Sickle cell disease (SCD) is an autosomal recessive condition in which red blood cells become sickle-shaped and fragile. This results in hemolytic anemia and recurrent vaso-occlusion in the microvasculature due to increased red blood cell adhesion and retention. Acute vaso-occlusion causes severe pain in the musculoskeletal system, abdomen, and other areas. Other acute vaso-occlusive complications include splenic sequestration and/or infarct and the acute chest syndrome associated with pulmonary infarcts. Large vessel stroke occurs in the setting of stenotic blood vessels due to chronic vessel wall injury.
Hemoglobin S (HbS) is characterized by a single change in the amino acid sequence of the β-globin chain and is responsible for creating the abnormal red cell morphology. Individuals who are heterozygous for the HbS gene generally have no symptoms or sequelae of SCD, but they are said to have sickle cell trait; i.e., they are carriers of the HbS gene. Their offspring could be affected if the other parent is heterozygous or homozygous for the gene or carries another abnormal hemoglobin gene.
Other SCD variants include hemoglobin SC, a heterozygous combination of HbS and hemoglobin C, and hemoglobin S and β-thalassemia (hemoglobin Sβ+-thalassemia or Sβo-thalassemia). These conditions cause SCD, although the symptoms and complications may be less severe than those in the homozygous condition. The remainder of this chapter will focus on SCD that results from homozygous HbS.
Acute signs and symptoms may include pain in the hands and feet, fever, serious bacterial infections due to splenic sequestration/infarction, priapism, chest pain, shortness of breath, fatigue, pallor, tachycardia, jaundice, and urinary symptoms. Chronic complications include delayed growth/puberty, retinopathy, chronic lung and kidney disease, cardiovascular disease, avascular necrosis of the hips and shoulders, bone infarcts, and leg ulcers.
The disease occurs most often among people whose ancestry can be linked to sub-Saharan Africa, Central and South America, the Caribbean, India, and the Middle East and Mediterranean regions. According to the Centers for Disease Control and Prevention, SCD affects up to 100,000 Americans. In Black Americans, the prevalence of SCD is 1 in 500, while sickle cell trait is present in up to 1 in 13. Among Hispanic Americans, the prevalence is 1 in 36,000. The risk in white Americans is approximately 300 times less than in Black Americans.
Prenatal screening for SCD is possible through chorionic villous sampling. Other prenatal tests may be routinely available in the future.
Universal newborn screening by electrophoresis (or other diagnostic testing) is performed in every US state. Sickle cell anemia is indicated by the presence of fetal hemoglobin (hemoglobin F) and hemoglobin S and an absence of hemoglobin A.
Electrophoretic findings for sickle cell anemia are:
Additional findings are likely to include a normochromic, normocytic anemia; reticulocytosis; and sickle cells (and other abnormal findings, including polychromasia and nucleated red blood cells visible on peripheral blood smear). Other findings consistent with hemolysis may also be present such as unconjugated hyperbilirubinemia, elevated lactate dehydrogenase, and low haptoglobin.
Subsequent to diagnosis, patients should undergo periodic testing, which includes complete blood count, iron studies, liver function tests, and tests of renal function, such as urinalysis, blood urea nitrogen, and creatinine. These data can be compared with those assessed during exacerbations to guide medical management.
In the acute pain setting, analgesics, warm compresses, and oral and intravenous fluids are appropriate interventions.
Comprehensive and multidisciplinary care is essential. Education of both patient and family may help prevent complications of the disease.
Influenza, meningococcal, and pneumococcal vaccines should routinely be used.
Pneumococcal prophylaxis (oral penicillin V 125-250 mg twice daily) should be taken continuously by children with sickle cell anemia until age 5. Children with a history of splenectomy or severe pneumonia may need further prophylaxis.
Folic acid should be taken in doses of 1 mg daily. Additionally, an iron-free multivitamin is recommended to ensure adequate intake of nutrients that are commonly deficient in those with SCD. Iron overload and subsequent oxidative stress may cause depletion of antioxidant vitamins.
Transcranial Doppler may identify children at risk for stroke. Those at higher risk should be offered a chronic blood transfusion program.
Routine eye exams should monitor for proliferative retinopathy.
Assessment for chronic complications, including chronic lung and kidney disease, should be performed periodically, especially in older children and adults.
For individuals who undergo multiple blood transfusions, screening for hepatitis C should be considered. Screening for hemochromatosis using MRI of the heart and abdomen is also recommended for patients when ferritin levels remain elevated.
In an outpatient setting, acetaminophen, acetaminophen-opioid combinations, and nonsteroidal anti-inflammatory medications (NSAIDs) are all appropriate for mild and temporary pain. Additionally, heat packs can provide additional pain relief. Cold therapies, such as ice, should be avoided. As pain increases, opioids of increasing strengths should be used.
Severe pain typically requires hospitalization and continuous narcotic provision. Initial boluses with patient-controlled analgesia for subsequent pain control are appropriate strategies.
Morphine sulfate and hydromorphone are first-line agents. Hydromorphone is more concentrated and therefore beneficial in fluid-restricted patients. Morphine synthetics, such as fentanyl, can also be used. Meperidine is not recommended.
Ketorolac, as well as other NSAIDs, are not typically recommended for inpatient pain management. There is no further benefit of adding an NSAID to opioid treatment of vaso-occlusive pain, and NSAID use increases the risk of gastrointestinal and cardiovascular complications. Further, it can lead to sometimes irreversible renal failure, especially in those with preexisting compromised renal status.
Infections cause a significant degree of SCD-induced mortality. Patients who have febrile episodes, even without other symptoms, should always be evaluated, and the need for empiric broad-spectrum antibiotic coverage (e.g., ceftriaxone) should be considered. Depending on the severity of the fever and prophylactic penicillin status (in children), antibiotics can be administered intravenously or intramuscularly and on an inpatient or outpatient basis.
Meningitis, bacteremia, osteomyelitis, urinary tract infections, and acute chest syndrome require specific antibiotic regimens.
Transfusions may be episodic or regularly scheduled and of the simple or exchange type. Exchange transfusions more effectively reduce the quantity of HbS erythrocytes and decrease the risk of iron overload.
There is evidence that long-term simple transfusion therapy is effective in decreasing the risk of primary stroke in children when transcranial Doppler studies are abnormal and for secondary prevention in those who have experienced a stroke. Additionally, regular transfusions can be used in those with recurrent priapism, pulmonary hypertension, and recurrent acute chest syndrome. Evidence for the use of long-term transfusion therapy for other complications is less clear. Established monitoring protocols should be followed by those who prescribe long-term transfusion therapy.
In acutely ill SCD patients who are not on a chronic transfusion regimen, transfusions should not aim to raise hemoglobin levels above 10 g/dL. Higher hemoglobin levels can lead to hyperviscosity. However, if patients need surgery that requires general anesthesia, they should be transfused to a hemoglobin of 10 g/dL to reduce risk of postoperative vaso-occlusive complications.
Partial-exchange transfusions may be required during a severe acute complication (e.g., acute chest syndrome, multiorgan failure, or acute stroke.).
Transfusion therapy is not indicated for uncomplicated SCD pain events or asymptomatic anemia.
Alloimmunization (antibody formation after blood transfusion) occurs in approximately 30% of SCD patients who undergo transfusion therapy. This rate is about 6 times higher than in those with other anemias. Alloimmunization causes delayed hemolytic transfusion reactions leading to worsening of anemia and other SCD symptoms. Minor red blood cell antigen matching (C, E, and K antigens) can decrease the risk of alloimmunization.
Long-term use of hydroxyurea reduces or prevents acute events and chronic complications of SCD. Hydroxyurea stimulates the production of hemoglobin F and, by various mechanisms, decreases vascular occlusion. Hydroxyurea decreases the frequency of vaso-occlusive events, painful crises, the need for transfusions, and mortality. Hydroxyurea is now approved for patients age 2 and older with sickle cell anemia and recurring moderate to severe painful crises.
Endari (L-glutamine oral powder) is approved for patients age 5 and older to help reduce acute complications including the frequency of crises.
Erythropoietin’s ability to stimulate production of hemoglobin F is less clear, but if hydroxyurea produces a less-than-adequate stimulus, substitution or addition of erythropoietin may be tried empirically.
Niprasan, an herbal product, has proven effectiveness in preventing pain episodes. It has been granted orphan drug status by the Food and Drug Administration, but commercial production is pending.
There is conflicting evidence on the efficacy of magnesium supplementation as a therapeutic measure. The use of clotrimazole (an antifungal medication) may improve SCD symptoms, but more research is required.
Hematopoietic cell transplantation is currently the only curative option for SCD patients, but the use of this therapy is still limited. Gene therapy also has the potential to be curative but remains experimental.
Patients with sickle cell anemia have greater-than-average requirements for both calories and micronutrients. During sickle cell crises, energy intake can be especially poor. Children frequently hospitalized for SCD commonly show poor linear growth, lean body mass, and reduced fat-free mass. For reasons that are poorly understood, many patients are deficient in essential micronutrients. A diet emphasizing fruits, vegetables, whole grains, and legumes will provide a greater proportion of essential nutrients than a typical Western diet, and appropriate supplementation (1-3 times the recommended intakes for most essential nutrients) can prevent deficiency and may decrease the likelihood of disease exacerbation.
High-calorie, nutrient-dense diet. The average energy intake of sickle cell patients is typically below the suggested allowance for calories during the quiescent phase of the disease, and it drops to roughly half the recommended levels during times of illness requiring hospitalization. As a result, children with SCD are at risk for impaired growth and significantly lower fat and fat-free mass, though obesity is also a risk, especially in female adolescents.,, Standard nutritional assessment methods used to calculate energy needs typically underestimate resting energy expenditure in persons with SCD., A careful nutritional assessment and the possible addition of energy supplements are indicated.
Adequate fluid consumptionto maintain hydration. Sickling of erythrocytes increases in SCD patients who exercise in the heat without consuming fluids, compared with those who maintain well-hydrated status.
Micronutrients. Blood levels of several vitamins and minerals, including vitamin A and carotenoids, vitamin B6, vitamin C, vitamin E, magnesium, and zinc, are often low in individuals with SCD.,,,,,,, These deficiencies cause a significant depreciation in blood-antioxidant status in these patients, and the resulting oxidative stress may precipitate vaso-occlusion–related acute chest syndrome., Studies indicate supplementation of zinc, magnesium, and vitamins A, C, and E or treatment with a combination of high-dose antioxidants can reduce the percentage of irreversibly sickled cells.,,, Antioxidant plant phenols, such as flavonoids, may also reduce the oxidative stress in SCD.
Omega-3 fatty acid supplements. The serum phospholipids of children with SCD contain reduced proportions of both the parent (alpha-linolenic acid) and the long-chain omega-3 polyunsaturated fatty acids (eicosapentanoic acid [EPA] and docosahexanoic acid [DHA]), compared with healthy controls., These long-chain omega-3 fatty acids increase the fluidity of red blood cell membranes, which may prevent sickle cell crisis., In a small double-blind, placebo-controlled study, supplemental EPA and DHA had significant therapeutic benefits including reduction of severe anemia.
See Basic Diet Orders chapter.
High-potency multiple vitamin with minerals, 1 tablet by mouth daily. For patients with iron overload due to frequent transfusions, supplements containing iron should be avoided.
Nutrition consultation for assessment, to advise patient regarding specific dietary recommendations, and to arrange follow-up as needed.
Protein-calorie supplements, per nutrition consultant.
Good nutrition can help safeguard healthy growth in children with sickle cell disease and may reduce the risk of complications in both children and adults. A registered dietitian can advise the patient and family on how to meet macronutrient and micronutrient needs. Supplemental nutrients may be required and ordered by the physician.