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: simona.roggero@unito.it
165 (F/M =84/81) PREVALENZA 1991: 0,008/1000 PREVALENZA 2011: 0,022/1000 Prevalenza SCD casi/anno Thalassemia Centre University of Torino
Kaplan-Meier analysis of survival in 168 consecutive SCD patients (2002-2012) Survival (%) 100% 98% 96% 94% 92% 90% 88% 86% 84% 82% 80% 78% 76% 74% 72% 70% 0 10 20 30 40 50 60 Years Thalassemia Centre University of Torino
Kaplan-Meier analysis of survival in 168 consecutive SCD patients (2002-2012) Survival (%) 100% 98% 96% 94% 92% 90% 88% 86% 84% 82% 80% 78% 76% 74% 72% 70% 0 10 20 30 40 50 60 Years Thalassemia Centre University of Torino
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
Severity of SCD varies widely between patients Pain Acute Chest Syndrome Cerebrovascular Accident Asymptomatic Moderate Severe Penicillin, folic acid, hydration Hydroxyurea Chronic transfusion Mariane de Montalembert TIF - 2008 Bone marrow transplantation
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
Asymptomatic Moderate Severe Penicillin, folic acid, hydration Hydroxyurea Chronic transfusion ACS = acute chest syndrome; CVA = cerebrovascular accident. Bone marrow transplantation
Asymptomatic Moderate Severe Penicillin, folic acid, hydration Hydroxyurea Chronic transfusion ACS = acute chest syndrome; CVA = cerebrovascular accident. Bone marrow transplantation
Priapism Upper airway obstruction Stroke Subarachnoid Hemorrhage Retinopathy The Clinical Problems of SCD by Age Age in years 0 5 10 15 Gallstones Avascular Necrosis Hyposthuria Delayed Growth and Development Modified from Davis SC, Wonke B. p.361. Bailleire s Clinical Hematology, Bailliere Tindall, London 1991
Priapism Upper airway obstruction Stroke Subarachnoid Hemorrhage Retinopathy The Clinical Problems of SCD by Age Age in years 0 5 10 15 Gallstones Avascular Necrosis Hyposthuria Delayed Growth and Development Modified from Davis SC, Wonke B. p.361. Bailleire s Clinical Hematology, Bailliere Tindall, London 1991
Severity of SCD varies widely between patients Asymptomatic Moderate Severe Hydroxyurea Chronic transfusion ACS = acute chest syndrome; CVA = cerebrovascular accident. Bone marrow transplantation
Terapia popolazione SCD età pediatrica (età < 14 anni) gennaio 2013 71 soggetti, età media 6,2 anni (range 0,2-14 anni) Prevenzione stroke trasfusione regolare HU follow-up tmo CRISI VASOCCLUSIVE OSSEE/ADDOMINALI RICORRENTI Sindrome toracica Sequestri splenici ricorrenti ANEMIA 85% Thalassemia Centre University of Torino
Two major Phenotypes of Sickle Cell Disease...prospettive terapeutiche future Viscocity-Vasocclusion Erythrocyte Sickling Haemolytic Endothelial Dysfunction Vaso-occlusive crisis Acute chest syndrome Avascular necrosis Pulmonary hypertension Leg ulcers Priapism Renal Insufficiency Stroke 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
CEREBRAL VASCULOPATHY Mild narrowing of vessel lumen Stenosis occlusio n Moya-moya aneurysm Velocity > 2 m/s ± Overt stroke ± Cerebral haemorhage
STOP I STROKE RISK INCREASES WITH TCD FLOW RATE 1 Probability of remaining stroke-free 0,9 0,8 0,7 0,6 0,5 0,4 < 170 cm/s 170 199 cm/s 200 cm/s p = 0.0001 0 5 10 15 20 25 30 35 Time (months) Adams RJ. Control Clin Trials. 1998;19:110-29. Neurologia - Ospedale Gradenigo settembre 2007 Thalassemia Centre University of Torino
STOP I STROKE RISK INCREASES WITH TCD FLOW RATE 1 Probability of remaining stroke-free 0,9 0,8 0,7 0,6 0,5 0,4 < 170 cm/s 170 199 cm/s 200 cm/s p = 0.0001 3/78 (3,8%) 0 5 10 15 20 25 30 35 Time (months) Thalassemia Centre University of Torino
1.4 Incidence d un premier AVC (pour 100 pt-années) 1.2 1.0 0.8 0.6 0.4 0.2 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Années Fullerton HJ, et al. Blood. 2004;104:336-9.
1.4 Incidence d un premier AVC (pour 100 pt-années) 1.2 1.0 0.8 0.6 0.4 0.2 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Années Fullerton HJ, et al. Blood. 2004;104:336-9.
1.4 Incidence d un premier AVC (pour 100 pt-années) 1.2 1.0 0.8 0.6 0.4 0.2 Arteria Cerebrale Anteriore 0 CI 1-2-3 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Arteria Cerebrale Media Tronco Basilare Arteria Cranica Posteriore
Thalassemia Centre University of Torino Neurologia ospedale Gradenigo settembre 2012
CAUSES OF DEATH IN CHILDREN WITH SCD 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].
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 DAL 2007-2012 Decessi per sepsi: 0 Sepsi da pneumococco: 0 Sepsi da salmonella : 1 Servizi vaccinali Centro regionale Pediatria territoriale Medico curante Sperimentazione clinica PVN 13
SINDROMI DREPANOCITICHE IN PIEMONTE Orientamenti terapeutici Strumenti di prevenzione Aderenza a presa in cura e follow-up
Profilo dei pz con SCD nota in Piemonte (31/12/2012) N totale casi 175 Età media casi (range) 19 anni (1 mese- 62 anni) Sindrome drepanocitica Origini etniche SS SβThal SC SOarab SHPHF Italia Non Italia - 70% - 19% - 9% - 1% - 1% - 15% - 85% 81% 15% 4% 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
aderenza alla presa in cura: punti di debolezza ETA alla diagnosi 6,2 vs 1,6 aa p<0,05 % SCD casi distribuzione per provincia di residenza Thalassemia Centre University of Torino
MOTIVI DI DIAGNOSI 2010-2012... SCD sintomi Familiarità Coppie a rischio follow-up di nati da coppie a rischio Programmi di screening Lieberman L, 2009 6,2 vs 1,6 aa p<0,05 Thalassemia Centre University of Torino
aderenza alla presa in cura: punti di debolezza ETA alla diagnosi 6,2 vs 1,6 aa p<0,05 % SCD casi distribuzione per provincia di residenza Raccolta cordone ombelicale Thalassemia Centre University of Torino
PROPOSTE... - Diagnosi precoce - nuovi genotipi (SC ) - portatori sani di HbS - RETE ASSISTENZIALE Thalassemia Centre University of Torino
Profilo delle emoglobinopatie in Piemonte. 2010 NECESSITA di PREVENZIONE POCHE coppie a rischio di SCD scelgono di ricorrere alla DPN Greenscross P,, J Med Screen 2006 INDAGINI HPLC- IEF BIOLOGIA MOLECOLARE - SEQUENZIAMENTO PRENATAL NEWBORN SCREENING
PROPOSTE... - Diagnosi precoce - nuovi genotipi (SC ) - portatori sani di HbS - RETE ASSISTENZIALE
Counselling delle emoglobinopatie in Piemonte.: PROSPETTIVE: RETE ASSISTENZIALE PRESA IN CURA da RETE ASSISTENZIALE Medico/Pediatra di famiglia ESPERTO Medicina/Pediatria di TERRITORIO S.C.D.U. MICROCITEMIA- PEDIATRIA A.O.U. SAN LUIGI GONZAGA DI ORBASSANO Centro regionale di riferimento per le emoglobinopatie
Rete assistenziale SCD the aims To establish for each patient a network of 3 physicians working in close collaboration: A general practitioner trained in SCD management; A local hospital; GPs 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 Local hospital SCD centre To increase knowledge among healthcare professionals patients and families Who does what?
Rete assistenziale SCD PROPOSTA: CENTRO SPECIALISTICO ITINERANTE GPs Local hospital SCD centre
It is necessary to look at the problems not solved, from a different perspective Not telling about what we do, but about what we do not do
Les infections 1 ère 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 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 Adamkiewicz, T. V. et al. Pediatrics 2008;121:562-569
NEONATAL SCD SCREENING APPLICAZIONE PRECOCE del PREVENTIVE care 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)
SINDROMI DREPANOCITICHE IN PIEMONTE Orientamenti terapeutici Strumenti di prevenzione Aderenza a presa in cura e follow-up
EMOGLOBINOPATIE: QUALE COUNSELLING? CON QUALI OBIETTIVI? -> INFORMARE/COMUNICARE -> SCELTE CONSAPEVOLI E INFORMATE PREVENTI ON Patient CARE
THE CLINICAL PROBLEMS OF SICKLE CELL DISEASE BY AGE Pain Dactylitis Long Bones Trunk Sequestrastion Splenic Hepatic Age in years 0 5 10 15 Chest syndrome Infection Girdle syndrome Pneumococcal Parvovirus Salmonella 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) 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. Mirre E, et al. Eur J Haematol 2010; 84: 259-65
Pazienti e metodi Criteri di inclusione: - DIAGNOSI: SINDROME DREPANOCITICA - ETÀ: < 1 ANNO E > 18 ANNI - NON PREGRESSO STROKE ISCHEMICO TCD (febbraio 2008 - novembre 2008) tecnica doppler sonda per TCD 2 MHz personale esperto non attendibilità: febbre/crisi vasococclusive nella settimana VM precedente (cm/sec) pianto inconsolabile non sufficiente stato di veglia 2 TCD ( doppio cieco da due operatori )
EMOGLOBINOPATIE: QUALE COUNSELLING? Profilo delle emoglobinopatie: Ereditarietà prevenzione possibile Cronicità cura possibile Eterogeneità Talassemie Varianti emoglobiniche
EMOGLOBINOPATIE: QUALE COUNSELLING? PREVENTI ON Patient CARE
EMOGLOBINOPATIE: QUALE COUNSELLING? CON QUALI OBIETTIVI? Comunicare:
EMOGLOBINOPATIE: QUALE COUNSELLING? CON QUALI OBIETTIVI? Comunicare: Motivo dell indagine: - Sospetto diagnostico - Screening (familiarità/etnia)
COUNSELLING CON QUALI OBIETTIVI? Comunicare: Motivo dell indagine: - Sospetto diagnostico - Screening (familiarità/etnia) Risultato dell indagine
EMOGLOBINOPATIE: QUALE COUNSELLING? CON QUALI OBIETTIVI? Comunicare: Motivo dell indagine: - Sospetto diagnostico - Screening (familiarità/etnia) 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 A 2 4.5 2.0-3.2 % Hb S 24 0 % Thalassemia Centre University of Torino
A.R., 27 anni, 17 w di gestazione.2010 -> counselling 2012 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 A 2 4.5 2.0-3.2 % Hb S 24 0 % Thalassemia Centre University of Torino
Nigeria Nigeria? ITALIA S.F., 18 MESI HB 5.5 g/dl Mcv 80 fl Hb S 80% Thalassemia Centre University of Torino HbS/HbS
Nigeria Nigeria? ITALIA S.F., 18 MESI HB 5.2 g/dl Mcv 80 fl Hb S 80% Thalassemia Centre University of Torino HbS/HbS
Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003859.
DIAGNOSI SEMPLICE, MA NON DIMENTICHIAMO LA COMUNICAZIONE!!!! Centro Microcitemie Università di Torino
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%)
DIAGNOSI SEMPLICE, MA NON DIMENTICHIAMO LA COMUNICAZIONE!!!! Piero C. Giordano Clinical Biochemistry 42 (2009) 1757 1766
NON MALATTIA.MA UN GENE ALTERATO
NON MALATTIA.MA UN GENE ALTERATO Piero C. Giordano Clinical Biochemistry 42 (2009) 1757 1766
NON MALATTIA.MA UN GENE ALTERATO
Dal CARRIER alla FAMIGLIA Tunisia Tunisia Nato in Piemonte Variante 30% ->HbC
Mcv 55 fl HBC 80% HbC/CD39 -Colelitiasi -Splenomegalia -Retinopatia Dal CARRIER Tunisia alla FAMIGLIA Nato in Piemonte Variante 30% ->HbC
MA. se compaiono sintomi? Spleen enlargement - Liver enlargement - Thalassemia-like bone modifications Hb MCV R.L.,2 years - 9.5 g/dl 55 fl HbA2 4.5% HbF 3% Reticulocytes LDH Erytrhoblasts count/ Growth Differentiation Factor 15/EPO Iron overload - Italia Microcitosi in accertamenti preoperaratori CD39/N Italia
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 - +/- +
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
EMOGLOBINOPATIE: QUALE COUNSELLING? CON QUALI OBIETTIVI? Comunicare: Motivo dell indagine: - Sospetto diagnostico - Screening (familiarità/etnia) Risultato dell indagine
Counselling di coppia delle emoglobinopatie 75 Modell (Londra) I DPN per β talassemia PRENATAL SCREENING 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 20 Age distribution of thalassemia patients 18 16 1977 14 12 1987 1997 number 10 8 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 AGE (years) 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 20 Age distribution of thalassemia patients 18 16 1977 14 12 1987 1997 number 10 8 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 AGE (years) In areas where haemoglobinopathies are common, dedicated centres are required in order to ensure adequate services for prevention and treatment. WHO, 2006
MADRE Carrier of: α + thal αo thal Hb S β thal δβ thal Hb Lepore Hb E Hb O Ar ab Hb C Hb D P unjab HPFH Not a carrier α+ thal αo thal Hb S β thal δβ thal PADRE Hb Lepore Hb E Hb O Hb C Ar ab Key: Serious risk Hb D P unjab HPFH Not a carrier Rischio di EMOGLOBINOPATIA MAGGIORE. eterogeneità Less serious risk Possible hidden risk of a 0 No risk Old JM, 2007
Carrier of: α + thal αo thal Hb S β thal δβ thal Hb Lepore Hb E Hb O Ar ab Hb C Hb D P unjab HPFH Not a carrier α+ thal αo thal Hb S β thal Β tal major δβ thal Hb Lepore Hb E Hb O Hb C Ar ab Key: Serious risk Hb D P unjab HPFH Not a carrier Less serious risk Possible hidden risk of a 0 No risk Old JM, 2007
Carrier of: α + thal αo thal Hb S β thal δβ thal Hb Lepore Hb E Hb O Ar ab Hb C Hb D P unjab HPFH Not a carrier α+ thal αo thal Hb S β thal Hb SS δβ thal Hb Lepore Hb E Hb O Hb C Ar ab Key: Serious risk Hb D P unjab HPFH Not a carrier Less serious risk Possible hidden risk of a 0 No risk Old JM, 2007
eterogeneità.markers predittivi di fenotipo? MORBIDITA / MORTALITA 15-20% 65-75% 10-15% LIEVE MODERATO SEVERO FENOTIPO Adattato da De Montalembert, BJM, 2008
Counselling coppie in Piemonte oggi. POCHE coppie a rischio di SCD scelgono di ricorrere alla DPN Greenscross P,, J Med Screen 2006 PRENATAL NEWBORN SCREENING
EMOGLOBINOPATIE: QUALE COUNSELLING? CON QUALI OBIETTIVI? Comunicare: Motivo dell indagine: - Sospetto diagnostico - Screening (familiarità/etnia) 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
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
THALASSEMIA MAJOR - SURVIVAL Adapted from B. Modell and V. Berdoukas, 1984
Age distribution of thalassemia patients 20 Thalassemia survival: IMPROVING IN MANAGEMENT number 18 16 14 12 10 8 1977 1987 1997 Transfusion+iron chelation 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 AGE (years) Adapted from B. Modell and V. Berdoukas, 1984
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
Earlier diagnosis positively impacts survival 100 98 HbSS diagnosed in newborn period Survival (%) 96 94 92 90 88 86 HbSS diagnosed after newborn period 0 10 20 30 40 10 Years Months HbSS = haemoglobin SS. Vichinsky E, et al. Pediatrics. 1988;81:749-55.
EARLY DIAGNOSIS APPLICAZIONE PRECOCE del PREVENTIVE care 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.
TEMPO 0 PRESA IN CURA
NEONATAL SCD SCREENING APPLICAZIONE PRECOCE del PREVENTIVE care 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)
Les signes : - Fatigue - Refus alimentaire - Essoufflement anormal - Pâleur : Paumes des mains Plantes des pieds Conjonctives = URGENCE HOSPITALIERE
Les signes : = URGENCE HOSPITALIERE
What to do in case of pain? + If : => or or
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
Role of Blood Transfusion in Preventing or Treating Thalassemia Intermedia Complications Andrea C., Thalassemia intermedia (β CD39/βIVSI-6) Diagnosis at 1.5 yrs of life At 3½ - no transfusion and Hb around 7,5 Thalassemia Centre University of Torino At 5 - after 2 yrs of regular transfusions
La sévérité de la drépanocytose est très variable selon les patients Formes modérées Douleur STA AVC Patients asymptomatiques Formes sévères Penicilline, acide folique, hydratation Hydroxyurée Transfusion chronique GMO
EMOGLOBINOPATIE: QUALE COUNSELLING...IN PIEMONTE?
Counselling delle emoglobinopatie in Piemonte.: PROSPETTIVE: COMUNICAZIONE E STRATEGIE DI PROPOSTA
Counselling delle emoglobinopatie in Piemonte. PROSPETTIVE: PREVENZIONE POCHE coppie a rischio di SCD scelgono di ricorrere alla DPN Greenscross P,, J Med Screen 2006 PRENATAL NEWBORN SCREENING INDAGINI HPLC- IEF BIOLOGIA MOLECOLARE - SEQUENZIAMENTO
EMOGLOBINOPATIE: QUALE COUNSELLING? GENETIC DISORDERS
Diagnosi semplice e importante,ma.. Centro Microcitemie Università di Torino
120 Transfusional Iron Overload in Thalassemia Iron (g) 100 80 60 40 20 0 1 3 5 7 9 11 13 15 17 19 Age (years) Diabetes Hypogonadism Cardiac arrhythmia Hypothyroidism Hepatic Fibrosis --> Cirrhosis Death Cardiac Failure Hypoparathyroidism Thalassemia Centre, Dept. of Pediatrics University of Turin, Italy
SURVIVAL KAPLAN MEIER ANALYSIS ON 257 CONSECUTIVE TRANSFUSION-DEPENDENT BETA THALASSEMIC PATIENTS IN TORINO Cumulative Proportion Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 High chelation = 15 Low chelation = 104 Cox's F test=23.6 p<0.00 0 5 10 15 20 25 30 35 40 45 years Piga A, 1993
CLINICAL FORMS OF THALASSEMIA Thalassemia minor ASYMPTOMATIC Thalassemia intermedia INTERMEDIATE Thalassemia major TRANSFUSION-DEPENDENT
Diagnosis and screening of hemoglobinopathies Thalassemia Centre University of Torino
CARE NO CARE AND PREVENTION: HOW MUCH DOES IT COST?
Barbuti-Ginevra BETA/S 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 β 6Glu->Val /N IVSI:110/N Note Grav. 8w Grav. 26w Diagnosi β S / N β thal / N
THE CARRIER OF THALASSEMIA AND PREGNANCY Genetic aspects Diagnosis Couple at risk Genetic counseling Prenatal diagnosis Clinic aspects Anemia Folate deficiency Iron deficiency/overload Others
Β-THALASSEMIA CLINICAL PHENOTYPES SILENT Carrier with normal phenotype Requires DNA testing for detection TRAIT Slight anemia with low MCV INTERMEDIA MAJOR 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
Emoglobinopatie: quale counselling nel 2012? ANTENATAL /PRENATAL SCREENING INFORMED CHOICE CARRIER DETECTION - ESTABLISHING A SCREENING STRATEGY - GENE FREQUENCY PREVEN TION Patient CARE NEWBORN SCREENING EARLY DIAGNOSIS AND EARLY CARE COMMUNITY INFORMATION
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 74 Modell (Londra) I prenatal diagnosis of hemoglobin disorders - routine antenatal screening for carriers was started in north London in 1977 Hemoglobinopathies are often the first condition requiring set up of PND service Model, Nature genetics, 2003 PRENATAL SCREENING 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
Profile of haemoglobinopathies -3 Genetic disorders Hemolytic anemia Children. if left untreated, result in death in the first few years of life Globally widespread Vichinsky et al. Pediatrics 2001
Prevalenza SCD casi/anno regione Piemonte OTHER HEMOGLOBINOPATHIES.. 1970s 1990s 2000s
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 Intermedia Major 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
THALASSEMIA PHENOTYPES AND TRANSFUSION DEGREE OF ANEMIA o Thal. minor ASYMPTOMATIC o Thal. intermedia mild MILD NO TRANSFUSION MODERATE o Thal. intermedia severe o Thal. major SEVERE TRANSFUSION TRANSFUSION-DEPENDENT Thalassemia Centre University of Torino
Β-THALASSEMIA CLINICAL PHENOTYPES SILENT Carrier with normal phenotype Requires DNA testing for detection TRAIT Slight anemia with low MCV INTERMEDIA MAJOR 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
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
Commonest genetic disorder 7% healthy carriers 300.000/400.000 annual births Births per 1000 infants with a major haemoglobinopathy Global distribution of haemoglobin disorders
Commonest genetic disorder. if left untreated, result in death in the first few years of life Births per 1000 infants with a major haemoglobinopathy Global distribution of haemoglobin disorders
Profile of haemoglobinopathies extremely heterogenous TALASSEMIA ANEMIA MEDITERRANEA DREPANOCITOSI ANEMIA FALCIFORME
TALASSEMIA ANEMIA MEDITERRANEA RIDOTTA SINTESI!!!! ANEMIA
TALASSEMIA ANEMIA MEDITERRANEA RIDOTTA SINTESI!!!! ERITROPOIESI INEFFICACE ANEMIA
Profile of haemoglobinopathies TALASSEMIA ANEMIA MEDITERRANEA DREPANOCITOSI ANEMIA FALCIFORME STRUTTURA ALTERATA!!!! (HbS, β codon 6 Glu Val)
NORMALE Profile of haemoglobinopathies: inherited disorders
Profile of haemoglobinopathies: inherited disorders NORMALE MALATO
Profile of haemoglobinopathies: inherited disorders NORMALE PORTATORE SANO MALATO
Profile of haemoglobinopathies: inherited disorders Centro Microcitemie Università di Torino
Profile of haemoglobinopathies: inherited disorders. impact of the diagnosis and treatment on family stability and family dynamics Centro Microcitemie Università di Torino
Haemoglobin disorders and World distribution of THALASSEMIA
Haemoglobin disorders and World distribution of THALASSEMIA World distribution of MALARIA The figure outlines the distribution of malaria before control programmes were established
Haemoglobin disorders and MALARIA World distribution of THALASSEMIA 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
Profilo delle sindromi drepanocitiche in Piemonte S.F., 18 MESI, nata in Italia HB 5.2 g/dl Mcv 80 fl Hb S 80% HbS/HbS
Thalassemia Centre University of Torino Diagnosis and screening of hemoglobinopathies Need of prevention ANTENATAL SCREENING PRENATAL SCREENING HPLC- IEF Mutations screening DNA sequencing PRENATAL NEWBORN SCREENING
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 Origin Men Women Total 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 New patients taken in charge in 2010 in Necker Hospital, Paris From neonatal screening: 50 (48 from Africa) mother alone parents together no data return to 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 mother alone parents together
Apprendre les urgences vitales fièvre > 38 5 douleur sévère les reconnaître Consulter en urgence anémie aiguë pâleur (SSA)
Prise en charge d un nouveau-né drépanocytaire éducation Physio pathologie Prévention infections (Oracilline, vaccins) douleur séquestration splénique URGENCES : fièvre anémie douleur
Les infections 1 ère 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!
Thalassemia.conventional treatment 1950s increased survival but significant morbidity 1960s 1970s good quality of life in childhood, but transfusional iron overload and cardiac death age a mean age of f 18 years
SURVIVAL KAPLAN MEIER ANALYSIS ON 257 CONSECUTIVE TRANSFUSION-DEPENDENT BETA THALASSEMIC PATIENTS IN TORINO Cumulative Proportion Surviving 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 High chelation = 153 Low chelation = 104 Cox's F test=23.6 p<0.0001 0 5 10 15 20 25 30 35 40 45 years
Haemoglobinopathie 2012: quale counselling nel 2012? ANTENATAL /PRENATAL SCREENING INFORMED CHOICE CARRIER DETECTION - ESTABLISHING A SCREENING STRATEGY - GENE FREQUENCY NEWBORN SCREENING EARLY DIAGNOSIS AND EARLY CARE COMMUNITY INFORMATION CRE
Talassemia Major Similar but different Talassemia Intermedia Talassemia Intermedia
EMOGLOBINOPATIE: QUALE COUNSELLING? GENETIC DISORDERS
Dedicated Thalassemia Centers GENETIC COUNSELLING 1970s 1990s
EMOGLOBINOPATIE: QUALE COUNSELLING?
Profile of haemoglobinopathies -2 Hemolytic anemia but remarkable diversity Thalassemia Sickle cell disease
Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003859.
Profile of haemoglobinopathies -1 Genetic disorders Hemolytic anemia Children Globally widespread
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 75 Modell (Londra) I DPN per β talassemia 1979: AMBULATORIO di Prenatal screening consulenza identificazione delle coppie a rischio DPN PRENATAL SCREENING 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
L M U C Courtesy of dr. Anna Rajab, Oman P.C. Giordano, Hemoglobinopathies Laboratory
Profilo delle emoglobinopatie in Piemonte. Malattie da immigrazione Anni 50-60- 70 TALASSEMIE Sindromi drepanocitiche (Sicilia) FREQUENZA DEI PORTATORI SANI DI β TA LA SSEMIA IN PIEMONT E 1959 0,9% 1977 3,8% Viora E, Piga A et al. - 1991
EMOGLOBINOPATIE: QUALE COUNSELLING? GENETIC DISORDERS
PROFILO DELLE EMOGLOBINOPATIE Malattie genetiche PREVENTION Portatore Sano Diagnosi semplice, ma ATTENZIONE Malato ridotta aspettativa di vita in assenza di cure esordio in eta infantile eterogenità fenotipica Patient CARE prevenzione secondaria decisiva per prognosi e qualità di vita
Counselling di coppia delle emoglobinopatie 1979: AMBULATORIO di Prenatal screening consulenza identificazione delle coppie a rischio DPN CENTRO MICROCITEMIE CENTRO REGIONALE DI RIFERIMENTO DELLE EMOGLOBINOPATIE: - Attività clinica (presa in cura) - Coordinamento/consulenza specialistica con il territorio - Divulgazione - Ricerca PRENATAL SCREENING (Centro regionale di emoglobinoptie) INDAGINI HPLC- IEF BIOLOGIA MOLECOLARE - SEQUENZIAMENTO 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
Profilo delle sindromi drepanocitiche in Piemonte S.F., 18 MESI, nata in Italia HB 5.2 g/dl Mcv 80 fl Hb S 80% HbS/HbS
Comunicare la diagnosi.mettre en place l annonce d une maladie sévère Les mots, les signes Le verdict de décès La vie, les projets L incompréhension, la honte La transmission génétique Le diagnostic prénatal? La rupture avec l Afrique quand? Comment?