The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria.

The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSß0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, ß = -0.39, P = 4.96 × 10-34) and HBS1L-MYB (lead SNP rs61028892, ß = 0.73, P = 1.18 × 10-9), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P < 0.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-'T', we identified a second haplotype, tagged by the rs7565301-'A' allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-'C' is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease.

Protocol for a comparative cross-sectional study on characterisation of auditory impairment in sickle cell disease and sickle cell trait and its impact on health-related quality of life in Nigeria.

INTRODUCTION: Sickle cell disease (SCD) and sickle cell traits (SCT) are genetically inherited red blood cell disorders common among people of African descent. Nigeria has a high prevalence of SCD, with a prevalence of 2.28%-3% and SCT, 25%-30%. Poorly managed SCD and SCT can lead to sensorineural hearing loss and health-related quality of life (HRQoL) issues. This research aims to assess these possible complications of SCD and SCT in Nigeria. METHODS AND ANALYSIS: The study will use a comparative cross-sectional design at study power 80% to investigate the association between SCD/SCT, hearing impairment and HRQoL. Participants will be divided into two groups: a cohort and a control group. Hearing levels will be assessed through audiometric assessments and categorised by type and severity of hearing impairments using WHO classifications. HRQoL will also be assessed using WHO Disability Assessment Schedule 2.0. Statistical analyses will be performed using the SAS V.9.4, with parametric or non-parametric analysis depending on the distribution. Relationship between key variables will be determined via correlational tests, χ2, Fisher's exact test and multivariable logistic regression analyses. ETHICS AND DISSEMINATION: The proposal has been fully reviewed and registered by the University of Cape Town's Faculty of Health Sciences Human Research Ethics Committee (HREC REF 228/2022) and the University of Abuja Teaching Hospital Human Research Ethics Committee (HREC/PR/2020/08/007). Information dissemination will be through conferences, peer-review publication and personal communications. The Strengthening the Reporting of Observational Studies in Epidemiology statement will be followed in writing the manuscript.

Looking ahead: ethical and social challenges of somatic gene therapy for sickle cell disease in Africa.

Somatic gene therapy will be one of the most exciting practices of genetic medicine in Africa and is primed to offer a "new life" for persons living with sickle cell disease (SCD). Recently, successful gene therapy trials for SCD in the USA have sparked a ray of hope within the SCD community in Africa. However, the high cost, estimated to exceed 1.5 million USD, continues to be a major concern for many stakeholders. While affordability is a key global health equity consideration, it is equally important to reflect on other ethical, legal and social issues (ELSIs) that may impact the responsible implementation of gene therapy for SCD in Africa. These include informed consent comprehension, risk of therapeutic misestimation and optimistic bias; priorities for SCD therapy trials; dearth of ethical and regulatory oversight for gene therapy in many African countries; identifying a favourable risk-benefit ratio; criteria for the selection of trial participants; decisional conflict in consent; standards of care; bounded justice; and genetic tourism. Given these ELSIs, we suggest that researchers, pharma, funders, global health agencies, ethics committees, science councils and SCD patient support/advocacy groups should work together to co-develop: (1) patient-centric governance for gene therapy in Africa, (2) public engagement and education materials, and (3) decision making toolkits for trial participants. It is also critical to establish harmonised ethical and regulatory frameworks for gene therapy in Africa, and for global health agencies to accelerate access to basic care for SCD in Africa, while simultaneously strengthening capacity for gene therapy.

Strategies to improve healthcare services for patients with sickle cell disease in Nigeria: The perspectives of stakeholders.

Background: Sickle cell disease (SCD) continues to pose physical and psychosocial burdens to patients, caregivers and health workers. Stakeholder engagement in the processes of policy making and implementation is increasingly becoming the cornerstone of best practices in healthcare. Aim and Objectives: To engage stakeholders with a view to assessing the knowledge of SCD; ascertain the challenges associated with accessibility and affordability of healthcare services; improve the quality of care, and thereby effect behavioral change through increasing attendance and follow-up of patients in the clinics. Methodology: A Stakeholders' Engagement meeting organized by the Sickle Pan Africa Research Consortium Nigeria Network (SPARC-NEt) was attended by patients, caregivers and members of patient support groups, healthcare providers and management/policymakers. The engagement was through PowerPoint presentations, structured questionnaires and an interactive session. The structured questionnaire assessed the knowledge of stakeholders about SCD; the quality of healthcare services; challenges with access and affordability; and SCD-related government policies. Results: Three hundred and twelve stakeholders attended the engagement meeting. Of the 133 that participated in the study, medical workers were the most represented. The majority had good knowledge of what causes SCD (96.2%) and the best place to get help during SCD crisis (98.5%). However, knowledge of the specific preventive measures of SCD and its crisis was not optimal. In terms of the role of community engagement and education, only about one-quarter of the study participants, 34 (25.6%) knew about their positive role in reducing the prevalence of SCD and alleviating SCD crises. Challenges identified include inadequate healthcare personnel and facilities, delay in obtaining laboratory results, long waiting time in the clinic, poor communication, absence of holistic consultation, uncoordinated healthcare services, high cost of care, ignorance, non-prioritization of SCD by government, lack of multisectoral collaboration and partnership with NGOs and international organizations. Strategies proffered to improve healthcare services include, community/stakeholder engagement and health education, sickle cell daycare services, access to a willing and dedicated multidisciplinary workforce, collaboration with support groups and government policies and programs. Conclusion: There is need for regular stakeholder engagement to improve access to healthcare services for SCD patients in Nigeria.

Determinants of hydroxyurea use among doctors, nurses and sickle cell disease patients in Nigeria.

BACKGROUND: Hydroxyurea (HU) is an evidence-based therapy that is currently the most effective drug for sickle cell disease (SCD). HU is widely used in high-income countries with consequent reduction of morbidity and mortality. In Nigeria, HU is prescribed by physicians while nurses are mainly involved in counseling the patients to ensure adherence. The extent of utilization and the determinant factors have not been sufficiently evaluated in Nigeria. OBJECTIVE: To assess the frequency of use of HU and factors affecting utilization among healthcare providers, patients, and caregivers for SCD. METHODS: A questionnaire was administered online and in- person to assess the frequency of HU use and the factors that promote and limit its use. The data were analyzed by descriptive statistics using IBM SPSS software version 23 and the result was presented in frequency tables and percentages. RESULT: A total of 137 physicians, 137 nurses, and 237 patients/caregivers responded to the survey. The rate of prescription of HU by doctors in the past 6 months was 64 (46.7%), 43 (31.4%) nurses provided counseling and 36 (15.6%) patients were on HU. Among doctors, adequate knowledge (91.3%), clinical benefits and safety (94.8%), and inclusion of HU in management guidelines (86.9%) were motivators for prescribing it while inadequate knowledge (60.9%) and unawareness of treatment guidelines (68.6%) constituted barriers. Among nurses, reduction of crisis (91.6%) and safety (64.8%) were the major motivators while barriers were high cost (79.1%) and intensive monitoring (63.1%) of HU treatment. Among the patients, the major motivator was the reduction of crises (80.3%) while poor knowledge (93.2%), high cost of the drug (92.2%) while monitoring (91.2%), non-availability (87.7%) and side effects (83.9%) were the major barriers for the utilization of HU. CONCLUSION: HU prescription and utilization are still poor among healthcare providers and patients. Inadequate knowledge, non-availability and high cost of HU as well as unawareness of treatment guidelines constitute major barriers to prescription and utilization.

Asplenia and spleen hypofunction.

Asplenia (the congenital or acquired absence of the spleen) and hyposplenism (defective spleen function) are common causes of morbidity and mortality. The spleen is a secondary lymphoid organ that is responsible for the regulation of immune responses and blood filtration. Hence, asplenia or hyposplenism increases susceptibility to severe and invasive infections, especially those sustained by encapsulated bacteria (namely, Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type b). Asplenia is predominantly due to splenectomy for either traumatic events or oncohaematological conditions. Hyposplenism can be caused by several conditions, including haematological, infectious, autoimmune and gastrointestinal disorders. Anatomical disruption of the spleen and depletion of immune cells, especially IgM memory B cells, seem to be predominantly responsible for the clinical manifestations. Early recognition of hyposplenism and proper management of asplenia are warranted to prevent overwhelming post-splenectomy infections through vaccination and antibiotic prophylaxis. Although recommendations are available, the implementation of vaccination strategies, including more effective and immunogenic vaccines, is needed. Additionally, screening programmes for early detection of hyposplenism in high-risk patients and improvement of patient education are warranted.

Contribution of malaria and sickle cell disease to anaemia among children aged 6-59 months in Nigeria: a cross-sectional study using data from the 2018 Demographic and Health Survey.

OBJECTIVES: To estimate the fraction of anaemia attributable to malaria and sickle cell disease (SCD) among children aged 6-59 months in Nigeria. DESIGN: Cross-sectional analysis of data from Nigeria's 2018 Demographic and Health Survey (DHS). SETTING: Nigeria. PARTICIPANTS: 11 536 children aged 6-59 months from randomly selected households were eligible for participation, of whom 11 142 had complete and valid biomarker data required for this analysis. Maternal education data were available from 10 305 of these children. PRIMARY OUTCOME MEASURE: Haemoglobin concentration. RESULTS: We found that 70.6% (95% CI: 62.7% to 78.5%) of severe anaemia was attributable to malaria compared with 12.4% (95% CI: 11.1% to 13.7%) of mild-to-severe and 29.6% (95% CI: 29.6% to 31.8%) of moderate-to-severe anaemia and that SCD contributed 0.6% (95% CI: 0.4% to 0.9%), 1.3% (95% CI: 1.0% to 1.7%) and 10.6% (95% CI: 6.7% to 14.9%) mild-to-severe, moderate-to-severe and severe anaemia, respectively. Sickle trait was protective against anaemia and was associated with higher haemoglobin concentration compared with children with normal haemoglobin (HbAA) among malaria-positive but not malaria-negative children. CONCLUSIONS: This approach used offers a new tool to estimate the contribution of malaria to anaemia in many settings using widely available DHS data. The fraction of anaemia among young children in Nigeria attributable to malaria and SCD is higher at more severe levels of anaemia. Prevention of malaria and SCD and timely treatment of affected individuals would reduce cases of severe anaemia.

Using dried blood spot on HemoTypeSC™, a new frontier for newborn screening for sickle cell disease in Nigeria.

Background: HemoTypeSC is a rapid, point-of-care testing (POCT) device for sickle cell disease (SCD) that traditionally uses the capillary blood from heel stick collected at the point of testing, a procedure that makes mass screening cumbersome and less cost-effective. Using dried blood spots (DBS) on HemoTypeSC could mitigate this challenge. Therefore, this study aimed to determine the feasibility of eluting blood from DBS to read on HemoTypeSC. Methods: DBS and fresh samples from heel sticks were collected from 511 newborns at the immunization clinics of six Primary Health Centers in Abuja, Nigeria. The two samples from each newborn were analyzed using HemoType SC and then compared with the result of the isoelectric focusing (IEF) test. Results: Of the 511 newborns, 241 were males and 270 were females. Standard HemoTypeSC (using fresh samples collected from heel sticks) and HemoTypeSC using DBS identified 404 (79.0%) HbAA, 100 (19.6%) HbAS, 6 (1.2%) HbSS, and 1 (0.2%) HbAC phenotypes. The IEF tests identified 370 (72.4%) HbAA, 133 (26.0%) HbAS, 5 (1.0%) HbSS, and 3 (0.6%) HbAC phenotypes. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy of HemoTypeSC using DBS, compared to standard HemoTypeSC POCT was 100%. IEF method showed for AA, AS, AC phenotypes; sensitivity; 84.7%, 67%,100% respectively, specificity; 67.6%, 86%, 99% respectively, PPV; 91.2%, 53%, 50% respectively, NPV; 52.7%, 91%, 100% respectively. For SS phenotype, IEF showed 100% specificity, sensitivity, PPV and NPV. Conclusion: HemoTypeSC test using dried blood spot is as accurate as the standard point-of-care HemoTypeSC test. The use of DBS on HemoTypeSC could ensure better efficiency and cost-effectiveness in mass newborn screening for SCD.

Establishing a database for sickle cell disease patient mapping and survival tracking: The sickle pan-african research consortium Nigeria example.

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.

The Consortium on Newborn Screening in Africa for sickle cell disease: study rationale and methodology.

Sickle cell disease (SCD) is a common condition within sub-Saharan Africa and associated with high under-5 mortality (U5M). The American Society of Hematology instituted the Consortium on Newborn Screening in Africa (CONSA) for SCD, a 7-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 U5M compared with 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 7 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 of 5 years. Effectiveness of these early interventions, along with culturally appropriate family education and counseling, will be evaluated by comparing U5M in the enrolled cohort to estimated preprogram data. Here, we describe the methodology planned for this trial.

Skills Capacity Building For Health Care Services and Research Through the Sickle Pan African Research Consortium.

Skills development, the building of human capacity, is key to any sustainable capacity building effort, however, such undertakings require adaptable and tailored strategies. The Sickle Pan-African Research Consortium (SPARCo) is building capacity in sickle cell disease (SCD) management and research in sub-Saharan Africa, including a multi-national SCD patient registry, this is underpinned by skills development activities in data, research, and SCD management. Method: The SPARCo Skills Working Group was set up with the mandate of coordinating skills development activities across the three SPARCo sites in Ghana, Nigeria and Tanzania. To tailor activities to the requirements of the consortium, a needs assessment was conducted at the start of the project which identified skills required for SCD management and research and catalogued existing external and internal training programmes. The needs assessment highlighted differences in skill levels between the sites and different organisational structures which required tailored skills development activities at individual, site and consortium levels. Strategy: Based on the needs and the resources available, different types of training activities were implemented: these included online, blended and face to face activities. In order to create a sustainable skills development programme, existing short, medium, long-term, on-job training activities were used wherever possible. World Sickle Cell Day (19th June) was leveraged for training and health education activities. Results: SPARCo has recorded 1,726 participants in skills development activities across the three sites. Skills have been enhanced in data management, SCD and research to underpin the core deliverables of SPARCo. Conclusion and Lessons Learned: The baseline needs assessments and continual review and adjustment were critical for development of an effective skill development strategy for the consortium. This adaptability was particularly valuable during the COVID-19 pandemic. The sustainability plan leveraged existing programmes and activities and has created a pool of people with required skills for health care and research in SCD. To be effective, skills development programmes need to take into account existing capacity, training opportunities and local conditions. The model was applied to SCD and is adaptable to other skills development in healthcare and research in low and middle- income countries.

Outcome of Hydroxyurea Use in SCD and Evaluation of Patients' Perception and Experience in Nigeria.

Introduction: Hydroxyurea (HU) has been shown to be beneficial in the management of sickle cell disease (SCD) as it improves treatment outcomes. However, despite the benefits of HU, its uptake among SCD patients in Nigeria remains low. Objective: This study aimed to assess the perception and experience of patients with SCD in Nigeria who are using or had used HU, thereby informing and promoting its use. Methodology: A multi-centre, cross-sectional study was conducted among 378 SCD patients aged 1-53 years who have enrolled on Sickle Pan African Research Consortium (SPARCO) registry as HU users. The SPARCO project was funded by the National Institutes of Health (NIH) to establish a sickle cell disease (SCD) registry, strengthen skills and plan research in three African countries. The Nigerian SPARCO registry had 6453 SCD patients at the time of this report with <15% of this population on HU. Data on sociodemographics, perception and experience about HU use were obtained and analysed using descriptive statistics. Findings: Out of the 378 participants, 339 (89.7%) were using HU while 39 (10.3%) had stopped using HU at the time of the study. 281 (74.3%) found HU expensive, while 194 (51.3%) reported none to minimal side effects while using HU. Among patients that stopped HU, cost (59%) and availability (51.3%) were the commonest reasons for discontinuing the drug. Furthermore, 347 (92.5%) had fewer pain crises, 173 (84.8%) had a fewer need for blood transfusion, 145 (86.3%) had improved PCV and 318 (84.6%) had fewer hospital admissions. Finally, the study also showed that 322 (85.2%) respondents would recommend the drug to other patients, whereas 14 respondents (3.7%) would not. Mean corpuscular volume (MCV) and fetal hemoglobin (HbF) levels were not collected in this study and may have improved findings. Conclusion: This study showed that the majority of the SCD patients had good perception and experience with the use of HU while a few had to stop the medication mostly on account of cost and availability. Patients' based advocacy could be leveraged to improve HU uptake while more efforts are needed to ensure that it is readily available and affordable.

HSC and miRNA Regulation with Implication for Foetal Haemoglobin Induction in Beta Haemoglobinopathies.

Sickle cell disease (SCD) is one of the most common haemoglobinopathies worldwide, with up to 70 % of global SCD annual births occurring in sub-Saharan Africa. Reports have shown that 50 to 80 % of affected children in these countries die annually. Efforts geared towards understanding and controlling HbF production in SCD patients could lead to strategies for effective control of globin gene expression and therapeutic approaches that could be beneficial to individuals with haemoglobinopathies. Hemopoietic stem cells (HSCs) are characterized by a specific miRNA signature in every state of differentiation. The role of miRNAs has become evident both in the maintenance of the "stemness" and in the early induction of differentiation by modulation of the expression of the master pluripotency genes and during early organogenesis. miRNAs are extra regulatory mechanisms in hematopoietic stem cells (HSCs) via influencing transcription profiles together with transcript stability. miRNAs have been reported to be used to reprogram primary somatic cells toward pluripotency. Their involvement in cell editing holds the potential for therapy for many genetic diseases. This review provides a snapshot of miRNA involvement in cell fate decisions, haemoglobin induction pathway, and their journey as some emerge prime targets for therapy in beta haemoglobinopathies.

Effect of Sickle Cell Trait on Human Immunodeficiency Virus Type 1 Infection.

Introduction: Whereas several studies show that homozygous (HbSS) sickle cell disease protects against human immunodeficiency virus infection, it is not clear if human immunodeficiency virus infection is affected by the heterozygous state of the sickle globin gene (HbAS or sickle cell trait). Objective: To evaluate the effects of sickle cell trait on the prevalence and severity of human immunodeficiency virus type 1 infection in a large patient population. Methods: Hemoglobin genotype was determined by high performance liquid chromatography (HPLC) in 1,226 HIV-1 patients in Nigeria. Their demographic data were documented. Blood CD4+ cell counts and HIV-1 viral load previously determined on the same blood samples to guide clinical care were used as indices of severity of HIV-1 infection. Statistical analysis of the data was done to evaluate the effects of sickle cell trait on the severity and prevalence of HIV-1 infection, relative to the prevalence of 1.4% in the general population of Nigeria. Results and Discussion: The distribution of hemoglobin genotypes among the HIV-1 patients was comparable to that in the general population of Nigeria (Chi-squared statistic =1.025; p value = 0.31, not significant). Neither viral load (p = 0.32) nor blood CD4+ cell count (p = 0.30) was significantly different between all HbAS versus all HbAA patients. There was a trend towards lower viral load in females and a significant interaction between gender and HbAS for viral load (P = 0.018), suggesting that sickle cell trait might be associated with the severity of HIV-1 infection in females. Conclusion: The findings suggest that sickle cell trait might be associated with severity of HIV-1 infection in female, but not all, patients. Larger, prospective studies are required to further investigate the effect of sickle cell trait on HIV-1 infection.

Development of multi-level standards of care recommendations for sickle cell disease: Experience from SickleInAfrica.

Introduction: Sickle Cell Disease (SCD) causes significant morbidity and mortality particularly in sub-Saharan Africa (SSA) where it contributes to early childhood deaths. There is need to standardize treatment guidelines to help improve overall SCD patient health outcomes. We set out to review existing guidelines on SCD and to set minimum standards for management of SCD for the different referral levels of healthcare. Methods: A standards of care working group (SoC-WG) was established to develop the SoC recommendations. About 15 available SCD management guidelines and protocols were reviewed and themes extracted from them. The first draft was on chosen themes with 64 major headings and subtopics. Using a summarised WHO levels of referral document, we were able to get six different referral levels of healthcare. The highest referral level was the tertiary facilities whilst the lowest level was the home setting. Recommendations for SCD management for the regional, district, sub-districts, health posts and CHPs compounds were also drafted. Results: The results from this review yielded a guidelines document which had recommendations for management of SCD on 64 topics and subtopic for all the six (6) different referral levels. Discussions: Every child with SCD need to receive comprehensive care that is coordinated at each level. This recommendation is unique in terms of the availability of recommendations for different levels of care as compared to the traditional guidelines which is more focused at the tertiary levels. Patients can access care at any of the other lower referral hospitals and be managed with recommendations that are in keeping with institutional resources at that level. When such patients need care that requires expertise that is not available at that level, the recommendations will be to refer to the appropriate referral level where those expertise are available. This encourages patients to have good clinical care nearer their homes but also having access to specialist screening modalities and expertise at the tertiary hospitals if need be. With this, patient are not limited to a specific referral level when interventions cannot be instituted for them. Conclusion: This SoC recommendations document is a useful material that can be used for consistent standards of treatment in SSA.

Child mortality from sickle cell disease in Nigeria: a model-estimated, population-level analysis of data from the 2018 Demographic and Health Survey.

BACKGROUND: Child mortality from sickle cell disease in sub-Saharan Africa is presumed to be high but is not well quantified. This uncertainty contributes to the neglect of sickle cell disease and delays the prioritisation of interventions. In this study, we estimated the mortality of children in Nigeria with sickle cell disease, and the proportion of national under-5 mortality attributable to sickle cell disease. METHODS: We did a model-estimated, population-level analysis of data from Nigeria's 2018 Demographic and Health Survey (DHS) to estimate the prevalence and geographical distribution of HbSS and HbSC genotypes assuming Hardy-Weinberg equilibrium near birth. Interviews for the survey were done between Aug 14 and Dec 29, 2018, and the embedded sickle cell disease survey was done in a randomly selected third of the overall survey's households. We developed an approach for estimating child mortality from sickle cell disease by combining information on tested children and their untested siblings. Tested children were aged 6-59 months at the time of the survey. Untested siblings born 0-14 years before the survey were also included in analyses. Testing as part of the DHS was done without regard to disease status. We analysed mortality differences using the inheritance-derived genotypic distribution of untested siblings older than the tested cohort, enabling us to estimate excess mortality from sickle cell disease for the older-sibling cohort (ie, those born between 2003 and 2013). FINDINGS: We analysed test results for 11 186 children aged 6-59 months from 7411 households in Nigeria. The estimated average birth prevalence of HbSS was 1·21% (95% CI 1·09-1·37) and was 0·24% (0·19-0·31) for HbSC. We obtained data for estimating child mortality from 10 195 tested children (who could be matched to the individual mother survey) and 17 205 of their untested siblings. 15 227 of the siblings were in the older-sibling cohort. The group of children with sickle cell disease born between 2003 and 2013 with at least one younger sibling in the survey had about 370 excess under-5 deaths per 1000 livebirths (95% CI 150-580; p=0·0008) than children with HbAA. The estimated national average under-5 mortality for children with sickle cell disease born between 2003 and 2013 was 490 per 1000 livebirths (95% CI 270-700), 4·0 times higher (95% CI 2·1-6·0) than children with HbAA. About 4·2% (95% CI 1·7-6·9) of national under-5 mortality was attributable to excess mortality from sickle cell disease. INTERPRETATION: The burden of child mortality from sickle cell disease in Nigeria continues to be disproportionately higher than the burden of mortality of children without sickle cell disease. Most of these deaths could be prevented if adequate resources were allocated and available focused interventions were implemented. The methods developed in this study could be used to estimate the burden of sickle cell disease elsewhere in Africa and south Asia. FUNDING: Sickle Pan African Research Consortium, and the Bill & Melinda Gates Foundation.