This current study took place at the support center for SCD created in the remote city of Mbujimayi in Kasai Oriental province in the DRC (around 2.5 million inhabitants) . It aimed to establish a reference center of sickle cell disease that would offer comprehensive outpatient and inpatient care to establish regular and standardized medical follow-ups of patients and to estimate whether this is feasible and affordable in a remote city. Additional goals were to observe the results after one year of implementation of a regular medical follow-up, to estimate the need for the introduction of treatment by hydroxyurea, and to determine if all the tools would be in place to ensure adequate medical follow-up for those who would be treated with hydroxyurea. A cohort of 143 SCD children with a median age of 10 years was followed for 2 years. In the first year, follow-up was limited to the management of acute complications of the disease (VOC, acute anemia, infection episodes, acute chest syndrome, etc.) without other specific interventions, and the second year included the implementation of standardized and regular follow-ups. Results after 12 months of regular, standardized medical follow-ups and parental education, without treatment introduction by hydroxyurea, showed an overall reduction in acute complications, i.e., vaso-occlusive crises, infectious episodes, acute chest syndrome, episodes of blood transfusions and hospitalizations, and improvement of anemia. The results show that the intervention of a newly established sickle cell referral center with evidence-based guidelines had a positive impact in reducing morbimortality. Regular follow-ups of SCD patients, including a hematological follow-up, are possible and applicable both before the introduction of hydroxyurea treatment and in the context of a remote city in the DRC.
Creating a support center located close to patients that organizes free-of-charge care allowed the current study to be conducted. This is one of the recommended strategies for effectively reducing the burden of SCD morbimortality . In the context of poverty, the goal of equal access to healthcare can only be achieved if health policies guarantee effective care for all patients. As described in Mali, providing centers and units of competence is vital . These structures, whose missions focus primarily on diagnosis and management, should be local community centers. They are stepstones necessary to promote access to timely care for a great number of SCD patients at an affordable cost. As reported by the Human Development Index, the majority of patients affected by SCD are those with a limited income , and in most African countries, only rich patients have access to basic treatments such as prophylactic oral penicillin; for example, in the DRC, the cost of SCD management is not affordable for approximately 95% of patients [37,39].
There are very few referral centers for the management of sickle cell disease in sub-Saharan Africa . The few centers of reference for sickle cell disease, if they exist, are in the capitals and large cities of these countries and not in remote areas. In the DRC, the sickle cell referral centers are in Kinshasa (Monkole Hospital and the SS Centre for Mixed Medicine and Anaemia (CMMASS) and Lubumbashi (SCD referral center at Nsendwe Hospital).
In sub-Saharan Africa, models of sickle cell disease management programs have been proposed in the capitals of some countries. Of note are the Center for Research and control for SCD (CRLD) in Bamako au Mali , the National Reference Centre for Sickle Cell Disease (CNRD) in Brazzaville, Republic of Congo , National Sickle Cell Disease Center in Cotonou, Benin . All these centers are almost entirely privately funded (including in the DRC). The model implemented was based on neonatal screening for SCD as part of a project and follow-up with long-term sickle cell patients. The cost of care for patient-dependent follow-up can be prohibitive. Although these projects have received government support in their implementation, these programs remain limited at the capital level, and the positive impetus for neonatal screening stops with the end of funding and/or remains non-systematic at the expense of patients and at a high cost to families. This model has not been integrated into the primary healthcare system, such as is the case with the treatment of malaria, tuberculosis, or HIV that are properly managed at health center levels even in remote areas of sub-Saharan Africa. A major barrier to progress has been the absence of large-scale early-life screening , the high cost of screening with conventional methods (hemoglobin electrophoresis) as well as the lack of standardized and systematic medical follow-up for all screened patients . In the last few years, novel inexpensive SCD point-of-care test kits have become widely available and have been successfully deployed 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 African 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 a large scale in Africa countries .
Outside the capitals, care centers are rare and can be found only in some large cities in sub-Saharan African countries. For example, in Senegal, an SCD center can be found at the Peace Hospital in Ziguinchor, a town in southern Senegal , but the model of the program remains the same as the one described above in the capitals. To date, these centers serve only sickle cell patients living in capitals and large cities and a few patients transferred from remote provinces with financial means. As rural areas in sub-Saharan Africa are destitute, many sickle cell patients in these areas are financially unable to travel to large cities for treatment. The solution that can be envisaged to take care of all patients is to open new centers for the management of sickle cell disease throughout these countries  and implement a model of integration into primary healthcare. However, a few questions are worth asking: What should the status be of a Sickle Cell Reference Center in Africa? What should its missions be? What should the policies for access of sickle cell patients to specific care in Africa be? How should the African States be involved in the design and implementation of these policies? How should the management of cases in poor rural areas with limited access to basic health structures be organized?. Sickle cell disease has been recognized to have global health significance by key institutions, including the World Health Organization in 2006 and the United Nations in 2008. In 2010, the WHO released national healthcare management goals and set targets for the control and management of SCD to be met by the countries of sub‐Saharan Africa. These are yet to be translated into action. To do this would require active and sustainable public–private partnerships for sustainable program development in these regions. Effective interventions should be integrated into existing health systems, with the best examples linking primary healthcare facilities to specialized SCD centers in regional and tertiary healthcare institutions . However, multiple constraints necessitate an organization based on a network of health professionals working in sickle cell referral centers with specific missions of research, communication, and teaching; the establishment of guidelines for diagnosis, treatment, and prevention; and centers of competence that focus primarily on the screening, diagnosis, and management of SCD patients while favoring equity in access to care . Despite the 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 meet the requirements of the Sustainable Development Goals. This endeavor would also require ongoing research focused on the unique needs and challenges of SCD patients and children, particularly in regions of high prevalence .
This study included SCD children for whom the initial diagnosis was not reported at birth. This initial diagnosis was mainly made based on only clinical features, especially the presence of VOC or anemia. These results are consistent with those of other authors who reported an average age of around 10 years in SCD patients and a first diagnosis at the age of 2 years or later [45,47–51]. VOC was also reported as the most frequent mode of first diagnosis [44,47,50,52].
In this study, patients were subjected to a 2-year follow-up process comprising a monthly planned medical visit with a clinical and hematological assessment. The first-year period (2017) passed without the application of any intervention, apart from the regulation and treatment of acute complications, while in the second year (2018), the systematic application of standardized and regular follow-ups at monthly medical visits was organized and included folic acid and daily oral penicillin prophylaxis, deworming, and antimalarial treatments as well as a hematological assessment at each visit. In addition, an enhanced adherence process and education to prevent crises were implemented. The results of the first year of follow-up showed that sickle cell children without any specific medical intervention presented severe clinical and hematological pictures with an annual average of four VOCs, four infectious episodes, one acute thoracic syndrome, and four hospitalizations, demonstrating the severity of the disease in a remote area of a developing country. Annual averages of acute events and degradation of biological parameters similar to the results of this study among SCD patients who have not been followed-up with in the past have been reported in the literature [47,50,53–55]; however, there were no reports on the impact of regular follow-ups in those studies.
The application of standardized and regular follow-ups for 12 months showed encouraging results, with a significant reduction in acute events of the disease, i.e., a reduction in episodes of VOC, infectious episodes, blood transfusions, acute thoracic syndromes, hospitalizations and an increase in the hemoglobin level from 50 to 70 g/L. The steady-state hemoglobin level of 50 g/L before regular follow-up was lower than that previously reported for large cities of the DRC or other African countries (70 g/L) [45,47,50,56]. This could be explained by the lack of optimal management of the disease in the past but, also, by other factors that should be explored. The study also showed a decrease in the number of white blood cells that occurred due to affected lymphocytes.
The results of this study provide important baseline data for a new referral center in a remote area of the DRC and how such a center can fill gaps to ensure comprehensive management of sickle cell patients. Similar results were observed during the implementation of a sickle cell disease management program in a tertiary hospital in a remote area of India. Indeed, a recent study conducted in a remote region of West India by a non-governmental organization reported the implementation of a comprehensive SCD program in a secondary level hospital. They registered 404 SCD patients between December 2015 and June 2017 and compared the uptake of proven interventions and indicators of disease severity from one year prior to registration until the end of the study (June 2018). After the introduction of standardized and regular monitoring, they observed a statistically significant decrease in VOC (277 vs. 53.4), hospitalizations number (49.8 vs. 42.2), and blood transfusions (27.4 vs. 17.8) . As for our results, they demonstrate that the implementation of a comprehensive SCD management program can significantly reduce the severity of the disease. This shows that it is possible to set up sickle cell disease centers in remote areas and to organize optimal management.
Studies carried out in high-income countries have sufficiently demonstrated the benefits of standardized and regular medical follow-up of sickle cell patients with a reduction in acute and chronic complications of the disease and improvement in the quality of life [58–66]. Prospective cohort studies of SCD patients are rare in Africa due to barriers to medical monitoring . However, a cohort study conducted in Benin in 2015 showed that the frequency of VOC was reduced to about once every two years, and some of the patients were crisis-free for as long as five years after implementing comprehensive healthcare management . In Jamaica, the establishment of early diagnosis and simple prophylactic measures, i.e., oral penicillin and diagnosis of splenic sequestration, led to a significant reduction in SCD-associated deaths .
No children enrolled in the new center and followed in this study were treated with hydroxyurea in the past; however, 94% of SCD patients included in this study were indicated for HU treatment. Indications of hydroxyurea treatment are common in Africa . In a Nigerian study, 65% of 206 SCD patients were indicated for hydroxyurea treatment . The use of hydroxyurea in the treatment of SCD is very low in low- and middle-income countries [14,15]. The efficacy and therapeutic benefits of hydroxyurea have been widely documented; it remains the appropriate basic treatment in the management of SCD for African countries and this study demonstrates that its side effects can be monitored [8,15,15,58,63,70–72]. However, in low- and middle-income countries, there are many barriers to hydroxyurea treatment. These barriers include ignorance, the non-prescription of the drug by doctors, and the cost of the drug [73,74]. The creation of care centers is needed to facilitate awareness and advocacy. The creation of referral centers and the organization of optimal management of SCD by doctors trained in major sickle cell syndrome would certainly increase the knowledge, prescription, and awareness of the drug. In a study in India, the number of SCD patients on hydroxyurea increased from 4% to 98% after the implementation of a comprehensive program of sickle cell disease management in a remote tribal area .
The creation of a new sickle cell referral center and its positive results is a new model for providing follow-up care and optimal treatment in remote areas. It represents the awareness and ongoing response to the management of SCD for the families concerned. However, in this study, the large number of patients lost during follow-up is worrying. Addressing this requires strong local strategies to strengthen adherence to care. The referral center must establish early detection and management of the disease. Neonatal screening provides many benefits such as in the prevention of infection through early implementation of antibiotic prophylaxis, folic acid, deworming, proper management of malaria, and immunizations against pneumococcal infections; this is feasible in Africa but requires political support . For this reason, our suggested strategies are to continue the offer of regular and standardized care, plan future research projects to study SCD screening of pregnant women during antenatal consultations, organize routine neonatal screening of all newborns for at-risk pregnancies (AS and SS women) and children under five years of age with indications (transfusion history, anemia, notions of pain or repeated fever, etc.), and introduction of hydroxyurea treatment to all eligible patients. The use of rapid sickle cell tests coupled with those for malaria and equipping reference centers with a confirmation technique, i.e., isoelectrofocusing, could also be a strategy to consider for remote areas of low- and middle-income countries. A final perspective is to advocate, at the government level, for free care for all sickle cell children to guarantee regular follow-ups.
The size as well as the severity of the disease of our cohort could be the result of selection bias. Data must be interpreted considering these two aspects. Even if treatment is free of charge, if the clinical expression is mild, families are unlikely to come to a medical center. A longer-term study would undoubtedly make it possible to approach these patients and to make known the benefits of a comprehensive care program among this patient population.