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.

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.

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.

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.

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.

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.

Utilization of Pneumococcal Vaccine and Penicillin Prophylaxis in Sickle Cell Disease in Three African Countries: Assessment among Healthcare Providers in SickleInAfrica.

Sickle cell disease is a genetic disease with a predisposition to infections caused by encapsulated organisms, especially Streptococcus pneumoniae. Pneumococcal vaccines and prophylactic penicillin have reduced the rate of this infection and mortality in sickle cell disease. However, implementation of these interventions is limited in Africa. The objectives of the study were to assess health care providers' behaviors with the implementation of pneumococcal vaccination and penicillin prophylaxis and to identify barriers to their use. A 25-item online questionnaire was administered through SickleinAfrica: a network of researchers, and healthcare providers, in Ghana, Nigeria, and Tanzania, working to improve health outcomes of sickle cell disease in Africa. Data was collected and managed using the Research Electronic Data Capture (REDCap), tools and data analysis was done using STATA version 13 and R statistical software. Eighty-two medical practitioners responded to the questionnaire. Only 54.0 and 48.7% of respondents indicated the availability of published guidelines on sickle cell disease management and pneumococcal vaccine use, respectively, at their facilities. The majority (54.0%) perceived that the vaccines are effective but over 20.0% were uncertain of their usefulness. All respondents from Ghana and Tanzania affirmed the availability of guidelines for penicillin prophylaxis in contrast to 44.1% in Nigeria. Eighty-five percent of respondents affirmed the need for penicillin prophylaxis but 15.0% had a contrary opinion for reasons including the rarity of isolation of Streptococcus pneumoniae in African studies, and therefore, the uncertainty of its benefit. Lack of published guidelines on the management of sickle cell disease and doubts about the necessity of prophylactic measures are potential barriers to the implementation of effective interventions.

Community based screening for sickle haemoglobin among pregnant women in Benue State, Nigeria: I-Care-to-Know, a Healthy Beginning Initiative.

BACKGROUND: Haemoglobin genotype screening at prenatal care offers women an opportunity to be aware of their genotype, receive education on sickle cell disease (SCD) and may increase maternal demand for SCD newborn screening. In developed countries, most pregnant women who access prenatal care and deliver at the hospital receive haemoglobin genotype screening. In settings with low prenatal care attendance and low hospital deliveries, community-based screening may provide similar opportunity for pregnant women. We assessed the feasibility and acceptability of integrating haemoglobin genotype screening into an existing community-based HIV program. METHODS: Onsite community-based integrated testing for HIV, hepatitis B virus and haemoglobin electrophoresis, were conducted for pregnant women and their male partners. Community Health Advisors implementing the NIH and PEPFAR-supported Healthy Beginning Initiative (HBI) program provided education on SCD, collected blood sample for haemoglobin electrophoresis and provided test results to participants enrolled into the HBI program. We concurrently conducted a cross-sectional study using a pretested, semi-structured, interviewer administered questionnaire to collect demographic data and assess awareness of individual haemoglobin "genotype" among HBI pregnant women participants. RESULTS: In this study, 99.9% (10,167/10,168) of pregnant women who received education on SCD accepted and completed the survey, had blood drawn for haemoglobin electrophoresis and received their results. A majority of participating pregnant women (97.0%) were not aware of their haemoglobin "genotype". Among the participants who were incorrect about their haemoglobin "genotype", 41.1% (23/56) of women who reported their haemoglobin "genotype" as AA were actually AS. The odds of haemoglobin "genotype" awareness was higher among participants who were in younger age group, completed tertiary education, had less number of pregnancies, and attended antenatal care. Overall prevalence of sickle cell trait (AS) was 18.7%. CONCLUSIONS: It is feasible to integrate haemoglobin "genotype" testing into an existing community-based maternal-child program. Most pregnant women who were unaware of their haemoglobin "genotype" accepted and had haemoglobin genotype testing, and received their test results. Increasing parental awareness of their own haemoglobin "genotype" could increase their likelihood of accepting newborn screening for SCD.

Applying the WHO ICD-MM classification system to maternal deaths in a tertiary hospital in Nigeria: A retrospective analysis from 2014-2018.

BACKGROUND: Addressing the problem of maternal mortality in Nigeria requires proper identification of maternal deaths and their underlying causes in order to focus evidence-based interventions to decrease mortality and avert morbidity. OBJECTIVES: The objective of the study was to classify maternal deaths that occurred at a Nigerian teaching hospital using the WHO International Classification of Diseases Maternal mortality (ICD-MM) tool. METHODS: This was a retrospective observational study of all maternal deaths that occurred in a tertiary Nigerian hospital from 1st January 2014 to 31st December,2018. The WHO ICD-MM classification system for maternal deaths was used to classify the type, group, and specific underlying cause of identified maternal deaths. Descriptive analysis was performed using Statistical Package for Social Sciences (SPSS). Categorical and continuous variables were summarized respectively as proportions and means (standard deviations). RESULTS: The institutional maternal mortality ratio was 831/100,000 live births. Maternal deaths occurred mainly amongst women aged 25-34 years;30(57.7%), without formal education; 22(42.3%), married;47(90.4%), unbooked;24(46.2%) and have delivered at least twice;34(65.4%). The leading causes of maternal death were hypertensive disorders in pregnancy, childbirth, and the puerperium (36.5%), obstetric haemorrhage (30.8%), and pregnancy related infections (17.3%). Application of the WHO ICD-MM resulted in reclassification of underlying cause for 3.8% of maternal deaths. Postpartum renal failure (25.0%), postpartum coagulation defects (17.3%) and puerperal sepsis (15.4%) were the leading final causes of death. Among maternal deaths, type 1, 2, and 3 delays were seen in 30(66.7%), 22(48.9%), and 6(13.3%), respectively. CONCLUSION: Our institutional maternal mortality ratio remains high. Hypertensive disorders during pregnancy, childbirth, and the puerperium and obstetric haemorrhage are the leading causes of maternal deaths. Implementation of evidence-based interventions both at the hospital and community levels may help in tackling the identified underlying causes of maternal mortality in Nigeria.

Barriers to Therapeutic Use of Hydroxyurea for Sickle Cell Disease in Nigeria: A Cross-Sectional Survey.

Background: Sickle cell disease, the inherited blood disorder characterized by anemia, severe pain and other vaso-occlusive complications, acute chest syndrome, disproportionate hospitalization, and early mortality, has significant financial, social, and psychosocial impacts and drains individuals, families, and health systems globally. Hydroxyurea could improve the health of the 300,000 individuals born each year with sickle cell disease in sub-Saharan Africa; however, challenges to adoption and adherence persist. This study assessed the barriers to therapeutic use of hydroxyurea for sickle cell disease within the Nigerian healthcare system, specifically from the level of the patient, provider, and health system. Methods: We used purposive sampling to recruit participants from 13 regions in Nigeria. A cross-sectional survey was administered to physicians (n = 70), nurses or counselors (n = 17), and patients or their caregivers (n = 33) at 13 health centers. Findings were mapped onto the appropriate Consolidated Framework for Implementation Research (CFIR) domains. Results: This study was able to identify factors that mapped onto the inner setting, outer setting, and characteristics of individuals domains of CFIR. The majority of physicians (74.3%) prescribe hydroxyurea, and half stated hydroxyurea is the standard of care. Among clinicians, barriers included limited knowledge of the drug, as well as low self-efficacy to prescribe among physicians and to counsel among nurses; perceived side effects; perceived patient preference for traditional medicine; cost for patient and expense of accompanying laboratory monitoring; and limited availability of the drug and equipment for laboratory monitoring. Among patients and caregivers, barriers included lack of knowledge; perceived side effects; cost; religious beliefs of disease causation; and lack of pediatric formulation. Conclusions: Findings suggest that patient, provider, and health systems-level interventions are needed to improve hydroxyurea uptake among providers and adherence among patients with sickle cell disease in Nigeria. Interventions such as patient education, provider training, and policy change could address the disproportionate burden of sickle cell disease in sub-Saharan Africa and thus improve health equity.

The Sickle Cell Disease Ontology: Enabling Collaborative Research and Co-Designing of New Planetary Health Applications.

Sickle cell disease (SCD) is one of the most common blood disorders impacting planetary health. Over 300,000 newborns are diagnosed with SCD each year globally, with an increasing trend. The sickle cell disease ontology (SCDO) is the most comprehensive multidisciplinary SCD knowledge portal. The SCDO was collaboratively developed by the SCDO working group, which includes experts in SCD and data standards from across the globe. This expert review presents highlights and lessons learned from the fourth SCDO workshop that marked the beginning of applications toward planetary health impact, and with an eye to empower and cultivate multisite SCD collaborative research. The workshop was organized by the Sickle Africa Data Coordinating Center (SADaCC) and attended by 44 participants from 14 countries, with 2 participants connecting remotely. Notably, from the standpoint of democratizing and innovating scientific meeting design, an SCD patient advocate also presented at the workshop, giving a broader real-life perspective on patients' aspirations, needs, and challenges. A major component of the workshop was new approaches to harness SCDO to harmonize data elements used by different studies. This was facilitated by a web-based platform onto which participants uploaded data elements from previous or ongoing SCD-relevant research studies before the workshop, making multisite collaborative research studies based on existing SCD data possible, including multisite cohort, SCD global clinical trials, and SCD community engagement approaches. Trainees presented proposals for systematic literature reviews in key SCD research areas. This expert review emphasizes potential and prospects of SCDO-enabled data standards and harmonization to facilitate large-scale global SCD collaborative initiatives. As the fields of public and global health continue to broaden toward planetary health, the SCDO is well poised to play a prominent role to decipher SCD pathophysiology further, and co-design diagnostics and therapeutics innovation in the field.

Implementing newborn screening for sickle cell disease as part of immunisation programmes in Nigeria: a feasibility study.

BACKGROUND: Sickle cell disease is highly prevalent in sub-Saharan Africa, where it accounts for substantial morbidity and mortality. Newborn screening is paramount for early diagnosis and enrolment of affected children into a comprehensive care programme. Up to now, this strategy has been greatly impaired in resource-poor countries, because screening methods are technologically and financially intensive; affordable, reliable, and accurate methods are needed. We aimed to test the feasibility of implementing a sickle cell disease screening programme using innovative point-of-care test devices into existing immunisation programmes in primary health-care settings. METHODS: Building on a routine immunisation programme and using existing facilities and staff, we did a prospective feasibility study at five primary health-care centres within Gwagwalada Area Council, Abuja, Nigeria. We systematically screened for sickle cell disease consecutive newborn babies and infants younger than 9 months who presented to immunisation clinics at these five centres, using an ELISA-based point-of care test (HemoTypeSC). A subgroup of consecutive babies who presented to immunisation clinics at the primary health-care centres, whose mothers gave consent, were tested by the HemoTypeSC point-of-care test alongside a different immunoassay-based point-of-care test (SickleSCAN) and the gold standard test, high-performance liquid chromatography (HPLC). FINDINGS: Between July 14, 2017, and Sept 3, 2019, 3603 newborn babies and infants who presented for immunisation were screened for sickle cell disease at five primary health-care centres using the ELISA-based point-of-care test. We identified 51 (1%) children with sickle cell anaemia (HbSS), four (<1%) heterozygous for HbS and HbC (HbSC), 740 (21%) with sickle cell trait (HbAS), 34 (1%) heterozygous for HbA and HbC (HbAC), and 2774 (77%) with normal haemoglobin (HbAA). Of the 55 babies and infants with confirmed sickle cell disease, 41 (75%) were enrolled into a programme for free folic acid and penicillin, of whom 36 (88%) completed three visits over 9 months (median follow-up 226 days [IQR 198-357]). The head-to-head comparison between the two point-of-care tests and HPLC showed concordance between the three testing methods in screening 313 newborn babies, with a specificity of 100% with HemoTypeSC, 100% with SickleSCAN, and 100% by HPLC, and a sensitivity of 100% with HemoTypeSC, 100% with SickleSCAN, and 100% by HPLC. INTERPRETATION: Our pilot study shows that the integration of newborn screening into existing primary health-care immunisation programmes is feasible and can rapidly be implemented with limited resources. Point-of-care tests are reliable and accurate in newborn screening for sickle cell disease. This feasibility study bodes well for the care of patients with sickle cell disease in resource-poor countries. FUNDING: Doris Duke Charitable Foundation, Imperial College London Wellcome Trust Centre for Global Health Research, and Richard and Susan Kiphart Family Foundation.

Caring for Africa's sickle cell children: will we rise to the challenge?

BACKGROUND: Most of the world's sickle cell disease (SCD) burden is in Africa, where it is a major contributor to child morbidity and mortality. Despite the low cost of many preventive SCD interventions, insufficient resources have been allocated, and progress in alleviating the SCD burden has lagged behind other public-health efforts in Africa. The recent announcement of massive new funding for research into curative SCD therapies is encouraging in the long term, but over the next few decades, it is unlikely to help Africa's SCD children substantially. MAIN DISCUSSION: A major barrier to progress has been the absence of large-scale early-life screening. Most SCD deaths in Africa probably occur before cases are even diagnosed. In the last few years, novel inexpensive SCD point-of-care test kits have become widely available and have been deployed successfully in African field settings. These kits could potentially enable universal early SCD screening. Other recent developments are the expansion of the pneumococcal conjugate vaccine towards near-universal coverage, and the demonstrated safety, efficacy, and increasing availability and affordability of hydroxyurea across the continent. Most elements of standard healthcare for SCD children that are already proven to work in the West, could and should now be implemented at scale in Africa. National and continental SCD research and care networks in Africa have also made substantial progress, assembling care guidelines and enabling the deployment and scale-up of SCD public-health systems. Substantial logistical, cultural, and awareness barriers remain, but with sufficient financial and political will, similar barriers have already been overcome in efforts to control other diseases in Africa. CONCLUSION AND RECOMMENDATIONS: Despite remaining challenges, several high-SCD-burden African countries have the political will and infrastructure for the rapid implementation and scale-up of comprehensive SCD childcare programs. A globally funded effort starting with these countries and expanding elsewhere in Africa and to other high-burden countries, including India, could transform the lives of SCD children worldwide and help countries to attain their Sustainable Development Goals. This endeavor would also require ongoing research focused on the unique needs and challenges of SCD patients, and children in particular, in regions of high prevalence.

Establishing a Multi-Country Sickle Cell Disease Registry in Africa: Ethical Considerations.

Sickle cell disease (SCD) is one of the most prevalent genetic conditions in sub-Saharan Africa. It is a chronic, lifelong disease often characterized by severe pain. However, SCD has received little investment terms of health research, though there is currently a growing pool of SCD data from health and research facilities in different countries. To facilitate research on SCD in Africa, the SickleInAfrica consortium has established a SickleInAfrica registry. The registry will store a systematic collection of longitudinal data from persons with SCD across sub-Saharan Africa, and currently, participants are being enrolled in Ghana, Nigeria, and Tanzania. In establishing this registry, the SickleInAfrica consortium decided to actively identify and anticipate possible ethical issues that may arise in the development and management of the registry. This was motivated, in part, by the near absence of well documented ethical issues for registry research in Africa, more-so for registries enrolling participants across multiple countries and for a genetic condition. The consortium aims to establish standards for the equitable use of data stored in the registry. This paper presents a comprehensive report on the ethical considerations that came up in setting up a genetic disease registry across multiple African countries and how they were addressed by the SickleInAfrica consortium. Major issues included: active involvement of patients in the initiation and management of the registry; questions of assent and re-consent; the importance of ensuring that fears of exploitation are not replicated in African-African research collaborations; and the importance of public engagement in the management of registries. Drawing on this experience, SickleInAfrica plans to set up an ethics helpdesk for genetic disease registries and research in Africa.

White Paper: Pathways to Progress in Newborn Screening for Sickle Cell Disease in Sub-Saharan Africa.

Sickle Cell Disease (SCD) is among the most common single-gene diseases in the world but evidence-based comprehensive health care has not been implemented where the highest prevalence of SCD occurs, in sub-Saharan Africa (SSA). It represents an urgent health burden, both in terms of mortality and morbidity with an estimated mortality of 8-16% in children under 5 years in SSA. Addressing the high mortality of SCD in SSA and for effective management of SCD, newborn screening (NBS) should be incorporated with prevention of infections (including pneumococcal septicaemia and malaria), parental education and support at all levels of healthcare provision to enable timely recognition. The NBS working group of the Africa Sickle Cell Research Network (AfroSickleNet) collaboration surveyed current projects in NBS in SSA, and current conditions that hinder more widespread implementation of NBS for SCD. Solutions based on new point-of-care testing technology to disseminate education, and implementation science approaches that leverage existing resources are proposed.

A Multi-centre Survey of Acceptability of Newborn Screening for Sickle Cell Disease in Nigeria.

Background Sickle cell disease (SCD) is a major genetic disease that manifests early in life and may lead to significant morbidities. One of the health care services that have been effective in reducing the burden of SCD in developed countries is newborn screening (NBS) followed by pneumococcal vaccines, penicillin prophylaxis, and hydroxyurea treatment. Yet, in sub-Saharan African countries, where about 75% of annual affected babies worldwide are born, NBS programmes are largely unavailable. It is not clear whether this is due to technical challenges associated with setting up such programmes, or significant cultural and social barriers to its acceptance in such settings. Objective Our aim was to ascertain the attitudes to and acceptability of NBS in Nigeria among various socio-demographic groups including health professionals, undergraduate students, parents of children with SCD and SCD patients. Methods Data on socio-demographic characteristics, knowledge of SCD and attitude towards NBS were collected using a semi-structured pre-tested questionnaire from April to July 2014 across 15 health institutions and university campuses in Nigeria. Data were collected from 1,301 respondents across Nigeria. Results There was good knowledge of SCD as an inherited blood disorder. Although 86% of respondents (n = 1,119) supported NBS, there was a statistically significant relationship between support for NBS and age (p = 003), educational status (p = 000) and religion (p = 000). Conclusion This study suggests that there is a good acceptability of NBS across Nigeria. The main barriers to its use are likely to be financial and practical, rather than social or cultural.

Preliminary Evaluation of a Point-of-Care Testing Device (SickleSCAN™) in Screening for Sickle Cell Disease.

Sickle cell disease affects about 150,000 births annually in Nigeria. Early diagnosis is hampered by factors such as centralized and urban localization of laboratories, high cost of diagnostic equipment and inadequate skilled manpower to operate them. The need for a low-cost, portable, easy-to-use diagnostic test for sickle cell disease is critical, especially in resource-poor countries. In this study, we evaluated the performance characteristics of a novel point-of-care testing device (SickleSCAN™), and its acceptability and feasibility, as a possible screening tool for sickle cell disease. In the first phase, we assessed the performance characteristics of SickleSCAN™ by evaluating 57 subjects comprising both children and adults attending a primary health center, for Hb SS (ßS/ßS; HBB: c.20A>T), Hb SC (ßS/ßC; HBB: c.19G>A) and Hb AS (ßA/ßS) using SickleSCAN™, cellulose acetate electrophoresis (CAE) and high performance liquid chromatography (HPLC). Performance characteristics such as diagnostic sensitivity and specificity were compared to HPLC as a standard method. We subsequently undertook a second phase wherein the acceptability and feasibility of the device for sickle cell disease screening, was evaluated using semi-structured and structured questionnaires among 197 healthcare personnel and 221 subjects, respectively. Sickle cell disease was carried by 3.4% of the subjects. The diagnostic sensitivity, specificity and test efficiency of SickleSCAN™ for sickle cell disease (Hb SS and Hb SC), were 100.0, 98.2 and 98.2%, respectively. Findings from this study showed SickleSCAN™ to be a viable screening tool that can easily be applied in community-based screening for early diagnosis of sickle cell disease with little expertise and low cost.

Blood transfusion services for patients with sickle cell disease in Nigeria.

BACKGROUND: Safe, timely red blood cell transfusion saves lives and chronic transfusion therapy (CTT) prevents or limits morbidities such as stroke, therefore improving quality of life of patients with sickle cell disease (SCD). METHODS: This questionnaire-based study assessed the ability of sickle cell centers in Nigeria to provide safe blood to patients with SCD between March and August 2014. RESULTS: Out of the 73 hospitals contacted, responses were obtained from 31. Twenty four (78%) hospitals were unable to transfuse patients regularly due to blood scarcity. Packed red blood cells were available in 14 (45%), while only one provided leukocyte-depletion. Most centers assessed donor risk and screened for HIV in 30 (97%), hepatitis B in 31(100%) and hepatitis C in 27 (87%) hospitals. Extended phenotyping and alloantibody screening were not available in any center. A quarter of the hospitals could monitor iron overload, but only using serum ferritin. Access to iron chelators was limited and expensive. Seventeen (55%) tertiary hospitals offered CTT by top-up or manual exchange transfusion; previous stroke was the most common indication. CONCLUSION: Current efforts of Nigerian public hospitals to provide safe blood and CTT fall short of best practice. Provision of apheresis machines, improvement of voluntary non-remunerated donor drive, screening for red cell antigens and antibodies, and availability of iron chelators would significantly improve SCD care in Nigeria.

Sickle cell disease and H3Africa: enhancing genomic research on cardiovascular diseases in African patients.

BACKGROUND: Sickle cell disease (SCD) has a high prevalence in sub-Saharan Africa. There are several cardiovascular phenotypes in SCD that contribute to its morbidity and mortality. DISCUSSION: SCD is characterised by marked clinical variability, with genetic factors playing key modulating roles. Studies in Tanzania and Cameroon have reported that singlenucleotide polymorphisms in BCL11A and HBS1L-MYB loci and co-inheritance of alpha-thalassaemia impact on foetal haemoglobin levels and clinical severity. The prevalence of overt stroke among SCD patients in Cameroon (6.7%) and Nigeria (8.7%) suggests a higher burden than in high-income countries. There is also some evidence of high burden of kidney disease and pulmonary hypertension in SCD; however, the burden and genetics of these cardiovascular conditions have seldom been investigated in Africa. CONCLUSIONS: Several H3Africa projects are focused on cardiovascular diseases and present major opportunities to build genome-based research on existing SCD platforms in Africa to transform the health outcomes of patients.