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 11 000 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 12 years, 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.

Expanding the human gut microbiome atlas of Africa.

Population studies are crucial in understanding the complex interplay between the gut microbiome and geographical, lifestyle, genetic, and environmental factors. However, populations from low- and middle-income countries, which represent ~84% of the world population, have been excluded from large-scale gut microbiome research. Here, we present the AWI-Gen 2 Microbiome Project, a cross-sectional gut microbiome study sampling 1,803 women from Burkina Faso, Ghana, Kenya, and South Africa. By intensively engaging with communities that range from rural and horticultural to urban informal settlements and post-industrial, we capture population diversity that represents a far greater breadth of the world's population. Using shotgun metagenomic sequencing, we find that study site explains substantially more microbial variation than disease status. We identify taxa with strong geographic and lifestyle associations, including loss of Treponema and Cryptobacteroides species and gain of Bifidobacterium species in urban populations. We uncover a wealth of prokaryotic and viral novelty, including 1,005 new bacterial metagenome-assembled genomes, and identify phylogeography signatures in Treponema succinifaciens. Finally, we find a microbiome signature of HIV infection that is defined by several taxa not previously associated with HIV, including Dysosmobacter welbionis and Enterocloster sp. This study represents the largest population-representative survey of gut metagenomes of African individuals to date, and paired with extensive clinical biomarkers, demographic data, and lifestyle information, provides extensive opportunity for microbiome-related discovery and research.

Identifying the prevalence and correlates of multimorbidity in middle-aged men and women: a cross-sectional population-based study in four African countries.

OBJECTIVES: To determine the prevalence of multimorbidity, to identify which chronic conditions cluster together and to identify factors associated with a greater risk for multimorbidity in sub-Saharan Africa (SSA). DESIGN: Cross-sectional, multicentre, population-based study. SETTING: Six urban and rural communities in four sub-Saharan African countries. PARTICIPANTS: Men (n=4808) and women (n=5892) between the ages of 40 and 60 years from the AWI-Gen study. MEASURES: Sociodemographic and anthropometric data, and multimorbidity as defined by the presence of two or more of the following conditions: HIV infection, cardiovascular disease, chronic kidney disease, asthma, diabetes, dyslipidaemia, hypertension. RESULTS: Multimorbidity prevalence was higher in women compared with men (47.2% vs 35%), and higher in South African men and women compared with their East and West African counterparts. The most common disease combination at all sites was dyslipidaemia and hypertension, with this combination being more prevalent in South African women than any single disease (25% vs 21.6%). Age and body mass index were associated with a higher risk of multimorbidity in men and women; however, lifestyle correlates such as smoking and physical activity were different between the sexes. CONCLUSIONS: The high prevalence of multimorbidity in middle-aged adults in SSA is of concern, with women currently at higher risk. This prevalence is expected to increase in men, as well as in the East and West African region with the ongoing epidemiological transition. Identifying common disease clusters and correlates of multimorbidity is critical to providing effective interventions.

Sickle Cell Disease Genomics of Africa (SickleGenAfrica) Network: ethical framework and initial qualitative findings from community engagement in Ghana, Nigeria and Tanzania.

OBJECTIVES: To provide lay information about genetics and sickle cell disease (SCD) and to identify and address ethical issues concerning the Sickle Cell Disease Genomics of Africa Network covering autonomy and research decision-making, risk of SCD complications and organ damage, returning of genomic findings, biorepository, data sharing, and healthcare provision for patients with SCD. DESIGN: Focus groups using qualitative methods. SETTING: Six cities in Ghana, Nigeria and Tanzania within communities and secondary care. PARTICIPANTS: Patients, parents/caregivers, healthcare professionals, community leaders and government healthcare representatives. RESULTS: Results from 112 participants revealed similar sensitivities and aspirations around genomic research, an inclination towards autonomous decision-making for research, concerns about biobanking, anonymity in data sharing, and a preference for receiving individual genomic results. Furthermore, inadequate healthcare for patients with SCD was emphasised. CONCLUSIONS: Our findings revealed the eagerness of patients and parents/caregivers to participate in genomics research in Africa, with advice from community leaders and reassurance from health professionals and policy-makers, despite their apprehensions regarding healthcare systems.

Prevalence and Factors Associated with Human Parvovirus B19 Infection in Sickle Cell Patients Hospitalized in Tanzania.

BACKGROUND: The distribution of human parvovirus B19 (HPV B19) infection is ubiquitous and occurs worldwide. The virus has high tropism to red blood cells progenitor's cells leading to temporary infection of bone marrow and transient arrest of erythropoiesis. People with frequent episodes of hemolytic anemia including sickle cell disease (SCD) and thalassemia are at increased risk of infection. This study aimed at assessing prevalence and factors associated with HPV B19 infections among hospitalized SCD patients. METHODOLOGY: This was a cross-sectional hospital-based study among SCD patients hospitalized at Muhimbili National Hospital. HPV B19 was detected using RT-PCR. Hematological and Chemistry tests were done using Sysmex XT2000i and Chemistry analyzer respectively. RESULTS: A total of 329 SCD patients, median age 15 years (interquartile range 7-22 years) were tested for HPV B19. The prevalence of HPV B19 was 29%. In multivariate logistic regression model, HPV B19 infection was associated with pain (OR=4.28, 95%CI: 1.20-15.19; p=0.025), low neutrophil counts (OR=0.57, 95%CI: 0.35-0.92, p=0.022) and MCH (OR=0.92, 95%CI: 0.85-0.99; p=0.033). Individuals infected with HPV B19 had slightly higher prevalence of severe anaemia (30.4% vs. 20.3%, p=0.054) and HIV infection (6.0% vs. 2.1%, p=0.083) in the univariate analysis. Considering the effect of HPV B19 virus on spleen, aplastic anemia and platelet counts in SCD patients, our study did not find any association with these parameters (p=0.244; p= 0.205 and p=0.567 respectively). CONCLUSION: The prevalence of HPV B19 among hospitalized SCD patients at MNH was high. SCD patients with HPV B19 were more likely to present with pain, low neutrophils levels, and MCH. HIV infection might be associated with a high risk of HPV infection in SCD patients; however, this requires further investigation.

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.

Newborn screening for sickle cell disease: an innovative pilot program to improve child survival in Dar es Salaam, Tanzania.

BACKGROUND: Sickle cell disease (SCD) is a recognized cause of childhood mortality. Tanzania has the fifth highest incidence of SCD (with an estimated 11 000 SCD annual births) worldwide. Although newborn screening (NBS) for SCD and comprehensive healthcare have been shown to reduce under-5 mortality by up to 94% in high-income countries such as the USA, no country in Africa has maintained NBS for SCD as a national health program. The aims of this program were to establish and evaluate NBS-SCD as a health intervention in Tanzania and to determine the birth prevalence of SCD. METHODS: Muhimbili University of Health and Allied Sciences conducted NBS for SCD from January 2015 to November 2016. Dried blood spot samples were collected and tested for SCD using isoelectric focusing. RESULTS: Screening was conducted on 3981 newborns. Thirty-one (0.8%) babies had SCD, 505 (12.6%) had sickle cell trait and 26 (0.7%) had other hemoglobinopathies. Twenty-eight (90.3%) of the 31 newborns with SCD were enrolled for comprehensive healthcare. CONCLUSIONS: This is the first report on NBS as a health program for SCD in Tanzania. The SCD birth prevalence of 8 per 1000 births is of public health significance. It is therefore important to conduct NBS for SCD with enrollment into a comprehensive care program.

Possible Risk Factors for Severe Anemia in Hospitalized Sickle Cell Patients at Muhimbili National Hospital, Tanzania: Protocol for a Cross-Sectional Study.

BACKGROUND: Sickle cell disease (SCD) is the most common inherited disorder worldwide, with the highest burden in sub-Saharan Africa. The natural history of SCD is characterized by periods of steady state interspersed by acute episodes. The acute anemic crises may be transient and are precipitated by treatable factors like infections, nutritional deficiencies, and sequestration. Anemia is almost always present, although it occurs at different levels of severity. OBJECTIVE: This paper describes the protocol of a cross-sectional study to determine the prevalence of severe anemia and associated factors among sickle cell patients hospitalized at the Muhimbili National Hospital. METHODS: This is an ongoing, descriptive, cross-sectional, hospital-based study among individuals with SCD, admitted to the Muhimbili National Hospital in Dares Salaam, Tanzania. A minimum sample size of 369 was calculated based on the previous prevalence of hospitalizations due to severe anemia (20%) in the same cohort. We are using a piloted standardized case report form to document clinical and laboratory parameters following informed consent. Data analysis will be performed using Stata software. Severe anemia is defined as Hb<5g/dL. Chi-square or Fisher's exact test will be used to ascertain association between categorical variables, and t-test will be used for numerical variables. Regression models for severe anemia against explanatory and confounding variables will be run, and results will be presented as adjusted odds ratio with 95% confidence intervals. A P value of <.05 will be considered significant. RESULTS: Enrolment commenced in January 2015 and concluded in September 2016. Complete data analysis will begin in February 2018. The study results are expected to be published in May 2018. CONCLUSIONS: This protocol paper will provide a useful and practical model for conducting cross-sectional studies in hospitalized patients that cover a wide ranging of clinical and laboratory variables.

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

BACKGROUND: The 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. METHODS: Archived 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. FINDINGS: In 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. INTERPRETATION: Hepcidin is lower in more severely anaemic children with SCD independent of inflammation or markers of erythropoiesis. FUNDING: Funding 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).

Limited Exchange Transfusion Can Be Very Beneficial in Sickle Cell Anemia with Acute Chest Syndrome: A Case Report from Tanzania.

Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD) with blood transfusion an integral part in its management. Red cell exchange (RCE) transfusion is usually regarded as preferable to top-up transfusion, because it reduces the proportion of Hemoglobin (Hb) S while at the same time avoiding circulatory overload. Despite its obvious benefits, RCE is underutilized, particularly in low-resource settings which may be due to scarcity of blood products and of expertise in carrying out exchange transfusion. We report on a young woman with SCD with severe ACS who responded promptly and dramatically to a RCE of only 0.95 L (instead of the recommended 1.4 L) and had in the end an HbS level of 48% (instead of the recommended level below 30%). Limited RCE resulted in significant clinical improvement. We suggest that limited RCE may be of benefit than no RCE in SCD patients with ACS, particularly in settings where RCE is not available.

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 ten year review of the sickle cell program in Muhimbili National Hospital, Tanzania.

BACKGROUND: Africa has the highest burden of Sickle cell disease (SCD) but there are few large, systematic studies providing reliable descriptions of the disease spectrum. Tanzania, with 11,000 SCD births annually, established the Muhimbili Sickle Cell program aiming to improve understanding of SCD in Africa. We report the profile of SCD seen in the first 10 years at Muhimbili National Hospital (MNH). METHODS: Individuals seen at MNH known or suspected to have SCD were enrolled at clinic and laboratory testing for SCD, haematological and biochemical analyses done. Ethnicity was self-reported. Clinical and laboratory features of SCD were documented. Comparison was made with non-SCD population as well as within 3 different age groups (< 5, 5-17 and ≥ 18 years) within the SCD population. RESULTS: From 2004 to 2013, 6397 individuals, 3751 (58.6%) SCD patients, were enrolled, the majority (47.4%) in age group 5-17 years. There was variation in the geographical distribution of SCD. Individuals with SCD compared to non-SCD, had significantly lower blood pressure and peripheral oxygen saturation (SpO2). SCD patients had higher prevalence of severe anemia, jaundice and desaturation (SpO2 < 95%) as well as higher levels of reticulocytes, white blood cells, platelets and fetal hemoglobin. The main causes of hospitalization for SCD within a 12-month period preceding enrolment were pain (adults), and fever and severe anemia (children). When clinical and laboratory features were compared in SCD within 3 age groups, there was a progressive decrease in the prevalence of splenic enlargement and an increase in prevalence of jaundice. Furthermore, there were significant differences with monotonic trends across age groups in SpO2, hematological and biochemical parameters. CONCLUSION: This report confirms that the wide spectrum of clinical expression of SCD observed elsewhere is also present in Tanzania, with non-uniform geographical distribution across the country. Age-specific analysis is consistent with different disease-patterns across the lifespan.