Sickle cell disease in sub-Saharan Africa

INTRODUCTION — The vast majority of individuals with sickle cell disease (SCD) are born in sub-Saharan Africa, where easy access to high-intensity medical care may be limited to varying degrees.

This topic discusses the challenges of SCD care in sub-Saharan Africa and a general approach to providing comprehensive care for patients with SCD in resource-poor settings.

Additional topic reviews discuss overviews of the management of SCD in resource-rich settings. (See "Overview of the management and prognosis of sickle cell disease" and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

PUBLIC HEALTH BURDEN OF SCD — The greatest burden of SCD is in sub-Saharan Africa, where access to medical care and public health strategies to decrease mortality and morbidity are not uniformly available [1-5]. Over 300,000 babies are born with SCD annually; this number is expected to increase to up to 400,000 individuals by 2050 [3].

The World Health Organization and United Nations have designated SCD as a global public health problem [6,7]. One of the World Federation of Public Health Associations millennium development goals was targeted at reducing child mortality by two-thirds between 1990 and 2015 [8]. Despite the major interventions in malaria, HIV, and immunization, most of the 19 countries estimated to have a persistently high mortality rate in individuals <5 years old by 2015 (above 50 per 1000) are in Africa. We believe that the high prevalence of undiagnosed non-communicable diseases, including SCD, contribute to excess mortality in children under five years.

Nearly 90 percent of the world's SCD population lives in three countries: Nigeria, India, and the Democratic Republic of Congo (figure 1), where the disease affects up to 2 percent of the population, and the carrier prevalence rate (sickle cell trait) is as high as 10 to 30 percent [3,4,9,10]. Nigeria alone has been estimated to have at least 150,000 newborns born with SCD annually. Estimates are challenging because of the lack of federal newborn screening programs; however, approximately 700,000 births occur per year and the prevalence of SCD in newborns was 3 percent in a regional newborn screening program [11,12].

The regions of Africa with a high incidence of SCD are also associated with the highest density of malaria [13,14]. Although the sickle mutation at one allele of the beta globin gene (heterozygosity) confers a survival advantage in malaria endemic areas, especially for children, inheritance of the mutation at both alleles (Hb SS) predisposes individuals to severe malaria and increased malaria mortality, as well as increased mortality from other complications of SCD [15,16]. The role of heterozygosity for the sickle mutation in protection from falciparum malaria is discussed separately. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Sickle cell variant'.)

In high-income countries, the survival of individuals with SCD has been steadily increasing, often well into adulthood (see "Overview of the management and prognosis of sickle cell disease", section on 'Overall survival'). In contrast, a study from 2011 reported SCD-related childhood mortality in Africa as high as 50 to 90 percent, with fewer than one-half of affected children reaching their fifth birthday [17]. A multicenter case-control study from 2022 assessed 1563 children with SCD and 4972 children without SCD living in the same neighborhood, using data from five countries in sub-Saharan Africa, and found the following mortality rates [18]:

●Age <1 year – 15.3 percent (95% CI 13.3-17.3)

●Age <5 years – 36.4 percent (95% CI 33.4-39.4)

●Age <10 years of age – 43.3 percent (95% CI 39.3-47.3)

These mortality rates were lower than the prior study from 2011 [17]; the differences may be related to variations in methodology.

OVERVIEW OF MANAGEMENT — Simple public health measures, such as newborn screening and parental/caregiver education on how to detect splenic sequestration and when to bring a febrile child to medical attention, can have a dramatic impact on survival in children with SCD living in resource-poor countries [19]. Generally, the principles of management are as follows; these are discussed in more detail in the sections below:

●Identification of newborns with SCD as soon after birth as possible (before the development of complications) – (See 'Identifying individuals with SCD' below.)

●Education regarding when to seek medical attention – (See 'Education' below.)

●Prevention of infection (vaccinations, penicillin prophylaxis, and malaria prophylaxis) – (See 'Bacterial infections (prophylaxis)' below and 'Malaria (prophylaxis)' below.)

●Prompt treatment of infections, especially invasive bacterial infections and malaria – (See 'Bacterial infections (treatment)' below and 'Malaria (treatment)' below.)

●Adequate pain control and hydration for vaso-occlusive pain – (See 'Pain episodes' below.)

●When possible, hydroxyurea to reduce the risk of vaso-occlusive complications, especially primary and secondary stroke prevention, administered at a fixed-dose with monitoring as discussed below – (See 'Stroke' below and 'Hydroxyurea' below.)

●Reserving blood transfusions for life-threatening anemia – (See 'Blood transfusion' below.)

●Monitoring for chronic complications such as stroke, kidney disease, pulmonary hypertension, and asthma/chronic lung disease; and close monitoring during pregnancy – (See 'Primary and secondary prevention (stroke)' below and 'Complications affecting the kidney' below and 'Pulmonary complications' below and 'Pregnancy' below.)

Of these, the most important are prophylaxis against bacterial infections and malaria, prompt treatment of acute bacterial and malarial infection, pain control, and limiting blood transfusion to severe, life-threatening anemia. Observational studies in resource-poor countries such as Benin and Nigeria have demonstrated that these simple measures can reduce morbidity and mortality [20,21].

The major challenges to implementing comprehensive care in sub-Saharan Africa include poverty, lack of universal health insurance in most countries, limited number of specialized care facilities located primarily in large cities, limited number of trained health care personnel, limited access to the technologies required to provide evidence-based medical care, and limited access to disease modifying therapies produced on the continent at an affordable cost, except for hydroxyurea which is produced in Nigeria below cost.

Our approach is consistent with strategies published by the World Health Organization (WHO), which identified the need for primary prevention of SCD, SCD screening in newborn period, genetic counseling, and accessible comprehensive care [22]. The specific objectives of the WHO regional meeting included identifying priority interventions for member states to develop and implement, programs and policies for SCD prevention and control at all levels, and establishing mechanisms for monitoring, evaluation, and research on SCD in African countries. Partnerships between centers in different parts of the world (so-called "North-South partnerships") may be a useful strategy for facilitating these goals [23].

IDENTIFYING INDIVIDUALS WITH SCD — Early diagnosis of SCD improves survival. However, only a few centers in sub-Saharan Africa are able to initiate newborn screening and deliver comprehensive health care at an early age [9,24]. Most other individuals are diagnosed when they present with a complication of disease.

Available diagnostic tests — Typically, hemoglobin electrophoresis is used to make the diagnosis in individuals suspected to have SCD based on clinical features and review of the blood smear. High performance liquid chromatography (HPLC) is used in some centers to confirm the diagnosis, depending on availability.

Point-of-care (POC) diagnostic testing for SCD is under development; some of the tests are summarized in the table (table 1). Once they become available, these tests may be especially useful in areas where it is not possible or convenient to transfer blood samples to a centralized laboratory.

Additional details about these diagnostic tests are presented in a separate topic review. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

Newborn screening — Diagnosis of SCD early in life improves survival. Early diagnosis allows for initiation of well-established public health measures for primary prevention including penicillin prophylaxis, routine childhood vaccinations, parental/caregiver education about prompt medical management for fever, and detection of splenic sequestration. These strategies have been demonstrated to minimize morbidity and improve outcomes and are the basis for newborn screening for SCD being performed in every state in the United States [25]. However, laboratory methods for diagnosis require an infrastructure that is not routinely available in sub-Saharan Africa. Only a few centers in sub-Saharan Africa are able to initiate newborn screening and deliver comprehensive health care at an early age due to the costs associated with such programs [9,24].

The importance of newborn screening in reducing mortality has been demonstrated in the following studies:

●United States – Reduced mortality was reported in a review that summarized 10 years of experience using newborn screening in the state of California from 1975 to 1985 [26]. Of over 80,000 newborns screened, SCD was diagnosed in approximately 0.1 percent and sickle cell trait in 2.6 percent. Mortality in the 81 patients diagnosed with SCD by newborn screening (coupled with education about detecting splenic sequestration and early warning signs of infection) was 1.8 percent over seven years, dramatically lower than the 8 percent mortality in a comparison group of patients diagnosed after three months of age.

●Africa – In a program in Kenya that identified infants with and without SCD in infancy and then followed them over several years, the survival difference was about the same in those with hemoglobin SS and normal hemoglobin and much higher in children with hemoglobin AS [27]. Modeling simulations also suggest that universal screening is especially cost effective in populations with a high frequency of the prevalence of SCD >0.2 to 0.5 per 1000 births [28]. The threshold for screening for SCD (0.5 per 1000 births) in many countries in Africa far exceeds the minimum threshold for cost-effectiveness for newborn screening. As an example, in Nigeria the rate of SCD is estimated to be 30 per 1000 births (3 percent) [12]. No federal newborn screening program for SCD has been established for any country in sub-Saharan Africa despite the clear economic and humanitarian basis for such programs; Ghana is close to implementing such a program.

The American Society of Hematology (ASH) has instituted the Consortium on Newborn Screening in Africa (CONSA) for SCD, a seven-country network of sites including Ghana, Kenya, Liberia, Nigeria, Uganda, Tanzania, and Zambia [29]. The main objectives are to establish universal screening and early interventions for SCD within clinical networks of CONSA partners and to assess clinical trial implementation. All seven countries have successfully launched their programs. Rapid, easy to use, accurate, and inexpensive point-of-care (POC) testing may be the key to making widespread screening possible and efficient. The most commonly used POC tests in Africa include the HemoTypeSC and Sickle SCAN [30-33]. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Point-of-care assays'.)

Several studies in multiple African countries including Nigeria, Mali, Ghana, and Cote D Ivoire have shown that POC tests are accurate and reliable in detecting SCD with high sensitivity and specificity. However, the cost of these POC tests may be high, approaching the cost of HPLC. (See "Diagnosis of sickle cell disorders", section on 'Newborn screening'.)

Childhood presentation — Most individuals in sub-Saharan Africa with SCD are not diagnosed by newborn screening and present with symptoms during childhood, at a mean age of two years. Very few are diagnosed during infancy. The most common presentations for previously undiagnosed SCD include dactylitis at six months to one year of age and splenic sequestration in the second year of life. Thus, we believe that children presenting with either dactylitis or splenic sequestration should be evaluated for SCD with a complete blood count (CBC) and hemoglobin analysis. (See 'Available diagnostic tests' above.)

As part of the Transfusion and Treatment of severe anemia in African Children Trial (TRACT; ISRCTN84086586), the investigators developed a diagnostic algorithm to identify SCD among all children admitted with severe anemia to African hospitals [34]. The algorithm included children <12 months of age with severe anemia, gross splenomegaly, negative malaria testing, high white blood count (WBC), higher mean corpuscular volume (MCV+), low platelet count, and family history of SCD. Based on the algorithm, they were able to detect 73 percent of all children with unknown SCD, with a number needed to test to identify one new SCD case of only two.

EDUCATION — All families in areas where SCD is endemic, especially those in which a family member has SCD, should be aware of common presenting findings of SCD and should understand the importance of being evaluated.

●Parents/caregivers of infants and young children with SCD are educated about the importance of prophylaxis and treatment of infections (see 'Infections' below):

•Infection prevention, which includes vaccinations and prophylactic penicillin to prevent bacterial infections, and mosquito netting and malaria prophylaxis.

•Prompt treatment of infection, including when to bring an ill infant or child to medical attention.

●Children and adults should be educated about the presenting symptoms of acute chest syndrome, splenic sequestration, and stroke. All patients should understand the use of transcranial Doppler screening (TCD), and those with prior stroke or elevated TCD measurement should understand the potential benefits (and risks) of hydroxyurea therapy. (See 'Vaso-occlusive events' below and 'Hydroxyurea' below.)

●Individuals of childbearing age should be educated about risks of having an affected child, and those who become pregnant should understand the importance of appropriate prenatal care, folic acid supplementation, and adequate hydration. Vaginal delivery should be targeted to 38 weeks gestation if possible. (See 'Pregnancy' below.)

●Adults should be counseled about possible chronic complications including renal, pulmonary, and orthopedic complications and available interventions to minimize morbidity. (See 'Chronic complications/adults' below.)

INFECTIONS

Bacterial infections

Bacterial infections (epidemiology and causes) — The risk of bacterial infection is dramatically increased in SCD, particularly for children less than five years of age [35]. This is especially true for encapsulated organisms because most patients become functionally asplenic early in life (eg, within the first year) due to repeated episodes of sickling-induced splenic infarction [36]. Additional contributing factors include abnormalities of opsonization, antibody production, the alternate complement pathway, leucocyte function defects, and cell-mediated immunity [37-39].

The increased incidence of bacterial infection in African populations with SCD was illustrated in a 2010 review of case-control or cohort studies that described bacteremia, meningitis, or pneumonia in patients with or without SCD [40]. The pooled odds ratio of invasive bacterial infection associated with SCD was 19 (95% CI 15-24).

The most common bacterial organisms in individuals with SCD include S. pneumoniae, H. influenzae type b, and non-typhoid salmonellosis [39,41,42]. Children under five years of age are at greatest risk for meningitis and septicemia, while all age groups may develop salmonella osteomyelitis [39,43]. The infections seen in Africa are similar to those seen in the United States prior to the institution of routine penicillin prophylaxis and vaccination for encapsulated organisms in the mid-1980s in children with SCD.

Asymptomatic bacteriuria (ASB) is more common in individuals with SCD compared with those without, although its significance is unclear. This was demonstrated in a 2017 study from Ghana that found a prevalence of ASB of 17 percent in individuals with SCD, compared with 8 percent in the control group [44]. ASB was found to be higher among females, and the spectrum of organisms and etiology of ASB in the SCD patients was more diverse compared with controls.

Bacterial infections (treatment) — Parents/caregivers should bring children to medical attention if they have definite or possible indications of infection. Definite indications of infection include fever, tachycardia, and hypotension; along with signs and symptoms suggestive of acute chest syndrome (eg, cough, chest pain), meningitis (eg, headache, nuchal rigidity, altered mental status) (table 2), or acute osteomyelitis (eg, bone pain, tenderness, limited range of motion). Very young infants may not complain about pain but may show decreased alertness or appetite and will exhibit tenderness of the affected extremities.

Laboratory evaluation includes complete blood count, blood and urine cultures, and chest radiography. Lumbar puncture with cerebrospinal fluid analysis and cultures are done for patients with concern for meningitis.

Patients with these findings should be treated promptly with broad-spectrum antibiotics. Common treatment of bacterial infections involves oral or intravenous antibiotics, generally selected based on known efficacy against likely causative organisms. Intravenous antibiotics are generally reserved for individuals who are acutely ill and hospitalized. Practice patterns may vary based on hospital resources but are generally similar to that used for asplenic individuals in other settings.

Bacterial infections (prophylaxis) — The two major interventions to reduce the incidence of bacterial infections are vaccinations, especially against encapsulated organisms, and penicillin prophylaxis. However, the availability of vaccinations is limited, and routine penicillin prophylaxis is unavailable in the majority of medical centers in sub-Saharan Africa [45].

●Vaccinations – We strongly believe that integration of routine childhood immunization against Streptococcus pneumoniae and Haemophilus influenzae into the standard of care in sub-Saharan African countries could substantially affect survival of children with SCD [43].

The administration of childhood vaccinations has been shown to lead to a remarkable decrease in the overall morbidity and mortality associated with infection in children with SCD. This is especially true for invasive pneumococcal disease and H. influenzae. This was demonstrated in a 2016 retrospective study that analyzed a cohort of children with SCD living in Gambia over a five-year period [46]. During the study period, there was a high level of coverage with Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccinations. The most frequent blood-borne isolate was Salmonella typhimurium, followed by Staphylococcus aureus and other enteric Gram-negative pathogens, with no bacteremia by caused by S. pneumoniae or H. influenzae. The low prevalence of S. pneumoniae and H. influenzae indicated that the conjugated vaccines can significantly decrease the rate of bacteremia in children with SCD in sub-Saharan Africa. (See "Overview of the management and prognosis of sickle cell disease", section on 'Pneumococcal disease' and "Prevention of Haemophilus influenzae type b infection".)

However, the conjugated vaccines against these organisms such as the heptavalent conjugate pneumococcal vaccine (PCV7), which offers protection against invasive pneumococcal infections, and the H. influenzae type b conjugate vaccine, which offers protection against meningitis and septicemia caused by H. influenzae, are only available in some medical centers in sub-Saharan Africa. Even when available, they are unaffordable to the majority of families.

●Penicillin – Penicillin prophylaxis is highly effective in preventing infection. We recommend monthly intramuscular penicillin prophylaxis rather than daily oral penicillin, based on evidence that adherence to oral penicillin is only 50 to 60 percent [47,48]. In contrast, adherence to monthly intramuscular penicillin is approximately 88 percent [49]. Use of intramuscular penicillin also avoids the requirement for refrigeration of oral penicillin suspension, which may be challenging in low-income countries. We continue penicillin prophylaxis until age five years if possible, and some pediatricians may elect to continue for a longer period of time.

However, routine penicillin prophylaxis is unavailable in the majority of medical centers.

Additional information about the efficacy of these interventions and typical schedules are presented in detail separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Infection prevention'.)

Malaria — Malaria infection in individuals with homozygous sickle hemoglobin S (Hb SS) is one of the most common causes of vaso-occlusive pain, one of the leading reasons for hospitalization, and one of the most important causes of mortality in sub-Saharan Africa, despite the evidence that Hb SS improves mortality in children <5 years [27,50,51]. The first five years of life are the highest risk for malaria because of the lack of immunity, regardless of the hemoglobin type (hemoglobin SS, AS, or AA) [52].

As discussed below, a randomized trial showed that administration of hydroxyurea did not increase the risk of malaria infection. (See 'Hydroxyurea' below.)

Malaria (prophylaxis) — Strategies for control and prevention of malaria include mosquito control, personal protection, and antimalarial prophylaxis. Hydroxyurea is not a form of prophylaxis, but it does decrease malaria risk, as discussed below. (See 'Hydroxyurea' below.)

For prophylaxis, we prefer daily proguanil (100 mg daily). This is based on our experience that patients are more likely to take this once daily medication with a single agent, and the lower frequency of side effects compared with intermittent therapy. Other possible regimens include [15,20,53,54]:

●Proguanil 100 mg daily (preferred, as noted above)

●Chloroquine 5 mg/kg every other day

●Pyrimethamine weekly

●Sulfadoxine-pyrimethamine monthly

●Intermittent therapy with one of the following [55]:

•Combination of mefloquine (MQ) with artesunate (AS)

•Combination of sulfadoxine-pyrimethamine (SP) with amodiaquine (AQ)

The risk of malaria in Africa was shown to be decreased with antimalarial prophylaxis using chloroquine 5 mg/kg every two days, proguanil 100 mg daily, weekly pyrimethamine or monthly sulfadoxine-pyrimethamine; along with the regular use of insecticide-treated bed nets [15,20,53,54].

Intermittent preventive therapy was demonstrated to have superior efficacy to (and to be better tolerated than) daily prophylaxis in a trial involving 270 children with SCD in Nigeria [55]. Intermittent therapy involved administration once every two months of either MQ with AS for three days (MQAS) or SP for one day plus AQ for three days (SPAQ). Compared with daily proguanil, both intermittent therapy regimens were associated with a lower incidence of malaria (events per person-year: proguanil, 0.20; MQAS, 0.08; SPAQ, 0.13); however, a similar number of hospital admissions was seen for all groups. Adherence to intermittent therapy (administered at clinic visits) was excellent; in contrast, pill counts suggested that 57 percent of patients assigned to daily proguanil took <75 percent of their daily doses. Serious adverse events were low in all groups (<1 percent); vomiting, body pain, and abdominal pain were more frequent with MQAS and SPAQ than with proguanil. However, as noted above, based on our experience we prefer daily single agent therapy due to its lower frequency of side effects and our impression of improved adherence.

Personal protection with insecticide-treated bed nets and mosquito repellents has shown varying success rates in malaria endemic areas in sub-Sahara Africa [56].

Malaria risk (likelihood of infection and/or severity) may be reduced in individuals taking hydroxyurea. (See 'Hydroxyurea' below.)

Additional information about these approaches, as well as a discussion about vaccine development, is presented separately. (See "Malaria: Epidemiology, prevention, and control".)

Malaria (treatment) — The prompt initiation of malaria treatment is important both for managing the infection as well as treating or reducing the associated manifestations of SCD such as vaso-occlusive pain and worsening hemolytic anemia.

In children with SCD, malaria infection is associated with severe hemolysis and typically presents with fever, brown-colored urine, acute fatigue, and vaso-occlusive pain. In adults with SCD, malaria infection causes a similar clinical presentation and is associated with vaso-occlusive pain episodes [57,58]. Thus, prompt initiation of antimalarial therapy among acutely ill patients with SCD and confirmed malaria infection is important in the management of both conditions [57-59].

The two most commonly used first-line antimalarial therapies in sub-Saharan Africa include the combination of artesunate-amodiaquine and the combination of artemether-lumefantrine [59]. These therapies have been shown to be efficacious and associated with relatively few and rare side effects [59,60]. Other artemisinin-based combinations used for treatment of acute malaria include artesunate-amodiaquine, dihydroartemisinin-piperaquine, chlorproguanil-dapsone-artesunate, artesunate-mefloquine, and artesunate-azithromycin [61].

These and other malaria treatment regimens are summarized in the tables and presented in more detail separately:

●Severe falciparum malaria (or species unknown) (table 3) – (See "Treatment of severe malaria".)

●Uncomplicated falciparum malaria (table 4 and table 5) – (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)

●Uncomplicated non-falciparum malaria (table 6) – (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

HIV — Human immunodeficiency virus (HIV) infection and SCD are considered to be endemic in some regions of Africa. Moreover, as noted in a systematic review, HIV and SCD both are associated with stroke, avascular necrosis of bone, severe splenic dysfunction, pulmonary hypertension, and sepsis, and their coexistence may synergize in increasing the risks of these SCD complications [62]. Other studies have shown that HIV infection in individuals with SCD is associated with an increased risk of pneumococcal infection [63]. At the same time, HIV infection may blunt the response to vaccination against pneumococcus.

Management of concomitant HIV and SCD presents challenges, especially in sub-Saharan Africa where the level of care is suboptimal [64,65]. Attention should be paid to the following:

●In areas with a high prevalence of HIV, families and patients should receive education about the importance of early detection and prompt treatment of infections, particularly those caused by pneumococcus.

●Attention should be paid to potential interactions between HIV and SCD (eg, in increasing the risk for stroke, avascular necrosis, splenic dysfunction, pulmonary hypertension, and sepsis) [62].

VASO-OCCLUSIVE EVENTS — Vaso-occlusive events in SCD include acute painful episodes and organ-specific complications such as stroke, acute chest syndrome (ACS), priapism, and dactylitis. (See "Overview of the clinical manifestations of sickle cell disease".)

Pain episodes — Painful episodes are a significant cause of morbidity, accounting for a large number of emergency department visits and hospital admissions [66]. In many of the health facilities in sub-Saharan Africa, opioid analgesics are not readily available to patients, with the majority of these centers dependent on only nonsteroidal anti-inflammatory drugs (NSAIDs) and some non-opioid analgesics, leading to inadequate management of pain [67]. Adequate hydration should be provided, including increased oral fluid intake at home and intravenous fluids if hospital admission is required.

Dactylitis is the first presentation of pain in children with SCD. When dactylitis is present, management should be identical to those provided in high-income countries. This involves supportive care that includes hydration, NSAIDs and/or opioid analgesics, and assessment for occult infection, particularly bacteremia and malaria.

Hydroxyurea has been demonstrated to reduce the frequency of acute painful events in SCD. (See "Hydroxyurea use in sickle cell disease", section on 'Indications and evidence for efficacy'.)

Although use in sub-Saharan Africa poses numerous additional challenges, we suggest hydroxyurea treatment in individuals with significant vaso-occlusive pain episodes (eg, three or more severe acute painful episodes per year), as long as appropriate monitoring can be performed, as discussed below. (See 'Hydroxyurea' below.)

Acute chest syndrome — Acute chest syndrome (ACS) is one of the life-threatening vaso-occlusive complications seen both in children and adults with SCD. ACS is associated with high mortality rate, especially in sub-Saharan Africa and other low-income countries.

The diagnosis of ACS in a high-income setting often relies on radiologic features of a new pulmonary radiodensity on chest radiograph and the use of pulse oximetry. However, pulse oximetry is not available in some medical centers. Therefore, the majority of clinicians rely on their clinical judgment for diagnosing ACS, which typically is based on fever, pain, and increased respiratory effort.

The Ghana combined obstetric and SCD clinic has operationalized a definition of ACS in low-income settings where the cost of a chest radiograph may be beyond reach for many families. Specifically, the definition includes the following [68,69]:

●Presence of at least two of the following criteria, including positive chest signs:

•Temperature >38⁰C

•Increased respiratory rate of >20 per minute

•Positive chest pain

•Positive findings on pulmonary auscultation

●Increased oxygen requirement (SpO₂ drop by >3 percent from a documented steady-state value on room air)

●Presence or absence of new radiodensity on chest roentgenogram

Typically, patients with this constellation of findings are treated with a broad-spectrum antibiotic to cover encapsulated organisms and a macrolide antibiotic to cover mycoplasma and chlamydia. Additional interventions include pain control (generally using NSAIDs) and hydration, along with supplementary oxygen and/or blood transfusion, if needed and available [24].

Additionally, a feasibility trial in northern Nigeria indicated that fixed-dose hydroxyurea (approximately 20 mg/kg/day) is an alternative to initial regular blood transfusion therapy [70]. Hydroxyurea has been demonstrated to reduce the frequency of ACS in SCD. (See "Hydroxyurea use in sickle cell disease", section on 'Indications and evidence for efficacy'.)

Uniform access to hydroxyurea in sub-Saharan Africa poses numerous additional challenges. (See 'Access to stroke prevention interventions' below.)

Despite financial and laboratory monitoring challenges, we suggest administration of hydroxyurea in individuals with either a single episode of life-threatening ACS that requires exchange transfusions or repeated significant episodes of ACS that require regular blood transfusion therapy, as long as appropriate monitoring can be performed, as discussed below. (See 'Hydroxyurea' below.)

Splenic sequestration — Splenic sequestration is a potentially life-threatening complication that occurs when blood pools rapidly in the spleen. Splenic sequestration is characterized by an acute fall in the hemoglobin level accompanied by a rapidly enlarging spleen or liver (>2 cm increase from the steady-state level) and increased reticulocytosis above the steady-state level. In some cases, splenic sequestration may be associated with malaria or another infection, particularly parvovirus B19 [71].

Management of splenic sequestration in resource-limited settings involves hospital admission with urgent laboratory testing (complete blood count [CBC], pretransfusion testing) and blood transfusion at a dose of 5 mL/kg (this is 50 percent of the typical amount, due to the risk of autotransfusion of red blood cells that were pooled in the spleen, which may result in life-threatening hyperviscosity syndrome) [72]. In some centers, exchange transfusion may be performed if feasible.

Repeated episodes of splenic sequestration are common, especially in malaria-endemic regions, and measures to reduce splenic sequestration are advisable. For patients who have had one or more episodes of splenic sequestration, splenectomy may be appropriate. We generally advise splenectomy following the first episode of splenic sequestration. There is no evidence that regular blood transfusion therapy prevents recurrent splenic sequestration [73].

In contrast, there is little evidence that regular blood transfusion or hydroxyurea therapy reduces the risk of splenic sequestration.

Stroke — Children with SCD are at increased risk of neurological complications including overt strokes and silent cerebral infarcts, both of which are associated with increased morbidity and mortality. Approximately 11 percent of children with SCD will have a stroke before age 18 without transcranial Doppler (TCD) screening and regular blood transfusions or low dose hydroxyurea therapy if TCD values are high. Without secondary prevention, more than one-half of these will have a recurrent stroke within two years of the initial stroke [74,75]. (See 'Primary and secondary prevention (stroke)' below.)

Acute management (stroke) — The standard radiologic imaging to determine the type of stroke is not available in the majority of medical centers in sub-Saharan Africa. Thus, diagnosis of stroke is made by clinical evaluation.

Tools to help in making the clinical diagnosis of stroke include the following:

●Evaluation of clinical features that may distinguish stroke from other neurologic complications of SCD such as cerebral malaria or bacterial meningitis (table 2)

●The Pediatric NIH Stroke Scale (NIHSS) (table 7) or the adult scale for adults (table 8)

●Online videos (eg, http://www.youtube.com/watch?v=gzHuNvDhVwE)

●The Pediatric Stroke Outcome Measure (PSOM) [76]

The standard management approach, including immediate blood transfusion followed by exchange blood transfusion to maintain the hemoglobin S (HbS) percentage below 30 percent, is not available in the majority of medical centers in sub-Saharan Africa [77-80].

Acute stroke management in resource-poor settings includes the following:

●Immediate admission into the hospital

●Assessment of vital signs

●Examination to assess the extent and severity of central nervous system involvement

●Maintenance of airway and breathing, and oxygen administration

●Assessment of laboratory values including evaluation for hypoglycemia, hyponatremia, and hypernatremia

●Treatment of fever with antipyretics and presumptive treatment of infection with antibacterial and antimalarial agents until results of cultures are available (see 'Bacterial infections (treatment)' above and 'Malaria (treatment)' above)

●Intravenous fluids

●Simple blood transfusion when available

●Where available, simple blood transfusion is followed by modified- or full-exchange blood transfusion, performed either manually or automated [81,82]

As noted above, imaging of the brain is not routinely performed.

Primary and secondary prevention (stroke) — Regardless whether children live in low- or high-income settings, the risk of stroke in children with SCA is approximately 11 percent by 18 years of age [74]. Further, once a child with SCA has a stroke, without treatment, approximately 50 percent will have second stroke [83].

Taken together, these data provide compelling evidence for primary and secondary stroke prevention with hydroxyurea. Preliminary data indicate fixed dose of hydroxyurea is effective in decreasing both transcranial Doppler ultrasound (TCD) measurements from abnormal to normal and for primary prevention of strokes [84-86]. Randomized controlled trials conducted in sub-Saharan Africa have also shown that hydroxyurea can be safely administered to children with abnormally high TCD measurements and effectively reduce TCD velocities [84,87,88].

●Primary prevention – Results of the SPRING (Stroke Prevention In Nigeria) trial indicate that starting most children on low-dose hydroxyurea (approximately 10 mg/kg daily) is an effective strategy for primary stroke prevention. (See 'Hydroxyurea' below.)

SPRING assessed the rate of stroke or transient ischemic attack in 220 children ages 5 to 12 years with SCD and abnormal TCD velocities who were randomly assigned to receive fixed low-dose hydroxyurea (approximately 10 mg/kg daily) or fixed moderate-dose hydroxyurea (approximately 20 mg/kg daily) [89]. An additional nine children crossed over from the control group to the hydroxyurea arms.

The trial was stopped early at 3 years of follow-up due to the low rates of stroke in both groups. In the low-dose hydroxyurea group (median dose, 10.8 mg/kg/day), 3 of 109 participants (3 percent) had strokes (incidence rate, 1.19 per 100 person-years). In the moderate-dose hydroxyurea group (median dose, 20.6 mg/kg/day), 5 of 111 participants (5 percent) had strokes (incidence rate, 1.92 per 100 person-years). The incidence rate ratio (IRR) showed a trend towards lower rates of stroke with low-dose hydroxyurea that was not statistically significant (IRR, 0.62 [95% CI 0.10-3.20], p = 0.77).

Use of hydroxyurea that was locally manufactured in Nigeria and made available to participants at cost made the treatment feasible during the trial and made continued use sustainable after the trial ended.

While initial stroke rates were not statistically different with low-dose versus moderate-dose hydroxyurea in SPRING, hospitalization for any reason was more frequent in the low-dose group (27.43 per 100 person-years with low dose versus 16.08 with moderate dose; IRR 1.71, 95% CI 1.15-2.57, p = 0.0071). Moderate-dose hydroxyurea was also associated with a significant decrease in vaso-occlusive pain events at home. No participant had to stop hydroxyurea for myelosuppression. For children with prior or concurrent high rates of hospitalization or vaso-occlusive pain events, shared decision making should be done to decrease the SCD morbidity rate; otherwise, for primary stroke prevention, a fixed dose of 10 mg/kg daily should be considered, with a CBC two times a year for monitoring.

●Secondary prevention – The 2020 American Society of Hematology (ASH) guidelines for secondary prevention of stroke in people with SCD recommend that when initial regular blood transfusion therapy is not available, moderate-dose hydroxyurea therapy (approximately 20 mg/kg/day) should be considered at a minimum [90]. (See 'Hydroxyurea' below.)

●The SPRINT trial (Stroke Prevention in Nigeria Trial) was published after the 2020 ASH guidelines. SPRINT randomly assigned 101 children with sickle cell anemia living in Nigeria to receive fixed oral moderate-dose hydroxyurea (20 mg/kg daily) or fixed oral low-dose hydroxyurea (10 mg/kg daily) for 30 days [91]. The trial was stopped due to no clinically meaningful difference in the incidence of recurrent strokes (7.1 and 6 per 100 person-years in the low- and moderate-dose groups, respectively; IRR 1.18, 95% CI 0.30-4.88). The authors concluded that for children with sickle cell anemia who are living in low-income settings without access to regular blood transfusion therapy, initial low-dose hydroxyurea is a minimum known effective dose for secondary stroke prevention.

The results of both the primary and secondary stroke prevention trials in Nigeria suggest that neurological benefit can be achieved with fixed low-dose hydroxyurea (10 mg/kg daily). However, based on the SPRING trial results, fixed moderate-dose hydroxyurea (20 mg/kg/day) should be used for children with frequent hospitalizations, increased rates of pain requiring a physician visit, or treatment at home. If hospitalization or vaso-occlusive pain events continue with the higher dose of hydroxyurea, we would consider maximum tolerated dose of hydroxyurea if the family can afford laboratory surveillance with frequent CBCs and the increase out-of-pocket expense for the hydroxyurea. (See 'Dosing and monitoring' below.)

Primary and secondary stroke prevention in resource-rich settings is discussed separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of a first ischemic stroke (primary stroke prophylaxis)' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)'.)

Access to stroke prevention interventions — To our knowledge, none of the sub-Saharan African countries have extensive government-supported health insurance to pay for hospitalizations, radiology imaging, and medications such as hydroxyurea. (See 'Hydroxyurea' below.)

Consequently, for the vast majority of children and adults with SCD in Africa, personal finances are the rate-limiting step to ensure evidenced-based medical care using evidence from randomized trials. In Nigeria, one of the wealthiest of the sub-Saharan African countries, 40 percent of the population lives on approximately USD $1.00 per day [92]. In the northern region of Nigeria, the cost of a complete blood count is USD $5.00. Without state or federal government support that includes access to hydroxyurea, a sustainable primary stroke prevention program with treatment will be unlikely.

Given these challenges, government leaders of three northern Nigerian states with at least 40,000 children with SCD elected to provide hydroxyurea free of charge to children with abnormal TCD measurements or children with strokes [93]. Further, TCD measurements are done without charge, and hydroxyurea is made available below cost for USD $0.15 from a Nigerian pharmaceutical company in which the corporate leadership acknowledges the humanitarian struggle of SCD in the region. The combination of state-supported stroke prevention programs for children with SCD coupled with access to low-cost hydroxyurea and streamlined laboratory monitoring has led to a significant increase in screening and treatment of children with SCD for primary and secondary stroke prevention [94].

PREGNANCY — With each passing year, more adolescents with SCD will reach childbearing age because of the increase in overall survival. Pregnancy in SCD is associated with higher rates of both maternal and fetal complications:

●Preconception counseling requires knowledge of sickle cell trait status, which in turn requires specific testing because carrier status is clinically silent. However, screening does not always translate into a reduced incidence of the disease [95].

●Maternal events include those associated with pregnancy such as eclampsia, anemia, and urinary tract infection; and those related to SCD, such as pulmonary complications and vaso-occlusive events (both antenatal and postnatal) [96-98]. Greater need for cesarean delivery and greater maternal death rates are often seen.

●Fetal complications include intrauterine growth restriction (IUGR), preterm delivery, fetal distress in labor, and low birth weight [96-98]. Perinatal mortality rates are also increased.

Prenatal counseling is appropriate if the hemoglobin phenotypes of both parents are known based on confirmed laboratory testing.

A multidisciplinary team including a hematologist, obstetrician, midwives, nurses, anesthetist, and intensive care team should be involved in pregnancy care to manage these risks. Involving a multidisciplinary care team can significantly decrease the rates of maternal and perinatal mortality in pregnant women with SCD in low-resource settings [99]. However, coordinated efforts are required to undertake this strategy.

During routine antenatal care, counseling should include the increased risks of acute painful episodes and pregnancy complications, including fetal loss, intrauterine growth restriction, eclampsia, and preeclampsia. A more frequent schedule of care should be planned between the obstetrician, hematologist, and specialist midwives.

All pregnant individuals should be given daily folic acid and antimalarial prophylaxis. Iron supplementation may be required, but only if the serum ferritin levels are low.

During each prenatal visit, the following should be monitored:

●Hemoglobin level

●Urinalysis

●Fetal monitoring

Fetal ultrasound testing is done frequently (eg, at 20, 26, 30, 34, and 38 weeks) and is the standard of care in major health facilities. Scans may be performed more frequently if there are concerns about fetal growth or the volume of amniotic fluid (also called liquor amnii), and umbilical artery Doppler scans may be added if appropriate.

Blood transfusion (preferably exchange transfusion) should be used for the treatment of acute anemia (a decrease in hemoglobin by at least 2 g/dL from baseline) and for acute chest syndrome.

Delivery is usually targeted for 38 weeks of gestation. The aim is to achieve a safe vaginal delivery. The mother should be well hydrated and oxygenated throughout labor. The fetus should be monitored throughout labor. Epidural anesthesia is preferable to general anesthesia if operative intervention is needed.

CHRONIC COMPLICATIONS/ADULTS — Advances in technology and improvement in medical care has significantly increased the survival of children with SCD, resulting in a substantial proportion reaching adult age [68,100]. Causes of morbidity in adults with SCD include complications associated with pregnancy and renal, pulmonary, and orthopedic complications [101-104]. A multidisciplinary team approach to care is shown to be effective in the management of individuals with SCD (especially adults, who may develop these chronic complications) and is recommended as the best practice approach in caring for these individuals.

A 2017 study of 2047 individuals living in sub-Saharan Africa evaluated the association between steady-state hemolysis and vascular complications of SCD [105]. Similar to findings in high-income countries, anemia was associated with elevated tricuspid regurgitant jet (TRJ) velocity, microalbuminuria, and leg ulcers [106,107]. Additionally, the authors emphasized that in Africa, the most common and important causes of severe anemia in SCD may be different from high-income countries, potentially including additional factors such as malnutrition (eg, iron deficiency) and infectious diseases such as malaria and helminth infestations.

Complications affecting the kidney — Complications affecting the kidney are common in SCD. As part of routine management of patients with SCD, urinalysis is recommended during every clinic visit at least twice a year to screen for hematuria and proteinuria.

Hematuria, when it occurs, is mainly due to papillary necrosis. Management involves admission into the hospital, intravenous fluids (approximately 100 to 150 mL/kg daily for children and approximately 4 to 6 L/daily in adults). Furosemide is given to improve urine volume and reduce the risk of urinary tract obstruction from clots. Blood transfusion may be required if hematuria is severe.

Optimal management of children and adults with kidney disease is not well established in low-middle or high-income settings. Preliminary data would indicate hydroxyurea may attenuate progressive albuminuria [108-111]. Patients with persistent proteinuria or other nephropathy are usually referred to the nephrologist for expert evaluation and medical management to reduce the risk and/or progression of sickle nephropathy. (See "Sickle cell disease effects on the kidney".)

Pulmonary complications — Pulmonary complications of SCD include pulmonary hypertension (PH) and asthma. Cardiopulmonary complications are among the most common complications in adults with SCD and among the leading causes of death in these individuals [112,113]; yet, the capacity to adequately diagnose and manage these complications is still lacking in majority of centers in Africa.

●PH – PH is one of the most common complications in adults with SCD, with a prevalence of about 6 to 10.5 percent [114-116]. Previous studies showed that adults with PH have an increased risk for early death [114-116]. One of the non-invasive methods for screening adults with SCD to determine those at risk of PH is the use of Doppler echocardiography to measure the tricuspid regurgitant velocity (TRV). Multiple studies demonstrated that increase in TRV >2.5 m/s is associated with increased mortality in adults with SCD [117,118]. A clinical practice guideline from the American Thoracic Society emphasized the benefits of hydroxyurea therapy in reducing this risk [118]. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Pulmonary hypertension'.)

All adult patients with SCD should be screened annually with Doppler echocardiograph to determine the TRV, and all patients with a TRV >2.5 m/s should be offered hydroxyurea as part of standard guidelines (see 'Hydroxyurea' below). However, this is a major challenge, as the majority of centers in Africa do not have access to echocardiography.

●Asthma and chronic lung disease – Chronic lung disease is defined by clinical, laboratory, and spirometry criteria [119]. In adults, SCD alone is an independent risk factor for recurrent wheezing, acute chest syndrome, and respiratory death, and low forced expiratory volume on spirometry is an independent risk factor for death in adults with SCD [119-123]. Based on these significant findings, we recommend that all patients with SCD should be asked about asthma symptoms, and all adults with SCD should have annual spirometry screening.

Those with symptoms or spirometry findings suggestive of asthma should receive standard asthma management interventions, including education, control of trigger factors and comorbid conditions, and pharmacologic therapy, as outlined in the tables for ages <4 years (table 9), 4 to 11 years (table 10), and 12 years and older (table 11), and discussed in detail separately. (See "An overview of asthma management" and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)

Orthopedic complications — Chronic osteomyelitis is common in children with sickle cell disease. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

Orthopedic complications are one of the most common sources of long-term morbidity in adults with SCD, typically avascular necrosis of the head of the femur [24]. The presentation is characterized by pain in the hips, limping, and progressive deformity of the hip joint. In low-income countries, management includes prolonged analgesics, which only provide temporal relief of pain. The standard treatment for these patients should include physical therapy and surgical interventions. In sub-Saharan Africa, only a few centers can provide surgical interventions; reasons include cost, inadequate staffing and personnel, and lack of expertise and equipment [24].

Priapism — Priapism is a major cause of SCD morbidity in males of all ages with SCD, including children, adolescents, and adults. The high prevalence of SCD in Africa has facilitated a better understanding of this complication.

In a cross-sectional study involving 500 males with SCD and 250 controls without SCD, the prevalence of priapism with SCD was 33 percent, versus 2 percent in controls [124]. Among the individuals with SCD-associated priapism, intermittent priapism episodes lasting <4 hours (also called stuttering priapism) occurred in 73 percent; the remainder had major priapism events lasting ≥4 hours. Priapism events that lasted at least three days were associated with penis deformity. Due to shame, lack of knowledge about the onset of priapism, and paucity of effective medical treatment to prevent or actively treat priapism, one-half of the affected individuals never sought medical attention. Individuals with priapism experienced sadness, frustration, fear, depression, and exhaustion. They used a range of self-care strategies to abate priapism episodes including but not limited to exercise, shower or baths, or hot packs.

We advise against using cold packs to the penis to relieve vaso-occlusive pain. We advise surgical aspiration for treating major episodes (at least two to four hours) of priapism and hydroxyurea for secondary prevention, as discussed separately. (See "Priapism and erectile dysfunction in sickle cell disease", section on 'Ischemic priapism: Acute management' and "Priapism and erectile dysfunction in sickle cell disease", section on 'Prevention'.)

DISEASE-MODIFYING OR CURATIVE THERAPIES

Hydroxyurea

Indications — Hydroxyurea has become the standard of care for reducing the risk of vaso-occlusive and other complications in children and adults with SCD in high-income countries, based on demonstration of its efficacy in reducing complications in all age groups (including infants). These benefits are summarized in the table (table 12). In high-income countries, hydroxyurea is administered in a maximum tolerated dose strategy that increases the dose until peripheral blood counts decrease. This approach requires intensive monitoring (clinical and laboratory) with frequent and ongoing dose adjustments. (See "Hydroxyurea use in sickle cell disease".)

As discussed above, we use hydroxyurea in individuals with severe acute pain episodes (three or more severe episodes per year), acute chest syndrome requiring transfusion, primary stroke prevention, and secondary stroke prevention. (See 'Vaso-occlusive events' above.)

Hydroxyurea does not worsen the risk of severe malaria and may in fact reduce the risk. (See 'Rationale' below.)

Dosing and monitoring — Dosing of hydroxyurea can be done either by a fixed-dose or by dose titration to mild neutropenia (absolute neutrophil count [ANC] <4000/microL, as done in the REACH and NOHARM MTD trials).

If cost and ease of administration are a concern, fixed-dose is preferred because it requires less intensive monitoring. Doses are as follows:

●Children – 20 mg/kg/day (moderate-dose)

●Adults – 15 mg/kg/day

For primary stroke prevention in children, based on the results of the SPRING trial, fixed low-dose hydroxyurea (10mg/kg/day) may be the initial recommended dose for children with abnormal transcranial Doppler (TCD) velocities who do not have other reasons to require moderate-dose hydroxyurea, such as frequent vaso-occlusive pain or acute chest syndrome [89]. Our preference for low-dose rather than moderate-dose hydroxyurea is based on the evidence of efficacy for primary stroke prevention and lower costs (see 'Primary and secondary prevention (stroke)' above). If there is an increase in vaso-occlusive pain episodes at home or an increase in physician visits for pain, or an increase in all-cause hospitalizations, then increasing to 20mg/kg/day should be considered.

To address the limitation of fixed capsule sizes with a fixed dose, we often provide intermittent or uneven doses to account for the 500 mg capsule size [125]. As an example, for a seven-year-old child who weighs 15 kg, the total weekly dose would be 20 mg/kg/day x 15 kg x 7 days = 2100 mg. Using 500 mg capsules, this could be provided as one capsule on Monday, Wednesday, Friday, and Saturday.

Laboratory surveillance is required to assess for cytopenias associated with hydroxyurea. Monitoring is done with a complete blood count (CBC) once every six months. This surveillance interval is based on evidence that a fixed-dose (low or moderate dose) is not associated with clinically significant myelosuppression and is practical in low-income settings [70,126].

Rationale — The choice of dosing schedule for hydroxyurea, between maximum tolerated dose (MTD) or fixed moderate-dose, should be based on shared decision between the patient, family/caregivers, and clinicians and should take into account available evidence regarding efficacy and safety.

For individuals with a low rate of vaso-occlusive events, we prefer starting with fixed low-dose hydroxyurea, since this provides similar efficacy as fixed moderate dose hydroxyurea for primary stroke prevention (see 'Primary and secondary prevention (stroke)' above). If rates of vaso-occlusive events (vaso-occlusive pain, acute chest syndrome) are high, we increase the dose to fixed moderate-dose hydroxyurea (20 mg/kg/day).

●Children – Regardless of whether fixed low-dose or fixed moderate-dose hydroxyurea is used, we are not strong advocates of routine hydroxyurea dose escalation (to maximum tolerated dose) in children for the following reasons:

•Moderate-dose hydroxyurea was shown to be effective in reducing and preventing morbidity associated with SCD. Specifically, the SCD team in northern Nigeria showed that moderate-dose hydroxyurea significantly decreased the incidence rates of stroke comparable with using chronic blood transfusion therapy. Fixed moderate-dose hydroxyurea was also associated with decreased uncomplicated pain requiring hospitalization when compared with a group of non-randomly allocated children with SCD who did not receive hydroxyurea. (See 'Supporting evidence' below.)

•The use of fixed moderate-dose hydroxyurea is practical for the majority of the population in Nigeria and other regions of Africa, where the out-of-pocket cost of hydroxyurea, CBCs, or both, are prohibitive. As described above, fixed-dose hydroxyurea can be safely administered with twice-yearly CBCs [89]. (See 'Primary and secondary prevention (stroke)' above.)

●Adults – Given the higher rates of symptomatic vaso-occlusive pain events in adults with SCD, our practice is to start all such individuals on fixed-moderate dose hydroxyurea and if continued SCD-related events to increase the dose to maximum tolerated dose after shared decision making. In many clinical situations, the perceived benefits of maximum tolerated dose hydroxyurea may be superior to fixed moderate-dose hydroxyurea for preventing the most common causes of hospitalization (pain and ACS).

If prevention of vaso-occlusive pain and ACS is the primary focus of treatment, and the costs and inconvenience of laboratory surveillance is not prohibitive, then maximum tolerated dose therapy may be the best option. However, if family financial constraints and resources do not allow for routine laboratory evaluation (CBC every two to three months) as done in high-income countries, then the strong consideration should be given to fixed moderate-dose therapy.

Clinical trials of hydroxyurea in malaria-endemic areas suggest that, compared with controls, individuals taking hydroxyurea had a lower risk of malaria infection than controls (when neither group was receiving malaria prophylaxis), or similar risk of infection as controls (when both groups were receiving malaria prophylaxis) [127-129]. An in vitro study of red blood cells (RBCs) from people with and without SCD found that hydroxyurea and similar drugs were able to reduce growth of P. falciparum, principally acting at the schizont stage [130].

Barriers to uptake of hydroxyurea — Hydroxyurea is not used as often in very young children in Africa as it is in high-resource countries, primarily due to concerns about the higher rate of mortality and life-threatening bacterial and malarial infection in affected individuals in Africa and the unknown effect of hydroxyurea therapy (eg, possible increased toxicity) in such a vulnerable group [17,43,131-134]. However, these concerns are lessening as more data on the safety of hydroxyurea in Africa become available.

Multiple barriers result in low hydroxyurea use in Africa, including poverty, the absence of a public health insurance program, and the lack of local production of hydroxyurea. Without state or federal support for purchasing hydroxyurea, there is limited opportunity for the majority of children and adults to start and continue hydroxyurea.

Other barriers include the large absolute numbers of individuals with SCD (see 'Public health burden of SCD' above), the lack of clinicians trained in the use of hydroxyurea, the uncertainty regarding the benefits and risks in a resource-poor setting where routine monitoring of blood counts is not available, and the relatively high costs of visits for follow-up, laboratory testing, and other monitoring when compared with the per capita income. For example, in Nigeria 40 percent of the population live on $1.00 per day, and the cost of a CBC is at least $5.00, a cost equivalent to one week's salary. Approaches to overcoming these barriers are possible [93].

The strategy to use maximum tolerated dose of hydroxyurea is a reasonable approach, particularly in light of the evidence of decrease vaso-occlusive events. However, this strategy can only be used in individuals who are able to bear these costs and at clinics that have the capacity to provide this level of care.

Supporting evidence — Despite the barriers to uptake of hydroxyurea, evidence from the trials discussed below demonstrates that hydroxyurea is effective in reducing serious complications in individuals in sub-Saharan Africa, with additional benefit from increasing the dose. We believe these data will lead to more widespread use of hydroxyurea.

●NOHARM and NOHARM MTD – A double-blinded, placebo-controlled trial from 2017 (the NOHARM [Novel Use of Hydroxyurea in an African Region with Malaria] trial) randomly assigned 207 children ages one to four years (average age, two years) in malaria-endemic Uganda to receive hydroxyurea at a fixed-dose (20 mg/kg daily) or placebo for one year [127]. Compared with controls, children treated with hydroxyurea had a lower rate of a composite endpoint that included vaso-occlusive pain, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion (69 versus 45 percent; p = 0.001). Overall mortality was low (<1 event per 100 patient-years), and the use of hydroxyurea was not associated with an increased incidence of malaria or other serious adverse events. The desired effects of hydroxyurea on laboratory parameters were seen (eg, increased total hemoglobin and fetal hemoglobin concentrations) despite dosing that did not approach the maximum tolerated dose strategy used in high-income countries.

At the end of the NOHARM trial, all children were treated with one year of hydroxyurea at a fixed-dose of 20 mg/kg daily (open label). This was extended to a new trial (NOHARM MTD), in which 187 participants were randomly assigned to continue this fixed-dose or to switch to dose-escalated hydroxyurea [128]. In the dose-escalation arm (referred to as maximum tolerated dose [MTD]), the hydroxyurea dose was raised by 5 mg/kg every two months until a cytopenia occurred (eg, absolute neutrophil count <1000/microL (calculator 1), absolute reticulocyte count <80,000/microL, platelet count <80,000/microL, or hemoglobin <4 g/dL). Blinding was maintained as the children on the fixed-dose arm periodically had dose adjustments for weight gain. The mean MTD dose was 29.5 mg/kg daily, versus the fixed-dose of 19.2 mg/kg daily.

The trial was stopped early (at one year) for benefit in the dose-escalation/MTD arm. Compared with the fixed-dose arm, children assigned to the dose-escalation arm had improvements in the following outcomes:

•Any sickle cell-related adverse event (105 versus 245; incidence rate ratio [IRR], 0.43, 95% CI 0.34-0.54)

•Vaso-occlusive pain (86 versus 200; IRR 0.43, 95% CI 0.34-0.56)

•Acute chest syndrome or pneumonia (8 versus 30, IRR 0.27; 95% CI 0.11-0.56)

•Transfusions (34 versus 116; IRR 0.30, 95% CI 0.20-0.43)

•Hospitalizations (19 versus 90; IRR 0.21, 95% CI 0.13-0.34)

Therapy was well-tolerated on both arms.

●REACH – A large study in 2018 demonstrated that hydroxyurea can be safely administered to children in Africa with dramatic clinical benefits. The REACH (Realizing Effectiveness Across Continents with Hydroxyurea) study enrolled 635 children with SCD in four sub-Saharan African countries (Angola, Democratic Republic of Congo, Kenya, and Uganda) to receive hydroxyurea at a fixed-dose of 15 or 20 mg/kg daily for six months, followed by dose escalation to maximum tolerated dose, defined in this study as mild bone marrow suppression (typically, an absolute neutrophil count [ANC] <4000/microL (calculator 1)) [135]. Major findings included the following:

•Efficacy – Hydroxyurea dramatically reduced vaso-occlusive and other sickle cell complications compared with pre-treatment parameters obtained at the time of screening. Examples of reductions in death and complications include the following (expressed per 100 patient-years):

-Mortality – From 3.6 to 1.1 (incidence rate ratio [IRR] 0.30, 95% CI 0.10-0.88)

-Total sickle cell-related complications – From 115 to 53 (IRR 0.47, 95% CI 0.38-0.57)

-Pain episodes – From 98 to 45 (IRR 0.45, 95% CI 0.37-0.56)

-Acute chest syndrome – From 9 to 5 (IRR 0.55, 95% CI 0.28-1.05)

-Stroke – From 1.8 to 0.7 (IRR 0.42, 95% CI 0.10-1.67)

-Malaria – From 47 to 23 (IRR 0.49, 95% CI 0.37-0.66)

-Non-malarial infections – From 143 to 90 (IRR 0.62, 95% CI 0.53-0.72)

-Laboratory correlates included a mean increase in hemoglobin level of 1 g/dL and a mean increase in fetal hemoglobin (Hb F) of 12.5 percent. Transfusions were reduced from 43 to 14 per 100-patient years.

•Safety – Therapy was well tolerated, with the expected hematologic toxicities used for dose adjustments. There were no significant increases in serious treatment-related adverse events.

•Adherence – At the three-year point, 94 percent of children were still participating in the study, and more than 98 percent of visits were completed. This adherence rate is better than many trials completed in high-resource countries, demonstrating the high level of motivation in this population.

•Dosing – Dose escalation after the first six months of treatment was done by increasing the daily dose by 2.5 to 5 mg/kg/day every two months until an ANC of <4000/microL was reached. The mean MTD dose was 22.5 mg/kg/day (mean doses in different countries ranged from 18.9 to 25.3 mg/kg/day), and the mean time to reach this dose was 11 months.

●SPRING – SPRING and other trials focused specifically on stroke prevention are discussed above. (See 'Primary and secondary prevention (stroke)' above.)

These trials document that tens of thousands of children with SCD in Africa might benefit from hydroxyurea therapy for preventing morbidity associated with the disease. We suggest hydroxyurea therapy, preferably in a clinical trial setting, for children and adults with indications described above, including frequent vaso-occlusive pain or acute chest syndrome, stroke, or high risk of stroke based on elevated transcranial Doppler (TCD) measurements. (See 'Vaso-occlusive events' above.)

Blood transfusion — We generally reserve blood transfusion for severe, life-threatening anemia and/or acute stroke management for patients with SCD in sub-Saharan Africa.

Blood transfusion is used in the management and prevention of several complications of SCD in children and adults in resource-rich countries. However, transfusion presents major challenges in sub-Saharan Africa [136]. These challenges include the unavailability of blood, the high cost associated with receiving blood transfusions, and in some areas a high risk of transfusion-associated infections [79]. Moreover, the majority of medical centers in sub-Saharan Africa rely on family replacement donation, which carries a higher risk of bloodborne infections than voluntary donors [137-139]. Other major difficulties that have been reported include red blood cell alloimmunization due to non-standardized blood banking systems and transfusion reactions [140].

In the few African centers where blood transfusion is available and chronic blood transfusion is practiced, the risk of iron overload and the exorbitant cost of iron chelation is not affordable to the majority of families [140-142]. As an example, the estimated annual cost of conducting chronic blood transfusion including iron chelation for a single patient in the United States is often over USD $50,000, with even higher costs associated with the oral iron chelation [142,143].

Hematopoietic stem cell transplantation — Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available cure for SCD [144,145]. This involves replacing the patient's bone marrow hematopoietic stem cells containing the sickle mutation with hematopoietic stem cells containing a normal beta-globin genotype (either heterozygous or homozygous).

HSCT is rarely performed in low-income countries in Africa, despite the advancements made in high-income countries. This disparity has been illustrated in several reports:

●A review of the global use of HSCT for any condition cataloged the rates of HSCT worldwide and trends in use of HSCT over the period from 2006 to 2008 [146]. This found that of 146,808 transplants performed over this period of time, only 3964 (2.7 percent) were performed in Africa and the eastern Mediterranean region. The majority were in the United Arab Emirates, Qatar, and Egypt.

●The first HSCT for SCD in Nigeria was conducted in 2011; this resulted in successful engraftment with normal hematologic parameters at two years of follow-up [147]. However, only four successful transplants have been conducted subsequently.

The challenges associated with setting up a transplant program in African countries have been highlighted by several authors [147-153]. These include poverty, shortages of personnel, inadequate infrastructure, ineffective health insurance policies, substandard facilities, and poor/inadequate supportive care. The most pressing challenge is the use of pay-for-service HSCT for SCD that may occur in Africa or elsewhere, referred to as medical tourism. Our experience has been that patients receive nonprotocol or clinical trial-associated transplant and return back to their home location where there is often inadequate medical expertise or support for timely and necessary post-HSCT care [154].

Additional details regarding HSCT in SCD including preferred donor, stem cell source, conditioning regimen, graft-versus-host disease prophylaxis, and the possibility of incorporating gene therapy, are presented separately. (See "Hematopoietic stem cell transplantation in sickle cell disease".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Over 300,000 babies with sickle cell disease (SCD) are born annually, the majority in sub-Saharan Africa. The world's SCD population is concentrated in three countries: Nigeria, India, and the Democratic Republic of Congo (figure 1), where the disease affects up to 2 percent of the population and the carrier state (sickle cell trait) prevalence is as high as 10 to 30 percent. (See 'Public health burden of SCD' above.)

●Diagnosis – Diagnosis of SCD early in life improves survival. Newborn screening to identify affected individuals before the development of complications is ideal. Most individuals in sub-Saharan Africa are diagnosed when they present with symptoms during childhood, at a mean age of two years. (See 'Identifying individuals with SCD' above.)

●Bacterial infection – The risk of bacterial infection is dramatically increased in SCD, particularly in children <5 years of age. The two major prophylactic interventions are vaccinations, especially against encapsulated organisms, and daily oral penicillin, at least until age five years. Patients should seek medical attention if they have fever, cough, chest pain, headache, nuchal rigidity, bone pain, or other signs of infection, and patients with these findings should be treated promptly with broad-spectrum antibiotics. (See 'Bacterial infections' above.)

●Malaria – Although the sickle mutation is somewhat protective against malaria, infection occurs and may be severe. Strategies for control and prevention of malaria include mosquito control, personal protection, and antimalarial prophylaxis. We prefer daily proguanil based on good compliance and low frequency of side effects. Treatment of malarial infections is described above. (See 'Malaria' above.)

●Acute vaso-occlusive events – Vaso-occlusive events including stroke, pain episodes, acute chest syndrome (ACS), and priapism cause significant morbidity and mortality. Management includes appropriate diagnostic evaluations, adequate pain control and hydration, and antibiotics when appropriate. For acute stroke, blood transfusion is used when possible. (See 'Vaso-occlusive events' above.)

●Disease-modifying therapy – Hydroxyurea is the main disease-modifying therapy for SCD; benefits are summarized in the table (table 12). We use hydroxyurea for children with a history of stroke or elevated transcranial Doppler (TCD) velocities, frequent severe pain episodes, or ACS requiring transfusions. Hydroxyurea can be administered at a fixed low-dose (10 mg/kg/day) or a fixed moderate-dose (20 mg/kg/day) with twice yearly complete blood count (CBC), or using dose escalation to a maximum tolerated dose, based on more frequently obtained CBC parameters.

•Fixed moderate-dose hydroxyurea for frequent vaso-occlusive events or prior stroke – For individuals with frequent vaso-occlusive events (vaso-occlusive pain, ACS) or prior stroke, we suggest hydroxyurea at a fixed dose of 20 mg/kg/day with monitoring, rather than fixed low-dose or maximum tolerated dose hydroxyurea (Grade 2C); this assumes the family can afford the costs and burdens of this therapy. (See 'Hydroxyurea' above.)

•Fixed low-dose hydroxyurea for primary stroke prevention – For individuals who do not have frequent vaso-occlusive events and have not had a stroke but do have elevated TCD velocities, we suggest hydroxyurea at a fixed dose of 10 mg/kg/day (Grade 2C). (See 'Hydroxyurea' above.)

•Escalation to maximum tolerated dose hydroxyurea or other approaches for selected individuals – For individuals with access to resources for more frequent monitoring and/or for whom continued complications occur with fixed-dose hydroxyurea, titration to an absolute neutrophil count (ANC) <4000/microL (maximum tolerated dose) may also be used if the patient, family/caregivers, and clinicians believe this would improve care. Transfusions and hematopoietic cell transplant may be options for selected individuals. (See 'Hydroxyurea' above and 'Blood transfusion' above and 'Hematopoietic stem cell transplantation' above.)

●Pregnancy – Pregnancy is managed by a multidisciplinary team to address maternal and fetal risks. Close monitoring is required. Folic acid is administered daily. (See 'Pregnancy' above and "Sickle cell disease: Obstetric considerations".)

●Other information – Overviews of SCD management in resource-rich settings are presented separately. (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Overview of the management and prognosis of sickle cell disease".)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.