Evaluation of treatment patterns, healthcare resource utilization and cost of illness for sickle cell disease in Ghana: a private medical insurance claims database study.

BACKGROUND: Sickle cell disease (SCD) is a major public health concern in sub-Saharan Africa, accounting for nearly 75% of the global disease burden. The current analysis evaluated patient characteristics, treatment patterns, healthcare resource utilization (HCRU) and associated costs in patients with SCD based on a Private Medical Insurance Database in Ghana. METHODS: This retrospective longitudinal cohort study was conducted using an e-claims database from Ghana (01 January 2015 to 31 March 2021). Patients were stratified by age (0 month to < 2 years, ≥ 2 years to ˂6 years, ≥ 6 years to < 12 years, ≥ 12 years to < 16 years; ≥16 years), vaso-occlusive crisis (VOC) (< 1, ≥ 1 to < 3, and ≥ 3 per year), and continuous enrolment. Study outcomes related to patient characteristics, comorbidities, treatment pattern, HCRU were evaluated for pre- and post-index period (index period was between July 2015 to March 2020). Descriptive analysis was used to analyse different study variables. RESULTS: The study included 2,863 patients (mean age: 20.1 years; Min age: 0; Max age: 83; females 56.1%). Overall, 52.2% (n = 1,495) of SCD patients were ≥ 16 years and 17.0% (n = 486) were in the ≥ 2 to ˂6-years age group. The majority of patients aged ≥ 16 years (62.5%) in the database did not have reported VOC episodes, 35.9% of patients had 1 to 3 VOCs per year and 1.5% had ≥ 3 VOCs per year during the follow-up period. Consultation-based prevalence of SCD was 0.5% [95% confidence interval (CI): 0-1.3%] - 1.4% [CI: 0.6-2.2%]. Malaria, upper respiratory tract infection (URTI) and sepsis were the common complications of SCD. Analgesics were the most frequently prescribed medications followed by anti-infectives, hematinics, and antimalarials. Hydroxyurea, a routine standard of care for SCD was under-utilized. SCD patients had median cost incurred for consultation/hospital services of $11.3 (Interquartile range [IQR] $6.2 - $27.2). For patients with VOC, maximum median cost was incurred for medications ($10.9 [IQR $5.0-$32.6]). Overall median healthcare cost was highest for individuals with ≥ 3 VOCs per year during the follow-up period ($166.8 [IQR $70.3-$223.5]). CONCLUSION: In this retrospective private insurance claims database analysis, SCD imposes a significant healthcare burden, especially in patients with VOC. There is a need for reimbursed treatment options that could reduce the long-term burden associated with SCD and VOC.

Sickle Cell Hemoglobin Genotypes Affect Malaria Parasite Growth and Correlate with Exosomal miR-451a and let-7i-5p Levels.

Malaria affects a significant portion of the global population, with 247 million cases in 2021, primarily in Africa. However, certain hemoglobinopathies, such as sickle cell trait (SCT), have been linked to lower mortality rates in malaria patients. Hemoglobin (Hb) mutations, including HbS and HbC, can cause sickle cell disease (SCD) when both alleles are inherited (HbSS and HbSC). In SCT, one allele is inherited and paired with a normal allele (HbAS, HbAC). The high prevalence of these alleles in Africa may be attributed to their protective effect against malaria. Biomarkers are crucial for SCD and malaria diagnosis and prognosis. Studies indicate that miRNAs, specifically miR-451a and let-7i-5p, are differentially expressed in HbSS and HbAS compared to controls. Our research examined the levels of exosomal miR-451a and let-7i-5p in red blood cells (RBCs) and infected red blood cells (iRBCs) from multiple sickle Hb genotypes and their impact on parasite growth. We assessed exosomal miR-451a and let-7i-5p levels in vitro in RBC and iRBC supernatants. Exosomal miRNAs exhibited distinct expression patterns in iRBCs from individuals with different sickle Hb genotypes. Additionally, we discovered a correlation between let-7i-5p levels and trophozoite count. Exosomal miR-451a and let-7i-5p could modulate SCD and malaria severity and serve as potential biomarkers for malaria vaccines and therapies.

A case-control and seven-year longitudinal neurocognitive study of adults with sickle cell disease in Ghana.

Ageing in sickle cell disease (SCD) is associated with a myriad of end-organ complications, including cerebrovascular damage and cognitive impairment (CI). Although CI is very common in SCD, little is known about cognitive functioning and how it changes with age. This study examines cognitive patterns of 63 adults with SCD and 60 non-SCD, age- and education-matched controls in Ghana. Of those adults with SCD, 34 completed the neuropsychological battery at baseline and again seven years later. In cross-sectional data, adults with SCD performed worse than controls in all cognitive test domains (p < 0.01 for all). The seven-year follow-up data showed that the group exhibited a significant decline in visuospatial abilities (ranging from Cohen's d = 1.40 to 2.38), and to a lesser extent, in processing speed and executive functioning. Exploratory analyses showed a significant time-by-education interaction, indicating that education may be protective from decline in cognitive performance. These findings have implications for clinical practice. Early neuropsychological surveillance coupled with early assessment and remedial programmes will provide avenues for enhancing the quality of life of adults living with SCD in Ghana.

The BLOODSAFE program: Building the future of access to safe blood in Sub-Saharan Africa.

BACKGROUND: The supply of blood in many low- and middle-income nations in Sub-Saharan Africa (SSA) does not meet the patient care needs. Lack and delay of blood transfusion cause harm to patients and slow the rate of progress in other parts of the health system. Recognizing the power of implementation science, the BLOODSAFE Program was initiated which supports three SSA research study teams and one data coordinating center (DCC) with the goal to improve access to safe blood transfusion in SSA. STUDY DESIGN AND METHODS: The study team in Ghana is focusing on studying and decreasing iron deficiency in blood donors and evaluating social engagement of blood donors through different approaches. The study team in Kenya is building a "vein to vein" workflow model to elucidate and devise strategies to overcome barriers to blood donation and improve infrastructural components of blood product production and use. The Malawi team is studying the infectious disease ramifications of blood donation as well as blood donor retention strategies aimed at blood donors who commence their donation career in secondary schools. RESULTS AND DISCUSSION: Together the project teams and the DCC work as a consortium to support each other through a shared study protocol that will study donor motivations, outcomes, and adverse events across all three countries. The BLOODSAFE Program has the potential to lead to generalizable improvement approaches for increasing access to safe blood in SSA as well as mentoring and building the research capacity and careers of many investigators.

Rational design of an essential diagnostics network to support Universal Health Coverage: a modeling analysis.

BACKGROUND: Diagnostic investigations, including pathology and laboratory medicine (PALM) and radiology, have been largely absent from international strategies such as the Sustainable Development Goals. Further, there is little international guidance on which health system tiers different diagnostics should be placed, a critical step in developing a country-level diagnostics network. We describe a modeling strategy to produce tier-specific diagnostic recommendations based on disease burden, current treatment pathways, and existing infrastructure in a country. METHODS: The relational model assumes that diagnostics should be available at the lowest tier where patients might receive medical management. Using Ghana as an exemplar, the 20 diseases forecasted by 2030 and 2040 to cause the greatest burden in low- and middle-income countries were mapped to three generalized tiers in the Ghanaian health system (Primary, Secondary, and Tertiary care) for three levels of each disease (triage, uncomplicated, and complicated). The lowest tier at which a diagnostic could potentially be placed was restricted by existing infrastructure, though placement still required there be a medical justification for the diagnostic at that tier. RESULTS: The model recommended 111 unique diagnostic investigations with 17 at Primary tier, an additional 45 at Secondary tier and a further 49 at Tertiary tier. Estimated capital costs were $8,330 at Primary tier and between $571,000 to $777,000 at Secondary tier. Twenty-eight different laboratory tests were recommended as send-outs from Primary to Secondary tier, and twelve as send-outs to Tertiary tier. CONCLUSIONS: This model provides a transparent framework within which countries can customize diagnostic planning to local disease priorities, health system patient treatment pathways, and infrastructural limitations to best support Universal Health Coverage.

Multidisciplinary care results in similar maternal and perinatal mortality rates for women with and without SCD in a low-resource setting.

In Africa, the maternal mortality rate in sickle cell disease (SCD) is ~10%. Our team previously demonstrated an 89% decrease in mortality rate in a before-and-after feasibility study among women with SCD living in low-resource setting in Ghana. In the same cohort including additional participants with and without SCD, we used a prospective cohort design to test the hypothesis that implementing a multidisciplinary care team for pregnant women with SCD in low-resource setting will result in similar maternal and perinatal mortality rates compared to women without SCD. We prospectively enrolled pregnant women with and without SCD or trait and followed them up for 6-week postpartum. We tested the newborns of mothers with SCD for SCD. We recruited age and parity matched pregnant women without SCD or trait as the comparison group. Maternal and perinatal mortality rates were the primary outcomes. A total of 149 pregnant women with SCD (HbSS, 54; HbSC, 95) and 117 pregnant women without SCD or trait were included in the analysis. Post-intervention, maternal mortality rates were 1.3% and 0.9% in women with and without SCD, respectively (P = 1.00); the perinatal mortality rates were 7.4% and 3.4% for women with and without SCD, respectively (P = 0.164). Among the mothers with SCD, ~15% of newborns had SCD. Multidisciplinary care of pregnant women with SCD may reduce maternal and perinatal mortality rates to similar levels in pregnant women without SCD in low-resource settings. Newborns of mothers with SCD have a high rate of SCD.

Implementation of multidisciplinary care reduces maternal mortality in women with sickle cell disease living in low-resource setting.

Sickle cell disease (SCD) is associated with adverse pregnancy outcome. In women with SCD living in low-resource settings, pregnancy is associated with significantly increased maternal and perinatal mortality rates. We tested the hypothesis that implementing a multidisciplinary obstetric and hematology care team in a low-resource setting would significantly reduce maternal and perinatal mortality rates. We conducted a before-and-after study, at the Korle-Bu Teaching Hospital in Accra, Ghana, to evaluate the effect of a multidisciplinary obstetric-hematology care team for women with SCD in a combined SCD-Obstetric Clinic. The pre-intervention period was assessed through a retrospective chart review to identify every death and the post-intervention period was assessed prospectively. Interventions consisted of joint obstetrician and hematologist outpatient and acute inpatient reviews, close maternal and fetal surveillance, and simple protocols for management of acute chest syndrome and acute pain episodes. Primary outcomes included maternal and perinatal mortality rates before and after the study period. A total of 158 and 90 pregnant women with SCD were evaluated in the pre- and post- intervention periods, respectively. The maternal mortality rate decreased from 10 791 per 100 000 live births at pre-intervention to 1176 per 100 000 at post-intervention, representing a risk reduction of 89.1% (P = 0.007). Perinatal mortality decreased from 60.8 per 1000 total births at pre-intervention to 23.0 per 1000 at post-intervention, representing a risk reduction of 62.2% (P = 0.20). A multidisciplinary obstetric and hematology team approach can dramatically reduce maternal and perinatal mortality in a low-resource setting.

Hematological Differences among Malaria Patients in Rural and Urban Ghana.

BACKGROUND: Scarce studies have addressed hematological differences of malaria in urban and rural regions. METHODS: Full or complete blood cell counts from 46 and 75 individuals (age range from < 1 to 92 years) with uncomplicated malaria infection living in urban (Accra) and rural (Dodowa) Ghana, respectively, were assessed. Sickle cell trait and patients were excluded from the study. RESULTS: Between overall groups, patients from Accra had significantly lower parasite count (p < 0.0001) and granulocyte number (p = 0.026). Children in Accra had a significantly lower parasitemia (p = 0.0013), hemoglobin (p = 0.0254), platelet count (p = 0.0148) and red blood cell levels (p = 0.0080) when compared with the children of Dodowa. In adults, mean cell hemoglobin (p = 0.0086) and parasite count (p < 0.0001) were significantly higher in Dodowa. CONCLUSION: These results indicate that children living in urban setting may experience a greater anemic effect to malaria as compared with those living in a rural setting.

Cervical precancer screening with HPV DNA testing and mobile colposcopy in women with sickle cell disease in Accra, Ghana.

Background: Worldwide, about 20-25 million people are affected by sickle cell disease (SCD), with 60% of patients living in sub-Saharan Africa. Despite recent therapeutic advancements resulting in improved life expectancy among SCD patients, the prevalence of high-risk human papillomavirus (hr-HPV) and cervical lesions have not been studied in women with SCD. We determined the prevalence of hr-HPV and cervical lesions among women with SCD and recommended strategies for reducing cervical cancer incidence in this cohort. Methods: Through the mPharma 10,000 Women Initiative, women with SCD attending routine visits at the Ghana Institute of Clinical Genetics SCD clinic were screened by trained nurses. Screening was performed via concurrent MA-6000 hr-HPV DNA testing and enhanced visual assessment (EVA) mobile colposcopy from mobileODT. Results: Among 168 participants screened (mean age, 43.0 years), the overall prevalence rates of hr-HPV infection and cervical lesions were 28.6% (95% CI, 21.7-35.4) and 3.6% (95% CI, 0.8-6.4), respectively. The hr-HPV prevalence rates stratified by haemoglobin genotype were 29.4% (95% CI, 19.7-39.1) and 28.6% (95% CI, 18.5-38.7) for genotypes SS and SC, respectively. None of the five women with the SF genotype tested hr-HPV positive, and the only patient with Sbthal genotype tested hr-HPV positive. Two women were EVA 'positive' but hr-HPV negative, whereas four were EVA positive and hr-HPV positive. Exploratory analysis revealed no significant associations between hr-HPV positivity and age, education level, marital status or parity. Conclusion: In the absence of a comprehensive national cervical screening programme aimed at including women with SCD as a special population, cervical cancer may increase in frequency among SCD patients. Thus, there is a need to build capacity and expand the scope of screening services for women with SCD.

Prospective identification of variables as outcomes for treatment (PIVOT): study protocol for a randomised, placebo-controlled trial of hydroxyurea for Ghanaian children and adults with haemoglobin SC disease.

BACKGROUND: Haemoglobin SC (HbSC) is a common form of sickle cell disease (SCD), especially among individuals of West African ancestry. Persons with HbSC disease suffer from the same clinical complications and reduced quality of life that affect those with sickle cell anaemia (HbSS/Sß0). Retrospective anecdotal data suggest short-term safety and benefits of hydroxyurea for treating HbSC, yet rigorous prospective data are lacking regarding optimal dosing, clinical and laboratory effects, long-term safety and benefits, and appropriate endpoints to monitor. Prospective Investigation of Variables as Outcomes for Treatment (PIVOT) was designed with three aims: (1) to measure the toxicities of hydroxyurea treatment on laboratory parameters, (2) to assess the effects of hydroxyurea treatment on sickle-related clinical and laboratory parameters, and (3) to identify study endpoints suitable for a future definitive phase III trial of hydroxyurea treatment of HbSC disease. METHODS: PIVOT is a randomised, placebo-controlled, double blind clinical trial of hydroxyurea. Approximately 120 children and 120 adults ages 5-50 years with HbSC disease will be enrolled, screened for 2 months, and then randomised 1:1 to once-daily oral hydroxyurea or placebo. Study treatment will be prescribed initially at 20 ± 5 mg/kg/day with an opportunity to escalate the dose twice over the first 6 months. After 12 months of blinded study treatment, all participants will be offered open-label hydroxyurea for up to 4 years. Safety outcomes include treatment-related cytopenias, whole blood viscosity, and adverse events. Efficacy outcomes include a variety of laboratory and clinical parameters over the first 12 months of randomised treatment, including changes in haemoglobin and fetal haemoglobin, intracranial arterial velocities measured by transcranial Doppler ultrasound, cerebral oxygenation using near infrared spectrometry, spleen volume and kidney size by ultrasound, proteinuria, and retinal imaging. Exploratory outcomes include functional erythrocyte analyses with ektacytometry for red blood cell deformability and point-of-sickling, patient-reported outcomes using the PROMIS questionnaire, and 6-min walk test. DISCUSSION: For children and adults with HbSC disease, PIVOT will determine the safety of hydroxyurea and identify measurable changes in laboratory and clinical parameters, suitable for future prospective testing in a definitive multi-centre phase III clinical trial. TRIAL REGISTRATION: PACTR, PACTR202108893981080. Registered 24 August 2021, https://pactr.samrc.ac.za.

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers.

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

Delayed diagnosis of polycythaemia vera in an adult female with non-cirrhotic portal hypertension.

Polycythaemia vera (PV) is a rare myeloproliferative neoplasm characterized primarily by erythrocytosis and an increased risk of thrombosis. We report a case of PV in a 60-year-old female with diabetes mellitus (DM) and a past history of recurrent abdominal pain and documented oesophageal varices who was followed up for 2 years as a case of non-cirrhotic portal hypertension of unknown cause. PV was only diagnosed after persistent complaints of vaso-motor symptoms and better scrutiny of full blood count results.

Immunophenotypic characterisation of non-Hodgkin lymphomas at a tertiary hospital in Ghana.

Background: Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of clonal lymphoid tumours originating from lymphocytes. They constitute about 90% of an estimated 3%-4% worldwide distribution of malignant lymphomas among various cancers. Despite the continuous rise and associated deaths, research on NHLs, and in particular the area of immunophenotypic spectrum is limited in Ghana and sub-Saharan Africa. Methods: A retrospective, descriptive study in which archived tissue blocks of histologically diagnosed NHLs at a tertiary hospital in Accra, Ghana, were used. Antigenic phenotypes were determined by immunohistochemistry. Results: A total of 66 cases of NHLs, with a mean age of 50.2 ± 16.1 years, were selected for the study. Among the targeted markers, cluster of differentiation 20 (CD20) was the most commonly expressed in 89.4% (59) cases. Immunohistochemistry studies revealed a greater proportion of B cell lymphomas of 89.4%. Five subtypes were successfully identified, of which diffuse large B cell lymphoma constitutes the predominant group (40.9%). A significant association was observed between phenotypic cell types and outcomes of NHLs (p = 0.011). Conclusion: Adult NHLs were mostly due to the malignant transformation of B cells with diffuse large B cell lymphoma being the commonest subtype. The present study therefore serves as preliminary data for further research towards the adoption of an improved treatment regimen and management of NHLs.

MicroRNAs miR-451a and Let-7i-5p Profiles in Circulating Exosomes Vary among Individuals with Different Sickle Hemoglobin Genotypes and Malaria.

Sickle cell disease (SCD) occurs when two alleles of mutated hemoglobin (HbS or HbC) are inherited (HbSS and HbSC) rather than one (HbAS or HbAC), which indicates a person carries the sickle cell trait. The high prevalence of these two alleles in Africa have been associated with reduced malaria susceptibility. Recent in vitro research has been shown that microRNAs (miRNAs) miR-451a and let-7i-5p are differentially expressed in HbSS erythrocytes compared to healthy controls (HbAA) and are overexpressed in Plasmodium-infected malaria erythrocytes. However, these miRNAs have not been fully examined in the plasma of people with different sickle hemoglobin genotypes. Plasma circulating miRNAs are commonly encapsulated in extracellular vesicles, such as exosomes, and are thought to play a role in disease development. Circulating exosomal miR-451a and let-7i-5p were quantified from individuals with various hemoglobin genotypes (HbAA, HbAS, HbAC, HbSS, HbSC, and HbCC) with (+) and without (-) malaria. The results showed a higher level of exosomal let-7i-5p and miR-451a in HbSS-. Exosomal let-7i-5p and miR-451a levels were lower in HbSS+ compared to other genotypes. Based on the area under the curve (AUC) of the Receiver Operating Characteristics (ROCs), both exosomal miRNAs may be useful disease biomarkers for SCD with malaria. Finally, miR-451a and let-7i-5p modulate genes involved in inflammation, making them potential biomarkers of pathogenesis for both diseases.

Multispectral imaging for MicroChip electrophoresis enables point-of-care newborn hemoglobin variant screening.

Hemoglobin (Hb) disorders affect nearly 7% of the world's population. Globally, around 400,000 babies are born annually with sickle cell disease (SCD), primarily in sub-Saharan Africa where morbidity and mortality rates are high. Screening, early diagnosis, and monitoring are not widely accessible due to technical challenges and cost. We hypothesized that multispectral imaging will allow sensitive hemoglobin variant identification in existing affordable paper-based Hb electrophoresis. To test this hypothesis, we developed the first integrated point-of-care multispectral Hb variant test: Gazelle-Multispectral. Here, we evaluated the accuracy of Gazelle-Multispectral for Hb variant newborn screening in 265 newborns with known hemoglobin variants including hemoglobin A (Hb A), hemoglobin F (Hb F), hemoglobin S (Hb S) and hemoglobin C (Hb C). Gazelle-Multispectral detected levels of Hb A, Hb F, Hb S, and Hb C/E/A2, demonstrated high correlations with the results reported by laboratory gold standard high performance liquid chromatography (HPLC) at Pearson Correlation Coefficient = 0.97, 0.97, 0.93, and 0.95. Gazelle-Multispectral demonstrated accuracy of 96.8% in subjects of 0-3 days, and 96.9% in newborns. The ability to obtain accurate results on newborn samples suggest that Gazelle-Multispectral can be suitable for large-scale newborn screening and for diagnosis of SCD in low resource settings.

Safe blood supply in sub-Saharan Africa: challenges and opportunities.

The low recruitment and retention of blood donors in sub-Saharan Africa is a grave concern for blood transfusion services in the region. This problem is exacerbated by factors such as a high prevalence of transfusion-transmissible infections and anaemia, over-reliance on family replacement donors, resource constraints, and poor communication with the public. To improve blood safety and availability, innovative intervention strategies must be developed and implemented. The primary objective of this Series paper is to discuss the available evidence in the region and to provide recommendations on how to improve safe blood supply in sub-Saharan Africa. These recommendations include a call for renewed attention to donor recruitment in blood transfusion centres, a consistent and structured educational intervention, the development and adherence to national policies on blood donor selection with focus on voluntary donations, and comprehensive screening of donations for transfusion-transmissible infections. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.