Background
Sickle cell disease (SCD), a noncommunicable disease, has the greatest burden in sub-sub-Saharan Africa and is the most frequent genetic haemoglobinopathy, with more than 300 000 children born annually, and this number is expected to increase to 400 000 by 2050 [
1‐
3]. The majority of these children (50–90%) die before their 5th birthday, with approximately 150,000–300,000 annual SCD child deaths in Africa, which can potentially account for 5–10% of the region’s total child mortality [
1,
4,
5]. Nearly 90% of SCD patients live in 3 countries: Nigeria, India and the Democratic Republic of the Congo. In these countries, nearly 2% of the population has SCD with a carrier rate and sickle cell trait ranging from 10–30% [
6]. However, it has recently been found that the distribution of all haemoglobin disorders is extremely diverse within different countries, even within small geographical distances [
7].
Sickle cell disease (SCD) is a genetic autosomal recessive disorder that results from the substitution of valine for glutamine at position 6 of the beta chain haemoglobin. The haemoglobin (HbSS) tetramer that results from the substitution of alpha 2 and beta S2 is poorly soluble and rigid when deoxygenated, resulting in vaso-occlusion, which in turn causes several complications [
8]. Moreover, there are different forms of sickle cell disease, including HbSS, HbSC, HbS beta-thalassaemia, HbSE, and HbSD, which occur throughout sub-Saharan Africa and in small pockets in the Mediterranean region, the Middle East and the Indian subcontinent [
9]. HbSC disease is restricted to parts of western and northern Africa, and HbS thalassemia is localised in parts of sub-Saharan Africa, some parts of the Middle East and the Indian subcontinent. Additionally, HbSE commonly occurs in India, Bangladesh, Myanmar and east and southeast Asia [
9].
Among SCD variants, HbSS is the most common in the sub-Saharan region and is associated with severe complications in comparison with the other variants. These complications include but are not limited to priapism, pulmonary emboli, and osteonecrosis and ultimately damage every organ system, including the spleen, retinae, kidneys and liver [
10].
In the sickle cell trait, the heterozygous form of HbS is the carrier state for sickle cell haemoglobin. These individuals inherit HbS from one parent and HbA from the other parent, making them heterozygous (HbAS). More than 100 million or approximately 5% of the world’s population has the sickle cell trait (SCT) [
11]. Most people with sickle cell traits live asymptomatically. Despite SCT being perceived as an asymptomatic condition, several case reports and reviews have reported an increased incidence of renal medullary carcinoma among young patients with SCT aged 9 to 69 years [
12‐
14]. Other forms of traits include HbAC and HbAE, although these are rare forms [
9].
The gene for sickle haemoglobin (HbS) is a prime example of natural selection. It is generally believed that its current prevalence in many tropical populations reflects selection for the carrier form (sickle cell trait (HbAS)) through a survival advantage against death from malaria [
15]. A study by Williams et al. [
15] showed that HbAS had no effect on the prevalence of symptomless parasitaemia but was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria.
Malaria remains a major public health problem in Namibia, mostly in the Kavango East and West, Ohangwena and Zambezi regions. Kavango East and West accounted for 81%, Zambezi accounted for 10% and Ohangwena accounted for 5% of the 4 regions, according to a recently published study (2023) by Katale and Gemechu [
16].
Early detection of sickle cell disease or disease-related traits is imperative for long-term outcomes, as treatment can be initiated early. In developed countries, newborn screening (NBS) has been shown to improve the survival of children with sickle cell disease, with under5 childhood mortality reduced tenfold due to interventions performed before the development of complications [
17].
Over the years, several techniques have been employed to diagnose and monitor SCD. High-performance liquid chromatography (HPLC) and isoelectric focusing (IEF) are the two main laboratory techniques for haemoglobinopathy screening that are currently suitable for routine use and have been used in developed countries and several studies in Africa [
18]. Molecular genetic tests are considered the gold standard tests because they target the affected genes and they can distinguish different mutations [
19]. These include restriction fragment length polymorphism (RFLP) partial restriction of deoxyribonucleic acid (DNA), real-time polymerase chain reaction (PCR) [
20] and DNA sequencing, which is the most expensive molecular method compared to RFLP and PCR.
Because of the reagents, instrumentation, personnel and review time required for analysis, it provides the most comprehensive data for the beta-globin gene [
20]. Point-of-care tests (POCTs), SCD screening methods validated in developing countries, are easier to perform and require less qualified personnel with results available within a short period of time [
21]. POCTs that have recently been developed include the HemotypeSC™, Sickle SCAN™, Heme Chip, Aqueous multiphase System (AMPS), Paper-based Sickle test (microfluid assessment) and microchip-based cellulose acetate electrophoresis test (‘Gazelle) [
22]. Gazelle uses Hb electrophoresis on a much smaller machine, which actually be used in the community, but unfortunately, skilled personnel are still required to carry out this process effectively [
22]. Sickle cell SCAN™, a lateral flow assay that reliably identifies HbA, HbS, and HbC, is easily performed by non‐skilled personnel and is easily interpreted, rapid test at the point of care [
21]. This test detected the correct presence of A, S, and C with an overall diagnostic accuracy of 99% at the bedsid [
23]. However, it is relatively more expensive than other POCTs.
Heme Chip is reliable and is able to distinguish most types of sickle cell disease, including compound heterozygotes. However, it requires skilled interpretation, is web-based, and is automated, and this approach is out of reach for most resource-limited region [
21]. Additionally, the aqueous multiphase system (AMPS) (density-based test to separate Hb in fluids with different densities) and paper-based sickle test (microfluid assessment) are inexpensive and require nonskilled personnel. However, interpretation may be difficult, and the latter requires a scanner for interpretation [
21,
24].
HemoTypeSC™, a POCT monoclonal antibody that targets Hb A, S, and C but not Hb F, is one of the newest techniques and yields results in 10 min [
25,
26]. Multiple studies have shown that HemoTypeSC™ has a sensitivity and specificity of more than 98% compared to the gold standard methods of HPLC and IEF [
23,
25,
27‐
31]. Various studies have shown that the HemotypeSC point-of-care testing device has high sensitivity and specificity for diagnosing sickle cell disease (SCD). A study by Olatunya et al. (2021) revealed that HemotypeSC had perfect concordance with PCR and 100% accuracy in diagnosing SCD, while Nnodu et al. (2019) reported a sensitivity of 93.4% and a specificity of 99.9% for SCD [
27,
32]. In addition, Okeke, 2022 further demonstrated the feasibility of using dried blood spots with HemotypeSC, with a sensitivity and specificity of 100% compared to the standard test [
31]. A further study by Adegoke et al. [
33] also revealed that HemotypeSC is more sensitive than alkaline cellulose acetate haemoglobin electrophoresis. These findings collectively suggest that the HemotypeSC is a reliable and accurate tool for SCD diagnosis. Although other POCT tests, such as Sickle SCAN, have been validated in some parts, Hemotype SC has been shown to be less expensive and easier to use [
34,
35].
Newborn screening for sickle cell disease has not yet been established in Namibia. Sick children tend to present to referral hospitals with SCD-related complications prior to diagnosis. The birth prevalence of sickle cell disease and sickle cell traits has not been documented in Namibia.
The aim of this study was to determine the birth prevalence of sickle cell disease and sickle cell traits using the HemotypeSC™ point-of-care test.
The POCT detects normal haemoglobin (HbAA), SCD (HbSS, HbSC), sickle cell trait (HbAS) and/ or homozygous and heterozygous for HbC (HbCC, HbAC). This study was the first in Namibia to carry out NBS for sickle cell disease and the first to use the point-of-care test Hemotype SC™. In addition, this study will guide policy on the need to introduce SCD and NBS in Namibia, as recommended by the World Health Organisation (WHO) African Region strategy, which provides a set of public health interventions to reduce the burden of SCD in Africa. This strategy focuses on improved awareness, disease prevention and early detection [
36].
Discussion
The birth prevalence of sickle cell disease or sickle cell traits varies across different countries in sub-Saharan Africa. Our study is the first in Namibia to determine the birth prevalence of sickle cell disease and sickle cell traits. A moderate incidence of sickle cell trait birth (9.4%) was reported. However, no participant had sickle cell disease. Similar findings on HbAS sickle trait carriage were reported in Malawi, with a prevalence ranging from 6.5% to 9% % in the studies [
45‐
47].
These findings are similar to those of a study by Munyanganizi in Rwanda, in which 987 participants did not have sickle cell disease [
48]. In a study in South Africa that focused on 3 countries, South Africa, Zambia and Zimbabwe, the sickle cell trait prevalence rates were 0%, 6.5% and 12%, % respectively. This study revealed a higher prevalence of SCT compared to a study in Mozambique, which reported a prevalence of 4% [
49]. Despite Rundu being closer to the Angolan border, the prevalence of SCT is twice lower than that of Angola ( prevalence 21%) [
34]. These differences may be due to the different ethnic groups and, genetic makeup of the participants. In addition, a modeling study by Piel et al. 2021 reported this diversity in the distribution of the HbS gene [
1].
Similar studies that used HemoTypeSC as the primary screening method in some parts of Africa reported sickle cell disease incidences ranging from 1.1 to 3.9%, with a prevalence of sickle cell traits ranging from 20.6 to as high as 31.6% [
27,
50,
51]. In these studies, laboratory-based confirmatory tests were performed, and HemoType SC, a point-of-care test, was highly sensitive.
Studies that validated the accuracy of HemoTypeSC reported a sensitivity of 94.4 to 100% and specificity of 99.9 to 100% in multicentre studies conducted in Ghana, Martinique and the USA and a separate study in Nigeria [
25,
27]. Therefore, our study findings may be a true representation of the actual haemoglobin types found in the participants considering the high sensitivity of the test. Considering that Namibia is a vast country with centralized laboratories which are from health facilities and limited laboratory personnel, the HemotypeSC is a potential tool for newborn screening for sickle cell disease also a cheap test for diagnosing SCD in symptomatic patients; children and adults alike. Health personnel can be trained at low-level facilities and perform the test and provide results at the one visit avoiding loss to follow up associated with centralized laboratory testing. The current test for diagnosing symptomatic patients, haemoglobin electrophoresis, has a turnaround time of between 7 to 14 days, requires highly skilled personnel and is much more expensive, costing between US$ 90 to US$200, which is 19–100 times more expensive than HemotypeSC, which costs between US$ 2 and US$5 [
28].
The main issue remaining is whether or not validation is required for the Namibia population. This study was carried out with the background of the test having been validated in several studies showing high sensitivity and specificity [
27,
31‐
33]. Perhaps the absence of detection of homozygous HbSS may raise the need for confirmatory tests in future studies prior to the introduction of NBS in Namibia.
Limitations of the study
The limitation of this study is that, the study was only carried out at one facility, yet the Kavango region has two district hospitals and some health centres that provide maternity care. In addition, participants with sickle cell disease might have been missed because they were born outside the health facility. Additionally, patients excluded from the study could have been carriers or have sickle cell disease. Therefore selection bias could have contributed to the results of the study. Future studies should therefore expand the facilities and consider community- based NBS and include all newborn babies regardless of gestational age to obtain an accurate representative birth prevalence of SCD and SCT in Namibia. Finally, our study reported on the level of maternal education which in some countries and cultures, greater education sometimes correlates with better information about genetics of sickle cell disease so that women avoid a mate with sickle trait or HbC trait and therefore skew their offspring toward fewer births with sickle cell disease [
52‐
54]. However we did not correlate level of education and uptake of newborn screening. Future studies could consider level of education, knowledge on SCD genetics and choice of mate.
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