%, poor: 22.6%, no information:3.1%

Compliance assessed on intake of daily penicillin and attendance to F.U. visits:

compliance: good for 19 children, poor for 12 Compliance related to the duration of migration and

presence/absence of father

MANAGEMENT PROBLEMS ARE MORE RELATED TO MOTHERS’ LONELINESS THAN TO LANGUAGE BARRIERS

Men Women Total Origin

Africa 13 26 39

Caribbean 2 7 9

North Africa 1 4 5

% of secondary school graduates African and North African

8/14(57%) 14/30(47%) 22/44(50%)

Caribbeans 0/2 (0%) 3/7 (43%) 3/9 (30%)

Non French reading/writing African and N. Africans Caribbeans

1/14 (7%) 0

2/30 (6.7%) 0

3/44 (6.8%) 0

De Montalembert et al. Genetic Counseling 1996;7:9-15

POOR SOCIO-ECONOMIC CONDITIONS OF THE MAJORITY OF FAMILIES

motheraloneparentstogetherno data

return toAfrica

motheraloneparentstogether

New patients taken in charge in 2010 in Necker Hospital, Paris

From neonatal screening: 50 (48 from Africa)

Arrival form Africa because of the SCD: 8

Mother alone: 13/44 pts with data: 29.5% Mother alone: 3/8: 37.5% 8 mothers alone had already 1 to 5 2 mothers alone had already 1 and 2 children children

Apprendre les urgences vitales

les reconnaître Consulter en urgence

fièvre > 38°5

anémie aiguë pâleur (SSA)

douleur sévère

Prise en charge d’un nouveau-né drépanocytaire

éducation

Physio pathologie

Prévention • infections (Oracilline, vaccins) • douleur • séquestration splénique

URGENCES : • fièvre • anémie • douleur

Les infections 1ère cause de décès car asplénie fonctionnelle (par micro-thrombose des vaisseaux). Risque d’infections fulminantes : • Chez le petit enfant : à pneumocoque • Chez l’enfant plus grand : à salmonelles => Éducation +++ des médecins de ville et des

familles sur CAT en cas de fièvre car risque vital !

1950s… 1960s…

Thalassemia….conventional treatment

1970s… increased survival but significant morbidity

good quality of life in childhood, but transfusional iron overload and cardiac death age a mean age of f 18 years

SURVIVALKAPLAN MEIER ANALYSIS ON 257 CONSECUTIVE

TRANSFUSION-DEPENDENT BETA THALASSEMIC PATIENTS IN TORINO

years

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0,00,10,20,30,40,50,60,70,80,91,0

0 5 10 15 20 25 30 35 40 45

High chelation = 153

Low chelation = 104Cox's F test=23.6 p<0.0001

Haemoglobinopathie 2012: quale counselling nel 2012?

CRE

ANTENATAL /PRENATAL SCREENING

INFORMED CHOICE

NEWBORN SCREENING

CARRIER DETECTION

- ESTABLISHING A SCREENING STRATEGY - GENE FREQUENCY

EARLY DIAGNOSIS AND EARLY CARE

COMMUNITY INFORMATION

Talassemia Intermedia

Talassemia Major

Talassemia Intermedia

Similar but different

GENETIC DISORDERS


1970s

GENETIC COUNSELLING

Dedicated Thalassemia Centers

1990s

• Hemolytic anemia …but remarkable diversity


Sickle cell disease

Thalassemia

Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003859.


• Genetic disorders • Hemolytic anemia • Children • Globally

widespread



• INFORMARE • COMUNICARE • MOTIVARE • INTERPRETARE BISOGNI • QUALI DESTINATARI? • QUALI OBIETTIVI? “Non siamo preoccupati delle cose, ma

dell’opinione che abbiamo di esse” Epitteto


PRENATAL SCREENING

’75 Modell (Londra) I DPN per β talassemia 1979: AMBULATORIO di

Prenatal screening consulenza – identificazione delle coppie a rischio – DPN

pediatra-ematologo esperto di emoglobinopatie

neuropsichiatra

ginecologo


SEQUENZIAMENTO

Profilo delle emoglobinopatie in Piemonte…. Malattie da immigrazione

Anni ‘50-’60-’70

Courtesy of dr. Anna Rajab, Oman L

C M U

P.C. Giordano, Hemoglobinopathies Laboratory

Profilo delle emoglobinopatie in Piemonte…. Malattie da immigrazione

FREQUENZA DEI PORTATORI SANI DI β TALASSEMIA IN PIEMONTE

1959 0,9%

1977 3,8%

Viora E, Piga A et al. - 1991

Anni ‘50-’60-’70

TALASSEMIE

Sindromi drepanocitiche (Sicilia)

GENETIC DISORDERS



• Malattie genetiche • Portatore Sano Diagnosi semplice, ma ATTENZIONE… • Malato ridotta aspettativa di vita in assenza di cure esordio in eta’ infantile eterogenità fenotipica prevenzione secondaria decisiva per prognosi e qualità

di vita

Patient CARE

PREVENTION



SEQUENZIAMENTO

PRENATAL SCREENING (Centro regionale di emoglobinoptie)

1979: AMBULATORIO di Prenatal screening consulenza – identificazione delle coppie a rischio – DPN

pediatra-ematologo esperto di emoglobinopatie

neuropsichiatra

ginecologo


CENTRO MICROCITEMIE CENTRO REGIONALE DI RIFERIMENTO DELLE EMOGLOBINOPATIE: - Attività clinica (presa in cura) - Coordinamento/consulenza specialistica con il territorio - Divulgazione - Ricerca

S.F., 18 MESI, nata in Italia

HB 5.2 g/dl Mcv 80 fL Hb S 80%

HbS/HbS

Profilo delle sindromi drepanocitiche in Piemonte

• Les mots, les signes

• Le verdict de décès La vie, les projets

• L’incompréhension, la honte

• La transmission génétique Le diagnostic prénatal ? quand ? Comment ?

• La rupture avec l’Afrique

Comunicare la diagnosi ….mettre en place l’annonce d’une maladie

sévère

censimento delle emoglobinopatie nella regione piemonte · prevalenza 1991: 0,008/1000 prevalenza...

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