Sickle Cell Disease

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
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Jun 19, 2016 | Posted by in PEDIATRICS | Comments Off on Sickle Cell Disease

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