Sickle cell disease (SCD) and its variants are genetic disorders resulting from the presence of a mutated form of hemoglobin, hemoglobin S (HbS) ^[1,2](see the image below). The most common form of SCD in North America is homozygous HbS disease (HbSS), an autosomal recessive disorder most oftren found in people of African and Mediterranean ancestry (seePathophysiology). SCD causes significant morbidity and mortality, although the severity, frequency of crisis, degree of anemia, and organ systems involved vary considerably from individual to individual.

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Signs and symptoms

Screening for HbS at birth is currently mandatory in the United States. For the first 6 months of life, infants are protected largely by elevated levels of fetal hemoglobin (HbF). SCD usually manifests early in childhood, in the following ways:

• Acute and chronic pain: Vaso-occlusive crisis; pain crises are Tthe most common clinical manifestation of SCD and the most distinguishing clinical feature of the disease

• Bone pain: Often seen in long bones of extremities, primarily due to bone marrow infarction

• Anemia: Universally present, chronic, and hemolytic in nature

• Aplastic crisis: Serious complication due to infection with parvovirus B19 (B19V)

• Splenic sequestration: Characterized by the onset of life-threatening anemia with rapid enlargement of the spleen and high reticulocyte count

• Infection: Organisms that pose the greatest danger include encapsulated respiratory bacteria, particularlyStreptococcus pneumoniae; adult infections are predominantly with gram-negative organisms, especiallySalmonella

• Growth retardation, delayed sexual maturation, being underweight

• Hand-foot syndrome: This is a dactylitis presenting as bilateral painful and swollen hands and/or feet in children

• Acute chest syndrome: Young children present with chest pain, fever, cough, tachypnea, leukocytosis, and pulmonary infiltrates in the upper lobes; adults are usually afebrile, dyspneic with severe chest pain, with multilobar/lower lobe disease

• Pulmonary hypertension: Increasingly recognized as a serious complication of SCD

• Avascular necrosis of the femoral or humeral head: Due to vascular occlusion

• Central nervous system (CNS) involvement: Most severe manifestation is stroke

• Ophthalmologic involvement: Ptosis, retinal vascular changes, proliferative retinitis

• Cardiac involvement: Dilation of both ventricles and the left atrium

• Gastrointestinal involvement: Cholelithiasis is common in children; liver may become involved

• Genitourinary involvement: Kidneys lose concentrating capacity; priapism is a well-recognized complication of SCD

• Dermatologic involvement: Leg ulcers are a chronic painful problem

Approximately half the individuals with homozygous HbS disease experience vaso-occlusive crises. The frequency of crises is extremely variable. Some individuals have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or have none at all. Each individual typically has a consistent pattern for crisis frequency. Triggers of vaso-occlusive crisis include the following:

• Hypoxemia: May be due to acute chest syndrome or respiratory complications
• Dehydration: Acidosis results in a shift of the oxygen dissociation curve
• Changes in body temperature (eg, an increase due to fever or a decrease due to environmental temperature change)

Many individuals with HbSS experience chronic low-level pain, mainly in bones and joints. Intermittent vaso-occlusive crises may be superimposed, or chronic low-level pain may be the only expression of the disease.

SeePresentation for more detail.

Diagnosis

SCD is suggested by the typical clinical picture of chronic hemolytic anemia and vaso-occlusive crisis. Electrophoresis confirms the diagnosis with the presence of homozygous HbS and can also document other hemoglobinopathies (eg, HbSC, HbS-beta+ thalassemia).

Laboratory tests used in patients with SCD include the following:

• Mandatory screening for HbS at birth in the United States; prenatal testing can be obtained via chorionic villus sampling
• Hemoglobin electrophoresis
• CBC with differential and reticulocyte count
• Serum electrolytes
• Hemoglobin solubility testing
• Peripheral blood smear
• Pulmonary function tests (transcutaneous O₂ saturation)
• Kidney function (creatinine, BUN, urinalysis)
• Hepatobiliary function tests, (ALT, fractionated bilirubin)
• CSF examination: Consider lumbar puncture in febrile children who appear toxic and in those with neurologic findings (eg, neck stiffness, positive Brudzinski/Kernig signs, focal deficits); consider CT scanning before performing lumbar puncture
• Blood cultures
• Arterial blood gases
• Secretory phospholipase A2 (sPLA2)

Imaging studies

Imaging studies that aid in the diagnosis of sickle cell anemia in patients in whom the disease is suggested clinically include the following:

• Radiography: Chest x-rays should be performed in patients with respiratory symptoms

• MRI: Useful for early detection of bone marrow changes due to acute and chronic bone marrow infarction, marrow hyperplasia, osteomyelitis, and osteonecrosis

• CT scanning: May demonstrate subtle regions of osteonecrosis not apparent on plain radiographs in patients who are unable to have an MRI ^[3]and to exclude renal medullary carcinoma in patients presenting with hematuria

• Nuclear medicine scanning:^99mTc bone scanning detects early stages of osteonecrosis; ¹¹¹In WBC scanning is used for diagnosing osteomyelitis

• Transcranial Doppler ultrasonography: Can identify children with SCD at high risk for stroke

• Abdominal ultrasonography: May be used to rule out cholecystitis, cholelithiasis, or an ectopic pregnancy and to measure spleen and liver size

• Echocardiography: Identifies patients with pulmonary hypertension

• Transcranial near-infrared spectroscopy or cerebral oximetry: Can be used to screen for low cerebral venous oxygen saturation in children with SCD

SeeWorkup for more detail.

Management

The goals of treatment in SCD are symptom control and management of disease complications. Treatment strategies include the following 7 goals:

• Management of vaso-occlusive crisis
• Management of chronic pain syndromes
• Management of chronic hemolytic anemia
• Prevention and treatment of infections
• Management of the complications and the various organ damage syndromes associated with the disease
• Prevention of stroke
• Detection and treatment of pulmonary hypertension

Pharmacotherapy

SCD may be treated with the following medications:

• Antimetabolites: Hydroxyurea
• P-selectin inhibitors (eg, crizanlizumab)
• Opioid analgesics (eg, oxycodone/aspirin, methadone, morphine sulfate, oxycodone/acetaminophen, fentanyl, nalbuphine, codeine, acetaminophen/codeine)
• Nonsteroidal analgesics (eg, ketorolac, aspirin, acetaminophen, ibuprofen)
• Tricyclic antidepressants (eg, amitriptyline)
• Antibiotics (eg, cefuroxime, amoxicillin/clavulanate, penicillin VK, ceftriaxone, azithromycin, cefaclor)
• Vaccines (eg, pneumococcal, meningococcal, influenza, and recommended scheduled childhood/adult vaccinations)
• Endothelin-1 receptor antagonists (eg, bosentan)
• Phosphodiesterase inhibitors (eg, sildenafil, tadalafil)
• Vitamins (eg, folic acid)
• L-glutamine
• Antiemetics (eg, promethazine)

Gene therapy

The following two therapies involve editing of a patient's own hematopoietic stem cells:

• Exagamglogene autotemcel – Results in high levels of HbF in RBCs
• Lovotibeglogene autotemcel – Adds functional copies of a modified form of the beta-globin gene, which codes for anti-sickling hemoglobin (HbAT87Q)

Other therapy

Additional approaches to managing SCD include the following:

• Stem cell transplantation: Can be curative
• Transfusions: For sudden, severe anemia due to acute splenic sequestration, parvovirus B19 infection, or hyperhemolytic crises
• Wound debridement
• Physical therapy
• Heat and cold application
• Acupuncture and acupressure
• Transcutaneous electric nerve stimulation (TENS)

Combination pharmacotherapy and non-pharmacotherapy

• Vigorous hydration (plus analgesics): For vaso-occlusive crisis
• Oxygen, antibiotics, analgesics, incentive spirometry, simple transfusion, and bronchodilators: For treatment of acute chest syndrome

SeeTreatment andMedication for more detail.

Carriers of the sickle cell trait (ie, heterozygotes who carry one HbS allele and one normal adult hemoglobin [HbA] allele) have some resistance to the often-fatalmalaria caused byPlasmodium falciparum. This property explains the distribution and persistence of this gene in the population in malaria-endemic areas. ^[4,5,6]

However, in areas such as the United States, where malaria is not a problem, the trait no longer provides a survival advantage. Instead, it poses the threat of SCD, which occurs in children of carriers who inherit the sickle cell gene from both parents (ie, HbSS).

Although carriers of sickle cell trait do not suffer from SCD, individuals with one copy of HbS and one copy of a gene that codes for another abnormal variant of hemoglobin, such as HbC or Hb beta-thalassemia, have a less severe form of the disease.

SCD denotes all genotypes containing at least one sickle gene, in which HbS makes up at least half the hemoglobin present. Major sickle genotypes described so far include the following:

• HbSS disease or sickle cell anemia (the most common form) - Homozygote for the S globin with usually a severe or moderately severe phenotype and with the shortest survival

• HbS/b-0 thalassemia - Double heterozygote for HbS and b-0 thalassemia; clinically indistinguishable from sickle cell anemia

• HbS/b+ thalassemia - Mild-to-moderate severity with variability in different ethnicities

• HbSC disease - Double heterozygote for HbS and HbC characterized by moderate clinical severity

• HbS/hereditary persistence of fetal Hb (S/HPHP) - Very mild or asymptomatic phenotype

• HbS/HbE syndrome - Very rare with a phenotype usually similar to HbS/b+ thalassemia

• Rare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia, HbO Arab, and others

Sickle cell trait or the carrier state is the heterozygous form characterized by the presence of around 40% HbS, absence of anemia, inability to concentrate urine (isosthenuria), and hematuria. Under conditions leading to hypoxia, it may become a pathologic risk factor.

SCD is the most severe and most common form. Affected individuals present with a wide range of clinical problems that result from vascular obstruction and ischemia. Although the disease can be diagnosed at birth, clinical abnormalities usually do not occur before age 6 months, when functional asplenia develops. Functional asplenia results in susceptibility to overwhelming infection with encapsulated bacteria. Subsequently, other organs are damaged. Typical manifestations include recurrent pain and progressive incremental infarction.

Newborn screening for sickle hemoglobinopathies is mandated in 50 states. Therefore, most patients presenting to the emergency department have a known diagnosis.

HbS arises from a mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG. This causes coding of valine instead of glutamate in position 6 of the Hb beta chain. The resulting Hb has the physical property of forming polymers under deoxy conditions. It also exhibits changes in solubility and molecular stability. These properties are responsible for the profound clinical expressions of the sickling syndromes.

Under deoxy conditions, HbS undergoes marked decrease in solubility, increased viscosity, and polymer formation at concentrations exceeding 30 g/dL. It forms a gel-like substance containing Hb crystals called tactoids. The gel-like form of Hb is in equilibrium with its liquid-soluble form. A number of factors influence this equilibrium, including oxygen tension, concentration of Hb S, and the presence of other hemoglobins.

Oxygen tension is a factor in that polymer formation occurs only in the deoxy state. If oxygen is present, the liquid state prevails. Concentration of Hb S is a factor in that gelation of HbS occurs at concentrations greater than 20.8 g/dL (the normal cellular Hb concentration is 30 g/dL). The presence of other hemoglobins is a factor in that normal adult hemoglobin (HbA) and fetal hemoglobin (HbF) have an inhibitory effect on gelation.

These and other Hb interactions affect the severity of clinical syndromes. HbSS produces a more severe disease than sickle cell HbC (HbSC), HbSD, HbSO Arab, and Hb with one normal and one sickle allele (HbSA).

When red blood cells (RBCs) containing homozygous HbS are exposed to deoxy conditions, the sickling process begins. A slow and gradual polymer formation ensues. Electron microscopy reveals a parallel array of filaments. Repeated and prolonged sickling involves the membrane; the RBC assumes the characteristic sickled shape. (See image below.)

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After recurrent episodes of sickling, membrane damage occurs and the cells are no longer capable of resuming the biconcave shape upon reoxygenation. Thus, they become irreversibly sickled cells (ISCs). From 5-50% of RBCs permanently remain in the sickled shape.

When RBCs sickle, they gain Na⁺ and lose K⁺. Membrane permeability to Ca⁺⁺ increases, possibly due, in part, to impairment in the Ca⁺⁺ pump that depends on adenosine triphosphatase (ATPase). The intracellular Ca⁺⁺ concentration rises to 4 times the reference level. The membrane becomes more rigid, possibly due to changes in cytoskeletal protein interactions; however, these changes are not found consistently. In addition, whether calcium is responsible for membrane rigidity is not clear.

Membrane vesicle formation occurs, and the lipid bilayer is perturbed. The outer leaflet has increased amounts of phosphatidyl ethanolamine and contains phosphatidylserine. The latter may play a role as a contributor to thrombosis, acting as a catalyst for plasma clotting factors. Membrane rigidity can be reversed in vitro by replacing HbS with HbA, suggesting that HbS interacts with the cell membrane.

Interactions with vascular endothelium

Complex multifactorial mechanisms involving endothelial dysfunction underlie the acute and chronic manifestations of SCD. ^[7]A current model proposes that vaso-occlusive crises in SCD result from adhesive interactions of sickle cell RBCs and leukocytes with the endothelium. ^[8]

In this model, the endothelium becomes activated by sickle cell RBCs, either directly, through adhesion molecules on the RBC surface, or indirectly through plasma proteins (eg, thrombospondin, von Willebrand factor) that act as a soluble bridge molecule. This leads, sequentiallly, to recruitment of adherent leukocytes, activation of recruited neutrophils and of other leukocytes (eg, monocytes or natural killer T cells), interactions of RBCs with adherent neutrophils, and clogging of the vessel by cell aggregates composed of RBCs, adherent leukocytes, and possibly platelets. ^[8]

Sickle cells express very late antigen–4 (VLA-4) on the surface. VLA-4 interacts with the endothelial cell adhesive molecule, vascular cell adhesive molecule–1 (VCAM-1). VCAM-1 is upregulated by hypoxia and inhibited by nitric oxide.

Hypoxia also decreases nitric oxide production, thereby adding to the adhesion of sickle cells to the vascular endothelium. Nitric oxide is a vasodilator. Free Hb is an avid scavenger of nitric oxide. Because of the continuing active hemolysis, there is free Hb in the plasma, and it scavenges nitric oxide, thus contributing to vasoconstriction.

In addition to leukocyte recruitment, inflammatory activation of endothelium may have an indispensable role in enhanced sickle RBC–endothelium interactions. Sickle RBC adhesion in postcapillary venules can cause increased microvascular transit times and initiate vaso-occlusion.

Several studies have shown involvement of an array of adhesion molecules expressed on sickle RBCs, including CD36, a-4-ß-1 integrin, intercellular cell adhesion molecule–4 (ICAM-4), and basal cell adhesion molecule (B-CAM). ^[9]Adhesion molecules (ie, P-selectin, VCAM-1, a-V-ß-3 integrin) are also expressed on activated endothelium. Finally, plasma factors and adhesive proteins (ie, thrombospondin [TSP], von Willebrand factor [vWf], laminin) play an important role in this interaction.

For example, the induction of VCAM-1 and P-selectin on activated endothelium is known to enhance sickle RBC interactions. In addition, a-V-ß-3 integrin is upregulated in activated endothelium in patients with sickle cell disease. a-V-ß-3 integrin binds to several adhesive proteins (TSP, vWf, red-cell ICAM-4, and, possibly, soluble laminin) involved in sickle RBC adhesion, and antibodies to this integrin dramatically inhibit sickle RBC adhesion.

In addition, under inflammatory conditions, increased leukocyte recruitment in combination with adhesion of sickle RBCs may further contribute to stasis.

Sickle RBCs adhere to endothelium because of increased stickiness. The endothelium participates in this process, as do neutrophils, which also express increased levels of adhesive molecules.

Deformable sickle cells express CD18 and adhere abnormally to endothelium up to 10 times more than normal cells, while ISCs do not. As paradoxical as it might seem, individuals who produce large numbers of ISCs have fewer vaso-occlusive crises than those with more deformable RBCs.

Other properties of sickle cells

Sickle RBCs also adhere to macrophages. This property may contribute to erythrophagocytosis and the hemolytic process.

The microvascular perfusion at the level of the pre-arterioles is influenced by RBCs containing Hb S polymers. This occurs at arterial oxygen saturation, before any morphologic change is apparent.

Hemolysis is a constant finding in sickle cell syndromes. Approximately one third of RBCs undergo intravascular hemolysis, possibly due to loss of membrane filaments during oxygenation and deoxygenation. The remainder hemolyze by erythrophagocytosis by macrophages. This process can be partially modified by Fc (crystallizable fragment) blockade, suggesting that the process can be mediated by immune mechanisms.

Sickle RBCs have increased immunoglobulin G (IgG) on the cell surface. Vaso-occlusive crisis is often triggered by infection. Levels of fibrinogen, fibronectin, and D-dimer are elevated in these patients. Plasma clotting factors likely participate in the microthrombi in the pre-arterioles.

Development of clinical disease

Although hematologic changes indicative of SCD are evident as early as the age of 10 weeks, symptoms usually do not develop until the age of 6-12 months because of high levels of circulating fetal hemoglobin. After infancy, erythrocytes of patients with SCD contain approximately 90% hemoglobin S (HbS), 2-10% hemoglobin F (HbF), and a normal amount of minor fraction of adult hemoglobin (HbA2). Adult hemoglobin (HbA), which usually gains prominence at the age of 3 months, is absent.

The physiologic changes in RBCs result in a disease with the following cardinal signs:

• Hemolytic anemia
• Painful vaso-occlusive crisis
• Multiple organ damage from microinfarcts, including heart, skeleton, spleen, and central nervous system

Silent cerebral infarcts are associated with cognitive impairment in SCD. These infarcts tend to be located in the deep white matter where cerebral blood flow is low. ^[10] However, cognitive impairment, particularly slower processing speed, may occur independent of the presence of infarction and may worsen with age. ^[11]

Musculoskeletal manifestations

The skeletal manifestations of SCD result from changes in bone and bone marrow caused by chronic tissue hypoxia, which is exacerbated by episodic occlusion of the microcirculation by the abnormal sickle cells. The main processes that lead to bone and joint destruction in sickle cell disease are as follows:

• Infarction of bone and bone marrow
• Compensatory bone marrow hyperplasia
• Secondaryosteomyelitis
• Secondary growth defects

When the rigid erythrocytes jam in the arterial and venous sinusoids of skeletal tissue, the result is intravascular thrombosis, which leads to infarction of bone and bone marrow. Repeated episodes of these crises eventually lead to irreversible bone infarcts andosteonecrosis, especially in weight-bearing areas. These areas of osteonecrosis (avascular necrosis/aseptic necrosis) become radiographically visible as sclerosis of bone with secondary reparative reaction and eventually result in degenerative bone and joint destruction.

Infarction tends to occur in the diaphyses of small tubular bones in children and in the metaphyses and subchondrium of long bones in adults. Because of the anatomic distribution of the blood vessels supplying the vertebrae, infarction affecting the central part of the vertebrae (fed by a spinal artery branch) results in the characteristicH vertebrae of SCD (steplike endplate depression; also known as the Reynold sign or codfish vertebrae). The outer portions of the plates are spared because of the numerous apophyseal arteries.

Osteonecrosis of the epiphysis of the femoral head is often bilateral and eventually progresses to collapse of the femoral heads. This same phenomenon is also seen in the humeral head, distal femur, and tibial condyles.

In summary, infarction of bone and bone marrow in patients with SCD can lead to the following changes (see images below):

• Osteolysis (in acute infarction)
• Osteonecrosis (avascular necrosis/aseptic necrosis)
• Articular disintegration
• Myelosclerosis
• Periosteal reaction (unusual in the adult)
• H vertebrae
• Dystrophic medullary calcification
• Bone-within-bone appearance

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The shortened survival time of the erythrocytes in SCD (10-20 days) leads to a compensatory marrow hyperplasia throughout the skeleton. The bone marrow hyperplasia has the resultant effect of weakening the skeletal tissue by widening the medullary cavities, replacing trabecular bone and thinning cortices.

Deossification due to marrow hyperplasia can bring about the following changes in bone:

• Decreased density of the skull
• Decreased thickness of the outer table of the skull due to widening of diploe
• Hair-on-end striations of the calvaria
• Osteoporosis sometimes leading to biconcave vertebrae, coarsening of trabeculae in long and flat bones, and pathologic fractures

In SCD, the abnormal maturation of bone can result in a variety of growth effects, such as the following

• Bone shortening (premature epiphyseal fusion)
• Epiphyseal deformity with cupped metaphysis
• Peg-in-hole defect of distal femur
• Decreased height of vertebrae (short stature and kyphoscoliosis)

Go toSkeletal Sickle Cell Anemia for complete information on this topic.

SCD can result in significant skeletal muscle remodeling and reduced muscle functional capacities, which contribute to exercise intolerance and poor quality of life. ^[12]In addition, changes in muscle and joints can result in altered posture and impaired balance control. ^[13]

Pulmonary hypertension

Blood entering the pulmonary circulation is deoxygenated, resulting in a high degree of polymer formation. The lungs develop areas of microinfarction and microthrombi that hinder the flow of blood. The resulting areas that lack oxygenation aggravate the sickling process. Pulmonary hypertension may develop. This may be due in part to the depletion of nitric oxide.

 Additional factors contributing to pulmonary hypertension include the following:

• Older age
• Kidney insufficiency
• Cardiovascular disease
• Cholestatic hepatopathy
• Systolic hypertension
• High hemolytic markers
• Iron overload
• History of priapism

Renal manifestations

Renal manifestations of SCD range from various functional abnormalities to gross anatomic alterations of the kidneys. SeeRenal Manifestations of Sickle Cell Disease for more information on this topic.

Splenic manifestations

The spleen enlarges in the latter part of the first year of life in children with SCD. Occasionally, the spleen undergoes a sudden very painful enlargement due to pooling of large numbers of sickled cells. This phenomenon is known as splenic sequestration crisis.

The spleen undergoes repeated infarction, aided by low pH and low oxygen tension in the sinusoids and splenic cords. Despite being enlarged, its function is impaired, as evidenced by its failure to take up technetium during nuclear scanning.

Over time, the spleen becomes fibrotic and shrinks. This is, in fact, an autosplenectomy. The nonfunctional spleen is a major contributor to the immune deficiency that exists in these individuals. Failure of opsonization and an inability to deal with infective encapsulated microorganisms, particularlyStreptococcus pneumoniae, ensue, leading to an increased risk of sepsis in the future.

Chronic hemolytic anemiaand vasculopathy

The anemia in SCD is a form of hemolytic anemia, with red cell survival of around 10-20 days. Approximately one third of the hemolysis occurs intravascularly, releasing free hemoglobin (plasma free hemoglobin [PFH]) and arginase into plasma. PFH has been associated with endothelial injury including scavenging nitric oxide (NO), proinflammatory stress, and coagulopathy, resulting in vasomotor instability and proliferative vasculopathy.

A hallmark of this proliferative vasculopathy is the development of pulmonary hypertension in adulthood. Plasma arginase degrades arginine, the substrate for NO synthesis, thereby limiting the expected compensatory increase in NO production and resulting in generation of oxygen radicals. Plasma arginase is also associated withpulmonary hypertension and risk of early mortality.

Infection

Life-threatening bacterial infections are a major cause of morbidity and mortality in persons with SCD. Recurrent vaso-occlusion induces splenic infarctions and consequent autosplenectomy, predisposing to severe infections with encapsulated organisms (eg,Haemophilus influenzae, Streptococcus pneumoniae).

Lower serum immunoglobulin M (IgM) levels, impaired opsonization, and sluggish alternative complement pathway activation further increase susceptibility to other common infectious agents, includingMycoplasma pneumoniae,Salmonella typhimurium,Staphylococcus aureus, andEscherichia coli. Common infections include pneumonia, bronchitis, cholecystitis, pyelonephritis, cystitis, osteomyelitis, meningitis, and sepsis.

Pneumococcal sepsis continues to be a major cause of death in infants in some countries.Parvovirus B19 infection causes aplastic crises.

SCD originated in West Africa, where it has the highest prevalence. It is also present to a lesser extent in India and the Mediterranean region. DNA polymorphism of the beta S gene suggests that it arose from five separate mutations: four in Africa and one in India and the Middle East. The most common of these is an allele found in Benin in West Africa. The other haplotypes are found in Senegal and Bantu, Africa, as well as in India and the Middle East.

The HbS gene, when present in homozygous form, is an undesirable mutation, so a selective advantage in the heterozygous form must account for its high prevalence and persistence. Malaria is possibly the selecting agent because a concordance exists between the prevalence of malaria and Hb S. Sickling might protect a person from malaria by either (1) accelerating sickling so that parasitized cells are removed or (2) making it more difficult for the parasite to metabolize or to enter the sickled cell. While children with sickle cell trait Hb SA seem to have a milder form of falciparum malaria, those with homozygous Hb S have a severe form that is associated with a very high mortality rate.

The sickling process that prompts a crisis may be precipitated by multiple factors. Local tissue hypoxia, dehydration secondary to a viral illness, or nausea and vomiting, all of which lead to hypertonicity of the plasma, may induce sickling. Any event that can lead to acidosis, such as infection or extreme dehydration, can cause sickling. More benign factors and environmental changes, such as fatigue, exposure to cold, and psychosocial stress, can elicit the sickling process. A specific cause is often not identified.

Vaso-occlusive crises are often precipitated by the following:

• Cold weather (due to vasospasm)
• Hypoxia (eg, flying in unpressurized aircraft)
• Infection
• Dehydration (especially from exertion or during warm weather)
• Acidosis
• Alcohol intoxication
• Emotional stress
• Pregnancy

Data also suggest a role for exertional stress, particularly when compounded with heat and hypovolemia.

Aplastic crises are often preceded by the following:

• Infection with parvovirus B19
• Folic acid deficiency
• Ingestion of bone marrow toxins (eg, phenylbutazone)

Acute chest syndrome has been linked to the following:

• Fat embolism
• Infections
• Pain episodes
• Asthma ^[14]

SCD is present mostly in people of sub-Saharan African descent. It also is found, with much less frequency, in eastern Mediterranean and Middle East populations. Individuals of Central African Republic descent are at an increased risk for overt kidney failure.

United States statistics

The sickle gene is present in approximately 8% of Black Americans. More than 2 million people in the United States, nearly all of them of African American ancestry, carry the sickle gene. The following statistics are available from the Centers for Disease Control and Prevention and the National Institutes of Health ^[15,16]:

• In the United States, it is estimated that approximately 100,000 people have SCD
• SCD occurs in about 1 out of every 365 Black or African-American births
• SCD occurs in about 1 of every 16,300 Hispanic-American births
• Approximately 1 in 13 Blacks or African Americans has sickle cell trait

Risk of chronic kidney disease (CKD) is increased in SCD, with one study showing an almost 30% prevalence of baseline CKD in a cohort with mean age 31.6 years, increasing to 41.8% over 5 years. Among US sickle cell trait carriers of African or Hispanic ancestry, the risk of CKD is about 1.5-2–fold higher than in noncarriers. ^[17]The prevalence of sickle cell trait is twice as high in African Americans with end-stage kidney disease compared with the general African-American population (15% versus 7%, P < 0.001). ^[18]

Certain gene variants have been linked with increased risk of kidney disease in SCD. In particular, patients who carryAPOL1 G1 and G2 risk variants (which confer protection against trypanosomiasis) have a 7-fold higher risk of CKD progression and a 7-30–fold greater risk of kidney failure. ^[19]

International statistics

In several parts of Africa, the prevalence of sickle cell trait (heterozygosity) is as high as 30%. Although the disease is most frequently found in sub-Saharan Africa, it is also found in some regions of Sicily, Greece, southern Turkey, and India, all of which have areas in which malaria is endemic.

The mutation that results in HbS is believed to have originated in several locations in Africa and India. Its prevalence varies but is high in these countries because of the survival advantage to heterozygotes in regions of endemic malaria. As a result of migration, both forced and voluntary, it is now found worldwide.

Sex distribution

The male-to-female ratio is 1:1. No sex predilection exists, since sickle cell anemia is not an X-linked disease.

Although no particular gender predilection has been shown in most series, analysis of the data from the US Renal Data System demonstrated marked male predominance of sickle cell nephropathy in affected patients. ^[20]

Clinical characteristics at different ages

Although hematologic changes indicative of the disorder are evident as early as the age of 10 weeks, clinical characteristics of SCD generally do not appear until the second half of the first year of life, when fetal Hb levels decline sufficiently for abnormalities caused by HbS to manifest. SCD then persists for the entire lifespan. After age 10 years, rates of painful crises decrease, but rates of complications increase. These include potentially fatal conditions such as kidney failure and pulmonary hypertension. ^[21,22]

Therapeutic advances have markedly improved the prognosis for patients with SCD. In earlier reports, approximately 50% of patients did not survive beyond age 20 years, and most did not survive to age 50 years. ^[23]In the United States at present, nearly all children with SCD survive to adulthood; nevertheless, the average life expectancy in people with SCD remains 20 years below that of the general population. ^[2]

Morbidity is highly variable in patients with SCD, partly depending on the level of HbF. Nearly all individuals with the condition are affected to some degree and experience multiple organ system involvement. Patients with Hb SA are heterozygous carriers and essentially are asymptomatic.

Vaso-occlusive crisis and chronic pain are associated with considerable economic loss and disability. Repeated infarction of joints, bones, and growth plates leads to aseptic necrosis, especially in weightbearing areas such as the femur. This complication is associated with chronic pain and disability and may require changes in employment and lifestyle.

In addition, with longer survival comes an increased likelihood of other chronic complications. Pulmonary hypertension has emerging as an important complication and is one of the leading causes of morbidity and mortality in adults with SCD. ^[22] The estimated glomerular filtration rate (eGFR) declines rapidly in over 30% of adults with SCD, and patients with SCD who develop kidney failure have higher mortality and are less likely to receive a kidney transplant, compared with patients without SCD. ^[21]

Prognostic factors

The following prognostic factors have been identified as predictors of an adverse outcome in SCD ^[24]:

• Hand-foot syndrome (dactylitis) in infants younger than 1 year
• Hb level of less than 7 g/dL
• Leukocytosis in the absence of infection

Hand-foot syndrome, which affects children younger than 5 years, has proved a strong predictor of overall severity (ie, risk of stroke, high pain rate, recurrent acute chest syndrome, death). Children who have an episode before age 1 year are at high risk of a severe clinical course. The risk is further increased if the child's baseline hemoglobin level is less than 7 g/dL or the baseline white blood cell count is elevated.

Pregnancy

Pregnancy represents a special area of concern. The rate of fetal loss is high, due to spontaneous abortion. Placenta previa and abruption are common, due to hypoxia and placental infarction. Premature birth and low birth weight are common.

Mortality

Mortality in SCD is elevated, especially in the early childhood years. However, childhood deaths have decreased markedly since the introduction of widespread penicillin prophylaxis and pneumococcal vaccination. The leading cause of death is acute chest syndrome. Children have a higher incidence of acute chest syndrome but a lower mortality rate than adults; the overall death rate from acute chest syndrome is 1.8% and 4 times higher in adults than in children. Causes of death arepulmonary embolism and infection.

Older cohort studies examined the natural history of SCD. The Cooperative Study of Sickle Cell Disease (CSSCD), initiated in 1977, estimated that the median survival for individuals with HbSS was 48 years for women and 42 years for men. ^[25]In a United Kingdom study, published in 1994, of a neonatal cohort followed in a hospital- and community-based program that included modern therapy with transcranial Doppler ultrasonography screening, the estimated survival of HbSS children at 16 years was 99%. ^[25] 

In the Dallas Newborn Cohort, which was initiated in 1983, a 2010 report estimated that overall survival at 18 years of age was 93.9% in HbSS and HbSβ⁰ patients, and was 98.4% in HbSC and HbSβ⁺ patients. Acute chest syndrome and multiorgan failure syndrome had become the leading causes of death, surpassing bacterial sepsis. ^[23]

In Africa, available mortality data are sporadic and incomplete. Many children are not diagnosed, especially in rural areas, and death is often attributed to malaria or other comorbid conditions.

This significant increase in life expectancy and survival of patients with SCD has been achieved thanks to early detection and introduction of disease-modifying therapies. Neonatal screening; penicillin prophylaxis for children; pneumococcal immunization; red cell transfusion for selected patients (with chelation therapy); hydroxyurea therapy; parental and patient education; and, above all, treatment in comprehensive centers, have all likely contributed to this effect on longevity.

Patients must be educated about the nature of their disease. They must be able to recognize the earliest signs of a vaso-occlusive crisis and seek help, treat all febrile illness promptly, and identify environmental hazards that may precipitate a crisis. Reinforcement should occur incrementally during the course of ongoing care.

Patients or parents should be instructed on how to palpate the abdomen to detect splenic enlargement, and the importance of observation for pallor, jaundice, and fever. Teach the importance of seeking medical care in certain situations, including the following:

• Persistent fever (>38.3°C)
• Chest pain, shortness of breath, nausea and vomiting
• Abdominal pain with nausea and vomiting
• Persistent headache not experienced previously

Patients should avoid the following:

• Alcohol
• Nonprescribed prescription drugs
• Cigarettes, marijuana, and cocaine
• Seeking care in multiple institutions

Families should be educated on the importance of hydration, diet, outpatient medications, and immunization. Emphasize the importance of prophylactic penicillin. Patients on hydroxyurea must be educated on the importance of regular follow-up with blood counts.

Patients (including asymptomatic heterozygous carriers) should understand the genetic basis of the disease, be educated about prenatal diagnosis, and know that genetic counseling is available. Genetic testing can identify parents at risk for having a child with sickle cell disease.

If both parents have the sickle cell trait, the chance that a child will have sickle cell disease is 25%. If one parent is carrying the trait and the other has the disease, the odds increase to 50% that their child will inherit the disease. Screening and genetic counseling theoretically have the potential to drastically reduce the prevalence of SCD. This promise has not been realized. Some authors have recommended emergency department screening or referral for patients unaware of their status as a possible heterozygote. ^[26]

Families should be encouraged to contact community sickle cell agencies for follow-up information, new drug protocols, and psychosocial support. Families should also follow the advances of gene therapy, bone marrow transplantation, and the usage of cord blood stem cells.

For patient education information, seeSickle Cell Disease. In addition, the Centers for Disease Control and Prevention offers a range of patient-centeredCommunication Resources on Sickle Cell Disease. ^[27]