censimento delle emoglobinopatie nella regione piemonte · prevalenza 1991: 0,008/1000 prevalenza...
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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
(%)
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
(%)
Thalassemia Centre University of Torino
Orientamenti terapeutici Strumenti di prevenzione Aderenza a presa in cura e follow-up
SINDROMI DREPANOCITICHE IN PIEMONTE
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.
Asymptomatic Moderate
Penicillin, folic acid, hydration
Severe
Hydroxyurea
Chronic transfusion
Bone marrow transplantation ACS = acute chest syndrome; CVA = cerebrovascular accident.
Asymptomatic Moderate
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
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
Asymptomatic Moderate
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
Thalassemia Centre University of Torino
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
SINDROMI DREPANOCITICHE IN PIEMONTE
Orientamenti terapeutici Strumenti di prevenzione Aderenza a presa in cura e follow-up
SINDROMI DREPANOCITICHE IN PIEMONTE
Orientamenti terapeutici Strumenti di prevenzione Aderenza a presa in cura e follow-up
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
Thalassemia Centre University of Torino
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%)
Thalassemia Centre University of Torino
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
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
Thalassemia Centre University of Torino
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
Orientamenti terapeutici Strumenti di prevenzione Aderenza a presa in cura e follow-up
SINDROMI DREPANOCITICHE IN PIEMONTE
Thalassemia Centre University of Torino
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
Thalassemia Centre University of Torino
aderenza alla presa in cura: punti di debolezza
% SCD casi distribuzione per provincia di residenza
Thalassemia Centre University of Torino
ETA’ alla diagnosi 6,2 vs 1,6 aa p<0,05
aderenza alla presa in cura: punti di debolezza
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
Thalassemia Centre University of Torino
MOTIVI DI DIAGNOSI 2010-2012.......
Lieberman L, 2009
% SCD casi distribuzione per provincia di residenza
Thalassemia Centre University of Torino
ETA’ alla diagnosi 6,2 vs 1,6 aa p<0,05
Raccolta cordone ombelicale
aderenza alla presa in cura: punti di debolezza
Thalassemia Centre University of Torino
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
SINDROMI DREPANOCITICHE IN PIEMONTE
Orientamenti terapeutici Strumenti di prevenzione Aderenza a presa in cura e follow-up
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
Age in years 0 5 10 15
THE CLINICAL PROBLEMS OF SICKLE CELL DISEASE BY AGE
Modified from Davis SC, Wonke B. p.361. Bailleire’s Clinical Hematology, Bailliere Tindall, London 1991
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:
EMOGLOBINOPATIE: QUALE COUNSELLING?
Profilo delle emoglobinopatie:
• Ereditarietà…prevenzione possibile • Cronicità…cura possibile • Eterogeneità
Talassemie Varianti emoglobiniche
Patient CARE
PREVENTION
EMOGLOBINOPATIE: QUALE COUNSELLING?
• CON QUALI OBIETTIVI? Comunicare:
EMOGLOBINOPATIE: QUALE COUNSELLING?
• CON QUALI OBIETTIVI? Comunicare:
Motivo dell’indagine:
- Sospetto diagnostico
- Screening (familiarità/etnia)
EMOGLOBINOPATIE: QUALE COUNSELLING?
COUNSELLING
• CON QUALI OBIETTIVI? Comunicare:
Risultato dell’indagine
Motivo dell’indagine:
- Sospetto diagnostico
- Screening (familiarità/etnia)
• CON QUALI OBIETTIVI? Comunicare:
Risultato dell’indagine
Motivo dell’indagine:
- Sospetto diagnostico
- Screening (familiarità/etnia)
EMOGLOBINOPATIE: QUALE COUNSELLING?
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 %
Thalassemia Centre University of Torino
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 %
Thalassemia Centre University of Torino
-> counselling 2012 ….2010
? Nigeria
S.F., 18 MESI HB 5.5 g/dl Mcv 80 fL Hb S 80% HbS/HbS
ITALIA
Nigeria
Thalassemia Centre University of Torino
? Nigeria
S.F., 18 MESI HB 5.2 g/dl Mcv 80 fL Hb S 80% HbS/HbS
ITALIA
Nigeria
Thalassemia Centre University of Torino
Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003859.
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
NON MALATTIA….MA UN GENE ALTERATO…
NON MALATTIA….MA UN GENE ALTERATO…
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 - +/- +
Thalassemia-like bone modifications
- + ++
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 + ++
Erytrhoblasts count/ Growth Differentiation Factor 15/EPO
+ ++
Iron overload - +/- +
MA…. se compaiono sintomi? RIVALUTARE ILCASO!!!
2 years 3 years 5 years
Spleen enlargement - + ++
Liver enlargement - +/- +
Thalassemia-like bone modifications
- + ++
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 + ++
Erytrhoblasts count/ Growth Differentiation Factor 15/EPO
+ ++
Iron overload - +/- +
CD39/N αααα/αα
MA…. se compaiono sintomi? RIVALUTARE ILCASO!!!
• CON QUALI OBIETTIVI? Comunicare:
Risultato dell’indagine
Motivo dell’indagine:
- Sospetto diagnostico
- Screening (familiarità/etnia)
EMOGLOBINOPATIE: QUALE COUNSELLING?
Counselling di coppia delle emoglobinopatie
PRENATAL SCREENING
’75 Modell (Londra) I DPN per β talassemia
INDAGINI HPLC- IEF – BIOLOGIA MOLECOLARE -
SEQUENZIAMENTO
Counselling di coppia delle emoglobinopatie
’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
Counselling di coppia delle emoglobinopatie
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
Counselling di coppia delle emoglobinopatie
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
Possible hidden risk of a0
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
Possible hidden risk of a0
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
POCHE coppie “a rischio” di SCD scelgono di ricorrere alla DPN Greenscross P, , J Med Screen 2006
• CON QUALI OBIETTIVI? Comunicare:
DIAGNOSI
PROGNOSI
Motivo dell’indagine:
- Sospetto diagnostico
- Screening (familiarità/etnia)
EMOGLOBINOPATIE: QUALE COUNSELLING?
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
PROFILO DELLE EMOGLOBINOPATIE
• 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
Adapted from B. Modell and V. Berdoukas, 1984
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
PROFILO DELLE EMOGLOBINOPATIE
• Malato ridotta aspettativa di vita in assenza di
cure…curare è possibile esordio in eta’ infantile: DIAGNOSI PRECOCE!!! prevenzione secondaria decisiva per prognosi e
qualità di vita
eterogenità fenotipica
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
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.
PRESA IN CURA
TEMPO 0
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
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.
PROFILO DELLE EMOGLOBINOPATIE
• Malato ridotta aspettativa di vita in assenza di
cure…curare è possibile esordio in eta’ infantile: DIAGNOSI PRECOCE!!! prevenzione secondaria decisiva per prognosi e
qualità di vita
eterogenità fenotipica
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
Masses of Extramedullary Erythropoiesis in Thalassemia Intermedia
Thalassemia Centre University of Torino
PROFILO DELLE EMOGLOBINOPATIE
• Malato ridotta aspettativa di vita in assenza di
cure…curare è possibile esordio in eta’ infantile: DIAGNOSI PRECOCE!!! prevenzione secondaria decisiva per prognosi e
qualità di vita
eterogenità fenotipica
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
Thalassemia Centre University of Torino
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
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
GENETIC DISORDERS
EMOGLOBINOPATIE: QUALE COUNSELLING?
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
Thalassemia Centre University of Torino
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.
CARE
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
Β-THALASSEMIA CLINICAL PHENOTYPES
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
Thalassemia Centre University of Torino
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
Adapted from B. Modell and V. Berdoukas, 1984
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
Profile of haemoglobinopathies: inherited disorders
PORTATORE SANO MALATO
NORMALE
Profile of haemoglobinopathies: inherited disorders
Centro Microcitemie Università di Torino
Profile of haemoglobinopathies: inherited disorders
Centro Microcitemie Università di Torino
…. impact of the diagnosis and treatment on family stability and family dynamics
Profile of haemoglobinopathies: inherited disorders
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
World distribution of THALASSEMIA
Haemoglobin disorders and MALARIA
World distribution of MALARIA The figure outlines the distribution of malaria before
control programmes were established
World distribution of THALASSEMIA
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
Thalassemia Centre University of Torino
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
EMOGLOBINOPATIE: QUALE COUNSELLING?
1970s
GENETIC COUNSELLING
Dedicated Thalassemia Centers
1990s
EMOGLOBINOPATIE: QUALE COUNSELLING?
• Hemolytic anemia …but remarkable diversity
Profile of haemoglobinopathies -2
Sickle cell disease
Thalassemia
Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003859.
• Genetic disorders • Hemolytic anemia • Children • Globally
widespread
Profile of haemoglobinopathies -1
EMOGLOBINOPATIE: QUALE COUNSELLING?
• INFORMARE • COMUNICARE • MOTIVARE • INTERPRETARE BISOGNI • QUALI DESTINATARI? • QUALI OBIETTIVI? “Non siamo preoccupati delle cose, ma
dell’opinione che abbiamo di esse” Epitteto
Counselling di coppia delle emoglobinopatie
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
INDAGINI HPLC- IEF – BIOLOGIA MOLECOLARE -
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
EMOGLOBINOPATIE: QUALE COUNSELLING?
PROFILO DELLE EMOGLOBINOPATIE
• 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
Counselling di coppia delle emoglobinopatie
INDAGINI HPLC- IEF – BIOLOGIA MOLECOLARE -
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
In areas where haemoglobinopathies are common, dedicated centres are required in order to ensure adequate services for prevention and treatment. WHO, 2006
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