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The GBD study predicts that the burden of disease in India will decrease from 338DALYs per thousand population in 1990 to 193 in 2020. This decline will occur dueto a projected decrease in infectious, perinatal and nutritional conditions. Althoughthe total health burden in the population is expected to be lower, the relative burdenfrom NCDs and injuries will increase from 44% in 1990 to 76% in 2020. This distinc-tion is important. NCDs and injuries are more difficult and expensive to prevent andtreat than most infectious, perinatal and nutritional conditions. NCDs tend to bechronic and affect economically active adults, particularly those who are educatedand in key positions in the private and public sectors.

Besides the emergence of NCDs and injuries, the GBD study also predicts a shiftin the proportion of DALY s contributed by each age group. In 1990, adults (45 yearsand older) contributed 18% of the total burden of disease in India. In 2020, this isprojected to increase to 44%.

If the GBD estimates are real and the projections do occur, then the increase ofNCDs and injuries and the shift towards disease burden among adults and the elderlyare likely to pose serious challenges to the health care system in India. A broad rangeof therapeutic and preventive interventions will be required to cope with theseemerging problems as well as the lingering burden of infectious, perinatal andnutritional conditions. However, several questions remain. How likely are calcula-tions made on a global level predictive of real occurrences on a local level? Whichspecific conditions are of greatest burden to the population? What are the importanthealth differences between regions in the country? If cardiovascular and neuropsy-chiatric disorders are truly on the rise in India, what are the risk factors amenable tointervention?

Despite the complex and rigorous methods used in the GBD study, the dataremained best-guess estimates and projections. The challenge will be to substantiatethese estimates and projections using national epidemiological assessments. Thefindings from the GBD study are provocative and likely to give rise to debate. I believeits greatest strength is not the actual numbers but its potential to induce policy-makersto think about burden of disease, collate national data to determine priority areas anddevelop possible cost-effective responses.

JACQUELINE L. DEEN

Medical Research CouncilFarafenni Field Station

BanjulThe Gambia

The Challenge of Haemoglobinopathies in IndiaInherited haemoglobinopathies, which include thalassaemia and sickle-cell disease,are major public health problems especially in the Mediterranean area, Middle East,Indian subcontinent, Far East and tropical Africa. It has been estimated that about 205million people are heterozygous for these disorders and at least 300 000 lethallyaffected homozygotes are born annually throughout the world.'

Beta-thalassaemia is the commonest single gene disorder in India. The prevalenceofthe p-thalassaemia gene varies in different populations (between 1% and 17%, witha mean of about 3.3%).2 Certain communities such as the Punjabis (who migratedfrom Pakistan), Sindhis, Bengalis (particularly E p-thalassaemia), Gujaratis,Bhanusahlis and Jains have a higher frequency of p-thalassaemia. The sickle-cellgene is commonly found in certain tribes of Madhya Pradesh, Maharashtra, Orissa,Gujarat and Kerala.v' The carrier frequency is astonishingly high (up to 30%) in someareas.' Alpha-thalassaemia has not been studied extensively in India but its frequency

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is reported to be high among tribal groups.' Its interaction with ~-thalassaemia and thesickle-cell gene is of interest because of its disease-modifying effects.

Bone marrow transplantation (BMT) is the only specific treatment for thesedisorders. However, the non-availability of HLA-identical donors, lack of expertiseand the high cost of tests and treatment are major prohibitive factors for BMT in India.Cord blood transplantation, though promising, is still under trial. Therefore, mostpatients are managed symptomatically. The cost of optimal management for a childwith ~-thalassaemia including regular blood transfusions, chelation therapy, investi-gations, hospitalization and specific vaccines is approximately Rs 125 000 perannum, not an affordable amount by most Indian families. The result is irregulartransfusions without chelation therapy, leading to complications of iron overload andearly death. Patients with sickle-cell disease do not require transfusions but aredisabled due to severe pain as a result of vaso-occlusive episodes and susceptibilityto infections. Splenic sequestration, haemolytic and aplastic crises may be 1ife-threatening. They require antibiotic prophylaxis, specific immunizations and fre-quent hospitalization.

The major impetus of managing these disorders currently is prevention by hetero-zygote screening, counselling and prenatal diagnosis. Preventive programmes basedon heterozygote detection and counselling alone (before the availability of foetaldiagnosis) have not been effective.' In contrast, preventive programmes based onscreening, counselling and prenatal dignosis have been highly effective.v' Selectionoflife partners based on heterozygous status is probably not feasible and too personalfor any intervention.

Carrier screening, though a key step in prevention of haemoglobinopathies, is adifficult task. The options available are screening of school/college-going students,high-risk communities, couples before or after marriage, inductive screening (screen-ing relatives of known carriers) and antenatal screening. The first three options are notfeasible in India due to socio-cultural (stigmatization of carriers, particularly girls)and economic problems. Inductive screening is acceptable in India and is beingpractised to some extent. In Sardinia, inductive screening led to identification of mostcouples at risk by screening only 11% of the population of child-bearing age." Themost feasible option in India is perhaps antenatal screening of mothers in earlypregnancy and testing the spouse, if the carrier status is confirmed. The utility is againlimited by the fact that in India only a small number of pregnant mothers attendantenatal clinics during pregnancy. A combination of antenatal and inductive screen-ing would probably be the most fruitful strategy in India.

Apart from when to screen, how to screen is also an important issue. Haemoglobinelectrophoresis is a definitive test for haemoglobinopathies except for silent ~-thalas-saemia carrier status. The test is too expensive for mass screening programmes.Simple screening tests need validation for routine use. Tests such as naked eye singletube osmotic fragility test (NESTROFf) and red cell indices have been found to bevery sensitive with a high negative predictive value.":" Experience of field-basedmass screening has also been promising." Some authors, however, suggest that itneeds further validation and refining." The utility of NESTROFf in other haemo-globinopathies is an added advantage." In our own experience of screening antenatalmothers, NESTROFf was found to have a sensitivity, specificity, positive predictivevalue and negative predictive value of91.5%, 95.4% 54.6% and 99.5%, respectively,taking HbA2 as the gold standard (Indian Council of Medical Research study,unpublished data). NESTROFf is an inexpensive test and can be used for massscreening. Positive and doubtful cases can be taken up for confirmatory tests. Red cellindices (low MCV and MCH) using electronic cell counters are also useful for carrierdetection. Combining red cell indices and NESTROFf would yield better results butroutine estimation of red cell indices is expensive" (Indian Council of MedicalResearch study, unpublished data). Molecular genetic tests for carrier detection willnot be cost-effective and should be reserved only for couples desiring prenataldiagnosis.

The article by S. Balgir in this issue deals with various options for in-depth

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heterozygote screening and suggests implementation strategies. 16 He rightly empha-sizes that the only option to reduce the burden of haemoglobinopathies in India isthrough carrier detection and prenatal diagnosis.

Very few centres in India have good experience of prenatal diagnosis. Foetaldiagnosis is being made on chorionic villus samples (CVS) using DNA-based testsand on cord blood samples by globin chain synthesis. Early prenatal diagnosis onCVS using DNA technology has been found to be very promising." Most centres areproviding prenatal diagnostic facilities to families with an affected child. Formalcarrier screening programmes do not function continuously, though short termproject-based experience has shown encouraging results (Indian Council of MedicalResearch study, unpublished data).

There have been no formal preventive programmes for sickle-cell disease in India,though many authors working in tribal areas have highlighted this problem. Ourcentre is presently conducting a large project for carrier detection, counselling andprenatal diagnosis of sickle-cell disease in the Wyanad district of Kerala where, insome areas, the carrier rate is as high as 30%. Community education through govern-mental and non-governmental agencies is a major component of the project. A similarapproach to reduce the burden of sickle-cell disease by carrier detection and prenataldiagnosis has been reported recently from Africa. 18

Implementing heterozygote screening and prenatal diagnosis on a nationwidebasis would require community education, creating awareness amongst paediatri-cians, obstetricians and peripheral health workers. They have a key role in counsellingand implementing carrier screening programmes. Three main messages that need tobe propagated are:

1. The carrier state has no disadvantage.2. The homozygous state is very severe and fatal.3. Prenatal diagnosis is available and safe.

Community education involving health professionals propagating these threemessages has been found to be of immense benefit in Sardinia, Cyprus and Greece. 19

An essential prerequisite before starting the awareness campaign on a war footingis to create adequate facilities to meet the gigantic demand for heterozygote screeningand prenatal diagnosis of haemoglobinopathies. Peripheral centres should be able toscreen couples at risk and refer them to tertiary centres. The handful of tertiary centresthemselves need strengthening and more centres should come forward to share theworkload.

The success of the prevention programme will depend entirely on the combinedefforts of health professionals, governmental and non-governmental organizationsand, above all, the people who need these services.

REFERENCESAngastiniotis M, Modell B, Englezos P, Boulyzhenkov V. Prevention and control of hemoglobinopathies. BullWorld Health Organ 1995;73:375-86.

2 Modell B, Boulyzhenkov V. Distribution and control of some genetic disorders. World Health Stat Q 1988;41:209-18.Roshan C. Prevalence of red cell genetic defects among tribals and their prevention. In: Singh B, Neeti MahantiPG (eds), Tribal health in India. (Tribal studies on India Series T 73). New Delhi:lnterindia, 1995:194-8.

4 Kaur M, Das GP, Verma IC. Sickle cell trait and disease among tribal communities in Orissa, Madhya Pradeshand Kerala. Indian J Med Res 1997;105:111-16.

5 Barai IV. Assessment of prospective genetic counselling in the Ferrare Area. Am J Med Genet 1990;6: 195-209.6 Cao A. Results of programmes for antenatal detection of thalassemia in reducing the incidence of the disorder.

Blood Rev 1987;1:169-76.7 Cao A, Rosatelli C, Galanello R. Population-based genetic screening. Curr Opin Genet Dev 1991;1:48-53.8 Cao A, Rosatelli C, Galanello R, Monni G, Olla G, Cossu P, et al. The prevention of thalassemia in Sardinia. Clin

Genet 1989;36:277-85.9 Thomas S, Srivastava A, Jeyaseelan L, Donnison D, Chandy M. NESTROFT as a screening test for the detection

of thalassaemia and common hemoglobinopathies: An evaluation against a high performance liquid chromato-graphic method. Indian J Med Res 1996;104:194-7.

IO Kattamis C, Efremov G, Pootrakul S. Effectiveness of one-tube osmotic fragility screening in detecting G-thalassaernia trait. J Med Genet 1981;18:266-70.

II Mehta BC, Gandhi S, MehtalB, Kamath P. Naked eye single-tube red cell osmotic fragility test for G-thalassemia:Population survey. Indian J HematoI1988;6:187-90.

12 Gorakshaker AC, Colah R, Nadkarni A, Desai S. Evaluation of the single-tube osmotic fragility test in detectionof B-thalassaemia trait. Natl Med J India 1990;3: 171-3.

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13 Raghavan K, Lokeshwar MR, Birewar N, Nigam V, Manglani MV, Raju NB. Evaluation of naked eye single-tubered cell osmotic fragility test in detecting B-thalassaemia trait. Indian Pediatr 1991;28:469-72.

14 Manglani MV, Lokeshwar MR, Vani VG, Bhatia N, Mhaskar V. NESTROFT. An effective screening test for beta-thalassemia trait. Indian Pediatr 1997;34:702-7.

15 Chouhan OM, Chouhan V. Epidemiology of thai as semi as. Indian J Hemal Blood Trans 1992;10:1-6.16 Balgir S. Control and prevention of the genetic load of haemoglobinopathies in India. NaIL Med J India 1999;

12:234-8.17 Saxena R, Jain PK, Thomas E, Verma IC. Prenatal diagnosis of beta-thalassemia: Experience in a developing

country. Prenat Diag 1998;18:1-7. .18 Akinyanju 00, Oisu RF, Akinde JA, Adewole TA, Otaigbe AI. Emuveyan EE. Initiation of prenatal diagnosis

of sickJe cell disorders in Africa. Prenat Diag 1999;19:299-304.19 Cao A, Rosatelli C. Screening and prenatal diagnosis of the hemoglobinopathies. Clin HematoI1993;6:264-88.

MADHULIKA KABRA

P. S. N. MENON

Genetic UnitDepartment of Paediatrics

All India Institute of Medical SciencesNew Delhi

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