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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 "Routine comprehensive care for children with sickle cell disease".)
PUBLIC HEALTH BURDEN OF SCD — SCD is one of the most common genetic diseases in the world. Over 300,000 babies with SCD are born annually; the majority of these are in sub-Saharan Africa, where access to medical care and public health strategies to decrease mortality and morbidity are not uniformly available [1-4]. This number is expected to increase to up to 400,000 individuals by 2050 .
The World Health Organization and United Nations have designated SCD as a global public health problem [5,6]. 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 . Despite the major interventions in malaria, HIV, and immunization, most of the 19 countries estimated to have a persistently high under-five mortality rate 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.
Half 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 [4,8,9]. 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 [10,11].
The regions of Africa with a high incidence of SCD are also associated with the highest density of malaria [12,13]. 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 (HbSS) predisposes individuals to severe malaria and increased malaria mortality, as well as increased mortality from other complications of SCD [14,15]. The role of heterozygosity for the sickle mutation in protection from falciparum malaria is discussed separately. (See "Protection against malaria in the hemoglobinopathies", section on 'Falciparum malaria and hemoglobin S'.)
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, SCD-related childhood mortality in Africa remains as high as 50 to 90 percent, with fewer than half of affected children reaching their fifth birthday . An indication of the extremely high mortality rate throughout childhood and adolescence is the observation that adult prevalence of HbSS is 10-fold less than the birth incidence (0.2 to 0.3 percent versus 2 to 3 percent) .
OVERVIEW OF MANAGEMENT — Simple public health measures, such as newborn screening and parental 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 . 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 affected individuals with SCD' below.)
●Education regarding when to seek medical attention – (See 'Education' below.)
●Adequate pain control and hydration for vaso-occlusive pain – (See 'Pain episodes' below.)
●Use of blood transfusions only when anemia is life threatening – (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 'Prevention (stroke)' below and 'Renal complications' 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 morbidity and mortality can be improved using simple measures such as these [18,19].
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 . 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.
IDENTIFYING AFFECTED INDIVIDUALS WITH SCD — The age at diagnosis for SCD is primarily dependent on whether newborn screening has been instituted in the region. Only a few centers in sub-Saharan Africa are able to initiate newborn screening and deliver comprehensive health care at an early age [8,21]. 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 may be especially useful in areas where it is not possible or convenient to transfer blood samples to a centralized laboratory. POC assays for SCD that are in development are discussed in a separate topic review. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Point-of-care assays'.)
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 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 . 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 [8,21].
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 . 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 . 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 . 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 300 per 1000 births . 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.
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 earlier (eg, during infancy). The most common presentations for previously undiagnosed SCD include dactylitis at six months to one year 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 and hemoglobin analysis.
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 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 immunizations 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.)
Bacterial infections — The risk of bacterial infection is dramatically increased in SCD, particularly for children less than five years of age . 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 . Additional contributing factors include abnormalities of opsonization, antibody production, the alternate complement pathway, leucocyte function defects, and cell-mediated immunity [28-30].
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 .
●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 .
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. (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 [33,34]. In contrast, adherence to monthly intramuscular penicillin is approximately 88 percent . 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'.)
Bacterial infections (treatment) — 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 . 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 Streptococcus pneumoniae, Haemophilus influenzae type b, and non-typhoid salmonellosis [30,37,38]. Children under five years of age are at greatest risk for meningitis and septicemia, while all age groups may develop salmonella osteomyelitis [30,32]. 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.
Parents 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) (table 1), 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 meningeal signs.
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.
Malaria — Malaria infection in individuals with homozygous sickle hemoglobin S (HbSS) 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 HbSS improves mortality in children <5 years [24,39,40]. 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) .
Malaria (prophylaxis) — Strategies for control and prevention of malaria include mosquito control, personal protection, and antimalarial prophylaxis.
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 [14,18,42,43]:
●Proguanil 100 mg daily (preferred, as noted above)
●Chloroquine 5 mg/kg every other day
●Intermittent therapy with one of the following :
•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 [14,18,42,43].
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 . 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), although 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), although vomiting, body pain, and abdominal pain were more frequent with MQAS and SPAQ than with proguanil. However, as noted above, we prefer daily single agent therapy due to its lower frequency of side effects and improved compliance in our experience.
Personal protection with insecticide-treated bed nets and mosquito repellents has shown varying success rates in malaria endemic areas in sub-Sahara Africa .
Additional information about these approaches, as well as a discussion about vaccine development, is presented separately. (See "Malaria in endemic areas: 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, Coke-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 [46,47]. Thus, prompt initiation of antimalarial therapy among acutely ill patients with SCD and confirmed malaria infection is important in the management of both conditions [46-48].
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 . These therapies have been shown to be efficacious and associated with relatively few and rare side effects [48,49]. Other artemisinin-based combinations used for treatment of acute malaria include artesunate-amodiaquine, dihydroartemisinin-piperaquine, chlorproguanil-dapsone-artesunate, artesunate-mefloquine, and artesunate-azithromycin .
These and other malaria treatment regimens are summarized in the tables and presented in more detail separately:
●Uncomplicated falciparum malaria (table 3 and table 4) – (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)
●Uncomplicated non-falciparum malaria (table 5) – (See "Overview of non-falciparum malaria in nonpregnant adults and children".)
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 . Other studies have shown that HIV infection in individuals with SCD is associated with an increased risk of pneumococcal infection . At the same time, HIV infection may blunt the response to vaccination against pneumococcus.
Management of concomitant HIV and SCD presents management challenges, especially in sub-Saharan Africa where the level of care is suboptimal [53,54]. 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 pneumococcal infection.
●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) .
VASO-OCCLUSIVE EVENTS — Vaso-occlusive events in SCD include acute painful episodes and organ-specific complications such as stroke, acute chest syndrome, priapism, and dactylitis. (See "Overview of the clinical manifestations of sickle cell disease" and "Mechanisms of vaso-occlusion in 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 . 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 . 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 is generally not used in very young children in Africa; the major hesitation is due to the higher rate of mortality and life-threatening bacterial and malarial infection and the unknown effect of hydroxyurea therapy in such a vulnerable group [16,57-59]. We believe the impact of hydroxyurea therapy in children <5 years of age in Africa should be studied, given the high expected rate of mortality in the age group.
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 relies on radiological features of new pulmonary infiltrate on chest radiograph and pulse oximetry, which are 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.
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 .
Splenic sequestration — Splenic sequestration is a potentially life-threatening complication that occurs when blood pools rapidly in the spleen. It is characterized by an acute fall in the hemoglobin level accompanied by a rapidly enlarging spleen or liver (greater than 2 cm increase from the steady state level) and increased reticulocytosis above the steady state level. It may be associated with malaria or another infection in some cases.
Management of splenic sequestration in resource-poor settings involves hospital admission with urgent laboratory testing (complete blood count, pretransfusion testing) and red blood cell transfusion at a dose of 10 mL/kg. 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 this complication are advisable. For patients who have had one or more episodes of splenic sequestration, splenectomy may be appropriate. We generally advise splenectomy following the second episode of splenic sequestration; occasionally, we do so after the first episode.
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 14, and without secondary prevention more than half of these will have recurrent stroke within two years of the initial stroke [60,61].
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 (table 1).
●Online videos (eg, https://www.youtube.com/watch?v=gzHuNvDhVwE).
●The Pediatric Stroke Outcome Measure (PSOM) .
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 [63-66].
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
●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)
●Simple blood transfusion when available
●Where available, simple blood transfusion is followed by modified- or full-exchange blood transfusion, performed either manually or automated [67,68]
As noted above, imaging of the brain is not routinely performed.
Prevention (stroke) — We believe the risks of recurrent stroke (for those with a history of stroke) and primary stroke (for those with elevated transcranial Doppler ultrasound [TCD] measurements) are unacceptably high in patients with SCD. The standard of care involves conducting annual TCD on all children from 2 to 16 years of age.
We believe that patients with SCD who have had a stroke or who have elevated TCD measurements of the internal carotid artery and/or middle cerebral artery (eg, TCD velocity >200 cm/sec based on a non-imaging technique [ie, flow waveform alone without visualization of the vasculature] or 180 cm/sec with an imaging technique) should be treated with hydroxyurea to reduce the risk of recurrent or initial stroke, respectively.
The efficacy of hydroxyurea for primary prevention of stroke immediately after detection of a high TCD velocity has not been demonstrated; however, the results of the TWiTCH (TCD with Transfusions Changing to Hydroxyurea) trial, which demonstrated non-inferiority of hydroxyurea compared with transfusions after an initial year of transfusions, are highly encouraging in this regard [69,70]. (See 'Hydroxyurea' below and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of a first ischemic stroke (primary stroke prophylaxis)'.)
Preliminary studies conducted in sub-Saharan Africa have shown that hydroxyurea can be safely administered to children with elevated TCD measurements and is effective in reducing TCD velocities [71-73]. In resource-rich settings, hydroxyurea was not as effective as regular transfusion therapy for secondary stroke prevention; however, it is superior to supportive care alone. Regular blood transfusion therapy for stroke prevention is not an option for children with SCD in sub-Saharan Africa for several reasons including but not limited to the high cost of transfusion, unavailability of blood, and unsafe transfusion practices . (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Chronic transfusions for secondary prophylaxis'.)
Primary and secondary stroke prevention in resource-rich settings, including the use of regular blood transfusions, is discussed in detail separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of a first ischemic stroke (primary stroke prophylaxis)'.)
PREGNANCY — Many girls with SCD will not reach childbearing age. In adult women with SCD, pregnancy 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 .
●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) [75-77]. 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 [75-77]. Perinatal mortality rates are also increased.
A multidisciplinary team including a hematologist, obstetrician, midwives, nurses, anesthetist, and intensive care team should be involved in managing pregnancy in women with SCD 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 . However, coordinated efforts are required to undertake this strategy.
During routine antenatal care, pregnant women with SCD should be counselled regarding 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 women 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:
Fetal ultrasound testing is done frequently (eg, at 20, 26, 30, 34, and 38 weeks). 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 and 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 [79,80]. Causes of morbidity in adults with SCD include complications associated with pregnancy and renal, pulmonary, and orthopedic complications [81-84]. 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.
Renal complications — Renal complications 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.
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 "Renal manifestations of sickle cell disease".)
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 [85,86]; 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 [87-89]. Further, these studies showed that adults with PH have an increased risk for early death [87-89]. 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 >3.0 m/s is associated with increased mortality in adults with SCD [90,91]. A clinical practice guideline from the American Thoracic Society emphasized the benefits of hydroxyurea therapy in reducing this risk . (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 >3.0 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 . 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 [92-96]. 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 0 to 4 years (figure 2), 5 to 11 years (figure 3), and 12 years and older (figure 4), and discussed in detail separately. (See "An overview of asthma management" and "Asthma in children younger than 12 years: Initiating therapy and monitoring control".)
Orthopedic complications — Orthopedic complications are one of the most common long-term sources of morbidity in adults with SCD, typically avascular necrosis of the head of the femur . 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. Regrettably in sub-Saharan Africa, only a few centers can provide surgical interventions, due to several reasons including cost, inadequate manpower, and lack of expertise and equipment .
DISEASE-MODIFYING OR CURATIVE THERAPIES
Hydroxyurea — Hydroxyurea has become the standard of care for management of children and adults with SCD in high-income countries, based on demonstration of its efficacy in reducing SCD complications in infants, children, and adults. (See "Hydroxyurea use in sickle cell disease".)
Hydroxyurea is used infrequently in sub-Saharan Africa. Contributing factors include the large absolute numbers of individuals with SCD (see 'Public health burden of SCD' above) and the uncertainty regarding the benefits and risks in a resource-poor setting where routine monitoring of blood counts is not available. The perceived hematological toxicity of hydroxyurea may be greater in sub-Saharan Africa compared with resource-rich settings due to the high incidence of malaria and bacterial infections in African patients [32,57,97]. Other barriers to use include the cost of laboratory monitoring and frequent follow-up, and lack of trained physicians on use of hydroxyurea in many of the health facilities.
However, despite these concerns, we believe that hydroxyurea should be used for primary and secondary stroke prevention in patients with elevated transcranial Doppler measurements or prior stroke, respectively. (See 'Stroke' above.)
In resource-rich countries, the dose of hydroxyurea is determined using frequent monitoring of the complete blood count (CBC) to ensure an increase in the percentage of HbF without excessive hematologic toxicity (cytopenias). This intensity of monitoring is not routinely available in sub-Saharan Africa. We use a hydroxyurea dose of 20 mg/kg daily for primary and secondary prevention. However, the optimal dose remains to be established in sub-Saharan Africa, where other causes of cytopenias such as HIV and malaria may coexist, especially in settings where routine hematologic monitoring is unavailable . Studies to determine the optimal hydroxyurea dosing are underway in Nigeria (NCT02560935).
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 . 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 . 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 [100-102]. Other major difficulties that have been reported include red blood cell alloimmunization due to non-standardized blood banking systems and transfusion reactions.
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 [103,104]. 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 [104,105].
Hematopoietic cell transplantation — Allogeneic hematopoietic cell transplantation (HCT) is the only available cure for SCD [106,107]. 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).
HCT 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 HCT for any condition cataloged the rates of HCT worldwide and trends in use of HCT over the period from 2006 to 2008 . This found that of 146,808 HCTs 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 HCT for SCD in Nigeria was conducted in 2011; this resulted in successful engraftment with normal hematologic parameters at two years of follow-up . However, only four successful transplants have been conducted subsequently.
The challenges associated with setting up an HCT program in African countries have been highlighted by several authors [109-114]. These include poverty, shortages of personnel, inadequate infrastructure, ineffective health insurance policies, substandard facilities, and poor/inadequate supportive care.
Additional details regarding HCT 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 cell transplantation in sickle cell disease".)
SUMMARY AND RECOMMENDATIONS
●Over 300,000 babies with sickle cell disease (SCD) are born annually, the majority in sub-Saharan Africa. Half 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. (See 'Public health burden of SCD' above.)
●Diagnosis of SCD early in life improves survival. Newborn screening to identify affected individuals before the development of complications is ideal. However, most individuals in sub-Saharan Africa are diagnosed when they present with symptoms during childhood, at a mean age of two years. (See 'Identifying affected individuals with SCD' above.)
●The risk of bacterial infection is dramatically increased in SCD, particularly in children less than five years of age. The two major prophylactic interventions for bacterial infections are vaccinations, especially against encapsulated organisms, and daily oral penicillin, at least until five years of age. 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.)
●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.)
●Vaso-occlusive events are a significant cause of morbidity and mortality. Management includes appropriate diagnostic evaluations, adequate pain control and hydration, antibiotics when appropriate, and blood transfusion if indicated and available. (See 'Vaso-occlusive events' above and 'Blood transfusion' above.)
●We use hydroxyurea for primary and secondary stroke prevention in patients with elevated transcranial Doppler measurements or prior stroke. The optimal dose in sub-Saharan Africa remains to be determined, due to potentially coexisting cytopenias and lack of routine monitoring; in the absence of high quality data, we use a dose of 20 mg/kg daily. (See 'Stroke' above and 'Hydroxyurea' above.)
●Overviews of SCD management in resource-rich settings are presented separately. (See "Routine comprehensive care for children with sickle cell disease" and "Overview of the management and prognosis of sickle cell disease".)
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