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Map of the distribution of the S gene in Africa Note: The map is based on representative indigenous population samples and is adapted from Figure 1b in Piel et al. 24 The figure shows the global distribution of the sickle cell gene and geographic confirmation of the malaria hypothesis.

Map of the distribution of the S gene in Africa Note: The map is based on representative indigenous population samples and is adapted from Figure 1b in Piel et al. 24 The figure shows the global distribution of the sickle cell gene and geographic confirmation of the malaria hypothesis.

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Article
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Sickle cell disease (SCD) is common throughout much of sub-Saharan Africa, affecting up to 3% of births in some parts of the continent. Nevertheless, it remains a low priority for many health ministries. The most common form of SCD is caused by homozygosity for the β-globin S gene mutation (SS disease). It is widely believed that this condition is...

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Context 1
... SCD is variably referred to as sickle cell anemia, Hb SS, SS, SS disease, or sickle cell disease-SS. The distribution of the S al- lele ( Figure 1) has re- cently been mapped globally using detailed geo-referenced data and displays a close associa- tion with the historical distribution of Plasmo- dium falciparum malar- ial endemicity. 24 Within Africa, the frequency of S , and accordingly SS, is highest in low-altitude equatorial regions. ...
Context 2
... data on the birth frequencies of SS and SC in Africa are needed. Frequencies of S alleles can vary considerably over relatively small distances (Figure 1). 24 For example, pilot newborn screening studies in the Democratic Republic of the Congo have indicated that the frequency of SS at birth varies by region from 0.8% to 1.7%, 54 and in neighboring Rwanda and Burundi, the frequency is considerably lower, 0.1% or less. ...
Context 3
... might be responsible for 5%-16% of under-5 mortality in some areas of sub-Saharan Africa according to published estimates. 59 Areas of high frequency of the S allele, shown in dark shading in Figure 1, indicate where homozygous SCD is a major public health prob- lem. As basic public health measures-including im- proved nutrition and interventions against malaria, pneumonia, and diarrhea-reduce the burden of infec- tious diseases, it is likely that the absolute burden of mortality attributable to SCD will decrease, but that the relative burden as a fraction of all under-5 mortality ac- tually might rise. ...

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... 3,4 In sub-Saharan Africa, about 8 in 10 children are born of SCD which is reported to be associated with a high mortality rate in such children. 5,6 In Ghana about 2 out of 100 newborns are diagnosed as having SCD with approximately 6 in 10 having the homozygous form (SS). 7 The current daily treatment regimen such as folic acid, hematinics, penicillin V and hydroxyurea has significantly improved the health outcomes of SCD patients as well as reduced the mortality rate of the disease. In sub-Saharan Africa, infection alone contributes to about 50.0% ...
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Background and aims: Penicillin V prophylaxis protects children living with sickle cell disease (SCD) from bacteria infections especially Streptococcus pneumonia. However, the uptake of penicillin V prophylaxis is difficult to assess and often poor among SCD patients. Therefore, this study sought to investigate oral penicillin V prophylaxis adherence among SCD children using urine assay and self-reported methods and the associated factors. Methods: The study employed an analytical cross-sectional design in the assessment of penicillin V prophylaxis adherence using both urine assay and self-reported methods. Multiple logistic regression analysis was used to determine the factors associated with penicillin V prophylaxis adherence. A p value < 0.05 was considered statistically significant. Results: Among the 421 SCD patients recruited, penicillin V prophylaxis adherence was observed to be 30.0% and 68.0% for the objective and subjective methods of assessment, respectively. For the objective method of assessment, being cared for by grandparents increased the odds of penicillin V adherence (adjusted odds ratio [aOR] = 3.68, confidence interval [CI] = 1.03-13.15). However, SCD patients within the ages of 10-14 years (aOR = 0.36, CI = 0.17-0.80), >14 years (aOR = 0.17, CI = 0.05-0.61), SCD patient cared for by married caregivers/parents (aOR = 0.32, CI = 0.14-0.72), SCD patient cared for by divorced caregivers/parents (aOR = 0.23, CI = 0.07-0.75), SCD patients taking homemade (herbal) preparations for the treatment of SCD (aOR = 0.42, CI = 0.21-0.83), and inappropriate intake of penicillin V prophylaxis (aOR = 0.27, CI = 0.11-0.67) reduced the odds of penicillin V adherence. For the subjective method of assessment, taking homemade preparation (herbal) for the treatment of SCD (aOR = 0.52, CI = 0.30-0.89) and inappropriate intake of penicillin V (aOR = 0.32, CI = 0.17-0.60) reduced the odds of penicillin V adherence. Conclusion: This study reports a relatively low adherence rate of penicillin V prophylaxis among children living with SCD. Educating and counseling both SCD patients and/or caregivers on the need to be adherent to penicillin V prophylaxis could prevent complications that may arise from nonadherence.
... [1][2][3] Initial efforts to model the mortality rates in children with SCA indicated 50-90% early-life mortality. 4 Through improved medical therapies and access to care, the survival of children with SCA has been substantially enhanced. 5 A recent multi-center and multi-country retrospective study in children with SCA living in sub-Saharan Africa estimated a significant decline in childhood mortality. ...
... 5 However, there continues to be excess mortality and morbidity in children with SCA living in sub-Saharan Africa. 1,[4][5][6] In the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria [Stroke Prevention in Nigeria (SPRING)] trial, the mortality in children aged 5-12 years with SCA was 2.38 per 100 person-years, with no significant difference between participants on low-or moderate dose treatment or those in the treatment or comparison group. 7 In contrast, children with SCA aged 5-14 in the United States have a death rate of <0.5 per 100,000 person-years. ...
Article
Undernutrition is a risk factor for under 5 mortality and is also postulated to be a risk factor for mortality in older children and adults with sickle cell anemia. We tested the hypothesis that underweight (weight-for-age z-score <-1) is associated with mortality in children aged 5-12 years with sickle cell anemia. We performed a secondary analysis of participants in the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria trial, a double-blind, parallel-group randomized controlled trial for low-dose (n=109) or moderate-dose (n=111) hydroxyurea in children with abnormal transcranial Doppler velocities and a comparison group (n=211) of participants with non-elevated transcranial Doppler velocities in northern Nigeria (NCT02560935). Nutritional status was classified as underweight (weight-for-age z-score), stunting (height-for-age z-score), and wasting (body mass index z-score) using the World Health Organization growth reference. The mean weight-for-age z-score was lower in children who died during the study than in those who survived (-2.6 vs. -2.1, p=0.016). Otherwise, the baseline characteristics of children who died during the study were not significantly different from those who survived. A pooled analysis of participants demonstrated that a lower weight-for-age z-score was associated with an increased hazard of death (HR=0.580, p=0.004, 95%CI 0.399-0.843). Underweight participants (weight-for-age z-score <-1) had a greater probability of death during follow-up than those not underweight (p=0.043). Underweight status in school-aged children with sickle cell anemia is a previously unrecognized risk factor for early mortality in Nigeria and can be easily applied to screen children at risk for death.
... Africa has the highest burden of sickle cell anaemia (SCA), accounting for 75% of the total 300 000 global births per year. 1 The prevalence of overt stroke in people with SCA living in African countries is 3%-17%, with children most commonly affected. 2,3 Transcranial Doppler screening and hydroxycarbamide (hydroxyurea) reduces overt stroke risk in African children. 4 However, little is known about the effect of silent cerebral infarction (SCI), which is also common in patients with SCA, 5 and may be the result of chronic, repetitive injury due to hypoxic or ischaemic exposure. ...
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Brain injury is a common complication of sickle cell anaemia (SCA). White matter (WM) and cortical and subcortical grey matter (GM), structures may have reduced volume in patients with SCA. This study focuses on whether silent cerebral infarction (SCI), vasculopathy or anaemia affects WM and regional GM volumes in children living in Africa. Children with SCA (n = 144; aged 5–20 years; 74 male) and sibling controls (n = 53; aged 5–17 years; 29 male) underwent magnetic resonance imaging. Effects of SCI (n = 37), vasculopathy (n = 15), and haemoglobin were assessed. Compared with controls, after adjusting for age, sex and intracranial volume, patients with SCA had smaller volumes for WM and cortical, subcortical and total GM, as well as bilateral cerebellar cortex, globus pallidus, amygdala and right thalamus. Left globus pallidus volume was further reduced in patients with vasculopathy. Putamen and hippocampus volumes were larger in patients with SCA without SCI or vasculopathy than in controls. Significant positive effects of haemoglobin on regional GM volumes were confined to the controls. Patients with SCA generally have reduced GM volumes compared with controls, although some subcortical regions may be spared. SCI and vasculopathy may affect the trajectory of change in subcortical GM and WM volume. Brain volume in non‐SCA children may be vulnerable to contemporaneous anaemia.
... About 150,000 children are born with this condition annually in this region. The incidence of SCD in Nigeria varies from 2% to 3% as reported by various investigators in the different regions of the Country (Grosse et al., 2011). ...
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Background: The Sickle Pan-African Research Consortium (SPARCO) and Sickle Africa Data Coordinating Center (SADaCC) were set up with funding from the US National Institute of Health (NIH) for physicians, scientists, patients, support groups, and statisticians to collaborate to reduce the high disease burden and alleviate the impact of Sickle Cell Disease (SCD) in Africa. For 5 years, SPARCO and SADaCC have been collecting basic clinical and demographic data from Nigeria, Tanzania, and Ghana. The resulting database will support analyses to estimate significant clinical events and provide directions for targeting interventions and assessing their impacts. Method: The Nigerian study sited at Centre of Excellence for Sickle Cell Disease Research and Training (CESRTA), University of Abuja, adopted REDCap for online database management. The case report form (CRF) was adapted from 1,400 data elements adopted by SPARCO sites. It captures 215 data elements of interest across sub-sites, i.e., demographic, social, diagnostic, clinical, laboratory, imaging, and others. These were harmonized using the SADaCC data dictionary. REDCap was installed on University of Abuja cloud server at https://www.redcap.uniabuja.edu.ng . Data collected at the sites are sent to CESRTA for collation, cleaning and uploading to the database. Results: 7,767 people living with sickle cell disease were enrolled at 25 health institutions across the six zones in Nigeria with 5,295 having had at least one follow-up visit with their clinical data updated. They range from 44 to 1,180 from 3 centers from South East, 4 from South, 5 from South West, 8 from North Central, 4 in North West and 3 in the North East. North West has registered 1,383 patients, representing 17.8%; North East, 359 (4.6%); North Central, 2,947 (37.9%); South West, 1,609 (20.7%); South, 442 (5.7%) and South East, 1,027 patients (13.2%). Conclusion: The database is being used to support studies including analysis of clinical phenotypes of SCD in Nigeria, and evaluation of Hydroxyurea use in SCD. Reports undergoing review in journals have relied on the ease of data access in REDCap. The database is regularly updated by batch and individual record uploads while we are utilizing REDCap’s in-built functions to generate simple statistic.
... [1][2][3][4][5] For the 300,000 to 400,000 babies born with SCD annually in sub-Saharan Africa, under-5-year (U5) mortality has been estimated as >50%. [6][7][8] This was confirmed in recent assessments and is several-fold higher than U5 mortality in children without SCD. [8][9][10][11] Deaths prior to SCD diagnosis lead to under-estimates of disease-associated mortality and underscore the importance of early population-based screening. ...
... [6][7][8] This was confirmed in recent assessments and is several-fold higher than U5 mortality in children without SCD. [8][9][10][11] Deaths prior to SCD diagnosis lead to under-estimates of disease-associated mortality and underscore the importance of early population-based screening. 4,9 Major causes of U5 mortality in sub-Saharan African children with SCD include malaria and other infections, severe anemia, respiratory and diarrheal illnesses, malnutrition and stroke. ...
Article
Sickle cell disease (SCD) is a common condition within sub-Saharan Africa and associated with high under-5 (U5) mortality. The American Society of Hematology instituted the Consortium on Newborn Screening in Africa (CONSA) for SCD, a seven-country network of sites to implement standardized newborn hemoglobinopathy screening and early intervention for children with SCD in sub-Saharan Africa. CONSA's overall hypothesis is that early infant SCD screening and entry into standardized, continuous care will reduce U5 mortality compared to historical estimates in the region. Primary trial objectives are to determine the population-based birth incidence of SCD and effectiveness of early standardized care for preventing early mortality consortium-wide at each country's site(s). Secondary objectives are to establish universal screening and early interventions for SCD within clinical networks of CONSA partners and assess trial implementation. Outcomes will be evaluated from data collected using a shared patient registry. Standardized trial procedures will be implemented among designated birth populations in seven African countries whose programs met eligibility criteria. Treatment protocol includes administering antibacterial and antimalarial prophylaxis and standard childhood vaccinations against infections commonly affecting children with SCD. Infants with a positive screen and confirmation of SCD within the catchment areas defined by each consortium partner will be enrolled in the clinical intervention protocol and followed regularly until age five years. Effectiveness of these early interventions, along with culturally appropriate family education and counseling, will be evaluated by comparing U5 mortality in the enrolled cohort to estimated pre-program data. Here we describe the methodology planned for this trial.
... Sickle cell anemia (SCA) afflicts over 300,000 newborns annually [1], and most of these children will be born in malaria-endemic regions of sub-Saharan Africa. In African settings, the mortality rate of SCA children is 20 times that of non-SCA children [2], and up to 90% of newborns with SCA die before the age of 5 years [3]. Broadly, this severity is the result of both hematologic and infectious complications, including severe anemia, vaso-occlusive (painful) crises, bacteremia and bacterial pneumonias, and malaria. ...
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Background: Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the comparative efficacy of prevention regimens is largely unknown. Methods and findings: We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited. Conclusions: In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted. Trial registration: clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165.
... Global distributions of sickle cell disease (SCD) and human immunodeficiency virus (HIV) intersect, with Africa serving as the center for both diseases [1,2]. The presence of haemoglobin SS (HbSS) and other structurally aberrant hemoglobin S variants (HbSC, HbC, HbS/ thalassemia, and combinations with other β chain variants) characterize SCD, a severe genetic illness [3]. ...
... According to the 2018 estimates from the World Health Organization, the global HIV infection of approximately 36.9 million people had its concentration in Africa [9]. Sub-Saharan Africa is home to a staggering 64% of the world's HIV-infected adults, 91% of its infected children under the age of 15 years, and about 10% to 40% of the world's SCD population [1,10]. With limited treatment options, both diseases have high morbidity and mortality rates. ...
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Objective: The aim of this systematic review was to investigate if SCD protects against HIV infection by determining the association between SCD and the incidence and virulence of HIV infection. Methods: This is a systematic review that used MEDLINE, PubMed, CINAHL, and Academic Search Complete as data sources. Articles describing the relationship of SCD with HIV infection were included in this review. Hence, the effect measures were converted to correlation coefficients and synthesized accordingly to examine the putative protective role of SCD over HIV infection. Independent full-text screening and data extraction were conducted on all eligible studies. The risk of bias was assessed using the mixed methods appraisal tool. We employed a random-effects model of meta-analysis to estimate the pooled prevalence. We computed Cochrane's Q statistics, I2, and prediction interval to quantify effect size heterogeneity. Results: SCD reduces the risk of HIV infection by 75% (OR = 0.25; r = -0.36, p < 0.001; I2 = 71.65). There was no publication bias (Egger's t-value = 0.411; p = 0.721) (Figure 2). Similarly, risk of HIV virulence was reduced by 77% (OR = 0.23; r= -0.38; p < 0.001; I2 = 63.07).The mechanisms implicated in the protective influence of SCD include autosplenectomy, reduced CCR5 expression, and increased expression of heme and iron-regulated genes. Conclusions: Sickle cell disease appears protective of HIV infection and slows HIV progression. PROSPERO registration Number: CRD42022304490.
... More than 75% of SCD cases occur in Africa (3), with approximately 150,000 infants born with the condition in Nigeria each year (4).In 2016, 0.7 percent of children in Uganda had SCD, and 13.3% had the sickle cell trait (5). SCD contributes to a high incidence of childhood mortality in children under the age of five in Africa, obstructing progress toward the UN Sustainable Development Goal 3: improving health and wellbeing, which includes lowering childhood mortality (6). SCD also has a social and economic impact on children and their families, as recurrent sickle cell crises disrupt the patient's and family's lives in terms of schooling, job, and psychological development (2). ...
... SCD is a major worldwide health problem, affecting between 300,000 and 400,000 neonates globally each year, and it is estimated that 75% of these births occur in Sub-Saharan Africa [1,2]. On the African continent, the disease has a mortality rate of 50-90% among undiagnosed children under the age of five, which may contribute up to 5% of child mortality [3,4]. Such is the case of Angola where 12,000 babies are estimated to be born with SCD each year, but most will die without a correct diagnosis [5]. ...
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Background Sickle Cell Anemia (SCA) is a genetic disease caused by the c.20 A > T mutation in HBB gene, generally characterized by sickle erythrocytes, chronic hemolytic anemia, and vaso-occlusive events. This study aimed to investigate genetic modulators of anemia severity, chronic hemolytic rate, and clinical manifestations in pediatric SCA patients from Angola, where the disease is a severe public health problem. Methods and Results The study was conducted on 200 SCA children living in Luanda or Caxito province. Their clinical phenotype was collected from patients’ hospital records. Hematological and biochemical phenotypes were characterized in steady state condition. Twelve polymorphic regions in VCAM1, CD36 and NOS3 genes were genotyped using PCR, RFLP, and Sanger sequencing. CD36 gene promoter variants showed a significant impact on anemia severity. Particularly, the rs1413661_C allele was associated with lower hemoglobin levels, and increased number of hospitalizations and transfusions. This is the first report associating this SNP with SCA phenotypic heterogeneity. Moreover, the rs1041163_C allele in VCAM1 was associated with lower LDH levels; inversely the rs2070744_C allele in NOS3 was related with higher LDH levels and number of hospitalizations, being a risk factor for increased hemolytic rate. Conclusion This study highlights, for the first time in the Angolan population, the importance of the genetic modifiers of vascular cell adhesion and nitric oxide metabolism in SCA pediatric phenotypic variability.
... The burden is bigger in SSA and India where there is severe morbidity and high mortality among children. Early-life mortality in Africa ranges between 50 and 90% of children born with SCD (2). In most of tropical African countries, including Nigeria, Congo and Cameroon, SCD has not yet received much attention compared to other diseases such as malaria, malnutrition, HIV/AIDS, and other neonatal illnesses (3,4). ...
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Article
Sickle Cell Disease (SCD) is a known public health burden in sub-Saharan Africa (SSA). The manifestation of SCD starts in early childhood and if not well-managed may lead to early death (before the age of 5 years). Understanding the underlying mechanisms that influence early SCD manifestation is of great importance for early disease and intervention management which will in turn, reduce both morbidity and mortality rates in children. One approach of achieving this is by establishing SCD birth cohorts that can be followed for a period of time (3–5 years) whilst documenting necessary information related to early childhood illnesses. To date, there are few SCD birth cohorts in Africa. To address this gap, we have established a birth cohort of babies with and without SCD (with sickle cell trait and healthy babies). These babies are followed up for 3 years with their study visits synchronized to the immunization schedule. During enrollment and follow-up visits, information on demographic, clinical, and laboratory parameters are collected. To date, we have enrolled a total of 341 babies with and without SCD. Out of these, a total of 311, 186, 133, 81, 44, and 16 babies have returned for their 1st, 2nd, 3rd, 4th, 5th, and 6th visits, respectively. We have collected both demographic and clinical information for these babies at enrollment and during follow-up. We have also utilized this platform to learn on the best approaches of establishing and maintaining a research birth cohort in an African context. We have analyzed the practical issues pertaining to the integration of the birth cohort with the immunization platform which seems to be the most effective and sustainable strategy for maintaining a birth cohort in our context.