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The Inherited Diseases of Hemoglobin are an Emerging
Global Health BurdenGlobal Health Burden
Suthat Fucharoen ([email protected])
Thalassemia Research CenterInstitute of Molecular Biosciences,
Mahidol University, Thailand
Acknowledgements
Prof. Prawase WasiMahidol University,
ThailandSir David Weatherall
Oxford UniversityUK
Contribution of genetic and congenital disorders Contribution of genetic and congenital disorders to infant and childhood mortality
in a typical developed countryin a typical developed country
Global distribution of hemoglobin disorders, in terms of births of affected infants per 1000 births (WHO, 1996)
Gl b l E id i l f H l bi Di dGlobal Epidemiology of Hemoglobin Disorders• Around 7% of the global population carries an
b l h l biabnormal hemoglobin gene
• 300,000-500,000 children are born with clinically i ifi t h l bi di d llsignificant hemoglobin disorders annually
• About 80% of affected children are born in developing countriesdeveloping countries
• About 70% are born with Sickle Cell Diseased th t ith Th l i S dand the rest with Thalassemia Syndromes
• 50-80% of children with SCD die each year in low and iddl i t imiddle income countries
• 50,000-100,000 children with thalassemia major die h i l d iddl i t ieach year in low and middle income countries
Hemoglobin disorders as a common entry pointas a common entry point
‐ They are highly prevalent in many populations
‐ Survival and quality of life can be greatly improves by simple protective measures, such as transfusion programs f th l ifor thalassemia
‐ Carriers can be detected by cheap and simple h l l d l b d dhematological tests, and carrier couples can be advised prospectively of their risk
‐ Prenatal diagnosis is highly acceptable to couple at risk
Diagnosis registers can be used for service auditg g
‐ Screening strategies and DNA‐based laboratory methods introduced for hemoglobin disorders can be extended to introduced for hemoglobin disorders can be extended to other inherited disorders
WHO Working Group, 1981 A B (L Ni i ) 8 A P t l ki (Ath G )1. A. Boyo (Lagos, Nigeria)
2. A. Cao (Sardinia, Italy)3. Der kalostian (Beirut, Lebanon)
4 J Hercules (Betheada USA)
8. A. Pantelakis (Athens, Greece)
9. A.Motulsky (Seattle, USA)
10. A. Piel (Geneva, Switzerland)
11 J Rosa (Paris France)4. J. Hercules (Betheada, USA)
5. A. Kuliev (Genewa, Switzerland)
6. D. Loukopoulos (Athens, Greece)
7 B Modell (London UK)
11. J. Rosa (Paris, France)
12. P. Wasi (Bangkok, Thailand)
13. D.J. Weatherall (Oxford, UK)
14 R Williamson (London UK)7. B. Modell (London, UK) 14. R. Williamson (London, UK)
List of relevant documentsList of relevant documents
WHO's Genomic Resource Centre ‐www.who.int/genomics/en
WHO, 1989. Report of the fifth WHO working group on the feasibility study on hereditary disease community control programmes (Hereditaryanaemias) .WHO, Geneva, Switzerland. (WHO/HDP/WG/HA/89.2)WHO G id li f th M t f Si kl C ll Di WHO G S it l d (WHO/HDP/SCD/ )WHO, 1991. Guidelines for the Management of Sickle Cell Disease.WHO, Geneva, Switzerland (WHO/HDP/SCD/91.2)WHO, 1993. Report of a joint WHO/TIF meeting on the prevention and control of haemoglobinopathies. WHO, Geneva, Switzerland (WHO/HDP/TIF/WG/93.1)WHO, 1994. Educational materials on prenatal diagnosis for Sickle‐cell disorder. WHO, Geneva, Switzerland (WHO/HDP/EM/PN.SCD/94.2).WHO, 1994. Guidelines for the Control of Haemoglobin Disorders. WHO, Geneva, Switzerland (WHO/HDP/HB/GL/94.1).WHO, 1995. Prevention and Control of Haemoglobinopathies. WHO Bulletin, v73(3):375‐386.WHO, 1997. Inherited Haemoglobin Disorders: an increasing global health problem. WHO Bulletin, v.75 (3):15‐39.WHO, 1999. Services for the Prevention and Management of Genetic Disorders and Birth Defects in Developing Countries. WHO, Geneva, Switzerland (WHO/HGN/WAOPBD/99.1)WHO, 2000. Primary Health Care Approaches for Prevention and Control of Congenital and Genetic Disorders.WHO, Geneva, Switzerland (WHO/HGN/WG/00.1)WHO 2002 Minutes of a WHO meeting on haemoglobin disorders WHO Geneva Switzerland (WHO/HGN/HB/02 4)WHO, 2002. Minutes of a WHO meeting on haemoglobin disorders. WHO, Geneva, Switzerland (WHO/HGN/HB/02.4)WHO, 2002. Report of the Advisory Committee on Health Research. Genomics and World Health. WHO, Geneva, Switzerland (ISBN 92 4 154554 2).WHO, 2003. Genetic Approaches to Haemoglobin Disorders and Primary health Care.WHO, Geneva, Switzerland (WHO/HGN/TIF/CONS/03.1)WHO, 2006. Report by Secretariat to Executive Board: Sickle‐cell anaemia. EB117, Doc. EB117/34. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. Report by Secretariat to World Health Assembly: Sickle‐cell anaemia. WHA59, Doc.A59/9. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. Report by Secretariat to Executive Board: Thalassaemia and Other Haemoglobinopathies. EB118, Doc. EB118/5. WHO, Geneva, Switzerland [ h i / b ][ www.who.int/gb ]WHO, 2006. Executive Board Resolution on Sickle Cell Anaemia. EB117.R3. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. World Health Assembly Resolution on Sickle Cell Anaemia.WHA59.20. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. Executive Board Resolution on Thalassaemia and Other Haemoglobinopathies. EB118.R1. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. Report of a joint WHO/MOD meeting on Management of Birth Defects and Haemoglobin Disorders.WHO, Geneva, Switzerland.WHO, 2008. Report of a joint WHO‐TIF meeting on Management of Haemoglobin Disorders.WHO, Geneva, Switzerland., p f j g g f g , ,WHO, 2010. World Health Assembly Resolution on Birth Defects.WHA63.17. WHO, Geneva, Switzerland [ www.who.int/gb
World Health OrganizationEB117 R3 Resolution 2006EB117.R3 Resolution, 2006
World Health OrganizationWHA59.20 Resolution, 2006,
World Health OrganizationEB118.R1 Resolution, 2006,
Resolutions on HemoglobinopathiesResolutions on HemoglobinopathiesThalassaemia and other Haemoglobinopathies U M b St tHaemoglobinopathies
EB118, May 2006 – Resolution EB118.R1Urges Member States: Implement and reinforce national
programs on HB disordersprograms on HB disorders Evaluate the impact of national
programs Intensify the training of all health
professionals Promote community educationy Promote international
cooperation Develop and strengthen medical Develop and strengthen medical
genetic services Support basic and applied
research
Sickle cell anaemiaWHA59, May 2006 – Resolution WHA59.20
research
Resolutions on HemoglobinopathiesResolutions on HemoglobinopathiesThalassaemia and other HaemoglobinopathiesHaemoglobinopathies
EB118, May 2006 – Resolution EB118.R1 Requests the Director-General provide technical support and p pp
advice to national programs expand the training and expertise
of personnelof personnel support the further transfer of
affordable technologiesdrafting guidelines on prevention drafting guidelines on prevention and management
fostering the establishment of regional groups of experts;regional groups of experts;
support needed researchSickle cell anaemiaWHA59, May 2006 – Resolution WHA59.20
NWHO meeting of expertsGeneva, 17-19 May 2006
Priorities:Priorities:• support continued research for the collection and refinement of data relevant for the control of birth defects and hemoglobin disorders
• provide practical advice and support for countries wishing to develop medical services for care and prevention of birthservices for care and prevention of birth defects and haemoglobin disorders
• promote human resource capacity• promote human resource capacity development and technology transfer
WHO-TIF Meeting of Experts, Cyprus,November 2007
A proposed 5-year plan of Action1 R i i th t t t f id i l d1: Reviewing the current status of epidemiology and
control services for Hemoglobin (Hb) disorders globally 2: Identification of local and regional problems needs and2: Identification of local and regional problems, needs and
priorities for improving control policies 3: Initiation of Guidelines for the control of Hb disorders4: Supporting the establishment of new and promoting the
services of existing expert centers5: Promotion of the establishment of regional expert
advisory groups6: Fund raising to support programs of control of Hb6: Fund raising to support programs of control of Hb
disorders 7: Development of cost-effective approaches and p pp
interventions for the control of Hb disorders 8: Promotion of the establishment of a World Day for
H l bi Di dHemoglobin Disorders9: Collaboration between potential stakeholders
List of WHA / EB resolutions (in genetics)
WORLD HEALTH ASSEMBLYWORLD HEALTH ASSEMBLY
WHA57.13WHA57.13 22 May 2004 Genomics and world health
WHAWHA5959..2020 27 May 2006 Sickle cell anaemia
WHA63 17WHA63 17 21 May 2010 Birth defectsWHA63.17WHA63.17 21 May 2010 Birth defects
EXECUTIVE BOARDEXECUTIVE BOARD
EB116/3EB116/3 26 May 2005 Control of genetic diseases
EBEB117117.R.R3 3 25 Jan 2006 Sickle cell anaemia
EB118 R1EB118 R1 29 May 2006 Thalassaemia and other EB118.R1EB118.R1 29 May 2006 Thalassaemia and other haemoglobinopathies
‐Thal/Hb E‐Thal 2/Hb E
( ‐Thal)2‐Thal 2Hb E
‐Thal
Hb H Disease ‐Thal 1/ ‐Thal‐Thal/Hb Ec ‐Thal 2‐
‐Thal 1 ‐Thal 1(‐Thal 1)2
Hb Bart’s Hydrops
‐Thal 1/Hb E
Hb Bart s Hydrops
Hb H Disease Hb AEBart,s Disease ‐Thal 1/Hb Ec Hb CS c Hb CS‐‐
Hb Constant Spring(Hb CS)
Hb E(Hb CS) 2 (Hb E) 2
(More than 60 genotypes )
Thailand, 1985
Pune,1Pune,1987
The Thalassemia Situation in CambodiaUntreated thalassemia
May 2005National Pediatric Hospital
19 year old male Hematocrit – 4 %
? Hb E/ thalassaemia? Hb E/ thalassaemia
Prevalence of Thalassemia & H l bi thi i M ldi
38%
Hemoglobinopathies in Maldives 23% 44%
8%
15%
10%Maldives
UNION OF MYANMARUNION OF MYANMAR
Myanmar – Thalassemia(Aung-Than-Batu et al 1968,1971)
• β thalassemia trait 0 5%• β thalassemia trait – 0.5%
• α thalassemia trait - 10%
• HbE trait - 26%
In Myanmar alone, 1‐4.9 per 1000 live birth suffer from severeform of thalassemia (Thalassemia major) (MODELL, 1986)
Assuming an annual birth rate of 1.4 million, 1400 –7000 new cases of severe thalassemia each and every year in Myanmar
500 Couples
HbE thalassemia HbE‐‐thalassemia, ONE in every 500 couples are at‐risk
HbH disease HbH disease TWO in every 500 couples are at‐risk
Hb Bartʼs Hydrops Fetalis Hb Bart s Hydrops Fetalis NONE in every 500 couples are at‐risk
(Ne Win et al, 2003 Myan Milit Med; 2005 Ann Rep)
The distribution and the frequency (%) of thalassemia beta carriers in Indonesiathalassemia beta carriers in Indonesia
‐thalassemia
1
Batak
3Day
ak
njar
5P’baru
sa
4 2
HbE
B 3D 0Ban5P
5Kaili
2
M’has
ng 8kasa
r
4nang
19
P’ban
i a
8
M’k
5ngka
8va
ork4
Min
63
1
1Bali
3Su
mba
5
Ba 8Jav
6Alo
5
Bim
a3
Sasa
k
46 4 337
A.S. Sofro & F. Lanni, University of Gajah Mada
4 337
Thalassemia situation in IndonesiaThalassemia situation in Indonesia
1400
Severe thalassemia patients in Jakarta
1200
1400
Type of thalassemias:
800
1000Type of thalassemias:• 52% Beta thalassemia
46% B t /HbE
400
600• 46% Beta/HbE• 2% HbH + others
0
200
1988 1998 20051988 1998 2005
INDONESIAINDONESIAEstimation of new -thalassemia patients
• Population 224 million• Annual birth rate: 2.3%• Carrier frequency 5% - 3,000 new patients/year• Only 3 000 patients registered• Only 3,000 patients registered
The expected number of th l i j ti tthalassemia major patients
Wahidiyat et al 1988Wahidiyat et al., 1988
Southeast/East Asia (2010)
No Country/Region
TotalPopulation (m)
0-thal(%)
+-thal(%)
-thal(%)
Hb E(%)
Hb S(%)Region Population (m) (%) (%) (%) (%) (%)
1 Bangladesh 143.9 0 41 2.5 4.0 02 Bhutan 2.1 0 32 + 4.0 03 DPR, Korea 24 ND ND ND ND ND4 India 1,210.2 0 41 1.6 1.0 1.95 Indonesia 237.4 + 7.7 4.0 1.9 06 Maldives 0.37 0 32 16 1.0 0.17 M anmar 59 1 0 4 32 2 2 25 07 Myanmar 59.1 0.4 32 2.2 25 08 Nepal 28.0 0 32 1.0 3.0 09 Sri Lanka 20.0 0 40.8 2.5 2.5 010 Thailand 64.7 5.0 21 5.3 33 011 Timor-Leste 1.13 ND ND ND ND ND
Grand Total 1,790.9
(Modified from Modell )
Thalassemia diagnosis in different SEARO countries
Country Blood Cell Analyzer
OF Hb Analysis DNA Analysis
Electrophoresis HPLC/LPLC/CE p
Bangladesh (+) - (+) (+) (+) (+)Bhutan ND ND ND ND ND ND
DPR Korea ND ND ND ND ND NDIndia (+) + + (+) + +
Indonesia (+) - + (+) (+) (+)Indonesia (+) + (+) (+) (+)Maldives (+) - + + (+) -Myanmar (+) - (+) - (+) (+)
Nepal ND ND ND ND ND NDSri Lanka + - + (+) (+) (+)Thailand + + + + + +Thailand + + + + + +
Timor-Leste ND ND ND ND ND ND
Thalassemia treatment available in different SEARO countries
Country Blood Transfusion
IronChelation
BM/Stem cell
Transplant
PND NationalProgram
DFO L1 ExjadeBangladesh (+) (+) (+) (+) - - -
Bhutan ND ND ND ND ND ND NDBhutan ND ND ND ND ND ND NDDPR Korea ND ND ND ND ND ND ND
India (+) (+) + + (+) (+) (+)Indonesia (+) (+) (+) (+) - (+) -Maldives + + + + - + +Myanmar (+) (+) + (+) - - -y ( ) ( ) ( )
Nepal ND ND ND ND ND ND NDSri Lanka + + + + - - (+)Th il d ( )Thailand + + + (+) + + +
Timor-Leste ND ND ND ND ND ND ND
Treatment of Thalassemia
1. Conventional Treatment- Blood Transfusion- Iron Chelation
2. Treatment of ComplicationI f ti- Infections
- Heart Failure etc.
2 l bi S i l i2. Hemoglobin F Stimulation4. Cure
- Bone Marrow and Stem CellsTransplantationTransplantation
- Gene Therapy
Estimated Direct Cost for the Management of gOne β‐Thalassemia Major for 30 Years: 2006
Items 1‐10 years 11‐20 years 21‐30 yearsItems 1 10 years 11 20 years 21 30 years
1. Blood transfusion plus filter/month
2,500 (1 unit) 5,000 (2 units) 7,500 (3 units)
2. Desferrioxamine Vial/month
5,000 (20 vials) 10,000 (40 vials) 150,000 (60 vials)
H it l 3. Hospital care 1 day/month
2,000 2,000 2,000
4. Other: Lab 1,000 1,000 1,0004tests/month
5. Total cost/month 10,500 18,500 26,500
6. Total cost/year 126,000 222,000 318,000
7. Total cost/10 years 1,260,000 2,220,000 3,180,000
Grand total 6,660,000 Baht (150,000 Euro )
(1 Euro = 44 Baht) (Leelahavarong P et al 2010)
Thalassemia in ThailandThalassemia in Thailand‐Thalassemia (‐thal1 and ‐thal2) 20 ‐ 30%
Hb Constant Spring (�-thal 2 like effect ) 1 ‐ 8%
� Th l i 3 9%�-Thalassemia 3 ‐ 9%
Hemoglobin E 10 ‐ 53%
Total number of thalassemic patients and the number of Total number of thalassemic patients and the number of births per year (total births = 800,000/year)births per year (total births = 800,000/year)
Diseases Couple at risk (per year)
Birth (per year)
Living patients
Homozygous � thalassemia 828 207 2 070Homozygous �-thalassemia 828 207 2,070�-Thalassemia/Hb E 12,852 3,213 96,390Hb Bart,s hydrops fetalis 3332 833 0Hb Bart s hydrops fetalis 3332 833 0Hb H disease 22,400 5,600 336,000
Total 39,412 9,853 434,460, , ,
Modified from Fucharoen S. and Winichagoon P., 1988
Comparison of the cost of treatment and and prevention ofsevere thalassemia in 1000 pregnant women in Thailand
Prevention Expected No. Birth
Treatment(av. life= 30 yrs)
Hb Bart’s hydrops fetus
48,280 B(US$ 1379) 2
42,500 B(US$ 1 214)fetus (US$ 1379) 2 (US$ 1,214)
Beta thalassemic 48,280 B **26,400,000 BDisease* (US$ 1379) 4# (US$ 754,285)
(* include both homozygous beta thalassemia and beta thal/HbE,#1 homozygous beta thalassemia and 3 beta thal/HbE , ** cost per case 6 660 000 B)** cost per case = 6,660,000 B)
C l PC l PControl ProgramControl Program
Strategy
1 • Treatment of Existing Cases
Strategy
1 g
• Prevention Birth of New Cases2 • Prevention Birth of New Cases
Preliminary data on serum ferritin in ADULT and pediatric patients after 6mths of GPO-L-ONE-2
3 mths 6mthsAverage s erum ferritin reduction after 6 mths of DFP
- 57.6 - 20.6- 934 -1260
Pediatrics
Adults-200
01 2 3
Average dose in ped. = 75-80 MKD
Average dose in adult = 50-55 MKD-600
-400
ng/m
L)
-1000
-800SF (n
-1400
-1200
0 3mths 6mths0 3mths 6mths
pediatrics (n=33) adults (n=30)
Prevention of Thalassemia
Screening Counseling
General
Screening Counseling
GeneralPremarital
PreconceptionalPrenatalPostnatal
-Screening test:- MCV/OF- DCIP
-Diagnostic test:- Hb typing- genotyping- DCIP - genotyping
Immunochromatographic Strip Test for -Thalassemia
3 h 4 R d lt1. 0.1 ml. blood
+ hemolysis t
2. Insert strip, leave 2 min.
3. wash 4. Read result
3 minutesagent
Tongsong T, Wanapirak C,Sirivatanapa P, Sanguansermsri T, Sirichotiyakul S, Piyamonkol W, Chanprapaph P.
Prenatal control of severe thalassemia: Chiang Mai strategy
Prenat Diagn 2000; 20: 229-234
Hb Bart’s Hydrops Fetalis
20 191920
11
15 Hydrops
10
23
5
0 0 0 0 00
‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03
Wanapirak C. et al, 2004
New registration for thal majorNew eg s o o jo
6
5
6
4
5
CMU h i l33
CMU hospital
1
2
0 0 0 0 0 0 0 00
ʻ94 ʻ95 ʻ96 ʻ97 ʻ98 ʻ99 ʻ00 ʻ01 ʻ02 ʻ0394 95 96 97 98 99 00 01 02 03Wanapirak C. et al, 2004
New registration for thal/Hb ENew registration for thal/Hb E
77
5 56
7
5 5
4
5 CMU hospital
23
4
1
2
11
2
0 0 0 00
ʻ94 ʻ95 ʻ96 ʻ97 ʻ98 ʻ99 ʻ00 ʻ01 ʻ02 ʻ0394 95 96 97 98 99 00 01 02 03Wanapirak C. et al, 2004
Case Registration (year)g (y )
40CMU MOPH
353130
3540
3126 24 22 22
25 2421
2530
ber
Hb E/beta-thal22 22
1511
21
111520
Num
b Hb E/beta-thalbeta-Thal major
11 9
3
11 10 95 4 35
10
3300
93 94 95 96 97 98 99 00 01 02YearYear
N i l P h P i dNational Program on the Prevention and Control of Thalassemia in Thailand
(Starting: 1994)
University Thalassemia Foundationof Thailandof Thailand
Ministry of Public Health
Thalassemia in Developing Countries1. Many communicable diseases
2. Poverty
Li it d d t f d l k f d t 3. Limited data on frequency and lack of data on economic issue
4. Lack of awareness: government/NGO
5. Ethical, social, religious and legal issues
ELSI and Thalassemia1. Should thalassemia be treated in poor
t ?country?
2 Lack of education2. Lack of education
3. Social and religious issues3 g
4. Government and social policy on PND
5. Lack of regulatory/ethics organization
Global Control of Hemoglobinopathies
1. North-south or north-south-south university partnershipspartnerships
2. Identification of local mutations3. Training and technology transfer4. National control program established5 Future: Regional network to be established5. Future: Regional network to be established
Country Report1 Australia (John Prior)1. Australia (John Prior) 2. Bangladesh (Syed Khairul Amin)3. Cambodia (Sam Vuthy, Robyn Devenish)3. C bod (S Vu y, oby eve s )4. China, Guangxi (Chen Ping)5. China, Hong Kong (Vivian Chan) Prawase Wasi
Mahidol University
6. India (Roshan Colah)7. Indonesia (Iswari Setianingsih)8 Laos (Douangdao Souk Aloun)8. Laos (Douangdao Souk Aloun)9. Malaysia (Elizabeth George) 10. Maldives (Naila Firdous) Sir David Weatherall( )11. Myanmar (Sann Sanda Khin) 12. Singapore (Hai Yang Law)
Oxford University
13. Sri Lanka (Shanthimala de Silva)14. Taiwan (Ching-Tien Peng)15 Thailand (Vichai Tienthavorn)15. Thailand (Vichai Tienthavorn) 16. Vietnam (Lam Thi My)
Alan BittlesEdith Cowan University
ASIAN NETWORK FOR THALASSAEMIA CONTROL
Miracle Grand Hotel
Bangkok, July 2-4, 2005
Organizers:- Thalassemia Research Center, Mahidol University, y- Department of Maternal and Child Health,
Ministry of Public Health, Thailandy ,- Thalassemia Foundation of Thailand
Asian Network for Thalassemia Control
July 4, 2005Miracle Grand HotelBangkok, Thailand
Conclusion:1. We have common problemsp2. Magnitude of problems is not well established in some countries 3. Different levels of knowledge and technologyin member countries4. Heterogeneity of disease severity
Proposed a Twin Center Concept:Bridge countries with knowledge and technology
to the one that just getting start.
Questions:Questions:How to get start? Where is the fund?
Proposes:
1) Set up Regional Working Group on Hemoglobinopathies(RWGH)(RWGH)2) Provides partial support to run the RWGH3) Have a regular annual meeting of the working group, rotate to all member countries4) The annual meeting should be mainly sponsored by local
t ( ith ti l t f SEARO)government (with partial support from SEARO)5) The RWGH can help local organizer (of annual meeting) toorganize education symposium or laboratory workshop fororganize education symposium or laboratory workshop forthe local people (administrators, doctors, technicians, nurses)6) The RWGH will help to develop lab manual (for diagnosis), GCP guidelines, etc.7) The RWGH will help training of personals (doctor, nurse, technicians counselor etc )technicians, counselor etc.)
SEARO should work in collaboration with other regions