Sickle Cell Disease

Clinical characteristics.

Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ system, including the bones, spleen, liver, brain, lungs, kidneys, and joints. Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD. In children, the spleen can become engorged with blood cells in a "splenic sequestration." The spleen is particularly vulnerable to infarction and the majority of individuals with SCD who are not on hydroxyurea or transfusion therapy become functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections. Acute chest syndrome is a major cause of mortality in SCD. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation. Individuals with the highest rates of hemolysis are predisposed to pulmonary artery hypertension, priapism, and leg ulcers but may be relatively protected from vaso-occlusive pain.

Diagnosis/testing.

SCD encompasses a group of disorders characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in HBB) and a second HBB pathogenic variant resulting in abnormal hemoglobin polymerization. Hb S/S (homozygous p.Glu6Val in HBB) accounts for 60%-70% of SCD in the United States. Other forms of SCD result from coinheritance of HbS with other abnormal β-globin chain variants, the most common forms being sickle-hemoglobin C disease (Hb S/C) and two types of sickle β-thalassemia (Hb S/β⁺-thalassemia and Hb S/β°-thalassemia); rarer forms result from coinheritance of other Hb variants such as D-Punjab, O-Arab, and E.

The diagnosis of SCD is established by identification of significant quantities of HbS with or without an additional abnormal β-globin chain variant by hemoglobin assay or by identification of biallelic HBB pathogenic variants where at least one allele is the p.Glu6Val pathogenic variant (e.g., homozygous p.Glu6Val; p.Glu6Val and a second HBB pathogenic variant) on molecular genetic testing.

All states in the US have included newborn screening for SCD since 2005. Newborn screening programs perform isoelectric focusing and/or high-performance liquid chromatography (HPLC) of an eluate of dried blood spots. A few newborn screening programs confirm results with molecular testing.

Management.

Treatment of manifestations: Management of pain episodes includes hydration, anti-inflammatory agents, and pain medication. Pain episodes are additionally managed with a multimodel approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). Fever and suspected infection is treated with appropriate antibiotics. Life-threatening or severe complications (e.g., severe acute chest syndrome, aplastic crisis, and stroke) are often treated with red blood cell transfusion. Splenectomy may be necessary for splenic sequestration. Severe priapism may require aspiration and irrigation.

Prevention of primary manifestations: Maintain hydration and avoid climate extremes. Chronic red blood cell transfusion in children at risk for stroke and individuals with pulmonary hypertension, chronic renal failure, recurrent acute chest syndrome, and severe end-organ damage. Hydroxyurea can decrease the frequency and severity of vaso-occlusive processes, reduce transfusion needs, and increase life span. Glutamine has received FDA approval for the prevention of acute complications in individuals with SCD age five years and older. Stem cell transplantation may be an option in selected individuals.

Prevention of secondary complications: Aggressive education on the management of fevers; prophylactic antibiotics, including penicillin in children; immunizations; folic acid supplementation; and iron chelation therapy for those with iron overload.

Surveillance: Periodic comprehensive medical and social evaluation, mental health and neurocognitive assessment, and routine dental care. Annual CBC and reticulocyte count, assessment of iron status, liver and renal function tests, urinalysis, LDH, and vitamin D level. Annual transcranial Doppler to determine risk of stroke in all children with Hb S/S and Hb S/β°-thalassemia and ophthalmologic evaluation in all with sickling disorders. There should be a low threshold to evaluate for end-organ damage including chest x-ray, ECG, abdominal ultrasound, and iron overload. Due to the high frequency and severity of cardiopulmonary complications there should be a particularly low threshold to obtain an echocardiogram, pulmonary function tests, and sleep study in individuals of any age with cardiac or pulmonary concerns.

Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, extremely high altitude, recreational drugs with vasoconstrictive or cardiac stimulation effects, and meperidine.

Evaluation of relatives at risk: Early diagnosis of at-risk family members allows education and intervention before symptoms or end-organ damage are present.

Pregnancy management: Women with SCD who become pregnant require close follow up and monitoring by a hematologist and obstetrician; an increased risk for preterm labor, thrombosis, infectious complications, and acute painful episodes has been reported during pregnancy; hydroxyurea should be discontinued during pregnancy.

Genetic counseling.

SCD is inherited in an autosomal recessive manner. If one parent is a carrier of the HBB HbS pathogenic variant and the other is a carrier of any of the HBB pathogenic variants (e.g., HbS, HbC, β-thalassemia), each child has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for common forms of SCD is most commonly accomplished by isoelectric focusing or HPLC. Prenatal and preimplantation genetic testing are possible if the HBB pathogenic variants have been identified in the parents.

Suggestive Findings

While there is no single finding suggestive of sickle cell, the presence of the following features should raise suspicion, especially when both clinical and laboratory features are present in a person of Sub-Saharan African, Indian, or Central American descent, or with a family history of SCD.

Clinical features

• Infants with spontaneous painful swelling of the hands and feet
• Recurrent episodes of severe pain with no other identified etiology
• Unexplained anemia not related to iron deficiency
• Pallor
• Jaundice
• Pneumococcal sepsis or meningitis
• Severe anemia with splenic enlargement
• Stroke, especially in a child

Note: Most individuals with SCD are healthy at birth and become symptomatic later in infancy or childhood after fetal hemoglobin levels decrease.

Laboratory features

• Normocytic anemia
• Sickle cells, nucleated red blood cells, target cells, and other abnormal red blood cells on peripheral blood smear; Howell-Jolly bodies indicate hyposplenism.
• Presence of hemoglobin S (HbS) on a hemoglobin assay (e.g., high-performance liquid chromatography [HPLC], isoelectric focusing, cellulose acetate electrophoresis, citrate agar electrophoresis) with an absence or diminished amount of HbA

(For information about advantages and disadvantages of various hemoglobin assays, click here.)

Newborn screening. Newborn screening programs perform isoelectric focusing and/or HPLC of an eluate of dried blood spots. A few newborn screening programs confirm results with molecular testing (see Hemoglobinopathies: Current Practices for Screening, Confirmation and Follow-up).

• The normal newborn screening result is "FA" (i.e., more fetal hemoglobin (HbF) compared to adult hemoglobin [HbA]). Note: Hemoglobins identified by newborn screening are reported in order of quantity.
• Specimens with "FS" are retested using a second confirmatory technique (e.g., HPLC, citrate agar electrophoresis, isoelectric focusing, or DNA-based assay).
• Infants with hemoglobins that suggest SCD require additional confirmatory testing of a separate blood sample by age six weeks (see Table 1).

Establishing the Diagnosis

The diagnosis of SCD is based on the evaluation of adult hemoglobins (HbA, HbS, and other beta globin variants [e.g., HbC, HbE]). Fetal hemoglobin (HbF) is normally the predominant hemoglobin in newborns and decreases over the first year of life.

• Identification of HbS as the sole adult beta chain on Hb assay indicates either Hb S/S or Hb S/β°-thalassemia. These can be distinguished by molecular testing, the combination of hemoglobin testing and other clinical studies, or in combination with family history.
• S/β°-thalassemia and S/β⁺-thalassemia are distinguished by the presence of HbA in individuals with S/β⁺-thalassemia, but HbA is below that observed in sickle cell trait.
• Identification of HbS and an additional beta-chain variant (e.g., HbC, D, O, or E) on Hb assay can establish the diagnosis in individuals who are compound heterozygous for specific HBB pathogenic variants (e.g., Hb S/C, Hb S/D, Hb S/O, Hb S/E).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of HBB is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found on sequence analysis.
• A multigene panel that includes HBB and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

The clinical manifestations of sickle cell disease (SCD) result from intermittent episodes of microvascular occlusion leading to tissue ischemia/reperfusion injury and chronic hemolysis, both of which contribute to multiorgan dysfunction. The severity of disease manifestations varies, even in individuals with the same HBB pathogenic variants.

Vaso-occlusive events are associated with ischemia/reperfusion damage to tissues that lead to pain and acute or chronic injury affecting any organ system. The bones/marrow, spleen, liver, brain, lungs, kidneys, and joints are often affected. The biologic markers associated with this "vaso-occlusive phenotype" include the following [Darbari et al 2012, Wood et al 2012]:

• A higher WBC count
• A lower HbF level
• Older age
• Coexisting alpha-thalassemia trait
• Iron overload (secondary to transfusions)
• Vessel flow resistance related to deoxygenation

Chronic hemolysis is associated with chronic anemia as well as vascular dysfunction [Morris 2011]. Individuals with the highest rates of hemolysis are at increased risk of developing pulmonary artery hypertension, priapism, and leg ulcers [Kato & Taylor 2010]. Biologic markers for this "hemolytic phenotype" include the following:

• Elevated plasma levels of lactate dehydrogenase (LDH)
• A low hemoglobin level
• A high reticulocyte count

Complications related to vaso-occlusive events

• Vaso-occlusive pain episodes are the most frequent cause of recurrent morbidity in individuals with SCD and account for the majority of SCD-related hospital admissions as well as school and work absences [Gill et al 1995]. Vaso-occlusion is due to multicellular aggregates that block blood flow in small blood vessels, depriving downstream tissues of nutrients and oxygen, resulting in tissue ischemia and tissue death in the affected vascular beds. Vaso-occlusion and ischemic tissue damage cause excruciating pain. Young children more often complain of pain in their extremities, whereas older individuals more commonly experience pain in the head, chest, abdomen, and back.
• Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD and occurs in infants and children. The dorsa of the extremities are most often involved; one or all four extremities can be involved. Although immediate sequelae are rare, dactylitis has been implicated as a risk factor for severe disease [Miller et al 2000].
• Splenic sequestration and infarction. Splenic sequestration occurs in 10%-30% of children with SCD, most commonly between age six months and three years, and may follow a febrile illness. Splenic sequestration is characterized by an acutely enlarging spleen with hemoglobin >2 g/dL below the affected individual's baseline value. Mild-to-moderate thrombocytopenia may also be present. Children with splenic sequestration may experience abdominal pain, nausea, vomiting, lethargy, or irritability. Blood transfusion may be required as severe splenic sequestration may progress rapidly to shock and death. Recurrent episodes (or difficult-to-manage acute episodes) may require splenectomy. Historically most children with Hb S/S or S/β°-thalassemia will have a dysfunctional spleen within the first year of life and complete auto-infarction and atrophy due to ischemia of the spleen by age five years, though this natural history may be altered by hydroxyurea and chronic transfusion therapy. This splenic dysfunction contributes to the increased risk of sepsis and infection.
• Infection. Young children with SCD and splenic dysfunction are at high risk for septicemia and meningitis due to encapsulated bacteria including Streptococcus pneumonia, Neisseria meningiditis, and Haemophilus influenza. Vaccination programs and prophylactic penicillin have significantly decreased the incidence of these infections [Adamkiewicz et al 2003].
• Individuals with SCD are also at increased risk for other infections such as osteomyelitis caused by Staphylococcus aureus or other organisms such as Salmonella species. Infectious agents implicated in acute chest syndrome include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Streptococcus pneumonia, as well as viruses. Parvovirus remains an important cause of aplastic crisis. Indwelling central venous catheters confer a high risk of bacteremia in individuals with SCD [Chulamokha et al 2006, Zarrouk et al 2006].
• Acute chest syndrome (ACS) is a complex process that can arise from multiple diverse etiologies. ACS is a major cause of mortality [Bakanay et al 2005]. Although the definition varies in the literature, the diagnosis typically is made by the presence of a new pulmonary infiltrate on chest radiography in a person with SCD. This is often in the presence of respiratory tract symptoms, chest pain, hypoxemia, and/or fever. ACS often develops in the setting of a vaso-occlusive episode or with other acute manifestations of SCD, frequently after two to three days of severe vaso-occlusive pain. ACS can progress rapidly (over several hours to days) to requiring intubation and mechanical ventilatory support. A high index of suspicion is indicated: the presenting signs and symptoms of ACS can be highly variable and affected individuals may have an initial normal physical examination [Morris et al 1999]. Multiple etiologies (e.g., fat emboli from bone marrow infarcts, pneumonia, pulmonary infarction, pulmonary embolus), often at the same time, can lead to acute chest syndrome [Mekontso Dessap et al 2011].

Neurologic complications in SCD include stroke, silent cerebral infarcts, cerebral hemorrhage, cerebral blood flow abnormalities including Moyamoya disease, and cerebral microvascular disease. Up to 50% of individuals with SCD will manifest some degree of cerebrovascular disease by age 14 years [Bernaudin et al 2011].

• Ischemic strokes, most often seen in children and older adults, are among the most catastrophic manifestations of SCD. Common presenting signs and symptoms include: hemiparesis, monoparesis, seizures, aphasia or dysphasia, cranial nerve palsies, and mental status changes. Overt strokes occur in as many as 11% of children with SCD, with the peak occurrence between ages two and nine years. Recurring strokes occur in 50%-70% of affected individuals within three years after the first event. Transfusion therapy instituted after the initial stroke significantly reduces this risk [Serjeant 2013]. Narrowing of cerebral vessels is a risk factor for stroke, and elevated flow velocity on transcranial Doppler (TCD) identifies most children at high risk [Adams et al 1998], allowing intervention prior to the development of stroke [DeBaun & Kirkham 2016].
• Silent cerebral infarcts (SCI) occur in approximately 22%-35% of individuals with SCD [Bernaudin et al 2011]. Silent cerebral infarcts are lesions identified on cerebral imaging studies without known focal neurologic symptoms; however, such lesions may be associated with neurocognitive deficits [Schatz et al 2001] and an increased risk for overt stroke [Miller et al 2001]. Thus, a "silent infarct" should not be thought of as a clinically insignificant condition. Cerebral arterial stenosis is noted to be a risk factor for SCI but is not always reflected by increased TCD velocities due to multiple variables, which influence individual vessel velocities. Additionally, accuracy of TCD measurements in demonstrating intracranial stenosis has not been firmly established. Utilization of methods to identify increased risk of stroke due to SCI, such as MRI/MRA, are being studied [Arkuszewski et al 2014, DeBaun & Kirkham 2016].

Complications related to hemolysis. A hyper-hemolysis syndrome marked by an elevated LDH, low hemoglobin level, and low reticulocyte count is associated with leg ulcers, priapism, pulmonary artery hypertension, systemic hypertension, and platelet activation [Hebbel 2011]. Other consequences of hemolysis include: chronic anemia, jaundice, predisposition to aplastic crisis, and cholelithiasis. While those with the highest rates of hemolysis may experience fewer pain episodes, the overall mortality rate for this group of individuals may be higher [Hebbel 2011, Kato et al 2017].

Aplastic crisis is the temporary interruption of red blood cell production, typically due to human parvovirus B19 infection in children, resulting in an acute and potentially life-threatening anemia. Sickle red blood cells survive for only about seven to 12 days, compared to 100-120 days for normal red blood cells. Thus parvovirus B19 infection, which can interrupt red blood cell production for eight to ten days, can result in a drop of hemoglobin level of 1 g/dL per day, leading to life-threatening levels in individuals with SCD that may require red blood cell transfusion.

Pulmonary hypertension. Pulmonary artery hypertension (PAH) affects approximately 6%-35% of adults with SCD and can have profound consequences [Parent et al 2011]. Although a similar proportion of children with SCD have PAH as diagnosed by echocardiography, PAH does not appear to be associated with the same dire outcomes as in adults [Lee et al 2009, Liem et al 2009, Hebson et al 2015].

While many have defined PAH in SCD by an elevated tricuspid regurgitant jet velocity (TRV) on transthoracic echocardiography (TTE), subsequent studies using direct measurement of PAP (pulmonary arterial pressure) by right heart catheterization indicate that this may over-diagnose PAH [Parent et al 2011]. PAH in adults is associated with markedly increased mortality [De Castro et al 2008] and significant morbidity, including exercise intolerance [Sachdev et al 2011]. Risk factors for PAH include markers of increased hemolysis, such as elevated LDH [Kato et al 2006], markers of cardiac strain, such as elevated brain natriuretic peptide (BNP) [Machado et al 2006], and the presence of obstructive sleep apnea [Hebson et al 2015]. Some individuals are relatively asymptomatic in the early stages of PAH. The relevance of these factors in children is less clear.

Priapism is very common among males with SCD, with a mean age of onset of 15 years [Adeyoju et al 2002]. These painful, unwanted erections occur spontaneously, with nocturnal erections, or with fever and dehydration. Males may have episodes of stuttering (intermittent) priapism lasting fewer than two to four hours that are often recurrent and may precede a more severe and persistent episode. "Severe priapism" episodes are persistent; those lasting more than two to four hours need rapid intervention because prolonged priapism may result in permanent erectile tissue damage and impotence [Rogers 2005].

Other complications of SCD include: avascular necrosis (typically involving the femoral head or humerus), nephropathy, restrictive lung disease, cholelithiasis, retinopathy, cardiomyopathy, and delayed growth and sexual maturation. Individuals with hemoglobin SC disease are at particularly high risk for retinopathy [Powars et al 2002]. Cardiopulmonary complications represent a major mortality risk in adults [Fitzhugh et al 2010].

Individuals who receive frequent red blood cell transfusion can develop problems with iron overload, with tissue iron deposition potentially damaging the liver, lungs, and heart [Kushner et al 2001], and alloimmunization that may interfere with the ability to obtain fully matched units of blood for transfusion [Vichinsky et al 1990].

Life expectancy. Previously, median survival in the US for those with SCD was estimated at age 42 years for men and age 48 years for women [Platt et al 1994]; however, survival of a subset of individuals with SCD beyond age 55 or 60 years has been described, though morbidity remains high [Serjeant 2013]. In addition, some evidence shows a shift towards longer survival over the last 20 years, with a significant decrease in childhood deaths [Hassell 2010, Quinn et al 2010].

The main causes of death are infection, acute chest syndrome, pulmonary artery hypertension, and cerebrovascular events [Bakanay et al 2005]. Causes of death in children tend to differ from those in adults. Children have higher rates of death from infection and sequestration crises whereas adult mortality is secondary to chronic end-organ dysfunction, thrombotic disease, and treatment-related complications [Manci et al 2003].

Heterozygotes for HbS have hemoglobins A and S (Hb A/S) (also called sickle cell trait). Heterozygous individuals are not anemic and have normal red cell indices with hemoglobin S percentages typically near 40%. In regions of the world where malaria is endemic, Hb A/S confers a survival advantage in childhood malaria; this is thought to be a major selective pressure for persistence of the HbS pathogenic variant (p.Glu6Val).

The amount of HbS present is insufficient to produce sickling manifestations under most circumstances and, thus, these individuals are usually asymptomatic but are at risk for several complications [Key & Derebail 2010]:

• Extremes of physical exertion, dehydration, and/or altitude can induce sickle cell vaso-occlusive events in some individuals with Hb A/S [Mitchell 2007]. Individuals with Hb A/S should maintain aggressive hydration during extreme physical exertion, with no formal activity restrictions recommended. There is increased awareness of the low but significant risks for pulmonary emboli, exertional rhabdomyolysis, and sudden death with extreme exertion in individuals with Hb A/S. This has led to the mandatory offering of testing to all NCAA Division I college athletes [Bonham et al 2010]. The full implications of this policy are unclear, and the role of genetic counseling in this setting is complex as there is debate about the impact and consequences of testing [Aloe et al 2011, Tarini et al 2012, Thompson 2013].
• Splenic infarct at high altitudes, impaired renal concentrating abilities, and intermittent micro- and macroscopic hematuria can occur in some individuals with Hb A/S.
• Renal medullary carcinoma is an extremely rare form of kidney cancer occurring almost exclusively in individuals with sickle cell trait [Goldsmith et al 2012] such that a high index of suspicion for this rare diagnosis should be given for individuals with sickle cell trait who present with hematuria.
• HB A/S may be associated with an increased risk for venous thromboembolism [Austin et al 2007].
• There has not been an association of sickle cell trait with avascular necrosis, stroke, leg ulcers, cholelithiasis, or end-stage renal disease [Goldsmith et al 2012, Naik et al 2017].

Genotype-Phenotype Correlations

Although a tremendous amount of individual variability occurs, individuals with Hb S/S and S/β°-thalassemia are generally more severely affected than individuals with Hb S/C or S/β⁺-thalassemia. Molecular and genetic factors that are responsible for this variability are being investigated [Steinberg & Adewoye 2006].

Individuals with Hb S/C have longer red cell life span and higher hemoglobin concentration associated with fewer vaso-occlusive pain episodes. Splenomegaly and the associated risk for splenic sequestration can persist well beyond early childhood. Proliferative retinopathy and avascular necrosis are more likely to develop than in those with other sickle hemoglobinopathies.

The presence of α-thalassemia may modify SCD severity (see Differential Diagnosis). In general, α-thalassemia improves red cell survival and decreases hemolysis in SCD. However, the clinical effect on SCD is unclear and can be variable including possible decreased complications arising from hemolysis and potentially increased complications from vaso-occlusive events [Steinberg 2005].

Nomenclature

Historically in the US, the term "sickle cell anemia" was used to describe persons homozygous for HbS. With increased awareness of the broad spectrum of clinically significant sickle hemoglobinopathies with varying degrees of anemia, the trend has been to use the umbrella term "sickle cell disease." The term sickle cell disease should be followed by a detailed genotypic description for the individual (e.g., Hb S/S, Hb S/C, or S/β°-thalassemia).

Prevalence

The HbS allele is common in persons of African, Mediterranean, Middle Eastern, and Indian ancestry and in persons from the Caribbean and parts of Central and South America, but can be found in individuals of any ethnic background.

Among African Americans, the prevalence of sickle cell trait (Hb A/S) is about 10%, resulting in the birth of approximately 1100 infants with SCD (Hb S/S) annually in the US. Approximately one in every 300-500 African Americans born in the US has SCD; more than 100,000 individuals are estimated to have SCD (Hb S/S) [Hassell 2010].

The prevalence of HBB alleles associated with SCD is even higher in other parts of the world. In many regions of Africa, the prevalence of the HbS pathogenic variant (p.Glu6Val) is as high as 25%-35%, with an estimated 15 million Africans affected by SCD and 200-300,000 affected births per year worldwide [Aliyu et al 2008, Mousa & Qari 2010]. SCD accounts for as many as 16% of deaths of children younger than age five years in Western Africa [Neville & Panepinto 2011].

Evaluations Following Initial Diagnosis

To establish the extent of end-organ damage and needs in an individual diagnosed with sickle cell disease (SCD), the following evaluations are recommended if they have not already been completed:

• Hematology consultation
• Consultation with a clinical geneticist and/or genetic counselor

Additional evaluations vary with the age and clinical status of the individual:

• Infants after 12 months should have baseline laboratory studies including the following:
  • CBC and reticulocyte count
  • Measurement of HbF (%)
  • Assessment of iron status
  • A thalassemia screen, which includes hemoglobin electrophoresis or HPLC and an inclusion body prep
  • Baseline vitamin D; renal and liver function tests
  • Extended red cell phenotyping so that antigen matched blood may be given if transfusion is urgently needed
• During childhood HLA typing should be offered to the affected individual and all full biologically matched sibs.
• Older individuals. See Surveillance.

Treatment of Manifestations

Lifelong comprehensive care is necessary to minimize morbidity, reduce early mortality, and maximize quality of life. See Published Guidelines / Consensus Statements.

Education of parents, caregivers, and affected individuals is the cornerstone of care:

• Families must appreciate the importance of routine health maintenance visits, prophylactic medications, and early intervention for both acute and chronic complications.
• Warning signs of acute illness such as fever, respiratory symptoms, pallor, lethargy, splenic enlargement, and neurologic changes must be reviewed regularly and must include education for the affected individual, as developmentally appropriate.
• A systematic approach to pain management should be reviewed regularly. This includes identifying and reversing common triggers for sickle cell pain (and distinguishing it from other etiologies of pain), hydration, warmth, ambulation, distraction, and other comfort maneuvers. Initiation of NSAIDs and appropriate use of opiates should be reviewed.
• All families should have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome, splenic sequestration, and stroke.
• Families should be provided baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.

General management of specific problems [NHS 2010, Bender & Seibel 2012, Brousse et al 2014, Yawn et al 2014] includes the following:

• Vaso-occlusive pain episodes (including dactylitis)
  • The initial focus should include the reversal of inciting triggers (e.g., cold, dehydration).
  • Pain episodes are optimally managed using a multimodel approach that may include warmth, hydration, massage, distraction, acupuncture, biofeedback, self-hypnosis, and pharmaceuticals.
  • Uncomplicated pain episodes may be managed at home with oral hydration and oral analgesics including nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates.
  • More severe pain episodes require hospitalization and administration of parenteral fluids and analgesics in addition to adjunctive treatments such as massage and physical therapy.
  • Optimal analgesia is generally achieved with morphine (or other opiate) given around the clock by a patient-controlled analgesia device (PCA) or by continuous infusion.
  • NSAIDs (e.g., ketorolac, ibuprofen, naproxen) may be used to augment the analgesic effect of opiates. NSAIDs can also decrease inflammation, which is part of the pathophysiology.
  • Adequate but not excessive hydration with IV fluids should be provided to maintain euvolemia, and individuals should be monitored closely for the development of other complications such as acute chest syndrome (ACS), splenic sequestration, or opiate-induced constipation.
  • A thorough evaluation for infection, including blood culture, urine culture, and chest x-ray should be considered based on the clinical scenario.
  Note: Transfusion and hydroxyurea are not useful treatments for acute pain episodes (see Prevention of Primary Manifestations).
• Fever/suspected infection. Individuals with temperature greater than 38.3° C or persistent temperature elevation above baseline require:
  • Rapid triage and physical assessment;
  • Urgent CBC and reticulocyte count;
  • Blood culture (and other cultures as clinically indicated) and a low threshold for chest x-ray when respiratory symptoms are present, as ACS can often present with a normal physical examination;
  • Parenteral broad-spectrum empiric antibiotics such as ceftriaxone pending culture results. A macrolide antibiotic should be added if pneumonia/ACS is a concern. Additional antibiotics should be added only for proven or suspected meningitis or other severe illness.
  Note: With the changing natural history of fever and sepsis in individuals with SCD in the US there is increasing evidence that empiric treatment with parenteral antibiotics without obtaining cultures may be appropriate for well-appearing, fully immunized children with fever <39 C; however, this work has not yet been replicated nor has it become accepted practice [Baskin et al 2013, Ellison et al 2015].
• Acute chest syndrome (ACS). The index of suspicion for ACS should be high when individuals with SCD have fever, chest pain, or respiratory signs or symptoms. Given the high mortality associated with ACS, an aggressive multimodal treatment strategy should be initiated [Miller 2011]:
  • Perform chest x-ray examination.
  • Provide aggressive treatment with oxygen, analgesics, and antibiotics (including a macrolide).
  • Incentive spirometry should be encouraged.
  • Hypoxemia can progress to need for intubation and mechanical ventilatory support.
  • Blood transfusion may be required for those who are critically ill, have multilobar disease, or have progressive disease despite conservative therapy.
• Aplastic crisis. Monitoring of hematocrit (both absolute and compared with the individual's baseline), reticulocyte count, and cardiovascular status are required. Blood transfusion may be necessary. Aplastic crisis caused by parvovirus B19 will often spontaneously resolve; however, if the reticulocyte count does not improve, intravenous gamma-globulin can be considered to assist in viral clearance. Any sibs or other close contacts with SCD should be monitored for red blood cell aplasia because the parvovirus is easily transmissible.
• Splenic sequestration. Severe episodes of splenic sequestration may progress rapidly to cardiovascular collapse and death; thus, emergency red blood cell transfusion is indicated when signs of cardiovascular instability are present. Parents should be taught how to monitor for splenic enlargement and recognize symptoms of sequestration and when to seek medical attention. Individuals who experience multiple severe episodes of splenic sequestration may require splenectomy.
• Pulmonary hypertension. Diagnostic criteria, as well as when and how to intervene, are becoming increasingly controversial [Hassell et al 2014, Klings et al 2014a, Klings et al 2014b, Hebson et al 2015]. Existing consensus guidelines are not fully accepted by experts in the field. Thus, discussion with local sickle cell and pulmonary hypertension experts should be used to guide care. The following general approach is reasonable:
  • Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
  • Optimization of SCD-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, oxygen therapy if hypoxemic)
• Stroke. Any history of an acute neurologic symptom or event warrants emergent evaluation including a CBC with reticulocyte count and a non-contrast brain CT examination. Cerebral hemorrhage requires immediate neurosurgical consultation. An MRI/MRA to define injury should be obtained as soon as available, but definitive treatment with exchange transfusion should never be delayed for these results.
  Treatment for children with acute ischemic stroke includes the following:
  • Monitor neurologic status and aggressively treat increased intracranial pressure and seizures, if present.
  • Exchange transfusion with the goal of decreasing HbS percentage to <30% of the total hemoglobin followed by a chronic transfusion program can significantly decrease repeat risk for stroke [Wang et al 2000]. Without continued therapy, as many as 60%-90% of individuals who have had a stroke have a second stroke within three years. Thus, in most individuals a preventive chronic transfusion protocol is initiated after a CNS event and continued indefinitely [Adams & Brambilla 2005] (see Prevention of Primary Manifestations).
  • Hydroxyurea has been studied as an alternative to transfusion therapy [Ware & Helms 2012]. While it does not provide the same protection as transfusion therapy, it may be an alternative for affected individuals who are unable to receive transfusion therapy (e.g., those living in limiting resource settings such as the Third World) or are difficult to transfuse due to alloimmunization [de Montalembert 2012].
    Chronic transfusion has been shown to reduce silent infarcts; however, unlike for overt infracts, there is not a universally accepted consensus regarding the management of individuals with silent infarcts [DeBaun et al 2014, Estcourt et al 2017].
• Priapism. Episodes of severe priapism require urgent evaluation and treatment, including hydration and analgesia, and may require aspiration and irrigation by an urologist.

Prevention of Primary Manifestations

Ongoing education is essential to help minimize morbidity and mortality. Education comprises a regular review of interventions including the following:

• Maintaining hydration and avoiding extremes of climate
• Monitoring for signs and symptoms requiring acute medical intervention
• Early detection of chronic complications
• Updates on new therapies

Disease-modulating therapies are discussed in several reviews [Vichinsky 2012, Kassim & DeBaun 2013, Ware et al 2017].

Chronic red blood cell transfusion therapy. The initial goal of chronic red blood cell transfusion therapy varies depending on indication but typically is to maintain the percentage of HbS <30% and suppress reticulocytosis. Chronic red blood cell transfusion therapy may be warranted for the following [Yawn et al 2014, Howard 2016, Ware et al 2017]:

• Primary prevention of stroke in individuals with an abnormal transcranial Doppler
• Prevention of stroke recurrence
• Treatment of chronic pain refractory to other therapies
• Pulmonary hypertension
• Chronic renal failure
• Recurrent episodes of ACS
• Severe end-organ damage

Complications of chronic red blood cell transfusion therapy include: iron overload, alloimmunization, and, rarely, infection. To limit alloimmunization and transfusion reactions, extended matching of red blood cell antigens should be performed and blood products should be leuko-reduced (removal of white blood cells from the transfusion product). Red blood cells antigen matched at the full Rh locus (D, C, E) and Kell have been suggested to decrease alloimmunization rates, as well as other alleles when possible [Lasalle-Williams et al 2011]. Approaches to decrease alloimmunization in the future include obtaining a better understanding of the process of alloimmunization as well as molecular genotyping. Defining antigens molecularly has multiple benefits including the ability to type cells when serologic reagents are not available [Yazdanbakhsh et al 2012, Matteocci & Pierelli 2014].

Hydroxycarbamide (hydroxyurea), until recently the only FDA-approved therapy for SCD, is only approved for adults. Hydroxyurea benefits individuals with SCD via several mechanisms [Platt 2008, Ware 2010] including:

• Induction of HbF synthesis resulting in decreased sickling and improved red-cell survival;
• Reduction of white blood cell (WBC), reticulocyte and platelet counts;
• Metabolism into nitric oxide, a potent vasodilator;
• Overall improvement in blood flow;
• Reduction of vascular inflammation.

Multiple NIH consensus statements have noted strong evidence to support its routine use in adults [Brawley et al 2008, Yawn et al 2014]. It has been demonstrated that hydroxyurea therapy is safe to use in children as young as nine months with no decrease in immune function [Ware 2010, Rogers et al 2011, Wang et al 2011, Strouse & Heeney 2012, Lederman et al 2014]. It is now very strongly recommended that every individual with S/S and S/β⁰-thalassemia age nine months or older be offered treatment with hydroxyurea [Yawn et al 2014]. This early initiation decreases clinical events [Thornburg et al 2012]. In addition, use of hydroxyurea has been associated with a decrease in healthcare costs [Wang et al 2013].

Hydroxyurea can have potentially significant toxicity, including myelosuppression. Individuals treated with hydroxyurea must be monitored closely with CBCs and reticulocyte counts. In order to balance the benefits with potential toxicities of hydroxyurea, many suggest a careful titration of the drug to find a dosing for each affected person that provides an appropriate reduction in WBC count without toxicity [Ware 2010, Strouse & Heeney 2012, Yawn et al 2014].

Glutamine has just received FDA approval for the prevention of acute complications in individuals age five years and older with SCD, whether on hydroxyurea or not. Due to its antioxidant properties and in vitro activity, glutamine has long been considered of potential benefit in the treatment of SCD. Though not published, a multicenter placebo-controlled clinical trial suggests that chronic use of oral glutamine can decrease the frequency of sickle cell pain-related episodes (clinicaltrials.gov/ct2/show/NCT01179217). Having a second FDA-approved drug opens the door to combination therapy using multiple agents.

Stem cell transplantation from a healthy donor or one with sickle cell trait can be curative in individuals with SCD and while the number of matched-sib transplants continues to rise, there is rapid evolution in the use of alternate donors. Children with SCD receiving stem cell transplantation using a matched sib donor can expect a 92% chance of cure with an overall survival of 95%. [King & Shenoy 2014, Nickel et al 2014, Walters 2015]. These phenomenal outcomes are balanced by potential long-term consequences including chronic-graft-versus host disease and infertility. There is debate now as to who should be transplanted and when. Transplanting with a matched sib early in life can subvert a life of debilitating complications and decreasing end-organ function – the latter making transplant at a later age more difficult. Notably, pediatric providers may overly worry about the risks of transplant, while not appreciating the high morbidity of sickle cell disease manifestations in adulthood. However, the comparative long-term benefits of supportive care (including hydroxyurea and improvements in sickle cell management) versus transplantation are not yet known.

Despite the great successes associated with transplantation, it is estimated that fewer than 30% of individuals with SCD have suitable matched-sib donors, few have suitable matched unrelated donors, and transplant for adults with SCD has been far more difficult due to regime-related toxicity. The field of transplantation for SCD is currently undergoing rapid expansion. Thus, the use of alternate donors (including unrelated donors and haploidentical donors) and cord blood is an active area of research [Alfraih et al 2016, Arnold et al 2016, Walters et al 2016].

Initial myeloablative regimes yielded too much toxicity for older individuals with SCD; the recent development of less toxic transplant regimens makes stem cell transplantation a more acceptable option for older individuals [Tisdale et al 2013].

While unrelated cord blood transplants are falling out of favor due to the high rate of graft failure, there is an increased use and success of haploidentical transplants, vastly broadening the number of individuals who could potentially be cured [Gluckman 2013, Tisdale et al 2013, Walters 2015, Alfraih et al 2016, Arnold et al 2016].

Gene therapy. As all allogenic transplants for SCD present a risk for graft-versus-host disease, there has been an explosion of research in gene therapy for SCD. While both gene editing and gene addition approaches are being activity pursued, only viral mediated gene therapy approaches are being used in clinical trials [Goodman & Malik 2016, Cavazzana et al 2017].

The criteria, risks, and benefits of transplantation are changing rapidly; thus, it is important for families and providers to discuss the risks and benefits with a transplantation center with expertise in SCD.

Prevention of Secondary Complications

Newborn screening has made presymptomatic diagnosis possible, allowing for early, aggressive education on management issues, such as management of fevers. The use of prophylactic penicillin, immunization, and education emphasizing access to healthcare have significantly decreased morbidity and mortality in children, primarily by reducing deaths from sepsis.

Penicillin prophylaxis prevents 84% of life-threatening episodes of childhood Streptococcus pneumoniae sepsis [Gaston et al 1986]:

• By age two months, all infants with SCD should receive penicillin V potassium prophylaxis, 125 mg orally, twice a day.
• At age three years, the dose is increased to 250 mg orally, twice a day, and then continued until at least age five years.

Prophylaxis for those allergic to penicillin can include erythromycin or azithromycin but care should be taken to avoid medications that alter metabolism and increase the risk of prolonged QTc syndrome [Gerber et al 2009].

Immunizations. Timely administration of vaccines is essential. Clinicians should follow the recommended vaccine schedule for functionally asplenic individuals, which includes additional vaccines such as the 23-valent pneumococcal polysaccharide vaccine, and an altered schedule for meningococcal vaccines. Persons with sickle cell are considered high priority for annual influenza vaccine [Yawn et al 2014].

Folic acid supplementation should be considered to support the increased RBC synthesis secondary to the high RBC turnover in sickle cell.

Iron overload. Individuals receiving prophylactic as well as chronic transfusions are at risk for iron overload and should be monitored closely, initially by tracking the amount of blood transfused and monitoring serum ferritin concentration. Those with high exposures or documented iron overload should have an assessment of organ iron accumulation. With its increasing availability and safety and the ability to assess iron in multiple organs while avoiding sampling bias, quantitative radiographic evaluation such as T₂*-weighted MRI is increasingly replacing biopsy [Wood 2007]. The noninvasive nature of monitoring iron overload via MRI or SQUID has led to significant improvements in the outcome of individuals with iron overload [Coates 2014]. Both oral or subcutaneous iron chelation therapy are recommended for those with documented excessive tissue iron deposition, with patient acceptance and use of medications being the main limiting factor [Coates & Wood 2017].

Surveillance

Surveillance should be tailored to an individual's specific phenotype and clinical history; however, most individuals benefit from routine age-dependent screening to allow for early detection and treatment of end-organ damage [NHS 2010, Yawn et al 2014]. The following are general guidelines compiled from several sources. Recently NHLBI has released updated guidelines that readers are encouraged to review. See Published Guidelines/Consensus Statements.

Comprehensive medical and social evaluation. Affected individuals should be seen routinely for evaluation of risks, review of care plan, education, and assessment of growth and development. Social work assessment with emphasis on support, resources, and the impact of disease on lifestyle should be performed. Routine dental care is recommended.

Mental health and neurocognitive assessment. Periodic mental health screening for signs of depression, anxiety, and isolation should occur. Neurocognitive testing should be performed prior to school entry and repeated periodically to identify learning difficulties that may be related to silent cerebral infarcts as well as other factors.

Annual laboratory assessment should include the following:

• CBC with differential and reticulocyte count
• Assessment of iron status
• Liver function tests (LFTs), BUN, serum creatinine, and urinalysis (UA)
• LDH as a marker of hemolysis
• Vitamin D level; may be indicated because of the high prevalence of deficiencies in this population

Baseline values should be given to parents for comparison during times of illness.

Extended red cell phenotyping should be done once to decrease risk of alloimmunization with transfusions.

Assessment of stroke risk. Historically more than 10% of young children with Hb S/S and Hb S/β°-thalassemia (as well as some others) had overt strokes. Yearly screening with transcranial Doppler (TCD) starting at age two years followed by initiation of chronic therapy for those with high-velocity blood flow has drastically decreased stroke incidence in SCD [Fullerton et al 2004]. Individuals with an abnormally high arterial blood flow velocity have a high rate of stroke, which can be prevented by chronic red blood cell transfusion therapy. Children with normal velocities require yearly reevaluation as a proportion of them convert to higher-risk velocities over time [Adams et al 2004]. Initial studies suggest that this approach is decreasing the incidence of overt stroke in individuals with SCD, but additional measure may be of benefit as well [Fullerton et al 2004, Jordan et al 2012, Webb & Kwiatkowski 2013].

End-organ evaluation. While there is a clear consensus for use of screening TCD starting at age two years through at least age 16 years, there is variability in recommendations for additional screening. The NHLBI [Yawn et al 2014] suggests screening for a proliferative retinopathy by an ophthalmologist starting age ten years, and additional screening based on clinical history that may include:

• Chest x-ray examination
• ECG
• Pulmonary function tests (PFTs)
• Abdominal ultrasound examination
• Echocardiogram to determine the tricuspid regurgitant (TR) jet with consideration of right heart catheterization depending on symptoms
• Six-minute walk test
• Pulmonary function testing
• Sleep study (to assess nighttime hypoxemia)
• Iron overload by MRI

Agents/Circumstances to Avoid

Education for individuals with SCD involves learning how to control one's environment to minimize the chance of exacerbations. Environmental controls include avoiding the following:

• Dehydration
• Extremes of temperature (e.g., swimming in cold water, which can trigger a pain episode)
• Physical exhaustion
• Extremely high altitude without oxygen supplementation
• Cocaine. While alcohol and illegal drugs are never endorsed, cocaine and its derivatives, with their vasoconstrictive and cardiac stimulation effects, are particularly dangerous drugs in the setting of SCD.
• The analgesic meperidine, which should be avoided as first-line therapy because of potential CNS toxicity

Evaluation of Relatives at Risk

Early diagnosis of at-risk family members may allow intervention before symptoms are present.

If born in the United States, sibs affected with SCD are diagnosed by universal newborn screening soon after birth (at which time referral to a pediatric hematologist is appropriate). Many states also identify sickle cell trait on newborn screening.

If newborn screening data is not available for at-risk sibs, several diagnostic approaches can be considered.

• If the HBB pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known, the gold standard is a combination of HPLC or isoelectric focusing combined with a CBC and reticulocyte count. As microcytosis helps guide interpretation of results, a measure of iron status such as a ZPP (zinc protoporphyrin) test or serum iron and TIBC (total iron binding capacity) is of benefit.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy complications in SCD can be minimized with close follow up and collaboration between hematology and obstetric teams [Naik & Lanzkron 2012]. Pregnancy in women with SCD involves increased risk for thrombosis, infectious complications, and acute painful episodes [Villers et al 2008, Naik & Lanzkron 2012, Alayed et al 2014, Costa et al 2015]. There is conflicting information as to whether the risks for preeclampsia, eclampsia, pre-term labor, and maternal death are increased [Villers et al 2008, Naik & Lanzkron 2012, Alayed et al 2014, Costa et al 2015]. The risk of pregnancy complications increases when access to prenatal care is limited, reinforcing the importance of close hematologic and obstetric follow up [Naik & Lanzkron 2012]. The benefits of a chronic transfusion program versus the use of "as-needed" transfusions has not been established [Okusanya and Oladapo 2016]. As hydroxyurea is recommended for (and increasingly used in) adults, the current recommendation is that it be discontinued during pregnancy. While reports of human infants exposed prenatally to hydroxyurea have not noted an increased risk of malformations, in experimental animal models hydroxyurea has been noted to lead to an increase in congenital anomalies. The role of chronic transfusions in lieu of hydroxyurea needs to be addressed.

More than 99% of births to women with SCD occurring after 28 weeks’ gestation are live births with normal Apgar scores [Smith et al 1996]. Several studies have reported increased rates of low birth weight and intrauterine growth retardation in babies born to women with SCD [Hassell 2005]. Attention to postnatal opiate withdrawal in the babies of mothers treated with high-dose opiates during pregnancy is warranted.

Infants with SCD are asymptomatic in the antenatal, perinatal, and immediate postnatal periods; they manifest disease symptoms when fetal hemoglobin production switches to adult hemoglobin.

Therapies Under Investigation

Currently only one drug – hydroxyurea – is FDA approved for SCD, and labeling does not include children. After decades of slow progress in the field, acknowledgment of the plethora of pathways modulating the severity of SCD has led to a diverse array of therapeutic agents that are being investigated [Archer et al 2015, Kato 2016].

Some examples emphasizing the diverse array of involved pathways and agents are listed below. The field is changing rapidly; refer to ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for the status of current studies.

Prevention of HbS polymerization. Hemoglobin S polymerizes in the T (tense) conformation associated with de-oxygenation, but not the R (relaxed) conformation associated with oxygenation. Thus, small molecules that block the T-state or stabilize the R-state are being assessed in clinical trials [Oder et al 2016].

Decreasing adhesion to the endothelium. Adhesion of WBC to the endothelium of the microcirculation slows blood flow, increasing HbS polymerization and worsening SCD. Agents that decrease cell adherence without compromising immune function are being pursued. E- and P-selectin specific agents are being tested with one showing promising results in a Phase III trial [Zhang et al 2016, Ataga et al 2017].

• Modifying inflammatory responses. Regadenoson is an adenosine A2A receptor agonist that modifies natural killer cell activity and has shown benefit in animal models. It has been evaluated in a Phase I study and a Phase II clinical trial is under way [Field et al 2013].
• Antioxidants therapy. Multiple antioxidants are being studied. One, glutamine, is a key factor in determining red cell red-ox state and its level has been a marker of disease severity [Morris et al 2008b]. Results for a Phase III clinical trial of glutamine supplementation are pending.
• Rejuvenation of nitric oxide (NO) stores. Arginine, the precursor of NO, has been studied in several contexts and a Phase II clinical trial has shown benefit in hospitalized people with sickle cell pain [Morris et al 2013]. As a result, arginine has been featured in multiple clinical trials.
• Induction of fetal hemoglobin. Multiple pathways and factors associated with the high-level expression of the fetal hemoglobin genes (HBG1 and HBG2) have been identified and are currently targets for intervention [Perrine et al 2014, Lettre & Bauer 2016]. Representative pathways include LSD-1 inhibitors [Shi et al 2013, Cui et al 2015], thalidomide inhibitors (e.g., pomolidomide) [Dulmovits et al 2016], nuclear factor erythroid 2-related factor 2 inhibitors (e.g., tert-butylhydroquinone) [Macari & Lowrey 2011, Macari et al 2013], HDAC inhibitors [Okam & Ebert 2012], short-chain fatty acids (e.g., butyrate or valproic acid), and antimetabolites (e.g., 2’ deoxy 5’ azacytidine [decitabine]) [Saunthararajah et al 2008]. A promising approach to therapy is the development of inhibitors to the protein Bcl11a. Bcl11a was identified as an HbF cell quantitative trait locus in a genome-wide association study [Menzel et al 2007]. Since then it has been shown to bind within the β-globin locus and to be critical for suppressing fetal globin gene expression in adult erythroid cells [Sankaran et al 2008, Sankaran et al 2010]. Knockdown or knockout of Bcl11a in model systems, as well as naturally occurring deletions that remove its binding site in humans, result in substantial increases in HbF. These elevated levels of HbF provide therapeutic benefits to individuals with both SCD and thalassemia [Sankaran et al 2011, Wilber et al 2011, Xu et al 2011]. Multiple approaches are being taken to inhibit Bcl11a function in vivo, including gene editing to disrupt the erythroid-specific enhancer of Bcl11a [Lettre & Bauer 2016].
• Phytomedicines, including some mixtures of plants, are under investigation. There are initial promising safety and efficacy data for Niprisan^® and SCD-101 [Oniyangi & Cohall 2015].

Gene therapy. As SCD arises from a defined single-nucleotide substitution in the β-globin gene whose expression is restricted to erythroid cells derived from bone marrow hematopoietic stem cells, SCD is an ideal candidate for gene therapy. Gene therapy provides the benefit of stem cell transplantation, but without the problems associated with the use of an allogenic source of stem cells. Ideally, gene therapy would lead to an increase in non-sickle β-like chains, while lowering the number of sickle chains, for example by replacing the HbS pathogenic variant (p.Glu6Val) with a normal allele.

The most progress has been made using viral vector-mediated addition of a normal β-like gene, potentially modified to have additional anti-sickling properties. This leaves the endogenous sickle allele intact. While multiple groups are moving towards these gene addition clinical trials, to date only one individual is reported to have been cured [Cavazzana et al 2017, Ribeil et al 2017]. The status of these trials is changing rapidly; refer to ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for the most up-to-date information.

Multiple gene therapy strategies that do not involve the addition of an additional, therapeutic globin gene are being pursued. A major obstacle to the above gene addition approaches is the requirement for long-term, high-level expression of the therapeutic gene, which requires the inclusion of large amounts of the major regulatory element, the locus control region. In contrast, these approaches involve the transduction and stable integration of therapeutic reagent for which low-level expression suffices. These include:

• Using transactivators to stimulate the minimally expressed delta gene or the fetal or embryonic genes;
• Inducing embryonic α-like chains that, when forming tetramers with sickle chains, are less likely to polymerize;
• Decreasing Bcl11a expression whether by knocking out erythroid regulatory elements or binding sites, knocking down mRNA, or altering protein interactions; and
• Inducing "looping" between the locus control region and the fetal globin genes resulting in activation of HbF.

Some of the above approaches have the additional benefit of reducing expression of the sickle gene while increasing expression of a therapeutic gene. However, they require long-term expression, typically from a viral vector integrated into the genome, leading to the very real risk of severe sequelae, such as leukemia, stemming from insertional mutagenesis [Cavazza et al 2013]. These detriments of routine gene therapy are avoided by "gene editing." As multiple techniques to modify the human genome with base pair accuracy are becoming increasingly easy and efficient, gene editing approaches are being aggressively pursued [Scharenberg et al 2013, Kim & Kim 2014]. Gene editing typically entails the generation of a break in the DNA at or near the site of interest and the presence of a "corrective template." Fortuitously, the cell’s endogenous DNA repair machinery inadvertently uses the therapeutic template when repairing the DNA, resulting in the incorporation of the corrective sequence. Gene editing is a "hit and run" approach, as it can be performed with the transient expression of the editing tools, thus avoiding the need for long-term expression as well as the risk for insertional mutagenesis, yet providing lifelong correction of the DNA. Two major approaches are being taken: removal of the sickle pathogenic variant and replacement with a normal sequence; and disruption of regulators of globin gene expression – such as Bcl11a, which in turn results in increased expression of the fetal genes. As this can be done in hematopoietic as well as induced pleuripotent stem cells, gene editing is the future of gene therapy.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.