BMJ  2005;330:432-433 (26 February), doi:10.1136/bmj.330.7489.432

Editorial

Mortality from sickle cell disease in Africa

Interventions used to reduce mortality in non-malarial areas may be inappropriate

After the first description of sickle cell disease in a Grenadian dental student in Chicago in 1910, subsequent reports indicated that the disease was confined to people of African origin. Over the next 40 years, the clinical features were recorded in Americans, but it was not until the late 1940s that reports began to appear from Africa itself. These documented the high prevalence of the sickle cell trait throughout equatorial Africa and its geographical coincidence with the distribution of Plasmodium falciparum malaria. Studies from west, east, and central Africa showed that individuals with the sickle cell trait had a relative protection against malaria during a critical period of early childhood. This was believed to offset the loss of sickle cell genes from the high mortality of homozygotes, illustrating the concept of balanced polymorphism. Although the sickle cell trait may have a survival advantage in malarial areas, the occurrence of malaria in homozygous sickle cell (SS disease) is almost certainly a major determinant of morbidity and mortality. The interaction of malaria with SS disease is likely to change many of the features of the disease and casts serious doubt on the relevance of interventions developed in non-malarial areas.

This may be illustrated by two interventions shown to reduce mortality in non-malarial areas. The early loss of splenic function in patients with SS disease renders them prone to overwhelming septicaemia especially in early childhood, 85-90% of which is due to Streptococcus pneumoniae.¹ Pneumococcal prophylaxis reduces morbidity and mortality^{2 3} and is now routine in the management of severe sickle cell syndromes. There is now pressure to implement similar prophylaxis for African patients, but what do the data show? Early reports from the then Belgian Congo and from Nigerian adults noted a high prevalence of S pneumoniae.^4-5 However, more recent studies of children with septicaemic sickle cell disease in Nigeria^6-8 and Uganda (Monica Etima, personal communication, 2004) have found that less than 10% of septicaemias were due to this organism and that septicaemia due to Staphylococci, Escherichia coli, Salmonella, and Klebsiella predominated.

S pneumoniae did not occur in any of 19 patients with bacteraemia in Lagos⁶ and was seen in only one among 54 patients in Benin City.⁷ Nor did it occur among 304 children admitted with acute illness in Kaduna,⁸ although the organism was isolated from the cerebrospinal fluid in three children. The most recent study in Uganda identified a bacterial cause in 55 patients of which S pneumoniae accounted for only two patients. That African patients with SS disease are less prone to infection with S pneumoniae seems inherently unlikely. Possible interpretations for the low occurrence of this organism include death of affected patients before reaching hospital, the widespread use of over the counter penicillin, or the intriguing possibility that malarial infection prolongs splenic function.⁸ Are we then to ignore these data and persuade governments to invest limited resources in pneumococcal prophylaxis, or is this a situation in which a clinical trial is required? If limited blood culture or bacteriological facilities threaten to compromise such a trial, the clinical data alone from a well designed study could provide justification for the costs of prophylaxis.

The other intervention significantly reducing mortality in the Jamaican cohort study was early parental diagnosis of acute splenic sequestration,⁹ but is this applicable to malarial areas? The presence of malaria might modify the splenic involution typical of patients with SS disease in non-malarial areas, and data on prevalence or natural history of acute splenic sequestration in patients with SS disease in malarial areas are unavailable.

These two examples illustrate the difficulties of transferring successful interventions from non-malarial to malarial environments, and emphasise the need to document the interactions of malaria with sickle cell disease. Who is going to do this? There are many excellently trained African clinicians, but they carry huge clinical loads and may have limited training and facilities for clinical research. In more developed areas, much clinical and research expertise exists, but mechanisms must be found for bringing these to the service of our African colleagues in effective collaborations.¹⁰ Without such help, African patients will continue to die young from sickle cell disease, interventions developed in non-malarial areas may be inappropriately applied, and the major needs of African patients remain undocumented.

Median survival for patients with SS disease in North America, Europe, and the Caribbean is now estimated to be 45-55 years.^{11 12} No figures are available for patients in the African continent, but it is likely to be less than five years. We cannot yet cure sickle cell disease, but we have learnt that simple interventions significantly improve morbidity and mortality. We need to extend these benefits to African patients urgently.

Sickle Cell Trust (Jamaica), 14 Milverton Crescent, Kingston 6, Jamaica, West Indies (grserjeant{at}cwjamaica.com)

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Competing interests: None declared.

References

1. Barrett-Connor E. Bacterial infection and sickle cell anemia. Medicine 1971;50: 97-112.[Medline]
2. John AB, Ramlal A, Jackson H, Maude GH, Sharma AW, Serjeant GR. Prevention of pneumococcal infection in children with homozygous sickle cell disease. BMJ 1984;288: 1567-70.
3. Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986;314: 1593-9.[Abstract]
4. Eeckels R, Gatti F, Vandepitte J, Debroise A. Susceptibility to severe infections in children with sickle-cell haemoglobinopathies. Proceedings of the 5th International Congress on Infectious Disease, Vienna 1970: 267-71.
5. Maharajan R, Fleming AF, Egler LJ. Pattern of infections among patients with sickle-cell anaemia requiring hospital admissions. Nig J Paediatr 1983;10: 13-7.
6. Akinyanju O, Johnson AO. Acute illness in Nigerian children with sickle cell anaemia. Ann Trop Paediatr 1987;7: 181-6.[ISI][Medline]
7. Okuonghae HO, Nwankwo MU, Offor EC. Pattern of bacteraemia in febrile children with sickle cell anaemia. Ann Trop Paediatr 1993;13: 55-64.[ISI][Medline]
8. Akuse RM. Variation in the pattern of bacterial infection in patients with sickle cell disease requiring admission. J Trop Pediatr 1996;42: 318-23.[Abstract/Free Full Text]
9. Emond AM, Collis R, Darvill D, Higgs DR, Maude GH, Serjeant GR. Acute splenic sequestration in homozygous sickle cell disease: natural history and management. J Pediatr 1985;107: 201-6.[CrossRef][ISI][Medline]
10. Weatherall DJ. A New Year's resolution after a lost decade. BMJ 2003;327: 1115-6.[Free Full Text]
11. Platt OS, Brambilla BJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330: 1639-44.[Abstract/Free Full Text]
12. Wierenga KJJ, Hambleton IR, Lewis NA. Survival estimates for patients with homozygous sickle-cell disease in Jamaica: a clinic-based population study. Lancet 2001;357: 680-3.[CrossRef][ISI][Medline]

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