Chapter 104: Sickle Cell Disease

• Sickle cell disease (SCD) is a chronic hemolytic anemia that is most common among African Americans but may occur in children of any ethnic background. Patients with a single abnormal gene for hemoglobin S (Hgb S) have sickle cell trait and remain essentially asymptomatic.

• Acute vasoocclusive events, or painful “crisis,” are the most common complication of SCD and are the most frequent cause of emergency department (ED) visits.

• Patients with SCD presenting with a new infiltrate on chest radiograph and chest pain, fever, and/or respiratory symptoms have acute chest syndrome (ACS) requiring hospitalization.

• A blood culture should be obtained and parenteral antibiotic given to every patient with SCD and fever due to the risk of sepsis from encapsulated bacteria, especially Pneumococcus.

• Splenic sequestration crisis occurs when RBCs become entrapped in the spleen, resulting in a rapidly enlarging spleen and a sudden drop in Hgb.

• Stroke occurs in 11% of patients with sickle cell anemia under 20 years of age. Patients with signs and symptoms concerning for stroke should have neuroimaging performed (preferably MRI and MRA) and consultation with a hematologist as soon as possible.

Hgb S is a variant resulting from a single nucleotide mutation of the β-globin gene leading to the substitution of hydrophobic valine for the normal hydrophilic glutamic acid. SCD occurs when an individual is homozygous for Hgb S or is a compound heterozygote for Hgb S and another interacting β-globin variant. The most common combination of hemoglobins leading to SCD are Hgb SS (sickle cell anemia), Hgb SC (hemoglobin SC disease), and Hgb S-β thalassemia (either β⁰ or β⁺). Although there is wide variability in individual severity of illness, patients with double heterozygous states such as Hgb SC, Hgb Sβ⁺ thalassemia, and are typically less seriously affected than those with Hgb SS or Hgb Sβ⁰ (no hemoglobin A production). Approximately 2600 children are born in North America each year with SCD, most commonly children of African descent.¹ However, Hgb S also occurs in people of Mediterranean, Indian, Central/South American, and Middle Eastern descent.

Patients with a single abnormal gene for HbS have sickle cell trait. The concentration of HbS is typically 40%, and the large percentage of normal hemoglobin allows the patients to remain asymptomatic except under the most severe hypoxic stress. Sickle trait should be considered a benign condition. Patients with SCD experience a number of complications that are likely to bring them to the ED.

Acute vasoocclusive events, or painful “crisis,” are the most common complication of SCD and are the most frequent cause of ED visits.² Pain episodes result from the obstruction of blood flow in the microcirculation leading to tissue ischemia and microinfarction. Vasoocclusion occurs via a combination of sickle cell interactions with endothelial cells and obstruction from nondeformable sickle cells.

Dactylitis, or hand–foot syndrome, is vasoocclusion in the marrow of the metacarpal or metatarsal bones (Fig. 104-1). This is often the earliest presentation of SCD, usually occurring between 6 and 18 months of life. Infants present with hand and foot swelling and tenderness, which may lead to refusal to walk and irritability. Dactylitis declines with age as hematopoiesis shifts to the long bones.

Older patients typically experience vasoocclusive events in the long bones, back, joints, and abdomen. Pain events may be precipitated by dehydration, hypoxia, cold exposure, or infection. However, often no instigating factor is identified. There is a great deal of individual variation in number and severity of painful crises. On average, patients with SCD experience 0.8 hospitalizations per patient-year, but 5% of patients have frequent pain crises and account for approximately one-third of all medical contacts for painful crisis.² Figure 104-2 outlines an approach to the management of severe acute pain in the ED.

As there is no diagnostic test or clinical finding that will identify patients in vasoocclusive crisis, the diagnosis is made on the basis of history alone. Patients with SCD and pain should be evaluated for other disease processes such as traumatic injuries, osteomyelitis, septic arthritis, and surgical abdominal problems. The formation of gallstones due to chronic hemolysis may lead to cholecystitis or pancreatitis and abdominal pain. A complete blood count (CBC) and reticulocyte count is indicated in every encounter with SCD patients. Typically, patients remain at baseline levels of Hgb during a painful event. Hydration at maintenance rate should be initiated to correct and prevent dehydration. Overhydration may lead to ACS and should be avoided. Oxygen has not been shown to be beneficial in the management of pain crises unless hypoxemia is present.

Pain should be assessed at least every 30 minutes using standardized pain scales. Prompt initiation of appropriate pain control is important. Pain relief is achieved with a variety of analgesics, depending on the severity of the crisis and what the patient has required in past crises. Oral agents such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and codeine used separately or in combination are the mainstays of treatment for mild-to-moderate pain. Usually, patients have unsuccessfully tried these therapies on a scheduled basis at home prior to presenting to the ED. For patients who have not attempted oral therapy at home, this should be initiated first. Parenteral opioids, preferably morphine or hydromorphone, are often necessary for severe pain. Anxiety about giving children narcotics leads to undertreatment of pain, which should be avoided. Meperidine is a poor choice for SCD pain. Its use results in the buildup of normeperidine, a toxic metabolite with poor analgesic effect, which can cause dysphoria, and increases the risk of seizures.³

Typically, patients in the ED receive scheduled oral opioid and NSAIDs and parenteral opioid analgesics and are observed for 3 or 4 hours. Patients will often require further doses of parenteral opioid. If the patient remains comfortable without further need for parenteral opioid, he or she may be discharged with continued scheduled oral opioid and NSAIDs at home. If adequate pain relief is not achieved, the patient is admitted for further parenteral analgesia. Analgesia should be provided at frequent regular time intervals to avoid breakthrough pain. In a crisis prn pain medications should be avoided. When pain recurs between doses, the recurring pain is more difficult to control. Hypoventilation as a result of opiate use may increase the risk of developing ACS. Incentive spirometry should be encouraged in order to decrease this risk.

ACS is the presence of a new lobar or segmental pulmonary infiltrate in the presence of fever, respiratory symptoms, and/or chest pain (Fig. 104-3). Various causes that contribute to ACS include infection, pulmonary infarction due to vasoocclusion, and fat emboli from marrow infarction.⁴ Chest pain from vasoocclusion may cause splinting and hypoventilation, leading to the development of ACS in a patient who initially presents with a painful episode. It is difficult to differentiate vasoocclusion from pneumonia in patients with ACS, since both etiologies cause similar manifestations. Infectious organisms associated with ACS include Pneumococcus in younger children and Mycoplasma or Chlamydia in adolescents. ACS may present with or rapidly progress to respiratory failure requiring mechanical ventilation.

All patients with ACS should be hospitalized. Laboratory evaluation should include a CBC, reticulocyte count, and blood culture. Antibiotic therapy directed at S. pneumoniae and atypical organisms such as a third-generation cephalosporin and a macrolide should be initiated. A type and crossmatch should be considered as red cell transfusion may be necessary. A chest X-ray is adequate; CT scans are not useful in establishing a diagnosis. Room air oxygen saturation should be checked and supplemental oxygen initiated via face mask or nasal cannula in hypoxemic patients. Initiate analgesia for chest pain but manage this carefully to prevent hypoventilation. Hydration should be limited to 1 to 1.25 times maintenance PO + IV in order to avoid fluid overload. Patients with hemoglobin >2 g below baseline, hypoxia, or a rapidly progressing process will most likely require blood transfusion. Transfusion reduces the percentage of Hgb S, increases oxygen carrying capacity, and may be either simple or by exchange depending on the severity of symptoms and level of anemia compared to the patient's baseline hemoglobin. Bronchodilators may benefit patients with a history of reactive airway disease.

Patients with SCD are at high risk for infection primarily due to functional asplenia. The major risk comes from encapsulated bacteria, especially Pneumococcus. Although prophylactic penicillin and vaccines for pneumococci and Haemophilus influenzae type B have reduced the incidence of sepsis in this vulnerable population, overwhelming pneumococcal sepsis remains a significant cause of death. Children younger than 3 years are particularly susceptible to bacteremia, which can occur as commonly as nine bacteremic events per 100 patient-years.⁵ The fatality rate is high, even though many of these children appear well at initial presentation.

Children with SCD who present to the ED with fever (>38.5°C) are at highest risk for bacteremia. After obtaining a CBC and blood culture, all persons with SCD should be promptly treated with parenteral antibiotics effective against S. pneumoniae and, if unimmunized, H. influenzae B. Meningitis does occur in children with SCD, but lumbar puncture in the absence of meningeal signs is not warranted. Hospital admission is necessary for any toxic-appearing child. Hospitalization should be considered in patients presenting with a temperature >40°C, a WBC count >30,000 per mm³, thrombocytopenia, hemoglobin significantly below baseline value, or in a situation where follow-up is uncertain or unlikely. Some institutions use a long-acting cephalosporin, such as ceftriaxone, along with close outpatient follow-up in nonseptic-appearing children. The risk for infection in SCD persists into adulthood; all patients should be evaluated as above regardless of age.

In addition to overwhelming sepsis, children with SCD are susceptible to other infections such as pneumonia, meningitis, and osteomyelitis. The etiology is most frequently encapsulated organisms. Unlike the general population, the most common organism identified as the cause of osteomyelitis in patients with SCD is Salmonella.

Overt stroke occurs in approximately 11% of children with sickle cell anemia before 20 years of age, and in 24% by 45 years of age.⁶ Stroke is very rare in children with Hgb SC and Hgb Sβ⁺. Most strokes in children are ischemic events, involving large arteries. Hemorrhagic events are more common in adults but may be seen in adolescents. Common presenting signs and symptoms of infarctive stroke include hemiparesis, refusal to use an arm or leg, aphasia, dysphasia, seizures, cranial nerve palsy, or coma. Initial management should include a careful history, focusing on any previous neurologic events and results of previous neuroimaging. A CBC, reticulocyte count, and type and crossmatch should be drawn. An MRI and MRA (Fig. 104-4) with diffusion-weighted imaging should be obtained as soon as possible, a noncontrast enhanced CT is only necessary if there will be a delay in obtaining MRI. Results of neuroimaging may be normal early in the event and the diagnosis of stroke may be made clinically. As there is no treatment proven to change the acute outcome, exchange or simple transfusion to reduce Hgb S to less than 30% is the management of choice. Care must be taken to maintain the patient's hemoglobin below 11 g/dL until Hgb S is known to be below 30%. Chronic transfusion to maintain Hgb S below 30% has been shown to reduce recurrent stroke events. The use of transcranial Doppler to measure flow velocities in the major cerebral blood vessels is now in use in most sickle cell centers to identify children with SCD at highest risk for stroke. Those found to have elevated velocities are often placed on chronic transfusion programs as primary stroke prevention.

Acute splenic sequestration crisis (ASSC) occurs when red cells become trapped in the spleen, resulting in a rapidly enlarging spleen, a sudden drop in Hgb, and the potential for shock. ASSC occurs most often in patients with Hgb SS between 3 months and 5 years of age. Repeated infarctions of the spleen in patients with Hgb SS lead to autosplenectomy by 3 to 5 years of age, decreasing the risk of ASSC. In patients with Hgb SC and Sβ⁺, ASSC is less common, but persistent splenomegaly may occur in adolescence or adulthood. ASSC may present with the sudden onset of weakness, pallor, tachycardia, tachypnea, or abdominal fullness. Parents of children with SCD are taught to palpate the spleen regularly at home and present to the ED for a newly palpable spleen or enlargement of a chronically enlarged spleen. Laboratory studies demonstrate marked anemia, an elevated reticulocyte count, and often thrombocytopenia.

The mainstay of therapy is simple blood transfusion. If the patient is unstable, fluid expansion may be used in the initial stages of resuscitation while waiting for blood to be available, but it must be used carefully as volume overload and congestive heart failure can result. Blood transfusion should be considered with a decline in hemoglobin of 2 g or more below baseline, hemoglobin below 5 g/dL, or in any patient with signs of cardiovascular compromise. Transfusion will support oxygen-carrying capacity, decrease the percent of Hgb S, and result in sequestered red cells being released from the spleen. Thus, the goal of transfusion is a hemoglobin of 9 g/dL. Sequestration frequently recurs, with up to 50% of children having a second ASSC.⁷ Splenectomy may be necessary in children with recurrent ASSC.

Infections with Parvovirus B19 may cause transient red cell aplasia. In normal children whose RBC lifespan is 120 days, brief marrow suppression with Parvovirus infection will not lead to a significant drop in Hgb. However, the shortened lifespan of the RBC in sickle cell anemia (10–25 days) may lead to a significant drop in hemoglobin with even a short period of red cell aplasia. With Parvovirus, reticulocytopenia begins 5 days post exposure and continues for 7 to 10 days. Patients may have fever, respiratory symptoms, nausea and vomiting, arthralgias, or myalgias but may also have minimal symptoms. Fatigue, pallor, tachycardia, and tachypnea may be present with severe anemia. A CBC will reveal a drop in the hemoglobin from baseline and a decreased reticulocyte count (usually <1%). Patients presenting in the recovery phase may have a high reticulocyte count and numerous nucleated RBCs noted on the blood smear. Mildly anemic and asymptomatic children can be managed with supportive care and close outpatient observation pending marrow recovery. Simple transfusion of RBCs is necessary in patients with hemoglobin below 5 g/dL or with cardiovascular compromise. Children with Hgb SC or Sβ⁺ rarely require transfusion with aplastic crisis because of the higher baseline hemoglobin and longer lifespan of the RBCs in these conditions. It is important to remember the patient is infectious and proper isolation procedures must be followed. Parents should be made aware of the risk to siblings or other family members with SCD.

Priapism, a prolonged painful erection of the penis, may occur in up to 50% of boys with SCD before 21 years of age.⁸ Priapism may occur in stuttering episodes that last less than 2 hours but with frequent recurrence or may occur as a sudden event lasting for hours. If episodes are prolonged, priapism may lead to impotence. No specific therapy is necessary for a single episode of stuttering priapism. Maneuvers such as hydration, warm showers or baths, opioid pain medication, or frequent urination may end an episode. Oral adrenergic agents such as pseudoephedrine may treat brief episodes, and are often used prophylactically in patients with frequent events. Events lasting longer than 2 hours require immediate medical management and evaluation by an experienced urologist.

Disease Modifying Therapy

There are limited therapeutic options available to minimize the development of complications in children with SCD. Hydroxyurea is a cytotoxic drug that has been found to increase the concentration of fetal hemoglobin and may be beneficial in people with SCD. The chronic use of hydroxyurea has been shown to decrease the frequency of pain crisis, ACS, and hospital admissions. The main side effect is dose dependent myelosuppression. Chronic blood transfusion corrects anemia, decreases the percentage of Hgb S, and suppresses the patient's production of further Hgb S. The major risks of chronic blood transfusion include the development of alloantibodies and iron overload, and as a result, its use is primarily limited to secondary stroke prevention. Hematopoietic stem cell transplant is the only curative therapy for SCD. Its use has been increasing and has been primarily limited to those with an HLA-compatible sibling without SCD.