Approach Considerations
Screening for HbS at birth is currently mandatory in the United States. This method of case finding allows institution of early treatment and control.
Prenatal diagnosis is also available. The laboratory procedures employed in prenatal testing are sensitive and rapid. Prenatal testing must be accompanied with genetic and psychological counseling. Chorionic villus sampling can be performed at 8-12 weeks' gestation to obtain DNA. This low-risk procedure is safe. DNA from amniotic fluid cells can be examined at 16 weeks' gestation. Investigational attempts are ongoing to isolate fetal cells from maternal blood for DNA assay.
Children with sickle cell disease (SCD) frequently have abnormal pulmonary function test (PFT) results. PFTs should be performed regularly in children with a history of recurrent acute chest episodes or low oxygen saturation. Because lung function declines with age, it is important to identify those who require close monitoring and treatment.
The 2003 British Committee for Standards in Haematology (BCSH) guidelines for the management of the acute painful crisis in sickle cell disease, their most recent SCD guideline (current as of June 2011), advise against the routine use of oxygen, but it may be appropriate if oxygen saturation is less than 95%.{Ref50}
Newer techniques for noninvasive assessment of the brain have also been used to identify children with asymptomatic brain disease. Transcranial near-infrared spectroscopy or cerebral oximetry is increasingly being used as a screening tool for low cerebral venous oxygen saturation in children with sickle cell disease. Measurement of blood flow by noninvasive transcranial Doppler ultrasound (TCD) has been shown to be a good predictor of stroke risk.[28]
Consider lumbar puncture to exclude meningitis if there is altered mental status, meningeal signs, or fever. When focal neurologic signs are present or intracranial hemorrhage is suspected, consider CT prior to lumbar puncture. Consider lumbar puncture if a subarachnoid hemorrhage is suspected and head CT is unrevealing.
Meningitis in children with SCD requires early recognition; aggressive diagnostic evaluation including CBC count, urinalysis, chest radiographs, and blood cultures; prompt administration of intravenous antibiotics active against S pneumoniae; and close observation.
Children younger than 12 months with a temperature of higher than 39°C who appear toxic, with an infiltrate on chest radiograph and an elevated WBC count, should be admitted to the hospital. Consider only outpatient treatment if no high-risk features appear on history, physical examination, or laboratory evaluation; if the child is older than 12 months; and if outpatient follow-up care can be ensured.
According to the 2003 BCSH guidelines, a full blood count is required for all patients who are admitted to the hospital, with other investigations performed as necessitated by the clinical situation. Intravenous fluids are not routinely indicated, but should be given if the patient is unable to drink, has diarrhea or is vomiting. Nasogastric fluids are an appropriate alternative to IV fluids.[29]
In acute chest syndrome, arterial blood oxygen saturation commonly falls to a greater degree than that seen in simple pneumonia of the same magnitude. Patients with acute chest syndrome often have progressive pulmonary infiltrates despite treatment with antibiotics. Infection may set off a wave of local ischemia that produces focal sickling, deoxygenation, and additional sickling.
The 2003 BCSH guidelines strongly advocate the use of incentive spirometry for patients with chest or back pain.[29]
Newborn hemoglobinopathy screening
The introduction of newborn screening has been one of the greatest advances in the management of sickle cell disease. Currently, 50 states and the District of Columbia have mandatory universal programs for newborn screening for hemoglobin disorders. Guidelines for screening for sickle cell disease in newborns have been established.[30] If results are positive, a repeat hemoglobin electrophoresis should be performed for confirmation.
Fetal hemoglobin is predominant in young infants. If results show only hemoglobin (Hb) F and S, the child has either sickle cell anemia or HbS–β-0 thalassemia. If results show HbF, S, and C, the child has HbSC disease. If results show HbF, S, and A, determine whether the child has received a transfusion.
If the child has not received a transfusion and S is greater than A, HbS–beta+ thalassemia is most likely the diagnosis. If A is greater than S, the child is presumed to have the sickle trait. If A and S concentrations are close, conduct a study of the parents to determine if one of them has the thalassemia trait. Repeat Hb electrophoresis on the child after several months.
Hemoglobin electrophoresis
Hemoglobin electrophoresis differentiates individuals who are homozygous for HbS from those who are heterozygous. It establishes the diagnosis of SCD by demonstrating a single band of HbS (in HbSS) or HbS with another mutant hemoglobin in compound heterozygotes.
In children with normocytic hemolytic anemia, if results of electrophoresis show only HbS with an HbF concentration of less than 30%, the diagnosis is sickle cell anemia. If HbS and HbC are present in roughly equal amounts, the diagnosis is HbSC disease.
In children with microcytic hemolytic anemia, order quantitative Hb A2 in addition to electrophoresis. If HbS is predominant, Hb F is less than 30% and Hb A2 is elevated, a diagnosis of HbS–beta-0 thalassemia can be inferred. If possible, perform a study of the parents. If the HbA2 level is normal, consider the possibility of concomitant HbSS and iron deficiency. If HbS is greater than A and HbA2 is elevated, a diagnosis of HbS–beta+ thalassemia can be inferred. If HbS and HbC are present in equal amounts, the diagnosis is HbSC disease.
A homozygous patient will have hemoglobin SS (HbSS, 80-90%), hemoglobin F (HbF, 2-20%), and hemoglobin A2 (HbA2, 2-4%). A carrier patient will have HbSS (35-40%) and hemoglobin A (HbA, 60-65%). The test is not accurate in a patient who has recently received blood transfusions.
Baseline Blood Study Abnormalities
Typical baseline abnormalities in the patient with SCD are as follows:
- Hemoglobin level is 5-9 g/dL
- Hematocrit is decreased to 17-29%
- Total leukocyte count is elevated to 12,000-20,000 cells/mm3 (12-20 X 109/L), with a predominance of neutrophils
- Platelet count is increased
- Erythrocyte sedimentation rate is low
- The reticulocyte count is usually elevated, but it may vary depending on the extent of baseline hemolysis
- Peripheral blood smears demonstrate target cells, elongated cells, and characteristic sickle erythrocytes
- Presence of RBCs containing nuclear remnants (Howell-Jolly bodies) indicates that the patient is asplenic
- Results of hemoglobin solubility testing are positive, but they do not distinguish between sickle cell disease and sickle cell trait
Findings on peripheral blood smears are shown in the images below.
Peripheral blood with sickled cells at 400X magnification. Image courtesy of Ulrich Woermann, MD. 
Peripheral blood smear with sickled cells at 1000X magnification. Image courtesy of Ulrich Woermann, MD. 
Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Image courtesy of Ulrich Woermann, MD. Suggested Routine Clinical Laboratory Evaluations
Obtaining a series of baseline values on each patient to compare with those at times of acute illness is useful. The table below shows a typical schedule of routine clinical laboratory evaluations.
Table. Schedule of Laboratory Tests for Patients With Sickle Cell Disease (Open Table in a new window)
| Tests | Age | Frequency |
| CBC count with WBC differential, reticulocyte count | 3-24 mo >24 mo | every 3 mo every 6 mo |
| Percent Hb F | 6-24 mo >24 mo | every 6 mo annually |
| Renal function (creatinine, BUN, urinalysis) | ≥ 12 mo | annually |
| Hepatobiliary function (ALT, fractionated bilirubin) | ≥ 12 mo | annually |
| Pulmonary function (transcutaneous O2 saturation) | ≥ 12 mo | every 6 mo |
Laboratory Studies in the Ill Child
Standard laboratory tests cannot be used to distinguish pain crisis from the baseline condition. If laboratory tests are obtained, they should be interpreted in light of baseline values.
There is a near ubiquitous recommendation to obtain "routine" CBC and reticulocyte counts in all sickle cell patients with an acute illness, including those presenting with apparently uncomplicated painful crisis. However, a meta-analysis found that "the routine use of complete blood count and reticulocyte count in sickle cell patients presenting with painful crisis does not alter management decisions. Selective use of these tests can be based on patient age, reported symptoms, vital signs, physical examination, and clinical judgment."[31]
Febrile children with SCD, especially those younger than 5 years, should have an aggressive investigation. The following are usually indicated:
- CBC with differential and reticulocyte count
- Liver function tests (LFTs)
- Urinalysis
- Blood cultures
Additional studies may be indicated, depending on the clinical presentation. Type and crossmatch blood in case transfusion is necessary.
On the CBC, anemia is often identified; however, a major drop in hemoglobin (ie, more than 2 g/dL) from previously recorded values indicates a hematologic crisis. Leukocytosis is expected in all patients with sickle cell anemia, but a major elevation in the WBC count (ie, >20,000 per mm3) with a left shift raises suspicion for infection. Leukopenia is suggestive of parvovirus infection. The platelet count is typically elevated. If it is low, consider hypersplenism.
The reticulocyte percentage documents the briskness of the marrow response. If the reticulocyte count is normal, splenic sequestration is the probable cause. If the reticulocyte count is low, an aplastic crisis is the probable cause. If the reticulocyte count is high, hyperhemolytic crisis is the probable cause.
Additional Tests
Measurement of blood urea nitrogen (BUN), serum creatinine, and serum electrolytes can be useful. Assays of lactic dehydrogenase and haptoglobin are useful but not required. Elevated levels of lactic dehydrogenase support the diagnosis of hemolysis being released from destroyed RBCs. Decreased levels of haptoglobin confirm the presence of hemolysis.
Arterial blood gases
Arterial blood gas measurements (ABGs) may be obtained in patients who are in respiratory distress, to supplement information provided by oxygen saturation monitoring. This will reflect the severity of pulmonary crisis. Serial ABGs are necessary to follow the response in pulmonary crisis.
Urinalysis
Perform urinalysis if the patient has fever or signs of urinary tract infection (UTI). Patients with sickle cell anemia often have hematuria and isosthenuria. If signs of UTI are present, obtain a urine Gram stain and culture.
Sickling test
Because of mandated newborn screening for sickle hemoglobinopathies, the diagnosis of SCD is already established in most patients with the disease who present for emergency care. If the diagnosis of sickle cell anemia is uncertain, a sickling test will establish the presence of HbS gene. It will not, however, differentiate between individuals who are homozygous and those who are heterozygous.
Secretory phospholipase A2
Secretory phospholipase A2 (sPLA2), an enzyme that cleaves fatty acids from triglycerides, is an accurate marker for identifying present or incipient acute chest syndrome in young patients with sickle cell pain crisis . Its serum concentration increases before acute chest syndrome becomes clinically apparent, peaks at the clinical onset of acute chest syndrome, and declines during its resolution.
Radiography
Chest radiography should be performed in patients with respiratory symptoms. Radiographic findings may initially be normal in patients with acute chest syndrome, however.
Plain radiography of the extremities is useful in evaluating subacute and chronic infarction and in assessing the number and severity of prior episodes of infarction. Plain radiographs are also excellent for evaluating deformities and other complications of bone infarction. Osteonecrosis is visible on plain images only in the later stages after the affected bone is substantially damaged.
In early dactylitis, plain radiographs will show only soft tissue swelling. Periosteal new-bone formation can be seen on radiographs 7-10 days later. Additionally, medullary expansion, cortical thinning, trabecular resorption, and resultant focal lucency may be seen 2-3 weeks after the onset of symptoms, but these findings usually resolve within weeks.
Radiography is not as sensitive as other studies for osteomyelitis in the first 1-2 weeks. However, plain images subsequently show cortical destruction, periosteal new bone, and (with time) sinus tracts and sequestra.
See Skeletal Sickle Cell Anemia for more information on imaging studies in SCD.
Magnetic Resonance Imaging
MRI can demonstrate avascular necrosis of the femoral and humeral heads and may distinguish between osteomyelitis and bony infarction in patients with bone pain. MRI is the best method for detecting early signs of osteonecrosis in patients with SCD and for identifying episodes of osteomyelitis.
MRI allows the early detection of changes in bone marrow due to acute and chronic bone marrow infarction, marrow hyperplasia, osteomyelitis, and osteonecrosis. Bone sequestra, sinus tracts, and subperiosteal abscesses are also clearly identified when present.
As with plain radiography, the sine qua non of diagnosing osteomyelitis on MRI is the identification of cortical destruction, for which MRI is exquisitely sensitive. MRI has a specificity of 98% and a sensitivity of 85-97% for identifying bone marrow infarcts.
Children with sickle cell disease who have "silent" cerebral infarcts revealed with MRI have a higher rate of abnormal neuropsychometric (NPM) findings and a higher risk of overt strokes. Stroke prevention strategies based on abnormal MRI results have not been tested, but children with abnormal MRI or NPM findings may be evaluated more frequently and carefully and considered for therapeutic measures.
According to the 2011 American Heart Association/American Stroke Association (AHA/ASA) primary stroke prevention guidelines, MRI and MRA findings for identifying children with SCD for primary stroke prevention have not been established. As such, these tests are not recommended in lieu of TCD for this purpose.[32]
Computed Tomography
Although CT is not an initial study in most patients, CT may be useful to demonstrate subtle regions of osteonecrosis not apparent on plain radiographs in patients who are unable to have an MRI.[33]
CT scanning is performed to exclude renal medullary carcinoma in patients presenting with hematuria. CT is not the test of choice for evaluation of acute osteomyelitis.
Nuclear Medicine Scans
Nuclear medicine scanning can be used to detect early osteonecrosis. This modality also plays a role in detecting osteomyelitis.
Technetium-99m (99m Tc) bone scanning can be used to detect early stages of osteonecrosis, and it is not as costly as MRI. Tc-99m bone-marrow scans demonstrate areas of decreased activity in marrow infarction.[34]
Indium-111 (111 In) white blood cell (WBC) scanning is useful for diagnosing osteomyelitis, which appears as an area of increased activity within bone. However, areas of marrow proliferation, which are common in patients with SCD, would also demonstrate increased activity on111 In WBC scans.
The combination of a bone scan and a bone marrow scan has been used to differentiate acute osteomyelitis from bone infarcts in patient with SCD, since the clinical presentation of these 2 conditions may be very similar. Acute osteomyelitis produces increased activity on the bone scan with normal activity on the bone-marrow scan, while bone infarction produces decreased activity on the bone-marrow scan with corresponding abnormal uptake on the bone scan.
Transcranial Doppler Ultrasonography
Transcranial Doppler ultrasonography (TCD) can identify children with SCD who are at high risk for stroke by documenting abnormally high blood flow velocity in the large arteries of the circle of Willis—the middle cerebral or internal carotid arteries. Velocity, which is usually increased by severe anemia, becomes elevated in a focal manner when stenosis reduces the arterial diameter. (MRI, with or without angiography, and NPM studies have also been used to detect these abnormalities.)
The upper limit of normal flow velocity varies with the method used. Values are lower for duplex Doppler (180 cm/s) than for non–duplex Doppler (200 cm/s).
Children with HbSS or HbS–β-0 thalassemia should be considered candidates for TCD screening. TCD screening should begin at age 2 years and continue to age 16 years.[35] The 2011 AHA/ASA guidelines for the primary prevention of stroke agree that screening for stroke risk in children with sickle cell disease using TCD should begin at age 2 years.[32] TCD is repeated annually if TCD results are normal or every 4 months if TCD results are marginal. Abnormal results should prompt a repeat TCD within 2-4 weeks.
According to the 2011 AHA/ASA primary prevention guidelines, while there is no established optimal screening interval, it is reasonable for younger children and those with borderline abnormal TCD velocities to be screened more often to detect incidence of high-risk TCD indications for intervention.[32]
The Stroke Prevention in Sickle Cell Anemia (STOP) trial demonstrated that a transfusion program in patients with abnormal TCD results normalizes the TCD results and reduces the risk of strokes.[36] A subsequent trial (STOPII) showed that when transfusions are discontinued, an unacceptably high percentage of patients show TCD reversion to high risk, and some suffer actual strokes.[37] On the other hand, TCD results normalize over time in some patients who do not receive transfusions.
Abdominal Ultrasonography
In patients with abdominal pain, abdominal ultrasonography can be used to rule out cholecystitis, cholelithiasis, or an ectopic pregnancy and to measure spleen and liver size. Assess liver and spleen size. Abdominal ultrasonography can be used to visualize stones and to detect signs of thickening gallbladder walls or ductal inflammation, indicating possible cholecystitis. Abdominal ultrasound is useful to document spleen size and the presence of biliary stones.
Ultrasonography of the kidneys is performed to exclude other causes of postrenal or obstructive uropathy (eg, nephrolithiasis) and may demonstrate papillary necrosis.
Echocardiography
Echocardiography is used to identify patients with pulmonary hypertension based on tricuspid regurgitant jet velocity. Patients with sickle cell disease may have an array of abnormalities of systolic and diastolic function. Adults should be tested for evidence of pulmonary hypertension with Doppler echocardiography. Cardiac echocardiography should be performed for patients with dyspnea.
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| Tests | Age | Frequency |
| CBC count with WBC differential, reticulocyte count | 3-24 mo >24 mo | every 3 mo every 6 mo |
| Percent Hb F | 6-24 mo >24 mo | every 6 mo annually |
| Renal function (creatinine, BUN, urinalysis) | ≥ 12 mo | annually |
| Hepatobiliary function (ALT, fractionated bilirubin) | ≥ 12 mo | annually |
| Pulmonary function (transcutaneous O2 saturation) | ≥ 12 mo | every 6 mo |
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