Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

82. Sickle Cell Disease

C. Y. Jennifer Chan and Melissa Frei-Jones


KEY CONCEPTS

 Images Sickle cell disease (SCD) is an inherited disorder caused by a defect in the gene for β-globin, a component of hemoglobin, and is called a qualitative hemoglobinopathy. Patients can have one defective gene (sickle cell trait that is not a disease) or two defective genes (SCD).

 Images Although SCD usually occurs in persons of African ancestry, other ethnic groups can be affected. Multiple mutation variants result in different clinical manifestations.

 Images SCD involves multiple organ systems. Usual clinical signs and symptoms include anemia, pain, splenomegaly, and pulmonary symptoms. SCD can be identified by routine neonatal screening programs. Early diagnosis allows early comprehensive care.

 Images Patients with SCD are at risk for infection. Prophylaxis against pneumococcal infection reduces death during childhood in children with sickle cell anemia.

 Images Hydroxyurea decreases the incidence of painful episodes, but patients treated with hydroxyurea should be carefully monitored.

 Images Neurologic complications caused by vasoocclusion can lead to stroke. Screening with transcranial Doppler ultrasound to identify children at risk accompanied by chronic transfusion therapy programs have been shown to be beneficial in decreasing the occurrence of overt stroke in children with SCD.

 Images Patients with fever greater than 38.5°C (101.3°F) should be evaluated, and appropriate antibiotics administered immediately, including coverage for encapsulated organisms, especially pneumococcal organisms.

 Images Pain episodes can often be managed at home. Hospitalized patients require parenteral analgesics. Analgesic options include opioids, nonsteroidal antiinflammatory agents, and acetaminophen. The patient characteristics and the severity of the pain should determine the choice of agent and regimen.

 Images Patients with SCD should be followed regularly for healthcare maintenance issues and monitored for changes in organ functions.


Images Sickle cell syndromes, which can be divided into sickle cell trait (SCT) and sickle cell disease (SCD), are a group of hereditary conditions characterized by the presence of sickle cell hemoglobin (HbS) in red blood cells (RBCs). SCT is the heterozygous inheritance of one normal β-globin gene producing HbA and one sickle gene producing HbS (HbAS) gene. Individuals with SCT are asymptomatic. SCD can be of homozygous or compounded heterozygous inheritance. Homozygous sickle cell hemoglobin (hemoglobin S) (HbSS) has historically been referred to as sickle cell anemia (SCA). The heterozygous inheritance of HbS with another qualitative or quantitative β-globin mutation results in sickle cell hemoglobin C (HbSC), sickle cell β-thalassemia (HbSβ+-thal and HbSβ0-thal), and some other rare phenotypes.1,2

Over the years, progress has been made in understanding the relationship between clinical severity and genotype, as well as the natural history of common morbidities associated with SCD. Ongoing research involves investigation of pharmacotherapies used to treat SCD. Recent advances in the care of SCD patients have increased life expectancy.17

SCD is a chronic illness with significant burden for family and society. Frequent hospitalizations can interrupt schooling and result in employment difficulties.810 Acute complications of the disease can be unpredictable, rapidly progressive, and life threatening. Later in life, chronic organ damage and cognitive or emotional impairments can develop.1,2 Because of the complexity and gravity of the illness, it is essential that comprehensive care is available to all patients and that all providers involved have a good understanding of the disease and its management.1,2,8,11

EPIDEMIOLOGY

Images SCD affects millions of people worldwide and is most common in people with African heritage.1,12 The most common SCD genotype is HbSS (~60% to 65%), followed by HbSC (~25% to 30%), HbSβ+-thal and HbSβ0-thal (~5% to 10%). Other variants account for less than 1% of patients.1,2 The disease is common among those with ancestors from sub-Saharan Africa, India, Saudi Arabia, and Mediterranean countries.2,13 In the United States, about 90,000 Americans have SCD with a prevalence of 1 in 2,500 newborns, 1 in 500 African Americans, and 1 in 36,000 Hispanic births.1,14,15 About 2 million Americans have SCT with a prevalence rate of 1 in 12 African Americans and 1 in 100 Hispanics.16

About 275,000 babies are born with SCD every year and 85% occur in Africa.2,12 The prevalence of SCD in the region is determined by the frequencies of SCT. The distribution of SCT reflects the survival advantage in regions (tropical areas) where malaria is endemic as the gene mutation offers partial protection against serious malarial infection. RBCs carrying the abnormal sickle hemoglobin prevent the normal growth and development of Plasmodium falciparum within RBCs. Individuals with SCT are more likely to survive the acute malarial illness whereas individuals with SCD-HbSS often present with more severe disease. The incidence of the sickle gene in a population correlates with the historical incidence of malaria and SCT results in partial resistance to the disease.1,2,12,17

The prevalence of SCD is highest in sub-Saharan Africa. Other areas where the sickle mutation can be found include the Arabian Peninsula, the Indian subcontinent, and the Mediterranean region. In Africa, the variants are Senegal (Atlantic West Africa), Benin (Central West Africa), Bantu (Central African Republic), and Cameroon. Arab-Indian haplotype is seen in certain areas of Saudi Arabia and India.2,13Haplotypes identified through newborn screening programs in the United States showed that the Benin haplotype was the most frequent (63%), followed by Bantu (14%), Senegal (9%), Cameroon (4%), and Saudi Arabian (2%).13 Genetic analysis shows that the mutation found in Arabic patients is different from the mutation in those of African descent. Sickle gene mutation variants have been associated with different geographic locations and may be responsible for variations in clinical manifestations.3,5,13

ETIOLOGY

Normal hemoglobin (hemoglobin A [HbA]) is composed of two α chains and two β chains (α2 β2). The biochemical defect that leads to the development of HbS involves the substitution of valine for glutamic acid as the sixth amino acid in the β-polypeptide chain. Another type of abnormal hemoglobin, hemoglobin C (HbC), is produced by the substitution of lysine for glutamic acid as the sixth amino acid in the β-chain. Structurally, the α-chains of HbS, HbA, and HbC are identical. Therefore, it is the chemical differences in the β-chain that account for sickling and its related sequelae.13

SCA or HbSS is the most common form of SCD and occurs when an individual inherits both maternal and paternal β-globin alleles that code for the HbS Figures 82-1 to 82-4 show the probability of inheritance with each pregnancy for the offspring of parents with HbA, SCT, and HbSS. If both parents are carriers, the offspring will have a 25% risk of inheriting SCD and a 50% risk of SCT (Fig. 82–1). β-Thalassemia is a quantitative hemoglobinopathy resulting from a genetic defect in β-globin production. β-Thalassemia can be co-inherited with HbS and may vary from no β-globin production (β0) to some β-globin production (β+). Individuals with HbSS and HbSβ0-thal have a more severe course than those with HbSC and HbSβ+-thal.2,13 As discussed earlier, several haplotypes characterize the sickle gene, resulting in different clinical and hematologic courses. Included among these types are the three most commonly found in the United States: the Bantu haplotype, characterized by severe disease; the Senegal haplotype, characterized by mild disease; and the Benin haplotype, characterized by a course intermediate to that of the other two haplotypes. Although there are a number of other haplotypes seen around the world, the major types outside of the United States include Saudi Arabian and Cameroon, both with milder courses of illness.2,3,5

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FIGURE 82-1 Sickle cell gene inheritance scheme for both parents with sickle cell trait (SCT). Possibilities with each pregnancy: 25% normal (AA); 50% SCT (AS); and 25% sickle cell anemia (SS). (A, normal hemoglobin; S, sickle cell hemoglobin)

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FIGURE 82-2 Sickle cell gene inheritance scheme for one parent with sickle cell trait (SCT) and one parent with no sickle cell gene. Possibilities with each pregnancy: 50% normal (AA); 50% SCT (AS). (A, normal hemoglobin; S, sickle cell hemoglobin)

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FIGURE 82-3 Sickle cell gene inheritance scheme for one parent with sickle cell trait (SCT) and one parent with sickle cell anemia (SCA). Possibilities with each pregnancy: 50% SCA (SS); 50% SCT (AS). (A, normal hemoglobin; S, sickle cell hemoglobin)

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FIGURE 82-4 Sickle cell inheritance scheme for one parent without sickle cell gene and one parent with sickle cell anemia (SCA). Possibilities with each pregnancy: 100% SCT (AS). (A, normal hemoglobin; S, sickle cell hemoglobin)

PATHOPHYSIOLOGY

Normal adult RBCs contain predominantly HbA (96% to 98%). Other forms of hemoglobin are HbA2 (2% to 3%) and fetal hemoglobin (HbF; less than 1%). Normal RBCs are biconcave shape and able to deform to squeeze through capillaries.13,18 HbF is present predominantly in fetal RBCs and is a tetramer of two α globin chains and two γ globin chains (α2γ2). Prior to birth, HbF is the predominant hemoglobin type. Around 32 weeks gestation, a switch from the production of γ chains to β chains occurs and, consequently, an increase in HbA production is seen. Increased HbF production is seen under severe erythroid stress, such as anemia, hematopoietic stem cell transplantation (HSCT), or chemotherapy or in the hereditary condition, hereditary persistence of fetal hemoglobin (HPFH) where a mutation in the β-globin gene cluster results in continued HbF production after birth. HPFH is a benign, asymptomatic condition.3,5,7,19

In the pathogenesis of SCD, the following are primarily responsible for the various clinical manifestations: impaired circulation, destruction of RBCs, and stasis of blood flow. These changes result directly from two major disturbances involving RBCs: abnormal hemoglobin polymerization and membrane damage Fig. 82–5).

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FIGURE 82-5 Pathophysiology of sickle cell disease. (Arg, arginine; ET-1, endothelin-1; Hb, hemoglobin; NO, nitric oxide; NOS, nitrous oxide synthase; VCAM-1, vascular cell adhesion molecule 1; XO, xanthine oxidase.) (From Kato GJ, Gladwin MT. Sickle cell disease. In: Hall JB, Schmidt GA, Wood LDH, eds. Principles of Critical Care, 3rd ed. New York: McGraw-Hill, 2005:1658.)

The solubilities of HbS and HbA are the same under conditions of normal oxygenation. Because of increased hydrophobicity as a result of the valine-substituting glutamic acid substitution, solubility of deoxygenated HbS is reduced. Saturation of deoxy-HbS leads to intermolecular binding and formation of thin bundles of fibers, which initially are unstable. However, the increased binding of deoxy-HbS eventually results in cross-linked fibers and stable polymers. This process is influenced by mean corpuscular hemoglobin concentration (MCHC), temperature, intracellular pH, and the circulating amount of HbS. Polymerization allows deoxygenated hemoglobin molecules to exist as a semisolid gel that protrudes into the cell membrane, leading to distortion of RBCs (sickle shaped) and loss of deformability. The presence of sickled RBCs increases blood viscosity and encourages sludging in the capillaries and postcapillary venules. Such obstructive events lead to local tissue hypoxia, which tends to accentuate the pathologic process.1,2,6

When reoxygenated, polymers within the RBCs are lost, the RBCs eventually return to normal shape. This process contributes to the vasoocclusive manifestation in that HbS is able to squeeze into microvasculature when oxygenated, but becomes sickled when deoxygenated. The cycle of sickling and unsickling results in damage to the cell membrane, loss of membrane flexibility, and rearrangement of surface phospholipids. Membrane damage also alters ion transport, resulting in potassium and water loss, which can lead to a dehydrated state that enhancing the formation of sickled forms. After continual repetitions of the process, the RBC membrane develops into rigid irreversibly sickled cell (ISC). Unlike the reversible sickled cells, which have normal morphology when oxygenated, ISCs are elongated cells and remain sickled when oxygenated. More rigid membranes of HbS-containing RBCs retard flow, particularly through the microcirculation. In addition, sickled RBCs tend to adhere to vascular endothelial cells, which further increase polymerization and obstruction.1,2,6

Intermolecular binding and polymer formation are reduced by HbF and to a lesser degree by HbA2. RBCs that contain HbF sickle less readily than cells without. ISCs, not surprisingly, have a low HbF level. Increased levels of HbF, as in the case of the Saudi Arabian genotype, result in more benign forms of SCD. The amount of HbF and HbA2 in relation to HbS influences the clinical manifestations and accounts for some of the variability in severity among SCD genotypes.2,5

Intravascular destruction of sickle cells can occur at an accelerated rate. The stresses of circulation and repetitive sickle–unsickle cycles lead to cell fragmentation. Damage to the cell membrane promotes cell recognition by macrophages. Rigid ISCs are easily trapped, resulting in short circulatory survival and chronic hemolysis. The typical sickled cell survives for about 16 to 20 days, whereas the life span of a normal RBC is 120 days. Anemia triggers the release of immature RBCs (reticuloctyes) from bone marrow prematurely. Surface adhesion proteins that maintain the reticulocytes inside the marrow adhere to the endothelium in postcapillary venules, further blocking the mature HbS-containing RBCs leading to complete occlusion of microvessels.6,18

In addition to sickling, other factors are also responsible for the clinical manifestations associated with SCD. Hemolysis releases free hemoglobin resulting in generation of reactive oxygen species, and alternation of nitric oxide (NO) metabolism. Obstruction of blood flow to the spleen by sickle cells can result in functional asplenia, defined as the loss of splenic function with an intact spleen. These patients can also have deficient opsonization. Impaired splenic function increases susceptibility to infection by encapsulated organisms, particularly pneumococcal bacteria. Coagulation abnormalities in SCD can be the result of continuous activation of the hemostatic system or disorganization of the membrane layer.2,6

CLINICAL PRESENTATION

Images SCD is usually identified by routine neonatal screening programs in the United States. Since 2006, universal neonatal screening for SCD is performed in all 50 states. The sensitivity and specificity of screening methods (isoelectric focusing high-performance liquid chromatography, or electrophoresis) approach 100%.20 For infants with a positive screening result, a second test should be performed by 2 months of age to confirm the diagnosis. More than 98% newborns in the United States are screened for SCD to identify the disease. Despite universal screening, some infants with SCD are not identified at birth because of extreme prematurity, prior blood transfusion, or inability to contact family.1921

SCD involves multiple organ systems, and its clinical manifestations vary greatly between genotypes Table 82–1). Persons with SCT are usually asymptomatic and SCT is not considered a disease. However, under certain extreme situations where hemoglobin oxygenation is altered, RBC sickling can occur. Individuals with SCT should be cautious when participating in exercise under extreme conditions, such as high altitude or military training. Sickling of RBCs in the renal medulla, an area with low oxygen tension, can result in the inability to concentrate urine. Individuals with such impairment are at risk of dehydration during periods in which the body normally conserves water. Microscopic hematuria has been observed, and gross hematuria can occur after heavy exercise. Other reported complications associated with SCT are venous thromboembolism, renal medullary carcinoma, and chronic kidney disease.14,17,22 An increased incidence of urinary tract infection in women, especially during pregnancy, was previously reported and specific screening guidelines should be followed.23

TABLE 82-1 Clinical Features of Sickle Cell Trait and Common Types of Sickle Cell Disease

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The cardinal features of SCD are hemolytic anemia and vasoocclusion. In individuals with HbSS, anemia usually develops from 4 to 6 months after birth. The delay in presentation is due to the presence of HbF in the infant’s RBCs. However, HbF production is gradually replaced by HbS, which typically leads the clinical manifestations of hemolysis and vasoocclusion, such as pain and swelling of the hands and feet, commonly referred to as hand-and-foot syndrome or dactylitis in infants.1,2

The common clinical signs and symptoms associated with HbSS include chronic anemia and pallor; fever; arthralgia; scleral icterus; abdominal pain; weakness; anorexia; fatigue; enlargement of the liver, spleen, and heart; and hematuria. Laboratory findings include the low hemoglobin level around 6 to 9 g/dL (3.72 to 5.58 mmol/L), elevated reticulocytes of 10% to 20%, and elevated platelet and white blood cell (WBC) counts. Mean corpuscular volume (MCV) is normal. The peripheral blood smear demonstrates sickled red cell forms.1,14,18

Individuals with HbSC disease present with less severe symptoms than that of HbSS and can be characterized primarily by mild anemia (hemoglobin levels of 9 to 11 g/dL [5.58 to 6.82 mmol/L] and reticulocytes of 3% to 10%), infrequent episodes of pain, persistence of splenomegaly into adult life, and excessive target cells in the peripheral blood smear. In individuals with heterozygous HbS-β-thalassemia syndrome, severity of disease depends on the thalassemia gene involved.1,18

The Cooperative Study of Sickle Cell Disease has previously reported that predictors for severe disease in children are dactylitis before 1 year of age, an average hemoglobin less than 7 g/dL (4.34 mmol/L) in the second year of life, and leukocytosis in the absence of infection. However, these variables could not be validated in a more recent study.24 Early acute chest syndrome (ACS) during the first 3 years of life is a predictor for recurrent episodes throughout childhood. Children with concomitant SCD and asthma have increased frequencies of ACS and pain episodes and increased mortality. Risk factors for early death in adults with SCD include complications such as sickle cell pain, anemic events, ACS, renal failure, and pulmonary disease.1,2527 With longer survival for SCD, chronic manifestations of the disease contribute to the increased prevalence of morbidity later in life.

COMPLICATIONS

Acute Complications

Fever and Infection

Functional asplenia and failure to make antibodies against encapsulated organisms contribute to the high risk of overwhelming sepsis in individuals with SCD. Penicillin prophylaxis and vaccination have significantly reduced the overall risk of Streptococcus pneumonia bacteremia, but an increased incidence of invasive pneumococcal infections with nonvaccine serotypes has been reported.2830 Other encapsulated organisms are Haemophilus influenzae, Neisseria meningitidis, and Salmonella, and the latter has been known to cause osteomyelitis and pneumonia in SCD. Mycoplasma pneumoniae and Chlamydia pneumoniae should be considered in older children with infiltrates on chest radiograph. Viral infections (e.g., influenza and parvovirus B19) can result in severe morbidity.1,2,18,28,29,31,32

All SCD patients with fever greater than 38.3°C (101°F) must be evaluated to determine the risk of infection or sepsis; workup should include physical examination, complete blood count with reticulocyte count, blood culture, chest radiograph, urinalysis, and urine culture. Lumbar puncture may be needed, especially in young and toxic-appearing children. A low threshold for empiric therapy compared to that in the general population is recommended.1,28,31,33

Children with SCD may experience a severe complication due to infection that results in impaired bone marrow production of RBCs. An aplastic crisis is characterized by a decrease in the reticulocyte count and the rapid development of severe anemia (Table 82–2). The bone marrow becomes hypoplastic and is most often associated with a viral infection, particularly parvovirus B19.1,14,31

TABLE 82-2 Acute Sickle Cell Complications

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Neurologic

Neurologic abnormalities and cognitive deficits are well documented in patients with SCD. Vasoocclusive processes can lead to cerebrovascular occlusion that manifests as signs and symptoms of overt stroke, such as headache, paralysis, aphasia, visual disturbances, facial droop, and convulsions. The risk of stroke is highest for HbSS and lowest for HbSβ+-thal. The occurrence of cerebral infarct in HbSS is 11% by age 20 years and 24% by age 45 years with a recurrence rate as high as 70% in 3 years. The highest risk occurs during the first decades, in particular ages 2 to 5. The risk is lowest before age 2 secondary to the protective effect of HbF. Ischemic strokes occur in 54% of cerebrovascular accidents with the highest risk before age 10 years and after 30 years of age; whereas hemorrhagic strokes are more common when patients are in their 20s and are associated with poor outcome.1,2,34

In addition to neurologic examination, evaluation of acute events include computed tomography (CT) scan and magnetic resonance imaging (MRI), magnetic resonance angiography for asymptomatic infarction, and transcranial Doppler (TCD) ultrasound to detect abnormal velocity and identify individuals at increased risk of stroke. In addition, electroencephalography (EEG) can be used if there is a history of seizure.1,2

About 10% to 30% of SCD who have HbSS with no prior history of stroke have been found to have changes on MRI of the brain consistent with infarction or ischemia. These “silent infarcts” can be associated with increased risk of stroke, decreased neurocognitive functions, behavioral changes, and poor academic performances. Finally, lower intelligence, visual-motor impairments, and neuropsychological dysfunctions have been reported in patients not affected by acute or silent strokes and are associated with severity of anemia.1,3437

Acute Chest Syndrome

ACS is the second most common cause of hospitalization and responsible for about 25% of death among individuals with SCD. ACS is defined as a new pulmonary infiltrate associated with one or more of the following: cough, dyspnea, tachypnea, chest pain, fever, wheezing, and new-onset hypoxia. As many as one-half of individuals with SCD experience at least one episode of ACS. Risk factors for ACS and recurrence include young age (peak incidence between age 2 to 4 years), higher Hb, lower HbF, higher leukocytes, history of asthma or bronchial hyper-responsiveness, and smoke exposure. Genotype and haplotype also influence the occurrence. Patients with HbSS and HbSβ0-thal have higher incidence than those with HbSC and HbSβ+-thal. The prevalence is higher with African haplotypes than that of Saudi Arabia.1,25,38,39

The primary etiology for ACS is pulmonary vascular occlusion. The most common cause of ACS is infectious and may be of bacterial, viral, or mycoplasma in origin. Infections, fat emboli released from bone marrow during pain crisis, or direct adhesion of RBC to the pulmonary vasculature leads to the inflammation and injury of the lung. Predictors for respiratory failure include extensive lobar involvement, platelet count less than 200,000 cells/mm3 (200 × 109/L), and history of cardiac or neurologic complications. In addition to physical examinations, evaluations should include chest radiographs. In severe cases, CT scan, perfusion scintigraphy, transthoracic echocardiography, and bronchoscopy should also be considered. Pulmonary changes often involve the lower lobes of the lungs and may cause pleural effusions. Bilateral infiltrates or multiple lobe involvements may be an indication of poor prognosis. The mortality rates for ACS are less than 1%, 3%, and 9% for children up to 9 years old, children 10 to 19 years old, and adults, respectively. Pulmonary manifestations must be recognized early and managed aggressively as ACS can rapidly progress to pulmonary failure and death.25,39,40

Priapism

Stasis and sickling of erythrocytes within the sinusoids of the corpora cavernosa is the primary mechanism of priapism, a sustained painful erection. In recent years, a better understanding of pathophysiology of priapism has identified other mechanisms at the molecular level, such as NO and adenosine pathways. Stuttering priapism is repeated intermittent attacks up to several hours before remission; whereas ischemic priapism is a persistent painful erection greater than 4 hours and should be considered as an emergency. Thirty to 45% of males with SCD will present with at least one episode of priapism during their lifetime and the first episodes often occur during childhood. Impotence has been reported after repeated episodes and is directly related to the duration prior to treatment. ASPEN (association of sickle cell disease, priapism, exchange transfusion, and neurologic events) syndrome has occurred one to 11 days after partial exchange transfusion in males who presented with priapism. This syndrome can range from headaches and seizures to obtundation requiring ventilation.4143

Sickle Cell Pain

Chronic hemolytic anemia in the SCD patient is periodically interrupted by acute episodes of pain and vasoocclusion, particularly in childhood (Table 82–2). Although fever, infections, dehydration, hypoxia, acidosis, and sudden temperature alterations can precipitate pain, multiple factors often contribute to its development.44

Sickle cell pain may be caused by bone or muscle infarction due to vasoocclusion and may affect a single site such as an arm, leg, or back or may involve multiple areas of the body. Acute painful episode is the most common reason of hospitalization. Individuals with HbSS disease experience frequent episodes of pain than those HbSC disease or some other variants.1,2,14 Biomarker for severity of pain during vasoocclusion episodes include C-reactive protein and lactate dehydrogenase (LDH).4,45 In addition, higher pain score at presentation and older age are predictors for admission and longer duration of hospitalization.46 Dactylitis (hand-and-foot syndrome) is a sub-type of sickle cell pain, occurring in infancy and early childhood and is characterized by redness and swelling of the dorsal aspects of the hands, feet, fingers, and toes. The episodes are painful but usually do not result in permanent damage.1

Splenic Sequestration

Splenic sequestration is the sudden massive enlargement of the spleen resulting from the sequestration of sickled RBCs in the splenic parenchyma (Table 82–2). Hematocrit and hemoglobin concentrations dramatically fall, with reticulocytosis and no evidence of marrow failure or accelerated hemolysis. Trapping of the sickled RBCs by the spleen also leads to a decrease in circulating blood volume, which can result in hypotension and shock. The condition is most often seen in infants and children because their spleens are intact, and can cause sudden death in young children. Splenic enlargement may also be acutely painful due to rapid capsular expansion. Over time, repeated splenic infarctions lead to autosplenectomy and the spleen can no longer become engorged; the incidence therefore declines as adolescence approaches.1,47

Chronic Complications

Pulmonary

Pulmonary hypertension as defined as an elevated tricuspid regurgitation (TR Jet) velocity has been reported to be a risk factor for death in adult patients with SCD.48 Diagnosis based on screening echocardiogram has been reported in children and adolescents, although its significance has not been established. Since recent studies have reported that screening echocardiogram alone has a high-false positive rate, pulmonary hypertension must be confirmed with right heart catheterization.48,49

The prevalence of asthma in children with SCD is similar to that of general population. However, asthma in individuals with SCD is associated with ACS and vasoocclusive pain episodes and increased mortality. Early screening for asthma starting at age 1 and pulmonary function test at least every 5 years starting at age 6 have been recommended. Medications such as inhaled corticosteroids and β-agonists for asthma exacerbation should be utilized for asthma control.1,27,48

Skeletal and Skin Diseases

Bone diseases are common in SCD and the vitamin D level has been suggested to be the biomarker.4 Osteonecrosis, particularly of the femoral or humeral heads, causes permanent damage and disability.14,50,51 Osteopenia associated with low bone formation has been reported in both males and females with SCD.52 Children with SCD also have an increased incidence of osteomyelitis; the organism most often responsible is Salmonella.31 In addition to necrosis of joints, chronic leg ulcers most commonly seen in the medial and lateral malleolus (ankles) can become a difficult and painful problem for adult. Ulcers are often seen after trauma or infection and are usually slow to heal.53

Ocular Manifestations

Ocular problems seen in patients with SCD include transient monocular blindness, visual field defects from retinal hemorrhage, retinal detachment, vitreous hemorrhage, venous microaneurysms, and neovascularization. The incidence of proliferative retinopathy in SCD patients varies from 5% to 10%. Vasoocclusion in the eye can occur as early as 20 months of age, and clinically detectable retinal diseases usually occur during adolescence and early adulthood. Despite the less systemic manifestations, individuals with HbSC develop serious retinal complications more often and earlier than those with HbSS. Annual examination with retinal evaluation is recommended for patients with SCD to prevent blindness from retinopathy and other complications.54

Gastrointestinal Diseases

Cholelithiasis is a common complication of SCD resulting from chronic hemolysis and increased bilirubin production, and leading to biliary sludge and/or stone formation. The risk of gallstones increases with age: 14% by age 10 years and 50% by age 22 years. Cholecystitis, exemplified by pain in the right upper quadrant, can be confused with an acute sickle pain episode in the abdomen. Cirrhosis occurred in 18% of young adults with SCD. Causes for development of chronic hepatic disease include repeated occlusion in the liver, iron overload, and hepatitis.1,14,55

Cardiac Diseases

Cardiovascular complications associated with anemia, including cardiac enlargement and various murmurs, can occur in patients with SCD. Patients experience various degrees of exertional dyspnea, tachycardia, and palpitation because of the decreased oxygen-carrying capacity of the blood. Left ventricular diastolic dysfunction has been reported in 18% of adults with SCD and is associated with increased mortality, especially in patients with pulmonary hypertension. Left ventricular stiffness and left ventricular hypertrophy have been reported, and the progression is speculated to lead to diastolic dysfunction later in life. Acute myocardial infarction in adults with SCD may be underrecognized due to the high incidence of sickle cell acute chest pain.56,57

Renal

Sickling in the renal medulla, an area with relative hypoxia and low pH, can lead to sickle cell nephropathy. Renal dysfunction in SCD begins during infancy evidenced by glomerular hyperfiltration. Other manifestations include inability to concentrate urine, hematuria, tubular acidosis, papillary necrosis, glomerulonephritis, microalbuminuria, and proteinuria. Enuresis, as a result of increased urine production, is a common complaint. Chronic renal failure has been reported in 30% of adults with SCD, and end-stage renal disease is associated with high mortality.2,14,58,59

Growth and Development

Delayed growth and sexual maturation are common in patients with SCD. Despite normal birth weight and length, growth retardation occurs between 6 months and 4 years with height, weight, and bone mass index being affected. The poor growth cannot be explained by nutritional factors alone. Alternations in growth factors as well as increased metabolic rate are factors contributing to the growth failure. Delay in puberty by 1 to 2 years is common in adolescents with SCD and fertility problems tend to occur more often in female SCD patients than in normal women.60,61

Psychiatric

Depression and anxiety are more common in children and adults with SCD than in the general population and have a significant impact on quality of life.62,63 Depression is associated with pain episodes in children with SCD. In addition, the level of depression has been reported to be associated with anxiety between mothers and children.64 DSM-IV psychiatric diagnosis in adolescents with SCD include attention-deficit-hyperactivity, oppositional defiant, conduct, major depressive, and anxiety disorders.65

Pregnancy

Pregnancy introduces an increased risk for the mother with SCD and for the fetus. Some women experience increased pain episodes during pregnancy and the anemia of SCD can lead to intrauterine growth retardation. Preterm labor and premature delivery are common in mothers with SCD, and the risk of spontaneous abortion is increased. The incidence of cesarean delivery and pregnancy-related complications are higher when compared to mothers who do not have SCD.14,66,67

TREATMENT

Sickle Cell Disease

Desired Outcomes

The goal of treatment is to reduce hospitalizations, complications, and mortality. Treatment for SCD involves the use of general measures to meet the unique demands for increased erythropoiesis. Additional interventions can be aimed at preventing or treating complications of the disease. When an acute complication occurs, the type and severity of the episode determine the appropriate therapeutic plan.

With availability of public health programs and comprehensive care, most children survive through childhood.12,26,68 The median survival rate is estimated to be 42 years for males and 48 years for females for HbSS, and 60 years for males and 68 years for females for HbSC.12 With increased life expectancy, management of SCD should include assessment of health-related quality of care in both adults and children.

Patients with SCD require lifelong multidisciplinary care. All patients with SCD should receive regularly scheduled comprehensive medical evaluations. Because of the complexity of the disease, a multidisciplinary team is needed to provide high-quality medical care, education, counseling, and psychosocial support. Appropriate comprehensive care can have a positive impact on both longevity and quality of life. This care includes the use of evidence-based treatment combining general symptomatic supportive care, preventative medical therapies, and more specific disease-modifying therapies aimed at altering hematologic capacity and function.

Routine Health Maintenance

Immunizations

Administration of routine immunizations is crucial preventive care in managing SCD. Impaired splenic function increases susceptibility to infection by encapsulated organisms, particularly Pneumococci. Prior to the routine use of penicillin prophylaxis and the development of pneumococcal vaccines, invasive pneumococcal disease was 20- to 100-fold more common in children with SCD than in healthy children. Reduced mortality has been associated with the introduction of pneumococcal vaccines.26,68

Two different pneumococcal vaccines are available. The 13-valent pneumococcal conjugate vaccine (PCV13; Prevnar®) induces good antibody responses in infants and children less than 2 years of age. Immunization with the PCV13 is recommended for all children, regardless of SCD status, younger than 24 months of age. Infants should receive the first dose after 6 weeks of age. Two additional doses should be given at 2-month intervals, followed by a fourth dose at age 12 to 15 months. The 23-valent pneumococcal polysaccharide vaccine (PPSV 23; Pneumovax®23) is recommended for all children with functional or acquired asplenia but must be given after 2 years of age because of poor antibody response. To cover different serotypes, PPSV 23 should be given starting at 2 years of age, and be administered 2 months after the last dose of the 7-valent pneumococcal conjugate vaccine (PCV7)/PCV13. A booster dose of PPSV 23 is recommended 5 years after the first dose. The recommended immunization schedule and catch-up schedule for PCV13 and PPV 23 are presented in Table 82–3. For children ages 2 to 18 years with SCD who did not receive PCV-13 during their routine immunization, a single dose of PCV-13 is recommended.69

TABLE 82-3 Pneumococcal Immunizations for Children with Sickle Cell Disease

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The risk of meningococcal disease is also higher in SCD and meningococcal vaccination is recommended for individuals with functional or acquired asplenia. Three different meningococcal vaccines are available. Meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine (Hib-MenCY-TT) are approved for age 6 weeks through 18 months. The quadrivalent (serogroups A, C, Y, and W-135) meningococcal conjugate vaccines, MenACWY-CRM and MenACWY-D, are approved for age 2 through 55 years. In addition, MenACWY-D is available as a two-dose series for age 9 months through 23 months. Infants with functional asplenia should be vaccinated with the four-dose series of Hib-MenCY-TT at age 6 weeks through 18 months. If the first dose of Hib-MenCY-TT is given at or after 12 months of age, two doses should be given at least 8 weeks apart. Infants 9 through 23 months of age should be vaccinated with the two-dose series of MenACWY-D. Children over 2 years and adults with functional or acquired asplenia should receive a primary immunization series with two doses of the quadrivalent vaccine given 8 weeks apart. A booster is recommended every 5 years for individuals with SCD.70,71 Finally, children 6 months and older and adults with SCD should receive influenza vaccine annually.27

Penicillin

Images Penicillin prophylaxis until at least 5 years of age is recommended in children with SCD HbSS or Hb Sβ0-thal, even if they have received PCV13 or PPSV 23 immunization as prophylaxis against invasive pneumococcal infections. Prophylactic treatment should begin at 2 months of age or earlier. An effective regimen that reduces the risk of pneumococcal infections by 84% is penicillin V potassium at a dosage of 125 mg orally twice daily until the age of 3 years, followed by 250 mg twice daily until the age of 5 years. An alternate regimen is benzathine penicillin, 600,000 units given intramuscularly every 4 weeks for children age 6 months to 6 years, and 1.2 million units every 4 weeks for those over 6 years of age for whom continued therapy is warranted. Individuals who are allergic to penicillin can be given erythromycin 20 mg/kg per day twice daily. Penicillin prophylaxis is not routinely given in older children, based on a study demonstrating no benefit over placebo beyond the age of 5 years. However, continuation of oral pneumococcal prophylaxis should be considered on a case-by-case basis, and is recommended for anyone with a history of invasive pneumococcal infection or surgical splenectomy.1,27


Clinical Controversy…

The need for routine penicillin prophylaxis in HbSC and HbSβ+-thal patients is controversial because these patients have less severe disease. The original trial showing decreased morbidity from invasive infection included children with HbSS or SCA.

Fetal Hemoglobin Inducers

HbF reduces polymer formation of HbS due to its high oxygen affinity. Increased HbF levels significantly correlate with decreased RBC sickling and RBC adhesion and observational studies show a relationship between HbF concentration and severity of SCD. Individuals with SCD and low HbF levels experience more frequent pain and higher mortality. HbF levels of 20% or greater reduce the risk of acute sickle cell complications. Based on these observations, HbF induction has become a treatment modality for patients with SCD.

Hydroxyurea

Hydroxyurea, a chemotherapeutic agent, increases HbF levels by stimulating HbF production. It also increases the number of HbF-containing reticulocytes and intracellular HbF. Its antineoplastic activity is related to inhibition of DNA synthesis by blocking the conversion of ribonucleoside to deoxyribonucleotides. The exact mechanism of HbF production is unknown, but is postulated that the cytotoxic effect in the bone marrow stimulates stress erythropoiesis and triggers rapid erythroid regeneration and shifts erythrocyte hemoglobin production to HbF. In addition, hydroxyurea increases NO levels, reduces neutrophils and monocytes, has antioxidant properties, alters the RBC membrane, increases RBC deformability by increasing intracellular water content, and decreases RBC adhesion to the endothelium.2,5,7

Hydroxyurea can prevent acute sickle cell pain and is FDA-approved for adults with SCD based on the result of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH Trial), a double-blind, placebo-controlled study. In this study, hydroxyurea significantly reduced the frequency of painful episodes, risk of ACS, need for blood transfusions, and number of hospitalizations.56 The study was terminated early after interim analyses showed significant benefits. The incidence of death, stroke, and hepatic sequestration in the hydroxyurea and placebo groups was not significantly different during the evaluation period. However, a follow-up study showed a 40% reduction in mortality with hydroxyurea over a 9-year period.2,27,72

Although hydroxyurea is not FDA approved for use in children and adolescents with SCD, the National Institutes of Health (NIH) has supported several clinical trials investigating its safety and efficacy.7Studies in pediatric patients have demonstrated similar results to the MSH Trial with no adverse effects on growth and development. In addition, some patients treated with hydroxyurea therapy had possible recovery or preservation of splenic and brain functions, including cognitive performances. In patients who cannot tolerate chronic transfusion therapy for stroke prevention, hydroxyurea can prevent recurrent strokes and reduce iron overload from transfusion.2,7,72 The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) evaluated hydroxyurea therapy in young children ages 9 to 18 months.73 Infants were randomized between hydroxyurea and a placebo; the primary endpoints were splenic and renal function. Investigators found no significant difference in the primary endpoints but did find fewer episodes of pain and dactylitis with no significant toxicities. Hydroxyurea reduced the risk of painful events, ACS, renal enlargement, hospitalizations, and transfusions. In addition, improved urine concentration ability, as demonstrated by higher urine osmolality, was reported. No increased risk of infections or genotoxicity was observed in hydroxyurea-treated children.7476

The most common side effect of hydroxyurea is bone marrow suppression, causing neutropenia, thrombocytopenia, anemia, and/or decreased reticulocyte count. These hematologic side effects usually recover within 2 weeks of therapy discontinuation. Other side effects include dry skin and hyperpigmentation of skin or nails.1,2,14 Long-term adverse effects of hydroxyurea therapy in patients with SCD are not fully known, although no serious adverse effects were reported in a long-term (17.5 years) follow-up study of the MSH trial.77 Studies in children have not demonstrated delays in growth or puberty.72Myelodysplasia, acute leukemia, and chronic opportunistic infection associated with T-lymphocyte abnormalities have been reported in other patient populations treated with hydroxyurea. Ongoing follow-up is needed to determine the carcinogenic or leukemogenic effects of hydroxyurea in SCD. Reproductive toxicity is also a concern. High-dose hydroxyurea has been shown to be teratogenic in animals, but normal pregnancies have been reported in women with SCD who received hydroxyurea during pregnancy.78

Clinical indications for hydroxyurea include frequent painful episodes, severe symptomatic anemia, a history of ACS, or other severe vasoocclusive complications. The starting dose for adult is 15 mg/kg per day as a single daily dose (Fig. 82–6). The Baby HUG study found that children can be safely started at 20 mg/kg.73 Dosage can be increased by 5 mg/kg up to a maximum of 35 mg/kg after 8 weeks if the patient can tolerate the adverse effects and blood counts are stable. Hydroxyurea dosage should be individualized based on response and toxicity. In general, 3 to 6 months of therapy are required before improvement is observed. Medication adherence can be an issue. Since the MCV generally increases as the level of HbF increases, monitoring MCV is an inexpensive and convenient method to monitor response and adherence.1,72,79

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FIGURE 82-6 Hydroxyurea use in sickle cell disease. (ACS, acute chest syndrome; ALT, alanine aminotransferase; ANC, absolute neutrophil count; CBC, complete blood cell count; Hb, hemoglobin; HbF, fetal hemoglobin; HbSS, homozygous sickle cell hemoglobin; HBSS β]0 , sickle cell β]0 -thalassemia; MCV, mean corpuscular volume; PE, physical examination; PRN, as needed; RBC, red blood cell.) (From McCavit, 1 Ware and Aygun72 Wang et al., 73Ballas et al., 78 and Heeney and Ware.79)

Images Patients receiving hydroxyurea should be closely monitored for toxicity. Blood counts should be checked every 4 weeks during dose titration and every 8 weeks thereafter. Treatment should be interrupted if hematologic indices fall below the following values: absolute neutrophil count, 2,000 cells/mm3 (2 × 109/L); platelet count, 80,000 cells/mm3 (80 × 109/L); hemoglobin, 5 g/dL (3.1 mmol/L); or reticulocytes, 80,000 cells/mm3 (80 × 109/L) if the hemoglobin concentration is less than 9 g/dL (5.58 mmol/L). Other laboratory abnormalities warranting temporary discontinuation of therapy are a 50% increase in serum creatinine and a 100% increase in transaminases. After recovery has occurred, treatment should be resumed at a dose that is 2.5 to 5 mg/kg per day lower than the dose associated with toxicity. If no toxicity occurs after 12 weeks with the lower dose, the dose can be increased by 2.5 to 5 mg/kg per day. If the increased dose produces hematologic toxicity, the patient should be maintained at the last tolerated dose with no further escalation except for normal growth or weight gain. If no increase in MCV is observed, possible explanations are that the marrow is unable to respond, the hydroxyurea dose is inadequate, or the patient is nonadherent.72,79

5-Aza-2′-Deoxycytidine (Decitabine)

5-Azacytidine and 5-aza-2′-deoxycytidine (decitabine) induce HbF by inhibiting DNA methylation, thus preventing the switch from γ- to β-globin production. Decitabine has been evaluated in a small number of patients with SCD who did not respond to hydroxyurea. In one study of adult patients who were resistant or intolerant to hydroxyurea, an increase in HbF was observed with 5-aza-2′-deoxycytidine at a dose of 0.2 mg/kg one to three times a week subcutaneously. Reduced acute sickle cell pain episodes and improved performance status were reported in four adult patients with severe SCD. The only significant toxicities observed were neutropenia and increased platelet count.5,7 Long-term clinical effects and adverse effects of decitabine have not been fully evaluated. This agent may have a role in treating patients who fail to respond to hydroxyurea. Currently, two trials investigating the use of decitabine in adults with severe SCD are actively recruiting patients (http://www.clinicaltrials.gov; NCT01375608 and NCT01685515).

Chronic Transfusion Therapy

RBC transfusions play an important role in the management of SCD. In acute illness, transfusions can be life saving and the guidelines for acute transfusion are discussed in a later section. Chronic transfusion programs can prevent serious complications of SCD. The primary indication for chronic transfusion is stroke prevention and amelioration of organ damage. Blood transfusion can be administered as a simple transfusion, a manual exchange, or an automated exchange called erythrocytaphresis. Exchange transfusion is associated with higher cost but has the advantage of limiting volume, minimizing hyperviscosity and transfusional iron overload.1,4,18

Images In children with an overt stroke, chronic transfusions are used as secondary stroke prevention and reduce stroke recurrence from about 50% to about 10% over 3 years. An initial stroke in SCD can be devastating and transfusions can be given for primary stroke prevention. Prophylactic transfusions significantly reduced the incidence of first stroke over a 2-year period in children 2 to 16 years of age who were at an increased risk for stroke based on TCD ultrasonography. The risk of stroke was reduced from 16% in patients receiving usual care to 2% in those who received prophylactic transfusions.1,18,34

Chronic transfusions can also reduce the frequency of vasoocclusive pain and ACS and prevent or delay progression of organ damage. They can also reverse preexisting organ dysfunction and improve quality of life, energy levels, exercise tolerance, growth, and sexual development. Chronic transfusions should be considered in selected children and adults with previous stroke or children with abnormal TCD measurements. Chronic transfusions have also been used in patients with severe or recurrent ACS, debilitating pain, splenic sequestration, recurrent priapism, chronic organ failure, intractable leg ulcers, severe chronic anemia with cardiac failure, and complicated pregnancies, although data supporting the efficacy of chronic transfusion in these situations are limited.2,14

The goal of transfusions is to achieve and maintain an HbS concentration of less than 30% of total hemoglobin in the primary and secondary prevention of neurologic complications. Transfusions are usually given every 3 to 4 weeks, but the frequency of transfusion is adjusted to maintain the desired HbS levels. The risk of recurrent stroke decreases after 2 years of transfusion therapy and, in the absence of recurrent stroke, many clinicians will liberalize the HbS goal to less than 50%.2,14,34 The optimal duration of primary prophylactic transfusion therapy in children with abnormal TCD is not clear, but discontinuation of transfusions has been associated with a 50% stroke recurrence rate within 12 months and abnormal blood flow velocity on TCD in children with SCD. For secondary stroke prevention, transfusions should be continued indefinitely.14,34 A pilot study suggested that hydroxyurea could be started prior to discontinuation of transfusion for secondary stroke prevention with at least a 6-month overlap with transfusions.34 However, the phase III trial of switching hydroxyurea for transfusion in secondary stroke prevention, the SWiTCH trial, was closed early due to an increased risk of recurrent strokes in the hydroxyurea arm when compared to transfusions.80

Although the benefits of transfusion therapy are clear in some clinical situations, its role in other situations such as an acute pain episode, priapism, and leg ulcer remains controversial.2,14,18 The risks of transfusion therapy must be weighed against possible benefits. The risks associated with transfusion therapy include alloimmunization (sensitization to the blood received), hyperviscosity, viral transmission, volume overload, iron overload, and nonhemolytic transfusion reactions. The use of leukocyte-reduced RBC transfusions in chronically transfused patients can reduce the risk of nonhemolytic transfusion reactions and viral transmission.2,18 Transfusion-related infections also remain a concern. All patients should be immunized with hepatitis A and B vaccines. Other viruses that can be transmitted through blood products are parvovirus B19, hepatitis C, and cytomegalovirus. The risk of contracting human immunodeficiency virus from blood transfusions, although still of concern, has decreased with routine blood screening.31

Alloimmunization or alloantibody formation occurs in 19% to 37% of SCD patients who receive RBC transfusions and results from antigen differences on the red cell surface between the primarily Caucasian donor pool and recipients with SCD. Alloimmunization can make it difficult to find cross-matched blood and cause delayed hemolytic transfusion reactions. To prevent alloimmunization, patients receiving chronic transfusions should receive the best cross-matched blood including extended typing of other red cell antigens especially C, E, and Kell or full RBC phenotyping.2,18,81

The development of alloimmunization can be life-threatening for individuals with SCD. Delayed hemolytic transfusion reactions (DHTR) usually occur within 7 to 10 days after transfusion but can occur as early as 2 days or as late as 20 days after transfusion. During a DHTR, patients develop symptoms consistent with hemolysis such as worsened pain, especially abdominal pain, severe anemia due to hemolysis of the transfused unit, and reticulocytopenia, further aggravating the anemia. Subsequent transfusions can further worsen the clinical situation because of the presence of multiple antibodies making cross-matching difficult. Life-threatening events can be treated with steroids and IV immunoglobulin. Recombinant erythropoietin has been used in patients with reticulocytopenia. Recovery, as evidenced by reticulocytosis with a gradual increase in the hemoglobin level, may occur only after further transfusions are withheld. Although some patients tolerate further transfusions after recovery, especially if the donor unit is negative for the offending alloantibody, others cannot avoid recurrent transfusions and may experience another hemolytic transfusion reaction. Rituximab has been used in two patients to prevent recurrent DHTR. It is generally preferable to prevent the development of DHTR by performing RBC phenotyping and, at a minimum, transfusing individuals with blood that is C, E, and Kell negative.2,18,81

Transfusional iron overload is another complication of RBC transfusions, and patients should be counseled to avoid excess dietary iron. Abnormal liver biopsy results showing mild-to-moderate inflammation or fibrosis have been reported. Chelation therapy should be considered after more than 1 year of chronic transfusions or when serum ferritin is greater than 1,500 to 2,000 ng/mL (1,500 to 2,000 mcg/L). Two chelating agents are available. Deferoxamine has been used as a chelating agent for decades but must be administered by subcutaneous or IV infusion. Deferasirox, an oral chelator given at a dose of 20 to 30 mg/kg once daily, has shown to be equally effective as deferoxamine and has demonstrated acceptable safety profile in a long-term study for up to 5 years. The most common side effects with deferasirox are transient skin rash and GI symptoms such as nausea, vomiting, diarrhea, and abdominal pain.27,8183

Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic HSCT is currently the only therapy that can cure patients with SCD. The overall survival rate and event-free survival rate for children and young adults with sibling matched donors have been reported at 93% to 97% and 82% to 86%, respectively.84 The largest series included 87 patients aged 2 to 22 years with severe SCD. Transplant-related deaths occurred in six patients, with graft-versus-host disease (GVHD) being the main cause of death in four patients.85 The reported incidences of acute and chronic GVHD ranged from 15% to 20% and 12% to 20%, respectively. Other complications included seizures, marrow rejection, and sepsis. Improved growth, stabilization or improvement of CNS abnormalities, and recovery of splenic dysfunction were observed in posttransplant SCD patients, but gonadal failure and delayed sexual development in females requiring hormonal replacements have been reported.84,86

The optimal candidates for allogeneic HSCT are SCD patients who are younger than 16 years of age; have a severe form of SCD and complications such as refractory pain, stroke, or recurrent ACS; and have an human leukocyte antigen (HLA)-matched sibling donor. Although allogeneic HSCT in young children before organ damage and alloimmunization occur are associated with an increased success, disease progression is unpredictable, making it difficult to determine the optimal time for transplantation. The risks associated with allogeneic HSCT must be carefully considered, as the transplant-related mortality rate is about 5% to 10%, and graft rejection is about 10%. Other risks associated with allogeneic HSCT include secondary malignancies. Neurologic events, such as intracranial hemorrhage and seizures during transplant, were seen more frequently in patients with a history of stroke.85,86

Experience with unrelated HLA-matched or related HLA-mismatched donor transplants is very limited. Unfortunately, many children who are eligible for allogeneic HSCT do not have an HLA-matched sibling donor and unrelated HLA-matched transplants are associated with higher transplant-related mortality. Umbilical cord blood is another potential donor source with specific advantages over marrow donors including a lower incidence of severe GVHD and a larger donor pool from which to select donors, but such advantages are balanced by longer time to engraftment and a higher rate of graft rejection.85Finally, a recent study of the use of nonmyeloablative allogeneic HSCT in 10 adult patients reported mixed donor-recipient chimerism and reversal of SCD and several open clinical trials continue to evaluate the role of reduced-intensity conditioning regimens.87

Treatment of Acute Complications

General Management

Parents and older children should be educated on the signs and symptoms of complications and conditions that require urgent evaluation. During acute illness, patients should be evaluated promptly, as deterioration can occur rapidly. Fluid balance should be maintained because dehydration and fluid overload can worsen complications associated with SCD. Oxygen saturation by pulse oximetry should be maintained at least 92% or at baseline. New or increasing supplemental oxygen requirements should be investigated.14,18

Episodic Transfusions

Indications for RBC transfusions include (a) acute exacerbation of baseline anemia, such as aplastic crisis if the anemia is severe, hepatic or splenic sequestration, or severe hemolysis; (b) ACS, stroke, or acute multiorgan failure; and (c) preparation for procedures that require the use of general anesthesia. Other patients in whom chronic transfusions can be useful include patients with complicated obstetric problems, refractory leg ulcers, or refractory and protracted painful episodes. Acute transfusion is not indicated for priapism, uncomplicated pain, or asymptomatic anemia. Simple transfusion or partial exchange transfusion can be used though red cell exchange has been shown to have superior outcomes when compared to simple transfusion in overt stroke. If simple transfusion is used, volume overload leading to congestive heart failure can occur if anemia is corrected too rapidly in patients with severe anemia. In addition, increases in hemoglobin levels to greater than 10 g/dL (6.2 mmol/L) can cause hyperviscosity and should be avoided.2,18,81

Infection and Fever

Patients with SCD should be evaluated as soon as possible for any fever greater than 38.5°C (101.3°F). Criteria for hospitalization include an infant younger than 1 year, history of previous bacteremia or sepsis, temperature greater than 40°C (104°F), WBC greater than 30,000 cells/mm3 (30 × 109/L) or less than 5,000 cells/mm3 (5 × 109/L) and/or platelets less than 100,000 cells/mm3 (100 × 109/L), and evidence of other acute complications or toxic appearance. Outpatient management can be considered in older nontoxic children with reliable family caregivers. Antibiotic choice should provide adequate coverage for encapsulated organisms.1,31

Images Ceftriaxone should be used for outpatient management because it provides coverage for 24 hours. If admitted, cefotaxime can also be used. For patients with cephalosporin allergy, clindamycin can be used. Vancomycin should be considered for acutely ill children or if Staphylococcus is suspected. A macrolide antibiotic should be added if M. pneumoniae is suspected such as in ACS. Penicillin prophylaxis should be discontinued while the patient is receiving broad-spectrum antibiotics. Acetaminophen or ibuprofen can be used for fever control. Increased fluid requirements may be present because of poor oral intake and/or increased insensible losses contributing to dehydration.1,2,31

Cerebrovascular Accidents

Patients with acute neurologic events must be hospitalized and monitored closely. Physical and neurologic examination should be performed every 2 hours. Acute treatment for children should include exchange transfusion to maintain hemoglobin at about 10 g/dL (6.2 mmol/L) and HbS less than 30%, anticonvulsants for patients with a seizure history, and therapy for increased intracranial pressure if needed. Chronic transfusion therapy should be initiated for children with ischemic stroke as discussed earlier. In adults presenting with ischemic stroke related to atherosclerotic disease and not occlusion by sickled red cells, thrombolytic therapy should be considered if it is less than 3 hours since the onset of symptoms.1,14,34

Acute Chest Syndrome

Patients with ACS should use incentive spirometry frequently (e.g., at least every 2 hours while awake) to reduce atelectasis development. In addition, proper management of pain is important. The goal is to provide relief while avoiding analgesic-induced hypoventilation. Appropriate fluid therapy is important as overhydration can cause pulmonary edema and exacerbate respiratory distress. Early use of broad-spectrum antibiotics, including a macrolide or quinolone in adults, is also recommended. Studies indicate that infection is the most common cause of ACS and can involve gram-positive, gram-negative, or atypical bacteria. Oxygen therapy is indicated for all patients who are hypoxic or in acute distress. In a patient with a history of reactive airway disease, asthma or wheezing on examination, a trial of bronchodilators is appropriate. Transfusions are indicated for severe ACS with worsening hypoxia and increased work of breathing.1,14,39

Steroids can decrease inflammation and endothelial cell adhesion. Glucocorticoids can decrease the duration of hospitalization and need for transfusions and other supportive care but can also increase the readmission rate for other SCA-related complications. Another promising therapy is the use of NO, which relaxes and dilates blood vessels. Its hematologic effects include inhibition of platelet aggregation and reduction in the polymerization tendency of HbS. Marked improvement of pulmonary status and cardiac output were reported in a patient with ACS. Inhaled NO and oral L-arginine, the precursor of NO, are being evaluated for management of ACS in both children and adults.1,27,39,40

Priapism

Stuttering priapism, episodes that last a few minutes to 2 hours, may resolve spontaneously with exercise, warm bath, and oral analgesics. Prolonged episodes lasting more than 2 to 3 hours require prompt medical attention. The initial goals of treatment are to provide appropriate analgesic therapy, reduce anxiety, produce detumescence, and preserve testicular function and fertility. Treatment given within 4 to 6 hours can usually reduce erection. Aggressive hydration and adequate pain control should be initiated. Use of ice packs is not recommended. Heat (hot water bottles, hot packs, or sitz baths) can provide comfort without precipitating pain crisis. Although transfusions have been given to these patients, the efficacy of this therapeutic intervention has not been established and is associated with severe neurologic sequelae.42,43

Clinicians have used both vasoconstrictors and vasodilators in the treatment of priapism. Vasoconstrictors, such as diluted phenylephrine (10 mcg/mL) or epinephrine (1:1,000,000), are thought to work by forcing blood out of the corpus cavernosum into the venous return. In one uncontrolled open-label study, aspiration followed by intrapenile irrigation with epinephrine was effective and well tolerated. In that study, blood was first aspirated from the corpus cavernosum, and then the area was irrigated with a 1:1,000,000 solution of epinephrine. The priapism resolved in 37 of the 39 occasions. A follow-up study reported that 3 out of 20 patients required a repeat procedure within 24 hours. The therapy was well tolerated with no serious immediate or long-term side effects, but on two occasions, a small intrapenile hematoma formed after treatment. Detumescence can be achieved more rapidly using penile irrigation than simple transfusion but the procedure should be performed by an urologist with experience in the treatment of priapism.43,8890

Vasodilators, such as terbutaline and hydralazine, relax the smooth muscle of the vasculature. This relaxation allows oxygenated arterial blood to enter the corpus cavernosum, which displaces or washes out the damaged sickle cells that are stagnant in the corpus cavernosum. Terbutaline has been used to treat priapism, but it has not been formally studied in patients with SCD.43,90 In one case report, a single oral sildenafil dose at onset of priapism aborted episodes. However, long-term studies of sildenafil have shown an increase in the frequency of pain episodes (http://www.clinicaltrials.gov NCT00492531). Surgical interventions used in severe refractory priapism have included a variety of shunt procedures. These surgical procedures have been successful in some cases, but they have a high failure rate and potential serious complications, which include impotence, skin sloughing, cellulitis, and urethral fistulas.42

Modalities to prevent priapism are limited and not well studied. Pseudoephedrine (30 or 60 mg/day given orally at bedtime) and leuprolide, a gonadotropin-releasing hormone, have been used to decrease the number of recurrent episodes of priapism. Hydroxyurea therapy can also be useful although the effect of hydroxyurea on the prevalence of priapism has not been formally investigated. Finally, antiandrogens (bicalutamide and finasteride) have been used in SCD for treatment of recurrent or refractory priapism without major side effects. The role of RBC transfusion in preventing priapism remains unclear and transfusion is not recommended for long-term management.1,43,90


Clinical Controversy…

Some clinicians transfuse patients to maintain an HbS level less than 30% to prevent recurrent priapism. Duration of such regimens should be limited to 6 to 12 months. Clinical practice guidelines do not recommend chronic transfusion to prevent recurrent priapism.

Aplastic Crisis

Treatment of aplastic crisis is primarily supportive, and most patients recover spontaneously in 5 to 10 days. The only treatment may be RBC transfusions if the anemia is severe or symptomatic. The reticulocyte count is used to detect the suppression of red cell production and the need for transfusion. The most common cause, parvovirus B19, is contagious and infected patients should be placed in isolation. In addition, contact with pregnant healthcare providers should be avoided because parvovirus infection during the midtrimester of pregnancy can result in hydrops fetalis and stillbirth.14,18,31

Splenic Sequestration

Splenic sequestration crisis is a major cause of mortality in young children with SCD. The sequestration of RBCs in the spleen can result in a rapid drop of hemoglobin, leading to hypovolemia, shock, and death. Immediate treatment with RBC transfusions is indicated to correct hypovolemia. Broad-spectrum antibiotic therapy, which includes coverage for pneumococci and H. influenzae, can also be beneficial if the patient is febrile as infection can precipitate sequestration.1

Recurrent episodes occur in about half of patients and are associated with increased mortality. Options for management of recurrence include observation, chronic transfusion, and splenectomy. Increased risk of invasive infection after splenectomy is a concern in very young children, but most experts agree individuals with HbSS develop splenic dysfunction as early as 6 months of age and have acquired asplenia by 5 years of age and by 10 to 12 years for those with Hb SC. Splenectomy is probably indicated, even after a single sequestration crisis, if that sequestration was life threatening. Splenectomy should be considered after repetitive episodes, even if they are less serious. For children younger than 2 years of age, chronic blood transfusions are recommended by some experts, though not supported by evidence, to prevent sequestration and delay splenectomy until the age of 2 years, when the risk of postsplenectomy septicemia is lower and pneumococcal vaccination has been completed. Finally, splenectomy should also be considered for patients with chronic hypersplenism.27,91

Acute Sickle Cell Pain

Hydration and analgesia are the mainstays of treatment for vasoocclusive (painful) episodes (Table 82–4). Patients with mild pain crisis can be treated as outpatients with rest, increased fluid intake, warm compresses, and oral analgesics. Hospitalization is necessary for moderate to severe pain or when oral analgesics fail to relieve pain. A pain episode may be precipitated by several risk factors including infection. In the setting of pain and fever, an infectious etiology should be evaluated, and appropriate empiric therapy should be initiated in patients who have fever or are critically ill. In patients with severe symptomatic anemia, transfusions may be indicated. Fluid replacement given IV or orally to correct or prevent hydration at 1 to 1.5 times the maintenance requirement is recommended. Close monitoring of fluid status is essential as aggressive hydration, particularly with sodium-containing fluids, can lead to volume overload, ACS, and heart failure.92,93

TABLE 82-4 Management of Acute Sickle Cell Pain

Images

The frequency and severity of acute pain episodes associated with SCD are variable. Pain should be assessed and analgesic therapy should be tailored for each patient and each individual episode. Several verbal and nonverbal pain assessment tools are available and should be used to measure the intensity of pain. Unfortunately, they have not been validated for sickle cell pain. However, pain scales validated for use in children, such as the Wong-Baker FACES scale, should be used in pediatric patients with SCD pain. The healthcare provider should choose one tool appropriate for age and use it routinely to assess pain. Other useful information to guide choice of analgesics should include previous effective agents and their dosages, response to therapy and previous clinical course, and duration of pain episodes.14,92,93

Images Aggressive therapy that relieves pain and enables the patient to attain maximum functional ability should be initiated in patients with acute pain. Mild-to-moderate pain should be treated with nonsteroidal antiinflammatory drugs (NSAIDs) or acetaminophen, unless there are contraindications to their use (Table 82–5). Ketorolac may be useful for patients requiring IV therapy. Because of concerns about GI bleeding, it is recommended to limit the duration of therapy to 5 days or less. Ketorolac has also been associated with acute nonreversible kidney failure in a patient with SCD and should be used with caution and renal function monitored appropriately. When acetaminophen is used, it is important to monitor the total dose of acetaminophen administered in patients who may also be receiving the agent for fever or another acetaminophen-containing product for pain. If mild-to-moderate pain persists, an opioid should be added. Effective combination therapy, such as an NSAID combined with an opioid, can enhance analgesic efficacy while decreasing side effects.14,9294

TABLE 82-5 Commonly Used Analgesics Dosing Table

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Severe pain should be treated aggressively until the pain is tolerable. Commonly used opioids include morphine, hydromorphone, fentanyl, and methadone (Table 82–5). The weak opioids, codeine and hydrocodone, are used to manage mild-to-moderate pain usually in the outpatient setting. Meperidine has no advantages as an analgesic and significant negative sequelae. Its duration of action is short compared with the half-life of the metabolite normeperidine, which accumulates and can cause CNS side effects, ranging from dysphoria to seizures. Meperidine is contraindicated for use in children to treat acute pain and should be avoided if possible and used only for a very brief duration in adult patients who are allergic or intolerant to other opioids.9294

Both prior history and current assessment should be considered in the management of acute sickle cell pain. For patients whose typical pain improves in a short time, preparations with a short duration of action are appropriate. For patients whose pain requires many days to resolve, sustained-release preparations combined with a short-acting product for breakthrough pain are more appropriate. If the patient has been on long-term opioid therapy at home, tolerance can develop. In these cases, the acute pain can be treated with an opioid of different potency or a larger dose of the same medication. IV administration provides a rapid onset of action and therefore is preferred for severe pain. Intramuscular injections should be avoided. Children may actually deny pain due to fear of injections. Analgesics should be titrated to pain relief. In patients with continuous pain, the analgesic should be given as a scheduled dose or continuous infusion. Continuous infusion has the advantage of less fluctuation of blood levels between dosing intervals. As needed dosing is only indicated for breakthrough pain. Patient-controlled analgesia (PCA) is commonly prescribed for severe pain episodes. When used properly, PCA allows patients to have control over pain therapy and minimizes the lag time between perception of pain and administration of analgesics. Studies have shown PCA reduced cumulative dosage required for pain control. The transdermal fentanyl patch has also been used successfully, but its role in sickle cell pain crisis is unclear because of its slow onset of onset of pain relief (12 to 16 hours) and fixed dosage form, which makes it difficult to titrate the dose. Other alternative pain management techniques such as physical therapy, massage, biofeedback, and relaxation therapy can be helpful as adjunct therapy.27,9294

Suboptimal pain relief has been reported in both emergency room and hospitalized patients. The most common cause of suboptimal pain control in children and adults with SCD is the suspicion of addiction. This obstacle is especially common in adolescents. In one study, 53% of emergency physicians believed that 20% of SCD patients are psychologically addicted to opioid analgesics. Another barrier to effective pain control is the difference in perception between patients, family, and healthcare providers. Patients with SCD often suffer from chronic pain, and they may cope with the pain by being inactive. Patients who have inadequate pain control can exhibit anxiety and drug-seeking behavior for fear of pain. Tolerance to opioids may also be misinterpreted as drug addiction by healthcare providers and families. Aggressive pain control, frequent monitoring of pain during episodes, and tapering medication according to response are factors that minimize physical dependence. The use of a protocol has been shown to result in optimal management of pain control in SCD.9294

Inhaled NO has been studied as therapy to abort pain at onset of episodes. Significant reduction of pain scores in adult patients received inhaled NO in the emergency room.95 However, no differences in duration of episodes, hospital stay, or opioid use when given to hospitalized adult and pediatric patients were observed.96 Systemic corticosteroids, methylprednisolone and dexamethasone, have also been evaluated as an adjunct therapy for pain control. Shorter duration of analgesic therapy and duration of hospitalization were reported but increased risk of readmission was also reported.97

PERSONALIZED PHARMACOTHERAPY

The mainstay of treatment in SCD involves medical therapy for supportive care and disease modification. Medical therapy is usually individualized by weight-based dosing. However, newer approaches are being evaluated to personalize therapy based on pharmacokinetics and pharmacodynamics. For example, many adults with SCD have abnormal renal function due to intrarenal sickling. The most important disease modifying medication, hydroxyurea, is renally excreted with urinary recovery of 40% of the administered dose in adults with SCD. A lower initial dose of 7.5 mg/kg per day is recommended for individuals with creatinine clearance of less than 60 mL/min.7,98Pharmacokinetic differences between adult and pediatric patients were not reported in the initial study of a small cohort of SCD patients.7 As a result, investigators designed a prospective clinical trial, the Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175), to evaluate interpatient variability among children taking hydroxyurea. For the first-dose pharmacokinetic studies, 51 of 87 patients showed a “fast” absorption profile with an earlier and higher maximum concentration after a single dose of 20 mg/kg. Pharmacodynamic analysis identified several parameters that were associated with maximum tolerated dose (MTD) and HbF at MTD. However, prediction of response to hydroxyurea based on pharmacokinetic and pharmacodynamic parameters was unsatisfactory and the investigators concluded that standardized dose escalation to myelosuppression remains to be the best option.99

Adults and children with SCD require the use of acute and chronic pain medications including opioids to control painful episodes. Some patients have inadequate relief to codeine. Children who failed oral therapy with codeine were found to have a polymorphism in the CYP2D6 gene which results in a poor metabolizer phenotype. The CYP2D6 enzyme mediates the conversion of codeine to morphine. These results can lead to early discontinuation of codeine analgesics in children with SCD if no response is observed after their first dose and the use of alternative oral analgesics for the treatment of pain at home. In patients with SCD, analgesia is sometimes not obtained even with very high IV opioid doses. Several enzymes that are involved in morphine metabolism may be altered in patients with SCD including UGT2B7, a morphine-metabolizing enzyme; OPRM1, a mu-opioid receptor or ABCB1, a transporter protein at the blood–brain barrier. Further studies are needed to evaluate the importance of genetic variations in these enzymes.100

The concept of personalized therapy in SCD is now evolving with the identification of single nucleotide polymorphisms (SNPs) associated with disease severity and HbF responses to hydroxyurea therapy. Genome-wide association studies have identified several loci in HbF expression. BCL11A is a transcription factor that regulates hemoglobin switching and could account for the variability of HbF levels between individuals with high and low HbF. Different biomarkers have been studied in SCD to identify complications and phenotypic variability. The potential use of biomarkers and genome-based modification of phenotype in SCD may allow personalized therapeutic approaches in the future.2,3,7

EVALUATION OF THERAPEUTIC OUTCOMES

Images SCD is a complex disorder that requires multidisciplinary comprehensive care. All patients should be medically evaluated regularly to provide preventive care, establish baseline symptoms and laboratory values, monitor changes, and provide education appropriate for age. For infants younger than 1 year old, medical evaluations every 2 to 4 months are needed. Beyond 2 years of age, evaluation can be extended to every 6 to 12 months with modifications depending on severity of the illness.

Routine laboratory evaluation including complete blood cell counts and reticulocyte counts every 3 to 6 months up to 2 years of age, then every 6 to 12 months; the HbF level should be screened annually until 2 years of age, then annually. Evaluation of renal, hepatobiliary, and pulmonary function should be done annually. TCD screening is recommended to start at age 2 years and performed annually for children with HbSS and HbSβ0. Ophthalmologic examination to screen for retinopathy is recommended at around age 10 to 12 years for those with HbSC and 14 years for HbSS. In patients with recurrent ACS, pulmonary function tests should be done to establish baseline values and identify declines in lung function as well as an evaluation by pulmonology to screen for lower airway hyperresponsiveness.

It is essential that immunizations and prophylactic antibiotics be given. When infections do occur, appropriate antibiotic therapy should be initiated, and the patient should be monitored for laboratory and clinical improvement. The efficacy of hydroxyurea can be measured as a decrease in the number, severity, and duration of sickle cell pain episodes. HbF concentrations or MCV values can also provide some indication of the patient’s response to therapy. When painful episodes do occur, the effectiveness of analgesics can be measured by subjective assessments made by the patient, family, and healthcare practitioners. The success of poststroke blood transfusions can be measured by clinical progression or the occurrence of subsequent strokes. Finally, indicators can be used for measurements of quality of care for children with SCD.

ABBREVIATIONS

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