Sickle Cell Disease In Tanzania Research Articles

Prevalence of Urinary Tract Infections and Antibiogram of Bacteria Isolated From Children With Sickle Cell Disease in Tanzania.

Introduction Individuals with sickle cell disease (SCD) are particularly vulnerable to urinary tract infections (UTIs) due to immunological deficits and renal abnormalities associated with the disorder. These infections can exacerbate underlying health issues and lead to severe complications if not managed promptly and effectively. Due to the heightened risk and potential consequences of UTIs in this population, this study aimed to determine their prevalence and explore the resistance patterns of causative pathogens among children attending the SCD Clinic at Muhimbili National Hospital (MNH), Dar es Salaam, Tanzania. Focusing on this demographic group, we sought to provide targeted insights to inform better clinical protocols and intervention strategies in regions heavily affected by SCD. Materials and methods This prospective cross-sectional study was conducted at the MNH, Dar es Salaam, Tanzania, with an enrollment over two months from 19th March to 21st May 2015. We diagnosed UTIs in children with SCD using dipstick and culture methods. Antibiotic susceptibility was assessed using the Kirby-Bauer disc diffusion method, evaluating resistance patterns to antibiotics such as ampicillin, cloxacillin, erythromycin, chloramphenicol, ceftriaxone, and trimethoprim-sulfamethoxazole. The diagnostic accuracy of the dipstick and culture methods was validated to ensure reliability in detecting UTIs. Statistical analysis was conducted using Statistical Product and Service Solutions (SPSS) software (Released 2019; IBM Corp., Armonk, New York, United States). Results Among the 250 children, 56 (22.4%) were UTI-positive according to the culture method and 62 (24.8%) were UTI-positive according to the dipstick test. Girls were more likely to be UTI-positive than boys (29.1% and 13.6%, respectively; p-value = 0.011). Escherichia coli was the most common uropathogen, followed by Klebsiella, Staphylococcus, Proteus, and Pseudomonas (44.2%, 26.9%, 21.2%, 3.8%, and 1.9%, respectively). All isolates were resistant to ampiclox. Resistance rates to ampicillin, erythromycin, cotrimoxazole, chloramphenicol, and ceftriaxone were 94.2%, 76.9%, 59.6%, 46.2%, and 21.2%, respectively. Conclusion This study indicated that dipsticks diagnosed more UTIs. The prevalence was higher in girls than in boys. Escherichia coli was the most commonly isolated antibiotic-resistant organism. High resistance levels were observed against the combination of ampicillin and cloxacillin. However,the isolates were less resistant to ceftriaxone. These results call for increased surveillance of resistant uropathogens in the pediatric population with SCD.

Infrastructure for bioinformatics applications in Tanzania: Lessons from the Sickle Cell Programme.

Sickle cell disease (SCD) is a common genetic disorder in Africa. Some ongoing work in SCD research includes the analysis and comparisons of variation in phenotypic presentations and disease outcomes with the genotypic signatures. This has contributed to the observed growth of molecular and genetic data in SCD. However, while the "omics" data continues to pile, the capacity to interpret and turn the genetic findings into clinical practice is still underdeveloped, especially in the developing region. Building bioinformatics infrastructure and capacity in the region is key to bridging the gap. This paper seeks to illustrate how the Sickle Cell Programme (SCP) at the Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania, modeled the integration of infrastructure for bioinformatics and clinical research while running day-to-day clinical care for SCD in Tanzania.

Lived Experiences of Adults with Sickle Cell Disease: A Qualitative Study, Dar es Salaam, Tanzania.

Sickle Cell Disease (SCD) is most common genetic disorder and its prevalence in sub-Saharan Africa is increasing. Despite increased survival rates, experiences of adults living with SCD in Tanzania is not well explored. This article provides perceived causes of pain crisis, pain self-management approaches and psychosocial implication of SCD. This study aimed at exploring experiences of adults living with SCD regarding pain triggering or aggravating factors; self-management for pain; psychosocial-economical implication of SCD and coping mechanism used by individuals living with SCD. A qualitative study design was chosen using in-depth interviews with adults living with SCD to explore their experience of living with SCD. Fifteen adults aged 18 years and above living with SCD were interviewed. Data were analyzed by using content analysis approach. Four categories emerged that described experiences of individuals with SCD. The four categories are; "Pain Triggering and Aggravating Factors" describing participants' perceived factors causing pain in SCD; "Self-care remedies for the pain" referring to participants' methods for self-management of pain; "Psychosocial-economic impact of illness" referring to participants' experience of implication of illness on social and economic life and "Dealing and coping with illness" referring to experience of participants on management and coping strategies used to live with the illness. Individuals with SCD experiences several episodes of pain that affect their quality of life. Pain episode can be triggered or aggravated by various factors. Several approaches are used by individuals with SCD to self-manage the pain including taking rest, drinking plenty of water or using pain relieving medication. Care for individuals with SCD should be comprehensive and include proper management of pain, health education on home-based intervention for sickle cell pain, supportive services to deal with psychosocial implications of SCD and improving coping strategies to live with the illness.

Barriers and Facilitators of Availability of Hydroxyurea for Sickle Cell Disease in Tanzania; A Qualitative Study of Pharmaceutical Manufacturers, Importers, and Regulators.

Despite three decades of proven safety and effectiveness of hydroxyurea in modifying sickle cell disease (SCD), its accessibility is limited in Sub-Saharan Africa, which shares 75% of the world's SCD burden. Therefore, it is time to explore the barriers and facilitators for manufacturing and importation of hydroxyurea for SCD in Tanzania. This was qualitative research that employed a case study approach. Purposive sampling followed by an in-depth interview (IDI) using a semi-structured questionnaire aspired by data saturation enabled us to gather data from 10 participants. The study participants were people with more than three years of experience in pharmaceuticals importation, manufacturing, and regulation. The audio-recorded data were verbatim transcribed and analyzed using thematic analysis. Two themes were generated. The first comprised barriers for importation and manufacturing of hydroxyurea with sub-themes such as inadequate awareness of SCD and hydroxyurea, limited market, and investment viability. The second comprised opportunities for importation and manufacturing of hydroxyurea with sub-themes such as awareness of activities performed by medicines regulatory authority and basic knowledge on SCD and hydroxyurea. Inadequate understanding of SCD, hydroxyurea, and orphan drug regulation are major issues that aggravate the concern for limited market and investment viability. Existing opportunities are a starting point towards increasing the availability of hydroxyurea.

Nasopharyngeal Carriage and Antibiogram of Pneumococcal and Other Bacterial Pathogens from Children with Sickle Cell Disease in Tanzania.

BackgroundBacterial infections contribute significantly to morbidity and mortality in sickle cell disease (SCD) patients, particularly children under five years of age. In Tanzania, prophylaxis against pneumococcal infection among children with SCD advocates the use of both oral penicillin V (PV) and pneumococcal vaccines (PNV). Therefore, this study aimed to investigate nasopharyngeal carriage and antibiogram of Streptococcal pneumoniae (S. pneumoniae) and Staphylococcus aureus (S. aureus) in children with SCD in Tanzania.MethodsThis cross-sectional study was undertaken at the two Sickle Pan-African Research Consortium (SPARCO) study sites in Dar es salaam, Tanzania. The study was conducted for six months and enrolled children with SCD between the ages of 6 to 59-months. A semi-structured questionnaire was used to collect patient data. Nasopharyngeal swabs were collected from all participants and cultured for Streptococcal pneumoniae and other bacterial isolates. Antimicrobial susceptibility tests of the isolates were done using the disc diffusion method.ResultsOut of 204 participants, the overall prevalence of bacterial carriage was 53.4%, with S. aureus (23.5%), coagulase-negative Staphylococci (CoNS) (23%) and S. pneumoniae (7.8%) being commonly isolated. In antibiotic susceptibility testing, S. aureus isolates were most resistant to penicillin (81.8%), whereas 81.3% of S. pneumoniae isolates were resistant to co-trimoxazole. The least antimicrobial resistance was observed for chloramphenicol for both S. aureus and S. pneumoniae isolates (6.3% versus 0%). The proportion of multi-drug resistance (MDR) was 66.7% for S. aureus isolates and 25% for S. pneumoniae isolates.ConclusionThere are substantially high nasopharyngeal carriage pathogenic bacteria in children with SCD in Dar es Salaam, Tanzania. The presence of MDR strains to the commonly used antibiotics suggests the need to reconsider optimizing antimicrobial prophylaxis in children with SCD and advocacy on pneumococcal vaccines.

Healthcare Workers' Knowledge and Resource Availability for Care of Sickle Cell Disease in Dar es Salaam, Tanzania.

Background: Sickle cell disease (SCD) is a global public health priority due to its high morbidity and mortality. In Tanzania, SCD accounts for 7% of under-five mortality. Cost-effective interventions such as early diagnosis and linkage to care have been shown to prevent 70% of deaths but require knowledge among healthcare workers and availability of resources at health facilities. In Tanzania, data on these critical determinants are currently lacking. Objective: To assess healthcare workers’ knowledge and resource availability for care of SCD at health facilities in Dar es Salaam, Tanzania. Methodology: A facility-based cross-sectional study was conducted between December 2020 and February 2021 among 490 nurses and clinicians at Regional Referral Hospitals (Temeke, Amana, and Mwananyamala) and Muhimbili National Hospital in Dar es Salaam, Tanzania. Data were collected using a pre-tested structured questionnaire consisting of 13 knowledge questions (scored good knowledge if correct response in >7) and an inventory check list to record available resources. Pearson’s χ2 was used to determine the association between level of knowledge and demographic factors. Multivariate logistic regression was used to ascertain the strength of associations. A two-tailed p-value <0.05 was considered to be statistically significant. Results: Of the 490 participants (median age 28 years [IQR = 26–35]), only 25.1% had good knowledge on SCD. The odds of good knowledge was 82% lower in nurses than clinicians (AOR = 0.177; 95% CI: 0.090, 0.349; p < 0.001); 95% lower in diploma than Master’s degree holders (AOR = 0.049; 95% CI: 0.008, 0.300; p = 0.001) and 4.6 times higher in those with 5–9 years than ≥10 years of experience (AOR = 4.564; 95% CI: 1.341, 15.525; p = 0.015). The regional-level hospitals lacked diagnostic tests and hydroxyurea therapy. Conclusion: There was general lack of knowledge on SCD among healthcare workers and limited availability of critical resources for the diagnosis and care of SCD, especially at regional-level hospitals. Efforts are needed for their improvement to enhance care to patients, thus reducing the morbidity and mortality due to SCD in Tanzania.

The prevalence of human immunodeficiency and of hepatitis B viral infections is not increased in patients with sickle cell disease in Tanzania

BackgroundTanzania ranks as the fourth country in the world with respect to the number of sickle cell disease (SCD) births; it is also endemic to the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV). This study was done to determine the prevalence of HIV and HBV infections among SCD patients in Dar es Salaam, Tanzania.MethodsA multicenter hospital-based descriptive cross sectional study was carried out among participants aged ≥ 16 years with a proven diagnosis of SCD. Socio-demographic and clinical data were recorded. Blood samples were drawn for HIV and HBV diagnosis. All categorical variables were summarized into frequencies.ResultsThere were 185/325 (56.9 %) females. The mean age (SD) was 23.0 ± 7.5 years. The prevalence of HIV was 1.8 %; the prevalence of HBV was 1.2 %.ConclusionsThe prevalence of both HIV and HBV in SCD patients is no greater than in the general population of Dar es Salaam or Tanzania. For associations, a large study would be needed. From a detailed blood transfusion history of SCD patients we found no evidence that HIV or HBV infection was transmitted through blood transfusion.

Making hydroxyurea affordable for sickle cell disease in Tanzania is essential (HASTE): How to meet major health needs at a reasonable cost.

Making hydroxyurea affordable for sickle cell disease in Tanzania is essential (HASTE): How to meet major health needs at a reasonable cost.

Influence of gender norms in relation to child's quality of care: follow-up of families of children with SCD identified through NBS in Tanzania.

Introducing newborn screening (NBS) services for sickle cell disease (SCD) in Africa has been proven to be one of the most cost-effective approach to reducing morbidity and mortality associated with this condition. In view of this evidence, efforts have been made by countries in Africa where SCD prevalence is high to pilot NBS programmes and to strengthen comprehensive care services for SCD. While it is important to reap the benefits of NBS for SCD in Africa in terms of overall quantitative measures, it is also important to understand how certain social and cultural conditions may disproportionately influence the outcomes of screening for some groups. The aim of this study was to analyse the role of gender norms before and after NBS for SCD in Tanzania, and to assess how they influence the quality of care of diagnosed children. Using qualitative methods, we did in-depth interviews with families of children with SCD identified through the NBS services and focus group sessions with nurses working in neonatal and postnatal sections of regional referral hospitals in Dar es Salaam. By analysing the experiences of both the families and nurses, we were able to provide evidence on, firstly, the gendered relations that undergird childcare and, secondly, how those relations influence the quality of care the child may potentially receive. The results emphasize the importance of studying the social implications of SCD in Africa, especially with regard to improving the quality of care for patients with SCD in the region. We propose simple interventions, including gender-conscious health education and genetic counselling, which can help to improve the community understanding of genetic diseases while also reducing gender-related inequalities related to SCD care in Africa.

Newborn Screening for Sickle Cell Disease in Tanzania: The Past, Present and Future

Sickle Cell Disease (SCD) is an inherited disorder of the Haemoglobin molecule of the red blood cells that is associated with serious complications and reduced life expectancy. Over 75% of people with SCD live in Sub-Saharan Africa (SSA), and this proportion are projected to increase to 85% by the year 2050. In Tanzania, approximately 11,000 babies are born with SCD each year, ranking 5th in the world. The high prevalence of SCD in SSA is compounded by the disproportionately higher mortality compared to that observed in the high-income countries. In Tanzania, SCD is a major contributor to under-five mortality and is estimated to account for 7% of all-cause mortality in this age group. Newborn screening (NBS) is the practice of testing babies right after delivery to ascertain whether they have diseases that are potentially lethal if not treated early. Where routinely practiced, NBS has significantly reduced morbidity and mortality associated with such diseases. The Sickle Cell Programme at Muhimbili University of Health and Allied Sciences (MUHAS) in Dar-es-salaam and Bugando Medical Center in Mwanza have both conducted pilot NBS for SCD, showing that the intervention is generally feasible and acceptable in Tanzania. The successful introduction and expansion of NBS in Tanzania will require careful planning and advocacy at community to national level.

Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania

BackgroundSickle cell disease (SCD) is a blood disorder caused by a point mutation on the beta globin gene resulting in the synthesis of abnormal hemoglobin. Fetal hemoglobin (HbF) reduces disease severity, but the levels vary from one individual to another. Most research has focused on common genetic variants which differ across populations and hence do not fully account for HbF variation.MethodsWe investigated rare and common genetic variants that influence HbF levels in 14 SCD patients to elucidate variants and pathways in SCD patients with extreme HbF levels (≥7.7% for high HbF) and (≤2.5% for low HbF) in Tanzania. We performed targeted next generation sequencing (Illumina_Miseq) covering exonic and other significant fetal hemoglobin-associated loci, including BCL11A, MYB, HOXA9, HBB, HBG1, HBG2, CHD4, KLF1, MBD3, ZBTB7A and PGLYRP1.ResultsResults revealed a range of genetic variants, including bi-allelic and multi-allelic SNPs, frameshift insertions and deletions, some of which have functional importance. Notably, there were significantly more deletions in individuals with high HbF levels (11% vs 0.9%). We identified frameshift deletions in individuals with high HbF levels and frameshift insertions in individuals with low HbF. CHD4 and MBD3 genes, interacting in the same sub-network, were identified to have a significant number of pathogenic or non-synonymous mutations in individuals with low HbF levels, suggesting an important role of epigenetic pathways in the regulation of HbF synthesis.ConclusionsThis study provides new insights in selecting essential variants and identifying potential biological pathways associated with extreme HbF levels in SCD interrogating multiple genomic variants associated with HbF in SCD.

Decreased Hepcidin Levels Are Associated with Low Steady-state Hemoglobin in Children With Sickle Cell Disease in Tanzania.

BackgroundThe contribution of hepcidin as a regulator of iron metabolism & erythropoiesis on the severity of anemia in sickle cell disease (SCD) remains poorly characterized, especially in Sub-Saharan African populations. The aims of the study were to determine if hepcidin is associated with severity of steady-state anemia in SCD and to investigate factors associated with hepcidin and anemia in SCD.MethodsArchived samples from 199 Tanzanian children, 56% boys aged 3–18 with laboratory-confirmed SCD were analysed based on recorded averaged steady-state hemoglobin (ASSH) quartiles (lowest vs. highest). Univariable and multivariable logistic regression was used to assess associations with ASSH quartiles.FindingsIn univariable analysis, hepcidin <5·5 ng/mL was associated with increased odds of being in the lowest ASSH quartile (OR 2·20; 95%CI 1·2–3·93) but which was limited to girls (OR 4·85, 95%CI 1·79–13·09, p = .046 for interaction). In multivariable analyses including either reticulocyte percentage or erythropoietin, lower hepcidin remained significantly associated with lowest ASSH quartile, although the hepcidin-sex interaction no longer reached statistical significance. No associations with ASSH quartile were observed for markers of inflammation, hemolysis or potential iron markers except for microcytosis, associated with higher ASSH, but which was confounded by reticulocyte percentage and alpha-thalassaemia status.InterpretationHepcidin is lower in more severely anaemic children with SCD independent of inflammation or markers of erythropoiesis.FundingFunding sources include The Wellcome Trust (080025, 095009, 094780 & 070114), MRC-UK (MC-A760-5QX00), NIHR Oxford Biomedical Research Centre, and the Bill and Melinda Gates Foundation (“Hepcidin and Iron in Global Health”, OPP1055865).

Simultaneous Point-of-Care Detection of Anemia and Sickle Cell Disease in Tanzania: The RAPID Study

▪Introduction. Anemia is a common cause of global morbidity and mortality, disproportionately affecting women and children living in resource-limited settings. The etiology of anemia is multifactorial, but sickle cell disease (SCD) is one of the most important causes and is associated with significant morbidity and early mortality. Simple, inexpensive, point-of-care (POC) diagnostic assays for both anemia and SCD could allow for timely, life-saving medical interventions. Recently developed POC assays have been evaluated in controlled laboratory settings by experienced US investigators, but their feasibility and accuracy have yet to be evaluated in a busy low-resource setting by minimally trained local end-users. In the Robust Assays for Point-of-care Identification of Disease (RAPID) study, we simultaneously evaluated POC assays for both anemia and SCD in Mwanza, Tanzania.Methods. RAPID was a prospective study performed at Bugando Medical Centre, a busy referral hospital in northwest Tanzania. Patients <21 years old were recruited from the sickle cell clinic, the outpatient pediatric clinic, the emergency department, and the inpatient pediatric ward. SCD status was determined using Sickle SCANTM (Biomedomics, Research Triangle Park, North Carolina), a POC lateral flow assay able to qualitatively identify the presence of HbS, HbC, and HbA. The presence and severity of anemia was determined using a first generation novel POC color-based assay that quantifies the hemoglobin concentration by chemically altering the sample's color and comparing it to a pre-defined color scale. Both assays are performed using 5-10 μL of blood collected by finger prick, providing results within 5 minutes. Hemoglobin electrophoresis and a complete blood count (CBC) were also completed for each participant. Both POC assays were independently interpreted by 2 care providers at the bedside, one being an experienced primary member of the RAPID study team and the other a minimally trained medical staff member. Interobserver agreement was calculated, and the sensitivity and specificity of each POC assay was determined using the electrophoresis and CBC results as the gold standard. The sickle cell POC devices were provided free-of-charge by Biomedomics. They had no access to the data or results.Results. RAPID recruited 752 participants (age range 1 day to 20 years, average age 5.2 ± 4.2 years), and data were available for 745. Children were primarily recruited from the inpatient pediatric ward (58.2%) or the sickle cell clinic (38.5%). Two individuals served as Scorer 1, and they interpreted 99% of the assays. Scorer 2 included 136 different Tanzanian pediatricians, interns, students, and nurses. Sensitivity and specificity for the SCD POC assay were excellent for both Scorer 1 (sensitivity 99.4%; specificity 94%) and Scorer 2 (sensitivity 98.1%; specificity 91.1%), with excellent interobserver agreement (Kappa = 0.95). The absolute difference (mean ± SD) between the color-based anemia POC assay and the CBC result was 1.0 ± 0.9 g/dL for Scorer 1 and 1.1 ± 0.9 g/dL for Scorer 2. There was a moderately strong correlation between the anemia POC assay and the measured hemoglobin concentration (r=0.65), and the POC assay had 83.2% sensitivity and 74.5% specificity for detection of severe anemia (Hb ≤7 g/dL, n=171). Interobserver agreement was excellent in the POC anemia assay (r = 0.96).Conclusions. RAPID provides practical feasibility data regarding two novel POC assays for the diagnosis of anemia and SCD in a real-world field evaluation within sub-Saharan Africa. The POC SCD device was highly sensitive and specific compared to the laboratory result, even when interpreted by numerous minimally trained personnel with variable expertise in clinical medicine. The first generation POC anemia assay demonstrated good correlation with the laboratory result and showed excellent interobserver agreement. Pilot results for the POC anemia assay are being used to design a subsequent generation, better suited for low-resource settings. Overall, the pilot data for these POC assays represent important steps toward refining and implementing them in limited resource settings where they are needed the most. DisclosuresTyburski:Sanguina, LLC: Equity Ownership. Lam:Sanguina, LLC: Equity Ownership. Ware:Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Simultaneous point-of-care detection of anemia and sickle cell disease in Tanzania: the RAPID study.

Both anemia and sickle cell disease (SCD) are highly prevalent across sub-Saharan Africa, and limited resources exist to diagnose these conditions quickly and accurately. The development of simple, inexpensive, and accurate point-of-care (POC) assays represents an important advance for global hematology, one that could facilitate timely and life-saving medical interventions. In this prospective study, Robust Assays for Point-of-care Identification of Disease (RAPID), we simultaneously evaluated a POC immunoassay (Sickle SCAN™) to diagnose SCD and a first-generation POC color-based assay to detect anemia. Performed at Bugando Medical Center in Mwanza, Tanzania, RAPID tested 752 participants (age 1day to 20years) in four busy clinical locations. With minimally trained medical staff, the SCD POC assay diagnosed SCD with 98.1% sensitivity and 91.1% specificity. The hemoglobin POC assay had 83.2% sensitivity and 74.5% specificity for detection of severe anemia (Hb ≤ 7g/dL). Interobserver agreement was excellent for both POC assays (r = 0.95-0.96). Results for the hemoglobin POC assay have informed the second-generation assay design to be more suitable for low-resource settings. RAPID provides practical feasibility data regarding two novel POC assays for the diagnosis of anemia and SCD in real-world field evaluations and documents the utility and potential impact of these POC assays for sub-Saharan Africa.

Fetal Hemoglobin is Associated with Peripheral Oxygen Saturation in Sickle Cell Disease in Tanzania

Fetal hemoglobin (HbF) and peripheral hemoglobin oxygen saturation (SpO2) both predict clinical severity in sickle cell disease (SCD), while reticulocytosis is associated with vasculopathy, but there are few data on mechanisms. HbF, SpO2 and routine clinical and laboratory measures were available in a Tanzanian cohort of 1175 SCD individuals aged≥5years and the association with SpO2 (as response variable transformed to a Poisson distribution) was assessed by negative binomial model with age and sex as covariates. Increase in HbF was associated with increased SpO2 (rate ratio, RR=1.19; 95% confidence intervals [CI] 1.04, 1.37 per natural log unit of HbF; p=0.0004). In univariable analysis, SpO2 was inversely associated with age, reticulocyte count, and log (total bilirubin) and directly with pulse, SBP, hemoglobin, and log(HbF). In multivariable regression log(HbF) (RR 1.191; 95%CI 1.04, 1.37; p=0.013), pulse (RR 1.01; 95%CI 1.00, 1.01; p=0.026), SBP (RR 1.008; 95%CI 1.00, 1.02; p=0.014), and hemoglobin (1.120; 95%CI 1.05, 1.19; p=0.001) were positively and independently associated with SpO2 while reticulocyte count (RR 0.985; 95%CI 0.97, 0.99; p=0.019) was independently inversely associated with SpO2. In SCD, improving SpO2, in part through cardiovascular compensation and associated with reduced reticulocytosis, may be a mechanism by which HbF reduces disease severity.

Sickle cell disease in Africa: an overview of the integrated approach to health, research, education and advocacy in Tanzania, 2004-2016.

Sickle cell disease (SCD) is the single most important genetic cause of childhood mortality globally. Tanzania has one of the highest annual births of SCD individuals in the world, estimated to reach 11000 births a year. Without intervention, 50-90% of children will die in childhood. However, cost-effective interventions have the potential to reduce childhood mortality by up to 70%. The effects of SCD are multi-dimensional, ranging from causing high morbidity and mortality, and reducing the quality of life, to imposing a high socio-economic burden on individuals, families and health systems. In the past 12years, the SCD programme in Tanzania has developed, with local and global partnerships, a systematic framework for comprehensive research that is integrated into providing healthcare, training and advocacy in SCD. This report outlines the approach and achievements of collective initiatives for management and control of SCD in Tanzania.

Genetic association of fetal-hemoglobin levels in individuals with sickle cell disease in Tanzania maps to conserved regulatory elements within the MYB core enhancer.

BackgroundCommon genetic variants residing near upstream regulatory elements for MYB, the gene encoding transcription factor cMYB, promote the persistence of fetal hemoglobin (HbF) into adulthood. While they have no consequences in healthy individuals, high HbF levels have major clinical benefits in patients with sickle cell disease (SCD) or β thalassemia. Here, we present our detailed investigation of HBS1L-MYB intergenic polymorphism block 2 (HMIP-2), the central component of the complex quantitative-trait locus upstream of MYB, in 1,022 individuals with SCD in Tanzania.MethodsWe have looked at 1022 individuals with HbSS or HbS/β0 in Tanzania. In order to achieve a detailed analysis of HMIP-2, we performed targeted genotyping for a total of 10 SNPs and extracted additional 528 SNPs information from a genome wide scan involving the same population. Using MACH, we utilized the existing YRI data from 1000 genomes to impute 54 SNPs situated within HIMP-2.ResultsSeven HbF-increasing, low-frequency variants (β > 0.3, p < 10−5, f ≤ 0.05) were located in two partially-independent sub-loci, HMIP-2A and HMIP-2B. The spectrum of haplotypes carrying such alleles was diverse when compared to European and West African reference populations: we detected one such haplotype at sub-locus HMIP-2A, two at HMIP-2B, and a fourth including high-HbF alleles at both sub-loci (‘Eurasian’ haplotype clade). In the region of HMIP-2A a putative functional variant (a 3-bp indel) has been described previously, but no such candidate causative variant exists at HMIP-2B. Extending our dataset through imputation with 1000 Genomes, whole-genome-sequence data, we have mapped peak association at HMIP-2B to an 11-kb region around rs9494145 and rs9483788, flanked by two conserved regulatory elements for MYB.ConclusionsStudies in populations from the African continent provide distinct opportunities for mapping disease-modifying genetic loci, especially for conditions that are highly prevalent there, such as SCD. Population-genetic characteristics of our cohort, such as ethnic diversity and the predominance of shorter, African-type haplotypes, can add to the power of such studies.

Genetic variants at HbF-modifier loci moderate anemia and leukocytosis in sickle cell disease in Tanzania.

Fetal hemoglobin (HbF) is a recognized modulator of sickle cell disease (SCD) severity. HbF levels are strongly influenced by genetic variants at three major genetic loci, Xmn1‐HBG2, HMIP‐2, and BCL11A, but the effect of these loci on the hematological phenotype in SCD, has so far not been investigated. In a cohort of individuals with SCD in Tanzania (HbSS and HbS/β° thalassemia, n = 726, aged 5 or older), HbF levels were positively correlated with hemoglobin, red blood cell (RBC) indices, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), and negatively with white blood cell (WBC) and platelet counts (all P < 0.0001). We subsequently assessed the contribution of the three HbF modifier loci and detected diverse effects, including a reduction in anemia, leukocytosis, and thrombocytosis associated with certain HbF‐promoting alleles. The presence of the ‘T’ allele at Xmn1‐HBG2 led to a significant increase in hemoglobin (P = 9.8 × 10−3) but no changes in cellular hemoglobin content. Xmn1‐HBG2 ‘T’ also has a weak effect decreasing WBC (P = 0.06) and platelet (P = 0.06) counts. The BCL11A variant (rs11886868‐‘C’) increases hemoglobin (P = 2 × 10−3) and one of the HBS1L‐MYB variants decreases WBC values selectively (P = 2.3 × 10−4). The distinct pattern of effects of each variant suggests that both, disease alleviation through increased HbF production, and ‘pleiotropic’ effects on blood cells, are involved, affecting a variety of pathways. Am. J. Hematol. 90:E1–E4, 2015. © 2014 Wiley Periodicals, Inc.