Piel, FB

Weatherall, DJ

Transactions of the Royal Society of Tropical Medicine and Hygiene

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PubMed

Frédéric B. Piel

David J. Weatherall

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Sickle-cell disease: a call to action

Spiral - Imperial College Digital Repository

Sickle-cell disease: a call to actionFrédéric B. Piela,* and David J. WeatherallbaDepartment of Zoology, University of Oxford, Oxford, OX1 3PS, UK; bMRC Molecular Haematology Unit,Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK*Corresponding author: Tel: +44 1865 271 132; E-mail: fred.piel@zoo.ox.ac.ukReceived 27 February 2015; revised 20 April 2015; accepted 20 April 2015Keywords: Genetic disorder, Health burden, Haemoglobinopathies, Sickle-cell anaemia, World Sickle Cell DayThe inherited disorders of haemoglobin are the commonestmonogenic diseases. It has been estimated that over 300 000babies are born each year with one of these conditions, eithersickle-cell disease or severe forms of thalassaemia.1 Normaladult haemoglobin (HbA) consists of two a- and two b-globinchains (a2b2), each with an associated heme group, which areregulated by duplicated HBA1 genes and a single HBB gene,respectively. Sickle-cell haemoglobin (HbS) results from a singlepoint mutation at position 6 in the HBB gene that causes the sub-stitution of glutamic acid for valine in the b-globin chain. In con-ditions of reduced oxygen tension, this leads to polymerisation, achange of shape of the red blood cells, and hence to chronicanaemia, acute painful crises due to blockage of small vessels,and often to progressive damage to multiple organs, includingthe brain, kidneys, lungs, bones and the cardiovascular system.2These complications are almost entirely restricted to those withsickle-cell anaemia, i.e., individuals who have inherited the sickle-cell mutation from both parents (SS); heterozygous carriers, whohave inherited a single copy of the gene (AS), are asymptomatic,except in conditions of exceptional hypoxia.While the clinical severity of sickle-cell disease has been clearlydescribed, its clinical course can be extremely variable and diffi-cult to anticipate.3 This is true for sickle-cell anaemia, as well asfor other sickle-cell disorders such as HbSC disease or HbSb-thalassaemia, and has important implications for the develop-ment of procedures for the prevention and treatment of these dis-orders. Although a few genes have been identified as modifiers ofthe clinical course of sickle-cell disease, much work remains to bedone in this important field. In contrast, the sickle-cell trait (AS)offers a very high degree of protection against infection withPlasmodium falciparum malaria.4 Recently, however, althoughthis observation has been widely confirmed, it has been foundthat parasite-infected blood from sickle-cell heterozygotes isseveral times more infectious to the Anopheles vector than thatof normal subjects.5 This suggests, of course, that the advantageof HbS heterozygotes is not only balanced by the cost of potentialhomozygous offspring but also by that of increased malaria trans-mission to the general population.There is still some doubt about the origins of the sickle-cellmutation and where it arose for the first time. Although thehypothesis of five independent origins, four in sub-SaharanAfrica (named Bantu, Benin, Cameroon and Senegal) and one inthe Middle East and India (Arab-India) is almost universallyaccepted, both early and recent work supported the alternativehypothesis of a single origin.6,7 Significant differences in thelevel of foetal haemoglobin (HbF) between the sub-SaharanAfrican haplotypes and the Asian might suggest that the sickle-cell mutation has arisen at least twice. While the Arab-Indiahaplotype is usually described as associated with a milder clinicalcourse of the disease, growing evidence indicates that its severitymight have been underestimated.8,9Sickle-cell disease is highly prevalent in sub-Saharan Africa,and parts of the Mediterranean region, the Middle East and theIndian subcontinent. Estimates suggest that 75% of annual con-ceptions with sickle-cell anaemia occur in sub-Saharan Africa anddemographic projections support the fact that this share is likelyto grow further in coming decades.10 The sickle-cell mutation waslater spread to the Americas and western Europe through thetrade of African slaves, and over recent decades to most countriesworldwide due to increasing international movements. Universalnewborn screening programmes were implemented more than adecade ago in the UK and across all states in the USA.11Meanwhile, the implementation of such national programmeshas not been possible in any African country, nor in India (despiterecent progress, especially in the States of Gujarat, Maharashtraand Chhattisgarh), where they would have had the most impact.# The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.EDITORIALTrans R Soc Trop Med Hyg 2015; 109: 355–356doi:10.1093/trstmh/trv035355 at Imperial College of Science Technology and Medicine on June 24, 2016http://trstmh.oxfordjournals.org/Downloaded from Clearly, much work requires to be done towards the preventionand management of sickle-cell disease. As regards to early man-agement, neonatal screening followed by prophylactic vaccin-ation and antibiotics has led to a dramatic decrease in themortality in early life in many high-income countries.12 There isnow increasing evidence that a similar approach would be ofgreat value in low- and middle-income countries.13 Regardingprenatal diagnosis and termination of pregnancy, this has beenmuch less widely applied than in the case of thalassaemia. Atleast in part, this is undoubtedly due to the ethical difficulties ofcounselling due to uncertainties about the future clinical courseof any particular patient. Clinical trials of hydroxyurea have nowshown that the drug is of definite value both in adult and paedi-atric populations.14 Bone marrow transplantation has also beenfairly limited for this disease, partly because of the paucity ofdonors and again because of the risks involved and the uncertain-ties in the prognosis for the disease. Nevertheless, there have beengenuine improvements in the management of sickle-cell diseaseand it is critical that these approaches become available to thelow- and middle-income countries.Although WHO recognised sickle-cell disease as a worldwidepublic health issue in 2006 and a resolution on the preventionand management of birth defects, including those resultingfrom sickle-cell disease, was adopted a couple of years later atthe 63rd World Health Assembly, a public health agenda to pre-vent and control this disease is still lacking in most countries ofhigh prevalence. As recently highlighted for infectious diseasessuch as Ebola and HIV, there is an urgent need for better health-care systems in low- and middle-income countries, particularly insub-Saharan Africa. While events and celebrations organised forthe World Sickle Cell Day on 19 June will hopefully contribute toraise awareness about this disease, such overall improvementsin public health access and care are a prerequisite to improvethe survival and quality of life of patients with sickle-cell diseasein tropical regions.Authors’ contributions: FBP and DJW conceived, wrote and revised thepaper, and read and approved the final manuscript. FBP and DJW areguarantors of the paper.Acknowledgements: The authors thank Carinna Hockham for usefulcomments on an earlier version of this manuscript and Liz Rose for helpin preparing this manuscript.Funding: FBP is funded by the Department of Zoology, University of Oxford,Oxford, UK. DJW is funded by the Medical Research Council, WellcomeTrust, and the Anthony Cerami and Ann Dunne Foundation for WorldHealth.Competing interests: None declared.Ethical approval: Not required.References1 Weatherall DJ. The inherited diseases of hemoglobin are an emergingglobal health burden. Blood 2010;115:4331–6. doi:10.1182/blood-2010-01-251348.2 Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376:2018–31. doi:10.1016/s0140-6736(10)61029-x.3 Steinberg MH. Predicting clinical severity in sickle cell anaemia. Br JHaematol 2005;129:465–81. doi:10.1111/j.1365-2141.2005.05411.x.4 Allison AC. Protection afforded by sickle-cell trait against subtertianmalareal infection. Br Med J 1954;1:290–4.5 Williams TN, Weatherall DJ. World distribution, population genetics,and health burden of the hemoglobinopathies. Cold Spring HarbPerspect Med 2012;2:a011692. doi:10.1101/cshperspect.a011692.6 Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of thehaemoglobinopathies. Baillieres Clin Haematol 1993;6:215–62.7 Bitoungui VJ, Pule GD, Hanchard N et al. Beta-globin gene haplotypesamong cameroonians and review of the global distribution: is therea case for a single sickle mutation origin in Africa? OMICS 2015;19:171–9. doi:10.1089/omi.2014.0134.8 Alsultan A, Alabdulaali MK, Griffin PJ et al. Sickle cell disease in SaudiArabia: the phenotype in adults with the Arab-Indian haplotype isnot benign. Br J Haematol 2014;164:597–604. doi:10.1111/bjh.12650.9 Italia K, Kangne H, Shanmukaiah C et al. Variable phenotypes of sicklecell disease in India with the Arab-Indian haplotype. Br J Haematol2015;168:156–9. doi:10.1111/bjh.13083.10 Piel FB, Hay SI, Gupta S et al. Global burden of sickle cell anaemia inchildren under five, 2010–2050: modelling based on demographics,excess mortality, and interventions. PLoS Med 2013;10:e1001484.doi:10.1371/journal.pmed.1001484.11 Piel FB, Patil AP, Howes RE et al. Global epidemiology of sicklehaemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 2013;381:142–51.doi:10.1016/S0140-6736(12)61229-X.12 Gaston MH, Verter JI, Woods G et al. Prophylaxis with oral penicillin inchildren with sickle cell anemia. A randomized trial. N Engl J Med1986;314:1593–9. doi:10.1056/nejm198606193142501.13 Williams TN, Uyoga S, Macharia A et al. Bacteraemia in Kenyan childrenwith sickle-cell anaemia: a retrospective cohort and case-control study.Lancet 2009;374:1364–70. doi:10.1016/s0140-6736(09)61374-x.14 Mulaku M, Opiyo N, Karumbi J et al. Evidence review of hydroxyurea forthe prevention of sickle cell complications in low-income countries.Arch Dis Child 2013;98:908–14. doi:10.1136/archdischild-2012-302387.F. B. Piel and D. J. Weatherall356 at Imperial College of Science Technology and Medicine on June 24, 2016http://trstmh.oxfordjournals.org/Downloaded from 

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