Sickle Cell Disease

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53 Sickle Cell Disease

Connie M. Piccone

More than 100,000 Americans are affected with sickle cell disease (SCD), making it one of the most prevalent genetic disorders in the United States. The majority of affected individuals are of African or Mediterranean descent; this is related in part to the “natural selection” process because being a carrier of sickle hemoglobin (Hb) confers some resistance to malarial infection and a resultant survival advantage. The carrier rate among African Americans is approximately 8% (one in 12). Individuals with SCD can exhibit significant morbidity and mortality related to chronic hemolysis. Each year in the United States, an average of 75,000 hospitalizations are attributable to SCD, costing approximately $475 million. Neonatal screening, confirmatory diagnostic testing, family education, and routine comprehensive care of patients with SCD are imperative in reducing the morbidity and mortality of this lifelong disease.

Etiology and Pathogenesis

SCD is a group of inherited hemoglobinopathies associated with hemolytic anemia and vaso-occlusive complications. All forms of SCD are inherited in an autosomal recessive fashion and are the result of mutations in the two β-globin genes. β-Globin is one of the major components of adult Hb and is part of a group of genes involved in oxygen transport. Two β-globin chains combine with two α-globin chains to form the predominant Hb found in human adults, HbA. In HbS, an amino acid substitution from glutamic acid to valine ultimately leads to the polymerization of HbS molecules, causing the “sickling” effect (Figure 53-1)

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Figure 53-1 Sickled red blood cells.

The most common form of SCD is homozygous SS. Other variants of SCD are the result of compound heterozygotes for HbS and other β-globin variants, including SC as well as Sβ+ thalassemia and Sβ0 thalassemia. All individuals who are homozygous or compound heterozygous for HbS exhibit some clinical manifestations of SCD. Symptoms usually appear by the first 6 months of life when fetal Hb dissipates, but there may be late presentations as well. There is considerable variability in clinical severity, which is related to genotype (Table 53-1). Patients with SS have the most severe clinical phenotype followed by individuals with Sβ0 thalassemia. Those with SC and Sβ+ thalassemia tend to have milder clinical phenotypes.

Table 53-1 Sickle Hemoglobinopathies: Neonatal Screening and Diagnostic Tests

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Whereas SCD was once seen as a disease in which morbidity and mortality were directly related to vascular occlusion by red blood cell (RBC) sickling alone, it is now evident that chronic hemolysis secondary to endothelial dysfunction and vasculopathy plays a significant role in morbidity. Researchers have found that the release of Hb and arginase from hemolyzed RBCs leads to nitric oxide (NO) bioavailability, thereby resulting in increased oxidative stress and accelerated intravascular hemolysis. SCD confers a state of NO resistance, and animal studies have provided evidence that a reduction in NO is associated with vasoconstriction, decreased blood flow, platelet activation, and end-organ injury.

Clinical Presentation

SCD has a variable presentation in pediatric patients. Symptoms common to many patients include pallor and scleral icterus from the chronic hemolytic anemia, vaso-occlusive episodes, acute chest syndrome, splenic sequestration, and susceptibility to bacterial infections. Infection is the most common cause of mortality among children with SCD. Two infection prevention strategies—vaccination and penicillin prophylaxis—have significantly reduced mortality.

Diagnostic Approach

Currently in the United States, SCD testing is a standard component of newborn screening. Approximately 2000 infants with SCD are identified annually by national newborn screening programs. Patients with an abnormal newborn screen concerning for SCD should be referred to a pediatric hematologist. Confirmatory testing should be performed with Hb identification, molecular genetic testing (if available), and parental testing. Most importantly, when reviewing the results of a newborn screen, all patients with SS, Sβ0 thalassemia, and SC will have no HbA present, and patients with Sβ+ thalassemia will have some HbA, but the predominant Hb is HbS. In patients with sickle cell trait, the newborn screening will reveal FAS, in which the predominant Hbs are HbF and HbA (see Table 53-1).

Management and Therapy

Acute Complications

Fever

Patients with SCD are at increased risk for certain bacterial infections secondary to functional asplenia, decreased opsonic activity in the serum, and poor antibody response to the polysaccharide component of the bacterial capsule. Bacterial sepsis remains one of the most common causes of death. Therefore, febrile illnesses are emergencies and require prompt medical evaluation and antibiotic administration. Immediate medical attention is required for all children with SCD who have temperatures greater than 38.4°C or 101°F. The evaluation should include a complete blood count (CBC), reticulocyte count, blood culture, physical examination, and pulse oximetry. Intravenous (IV) antibiotics should be given promptly and should have adequate coverage against Streptococcus pneumoniae and Haemophilus influenza; ceftriaxone is frequently used. A chest radiograph should be considered in patients younger than 3 years of age in whom an adequate lung examination may not be able to be obtained.

Vaso-occlusive Episodes

Patients with acute pain require prompt evaluation and treatment. At initial presentation, it is important to determine the cause of pain based on location and patient presentation because pain is not always related to SCD (Table 53-2). Assessment of pain should include age- and developmentally appropriate tools. Uncomplicated pain crises can be managed at home. Nonpharmacologic measures to help manage pain symptoms can be extremely helpful and include a heating pad or hot packs, massage, and play activities. Pharmacologic management of vaso-occlusive episodes (VOEs) includes a combination of nonsteroidal antiinflammatory drugs (NSAIDs such as ibuprofen or ketorolac) and oral or IV analgesics (Tylenol, codeine, morphine, hydromorphone) (Table 53-3). It is important to adjust therapy according to the degree of pain (i.e., switching from oral to IV formulations) and to order medications to be given at scheduled intervals.

Table 53-2 Differential Diagnosis and Further Evaluation of Pain

Location of Pain Other Conditions to Consider Additional Studies to Consider
Head or face
• Hemorrhagic stroke
• Sinusitis
• Migraines
• Meningitis

• MRI or MRA
• CT
• LP

Neck or throat
• Meningitis
• Torticollis
• Pharyngitis or tonsillitis

• LP
• Throat culture

Chest
• Acute chest syndrome, pneumonia, RAD
• Costochondritis
• Cardiac
• GER
• Chest radiography
• ECG or echocardiography
Abdomen
• Appendicitis
• Cholelithiasis or cholecystitis
• Pancreatitis
• Splenic sequestration
• Urinary tract infection or pyelonephritis
• Abdominal radiography
• Abdominal ultrasonography
• Amylase or lipase
• UA, ÷±culture
Limb or joint
• Osteomyelitis
• Septic joint
• Avascular necrosis
• Painless limp may indicate stroke
• Plain radiography
• Ultrasonography
• MRI or MRA

CT, computed tomography; ECG, electrocardiography; GER, gastroesophageal reflux; LP, lumbar puncture; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; RAD, reactive airway disease; UA, urinalysis.

Adapted from Children’s Hospital of Philadelphia Department of Hematology: Guidelines for Patient Management, July 1999.

Table 53-3 Guide to Common Pain Medications

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Acute Chest Syndrome

Acute chest syndrome (ACS) is a common complication in SCD and is defined by respiratory symptoms (i.e., cough, chest pain), fever, and evidence of a pulmonary infiltrate on chest radiography. Fever and cough are the most common presenting symptoms in patients with ACS. Radiographic findings are somewhat variable and, in the absence of an infiltrate, patients should be treated presumptively for ACS if there is a strong clinical suspicion. Infiltrates may not appear on chest radiography. until 2 to 3 days after initial presentation. The cause of ACS is diverse and includes microbial infection, vaso-occlusion, fat embolism from ischemic bone marrow, and thromboembolism. In the 1970s, clinicians believed that most cases of ACS were caused by infection by S. pneumoniae, but more recent epidemiologic studies have revealed a change in ACS infectious epidemiology. Mycoplasma spp. and Chlamydia pneumoniae are also common bacterial causes of infection as well as respiratory viruses. The current antibiotic treatment for ACS should include coverage for S. pneumoniae and atypical microorganisms, for example, erythromycin and a cephalosporin. Patients may develop an oxygen requirement, and close monitoring is essential to prevent significant morbidity, including respiratory failure necessitating intubation. Patients with more severe symptoms benefit from a simple blood transfusion to improve oxygen-carrying capacity and decrease sickle Hb levels.

Splenic Sequestration

Acute splenic sequestration is defined as a decrease in Hb in association with a rapidly enlarging spleen and evidence of increased bone marrow activity. Parental education helps establish early diagnosis, and prompt medical treatment decreases morbidity and mortality. Parents should be instructed on how to palpate the spleen and monitor for signs of splenomegaly and sequestration at home. Patients who require hospital admission should have an IV line placed with the administration of IV fluids. Blood should be sent for CBC, reticulocyte count, and type and screen. The spleen size should be documented and monitored closely. The CBC and physical examination should be repeated at frequent intervals to assess the degree of sequestration and the potential need for RBC transfusion. Children who experience splenic sequestration are at risk for recurrent events. In children with recurrent events, prevention strategies should be considered, including either chronic transfusion or splenectomy.

Transient Red Blood Cell Aplasia

Approximately 70% to 100% of transient RBC aplasia in patients with SCD is caused by parvovirus B19 infection. Infection with parvovirus causes a reticulocytopenia for approximately 7 to 10 days. Because patients with SCD have a decreased RBC lifespan of 10 to 20 days (normal RBC life span is 90-120 days), they develop significant anemia during the period of reticulocytopenia. Clinically, patients can present with pallor, headache, and a marked decrease in their Hb level. The hallmark is a low reticulocyte count, indicating suppression of bone marrow activity. Blood transfusion is indicated in patients with significant anemia who are symptomatic.

Acute Stroke

Stroke is a major complication of SCD and occurs in approximately 11% of pediatric patients. The most common cause of stroke is obstruction of a distal intracranial internal carotid artery or proximal middle cerebral artery. The cause of stroke in this population is thought to be secondary to an arterial vasculopathy from progressive intimal hyperplasia. Signs and symptoms can include mild weakness to frank hemiparesis, visual and language disturbances, seizures, and altered mental status. If neurologic symptoms resolve in less than 24 hours and there is no evidence of brain ischemia, those events are termed transient ischemic attacks. If a patient presents with concern for an ischemic event, prompt evaluation and treatment are warranted. After initial stabilization, patients should undergo noncontrast computed tomography scan of the brain to rule out hemorrhage or other non-ischemic causes of symptoms followed by imaging with magnetic resonance imaging (MRI) and angiography (MRA). The treatment for patients with an acute stroke is RBC transfusion to decrease the percent HbS to less than 30%. If possible, exchange transfusion is preferred because it avoids the risk of hyperviscosity, which can lead to further cerebral injury.

Priapism

Priapism is defined as a sustained, painful penile erection. Related to vaso-occlusion, priapism occurs because there is an obstruction to the venous drainage of the penis. Prolonged priapism (an erection lasting more than 3 hours) is an emergency that requires prompt urologic consultation and evaluation. Treatment should include hydration and pain control. Prolonged episodes may require penile aspiration. Additional medications have also been used, including α-agonists (pseudoephedrine) and β-agonists (terbutaline). Recurrent episodes can lead to penile fibrosis and often impotence.

Routine Health Maintenance

Immunizations

Children with SCD should receive all routine childhood immunizations. In addition, patients should receive the 23-valent pneumococcal vaccine (Pneumovax) at age 2 years with a booster shot given at 5 years of age. They should also receive the influenza vaccine annually.

Penicillin Prophylaxis

Penicillin prophylaxis for SCD was widely introduced after the PCN Prophylaxis Studies of the 1980s found a significantly reduced incidence of pneumococcal infections in individuals younger than 5 years of age. Prophylaxis should be started at 2 months of age with oral penicillin VK; children younger than 3 years of age should take 125 mg twice daily, and those 3 years and older should take 250 mg twice daily. Patients with a penicillin allergy can take erythromycin 10 mg/kg/dose twice a day. Prophylaxis after the age of 5 years does not appear to significantly reduce the risk of pneumococcal infection compared with placebo. Continuation of penicillin prophylaxis after the age of 5 years is optional.

Folic Acid

Daily folic acid supplementation (1 mg/d) is recommended for patients with SCD secondary to increased RBC production and to prevent bone marrow aplasia from folate deficiency.

Nutrition and Growth

Children with SCD may have deficiencies in some vitamins and minerals, including fat-soluble vitamins and zinc. Additionally, patients have a delay in growth likely related to increased caloric requirements caused by chronic anemia. Families should be encouraged to adopt healthy eating habits, and patients should be monitored closely for growth and development. Nutritional supplements can be initiated if there are concerns about increasing growth delay. Patients can also take a daily multivitamin without iron.

Stroke Screening

As mentioned previously, stroke is a major complication of SCD. Patients with silent infarctions as well as overt stroke can experience significant neurocognitive impairment, making routine evaluation imperative. The use of screening transcranial Doppler (TCD) ultrasonography has lead to the early identification of vessel abnormalities and the identification of patients who are at high risk for stroke. Patients with SCD, type SS and Sβ0 thalassemia, should have a yearly TCD performed beginning at 2 years of age. Normal TCD rates are less than 170 cm/sec, patients with a conditional TCD (170-199 cm/sec) should be followed more closely, and those with an abnormal TCD (>200 cm/sec) should have an MRI or MRA of the brain performed and a chronic transfusion protocol initiated with the goal of maintaining the patient’s trough HbS level at less than 30%.

Eye Examinations

All SCD patients should have yearly ophthalmologic screening, including a dilated funduscopic exam, to monitor for vascular retinopathy, starting at age 5 years.

Chronic Issues

Transfusion and Chelation Therapy

Chronic RBC transfusion is a treatment modality in SCD used to treat and prevent disease-related complications, including stroke, recurrent VOE, and recurrent ACS. Prevention of neurologic complications is the most common reason for initiating a transfusion program. Transfusions help by decreasing the overall HbS percentage and increasing oxygen-carrying capacity. However, risks are associated with chronic transfusion, including alloimmunization (patients develop RBC antibodies) and iron overload. Because humans are unable to effectively excrete excess iron, it is necessary to use medications for iron chelation in patients with transfusional iron overload. The chelators currently in use include deferoxamine (Desferal), which is typically given as a 12-hour infusion IV or subcutaneously, and deferasirox (Exjade), an oral medication given once daily.

Excess iron deposits primarily in the heart and liver can lead to significant organ dysfunction and subsequent organ failure if not treated. MRI can be used to assess both cardiac and hepatic iron overload. Serum ferritin levels are also used to monitor iron overload, although ferritin measurements can be unreliable in patients with SCD because ferritin is an acute phase reactant and SCD is a chronic inflammatory state. Another option to minimize iron loading is erythrocytapheresis. Erythrocytapheresis (or RBC exchange) involves removing a patient’s RBCs and replacing them with normal RBCs. With exchange transfusion, there is less overall iron loading. However, erythrocytapheresis requires more blood per procedure compared with a simple transfusion, thus exposing patients to more donor units.

Hydroxyurea

Hydroxyurea is a drug used to increase fetal Hb levels, thereby increasing oxygen-carrying capacity, decreasing sickle Hb levels, and reducing many of the morbidities related to chronic hemolysis and hypoxia. Overall, it is a well-tolerated medication, but it can cause myelosuppression, so patients taking this drug are monitored closely.

Avascular Necrosis

Generally seen in patients with Hb SS, avascular necrosis (AVN, also known as osteonecrosis) is a painful destruction of bone related to sickle vasculopathy with thrombosis and joint ischemia. The femoral and humeral heads are most often involved. In pediatric patients, initial treatment is conservative and includes analgesics, NSAIDs, and physical therapy for weight-bearing recommendations. Joint-preserving surgical procedures can be used, including core decompression and osteotomy. No treatment has been found that can reverse or stop the progression of AVN. There is progressive flattening and eventual bony collapse of the femoral or humeral head. If the joint has collapsed, patients can have a joint replacement after the growth plate has closed.

Future Directions

Bone marrow transplantation (BMT) has been successful in multiple centers across the globe but has not become standard practice because of treatment-related complications and morbidities as well as disagreement on the timing of BMT in SCD patients. The first case report of BMT for SCD was published in 1984. Since that time, several groups have studied the efficacy of BMT in treating SCD in children with more severe complications, but there have not been any randomized controlled trials to provide clear evidence for the use of BMT in pediatric SCD. Newer BMT protocols using reduced-intensity conditioning may result in an increase in BMT referrals, but attempts at limiting side effects from conditioning may ultimately result in graft failure. In sum, the decision to recommend BMT for a pediatric SCD patient must be made carefully with input from the primary hematologist, the transplant team, and the family.

Suggested Readings

Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (Hb S) and sickle cell disease: a HuGE review. Am J Epidemiol. 2000;151(9):839-845.

Dunlop RJ, Bennett KCLB: Pain management for sickle cell disease, Cochrane Database Syst Rev (2):CD003350, 2006.

Johnson CS. The acute chest syndrome. Hematol Oncol Clin North Am. 2005;19:857-879.

Jones AP, et al: Hydroxyurea for sickle cell disease, Cochrane Database Syst Rev (2):CD002202, 2001.

Kwiatkowski JL, Cohen AR. Iron chelation therapy in sickle-cell disease and other transfusion-dependent anemias. Hematol Oncol Clin North Am. 2004;18:1355-1377.

Lee MT, Piomelli S, Granger S, et alSTOP Study Investigators. Stroke prevention trial in sickle cell anemia (STOP): extended follow-up and results. Blood. 2006;108(3):847-852.

National Institute of Health, Division of Blood Diseases and Resources. The Management of Sickle Cell Disease. Available at http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf

Oringanje C, Nemecek E, Oniyangi O: Hematopoietic stem cell transplantation for children with sickle cell disease, Cochrane Database Syst Rev (1):CD007001, 2009.

Sickle Cell Disease Association of America. Available at http://www.sicklecelldisease.org/index.phtml

Sickle Cell Kids. Available at http://www.sicklecellkids.org

Wood KC, Hsu LL, Gladwin MT. Sickle cell disease vasculopathy: a state of nitric oxide resistance. Free Radic Biol Med. 2008;44(8):1506-1528.

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