Hindawi Publishing Corporation
The Scientific World Journal
Volume 2013, Article ID 193252, 16 pages
http://dx.doi.org/10.1155/2013/193252
Review Article
Sickle Cell Disease: New Opportunities and Challenges in Africa
J. Makani,1,2 S. F. Ofori-Acquah,3,4 O. Nnodu,5 A. Wonkam,6,7 and K. Ohene-Frempong8
1 Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences,
P.O. Box 65001, Dar es Salaam, Tanzania
2Nuffield Department of Medicine, University of Oxford, Oxford, UK
3Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
4 School of Allied Health Sciences, College of Health Sciences, University of Ghana, Ghana
5Department of Haematology and Blood Transfusion, College of Health Sciences, University of Abuja, Abuja, Nigeria
6Division of Human Genetics, Faculty of Heath Sciences, University of Cape Town, South Africa
7 Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Cameroon
8Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Correspondence should be addressed to J. Makani; julie.makani@muhimbili-wellcome.org
Received 23 April 2013; Accepted 9 June 2013
Academic Editors: Y. Al-Tonbary, M. A. Badr, A. El-Beshlawy, A. Mansour, and F. Tricta
Copyright © 2013 J. Makani et al.This is an open access article distributed under theCreative CommonsAttribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sickle cell disease (SCD) is one of the most common genetic causes of illness and death in the world. This is a review of SCD in
Africa, which bears the highest burden of disease. The first section provides an introduction to the molecular basis of SCD and the
pathophysiologicalmechanism of selected clinical events.The second section discusses the epidemiology of the disease (prevalence,
morbidity, and mortality), at global level and within Africa. The third section discusses the laboratory diagnosis and management
of SCD, emphasizing strategies that been have proven to be effective in areas with limited resources.Throughout the review, specific
activities that require evidence to guide healthcare in Africa, as well as strategic areas for further research, will be highlighted.
1. Introduction population specificity of the haplotypes, it is believed that the
sickle cell mutation arose independently in these populations
Sickle cell disease (SCD) consists of a group of disorders char- and remained to this day [4].
acterised by the presence of sickle haemoglobin. Although
over 700 structural hemoglobin (Hb) variants have been 1.1. Normal Human Hemoglobin. Human Hb is encoded by
identified, only two (Hb S, Hb C) reach high frequencies in a cluster of genes located on chromosomes 11 and 16 that
Africa. The common SCD syndromes in this region include are expressed in a developmentally regulated manner. They
homozygous HbSS disease (HbSS) commonly known as are tetramers of two pairs of 𝛼-like and 𝛽-like globin chains.
sickle cell anaemia (SCA) and Hb SC disease. SCD was Adult and fetal hemoglobin have 𝛼𝛽(Hb A, 𝛼 𝛽 ), 𝛿(Hb
known in some parts of Africa before the twentieth century: 2 2A2, 𝛼 𝛿 ), or 𝛾 chains (Hb F, 𝛼 𝛾 ), whereas in the embryo,
inhabitants of western Africa gave the disease-specific names 2 2 2 2𝛼-like chains—termed 𝜁 (Hb Portland, 𝜁 𝛾 ) or 𝜀 𝜁 𝜀 —and
that evoke acute, painful episodes or death or refer to children 𝛾 2 2 2 2𝛼 and 𝜀 chains form Hb Gower 2 (𝛼 𝜀 ) (Figure 1) [5].
destined to die and to be reborn as their own siblings [1, 2]. 2 2Embryonic hemoglobin production is confined to the
Africa is the major origin of the sickle (𝛽S) mutations [3]. yolk sac. Thereafter the major site of synthesis is the fetal
There are four chromosomal haplotypes that are associated liver. HbF is the predominant type of hemoglobin in fetal life,
with the 𝛽S mutation. They are named after the regions but around birth there is a switch from fetal to adult globin
where they have the highest frequency: Benin, Senegal, gene expression, when HbF is gradually replaced by adult
Bantu (Central African Region (CAR)), and Arab-Indian. hemoglobin, such that by 6 months of age the major Hb is
The haplotypes are defined by restriction fragment length HbA (𝛼 𝛽 ). Residual amounts of HbF, however, continue to
2 2
polymorphisms (RFLPs) in the 𝛽-globin locus. Due to the be synthesized throughout adult life, and the amounts vary
2 The Scientific World Journal
Chromosome 11
𝛽-LCR
5 4 3 2 1
𝜀 G𝛾 A𝛾 𝜓𝛽 𝛿 𝛽
Cell
type Megaloblast Macrocyte Normocyte
Site of Liver Bone marrow
erythropoiesis
50 Yolk sac Spleen
𝛼
40 𝛾 𝛽
30
20 𝜀
10 𝜁 𝛽
𝛾
6 12 18 26 30 36 1 6 12 18 24 30 36 42 48
Post-conceptual age (weeks) Birth Postnatal age (weeks)
Chromosome 16
HS-40
5
𝜁2 𝜓𝜁1 𝜓𝛼2 𝜓𝛼1 𝛼2 𝛼1 𝜃
Figure 1: Developmental control of human haemoglobin (Hb) expression [6].
considerably, with the majority of adults having less than 1% pathogenesis of the various clinical events, both acute and
HbF. chronic, results from a series of complex mechanisms which
are not limited to theRBC [7].These relate to concentration of
1.2. Pathophysiology of Clinical Events. Sickle haemoglobin HbS and other haemoglobin variants such as HbF within the
(HbS) results from a substitution of one amino acid (Valine) cell which reduces its ability to polymerise [8], disturbances
for another amino acid (Glutamic acid) at position six of the in the red cell membrane making the cell less responsive
𝛽-globin polypeptide chain. This substitution is caused by a to oxidant stress, and altered membrane lipids resulting in
single-base mutation in codon 6 within the 𝛽-globin gene on increased rigidity [9–11]. Additionally, adhesion molecules
chromosome 11, where the sequence GAG occurs instead of such as integrins (𝛼 𝛽 ), (𝛼V𝛽 ), their receptors (VCAM-4 1 3
GTG. 1, ICAM-4), selectins interact with endothelial cells, RBC,
Due to the abnormal amino acid in the 𝛽-globin chain, and a variety of soluble proteins within the plasma, such
HbS forms long, insoluble polymers when deoxygenated, as thrombospondin (from platelets) and von Willebrand
and the red blood cells (RBCs) containing HbS become factor from endothelial cells to mediate vasoocclusion within
less deformable and form a “sickle” shape. It was previously the macro- and microvasculature [12–16]. Finally there is
thought that the clinical consequences were simply due to compelling evidence of the role of nitric oxide (NO) in
this abnormal, rigid sickle red blood cell occluding small SCD [17]. NO is a potent regulator of basal vasodilator
blood vessels. However, there is increasing evidence that the tone. It also inhibits the expression of cellular adhesion
Total globin synthesis
(%)
The Scientific World Journal 3
Neurological
Stroke
Haematology Cognitive disability
Haemolytic anaemia Retinopathy
RBC aplasia
Chest
Abdomen Infection/infraction
Cholelithiasis Pulmonary hypertension
Renal disease
Vasoocclusion Infection
Splenic sequestration Malaria
Painful crises (abdominal, bone) Bacterial infections
Ulcers
Priapism Osteomyelitis
Figure 2: Selected clinical consequences of SCD.
molecules [18]. The increase in haemolysis in SCD results described in SCD and is a significant cause of mortality [20].
in an excess of haemoglobin in the plasma, which exceeds Anaemia may be secondary to infections such as malaria,
the scavenging capacity of haptoglobin. The result is that bacterial and viral diseases. Of the latter, RBC aplasia in
there is abnormal “cell-free” haemoglobin, which circulates the bone marrow has been notably described and has been
in plasma, binding to and consuming NO, so causing a associated with infection with parvovirus serotype B19 [21].
reduction in the concentration of NO [19]. This results
in vasoconstriction, increased adhesiveness of erythrocytes, 3. Vasoocclusion
leukocytes and endothelial cells, and platelet aggregation.
Vasoocclusion (VOC) is thought to be the underlying cause
1.3. Clinical Events in SCD. Although SCD stems from an of painful crises, acute splenic sequestration, and priapism
abnormality of the RBC, it is essentially a multisystem (painful and prolonged penile erection). Painful crises, con-
disorder, affecting almost every organ system of the body, as sidered the hallmark of SCD, are defined as severe pain
shown in Figure 2. The clinical consequences can be divided lasting for 2 or more hours that is attributable to SCD. The
into 4 groups: haemolysis and haematological complications, sites that are normally affected include the arms, legs, back,
vasoocclusion, infection, and organ dysfunction. abdomen, chest, and head. Painful crises do not include other
causes/types of pain in SCD such as dactylitis, acute chest
syndrome, right upper quadrant syndrome, osteomyelitis,
2. Haemolysis and Haematological and appendicitis. It is the most common cause of hospitali-
Complications sation and frequent pain (defined as 2 or more painful events
a year for three years) is associated with poor quality of life
At birth, individuals with SCD do not have anaemia, but with and increased risk of death [22].
the synthesis of adult Hb, they develop chronic haemolytic
anaemia that is present throughout life. This may be inter- 4. Infection
spersed with acute episodes of reduction in haemoglobin
“anaemic crises”. Hyperhemolysis crises are defined by a Individuals with SCD are reported to be susceptible to
sudden fall in steady state haemoglobin accompanied by infections with encapsulated organisms such as Streptococcus
increased reticulocytosis and exaggerated hyperbilirubine- pneumoniae [23–25]. The use of oral penicillin in the USA
mia. The chronic haemolysis in SCD may result in gall had a significant impact on reduction in mortality [26],
bladder disease due to high levels of bilirubin. Although the and it is now policy in many high-income countries to
main cause of anaemia in SCD is chronic haemolysis, there give penicillin prophylaxis and antipneumococcal vaccina-
are other types of anaemia that may occur. Acute splenic tion to SCD patients [27]. It was previously thought that
sequestration, when there is rapid onset of trapping of red the situation in Africa may be different. Aside from the
blood cells in the spleen, is characterised clinically by a fact that the data regarding the clinical spectrum of SCD
sudden increase in splenic size, at least 2 cm below the left are limited, there was controversy regarding the role and
coastal margin, accompanied by a reduction in haemoglobin significance of pneumococcal disease in causing morbidity
or haematocrit by 20% of baseline level. This has been and mortality in SCD in this setting [28]. However, there is
4 The Scientific World Journal
emerging evidence to confirm that pneumococcal disease is Table 1: Clinical syndromes and common causative organisms re-
a significant cause of bacteraemia in SCD [29], with calls to ported in SCD.
introduce interventions for preventing infections as a critical
factor in improving survival [30, 31]. The various factors Syndrome Organisms Reference
that are associated with increased infections in SCD may be S. pneumoniae, H. influenza,
directly related or unrelated to the immune system. Some Septicaemia Salmonella spp, E. Coli, S. [28, 29, 50]
infections may be the result of a complication or treatment Aureus, andM. Pneumoniae
of SCD itself. SCD patients are at high risk of transfusion- S. pneumoniae,M.
transmissible infections particularly with human immunod- Pneumonia Pneumoniae,
eficiency virus and viral hepatitis since they receive frequent, Chlamydiae pneumonia
often unplanned emergency blood transfusion (BT) [32– Meningitis S. pneumoniae
35]. This is particularly important in Africa, given the high Salmonella spp., E. Coli, Gram
prevalence of HIV infection and the operational problems Osteomyelitis negative organisms, and S. [37, 51, 52]
in providing adequate blood-transfusion services. Long-term Aureus
BT may result in iron overload, which in itself is associated Aplastic anaemia Parvovirus [21, 38, 39]
with infections due toYersinia Enterocolitica [36]. SCD causes AIDS and Hepatitis HIV Viral hepatitis B,C [32, 33, 53]
end-organ damage to the lung, liver, kidney, and skin,making
Abdominal pain Helicobacter pylori, Yersiniathese sites susceptible to infection by unusual organisms. In enterocolitica [36]
addition, skeletal complications, poor perfusion, and blood
supply to bone tissue are also thought to contribute to
increased susceptibility to infections of the bone, osteomyeli- in failure of SCD patients to phagocytose invading organ-
tis, which is often due to salmonella infections [37]. Other isms, particularly Streptococcus pneumoniae. The distinction
factors include high bone marrow turnover due to chronic between factors directly related to the immune system or not
haemolysis which results in increased susceptibility to viral is somewhat arbitrary as there is a lot of overlap between the
infection. Parvovirus B19 infections are one of the viral various factors. Although there have been reports of different
infections that predispose to poor outcome with erythrocytic patterns of infections in patients with SCD, summarised in
aplasia that may lead to life-threatening anaemia [21, 38, Table 1, this review focuses on invasive bacterial infections
39]. However, the epidemiology of this virus in Africa is as detected by blood culture. In the absence of prophylaxis,
poorly defined [40–42]. Individuals with SCD may have infections are thought to be the leading cause precipitating
impairment of the immune system, involving both cellular clinical events and associated with increased mortality [23,
immunity and humoral immunity. The most well-described 49].
immune defect is caused by reduced function of the spleen.
Patients with SCD have repeated splenic infarction due to
vasoocclusion which causes loss of the splenic vasculature 5. End-Organ Dysfunction
leading to hyposplenism [43]. Reports have suggested that
14% patients with SS-SCD are functionally asplenic at 6 With increase in survival, major organs in individuals with
months of age, with this number gradually increasing: 28% SCD are eventually damaged. The brain and lungs are partic-
at 1 year, 58% at 2 years, 78% at 3 years, and by 5 years, 94% ularly affected, with stroke, defined as an acute neurological
are affected [44]. This is from an area without malaria. One syndrome due to vascular occlusion or haemorrhage inwhich
of the roles of the spleen is filtration of unopsonised bacteria symptoms and signs last for more than 24 hours, being a
and remnants of red blood cells from intravascular space as well-described event. Acute chest syndrome (ACS) is an acute
well as opsonised bacteria [45]. Furthermore, the spleen is respiratory illness characterised by new pulmonary infiltrates
involved in the synthesis of soluble mediators of immunity. on chest X-ray and falling arterial oxygen saturation [54, 55].
Therefore patients with SCD, with a functional asplenia, Both these events have been reported to occur with high
have been reported to have impaired antibody responses prevalence in SCD and are also risk factors for death [23, 55,
as well as lacking specific antibodies, particularly against 56].
Salmonella species and Streptococcus pneumonia [46]. This
is thought to be due to deficiency of a complement factor 6. Heterogeneity of Clinical Events in SCD
involved in the activation of the immune system. The classic
pathway is activated by antigen-antibody interaction which The clinical expression of SCD is heterogeneous (Table 2).
causes fixation of complement components C1, C2, and C4 There is interindividual variability ranging from near com-
which then activate C3, whereas in the alternate pathway the plete asymptomatic to severe debilitating illness.There is also
antigen directly activates C3. Activation of C3, which is an variability within an individual, with changes in the type
opsonin, results in fixing of antigens on the microorganism and frequency of clinical events with age. Finally, there is
[47] making them susceptible to enhanced phagocytosis variability in clinical events depending on the geographical
by neutrophils and monocytes/macrophage. Johnston et al. location. This is due to the differences in environmental
illustrated that patients with SCD have an abnormality in factors such as nutrition, socioeconomic status, and climate
the activation of this pathway with failure of full activation that will influence the natural history of disease. The general
and fixing of C3 to encapsulated bacteria [48]. This results pattern of clinical disease is characterised by quiescent
The Scientific World Journal 5
Table 2: The prevalence of selected clinical consequences of SCD.
Clinical event Prevalence References
Haemolysis
Anaemia Chronic [57–59]
Cholelithiasis Prevalence is 40% by adolescence [60, 61]
Aplastic anaemia Associated with parvovirus B19 infection [61–63]
Hyperhemolysis Limited reports from Africa [64–67]
Vasoocclusion
More than 60% patients
Pain Most common cause of admission [22, 23, 68, 69]
Frequent pain is a risk factor for mortality
Acute splenic sequestration (ASS) Frequently occurs before the age of 3 yrs [23, 70, 71]
Leg ulcers Prevalence is 10–25% adults [72, 73]
Priapism Prevalence is 10–40% malesOccurs frequently in 5–14 years age group [74]
Organ dysfunction
Neurological events
Prevalence is 10% in children risk factor for mortality
Stroke High rate of recurrence [75]
Leads to poor quality of life
Prevalence is 20%
Cognitive/silent Risk factor for overt stroke [76–79]
Leads to impairment of executive function
Retinopathy Prevalence is >30% in HbSC [80]
Chest
Prevalence is 40%
Acute chest syndrome (ACS) Occurs frequently in children [54–56]
Has severe consequences in adults 12.8 per 100-patient years 59
Pulmonary hypertension Prevalence is 30%Risk factor for mortality [79, 81–84]
Avascular necrosis of femoral head Prevalence is 10–50% in adults [85–87]
Renal disease Prevalence of chronic renal failure is 5%–20% [88]
Infections
There is low prevalence of malaria in SCD. However, when malaria
Malaria occurs in SCD it is associated with increased risk of morbidity due to [89, 90]
severe anaemia and mortality
Bacterial infections 10% children under 5 years [91]
Modified from [92, 93].
periods interspersed with acute events, which are referred to (2) the HMIP locus (HBS1L-MYB intergenic polymorphism)
as crises. on chromosome 6q [97]; and (3) the oncogene BCL11A on
The reasons for this heterogeneity are not fully under- chromosome 2 [98]. These variants have been well reported
stood [94]. Interindividual variation in fetal hemoglobin in nonanemic Northern Europeans and Sardinians, a 𝛽-
(HbF) levels is one of the main modifiers that contribute to thalassemia cohort, in SCD patients from Brazil, and in the
the clinical heterogeneity observed in SCD patients. Higher African-American Cooperative Study of Sickle Cell Disease
expression of HbF in adulthood ameliorates morbidity and (CSSCD) [99–101]. There is very little description of the
mortality in SCD [56, 95]. three main genetic polymorphisms explaining phenotypic
It is now clear that common HbF variation is a quan- variation in HbF levels and clinical phenotype in native
titative genetic trait shaped by common polymorphisms. African SCD patients [97, 102].
Multiple genes, together with an environmental component,
determine themeasured value ofHbF in any given individual.
Genetic variation at three major loci accounts for a relatively 7. Epidemiology of Sickle Cell Disease
large proportion (20%–50%) of the phenotypic variation in 7.1. Prevalence. The prevalence of SCD can be objectively
HbF levels: (1) a single-base substitution (T/C) at position determined by calculating the birth prevalence of affected
−158 of the 𝐺𝛾 globin gene, termed XmnI 𝐺𝛾 site [96]; children, which requires accurate diagnosis and registration
6 The Scientific World Journal
at birth. Since this is not done in most African countries, chest syndrome [23, 49, 118, 119] with the highest incidence
an alternative method is to use the prevalence of the carrier between 1 and 3 years of age.
or heterozygous states (HbAS) to calculate the expected
birth rate of SCA based on the gene frequency and Hardy- 8. Laboratory Diagnosis of Sickle Cell Disease
Weinberg equation. Approximately 300,000 children are born
every year with SCD in the world, and countries such as The laboratory diagnosis of SCD is based on the demonstra-
the United States of America, United Kingdom, and Jamaica tion of HbS and the absence or significant reductions inHbA,
have well-documented SCD population. However, this SCD with variation in the percentage of two other hemoglobins—
population constitutes only 1% of the global population of HbF,HbA —inRBCs. Commonly available screening tests in
2
SCD, as over 75% are in Sub-Saharan Africa [103, 104]. It has Africa include sodiummetabisulphite sickling test and sickle
been estimated that SCD results in the annual loss of several solubility tests and confirmatory tests using electrophore-
millions of disability-adjusted life years, particularly in the sis and chromatography to confirm the sickle phenotype
developing world [105]. Hemoglobinopathies alone represent (SS/AS/SC/S𝛽−thalassaemia). The three tests widely used are
a health burden comparable to that of communicable and haemoglobin electrophoresis, isoelectric focusing (IEF), and
other major diseases [106]. high performance liquid chromatography (HPLC). DNA-
based assays precisely describe the genotype; however, for
7.2. Population Genetics and Dynamics: SCD, Malaria, and clinical purposes, diagnosis usually involves screening (sick-
Migration. Compared to noncarriers, healthy carriers of ling or solubility test) followed by confirmation of the sickle
recessive genes for SCD have a well-documented survival phenotype using gel electrophoresis, IEF or HPLC.
advantage against the lethal effects ofmalaria. As a result, car-
riers are more likely to reach reproductive age. Consequently, 8.1. Screening Tests. In most African hospitals, screening is
the birth prevalence of SCD is high in Africa [107–109]. The done, using the “sickling test”, which involves making a thin
resurgence of malaria in many parts of the world will serve to blood filmwhich is then put under hypoxic conditions by the
maintain these polymorphisms, but even if this selective force addition of sodium metabisulphite. This will result in RBCs
were removed it would take many generations for the gene containing HbS becoming deformed (i.e., forming sickle
frequencies of these conditions to fall significantly [110]. Any cells) as detected by light microscopy. A “positive” sickling
changes resulting from variation in selection or population test identifies the presence of sickled RBCs, which occurs in
dynamics will, however, be very small compared with the both homo- (SS) and heterozygous (AS) states. The sickle
effect of the demographic transition thatmany countries have solubility test is another method used for screening which is
undergone over recent years [110]. Specifically, there is a high based on the principle that HbS becomes insoluble when it
prevalence of hemoglobin S (HbS) in Africa and hemoglobin is deoxygenated. Additional confirmatory tests are required
C (HbC) in parts of West Africa [111]. Since subjects that to confirm SS-SCD or SCD involving other Hb types, when
are homozygous for HbC do not present with severe disease these screening assays are used.
like HbSS, it is anticipated that the frequency of HbC will
progressively increase even if malaria is not controlled [112]. 8.2. Confirmatory Tests. These tests are based on the principle
Internal migration in Africa has led to SCD, which was that different haemoglobin isoforms have different overall
previously rare, being introduced in South Africa through ionic charge, which makes them migrate with different
an influx of migrants from West and Central Africa [113]. velocities in an electric field. HBE can be done under alkaline
The high birth prevalence of SCD has highlighted the burden or acidic conditions. HbA, HA , HbF, and HbS migrate2
of SCD, such that in 2006, the World Health Organization towards the anode under an electric field with different rate
(WHO) recognized SCD as a public health priority [114]. ofmobility. During alkalineHb electrophoresis the resolution
There is limited information about the burden of SCD to the betweenHbS andHbF can be poor, particularly in individuals
health system and the impact that it has on individuals. with high HbF levels, for example, neonates. Under acidicconditions, HbF migrates relatively more rapidly and is
therefore distinguishable from both HbA and HbS. Isoelec-
7.3. Mortality. There is a higher rate of mortality among indi- tric focusing uses the same principles but is slightly more
viduals with SCD, with reports suggesting that if untreated expensive than HBE. However, it is able to identify more
most children with SCD die in early childhood. Studies done Hb variants that would not be detected by HBE. It also has
in Nigeria, reported mortality of up to 90% [115] but recent the advantage that it does not require commercial reagents.
estimates suggest that mortality rate has decreased and is HPLC uses cation exchange chromatography to identify the
more likely to be up to 50% by 20 years. This mortality various hemoglobins in an individual. It has the advantage in
rate in Africa is similar to those reported in the early that it can also accurately quantify the Hb levels. In resource-
1960s in the United States of America and United Kingdom. rich countries, screening has largely been replaced by HPLC
However, with early diagnosis and comprehensive treatment, and confirmation is then done by IEF or HBE.This is mainly
significant reductions in mortality have been achieved, with because HBE and IEF are labour intensive, time consuming
recent reports of improved survival; 85.6% survive to 18 years and would not identify abnormal bands or quantify Hb.
in the USA [116], 84% in Jamaica, and 99.0% to 16 years in the Furthermore, the quantification of Hb fractions by HPLC is
UK [117]. The common causes of death in the USA, UK, and used to monitor patients who are on Hydroxyurea therapy or
Jamaica are infections, acute splenic sequestration, and acute exchange blood transfusion.
The Scientific World Journal 7
8.3. Molecular Diagnosis of SCA. The most popular molec- accompanied by enrolment into programmes that provide
ular diagnosis of 𝛽S mutation, based on restriction enzyme comprehensive care by multidisciplinary teams comprising
digestion, is performed on HBB PCR products. The point nurses, genetic counsellors, social workers, paediatricians,
mutation, which results in SCD, abolishes the restriction site haematologists, orthopaedic surgeons, ophthalmologists, and
for the restriction enzymeDdeI. Digestion ofDNAof individ- internists. These programmes provide appropriate advice,
uals homozygous for HbAA would result in two fragments counseling, and support to parents and affected individuals.
188 bp and 192 bp. Analysis of heterozygous HbAS samples This includes advice such as drinking adequate quantities of
would result in three fragments one of 380 bp and the two fluid to avoid dehydration andwearing warm clothing in cold
digested fragments of 180 bp and 192 bp. Homozygous HbSS weather. Specific health education that will enable them to
samples would result in 380 bp fragments being produced recognise acute events and seek medical care is also essential.
(Figure 3).This method is simple and cost effective and could Teachingmothers to recognise enlargement of the spleen and
be used for prenatal genetic diagnosis in African settings anaemia was effective in diagnosing and treating anaemia
[120]. due to ASS [71, 124]. Patients are also seen on a regular basis
and provided with folic acid supplements. The evidence for
the burden of folate deficiency in SCD is limited. Prompt
9. Management of Sickle Cell Disease treatment of crises (fever and pain), particularly at outpatient
As a chronic disease, the natural history of SCD is char- or in day-care facilities, has been found to be effective
acterised by quiescent periods interspersed by acute events, and reduces the burden of hospitalization to the individual
known as crises, leading to patients seeking health care and and the health system [125–128]. Long-term care should be
frequent hospitalisation. The “crises” range from defined provided by a multidisciplinary team including professionals
syndromes such as acute chest syndrome (ACS), acute splenic who have specialized in haematology and blood transfusion
sequestration (ASS), to less well-defined symptoms that for adults and paediatric haematologists in children. In
include pain, fever, anaemia, worsening of jaundice, and leg settings where there is a low prevalence of SCD or limited
ulcers. Other circumstances include pregnancy, dehydration, number of health care professionals, SCDpatients can receive
and extreme cold weather. With the increased life span of care from general health care workers. In such a setting,
individuals with SCD, there has been an increasing awareness guidelines for management can be provided to general health
of the importance of improving the quality of life as well care workers with a system of referral to specialised centres.
as preventing damage to major organs. SCD is associated
with increased mortality.The causes of mortality in the USA,
UK, and Jamaica included infections, ACS, ASS, and aplastic 9.3. Prevention and Treatment of Infections. In the absence
crises [23, 49, 118, 119]. The management of patients with of intervention, bacterial infection is the leading cause of
SCD involves interventions that improve survival, prevent mortality in individuals with SCD, and the age group that is
complications, treat acute events, and reduce end-organ most affected is 1 to 3 years [37, 49, 118]. Bacterial infection
damage. Specific conditions or circumstances when SCD in SCD is mainly due to Streptococcus pneumoniae, resulting
patients require extra care include surgery requiring general in pneumonia, sepsis, and meningitis. The highest incidence
anaesthesia, due to increased risk of developing acute sickling of invasive pneumococcal disease is in children less than 6
complications and sudden death. Over the past 3 decades years of age [91, 118]. In a landmark study in the USA, Gaston
there has been an improvement in the understanding of and colleagues demonstrated an 84% reduction in incidence
the different pathogenic mechanisms responsible for sickle of pneumococcal infection with the use of oral penicillin
cell events and organ dysfunction. Through a series of [26]. Interventions with daily oral penicillin and vaccination
clinical trials, effective interventional strategies have been against pneumococcal infections have successfully reduced
established. mortality in developed countries [26, 116, 129]. In Africa,
these interventions have not been implemented as the evi-
dence to demonstrate a similar role of bacterial infectionswas
9.1. Newborn Screening (NBS). Thehighest incidence of death lacking. This made it difficult for hospitals and governments
occurs in the first 3 years of life [23, 49, 118, 121]. Identi- in developing countries to implement these interventions.
fication of children at birth by newborn screening (NBS), Furthermore, published reports have actually questioned the
and institution of preventative care has improved survival role of prophylaxis against Streptococcus pneumoniae (SPN),
[116, 122, 123]. Patients who are identified at birth can be in Africa [28]. However, there has been increasing evidence
given counselling and advice about the course of illness.They of the role of bacterial infections, particularly due to SPN
can then be enrolled in comprehensive care programmes that in causing high childhood mortality [130, 131]. Since SCD
provide prompt and effective care of acute events and pro- patients are highly susceptible to SPN infections due to
phylaxis against complications, resulting in overall positive impaired immunity, this makes it even more likely that
impact on survival and quality of life. Countries with large SPN infections will have a more significant role in SCD
SCD populations and adequate resources have started NBS mortality. Therefore, there has been an increase in the appeal
programmes. to implement these interventions [30, 132].
Malaria is widely considered to be one of the major
9.2. Comprehensive Care Including Dedicated Day Care causes of illness and death in patients living with SCD in
Facilities. The identification of SCD at birth has to be SSA [90, 104]. Although, SCD individuals have an element
8 The Scientific World Journal
500 bp
400 bp 380 bp
188/192 bp
Figure 3: RFLP of HBB fragment with DdeI. Lane 1: undigested control, Lane 2: HbAA control, Lane 3: HbAS control, and Lane 4: HbSS
MW: molecular weight marker.
of protection against malaria; with a lower prevalence of packed RBCs) and the method of transfusion (simple or
malaria infection [133–135] and a lower parasite density exchange) are determined by the clinical situation, availability
[136], the risk of mortality when SCD patients get malaria of resources, and the capacity to provide the blood product
is significantly higher [137]. It is recommended that individ- and establish venous access [139]. Blood transfusion is also
uals with SCD who live in a malaria endemic area should effective in other situations, such as acute stroke [140], ACS
receive prophylaxis against malaria [138]. There is ongoing [141], and perioperatively [142]. Blood transfusion works by
debate as to what is the most appropriate agent that can increasing the level of Hb, thus improving oxygen delivery. It
be used for chemoprophylaxis. The increasing resistance by also reduces the proportion of sickle RBCs in the circulation.
Plasmodium falciparum parasites to chloroquine has meant Exchange or red cell transfusion has also been shown to be
that most countries have had to stop using chloroquine. effective in reducing the level of HbS to less than 30% [143–
Sulphadoxinepyrimethamine has antifolate properties and is 146]. This is thought to reduce the deleterious effects of HbS
not recommended for prophylaxis in patients with SCD who and improve outcome. Long-term blood transfusion therapy
are considered to be folate deficient. Most malaria-endemic (LTBT) has been found to be effective in the prevention
countries have therefore been unable to decide which drug of brain injury due to cerebrovascular disease [140]. Blood
to use for prophylaxis in SCD, with options limited to transfusion is associated with risks which have to be weighed
proguanil (paludrine), mefloquine (Lariam), Malarone, or against the benefits when considering implementing this as
Doxycycline. Current practice in malaria-endemic countries an intervention. These will be reviewed in the section on
involves use of insecticide-treated nets and prompt diagnosis stroke.
and treatment of malaria.
9.5. Pain. Pain, the defining feature of SCD and its com-
9.4. Blood Transfusion (BT). SCD is contributing to the monest symptom, starts early in life and persists throughout
anaemia in under fives and pregnant women in areas of life. It is the commonest symptom of SCD and is related to
high prevalence. Patients with SCD have a compensated disease severity. Studies in children in developed countries
chronic haemolytic anaemia which allows them to carry suggest that painful episodes and acute chest syndrome were
on with normal activities at steady-state haemoglobin with the most frequent complications of sickle cell disease and
narrow reserve capacity to accommodate strenuous phys- that the pain crises are a major predictor of adverse outcome
ical activities. The steady state haemoglobin varies from in children along with anaemia and leucocytosis. In adults,
person to person and is related to the level of HbF, co- large proportion of patients die during an acute episode of
inheritance of alpha thalassaemia, or heterozygosity for pain, making it a risk factor for early death along with acute
another haemoglobin type such as HbC. Although individ- chest syndrome and stroke. However due to its subjective
uals with SCD have chronic anaemia which is tolerated, nature, patients with SCD may not be having appropriate
rapidly worsening anaemia can occur, and this presents as an assessment and adequate pain management necessary to
emergency. It can be caused byASS, aplastic crises, andhyper- prevent complications relating to the pain such as the devel-
hemolysis or associated with other events such as bacterial opment of a chronic pain syndrome resulting in worsening
infections and malaria. Under these circumstances, anaemia of the sickle cell condition. Training is essential for adequate
is life threatening and requires prompt treatment with blood assessment of pain intensity, reporting, documentation by
transfusion. The products that are used (whole blood or patients, care giver, and health workers. Promptmanagement
The Scientific World Journal 9
of pain requires attention to the precipitating causes (stress, Table 3: Summary of study outcomes for hydroxyurea use in adults
infection, dehydration, acidosis, and allodynia). Adequate and children.
oral analgesic should be administered for mild pain and Impact Impact in
parenteral for moderate to severe pain according to WHO Outcome in adults adolescents
step ladder for analgesia in patients.When the expected relief
is not obtained in response to adequate doses of analgesics, Clinical outcomes
this should alert to the condition of opioid-induced hyperaes- Pain crises ↓↓↓ ↓↓
thesia, allodynia, or the progression of acute pain to chronic Hospitalisations ↓↓↓ ↓↓↓
pain [147–149]. However, many health facilities in Africa do Blood transfusion therapy ↓↓↓ ↔ (insufficient data)
not have access to opioids. Acute chest syndrome ↓↓↓ ↔ (insufficient data)
Laboratory markers
9.6. Hydroxyurea. Hydroxyurea (HU) (also known as hy- Foetal haemoglobin ↑↑↑ ↑↑↑
droxycarbamide) has been reported to be effective in improv- ↔ (not significantly
ing survival and reducing morbidity in some SCD patients Haemoglobin ↑↑↑ significant)
(Table 3). The clinical outcomes include reduction in fre-
quency of painful episodes and hospital admissions [150]. Mean corpuscular haemoglobin ↑↑↑ ↑↑↑
Hydroxyurea therapy is also monitored by a number of White blood cell count ↓↓↓ ↓↓↓
laboratory parameters which include increased HbF levels, Prevention of end organ damage
mean corpuscular volume (MCV), and reduction in WBC Brain ↔ ↔
count. Hydroxyurea has been found to be effective in the Spleen ↔ ↔
prevention of brain injury due to cerebrovascular disease Kidney ↔ ↔
[151]. Mortality ↓ ↔=
↓↓↓: high-grade evidence for decrease; ↓: low-grade evidence for a decrease;
9.7. Nitric Oxide. Lung dysfunction results from a com- ↑↑↑: high-grade evidence for increase; ↑: low-grade evidence for an increase;
bination of repeated pulmonary infections and infarctions ↔: not evaluated/not significantly different/insufficient data. Source [152].
as well as increased vasoconstriction leading to pulmonary
hypertension [54, 55]. The latter has recently been shown to
be associated with reduced bioavailability of nitric oxide [19], 9.9. Gene Therapy. Since SCD is caused by a defective gene,
which has resulted in the development of potential therapies definitive treatment would involve replacement of this gene
such as L-arginine, citrulline, and inhaled nitric oxide which with a normal gene. This has been done successfully in the
is aimed at increasing NO levels through different pathways sickle transgenic mouse [163], but progress in humans has
[153–157]. been limited by identification of appropriate vectors andefficacy for gene transfer and low level expression of globin
genes.
9.8. Stem Cell Transplant. The only cure that is available for
SCD is stem cell transplantation (SCT), which replaces the 9.10. Role of Programmes for Control andManagement of SCD.
host’s bone marrow with stem cells containing normal 𝛽- From a public health perspective, the policy for approaching
globin genotype. Since the first successful transplant reported the control of SCD in national health programmes needs
in 1984 [158], there has been significant reduction in risks due to work in the context of countries with limited resources
to SCT and increasing success, with the best results, of up to in health. Although, there is ongoing debate whether care
85% event free survival, occurring withHLA-matched sibling of SCD should be integrated into existing health care ser-
donors and transplantation early in the course of the disease vices or whether there should be separate disease-specific
before end-organ damage occurs [159]. One limitation of programmes for SCD, the WHO recommends [164] that, for
SCT is the availability of sibling donors [160], and therefore countries where the birth rate of affected infants is above 0.5
there have been attempts to improve survival for unrelated per 1,000 births, they should develop separate programmes
stem-cell donors [161, 162]. The second limitation of SCT is for these conditions. It is recommended that counties with
that this line of treatment requires tremendous resources, a high prevalence of SCD start planning effective control
and it becomes increasingly difficult for transplant physicians measures. In this context, control of SCD encompasses two
practicing in the developing world to reconcile the difference elements: providing best possible care for affected individuals
between what is possible and what is available. Moreover, it is and preventing the birth of affected individuals.
more difficult to address because the clinical course of SCD is With regard to providing best possible care, the following
extremely heterogeneous. Despite the knowledge of various are options, depending on available resources, that have been
genetic and environmental factors known to alter disease recommended by Weatherall et al. in 2006 [105].
severity, it is still difficult to accurately identify children with
risk of severe disease before extensive damage has occurred. Option one: best possible patient care with the use of
Until such time that a low-risk, definitive cure is available, the prophylactic penicillin following diagnosis, together
cornerstone of management of SCD is the prevention of early with retrospective genetic counselling.
mortality, prevention of end organ damage, and improvement Option two: best possible patient care, together with a
of the quality of life. newborn screening program and the use of penicillin
10 The Scientific World Journal
for all homozygous babies, together with retrospec- neither health services nor families can afford to pay for
tive screening and counselling. long-term treatment of SCA [165]. Close to two-thirds of
Option three: best possible patient care, together a sample of 130 Cameroonian parents with affected chil-
with newborn screening and the use of prophylactic dren reported they would accept termination of an affected
penicillin from birth for homozygotes, together with pregnancy for SCA [120], a considerably higher proportion
population screening and prospective genetic coun- when compared to the Cameroonian preclinical, clinical
selling. medical student, and physicians in a previous study (22.4,
Option four: option three, plus the availability of 10.8 and 36.1%, resp.) [166]. Trends reported in Nigerian
prenatal diagnosis, bone marrow transplantation, or parents were slightly different where 92% of a sample of 53
both. SCAheterozygous carriermothers favored prenatal diagnosisand 63% indicated they would opt for termination of an
The management of SCD involves early diagnosis of affected pregnancy [167]. However, in a survey of 403 health
affected people, the provision of the most appropriate basic, workers in a tertiary health care centre in Nigeria, only one-
cost-effective treatment, and genetic counselling and psy- third of the respondents accept termination of pregnancy as
chosocial support. The long-term goal is to ensure appro- an option if prenatal screening is positive for SCA, whereas
priate management at different levels of health care with close to half of the respondents (42%) were against the
development of referral centres for specialised diagnosis and idea. Another study reported that 21.4% of Nigerian doctors
treatment. This approach ensures a cost-effective way of would accept termination of an affected pregnancy for SCA
effectively dealing with a highly prevalent condition in areas [168]. Experience of the effective practice of prenatal genetic
where the resources are limited. However, it is important diagnosis for SCD (amniocentesis and fetal DNA analysis)
that these centres are not limited to urban areas or centred was reported in Nigeria and Cameroon [169, 170]. The views
on academic or research oriented health facilities. In order of parents towards prenatal diagnosis and in some cases
to avoid this, there must be active strategies to ensure that medical termination of pregnancy may be associated with
appropriate management is built into services at all levels their experience of affected patients and the psychosocial
of health care with adequate support from these specialised and/or economic impact of SCAon families. Nevertheless the
centres. Management of SCD needs to be accompanied by discrepancy between perception of a professional and parents
strategies that aimed at two levels of prevention: tertiary underscores the necessity for more studies to unravel the
prevention which involves early diagnosis of SCD and pre- ethical dilemma around prenatal genetic diagnosis to offer a
vention of complications and more ambitiously secondary service that does not conflict with social and cultural values of
prevention which tries to reduce the number of children that the affected population. Preimplantation genetic diagnosis is
are born with SCD. (Note that primary prevention aims to a mechanism for accurate genetic diagnosis, careful selection
ensure that individuals are born free of SCD). Preventative of unaffected embryo and implantation to allow fertile or
services involve community education, population screening, infertile couples to have offspring without SCA. It is an
and genetic counselling that would encourage people to expensive procedure using assisted conception by in vitro
undergo screening before conception, during the antenatal fertilization or intracytoplasmic sperm injection. It requires
or postnatal period. There are several issues that need to close collaboration between fertility specialists, molecular
be addressed with regard to prevention of SCD. The aim biologists, geneticists, and genetic and fertility counselors and
of screening is to detect SCD in the foetus, discuss the may be an option to individuals who may object to prenatal
consequences of a diagnosis of SCD, and provide options for diagnosis followed by termination.
treatment and prognosis. Since SCD is a recessive disorder, Although SCA is the most severe form of the disease
during pre-conception screening, the chances of getting an (compared to SC/S𝛽 thalassaemia, etc.), there is still wide
affected child are variable. There is difficulty in advising a variability in disease severity.Therefore, evenwith the correct
couple not to have children as the risk of getting an affected identification and diagnosis of SS with screening, it would be
child may be relatively low (1 in 4) and does not increase with difficult to predict those who would develop severe disease
each pregnancy.The highest risk would be for two individuals and have a poor outcome.
who are SS who wish to have children. This is different
from thalassaemia, where children with the most severe 10. Conclusion and Future Challenges
form, thalassaemia major, will inevitably have severe disease.
Therefore, one could argue that this therefore justifies the Because of their uneven distribution in high-frequency
use of prenatal diagnosis as this would identify pregnancies populations, reflecting their complex population genetics,
with SCD children, and then parents would be given the the true magnitude of burden of SCD is still unknown.
appropriate information regarding the consequences and In many African countries there are few or virtually no
prognosis of SCD and allow more reproductive options to facilities for appropriate diagnosis and management of SCD.
families. Prenatal genetic diagnosis represents one type of There is limited data about frequency, clinical course, or
reproductive option as it provides parents with the option mortality. Without this information it will be impossible
to test at-risk pregnancies and make decisions regarding to persuade African governments about the burden of this
affected pregnancies. The availability and acceptability of disease. The WHO Africa has recommended a set of public
prenatal diagnosis and termination of an affected pregnancy health interventions to reduce the burden of SCD in African
are of particular importance in low-resource countries where region, namely, improving awareness, preventing the disease,
The Scientific World Journal 11
early detection, improving the provision of health care for [13] P. S. Frenette, “Sickle cell vasoocclusion: heterotypic, multicel-
affected individuals by providing effective clinical, laboratory, lular aggregations driven by leukocyte adhesion,”Microcircula-
diagnostic, and imaging facilities adapted to different levels of tion, vol. 11, no. 2, pp. 167–177, 2004.
the health system, screening of newborns, training of health [14] I. Okpala, “Leukocyte adhesion and the pathophysiology of
care workers, developing protocols for treatment, providing sickle cell disease,” Current Opinion in Hematology, vol. 13, no.
genetic counseling, patient support groups, advocacy, and 1, pp. 40–44, 2006.
research [171].The situationwill be improved by commitment [15] K. I. Ataga and E. P. Orringer, “Hypercoagulability in sickle cell
by member states to integrate SCD prevention and control disease: a curious paradox,” American Journal of Medicine, vol.
in national health plans and provide conducive environment 115, no. 9, pp. 721–728, 2003.
for various stakeholders to contribute to the reduction of [16] J.-L. Wautier and M.-P. Wautier, “Erythrocytes and platelet
SCD prevalence, morbidity, and mortality. It will also require adhesion to endothelium are mediated by specialized molecu-
concerted action on the part of the international community les,” Clinical Hemorheology and Microcirculation, vol. 30, no. 3-
of the richer countries, together with input from other major 4, pp. 181–184, 2004.
international health organizations and funding agencies [172, [17] J. Villagra, S. Shiva, L. A. Hunter, R. F. Machado, M. T. Gladwin,
173]. andG. J. Kato, “Platelet activation in patients with sickle disease,hemolysis-associated pulmonary hypertension, and nitric oxide
scavenging by cell-free hemoglobin,” Blood, vol. 110, no. 6, pp.
References 2166–2172, 2007.
[18] M. T. Gladwin and G. J. Kato, “Hemolysis-associated hyperco-
[1] J. K. Onwubalili, “Sickle cell anaemia and reincarnation beliefs agulability in sickle cell disease: the plot (and blood) thickens!,”
in Nigeria,”The Lancet, vol. 2, no. 8364, p. 1423, 1983. Haematologica, vol. 93, no. 1, pp. 1–3, 2008.
[2] E. Nzewi, “Malevolent ogbanje: recurrent reincarnation or [19] C. D. Reiter, X.Wang, J. E. Tanus-Santos et al., “Cell-free hemo-
sickle cell disease?” Social Science and Medicine, vol. 52, no. 9, globin limits nitric oxide bioavailability in sickle-cell disease,”
pp. 1403–1416, 2001. Nature Medicine, vol. 8, no. 12, pp. 1383–1389, 2002.
[3] S. E. Antonarakis, C. D. Boehm, G. R. Serjeant, C. E. Theisen,
G. J. Dover, and H. H. Kazazian Jr., “Origin of the (S) globin [20] M. de Montalembert, M. Guilloud-Bataille, J. Feingold, and R.𝛽
gene in Blacks: the contribution of recurrent mutation or gene Girot, “Epidemiological and clinical study of sickle cell disease
conversion or both,” Proceedings of the National Academy of in France, French Guiana and Algeria,” European Journal of
Sciences of the United States of America, vol. 81, no. 3, pp. 853– Haematology, vol. 51, no. 3, pp. 136–140, 1993.
856, 1984. [21] J. R. Pattison, S. E. Jones, J. Hodgson et al., “Parvovirus infec-
[4] A. E.Kulozik, J. S.Wainscoat, G. R. Serjeant et al., “Geographical tions and hypoplastic crisis in sickle-cell anaemia,” The Lancet,
survey of𝛽(S)-globin gene haplotypes: evidence for an indepen- vol. 1, no. 8221, pp. 664–665, 1981.
dent Asian origin of the sickle-cell mutation,”American Journal [22] O. S. Platt, B. D.Thorington, D. J. Brambilla et al., “Pain in sickle
of Human Genetics, vol. 39, no. 2, pp. 239–244, 1986. cell disease—rates and risk factors,”TheNew England Journal of
[5] D. J. Weatherall, “Towards molecular medicine; reminiscences Medicine, vol. 325, no. 1, pp. 11–16, 1991.
of the haemoglobin field, 1960–2000,” British Journal of Haema- [23] F. M. Gill, L. A. Sleeper, S. J. Weiner et al., “Clinical events in the
tology, vol. 115, no. 4, pp. 729–738, 2001. first decade in a cohort of infants with sickle cell disease,” Blood,
[6] D. J. Weatherall, “Phenotype-genotype relationships in mono- vol. 86, no. 2, pp. 776–783, 1995.
genic disease: lessons from the thalassaemias,” Nature Reviews [24] T. B. West, D. W. West, and K. Ohene-Frempong, “The presen-
Genetics, vol. 2, no. 4, pp. 245–255, 2001. tation, frequency, and outcome of bacteremia among children
[7] M. J. Stuart and R. L. Nagel, “Sickle-cell disease,”TheLancet, vol. with sickle cell disease and fever,” Pediatric Emergency Care, vol.
364, no. 9442, pp. 1343–1360, 2004. 10, no. 3, pp. 141–143, 1994.
[8] R. L. Nagel, R. M. Bookchin, and J. Johnson, “Structural bases [25] K. J. J. Wierenga, I. R. Hambleton, R. M. Wilson, H. Alexander,
of the inhibitory effects of hemoglobin F and hemoglobin A2 B. E. Serjeant, and G. R. Serjeant, “Significance of fever in
on the polymerization of hemoglobin S,” Proceedings of the Jamaican patients with homozygous sickle cell disease,”Archives
National Academy of Sciences of the United States of America, of Disease in Childhood, vol. 84, no. 2, pp. 156–159, 2001.
vol. 76, no. 2, pp. 670–672, 1979. [26] M. H. Gaston, J. I. Verter, and G. Woods, “Prophylaxis with
[9] C. T. Noguchi, D. A. Torchia, and A. N. Schechter, “Intracellular oral penicillin in childrenwith sickle cell anemia. A randomized
polymerization of sickle hemoglobin. Effects of cell heterogene- trial,”The New England Journal of Medicine, vol. 314, no. 25, pp.
ity,”The Journal of Clinical Investigation, vol. 72, no. 3, pp. 846– 1593–1599, 1986.
852, 1983. [27] “American Academy of Pediatrics. Committee on Infectious
[10] C. Brugnara, H. F. Bunn, and D. C. Tosteson, “Regulation of Diseases. Policy statement: recommendations for the preven-
erythrocyte cation and water content in sickle cell anemia,” tion of pneumococcal infections, including the use of pneumo-
Science, vol. 232, no. 4748, pp. 388–390, 1986. coccal conjugate vaccine (Prevnar), pneumococcal polysaccha-
[11] M. P. Westerman, L. Unger, O. Kucuk, P. Quinn, and L. J. Lis, ride vaccine, and antibiotic prophylaxis,” Pediatrics, vol. 106, no.
“Phase changes in membrane lipids in sickle red cell shed- 2, part 1, pp. 362–366, 2000.
vesicles and sickle red cells,” American Journal of Hematology, [28] M. E. Kizito, E. Mworozi, C. Ndugwa, and G. R. Serjeant,
vol. 58, no. 3, pp. 177–182, 1998. “Bacteraemia in homozygous sickle cell disease in Africa: is
[12] R. P. Hebbel, M. A. B. Boogaerts, J. W. Eaton, and M. H. pneumococcal prophylaxis justified?” Archives of Disease in
Steinberg, “Erythrocyte adherence to endothelium in sickle-cell Childhood, vol. 92, no. 1, pp. 21–23, 2007.
anemia. A possible determinant of disease severity,” The New [29] T. N. Williams, S. Uyoga, A. Macharia et al., “Bacteraemia
England Journal of Medicine, vol. 302, no. 18, pp. 992–995, 1980. in Kenyan children with sickle-cell anaemia: a retrospective
12 The Scientific World Journal
cohort and case-control study,” The Lancet, vol. 374, no. 9698, [46] J. A.Winkelstein and R. H. Drachman, “Deficiency of pneumo-
pp. 1364–1370, 2009. coccal serum opsonizing activity in sickle-cell disease,”TheNew
[30] S. Obaro, “Pneumococcal infections and sickle cell disease in England Journal of Medicine, vol. 279, no. 9, pp. 459–466, 1968.
Africa: does absence of evidence imply evidence of absence?” [47] S. Ruddy, L. G. Hunsicker, and K. F. Austen, “C3b inactivator of
Archives of Disease in Childhood, vol. 94, no. 9, pp. 713–716, man. 3. Further purification and production of antibody to C3b
2009. INA,” Journal of Immunology, vol. 108, no. 3, pp. 657–664, 1972.
[31] L. Tshilolo, E. Kafando,M. Sawadogo et al., “Neonatal screening [48] R. B. Johnston Jr., S. L. Newman, and A. G. Struth, “An
and clinical care programmes for sickle cell disorders in sub- abnormality of the alternate pathway of complement activation
Saharan Africa: lessons from pilot studies,” Public Health, vol. in sickle-cell disease,”TheNew England Journal of Medicine, vol.
122, no. 9, pp. 933–941, 2008. 288, no. 16, pp. 803–808, 1973.
[32] O. Bagasra, R. M. Steiner, and S. K. Ballas, “Viral burden and [49] S. L. Leikin, D. Gallagher, T. R. Kinney, D. Sloane, P. Klug, and
disease progression in HIV-1-infected patients with sickle cell W. Rida, “Mortality in children and adolescents with sickle cell
anemia,”American Journal ofHematology, vol. 59, no. 3, pp. 199– disease,” Pediatrics, vol. 84, no. 3, pp. 500–508, 1989.
207, 1998. [50] H. O. Okuonghae, M. U. Nwankwo, and E. C. Offor, “Pattern of
[33] I. Diagne, G. M. Soares, A. Gueye et al., “Infections in Sen- bacteraemia in febrile children with sickle cell anaemia,”Annals
egalese children and adolescents with sickle cell anemia: epi- of Tropical Paediatrics, vol. 13, no. 1, pp. 55–64, 1993.
demiological aspects,” Dakar Médical, vol. 45, no. 1, pp. 55–58, [51] E. W. Hook, C. G. Campbell, H. S. Weens, and B. R. Cooper,
2000. “Salmonella osteomyelitis in patients with sickle-cell anemia,”
[34] M. Hassan, S. Hasan, S. Giday et al., “Hepatitis C virus in sickle The New England Journal of Medicine, vol. 257, no. 9, pp. 403–
cell disease,” Journal of the National Medical Association, vol. 95, 407, 1957.
no. 10, pp. 939–942, 2003. [52] W. W. Ebong, “Acute osteomyelitis in Nigerians with sickle cell
[35] L. M. Tshilolo, R. K. Mukendi, and S. O. Wembonyama, “Blood disease,” Annals of the Rheumatic Diseases, vol. 45, no. 11, pp.
transfusion rate in congolese patients with sickle cell anemia,” 911–915, 1986.
Indian Journal of Pediatrics, vol. 74, no. 8, pp. 735–738, 2007. [53] L. Tshilolo, R. Mukendi, and R. Girot, “Sickle cell disease in
[36] F. Blei and D. R. Puder, “Yersinia enterocolitica bacteremia south Zaire. Study of two series of 251 and 340 patients during
in a chronically transfused patient with sickle cell anemia: the period 1988–1992,” Archives de Pediatrie, vol. 3, no. 2, pp.
case report and review of the literature,” American Journal of 104–111, 1996.
PediatricHematology/Oncology, vol. 15, no. 4, pp. 430–434, 1993. [54] O. Castro, D. J. Brambilla, B. Thorington et al., “The acute chest
[37] E. Barrett-Connor, “Bacterial infection and sickle cell anemia. syndrome in sickle cell disease: incidence and risk factors,”
An analysis of 250 infections in 166 patients and a review of the Blood, vol. 84, no. 2, pp. 643–649, 1994.
literature,”Medicine, vol. 50, no. 2, pp. 97–112, 1971. [55] E. P. Vichinsky, L. D. Neumayr, A. N. Earles et al., “Causes and
[38] G. R. Serjeant, B. E. Serjeant, P. W. Thomas, M. J. Anderson, outcomes of the acute chest syndrome in sickle cell disease,”The
G. Patou, and J. R. Pattison, “Human parvovirus infection in NewEngland Journal ofMedicine, vol. 342, no. 25, pp. 1855–1865,
homozygous sickle cell disease,” The Lancet, vol. 341, no. 8855, 2000.
pp. 1237–1240, 1993. [56] O. S. Platt, D. J. Brambilla, W. F. Rosse et al., “Mortality in sickle
[39] K. Smith-Whitley, H. Zhao, R. L. Hodinka et al., “Epidemiology cell disease—life expectancy and risk factors for early death,”
of human parvovirus B19 in children with sickle cell disease,” TheNew England Journal of Medicine, vol. 330, no. 23, pp. 1639–
Blood, vol. 103, no. 2, pp. 422–427, 2004. 1644, 1994.
[40] P.H. Jones, L. C. Pickett,M. J. Anderson, andG. Pasvol, “Human [57] R. J. Hayes, M. Beckford, Y. Grandison, K. Mason, B. E.
parvovirus infection in children and severe anaemia seen in Serjeant, and G. R. Serjeant, “The haematology of steady state
an area endemic for malaria,” Journal of Tropical Medicine and homozygous sickle cell disease: frequency distributions, varia-
Hygiene, vol. 93, no. 1, pp. 67–70, 1990. tionwith age and sex, longitudinal observations,”British Journal
[41] T. Teuscher, B. Baillod, and B. R. Holzer, “Prevalence of human of Haematology, vol. 59, no. 2, pp. 369–382, 1985.
parvovirus B19 in sickle cell disease and healthy controls,” [58] M. A. F. El-Hazmi, F. A. Jabbar, F. Z. Al-Faleh, A. R. Al-
Tropical and Geographical Medicine, vol. 43, no. 1-2, pp. 108–110, Swailem, and A. S. Warsy, “The haematological, biochemical
1991. and clinical—presentation of haemoglobin S in SaudiArabia (i).
[42] J. Yeats, H. Daley, andD. Hardie, “Parvovirus B19 infection does Haematological & clinical expression,” Tropical and Geographi-
not contribute significantly to severe anaemia in children with cal Medicine, vol. 39, no. 2, pp. 157–162, 1987.
malaria in Malawi,” European Journal of Haematology, vol. 63, [59] G.Akenzua,O.Akinyanju, A. Kulozik et al., “Sickle cell anaemia
no. 4, pp. 276–277, 1999. in Nigeria: a comparison between Benin and Lagos,” African
[43] H. A. Pearson, R. P. Spencer, and E. A. Cornelius, “Functional Journal of Medicine and Medical Sciences, vol. 23, no. 2, pp. 101–
asplenia in sickle-cell anemia,” The New England Journal of 107, 1994.
Medicine, vol. 281, no. 17, pp. 923–926, 1969. [60] J. W. Childs, “Sickle cell disease: the clinical manifestations,”
[44] A. K. Brown, L. A. Sleeper, S. T. Miller, C. H. Pegelow, F. M. Journal of the American Osteopathic Association, vol. 95, no. 10,
Gill, and M. A. Waclawiw, “Reference values and hematologic pp. 593–598, 1995.
changes from birth to 5 years in patients with sickle cell disease,” [61] M. G. Neonato, M. Guilloud-Bataille, P. Beauvais et al., “Acute
Archives of Pediatrics andAdolescentMedicine, vol. 148, no. 8, pp. clinical events in 299 homozygous sickle cell patients living in
796–804, 1994. france,” European Journal of Haematology, vol. 65, no. 3, pp. 155–
[45] G. J. Noel, S. Katz, and P. J. Edelson, “Complement-mediated 164, 2000.
early clearance of Haemophilus influenzae type b from blood [62] G. R. Serjeant, J. M. Topley, K. Mason et al., “Outbreak of
is independent of serum lytic activity,” Journal of Infectious aplastic crises in sickle cell anaemia associated with parvovirus-
Diseases, vol. 157, no. 1, pp. 85–90, 1988. like agent,”The Lancet, vol. 2, no. 8247, pp. 595–597, 1981.
The Scientific World Journal 13
[63] A. I. Juwah, E. U. Nlemadim, and W. Kaine, “Types of anaemic [79] R. Marouf, R. Gupta, M. Z. Haider, and A. D. Adekile, “Silent
crises in paediatric patients with sickle cell anaemia seen in brain infarcts in adult Kuwaiti sickle cell disease patients,”
Enugu, Nigeria,” Archives of Disease in Childhood, vol. 89, no. American Journal of Hematology, vol. 73, no. 4, pp. 240–243,
6, pp. 572–576, 2004. 2003.
[64] V. G. Nolan, D. F. Wyszynski, L. A. Farrer, and M. H. Steinberg, [80] R. J. Hayes, P. I. Condon, and G. R. Serjeant, “Haematological
“Hemolysis-associated priapism in sickle cell disease,” Blood, factors associated with proliferative retinopathy in sickle cell-
vol. 106, no. 9, pp. 3264–3267, 2005. haemoglobin C disease,” British Journal of Ophthalmology, vol.
[65] G. J. Kato, V. McGowan, R. F. Machado et al., “Lactate dehy- 65, no. 10, pp. 712–717, 1981.
drogenase as a biomarker of hemolysis-associated nitric oxide [81] O. Castro, M. Hoque, and B. D. Brown, “Pulmonary hyperten-
resistance, priapism, leg ulceration, pulmonary hypertension, sion in sickle cell disease: cardiac catheterization results and
and death in patients with sickle cell disease,” Blood, vol. 107, survival,” Blood, vol. 101, no. 4, pp. 1257–1261, 2003.
no. 6, pp. 2279–2285, 2006. [82] M. T. Gladwin, V. Sachdev, M. L. Jison et al., “Pulmonary
[66] S. K. Ballas and M. J. Marcolina, “Hyperhemolysis during the hypertension as a risk factor for death in patients with sickle
evolution of uncomplicated acute painful episodes in patients cell disease,”The New England Journal of Medicine, vol. 350, no.
with sickle cell anemia,” Transfusion, vol. 46, no. 1, pp. 105–110, 9, pp. 886–895, 2004.
2006. [83] K. I. Ataga, C. G. Moore, S. Jones et al., “Pulmonary hyperten-
[67] J. G. Taylor VI, V. G. Nolan, L. Mendelsohn, G. J. Kato, M. T. sion in patients with sickle cell disease: a longitudinal study,”
Gladwin, and M. H. Steinberg, “Chronic hyper-hemolysis in British Journal of Haematology, vol. 134, no. 1, pp. 109–115, 2006.
sickle cell anemia: association of vascular complications and [84] G. J. Kato, O. C. Onyekwere, and M. T. Gladwin, “Pulmonary
mortality with less frequent vasoocclusive pain,” PLoS One, vol. hypertension in sickle cell disease: relevance to children,”
3, no. 5, Article ID e2095, 2008. Pediatric Hematology and Oncology, vol. 24, no. 3, pp. 159–170,
[68] J. O. Olabode and W. A. Shokunbi, “Types of crises in sickle 2007.
cell disease patients presenting at the haematology day care unit [85] J. Griffiths, “Avascular necrosis of femoral head in Kenyan
(HDCU), University College Hospital (UCH), Ibadan,” West africans,” East African Medical Journal, vol. 45, no. 9, pp. 613–
African Journal of Medicine, vol. 25, no. 4, pp. 284–288, 2006. 618, 1968.
[69] C. T.Quinn, E. P. Shull, N.Ahmad,N. J. Lee, Z. R. Rogers, andG. [86] W.W. Ebong, “Avascular necrosis of the femoral head associated
R. Buchanan, “Prognostic significance of early vaso-occlusive with haemoglobinopathy,” Tropical and Geographical Medicine,
complications in children with sickle cell anemia,” Blood, vol. vol. 29, no. 1, pp. 19–23, 1977.
109, no. 1, pp. 40–45, 2007. [87] R. E. J. Lee, J. S. R. Golding, and G. R. Serjeant, “The
[70] J. M. Topley, D.W. Rogers, M. C. G. Stevens, and G. R. Serjeant, radiological features of avascular necrosis of the femoral head
“Acute splenic sequestration and hypersplenism in the first five in homozygous sicke cell disease,”Clinical Radiology, vol. 32, no.
years in homozygous sickle cell disease,” Archives of Disease in 2, pp. 205–214, 1981.
Childhood, vol. 56, no. 10, pp. 765–769, 1981. [88] K. C. Abbott, I. O. Hypolite, and L. Y. Agodoa, “Sickle cell
[71] A. M. Emond, R. Collis, and D. Darvill, “Acute splenic seques- nephropathy at end-stage renal disease in the United States:
tration in homozygous sickle cell disease: natural history and patient characteristics and survival,” Clinical Nephrology, vol.
management,” Journal of Pediatrics, vol. 107, no. 2, pp. 201–206, 58, no. 1, pp. 9–15, 2002.
1985. [89] A. F. Fleming, J. Storey, L. Molineaux, E. A. Iroko, and
E. D. Attai, “Abnormal haemoglobins in the Sudan savanna
[72] M. Koshy, R. Entsuah, A. Koranda et al., “Leg ulcers in patients of Nigeria. I. Prevalence of haemoglobins and relationships
with sickle cell disease,”Blood, vol. 74, no. 4, pp. 1403–1408, 1989. between sickle cell trait, malaria and survival,” Annals of
[73] M. A. Durosinmi, S. M. Gevao, and G. J. Esan, “Chronic leg Tropical Medicine and Parasitology, vol. 73, no. 2, pp. 161–172,
ulcers in sickle cell disease: experience in Ibadan, Nigeria,” 1979.
African Journal of Medicine and Medical Sciences, vol. 20, no. [90] A. F. Fleming, “The presentation, management and prevention
1, pp. 11–14, 1991. of crisis in sickle cell disease in Africa,” Blood Reviews, vol. 3, no.
[74] A. D. Gbadoé, A. Géraldo, K. Guédénon, S. Koffi, K. Agbétiafa, 1, pp. 18–28, 1989.
and P. Akpako, “Stuttering priapism in children with sickle cell [91] G. D. Overturf, D. Powars, and L. J. Baraff, “Bacterial meningitis
anemia in Togo,”Archives de Pediatrie, vol. 14, no. 7, pp. 861–863, and septicemia in sickle cell disease,” American Journal of
2007. Diseases of Children, vol. 131, no. 7, pp. 784–787, 1977.
[75] K. Ohene-Frempong, S. J. Weiner, L. A. Sleeper et al., “Cere- [92] P. J. Campbell, P. O. Olatunji, K. E. Ryan, and S. C. Davies,
brovascular accidents in sickle cell disease: rates and risk “Splenic regrowth in sickle cell anaemia following hypertrans-
factors,” Blood, vol. 91, no. 1, pp. 288–294, 1998. fusion,” British Journal of Haematology, vol. 96, no. 1, pp. 77–79,
[76] M. R. DeBaun, J. Schatz, M. J. Siegel et al., “Cognitive screening 1997.
examinations for silent cerebral infarcts in sickle cell disease,” [93] A. Yardumian and C. Crawley, “Sickle cell disease,” Clinical
Neurology, vol. 50, no. 6, pp. 1678–1682, 1998. Medicine, vol. 1, no. 6, pp. 441–446, 2001.
[77] T. R. Kinney, L. A. Sleeper, W. C. Wang et al., “Silent cerebral [94] M. H. Steinberg, “Pathophysiology of sickle cell disease,” Bail-
infarcts in sickle cell anemia: a risk factor analysis,” Pediatrics, liere’s Clinical Haematology, vol. 11, no. 1, pp. 163–184, 1998.
vol. 103, no. 3, pp. 640–645, 1999. [95] H. F. Bunn, “Pathogenesis and treatment of sickle cell disease,”
[78] S. T.Miller, E. A.Macklin, C. H. Pegelow et al., “Silent infarction The New England Journal of Medicine, vol. 337, no. 11, pp. 762–
as a risk factor for overt stroke in children with sickle cell 769, 1997.
anemia: a report from the Cooperative Study of Sickle Cell [96] D. Labie, J. Pagnier, C. Lapoumeroulie et al., “Common haplo-
Disease,” Journal of Pediatrics, vol. 139, no. 3, pp. 385–390, 2001. type dependency of high (G)𝛾-globin gene expression and high
14 The Scientific World Journal
Hb F levels in 𝛽-thalasssemia and sickle cell anemia patients,” [113] P. Beighton and M. C. Botha, “Inherited disorders in the
Proceedings of the National Academy of Sciences of the United black population of southern Africa—part I: historical and
States of America, vol. 82, no. 7, pp. 2111–2114, 1985. demographic background; genetic haematological conditions,”
[97] L. E. Creary, P. Ulug, S. Menzel et al., “Genetic variation on South African Medical Journal, vol. 69, no. 4, pp. 247–249, 1986.
chromosome 6 influences F cell levels in healthy individuals of [114] World Health Organisation, Genomics and World Health,
African descent andHbF levels in sickle cell patients,”PLoSOne, Report of the Advisory Committee on Health Research, World
vol. 4, no. 1, Article ID e4218, 2009. Health Organisation, Geneva, Switzerland, 2002.
[98] M. Uda, R. Galanello, S. Sanna et al., “Genome-wide asso- [115] L. Molineaux, A. F. Fleming, and R. Cornille-Brogger, “Abnor-
ciation study shows BCL11A associated with persistent fetal mal haemoglobins in the Sudan savanna of Nigeria. III. Malaria
hemoglobin and amelioration of the phenotype of 𝛽-thalasse- immunoglobulins and antimalarial antibodies in sickle cell
mia,” Proceedings of the National Academy of Sciences of the disease,” Annals of Tropical Medicine and Parasitology, vol. 73,
United States of America, vol. 105, no. 5, pp. 1620–1625, 2008. no. 4, pp. 301–310, 1979.
[99] G. Lettre, V. G. Sankaran, M. A. C. Bezerra et al., “DNA [116] C. T. Quinn, Z. R. Rogers, and G. R. Buchanan, “Survival of
polymorphisms at the BCL11A, HBS1L-MYB, and 𝛽-globin loci childrenwith sickle cell disease,”Blood, vol. 103, no. 11, pp. 4023–
associate with fetal hemoglobin levels and pain crises in sickle 4027, 2004.
cell disease,” Proceedings of the National Academy of Sciences of
the United States of America, vol. 105, no. 33, pp. 11869–11874, [117] P. Telfer, P. Coen, S. Chakravorty et al., “Clinical outcomes in
2008. children with sickle cell disease living in England: a neonatal
[100] A. E. Sedgewick, N. Timofeev, P. Sebastiani et al., “BCL11A is cohort in East London,” Haematologica, vol. 92, no. 7, pp. 905–
a major HbF quantitative trait locus in three different popula- 912, 2007.
tions with 𝛽-hemoglobinopathies,” Blood Cells, Molecules, and [118] A. N.Thomas, C. Pattison, and G. R. Serjeant, “Causes of death
Diseases, vol. 41, no. 3, pp. 255–258, 2008. in sickle-cell disease in Jamaica,” British Medical Journal, vol.
[101] S. L.Thein and S. Menzel, “Discovering the genetics underlying 285, no. 6342, pp. 633–635, 1982.
foetal haemoglobin production in adults,” British Journal of [119] M. Brozovic and E. Anionwu, “Sickle cell disease in Britain,”
Haematology, vol. 145, no. 4, pp. 455–467, 2009. Journal of Clinical Pathology, vol. 37, no. 12, pp. 1321–1326, 1984.
[102] J. Makani, S. Menzel, S. Nkya et al., “Genetics of fetal [120] V. G. Sankaran andM. V. Sapp, “Persistence of fetal hemoglobin
hemoglobin in Tanzanian and British patients with sickle cell expression in an older child with trisomy 13,” Journal of
anemia,” Blood, vol. 117, no. 4, pp. 1390–1392, 2011. Pediatrics, vol. 160, no. 2, p. 352, 2012.
[103] World Health Organisation, “Sickle cell anaemia. Agenda item [121] A. Lee, P. Thomas, L. Cupidore, B. Serjeant, and G. Serjeant,
11.4,” in 59thWorldHealthAssembly, 27May 2006,WorldHealth “Improved survival in homozygous sickle cell disease: lessons
Organisation, Geneva, Switzerland, 2006. from a cohort study,” British Medical Journal, vol. 311, no. 7020,
[104] D.Diallo andG. Tchernia, “Sickle cell disease inAfrica,”Current pp. 1600–1602, 1995.
Opinion in Hematology, vol. 9, no. 2, pp. 111–116, 2002. [122] E. Vichinsky, D. Hurst, A. Earles, K. Kleman, and B. Lubin,
[105] D. J. Weatherall, O. Akinyanju, S. Fucharoen, N. F. Olivieri, and “Newborn screening for sickle cell disease: effect on mortality,”
P. Musgrove, “Inherited disorders of hemoglobin,” in Disease Pediatrics, vol. 81, no. 6, pp. 749–755, 1988.
Control Priorities in Developing Countries, D. Jamison, Ed., pp. [123] T. Frempong and H. A. Pearson, “Newborn screening coupled
663–680, Oxford University Press, New York, NY, USA, 2006. with comprehensive follow-up reduced early mortality of sickle
[106] D. J. Weatherall, “Hemoglobinopathies worldwide: present and cell disease in Connecticut,” Connecticut Medicine, vol. 71, no. 1,
future,” Current Molecular Medicine, vol. 8, no. 7, pp. 592–599, pp. 9–12, 2007.
2008. [124] Z.M.Al-Hawsawi andG.A. Ismail, “Acute splenic sequestration
[107] A. Enevold, J. P. Lusingu, B. Mmbando et al., “Reduced risk crisis in children with sickle cell disease,” SaudiMedical Journal,
of uncomplicated malaria episodes in children with alpha+- vol. 22, no. 12, pp. 1076–1079, 2001.
thalassemia in Northeastern Tanzania,” American Journal of
Tropical Medicine and Hygiene, vol. 78, no. 5, pp. 714–720, 2008. [125] J. A. Wilimas, P. M. Flynn, S. Harris et al., “A randomized study
[108] T. N. Williams, S. Wambua, S. Uyoga et al., “Both heterozygous of outpatient treatment with ceftriaxone for selected febrile
and homozygous 𝛼+ thalassemias protect against severe and children with sickle cell disease,” The New England Journal of
fatal Plasmodium falciparum malaria on the coast of Kenya,” Medicine, vol. 329, no. 7, pp. 472–476, 1993.
Blood, vol. 106, no. 1, pp. 368–371, 2005. [126] M.C. Rahimy,A.Gangbo,G.Ahouignan, S. Anagonou,V. Boco,
[109] M. Aidoo, D. J. Terlouw, M. S. Kolczak et al., “Protective effects and E. Alihonou, “Outpatient management of fever in children
of the sickle cell gene against malaria morbidity and mortality,” with sickle cell disease (SCD) in an African setting,” American
The Lancet, vol. 359, no. 9314, pp. 1311–1312, 2002. Journal of Hematology, vol. 62, no. 1, pp. 1–6, 1999.
[110] D. J. Weatherall and J. B. Clegg, “Inherited haemoglobin [127] R. E.Ware, S. A. Zimmerman, andW.H. Schultz, “Hydroxyurea
disorders: an increasing global health problem,” Bulletin of the as an alternative to blood transfusions for the prevention of
World Health Organization, vol. 79, no. 8, pp. 704–712, 2001. recurrent stroke in children with sickle cell disease,” Blood, vol.
[111] D. Modiano, G. Bancone, B. M. Ciminelli et al., “Haemoglobin 94, no. 9, pp. 3022–3026, 1999.
S and haemoglobin C: ‘quick but costly’ versus ‘slow but [128] M. C. Rahimy, A. Gangbo, G. Ahouignan et al., “Effect of
gratis’ genetic adaptations to Plasmodium falciparum malaria,” a comprehensive clinical care program on disease course in
Human Molecular Genetics, vol. 17, no. 6, pp. 789–799, 2008. severely ill children with sickle cell anemia in a sub-Saharan
[112] J. Simpore, S. Pignatelli, S. Barlati, and S. Musumeci, “Modifi- African setting,” Blood, vol. 102, no. 3, pp. 834–838, 2003.
cation in the frequency of Hb C and Hb S in Burkina Faso: an [129] J. Knight-Madden and G. R. Serjeant, “Invasive pneumococcal
influence ofmigratory fluxes and improvement of patient health disease in homozygous sickle cell disease: Jamaican experience
care,” Hemoglobin, vol. 26, no. 2, pp. 113–120, 2002. 1973–1997,” Journal of Pediatrics, vol. 138, no. 1, pp. 65–70, 2001.
The Scientific World Journal 15
[130] J. A. Berkley, B. S. Lowe, I. Mwangi et al., “Bacteremia among [146] K. Ohene-Frempong, “Indications for red cell transfusion in
children admitted to a rural hospital in Kenya,” The New sickle cell disease,” Seminars in Hematology, vol. 38, no. 1,
England Journal of Medicine, vol. 352, no. 1, pp. 39–47, 2005. supplement 1, pp. 5–13, 2001.
[131] A. Roca, B. Sigaúque, L. Quintó et al., “Invasive pneumococcal [147] R. J. Dunlop andK.C. Bennett, “Painmanagement for sickle cell
disease in children >5 years of age in rural Mozambique,” disease,”Cochrane Database of Systematic Reviews, no. 2, Article
Tropical Medicine and International Health, vol. 11, no. 9, pp. ID CD003350, 2006.
1422–1431, 2006. [148] D. C. Rees, A. D. Olujohungbe, N. E. Parker, A. D. Stephens,
[132] M. deMontalembert, V. Brousse, and J.-R. Zahar, “Pneumococ- P. Telfer, and J. Wright, “Guidelines for the management of
cal prophylaxis for children with sickle cell disease in Africa,” the acute painful crisis in sickle cell disease,” British Journal of
Archives of Disease in Childhood, vol. 93, no. 8, pp. 715–716, Haematology, vol. 120, no. 5, pp. 744–752, 2003.
2008. [149] S. K. Ballas, “Pain management of sickle cell disease,” Hematol-
[133] J. R. Aluoch, “Higher resistance to Plasmodium falciparum ogy/Oncology Clinics of North America, vol. 19, no. 5, pp. 785–
infection in patients with homozygous sickle cell disease in 802, 2005.
Western Kenya,” Tropical Medicine and International Health, [150] S. Charache, M. L. Terrin, R. D. Moore et al., “Effect of
vol. 2, no. 6, pp. 568–571, 1997. hydroxyurea on the frequency of painful crises in Sickle cell
[134] H. O. Okuonghae, M. U. Nwankwo, and E. Offor, “Brief anemia,”The New England Journal of Medicine, vol. 332, no. 20,
reports malarial parasitaemia in febrile children with sickle cell pp. 1317–1322, 1995.
anaemia,” Journal of Tropical Pediatrics, vol. 38, no. 2, pp. 83–85, [151] R. E. Ware, M. H. Steinberg, and T. R. Kinney, “Hydroxyurea:
1992. an alternative to transfusion therapy for stroke in sickle cell
[135] R. Kotila, A. Okesola, and O. Makanjuola, “Asymptomatic ma- anemia,”American Journal ofHematology, vol. 50, no. 2, pp. 140–
laria parasitaemia in sickle-cell disease patients: how effective 143, 1995.
is chemoprophylaxis?” Journal of Vector Borne Diseases, vol. 44, [152] National Institutes of Health, National Institutes of Health:
no. 1, pp. 52–55, 2007. Consensus Development Conference Statement: Hydroxyurea
[136] O.Awotua-Efebo, E.A.Alikor, andK. E.Nkanginieme, “Malaria Treatment for Sickle Cell Disease, National Institutes of Health,
parasite density and splenic status by ultrasonography in sta- 2008.
ble sickle-cell anaemia (HbSS) children,” Nigerian Journal of [153] W.H.Waugh, C.W.Daeschner III, B. A. Files,M. E.McConnell,
Medicine, vol. 13, no. 1, pp. 40–43, 2004. and S. E. Strandjord, “Oral citrulline as arginine precursor may
[137] J. Makani, A. N. Komba, S. E. Cox et al., “Malaria in patients be beneficial in sickle cell disease: early phase two results,”
with sickle cell anemia: burden, risk factors, and outcome at the Journal of the National Medical Association, vol. 93, no. 10, pp.
outpatient clinic and during hospitalization,” Blood, vol. 115, no. 363–371, 2001.
2, pp. 215–220, 2010. [154] C. R.Morris, E. P. Vichinsky, J. vanWarmerdam et al., “Hydrox-
yurea and arginine therapy: impact on nitric oxide production
[138] O. Oniyangi and A. A. Omari, “Malaria chemoprophylaxis in in sickle cell disease,” Journal of Pediatric Hematology/Oncology,
sickle cell disease,”CochraneDatabase of Systematic Reviews, no. vol. 25, no. 8, pp. 629–634, 2003.
4, Article ID CD003489, 2006. [155] M. Oppert, A. Jörres, D. Barckow, K.-U. Eckardt, U. Frei, and
[139] S. Wahl and K. C. Quirolo, “Current issues in blood transfusion U. Kaisers, “Inhaled nitric oxide for ARDS due to sickle cell
for sickle cell disease,” Current Opinion in Pediatrics, vol. 21, no. disease,” Swiss Medical Weekly, vol. 134, no. 11-12, pp. 165–167,
1, pp. 15–21, 2009. 2004.
[140] R. J. Adams, V. C. McKie, L. Hsu et al., “Prevention of a first [156] D. L. Weiner and C. Brugnara, “Hydroxyurea and sickle cell
stroke by transfusions in children with sickle cell anemia and disease: a chance for every patient,” Journal of the American
abnormal results on transcranial Doppler ultrasonography,”The Medical Association, vol. 289, no. 13, pp. 1692–1694, 2003.
New England Journal of Medicine, vol. 339, no. 1, pp. 5–11, 1998. [157] M. T. Gladwin, J. H. Shelhamer, F. P. Ognibene et al., “Nitric
[141] J. M. Turner, J. B. Kaplan, H. W. Cohen, and H. H. Billett, oxide donor properties of hydroxyurea in patients with sickle
“Exchange versus simple transfusion for acute chest syndrome cell disease,” British Journal of Haematology, vol. 116, no. 2, pp.
in sickle cell anemia adults,” Transfusion, vol. 49, no. 5, pp. 863– 436–444, 2002.
868, 2009. [158] F. L. Johnson, A. T. Look, and J. Gockerman, “Bone-marrow
[142] E. P. Vichinsky, C. M. Haberkern, L. Neumayr et al., “A com- transplantation in a patient with sickle-cell anemia,” The New
parison of conservative and aggressive transfusion regimens in England Journal of Medicine, vol. 311, no. 12, pp. 780–783, 1984.
the perioperative management of sickle cell disease,” The New [159] M. C. Walters, R. Storb, M. Patience et al., “Impact of bone
England Journal of Medicine, vol. 333, no. 4, pp. 206–213, 1995. marrow transplantation for symptomatic sickle cell disease: an
[143] K. A. Stegenga, P. Ward-Smith, P. S. Hinds, J. A. Routhieaux, interim report,” Blood, vol. 95, no. 6, pp. 1918–1924, 2000.
and G. M. Woods, “Quality of life among children with sickle [160] L. Krishnamurti, S. Abel, M. Maiers, and S. Flesch, “Availability
cell disease receiving chronic transfusion therapy,” Journal of of unrelated donors for hematopoietic stem cell transplantation
Pediatric Oncology Nursing, vol. 21, no. 4, pp. 207–213, 2004. for hemoglobinopathies,” BoneMarrow Transplantation, vol. 31,
[144] R. Prasad, S. Hasan, O. Castro, E. Perlin, and K. Kim, “Long- no. 7, pp. 547–550, 2003.
term outcomes in patients with sickle cell disease and frequent [161] P. Woodard, B. Lubin, and M. C. Walters, “New approaches to
vaso-occlusive crises,”American Journal of theMedical Sciences, hematopoietic cell transplantation for hematological diseases in
vol. 325, no. 3, pp. 107–109, 2003. children,” Pediatric Clinics of North America, vol. 49, no. 5, pp.
[145] M. J. Telen, “Principles and problems of transfusion in sickle 989–1007, 2002.
cell disease,” Seminars in Hematology, vol. 38, no. 4, pp. 315–323, [162] T.V.Adamkiewicz, P. S.Mehta,M.W. Boyer et al., “Transplanta-
2001. tion of unrelated placental blood cells in childrenwith high-risk
16 The Scientific World Journal
sickle cell disease,” Bone Marrow Transplantation, vol. 34, no. 5,
pp. 405–411, 2004.
[163] R. Pawliuk, K. A. Westerman, M. E. Fabry et al., “Correction of
sickle cell disease in transgenic mouse models by gene therapy,”
Science, vol. 294, no. 5550, pp. 2368–2371, 2001.
[164] World Health Organisation, Guidelines for the Control of
Haemoglobin Disorders, World Health Organisation, Geneva,
Switzerland, 1994.
[165] A. Alwan and B. Modell, “Recommendations for introducing
genetics services in developing countries,” Nature Reviews
Genetics, vol. 4, no. 1, pp. 61–68, 2003.
[166] A.Wonkam,A. K.Njamnshi, and F. F. Angwafo III, “Knowledge
and attitudes concerning medical genetics amongst physicians
and medical students in Cameroon (sub-Saharan Africa),”
Genetics in Medicine, vol. 8, no. 6, pp. 331–338, 2006.
[167] M. A. Durosinmi, A. I. Odebiyi, I. A. Adediran, N. O. Akinola,
D. E. Adegorioye, andM.A.Okunade, “Acceptability of prenatal
diagnosis of sickle cell anaemia (SCA) by female patients and
parents of SCA patients inNigeria,” Social Science andMedicine,
vol. 41, no. 3, pp. 433–436, 1995.
[168] A. S. Adeyemi and D. A. Adekanle, “Knowledge and attitude of
female health workers towards prenatal diagnosis of sickle cell
disease,”Nigerian Journal ofMedicine, vol. 16, no. 3, pp. 268–270,
2007.
[169] O. O. Akinyanju, R. F. Disu, J. A. Akinde, T. A. Adewole, A. I.
Otaigbe, and E. E. Emuveyan, “Initiation of prenatal diagnosis
of sickle-cell disorders in Africa,” Prenatal Diagnosis, vol. 19, no.
4, pp. 299–304, 1999.
[170] J. Xu, C. Peng, V. G. Sankaran et al., “Correction of sickle cell
disease in adult mice by interference with fetal hemoglobin
silencing,” Science, vol. 334, no. 6058, pp. 993–996, 2011.
[171] World Health Organisation, Sickle Cell Disease: A Strategy for
the WHO Africa Region, R.o.t.R. Director, 2010.
[172] D. J. Weatherall, “Genomics and global health: time for a reap-
praisal,” Science, vol. 302, no. 5645, pp. 597–599, 2003.
[173] D. Weatherall, K. Hofman, G. Rodgers, J. Ruffin, and S.
Hrynkow, “A case for developing North-South partnerships for
research in sickle cell disease,” Blood, vol. 105, no. 3, pp. 921–923,
2005.