Sickle cell disease (SCD) is a hemoglobinopathy affecting one in 375 African Americans; it is the most common single gene disorder in African Americans. Sickle cell disease encompasses several entities: sickle cell anemia (SS), sickle cell-hemoglobin C (SC) disease, and sickle cell-beta-thalassemia. All of these manifestations of sickle cell disease can produce many of the clinical features of sickle cell anemia, but this paper will concentrate on sickle cell anemia (SS).
Sickle cell anemia is a genetic disorder, inherited in an autosomal recessive fashion. In sickle cell anemia, a single gene mutation results in the substitution of valine for glutamic acid in the sixth amino acid position of the beta globin chain, creating hemoglobin S. Under conditions of deoxygenation, hemoglobin S forms a poorly soluble tetramer that that causes red blood cells to deform into sickle shapes. This malformed hemoglobin causes occlusion in small vessels (“vaso-occlusion”), and causes slowed blood flow in larger vessels. Severe, chronic hemolytic disease, as well as various manifestations of vaso-occlusive disease, characterize sickle cell disease.
Sickle cell disease can be diagnosed in patients of any age by hemoglobin electrophoresis (revealing hemoglobin with mobility between Hb A and Hb A2), isoelectric focusing, or DNA analysis. At present, all 50 states mandate newborn screening for the presence of sickle cell disease. Such a program has permitted early diagnosis of SCD, which – along with the implementation of a comprehensive system of care – has decreased the incidence of pneumococcal sepsis in young infants with SCD.
Two major pathologic features characterize SCD: hemolytic anemia and vaso-occlusion. The following manifestations are common in patients with SCD.
- Infection - due to RBC sickling, progressive infarction of the spleen is nearly universal in patients with SCD (typically by age 4). Functional asplenia results, leaving patients susceptible to multiple bacterial infections, particularly encapsulated organisms such as S. pneumoniae, Salmonella, and H. influenza. Pneumococcal sepsis is the particular risk in these patients.
- Vaso-occlusive pain episodes – the most common clinical manifestations of sickle cell disease. The first manifestation is frequently dactylitis (hand-foot syndrome), severe pain that occurs in the hands and feet, often in toddlers. Pain can also occur in other locations, such as the arms, legs, chest and ribs, and frequently lasts from two to seven days.
- Splenic sequestration — this is a common cause of morbidity and mortality in young children with sickle cell disease. The diagnosis is based on the sudden enlargement of the spleen accompanied by sharp drop in hematocrit and rise in the reticulocyte count. The enlargement of the spleen is due to entrapped blood. This can happen precipitously and circulatory compromise can occur.
- Acute chest syndrome – acute pulmonary injury is the leading cause of death in patients with sickle cell disease. Acute chest syndrome is defined as a new pulmonary infiltrate in combination with chest pain, fever or respiratory symptoms. Acute chest syndrome can result from infection (including RSV, Strep pneumo, Staph aureus, C. pneumoniae) as well as non-infectious causes like pulmonary fat emboli and infarction.
- Neurologic sequelae – neurologic complications such as stroke and hemorrhage can occur in children with SCD. Up to 12% of children with SCD will suffer from a stroke, and an additional 20% will show asymptomatic evidence of cerebral infarction on MRI. Focal neurologic findings should alert the physician to possible neurologic issue.
- Anemia — patients with HbSS have a hemolytic anemia, which is generally well-tolerated unless a splenic sequestration episode or aplastic crisis occurs. These complications cause an acute drop in the hemoglobin level. Aplastic crisis is most often the result of infection with Parvovirus B19, which results in a temporary cessation of RBC production.
- Renal and Genitourinary – hematuria, renal failure, and priapism may occur.
- Avasuclar Necrosis — AVN of the femoral and humeral heads is a common manifestation of sickle cell disease, and is caused by multiple vaso-occlusive episodes in the bone.
- Cholelithiasis — due to severe hemolysis, patients with SCD can develop cholelithiasis and acute cholecystitis due to the formation of pigmented gallstones. Any child with SCD with persistent RUQ pain should be evaluated with ultrasound for gallbladder pathology.
Cure: A life-long cure for SCD is available only through hematopoietic stem cell transplantation, which carries its own toxicities and risks. Currently it is limited in use and reserved for patients under 16 years of age.
Much of the treatment of sickle cell disease is dependent on early diagnosis and continual preventative care. Children diagnosed with SCD should be referred to an early intervention program. The maintenance of full immunization status is essential, and additional vaccinations against pneumococcus and influenza virus are necessary. The 13-valent conjugate vaccine series for pneumococcus should be started at 2 months, and the 23-valent vaccine should be given at 2 years. The influenza vaccine should be given yearly. Prophylactic oral penicillin should be started at 4 months of age, dosed at 125 mg BID until age 2; in children aged 2-5, oral penicillin should be dosed at 250 mg BID. Folic acid supplementation should be started at 1 year of age.
The use of hydroxyurea is a mainstay in the overall management of individuals with SCD as it reduces the incidence of acute painful episodes and hospitalization rates, and prolongs survival. Hydroxyurea acts by increases production of HbF. In general, hydroxyurea is often used in children over two years of age who suffer from frequent vaso-occlusive pain events (including dactylitis), have a history of acute chest syndrome, or have severe symptomatic anemia.
Caregivers of SCD patients should be counseled about signs and symptoms of illness. Caregivers must be taught to palpate the child’s spleen to screen for splenic sequestration. Additionally, parents should be instructed to seek immediate attention for the following signs: rapidly enlarging spleen, fever, respiratory symptoms, pain, or inability of child to move extremities.
- Infection — if a child with SCD has a fever greater than 38.5, she must be seen and evaluated immediately with a physical exam, CBC, CXR, and blood and urine cultures. Broad spectrum antibiotics (frequently ceftriaxone) should be started while awaiting results of the cultures.
- Vaso-occulsive pain events — adequate pain control for the SCD patient is an important goal, but is challenging to achieve. In young children, or in patients with mild pain, Ibuprofen or Tylenol, with or without codeine, is preferred. Older children or children with more sever pain may require stronger narcotic analgesics. In the adolescent, a PCA pump (patient controlled analgesia) is often a good choice, as it allows the patient to self-titrate the medication.
- Splenic sequestration — severe sequestration can result in severe hypovolemia and circulatory compromise. An emergent red cell transfusion and fluid recussitation can be life saving measures.
- Acute-chest syndrome — the child with acute chest syndrome should be hospitalized and monitored intensely, often in an ICU. The patient should be evaluated with serial CXRs and should be treated with oxygen or exchange transfusions as necessary. The patient should be started on a cephalosporin and a macrolide to cover infectious causes of acute chest syndrome.
- Stroke — strokes in children with SCD often occur without warning, but can be preceded by a severe headache or focal neurologic deficit. Strokes are diagnosed with CT or MRI. The only treatment currently available for strokes is the use of monthly exchange transfusions to decrease the amount of HbS.
- Anemia —is usually well tolerated, except in the event of splenic sequestration or aplastic crisis. In these cases, red cell transfusion is indicated.
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