AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Sickle cell disease denotes all genotypes that contain at least 1 sickle gene in which hemoglobin S (HbS) makes up at least half of the hemoglobin present. In addition to homozygotic HbSS (sickle cell anemia), in which only HbS is produced, at least 5 other major genotypes are linked to the disease. These include the following:

• HbS–beta-0 thalassemia - Severe double heterozygote for HbS and beta-0 thalassemia; almost indistinguishable from sickle cell anemia phenotypically
• HbSC disease - Double heterozygote for HbS and HbC, with intermediate clinical severity
• HbS/hereditary persistence of fetal hemoglobin (S/HPHP) - Mild form or symptom free
• HbS/HbE syndrome - Rare and generally mild clinical course
• Rare combinations of HbS with HbD Los Angeles, HbO Arab, G-Philadelphia, among others

Sickle cell anemia is the most severe and most common form. Affected individuals present with a wide range of clinical problems that result from vascular obstruction and ischemia. Although a diagnosis of the disease can be made at birth, clinical abnormalities usually do not occur before age 6 months, when functional asplenia develops. Functional asplenia results in susceptibility to overwhelming infection with encapsulated respiratory bacteria. Subsequently, other organs are damaged. Typical manifestations include recurrent pain and progressive incremental infarction.

Pathophysiology

The basic abnormality responsible for the diverse manifestations of sickle cell disease is the substitution of valine for glutamic acid at the sixth position of the beta-globin chain. The association of heme plus 2 normal alpha-globin and 2 abnormal beta-globin chains forms HbS. It carries oxygen normally but begins to form semisolid aggregate structures once oxygen is unloaded to the tissues. These HbS aggregates distort RBCs and cause them to lose their normal elasticity.

At first, HbS retains its ability to return to its soluble form, and red cells can regain their elasticity upon reoxygenation. However, this process harms red cells, and, with repeated deoxygenation cycles, permanent red-cell damage ensues. Although HbS polymerization and red-cell sickling under deoxygenated conditions are central to the pathophysiology of this disease, growing evidence indicates that sickle cell disease is a state of inflammation characterized by vascular endothelium activation and increased blood cell–endothelium interactions. Abnormal interaction of sickle red cells with vascular endothelium is considered a key contributor to the initiation of vaso-occlusion in this disease.

Adhesion of sickle red cells involves contribution from both sickle red-cell abnormalities (induced by repeated sickling, expression of adhesion molecules, and dense red-cell formation) and up-regulation of endothelial adhesion molecules. Ischemic and reperfusion events in the microcirculation may lead to endothelial oxidant generation, endothelial activation, and up-regulation of adhesion molecules.

In addition to leukocyte recruitment, inflammatory activation of endothelium may have an indispensable role in enhanced sickle red-cell–endothelium interactions. Sickle red-cell adhesion in postcapillary venules can cause increased microvascular transit times and initiate vaso-occlusion. Several studies have shown involvement of an array of adhesion molecules expressed on sickle red cells (CD36, alpha-4-beta-1 integrin, ICAM-4, basal cell adhesion molecule [B-CAM]), activated endothelium (P-selectin, vascular cell adhesion molecule-1 [VCAM-1], alpha-V-beta-3 integrin), and an important role of plasma factors and adhesive proteins (thrombospondin [TSP], von Willebrand factor [vWf], laminin) in this interaction.

For example, the induction of VCAM-1 and P-selectin on activated endothelium is known to enhance sickle red-cell interactions. In addition, alpha-V-beta-3 integrin is up-regulated in activated endothelium in patients with sickle cell disease. Alpha-V-beta-3 integrin binds to several adhesive proteins (TSP, vWf, red-cell ICAM-4, and, possibly, soluble laminin) involved in sickle red-cell adhesion, and antibodies to this integrin dramatically inhibit sickle red-cell adhesion. In addition, under inflammatory conditions, increased leukocyte recruitment in combination with adhesion of sickle red cells may further contribute to stasis.

Frequency

United States

In the United States, approximately 8% of African Americans have the sickle trait, and 1 in 500 have the disease. Prevalence among individuals whose families originated from the Caribbean, Central America, or South America is approximately 4%, and their disease prevalence at birth is approximately 1 in 2000.

International

the mutation that results in HbS is believed to have originated in several locations in Africa and India. Its prevalence varies but is high in these countries because of the survival advantage to heterozygotes in regions of endemic malaria. As a result of migration, both forced and voluntary, it is now found worldwide.

Mortality/Morbidity

Data generated prior to the use of penicillin prophylaxis demonstrated a median survival age of 42 years for men and 48 years for women, which was 25-30 years lower than expected for the African American population. Earlier diagnosis and improved supportive care were expected to substantially decrease mortality for children. A careful study of a large cohort, identified through newborn screening and treated in a single comprehensive sickle cell center, found the predicted overall survival rate of patients with HbSS and Hb S–beta-0 at age 18 years to be 86%.

Race

In the United States, sickle cell disease is found primarily in the African American population. Sickle cell disease is also found in individuals who are originally from Central America, South America, and the Caribbean. The disease also occurs in individuals of Arab, East Indian, Greek, or Italian descent.

Sex

HbS is transmitted as an autosomal codominant characteristic. The male-to-female ratio is equal.

Age

Clinical characteristics are generally not seen in children younger than 6 months, when fetal hemoglobin levels decline sufficiently for abnormalities caused by HbS to be recognized.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Sickle cell anemia results in several complications. Clinical severity varies considerably, and patients may exhibit some or all of the symptoms described.

• Anemia
• • Repeated cycles of deoxygenation and morphologic sickling irreversibly damage red-cell membranes and result in hemolysis. Bone marrow increases red-cell production but is unable to compensate for the rate of hemolysis. This results in moderate-to-severe anemia.
  • Children exhibit few manifestations of anemia, since they readily adjust by increasing heart rate and stroke volume; however, they have decreased stamina, which may be noted on the playground or when participating in physical education class.
  • Acute anemic episodes may be due to many causes, including aplastic crisis, splenic sequestration crisis, delayed transfusion reactions from alloantibodies, or, rarely, through hepatic sequestration or hyperhemolysis.
  • Infection with parvovirus B-19 frequently causes aplastic crises. This virus causes "fifth disease," a normally benign childhood disorder associated with fever, malaise, and a mild rash. The virus has trophism for erythroid progenitor cells and impairs cell division for a few days during the infection. Healthy people experience, at most, a slight drop in hematocrit, since the half-life of erythrocytes in the circulation is 40-60 days.
  • The picture is different in patients with hemolytic anemias, who maintain reasonable hematocrits only through increased production of new red cells. A shutdown in erythroid production for a few days in these patients can lead to potentially deadly declines in hematocrit. Often, but not always, aplastic crises coincide with painful crises. In patients with sickle cell disease, the reticulocyte count should be checked upon admission to the emergency room or to the hospital. Treatment of aplastic crisis is supportive, with transfusions to maintain an acceptable hematocrit until marrow activity is restored.
  • Splenic sequestration episodes occur with highest frequency during the first 5 years of life in children with sickle cell anemia. Splenic sequestration occurs at any age in individuals with other sickle syndromes. This complication is characterized by the onset of life-threatening anemia with rapid enlargement of the spleen and high reticulocyte count.
  • Splenic sequestration crisis is a medical emergency that demands prompt and appropriate treatment. Parents should be familiar with the signs and symptoms of splenic sequestration crisis. Children should be seen as rapidly as possible in the emergency room. Treatment of the acute episode requires early recognition, careful monitoring, and aggressive transfusion support. Because these episodes tend to recur, many advocate long-term transfusion in young children and splenectomy in older children.
• Infection
• • As HbS replaces fetal hemoglobin in the early months of life, problems associated with sickling and red-cell membrane damage begin. The resulting rigid cells progressively obstruct and damage the spleen, which leads to functional asplenia. This, along with other abnormalities, results in extreme susceptibility to infection.
  • Organisms that pose the greatest danger are encapsulated respiratory bacteria, particularly Streptococcus pneumoniae. The mortality rate of such infections has been reported to be as high as 10-30%. Consider osteomyelitis when dealing with a combination of persistent pain and fever. Bone that is involved with infarct-related vaso-occlusive pain is prone to infection. Staphylococcus and Salmonella are the 2 most likely organisms responsible for osteomyelitis.
  • Meningitis is 200 times more common in children with HbSS. Consider lumbar puncture in children with fever who appear toxic and in those with neurologic findings such as neck stiffness, positive Brudzinski or Kernig signs, or focal deficits. Meningeal signs are not reliable if the children are irritable and inconsolable.
  • Treatment includes 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 390C 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.
• Acute chest syndrome
• • Acute chest syndrome (ACS) refers to the combination of respiratory symptoms, new lung infiltrates, and fever. Because the appearance of radiographic changes may be delayed, the diagnosis may not be recognized immediately. Children have a higher incidence of acute chest syndrome but a lower mortality rate than adults. In children, acute chest syndrome is usually due to infection. Other etiologies include pulmonary infarction and secondary fat embolism due to sickling with bone infarction. Recognition of the specific cause is less critical in the management of acute chest syndrome than the ability to assess the management and pace of the lung injury.
  • 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.
  • Treatment measures include oxygen therapy with close monitoring for hypoxemia with continuous pulse oximetry or frequent assessment of blood gases, empiric treatment with intravenous antibiotics active against S pneumoniae after appropriate cultures are obtained, and empiric addition of a macrolide antibiotic since chlamydial and mycoplasmal infections are common. Antibiotic changes are based on response to therapy and results of cultures and sensitivities.
  • Simple transfusion administered early may halt progressive respiratory deterioration, preventing complications such as increasing tachypnea and need for supplemental oxygen. Transfused red cells should be matched for C, D, E, and Kell antigens to minimize the risk of alloimmunization.
  • Analgesics are required. Agents that do not suppress respiration, including acetaminophen and nonsteroidal anti-inflammatory medications, can be used. Narcotic agents may be used judiciously for more severe pain. Other supportive measures include careful hydration that avoids volume overload, which may contribute to pulmonary infiltrates and exacerbate hypoxia. The role of corticosteroids in nonasthmatic patients with acute chest syndrome remains a topic of clinical research.
  • For episodes of severe hypoxia, rapid progression, diffuse pulmonary involvement, and failure to improve, erythrocytapheresis is indicated. Intensive care is indicated for patients in severe hypoxia or respiratory distress, as respiratory decompensation can rapidly require mechanical ventilation.
• Pain
• • Pain, resulting from vascular occlusion and ischemia, is the most common feature of sickle cell disease and can affect any body part. Bone pain is often due to bone marrow infarction. Certain patterns are predictable since pain tends to involve bones with the most bone marrow activity and because marrow activity changes with age. During the first 18 months of life, the metatarsals and metacarpals can be involved, presenting as dactylitis or hand-foot syndrome.
  • Hand-foot syndrome, which affected children develop by age 10 years, has been a strong predictor of overall severity (ie, death, risk of stroke, high pain rate, recurrent acute chest syndrome). Those that have an episode before age 1 year are at high risk of a severe clinical course. The risk is further increased if the child's baseline hemoglobin level is less than 7 g/dL or the baseline WBC count is elevated.
  • As the child grows older, pain often involves the long bones of the extremities, sites that retain marrow activity during childhood. Proximity to the joints and occasional sympathetic effusions lead to the belief that the pain involves the joints. As marrow activity recedes further during adolescence, pain involves the vertebral bodies, especially in the lumbar region. Although the above patterns describe commonly encountered presentations, any area with blood supply and sensory nerves can be affected. Abdominal pain can result from referred pain from other sites or intraabdominal solid organ or soft tissue infarction. Reactive ileus leads to intestinal distention and pain.
  • Triggers: Since deoxygenated HbS becomes semisolid, the most likely physiologic trigger is hypoxemia. This may be due to acute chest syndrome or accompany respiratory complications. Dehydration can precipitate pain, since acidosis results in a shift of the oxygen dissociation curve (Bohr effect), causing hemoglobin to desaturate more readily. Hemoconcentration is a common mechanism, as is a lowered body temperature, likely the result of peripheral vasoconstriction. Patients should wear proper clothing and avoid exposure to ensure normal core temperature. Ironically, swimming during the heat of summer is more likely to decrease the core temperature, which is always cooler than the body temperature.
  • Prevention: Family counseling is useful in preventing the above-mentioned triggers, whenever possible. Hydroxyurea may decrease frequency and severity of pain episodes. Chronic transfusion therapy designed to maintain the HbS concentration at less than 30% may prevent pain episodes in patients with recurrent debilitating painful crises.
• Stroke
• • Although stroke in children is unusual, approximately 11% of patients with sickle cell anemia experience strokes before they reach age 20 years. Hemiparesis is the usual presentation. Other deficits may be found, depending on the location of the infarct.
  • Convulsions are frequently associated with stroke. Convulsions occur as an isolated event but also appear in the setting of evolving acute chest syndrome, pain crisis, aplastic crisis, and priapism. Rapid and excessive blood transfusion to a hemoglobin level of greater than 12 g/dL increases blood viscosity and can lead to stroke.
  • Children with sickle cell disease may have various anatomic and physiologic abnormalities that involve the CNS even if they appear to be neurologically healthy. Abnormalities may be associated with deterioration in cognitive function with effects on learning and behavior and may increase the potential risk for clinical and subclinical damage to the CNS.
  • Primary stroke prevention: Transcranial Doppler ultrasound (TCD) is a useful tool to identify children at high risk for stroke before they have suffered a clinical stroke. Children with HbSS or HbS–beta-0 thalassemia aged 2-16 years should be considered candidates for annual TCD screening. A clinical trial demonstrated that transfusion therapy decreased the risk of stroke in children with abnormal TCD blood flow patterns.
  • Secondary stroke prevention: Transfusion therapy has been shown to reduce the recurrence of ischemic neurologic events in patients with sickle cell disease. Many believe that life-long transfusions are necessary to eliminate recurrences completely. Iron overload requires chelation therapy after 2-3 years. Erythrocytapheresis is now increasingly used as alternative therapy. This procedure allows rapid dilution of HbS concentrations to less than 30% without significantly increasing total hemoglobin concentration posttransfusion. For children with a human leukocyte antigen (HLA–matched sibling, a consortium has demonstrated that the risk of recurrent stroke can be greatly reduced with allogeneic bone marrow transplantation (an alternative to long-term transfusion and iron chelation).
• Cholecystitis
• • Because of chronic hemolysis, cholelithiasis is common in children who are affected.
  • Cholecystitis or common bile duct obstruction can occur. Consider cholecystitis in a child who presents with right upper quadrant pain, especially if associated with fatty food.
  • Consider common bile duct blockage when a child presents with right upper quadrant pain and dramatically elevated conjugated hyperbilirubinemia.
  • Treatment of acute cholecystitis in patients with sickle cell disease does not differ from that for the general population. Patients receive antibiotics and general supportive care and may consider elective cholecystectomy several weeks after the acute episode subsides. Elective laparoscopic cholecystectomy in a well-prepared patient has become the standard approach for symptomatic patients.
• Avascular necrosis of the femoral or humeral head
• • Vascular occlusion can result in avascular necrosis (AVN) and subsequent infarction and collapse at either site.
  • AVN of the femoral head presents a greater problem because of weight bearing.
  • Patients with high baseline hemoglobin levels are at increased risk.
  • Approximately 30% of all patients have hip pathology by age 30 years.
  • The natural history of symptomatic hip disease in patients with sickle cell disease who are treated conservatively varies with the patient's age. In skeletally immature patients aged 12 years or younger, treatment with analgesics, nonsteroidal anti-inflammatory drugs, and protected weight bearing usually results in healing and remodeling of the involved capital epiphysis, similar to that observed in Legg-Calve-Perthes disease. This approach results in preservation of the joint despite the persistence of deformity, such as coxa magna and coxa plana. In contrast, conservative management of osteonecrosis usually fails in older adolescents and adults. Progressive flattening and collapse of the femoral head results in painful secondary degenerative arthritis.
  • The use of joint-preserving surgical procedures such as core decompression and osteotomy has been reported in patients with sickle cell disease who have precollapse femoral head involvement.
• Priapism
  • Priapism, defined as a sustained, painful, and unwanted erection, is a well-recognized complication of sickle cell disease. According to one study, the mean age at which priapism occurs is 12 years, and, by age 20 years, as many as 89% of males with sickle cell disease have experienced one or more episodes of priapism.
  • Priapism can be classified as prolonged if it lasts for more than 3 hours or as stuttering if it lasts for more than a few minutes but less than 3 hours and resolves spontaneously. Stuttering episodes may recur or develop into more prolonged events. Prolonged priapism is an emergency that requires urologic consultation.
  • Recurrent episodes of priapism can result in fibrosis and impotence, even when adequate treatment is attempted.

Physical

In the absence of one of the above-described complications of the disease process, a child may simply be jaundiced or pale.

• Splenic enlargement may be present. Spleen size should be measured, and parents should be made aware of it. A tongue blade may be used as a "spleen stick" in a small child, with the upper end of the blade corresponding to the nipple in the midclavicular line and a marking made on the stick corresponding to the edge of the spleen.
• Almost all patients with sickle cell disease with moderate-to-severe anemia have a cardiac systolic flow murmur that usually does not require further evaluation.
• Growth parameters show patients falling below the growth isobars. This usually occurs around the prepubertal age because of delayed puberty. Bone marrow expansion often causes maxillary hypertrophy with overbite; orthodontics are recommended to prevent or correct this problem.

Causes

Sickle cell disease denotes all genotypes that contain at least 1 sickle gene in which HbS makes up at least half the hemoglobin present. Sickle cell anemia is the most severe and most common form.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

HbS–beta-0 thalassemia

HbS–beta plus thalassemia

HbSC disease

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Newborn hemoglobinopathy screening
• • The introduction of newborn screening is one of the greatest advances in the management of sickle cell disease. Currently, 49 states and the District of Columbia have mandatory universal programs for newborn screening for hemoglobin disorders. If results are positive, a repeat hemoglobin electrophoresis should be performed for confirmation.
  • Fetal hemoglobin is predominant in young infants.
  • If results show only Hb F and S, the child has either sickle cell anemia or HbS–beta-0 thalassemia.
  • If results show Hb F, S, and C, the child has HbSC disease.
  • If results show Hb F, 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 plus 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 hemoglobin electrophoresis on the child after several months.
• Normocytic hemolytic anemia
• • If results of electrophoresis show only HbS with a Hb F concentration of less than 30%, the diagnosis is sickle cell anemia.
  • If HbS and Hb C are present in roughly equal amounts, the diagnosis is HbSC disease.
• Microcytic hemolytic anemia
• • If the child has 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 Hb A₂ level is normal, consider the possibility of concomitant HbSS and iron deficiency.
  • If HbS is greater than A and Hb A₂ is elevated, a diagnosis of HbS–beta plus thalassemia can be inferred.
  • If HbS and Hb C are present in equal amounts, the diagnosis is HbSC disease.
• It is useful to collect a series of baseline values on each patient to compare with those at times of acute illness. The table below shows a typical schedule of routine clinical laboratory evaluations.

  Table 1. Suggested routine clinical laboratory evaluations

  Tests	Age	Frequency
  CBC with WBC differential, reticulocyte count	3 mo - 24 mo >24 mo	every 3 mo every 6 mo
  Percent Hh F	6 mo - 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

Imaging Studies

• The brain and lungs are among the organs susceptible to serious damage in sickle cell disease. Early detection of dysfunction may allow intervention to reduce risk of further damage.
• Brain
• • Transcranial Doppler ultrasonography (TCD), magnetic resonance imaging (MRI) with or without angiography, and neuropsychometric (NPM) studies have been used extensively to evaluate children with sickle cell disease. An abnormally high blood flow velocity determined with TCD in the middle cerebral or internal carotid arteries is associated with an increased risk of stroke; however, blood flow results should be interpreted cautiously because they depend on the technique used.
  • Physicians recommend beginning TCD screening of children with sickle cell disease at age 2 years and continuing 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. The STOP (Stroke Prevention in Sickle Cell Anemia) trial in 1997 demonstrated that a transfusion program reduces the risk of strokes in patients with abnormal TCD results.
  • Children with sickle cell disease who have "silent" cerebral infarcts revealed with MRI have a higher rate of abnormal 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.
  • 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.
• Lungs: Children with sickle cell disease frequently have abnormal pulmonary function test (PFT) results. PFTs should be performed regularly in those 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.
• Heart: 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.
• Abdominal ultrasonography: This can be used to visualize stones and to detect signs of thickening gall bladder walls or ductal inflammation, indicating possible cholecystitis.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

• Anemia
• • No scientific evidence shows that patients develop folate deficiency; however, folic acid (1 mg/d) is commonly prescribed for adults to prevent development of megaloblastic anemia due to increased folate requirements caused by hemolysis.
  • For anemic crisis with splenic sequestration, give early red-cell transfusions, since the process can progress rapidly to shock. Do not allow hemoglobin levels to rise to more than 10 g/dL, since the spleen may disgorge trapped cells, which can create a relative polycythemia and increased blood viscosity. Children who experience a single sequestration event frequently have recurrences. Surgical splenectomy or a short-term transfusion regimen has been suggested for this complication.
  • Transfusion is required in an aplastic crisis if the anemia is symptomatic (eg, dyspnea, signs of hypovolemia). Since aplastic crises are self-limited, transfusion may be avoided if the child is stable and can be adequately observed. If hospitalization is required, use precautions to prevent transmission of parvoviral infection to patients who are immunosuppressed or caretakers who are pregnant.
• Infection
• • Penicillin prophylaxis significantly reduces the incidence of S pneumoniae infection and may decrease the mortality rate. Begin at age 2-4 months with 125 mg bid; at 3 years, increase the dose to 250 mg bid. As with all long-term medication regimens, compliance is a serious problem; therefore, remind parents of the importance at each visit.
  • Protein-conjugated pneumococcal vaccines (PCVs) that effectively protect children against invasive infections are now extensively used. The 7-serotype PCV (PCV7) in combination with penicillin prophylaxis and PPV23 booster vaccination offers the best hope for improved prevention against S pneumoniae infection. In a recent study, more than two thirds of S pneumoniae isolates stereotyped were PCV7 serotypes and included most penicillin-nonsusceptible strains. Most nonvaccine-serotype isolates were penicillin-sensitive.
• Acute chest syndrome
• • Obtain appropriate cultures, but treat expectantly for Streptococcus pneumoniae and Mycoplasma pneumoniae.
  • Administer oxygen if saturation is less than 94%.
  • If that level cannot be maintained at a fraction of inspired oxygen (FiO₂) of 0.4, provide simple transfusion (avoid raising hematocrit to more than 36%). If no improvement is seen, reduce the HbS level to 30% with erythrocytapheresis or exchange transfusion.
  • The process can progress rapidly to respiratory failure. Ventilatory assistance may be required.
• Pain
• • Inform parents and children that recurring pain is expected. Assist them in developing an approach that allows continued normal activities even with pain. Instruct parents and family members to provide sympathy, but with encouragement and support designed to help the child accept pain, not submit to it. Parents and family members are encouraged to provide local measures and over-the-counter drugs for mild pain. Physicians suggest keeping on hand a small supply of a mild narcotic analgesic for pain that does not respond to lesser measures.
  • Pain that does not respond to the above measures almost always requires hospitalization. Avoid providing 1-2 doses of parenteral narcotics in the emergency department, since moderately severe sickle cell pain is expected to persist for several days. For pain severe enough to require hospitalization, treat with morphine or other major narcotic analgesics in doses sufficient to provide a reasonable degree of relief. Continuous infused morphine is most effective. Choose dosage to provide reasonable pain relief with precautions to avoid oversedation and respiratory depression. A starting dose of morphine (0.05-0.01 mg/kg/h) is suggested following a bolus dose to provide a reasonable degree of pain relief. Adjust according to patient response. Patient-controlled analgesia with self-administered bolus morphine and low-dose continuous IV infusion is effective and well accepted by patients.
  • Fentanyl and nalbuphine have also been used as continuous IV infusion. Ketorolac can be given along with opioid analgesics and typically reduces the opioid dose required to achieve the desired effect.
  • Dependence seldom occurs, since the duration of sickle pain is brief (5-7 d). Addiction, described as narcotic-seeking behavior, is rarely encountered. It can result if a patient uses narcotics for euphoriant or stimulant effects rather than analgesia. Narcotic addiction in people with sickle cell disease is no more common than in the general population and may be minimized with a carefully designed analgesic regimen.
• Stroke
• • Unless long-term transfusion therapy is provided, 70-90% of children who experience a single stroke have subsequent events.
  • The ultimate goal of transfusion is to maintain the HbS level at less than 30%.
  • Do not raise the total hemoglobin level to more than 10-12 g/dL while the HbS level is more than 30%, since the resulting high viscosity can cause progression or additional areas of infarction.
• Cholecystitis
• • If patients present with right upper quadrant abdominal pain, evaluate the gall bladder with ultrasonography.
  • Provide appropriate medical and supportive care for cholecystitis if stones are visualized, if gall bladder walls are thickening, or upon signs of ductal inflammation.
  • Arrange for elective cholecystectomy when inflammation resolves.
  • Avascular necrosis of femoral or humeral head
  • Decrease weight bearing of an affected lower extremity using crutches and touchdown gait.
  • Femoral head core decompression is under investigation to determine if use in the early stages of the process may prevent progression.
  • Potent nonsteroidal anti-inflammatory agents are necessary when chronic changes are present.
  • Hip replacement may be required after full linear growth is achieved.
• Priapism
• • At the onset of priapism, patients should be advised to drink extra fluids, use oral analgesics, and attempt to urinate. A nightly dose of pseudoephedrine (30 mg PO) may prevent priapism in some cases. For episodes that last more than 2 hours, patients should go to the emergency department to receive intravenous hydration and parenteral analgesia. According to one protocol, if detumescence does not occur within 1 hour after arrival in the emergency department, penile aspiration followed by irrigation of the corpora with a 1:1,000,000 solution of epinephrine in saline is initiated. (The procedure should be performed within 4-6 h of priapism onset.)
  • The concomitant use of automated red-cell exchange transfusions to reduce the sickle hemoglobin (HbS) level to less than 30% may also be considered, especially if early intervention with irrigation fails.
  • Should the condition recur despite aspiration and local instillation of vaso-active drugs, consider shunting. In this procedure, known as the Winter procedure, a shunt is created between the glans penis and the distal corpora cavernosa; this allows blood from the distended corpora cavernosa to drain into the uninvolved corpus spongiosa. A larger shunt may be created if this is not successful.
  • Complications of priapism and treatment include bleeding from the holes placed in the penis as part of the aspiration or shunting procedures, infections, skin necrosis, damage or strictures of the urethra, fistulas, and impotence. If impotence persists for 12 months, the patient may wish to consider implantation of a semirigid penile prosthesis.
• Transfusion
• • Alloimmunization is a common problem that arises from the differences in certain minor red-cell antigens found in the predominantly African American patient population and the mostly white blood donors. Matching for C, E, Kell, JKB (Kidd), and Fya (Duffy) antigens can significantly reduce alloimmunization.
  • Intraoperative and postoperative complications may result from hypoxia, dehydration, or hypothermia that occurs during or after a surgical procedure. They may be minimized or avoided if transfusions are given before the procedure.
  • While a recent study demonstrated no overall difference in the complication rate among subjects who received either preoperative exchange or simple transfusion, it provided little guidance for what type of transfusion would be best in individual situations.
  • In general, raising the hemoglobin concentration to a level of more than 10 g/dL but less than 12 g/dL provides the patient with approximately 20-30% hemoglobin A. The presence of this fraction of normal hemoglobin may provide some protection from complications.
  • Many anesthesiologists require a hemoglobin concentration of more than 10 g/dL prior to the procedure.
  • More complex procedures or longer duration of anesthesia times are more likely to lead to acute chest syndrome or other complications. Providing preoperative transfusion may decrease the risk.
  • The approach is less certain for patients whose baseline hemoglobin level is more than 10 g/dL. If complexity of the surgical procedure or duration and risk of anesthesia is considerable, exchange transfusion or erythrocytapheresis can reduce the HbS concentration to 30%, while keeping the total hemoglobin level at less than 12 g/dL.
  • In patients undergoing retinal surgery, the HbS concentration or combined concentration of HbS and C needs to be reduced to less than 30% (increase the hemoglobin A concentration to 70%).
  • Individualize all other situations based on the complexity of the procedure and underlying medical condition.
• Erythrocytapheresis
• • Erythrocytapheresis is an automated red-cell exchange procedure that removes blood that contains HbS from the patient while simultaneously replacing that same volume with packed red cells free of HbS. Transfusion usually consists of sickle-negative, leuco-reduced, and phenotypically matched blood for red-cell antigens C, E, K, Fy, and Jkb.
  • The procedure is performed on a blood cell processor (pheresis machine) with a continuous-flow system that maintains an isovolemic condition. Red cells are removed and simultaneously replaced first with normal saline followed by transfused packed RBCs along with the patient's plasma. The net RBC mass/kg is calculated for each procedure based on the measured hematocrit of the transfused and removed blood and the total RBC volume transfused.
  • Erythrocytapheresis thus has the advantage of controlling iron accumulation in patients with sickle cell disease who undergo long-term transfusion, and the ability to achieve adequate Hb and HbS concentrations without exceeding the normal concentration. This precision is achieved because the computer in the pheresis machine is able to use various physiologic parameters before transfusion such as height, weight, and Hb level to compute the expected amount of packed RBCs required to obtain a specific posttransfusion hemoglobin level. Further, erythrocytapheresis requires the least amount of time when compared to using similar blood volumes on patients receiving simple blood transfusions.
  • Although erythrocytapheresis is more expensive than simple transfusion, if the cost of chelation and organ damage due to iron overload is considered, erythrocytapheresis without chelation costs less than simple transfusion programs. Central venous access devices can safely be used for long-term erythrocytapheresis in patients with sickle cell disease with a low rate of complications.
• Bone marrow transplantation
• • While sickle cell disease can be resolved with allogeneic marrow transplantation, the current application of bone marrow transplantation (BMT) is complex. Results indicate an event-free survival rate of approximately 84% and a mortality rate of less than 6%.
  • The risk-benefit ratio has led to the establishment of certain guidelines. Two restrictions limit BMT applicability to approximately 5% of children who qualify through hematologic diagnosis. Donors must be HLA compatible and full siblings (those with sickle trait are acceptable) and candidates should be limited to patients younger than 16 years with HbSS or HbS–beta-0 thalassemia who have evidence of disease severity demonstrated by the following:
  • • Stroke
    • Recurrent acute chest syndrome
    • Recurrent severe crisis pain (>2 episodes/y for several years)
    • Recurrent priapism
    • Impaired neuropsychological function with evidence of cerebral infarction
    • State I or II sickle lung disease
    • Sickle cell nephropathy
    • Bilateral proliferative retinopathy and major visual impairment in at least one eye
    • Osteonecrosis of multiple joints
    • Red-cell alloimmunization to more than 2 antibodies during long-term transfusion therapy

Diet

• An age-appropriate, well-balanced diet is suggested. No special requirements are indicated.

Activity

• Encourage children to participate in physical activities. Because of anemia, they have less stamina than their hematologically healthy playmates. Advise supervising adults of this limitation, particularly teachers and coaches who may require children to run designated distances.
• Arrange for children to have ready access to liquids and a place to rest and cool off.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Drug Category: Analgesics

Pain is the hallmark of sickle cell disease. While frequency and severity vary greatly, most patients have interval symptoms. Once pain has begun, no therapy reverses the process. Analgesics may provide a reasonable degree of comfort. While certain dosing guidelines are available, the amount of drug given should be titrated to the degree of pain experienced.

Drug Category: Anti-sickling agents

Considerable effort is being expended to identify agents whose ultimate effect interferes with the sickling process and prevents the many complications of sickle cell disease.

Drug Category: Antibiotics

Antibiotic prophylaxis reduces the incidence of infection and may have positive effects on mortality.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• For infants, provide a suggested schedule for well-child visits to ensure that immunizations and other aspects of routine pediatric care are followed.

Further Outpatient Care

• For children aged 1-3 years, consider visits every 3 months for children with HbSS and HbS–beta-0 thalassemia to be certain that parents have sufficient penicillin for prophylaxis and to encourage compliance.

In/Out Patient Meds

• Children older than 3 years and children with HbSC disease and S-beta plus-thalassemia, can visit every 6 months.

Patient Education

• Emphasize the importance of prophylactic penicillin to the patient and family.
• Provide parents with information about appropriate response to febrile illness.
• Teach parents how to palpate the abdomen for signs of splenic enlargement and discuss its significance.
• Discuss with the parents the proper approach to pain episodes.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Sickle Cell Crisis and Anemia.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Document efforts at making contact and ensuring initial confirmatory testing.
• Document efforts to ensure follow-up appointments to provide parents with a supply of penicillin for prophylaxis.
• Approach the febrile child who has sickle cell anemia with great care. If the physician chooses not to hospitalize the patient, obtain blood culture, give intravenous ceftriaxone, instruct parents on the need to return if condition changes, and arrange for a return visit within 24 hours.
• If the hemoglobin level is significantly below the patient's baseline, palpate the spleen and evaluate reticulocyte and platelet counts. Splenic sequestration can rapidly progress to hypovolemic shock and death.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Charles Pegelow, MD to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Molecular and cellular changes of hemoglobin S.
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Media file 2:  Effects of therapy with hydroxyurea.
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Media file 3:  Peripheral blood with sickled cells at 400X magnification. Photograph by Dr Ulrich Woermann.
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Media file 4:  Peripheral blood smear with sickled cells at 1000X magnification. Photograph by Dr Ulrich Woermann.
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Media file 5:  Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Photograph by Dr Ulrich Woermann.
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REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

• Adamkiewicz TV, Sarnaik S, Buchanan GR, et al. Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination. J Pediatr. Oct 2003;143(4):438-44. [Medline].
• Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. Jul 2 1998;339(1):5-11. [Medline].
• Brown AK, Sleeper LA, Miller ST, et al. Reference values and hematologic changes from birth to 5 years in patients with sickle cell disease. Cooperative Study of Sickle Cell Disease. Arch Pediatr Adolesc Med. Aug 1994;148(8):796-804. [Medline].
• Buchanan GR, DeBaun MR, Quinn CT, Steinberg MH. Sickle cell disease. Hematology Am Soc Hematol Educ Program. 2004;35-47. [Medline].
• Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood. Jul 15 1994;84(2):643-9. [Medline].<