From Williams JA, Flynn PM, Harris S et al: A randomized study of outpatient treatment with ceftriaxone for selected febrile children with sickle cell disease, N Engl J Med 329:472–476, 1993.

Children who have sickle cell disease and who are treated with ceftriaxone can develop severe, rapid, and life-threatening immune hemolysis; the established risks of outpatient management must be balanced against the perceived benefits. Regardless of the clinical management strategy, all patients with any type of sickle cell disease and fever should be evaluated and treated immediately for occult bacteremia with either IV or IM antibiotics. Those with poor adherence, limited financial resources, or established risk factors for bacteremia should be admitted for at least 24 hr. For patients with positive blood cultures, pathogen-specific therapy should be considered. In the event that Salmonella spp. or Staphylococcus aureus bacteremia occurs, strong consideration should be given to evaluation of osteomyelitis with a bone scan, given the increased risk of osteomyelitis in children with sickle cell anemia when compared to the general population.

Dactylitis, often referred to as hand-foot syndrome, is often the first manifestation of pain in children with sickle cell anemia, occurring in 50% of children by their 2nd year (Fig. 456-1). Dactylitis often manifests with symmetric or unilateral swelling of the hands and/or feet. Unilateral dactylitis can be confused with osteomyelitis, and careful evaluation to distinguish between the two is important, because treatment differs significantly. Dactylitis requires palliation with pain medications, such as acetaminophen with codeine, whereas osteomyelitis requires at least 4-6 wk of IV antibiotics.

Figure 456-1 Roentgenograms of an infant with sickle cell anemia and acute dactylitis. A, The bones appear normal at the onset of the episode. B, Destructive changes and periosteal reaction are evident 2 wk later.

Splenic Sequestration

Acute splenic sequestration is a life-threatening complication occurring primarily in infants and can occur as early as 5 wk of age. Approximately 30% of children with sickle cell anemia have a severe splenic sequestration episode, and a significant percentage of these episodes are fatal.

Appropriate anticipatory guidance should include teaching parents and primary caregivers how to palpate the spleen to determine if the spleen is enlarging. The etiology of splenic sequestration is unknown. Clinically, splenic sequestration is associated with engorgement of the spleen, subsequent increase in spleen size, evidence of hypovolemia, and decline in hemoglobin of ≥2 g/dL from the patient’s baseline hemoglobin; reticulocytosis and a decrease in the platelet count may be present. These events can be accompanied by upper respiratory tract infections, bacteremia, or viral infection. Treatment includes early intervention and maintenance of hemodynamic stability using isotonic fluid or blood transfusions. If blood is required, typically 5 mL/kg of packed red blood cells (RBCs) is given. Repeated episodes of splenic sequestration are common, occurring in ~50% of patients. Most recurrent episodes develop within 6 mo of the previous episode. Prophylactic splenectomy performed after an acute episode has resolved is the only effective strategy for preventing future life-threatening episodes. Although blood transfusion therapy has been used to prevent subsequent episodes, evidence strongly suggests this strategy does not reduce the risk of recurrent splenic sequestration when compared to no transfusion therapy.

Pain

The cardinal clinical feature of sickle cell anemia is pain. No written definition can describe the visual picture of a child with sickle cell anemia in pain. The pain is characterized as unremitting discomfort that can occur in any part of the body but most often occurs in the chest, abdomen, or extremities. These painful episodes are often abrupt and can cause disruption of daily life activities and anguish for children and their families. The only measure for pain is the patient. Health care providers working with children with sickle cell anemia should develop a consistent, validated pain scale, such as the Wong-Baker FACES Scale for determining the magnitude of the pain. Although pain scales have proved useful for some children, others require prenegotiated activities to determine when opioid therapy should be initiated and decreased. For instance, sleeping through the night might be an indication for decreasing pain medication by 20% the following morning. The majority of painful episodes in patients with sickle cell anemia are managed at home with comfort measures, such as heating blanket, relaxation techniques, massage, and pain medication. A patient with sickle cell anemia has ~1 painful episode per year that requires medical attention.

The exact etiology of pain is unknown, but the pathogenesis is initiated when blood flow is disrupted in the microvasculature by sickle cells, resulting in tissue ischemia. Precipitating causes of painful episodes can include physical stress, infection, dehydration, hypoxia, local or systemic acidosis, exposure to cold, and swimming for prolonged periods. Successful treatment of painful episodes requires education of both the parents and the patients regarding the recognition of symptoms and the optimal management strategy. Given the absence of any reliable objective laboratory or clinical parameter associated with pain, trust between the patient and the treating physician is paramount to a successful clinical management strategy. Specific therapy for pain varies greatly but generally includes the use of acetaminophen or a nonsteroidal agent early in the course of pain, followed by escalation to acetaminophen with codeine or a short- or long-acting oral opioid.

Some patients require hospitalization for administration of IV morphine or derivatives of morphine. The incremental increase and decrease in the use of the medication to relieve pain roughly parallels the 8 phases associated with a chronology of pain and comfort (Table 456-2). The average hospital length of stay for children admitted in pain is 4.4 days. The American Pain Society has published clinical guidelines for treating acute and chronic pain in patients with sickle cell disease of any type. These recommendations are comprehensive and represent a starting point for treating pain (www.ampainsoc.org/pub/sc.htm).

Table 456-2 SUMMARY OF THE CHRONOLOGY OF PAIN IN CHILDREN WITH SICKLE CELL DISEASE

PHASE	PAIN CHARACTERISTICS	SUGGESTED COMFORT MEASURES USED
1 (Baseline)	No vaso-occlusive pain; pain of complications may be present, such as that connected with avascular necrosis of the hip	No comfort measures used
2 (Pre-pain)	No vaso-occlusive pain; pain of complications may be present; prodromal signs of impending vaso-occlusive episode may appear, e.g., “yellow eyes” and/or fatigue	No comfort measures used; caregivers may encourage child to increase fluids to prevent pain event from occurring
3 (Pain start point)	First signs of vaso-occlusive pain appear, usually in mild form	Mild oral analgesic often given; fluids increased; child usually maintains normal activities
4 (Pain acceleration)	Intensive of pain increases from mild to moderate Some children skip this level or move quickly from phase 3 to phase 5	Stronger oral analgesic are given; rubbing, heat, or other activities are often used; child usually stays in school until the pain becomes more severe, then stays home and limits activities; is usually in bed; family searches for ways to control the pain
5 (Peak pain experience)	Pain accelerates to high moderate or severe levels and plateaus; pain can remain elevated for extended period Child’s appearance, behavior, and mood are significantly different from normal	Oral analgesics are given around the clock at home; combination of comfort measures is used; family might avoid going to the hospital; if pain is very distressing to the child, parent takes the child to the emergency department After child enters the hospital, families often turn over comforting activities to health care providers and wait to see if the analgesics work Family caregivers are often exhausted from caring for the child for several days with little or no rest
6 (Pain decrease start point)	Pain finally begins to decrease in intensity from the peak pain level	Family caregivers again become active in comforting the child but not as intensely as during phases 4 and 5
7 (Steady pain decline)	Pain decreases more rapidly, become more tolerable for the child Child and family are more relaxed	Health care providers begin to wean the child from the IV analgesic; oral opioids given; discharge planning is started Children may be discharged before they are pain free
8 (Pain resolution)	Pain intensity is at a tolerable level, and discharge is imminent Child looks and acts like “normal” self Mood improves	May receive oral analgesics

Adapted from Beyer JE, Simmons LE, Woods GM, et al: A chronology of pain and comfort in children with sickle cell disease, Arch Pediatr Adolesc Med 153:913–920, 1999.

Several myths have been propagated regarding the treatment of pain in sickle cell anemia. The concept that painful episodes in children should be managed without opioids is without foundation and results in unwarranted suffering on the part of the patient. There is no evidence that blood transfusion therapy during an existing painful episode decreases the intensity or duration of the painful episode. Blood transfusion should be reserved for patients with a decrease in hemoglobin resulting in hemodynamic compromise, respiratory distress, or a falling hemoglobin concentration, with no expectation that a safe nadir will be reached, such as when the child has both a falling hemoglobin level and reticulocyte count with a parvovirus B19 infection. IV hydration does not relieve or prevent pain and is appropriate when the patient is unable to drink as a result of the severe pain or is dehydrated. Opioid dependency in children with sickle cell anemia is rare and should never be used as a reason to withhold pain medication. However, patients with multiple painful episodes requiring hospitalization within a year or with pain episodes that require hospital stays >7 days should be evaluated for comorbidities and psychosocial stressors that might contribute to the frequency or duration of pain.

Hydroxyurea, a myelosuppressive agent, is the only effective drug proved to reduce the frequency of painful episodes. A clinical trial in adults with sickle cell anemia and ≥3 painful episodes per year demonstrated the efficacy of hydroxyurea. Hydroxyurea was found to decrease the rate of painful episodes by 50% and the rate of ACS episodes and blood transfusions by ~50%. In children with sickle cell anemia, only a safety feasibility trial of hydroxyurea has been conducted. This study demonstrated that hydroxyurea was safe and well tolerated in children >5 yr of age. No clinical adverse events were identified in this study; the primary toxicities were limited to myelosuppression that reversed upon cessation of the drug.

Given the short-term safety profile in children and the established efficacy in adults, hydroxyurea is commonly used in children with multiple painful episodes. The long-term toxicity associated with hydroxyurea in children has not been established, but all evidence to date suggests that the benefits far outweigh the risks. For these reasons and others, children >5 yr of age receiving hydroxyurea require well-informed parents and medical care by pediatric hematologists or at least comanagement by a physician with expertise in managing chemotherapy. The typical starting dose of hydroxyurea is 15-20 mg/kg given daily, with an incremental dosage increase every 8 wk of 2.5-5.0 mg/kg, if no toxicities occur, up to a maximum of 35 mg/kg per dose. Achievement of the therapeutic effect of hydroxyurea can require several months. Monitoring children on hydroxyurea is labor intensive, with initial visits every 2 wk to monitor for hematologic toxicity with dose escalations and then monthly after a therapeutic dose has been identified. Close monitoring of the patient requires a commitment by the parents and patient as well as diligence by a physician to monitor for toxicity.

Priapism

Priapism is defined as an involuntary penile erection lasting for longer than 30 minutes and is a common problem in sickle cell anemia. The persistence of a painful erection beyond several hr suggests priapism. On examination, the penis is erect. The ventral portion and the glans of the penis are typically not involved, and their involvement necessitates urologic consultation based on the poor prognosis for spontaneous resolution. Priapism occurs in 2 patterns, stuttering and refractory, with both types occurring in patients from early childhood to adulthood. No formal definitions have been established for these terms, but generally stuttering priapism is defined as self-limited, intermittent bouts of priapism with several episodes over a defined period. Refractory priapism is defined as prolonged priapism beyond several hours.

Approximately 20% of patients between 5 and 20 yr of age report having at least 1 episode of priapism. Most episodes occur between 3 AM and 9 AM. The mean age at first episode is 12 yr, and the mean number of episodes per patient is ~16, with a mean duration of ~2 hr. The actuarial probability of a patient’s experiencing priapism is ~90% by 20 yr of age.

The optimal treatment for priapism is unknown, but treatment strategies can be divided into acute treatment and preventive therapy. For acute treatment, supported therapy, such as sitz bath or pain medication, is commonly employed. Priapism lasting >4 hr should be treated by aspiration of blood from the corpora cavernosa followed by irrigation with dilute epinephrine to produce immediate and sustained detumescence. Urology consultation is required to initiate this procedure, with appropriate input from a hematologist. Either simple blood transfusion therapy or exchange transfusion has been proposed for the acute treatment of priapism. However, evidence suggests that exchange transfusion therapy is not effective in enhancing detumescence.

For the prevention of recurrent priapism, hydroxyurea appears to have promise; the use of etilefrine, a sympathomimetic amine with both α₁ and β₁ adrenergic effects, appears safe and promising in the secondary prevention of priapism. The long-term effects of recurrent or prolonged priapism episodes in prepubertal children are not known. In adults, infertility and impotence are potential consequences.

Neurologic Complications

Neurologic complications associated with sickle cell anemia are varied and complex. Approximately 11% and 20% of children with sickle cell anemia will have overt and silent strokes, respectively, before their 18th birthday (Figs. 456-2 and 456-3). An overt stroke is defined as a focal neurologic deficit lasting >24 hr. However, this definition is outdated because many patients with sickle cell anemia will be treated with blood therapy that can hasten their recovery to baseline. A more functional definition is the presence of a focal neurologic deficit that lasts for >24 hr and/or increased signal intensity with a T2-weighted MRI of the brain indicating a cerebral infarct, corresponding to the focal neurologic deficit. The definition of silent cerebral infarct is the absence of a focal neurologic deficit lasting >24 hr in the presence of a lesion on T2-weighted MRI indicating a cerebral infarct. Evidence of a stroke can be found as early as 1 yr of age. Other neurologic complications include headaches that may or may not be related to sickle cell anemia, seizures, cerebral venous thrombosis, and reversible posterior leukoencephalopathy syndrome (RPLS). Children with other types of sickle cell disease such as Hb SC or Hb Sβ-thalassemia plus might have overt or silent cerebral infarcts as well.

Figure 456-2 T2-weighted MRI and magnetic resonance angiography (MRA) of the brain. A, T2-weighted MRI shows remote infarction of the territories of the left anterior cerebral artery and middle cerebral artery. B, MRA shows occlusion of the left internal carotid artery siphon distal to the takeoff of the ophthalmic artery.

Figure 456-3 Fast fluid-attenuated inversion-recovery-sequence (FLAIR) MRI of the brain showing a right hemisphere border-zone cerebral infarction in a child with sickle cell anemia.

(From Switzer JA, Hess DC, Nichols F, et al: Pathophysiology and treatment of stoke in sickle-cell disease: present and future, Lancet Neurol 5:501–512, 2006.)

For patients presenting with an acute focal neurologic deficit, a prompt pediatric neurologic evaluation is recommended. In addition, oxygen administration to keep oxygen saturations >96% and simple blood transfusion within 1 hr of presentation with a goal of increasing the hemoglobin to a maximum of 10 g/dL is warranted. To exceed this hemoglobin threshold might limit oxygen delivery to the brain because hyperviscosity of the blood can decrease oxygen delivery. Subsequently, prompt treatment with an exchange transfusion should be considered, either manually or with erythrocytapheresis, to reduce the Hb S percentage to at least <50% and ideally <30%. CT to exclude cerebral hemorrhage should be performed as soon as possible, and if available, MRI of the brain with diffusion-weighted imaging should be performed to distinguish between ischemic infarcts and RPLS. MR venography is also useful to evaluate the possibility of cerebral venous thrombosis.

The clinical presentation of RPLS or central venous thrombosis can mimic a stroke. The diagnosis of either RPLS or cerebral venous thrombosis requires a different course of treatment than a stroke. For both RPLS and cerebral venous thrombosis, the optimal management has not been defined in patients with sickle cell disease, resulting in the need for consultation with both a pediatric neurologist and a pediatric hematologist.

Primary prevention of stroke can be accomplished by transcranial Doppler (TCD) assessment of the blood velocity in the terminal portion of the internal carotid and the proximal portion of the middle cerebral artery. Children with sickle cell anemia with a time-averaged mean maximum (TAMM) blood-flow velocity ≥200 cm/sec are at increased risk for a cerebrovascular event. This value defines the transfusion threshold, and chronic blood transfusion therapy is instituted to maintain Hb S levels <30%. This strategy results in an 85% reduction in the rate of overt strokes. Once transfusion therapy is initiated, patients are expected to continue it indefinitely. The optimal age to start and end TCD measurement in children with sickle cell anemia has not been established; many hematologists initiate TCD screening at 2 yr of age when most patients no longer require sedation. A TAMM measurement of <200 cm/sec but ≥180 cm/sec represents a conditional threshold. A repeat measurement is suggested within several months because of the high rate of conversion to a TCD velocity >200 cm/sec in this group of patients. The optimal interval for TCD measurements is not known, but most experts advise measurements every 12-18 mo from 2 yr of age up to 16 yr of age. TCD measurement for patients >16 yr of age has not been proved to have any benefit. Given that blood transfusion therapy and acute illness can alter the TCD measurements, patients are commonly screened when their hemoglobin is near their baseline and when they are not acutely ill.

Two distinct methods of measuring TCD velocity exist, a nonimaging and an imaging technique. The nonimaging technique was the method used in the TCD trial sponsored by the National Institutes of Health; however, the imaging technique is more commonly used by pediatric radiologists in practice. When compared to each other, the imaging technique has values that are 10-15% below that of the nonimaging technique. The imaging technique uses the time-averaged mean of the maximum velocity (TAMX), and this measure is believed to be equivalent to the nonimaging calculation of TAMM. A downward adjustment for the transfusion threshold is appropriate for centers that conduct the imaging method to assess TCD velocity. The magnitude of the downward adjustment is unclear, but for the imaging technique, a transfusion threshold of a TAMX of 185 cm/sec and a conditional threshold of TAMX of 165 cm/sec seems reasonable.

The primary approach for secondary prevention of strokes is blood transfusion therapy aimed at keeping the maximum Hb S concentration <30% in the first 2 yr following any new stroke and <50% thereafter. Despite regular blood transfusion therapy, ~20% of patients will have a second stroke and 30% of this group will have a third stroke. The primary toxic effect of blood transfusion therapy relates to excessive iron stores, which can result in organ damage and premature death. A unit of blood contains ~200 mg of iron. In the United States, 2 chelating agents are commercially available and approved for use in transfusional iron overload. Deferoxamine is administered subcutaneously 5 of 7 nights per week for 10 hr a night, and deferasirox is an effervescent tablet that is dissolved in liquid and taken by mouth daily. Deferasirox, the newest and only orally administered chelator, was approved by the FDA in 2005 for use in patients age ≥2 yr.

Excessive Iron Stores

The assessment of excessive iron stores in children receiving regular blood transfusions is difficult. The gold standard involves biopsy of the liver, which is an invasive procedure exposing children to the risk of general anesthesia, bleeding, and pain. Liver biopsy alone does not accurately estimate total body iron because the amount of iron deposited in the liver is not homogenous and the degree of iron deposition varies among the affected organs; for example, the amount of iron in the liver is not the same as the amount of iron in cardiac tissues. The most commonly used and least-invasive method of estimating total body iron involves serum ferritin levels; however, ferritin measurements have significant limitations, because ferritin levels rise during acute inflammation and correlate poorly with excessive iron in specific organs after 2 yr of regular blood transfusion therapy. MRI of the liver is a reasonable alternative to biopsy and more accurate than serum ferritin in measuring iron content in heart and liver, the two most commonly affected organs associated with increased total body iron stores. MRI T2* and MRI R2 and R2* sequences are used to estimate iron levels in the heart and liver.

Three methods of blood transfusion therapy are available: erythrocytapheresis, manual exchange transfusions (phlebotomy of a set amount of the patient’s blood followed by rapid administration of donated packed RBCs), and simple transfusion. Erythrocytapheresis is the preferred method because there is a minimum net iron balance after the procedure. Simple transfusion therapy is the least preferable method because this strategy results in the highest net positive iron balance after the procedure. Despite being the preferred method, erythrocytapheresis is less commonly performed because of the requirement for technical expertise, access to a large vein, and an available pheresis machine.

For patients who either will not or cannot continue blood transfusion therapy to prevent subsequent strokes, hydroxyurea therapy may be a reasonable alternative. The efficacy and toxicity of hydroxyurea as an option for preventing secondary stroke is being addressed in a clinical trial setting. Alternatively, human leukocyte antigen (HLA) matched hematopoietic stem cell transplantation from a sibling donor is a reasonable approach for patients with strokes, although only a few children have suitable donors. Hematopoietic stem cell transplantation using unrelated donors is the subject of an open clinical trial that is too premature to comment on.

Lung Disease

Lung disease in children with sickle cell anemia is the second most common reason for admission to the hospital and a common cause of death. ACS refers to a constellation of findings that include a new radiodensity on chest radiograph, fever, respiratory distress, and pain that occurs often in the chest, but it can also include the back and/or abdomen only (Fig. 456-4). Even in the absence of respiratory symptoms, all patients with fever should receive a chest radiograph to identify ACS because clinical examination alone is insufficient to identify patients with a new radiographic density, and early detection of acute syndrome will alter clinical management. The radiographic findings in ACS are variable but can include involvement of a single lobe (predominantly the left lower lobe) or multiple lobes (most often both lower lobes) and pleural effusions (either unilateral or bilateral).

Figure 456-4 Probable pulmonary infarction in a 15 yr old patient with sickle cell anemia. A, Frontal radiograph shows consolidation and a small pleural effusion posteriorly in the right lower lobe. B, Radiograph obtained <24 hr later shows massive right middle and lower lobe consolidation and effusion. No organisms could be cultured. The diagnosis of probable pulmonary infarction was established clinically.

(Courtesy of Dr. Thomas L. Slovis, Children’s Hospital of Michigan, Detroit, MI. From Kuhn JP, Slovis TL, Haller JO: Caffey’s pediatric diagnostic imaging, vol 1, ed 10, Philadelphia, 2004, Mosby, p 1087.)

Given the clinical overlap between ACS and common pulmonary complications such as bronchiolitis, asthma, and pneumonia, a wide range of therapeutic strategies have been used (Table 456-3). Oxygen administration and blood transfusion therapy, either simple or exchange (manual or automated), are the most common interventions used to treat ACS. Supplemental oxygen should be administered when the room air oxygen saturation is >90%. The decision about when to give blood and whether the transfusion should be a simple or exchange transfusion is less clearly defined. Commonly, blood transfusions are given when at least one of the following clinical features is present: decreasing oxygen saturation, increase work of breathing, rapid change in respiratory effort either with or without a worsening chest radiograph, or previous history of severe ACS requiring admission to the intensive care unit.

Table 456-3 OVERALL STRATEGIES FOR THE MANAGEMENT OF ACUTE CHEST SYNDROME

PREVENTION

Incentive spirometry and periodic ambulation in patients admitted for vaso-occlusive crises, surgery, or febrile episodes

Watchful waiting in any hospitalized child or adult with sickle cell disease (pulse oximetry monitoring and frequent respiratory assessments)

Avoidance of overhydration

Intense education and optimum care of patients who have sickle cell anemia and asthma

DIAGNOSTIC TESTING AND LABORATORY MONITORING

Blood cultures

Nasopharyngeal samples for viral culture (respiratory syncytial virus, influenza)

Blood counts every day and appropriate chemistries

Continuous pulse oximetry

Chest radiographs

TREATMENT

Blood transfusion (simple or exchange)

Supplemental O₂ for drop in pulse oximetry by 4% over baseline, or values <90%

Empirical antibiotics (cephalosporin and macrolide)

Continued respiratory therapy (incentive spirometry and chest physiotherapy as necessary)

Bronchodilators and steroids for patients with asthma

Optimum pain control and fluid management

The majority of patients with ACS do not have an identifiable cause. Infection is the best-known etiology, but only ~30% of ACS episodes are associated with positive sputum or bonchoalveolar culture. The most common illness preceding ACS is a painful episode requiring opioids. The risk of ACS is influenced by the type of opioid (morphine conveys a greater risk than nalbuphine hydrochloride) and the route of administration of the opioid (oral carries a greater risk than IV opioid). Under no circumstance should opioid administration be limited in order to prevent ACS. In patients with chest pain, regular use of an incentive spirometer at 10-12 breaths every 2 hr can significantly reduce the frequency of subsequent acute chest pain episodes. Fat emboli have also been implicated as a cause of ACS, are believed to arise from infarcted bone marrow, and can be life threatening if large amounts are released to the lungs. As a result of the clinical overlap between pneumonia and ACS, all episodes should be treated promptly with antimicrobial therapy, including at least a macrolide and a third-generation cephalosporin to treat the most common pathogens associated with ACS, namely Streptococcus pneumoniae, Mycoplasma pneumoniae, and Chlamydia spp. A previous diagnosis of asthma should prompt treatment with steroids and bronchodilators even when the patient does not have evidence of wheezing. Lower respiratory symptoms alone are sufficient to initiate such therapy in a patient with only asthma. The presence of ACS does not negate the recommended management of a patient with asthma who has findings suggestive of an asthma exacerbation.

The diagnosis of pulmonary hypertension has been identified as a major risk factor for death in adults with sickle cell anemia. The natural history of pulmonary hypertension in children with sickle cell anemia is unknown, and therefore the optimal diagnostic and therapeutic strategy for pulmonary hypertension has not been identified.

Kidney Disease

Renal disease among patients with sickle cell anemia is a major comorbid condition that can lead to premature death. Seven sickle cell anemia associated nephropathies have been identified: gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, hyposthenuria, pyelonephritis, and renal medullary carcinoma. The presentation of these entities is varied but can include hematuria, proteinuria, renal insufficiency, concentrating defects, or hypertension. The treatment of asymptomatic proteinuria with angiotensin-converting enzyme (ACE) inhibitors can decrease renal insufficiency. Suspicion of renal medullary carcinoma, an aggressive malignant epithelial neoplasm, is important because most patients present with late-stage disseminated disease that responds poorly to chemotherapy and radiation therapy. The youngest reported patient with medullary carcinoma was a 6 yr old African-American with sickle cell trait, presenting with gross hematuria.

Cognitive and Psychological Complications

As with any child with a chronic illness, good health maintenance must include psychological and social assessment. Ongoing evaluation of the family unit and identification of the resources available to cope with a chronic illness are critical for optimal management. Further, children with sickle cell anemia are at great risk for academic failure and have a poor high school graduation rate, ~20%. One of the reasons behind the low high school graduation rate is that ~30% of children with sickle cell anemia have had a cerebral infarct, either a silent cerebral infarct or an overt stroke. Children with cerebral infarcts require ongoing cognitive and school performance assessment so that education resources can be focused to optimize educational attainment. Relevant support groups and attendance in group activities such as camps for children with sickle cell anemia may be of direct benefit by improving self-esteem and establishing peer relationships.

Other Complications

In addition to organ dysfunctions, patients with sickle cell anemia can have other significant complications. Examples of these complications include sickle cell retinopathy, delayed onset of puberty, avascular necrosis of the femoral and humeral heads, and leg ulcers. Optimal treatment for each of these entities has not been determined, and individual management requires consultation with the disease-specific specialist, a hematologist, and the primary care physician. Preparation for surgery for children with sickle cell disease requires a coordinated effort between the hematologist, surgeon, and primary care provider. ACS and pain are the two most common postoperative complications, and ACS is a significant risk factor for postoperative death.

Blood transfusion before surgery for children with sickle cell anemia designed to raise the hemoglobin level preoperatively to 10 g/dL is desirable; however, achieving a level of at least 10 g/dL is not necessary to provide benefit from simple transfusion. When preparing a child with sickle cell anemia for surgery with a simple blood transfusion, caution must be used to avoid elevating the hemoglobin beyond 10.5 g/dL because of the risk of hyperviscosity syndrome. For children with sickle cell anemia, exchange transfusion before surgery is of no greater benefit than simple blood transfusion and carries significantly higher risk of RBC alloimmunization. For children with Hb SC disease or other sickle syndromes with hemoglobins >10.0 g/dL, a decision must be made on a case-by-case basis as to whether an exchange transfusion is warranted because a simple transfusion can raise the hemoglobin to an unacceptable level.

Diagnosis

Every state in the United States has instituted a mandatory newborn screening program for sickle cell disease. Such programs identify newborns with the disease, provide prompt diagnosis and anticipatory guidance for parents, and are responsible for initiating penicillin before 4 mo of age.

The most commonly used procedures for newborn diagnosis include thin layer/isoelectric focusing and high-performance liquid chromatography (HPLC). A 2-step system is recommended, with all patients who have initially abnormal screens being retested during the first clinical visit and after 6 mo of age to determine the final hemoglobin phenotype. In addition, a complete blood cell count (CBC) and hemoglobin analysis are recommended on both parents to confirm the diagnosis and to provide an opportunity for genetic counseling. Table 456-4 correlates the initial hemoglobin phenotype at birth with the type of hemoglobinopathy, baseline hemoglobin range, and requirement for a hematologist.

Table 456-4 VARIOUS NEWBORN SICKLE CELL DISEASE SCREENING RESULTS WITH BASELINE HEMOGLOBIN

In newborn screening programs, the hemoglobin with the greatest quantity is reported first followed by the other hemoglobins in decreasing quantity. In newborns with a hemoglobin analysis result of FS, the pattern supports Hb SS, hereditary persistent fetal hemoglobin, or Hb S β-thalassemia zero. In a newborn with a hemoglobin analysis of FSA, the pattern is supportive of diagnosis Hb S β-thalassemia+. The diagnosis of Hb S β-thalassemia+ is confirmed if at least 50% of the hemoglobin is Hb S, HbA is present, and the amount of Hb A₂ is elevated (typically >3.5%), although Hb A₂ is not elevated in the newborn period. In newborns with a hemoglobin analysis of FSC, the pattern supports a diagnosis of Hb SC. In newborns with a hemoglobin analysis of FAS, the pattern supports a diagnosis of Hb AS (sickle cell trait).

A newborn with a hemoglobin analysis of AFS has been transfused with red blood cells before obtaining the laboratory test because the amount of Hb A is greater than the amount of Hb F or there has been an error. The patient may have either sickle cell disease or sickle cell trait, and should be started on penicillin prophylaxis until the final diagnosis can be determined. Given the implications of a diagnosis of either sickle cell disease or sickle cell trait in a newborn, repeating the hemoglobin analysis in the patient and obtaining a hemoglobin analysis and CBC to evaluate the smear and RBC parameters in the parents for genetic counseling cannot be overemphasized. Unintended mistakes do occur in state newborn screening programs. Newborns who have the initial phenotype of Hb FS but whose final true phenotype included Hb S β-thalassemia+ have been described as one of the more common errors identified in newborn screening hemoglobinopathy programs.

Other Sickle Cell Syndromes

The most commonly occurring sickle cell syndromes besides Hb SS are Hb SC, Hb S/β-thalassemia zero, and Hb S/β-thalassemia+. The other syndromes—Hb SD, Hb SO Arab, hereditary persistence of fetal hemoglobin (HPFH), and other variants—are much less common. Patients with Hb S/β-thalassemia zero have a clinical course like the course in patients with Hb SS. Hb SC does not polymerize like Hb SS, but crystals of Hb C interact with the membrane ion transport, dehydrating red cells and inducing sickling. Children who have Hb SC disease can experience the same symptoms and complications as those with severe Hb SS disease, but the frequency is less. Children with Hb SC also have increased incidence of retinopathy, chronic hypersplenism, splenic sequestration, and renal medullary carcinoma. The natural history of the other sickle cell syndromes is variable and difficult to predict due to the lack of systematic evaluation.

There is no validated model that can predict the clinical course of an individual with sickle cell disease. A patient with Hb SC can have a more-severe clinical course than a patient with Hb SS. Management of end-organ dysfunction in children with sickle cell syndromes requires the same general principles as managing patients with sickle cell anemia; however, each situation should be managed on a case-by-case basis and requires consultation with a pediatric hematologist.

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Enninful-Eghan H, Moore RH, Ichord R, et al. Transcranial Doppler ultrasonography and prophylactic transfusion program is effective in preventing overt stroke in children with sickle cell disease. J Pediatr. 2010;157:479-484.

Frei-Jones M, Baxter AL, Rogers ZR, et al. Vaso-occlusive episodes in older children with sickle cell disease: emergency department management and pain assessment. J Pediatr. 2008;152:281-285.

Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med. 2008;359:2254-2265.

Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. 2007;44:1428-1433.

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Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009;361:2309-2317.

Jain R, Sawhnet S, Rizvi SG. Acute bone crisis in sickle cell disease: the T1 fat-saturated sequence in differentiation of acute bone infarcts from acute osteomyelitis. Clin Radiol. 2008;63:59-70.

Jordan LC, McKinstry RC, Kraut MA, et al. Incidental findings on brain magnetic resonance imaging of children with sickle cell disease. Pediatrics. 2010;126(1):53-61.

Komba AN, Makani J, Sadarangani M, et al. Malaria as a cause of morbidity and mortality in children with homozygous sickle cell disease on the coast of Kenya. Clin Infect Dis. 2009;49:216-222.

Kopecky EA, Jacobson S, Joshi P, Koren G. Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease. Clin Pharmacol Ther. 2004;75:140-146.

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Mazumdar M, Heeney MM, Sox CM, et al. Preventing stroke among children with sickle cell anemia: an analysis of strategies that involve transcranial Doppler testing and chronic transfusion. Pediatrics. 2007;120:e1107-e1116.

McCavit TL, Quinn CT, Techasaensiri C, et al. Increase in invasive Streptococcus pneumoniae infections in children with sickle cell disease since pneumococcal conjugate vaccine licensure. J Pediatr. 2011;158:505-507.

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Norris CF, Smith-Whitley K, McGowan K. Positive blood cultures in sickle cell disease: time to positivity and clinical outcome. J Pediatr Hematol Oncol. 2003;5:390-395.

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Patel K, Livni N, Macdonald D. Renal medullary carcinoma, a rare cause of haematuria in sickle cell trait. Br J Haematol. 2005;132(1):1.

Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358(13):1362-1369.

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456.2 Sickle Cell Trait (Hemoglobin AS)

Michael R. DeBaun, Melissa Frei-Jones, and Elliott Vichinsky

The prevalence of sickle cell trait varies throughout the world; in the United States the incidence is 7-10% of African-Americans. Because screening for sickle cell disease is performed by all state newborn programs, sickle cell trait status is first identified on newborn screening, allowing early communication to parents and health care providers. Tracking of the sickle cell trait status from infancy to young adulthood for the patient, family, and health care providers has been inconsistent.

The amount of Hb S is influenced by the number of α-thalassemia genes present, and the amount in most persons with sickle cell trait (Hb AS) is <50%. The life span of people with sickle cell trait is normal, and serious complications are very rare. The CBC is within the normal range. Hemoglobin analysis is diagnostic, revealing a predominance of Hb A, typically >50%, and Hb S <50%. Complications of sickle cell trait include sudden death during rigorous exercise, splenic infarcts at high altitude, hematuria, hyposthenuria, bacteriuria, and susceptibility to eye injury with formation of a hyphema (Table 456-5). Renal medullary carcinoma is also associated with sickle cell trait and occurs predominantly in young adults and children.

Table 456-5 COMPLICATIONS ASSOCIATED WITH SICKLE CELL TRAIT

DEFINITE ASSOCIATIONS

Renal medullary cancer

Hematuria

Renal papillary necrosis

Hyposthenuria

Splenic infarction

Exertional rhabdomyolysis

Exercise-related sudden death

Protection against severe falciparum malaria

PROBABLE ASSOCIATIONS

Complicated hyphema

Venous thromboembolic events

Fetal loss/demise

Low birthweight

POSSIBLE ASSOCIATIONS

Acute chest syndrome

Asymptomatic bacteriuria in pregnancy

Proliferative retinopathy

UNLIKELY OR UNPROVEN ASSOCIATIONS

Avascular necrosis of the femoral head

From Tsaras G, Owusu-Ansah A, Boateng O, et al: Complications associated with sickle cell trait: a brief narrative review, Am J Med 122:507–512, 2009.

In general, children with sickle cell trait should not have any restrictions on activities. Sudden death in persons with sickle cell trait while exercising under extreme conditions has been reported. It is unclear whether this association is causal. All patients with sickle cell trait who participate in rigorous athletic activities should receive maximum hydration and appropriate rest during exertion. The presence of sickle cell trait should never be a reason to exclude a person from athletic participation but rather should serve as an indication that prudent surveillance is necessary to ensure appropriate hydration and prevention of exhaustion from heat or other strenuous exercise. These requirements are applicable to all athletes during rigorous training and should not be limited to athletes with sickle cell trait.

The National Association of Athletic Trainers (NATA) has made specific recommendations for the training of athletes with sickle cell trait, including the rapid recognition and treatment of exertional sickling or sickling collapse, which occurs when sickled RBCs occlude vessels and lead to ischemic rhabdomyolysis (Table 456-6). An important component of the screening of athletes is that adequate knowledge about sickle cell trait status identified at birth is later communicated to the adolescent before transitioning to adulthood.

Table 456-6 NATIONAL ATHLETIC TRAINER’S ASSOCIATION GUIDELINES FOR ATHLETES WITH SICKLE CELL TRAIT

GENERAL RECOMMENDATIONS FOR ATHLETES WITH SICKLE CELL TRAIT

There is no contraindication to participation in sport for the athlete with sickle cell trait.

Red blood cells can sickle during intense exertion, blocking blood vessels and posing a grave risk for athletes with sickle cell trait.

Screening and simple precautions may prevent deaths and help athletes with sickle cell trait thrive in their sport.

Efforts to document newborn screening results should be made during the pre-sports physical exam (PPE).

In the absence of newborn screening results, institutions should carefully weigh the decision to screen based on the potential to provide key clinical information and targeted education that may save lives.

Irrespective of screening, institutions should educate staff, coaches, and athletes on the potentially lethal nature of this condition.

Education and precautions work best when targeted at those athletes who need it most; therefore, institutions should carefully weigh this factor in deciding whether to screen. All told, the case for screening is strong.

SYMPTOMS OF SICKLING COLLAPSE* VERSUS HEAT CRAMPING
Sickling Collapse	Heat Cramping
No prodrome	Prodrome of muscle twinges
Pain is less excruciating	Pain is more excruciating
Sickling players slump to the ground with weak muscles	Athletes stop due to “locked-up” muscles
Athletes with sickling lie fairly still, not yelling in pain, with muscles that look and feel normal	Athletes writhe and yell in pain, with muscles visibly contracted and rock-hard
If caught early, sickling players recover faster	Even with treatment heat cramping has delayed resolution

PREVENTION OF SICKLING COLLAPSE*

Build up slowly in training with paced progressions, allowing longer periods of rest and recovery between repetitions.

Encourage participation in preseason strength and conditioning programs to enhance the preparedness of athletes for performance testing, which should be sports-specific. Athletes with sickle cell trait should be excluded from participation in performance tests such as mile runs, serial sprints, etc., as several deaths have occurred from participation in this setting.

Cessation of activity with onset of symptoms: muscle “cramping,” pain, swelling, weakness, tenderness, inability to “catch breath,” or fatigue

If sickle-trait athletes can set their own pace, they seem to do fine.

All athletes should participate in a year-round, periodized strength and conditioning program that is consistent with individual needs, goals, abilities, and sport-specific demands. Athletes with sickle cell trait who perform repetitive high speed sprints and/or interval training that induces high levels of lactic acid should be allowed extended recovery between repetitions since this type of conditioning poses special risk to these athletes.

Ambient heat stress, dehydration, asthma, illness, and altitude predispose the athlete with sickle trait to an onset of crisis in physical exertion.

• Adjust work/rest cycles for environmental heat stress

• Emphasize hydration

• Control asthma

• No workout if an athlete with sickle trait is ill

• Watch closely the athlete with sickle cell trait who is new to altitude. Modify training and have supplemental oxygen available for competitions.

Educate to create an environment that encourages athletes with sickle cell trait to report any symptoms immediately; any signs or symptoms such as fatigue, difficulty breathing, leg or low back pain, or leg or low back cramping in an athlete with sickle cell trait should be assumed to be sickling.

TREATMENT OF SICKLING COLLAPSE*

Check vital signs.

Administer high-flow oxygen, 15 L/min (if available), with a non-rebreather face mask.

Cool the athlete, if necessary.

If the athlete is obtunded or as vital signs decline, call 911, attach an automated external defibrillator, start an IV, and get the athlete to the hospital fast.

Tell the doctors to expect explosive rhabdomyolysis and grave metabolic complications.

Proactively prepare by having an emergency action plan and appropriate emergency equipment for all practices and competitions.

* Sickling collapse or exertional sickling occurs when sickled red blood cells accumulate in the blood stream during intense exercise and cause ischemic rhabdomyolysis, precipitating severe metabolic consequences.

456.3 Other Hemoglobinopathies

Michael R. DeBaun, Melissa Frei-Jones, and Elliott Vichinsky

Hemoglobin C

The mutation for Hb C is at the same site as Hb S, with lysine instead of valine substituted for glutamine. In the USA, Hb AC occurs in 1 : 50 and Hb CC occurs in 1 : 5,000 African-Americans. Hb AC is asymptomatic. Hb CC can result in a mild anemia, splenomegaly, and cholelithiasis; rare cases of spontaneous splenic rupture have been reported. Sickling does not occur. This condition is usually diagnosed through newborn screening programs. Hb C crystallizes, disrupting the red cell membrane.

Hemoglobin Eβ

Hb Eβ is the second most common globin mutation worldwide. In California, Hb Eβ-thalassemia is found almost exclusively in Southeast Asians, with a prevalence of 1 : 2,600 births.

Hemoglobin D

At least 16 variants of Hb D exist. Hb D-Punjab (Los Angeles) is a rare hemoglobin that is seen in 1-3% of Western Indians and in some Europeans with Asian Indian ancestry and produces symptoms of sickle cell disease when present in combination with Hb S. Heterozygous Hb D is clinically silent. Homozygous Hb DD produces a mild to moderate anemia with splenomegaly.

456.4 Unstable Hemoglobin Disorders

Michael R. DeBaun, Melissa Frei-Jones, and Elliott Vichinsky

At least 200 rare unstable hemoglobins have been identified; the most common is Hb Köln. Most patients seem to have de novo mutations rather than inherited hemoglobin disorders. Unstable hemoglobins whose mutation causes unstable heme binding eventually leading to the denaturation of the hemoglobin molecule are the best studied. The denatured hemoglobin can be visualized during severe hemolysis or after splenectomy as Heinz bodies. Unlike the Heinz bodies seen after toxic exposure, in unstable hemoglobins, Heinz bodies are present in reticulocytes and older red cells (Fig. 456-5). Heterozygotes are asymptomatic.

Figure 456-5 Red blood cell (RBC) morphology associated with hemoglobin disorders. A, Sickle cell anemia (Hb SS): target cells and fixed (irreversibly sickled) cells. B, Sickle cell trait (Hb AS): normal RBC morphology. C, Hemoglobin CC: target cells and occasional spherocytes. D, Congenital Heinz body anemia (unstable hemoglobin): RBCs stained with supravital stain (brilliant cresyl blue) reveal intracellular inclusions. E, Homozygous β⁰-thalassemia: severe hypochromia with deformed RBCs and normoblasts. F, Hemoglobin H disease (α-thalassemia): anisopoikilocytosis with target cells.

(Courtesy of Dr. John Bolles, The ASH Collection, University of Washington, Seattle.)

Children with homozygous gene mutations can present in early childhood with anemia and splenomegaly or with unexplained hemolytic anemia. Hemolysis is increased with febrile illness and with the ingestion of oxidant medications (similar to glucose-6-phosphate dehydrogenase [G6PD] deficiency) with some unstable hemoglobins. If the spleen is functional, the blood smear can appear almost normal or have only hypochromasia and basophilic stippling. A diagnosis may be made by demonstrating Heinz bodies, hemoglobin instability, or an abnormal electrophoresis (although some unstable hemoglobins have normal mobility and are not detected on an electrophoresis).

Treatment is supportive. Transfusion may be required during hemolytic episodes in severe cases. Oxidative drugs should be avoided, and folate supplementation should be provided. Splenectomy has been performed, but the complications of splenectomy, including bacterial sepsis and the possibility of developing pulmonary hypertension, should be considered before this therapy.

456.5 Abnormal Hemoglobins with Increased Oxygen Affinity

Michael R. DeBaun, Melissa Frei-Jones, and Elliott Vichinsky

More than 110 high-affinity hemoglobins have been characterized. These mutations affect the state of hemoglobin configuration during oxygenation and deoxygenation. Hemoglobin changes structure when in the oxygenated versus the deoxygenated state. The deoxygenated state is termed the T (tense) state and is stabilized by 2,3-diphosphoglycerate (2,3-DPG). When fully oxygenated, hemoglobin assumes the R (relaxed) state. The exact molecular interactions between these 2 states are not known. High-affinity hemoglobins contain mutations that either stabilize the R form or destabilize the T form. The interactions between these 2 forms are complex, and the mechanisms of the mutations are not known. In most cases, the high-affinity hemoglobins can be identified by hemoglobin analysis; about 20% must be characterized under controlled conditions of measurements of the P₅₀, which are 9-21 mm Hg (normal: 23-29 mm Hg). The decrease in P₅₀ causes most of these hemoglobins to produce an erythrocytosis with hemoglobin levels of 17-20 g/dL. Levels of erythropoietin and 2,3-DPG are normal. Patients are usually asymptomatic and do not need phlebotomy. If phlebotomy is performed, oxygen delivery could be problematic owing to a lowered hemoglobin.

456.6 Abnormal Hemoglobins Causing Cyanosis

Michael R. DeBaun, Melissa Frei-Jones, and Elliott Vichinsky

Abnormal hemoglobins causing cyanosis are rare. The major group is the M hemoglobins, of which there are seven. Hb M variants have mutations in either the α or the β chain, confined to the heme pocket of the hemoglobin molecule. Six of the seven have a tyrosine residue that covalently binds to the heme iron, stabilizing it in the oxidized form. These unstable hemoglobins lead to a hemolytic anemia, most pronounced in the β forms. Clinically, these children are cyanotic from birth without other signs or symptoms of disease if the tyrosine is on the α chain (Hb M Boston, Hb M Iwate). Infants with β-chain mutations become cyanotic later in infancy owing to the fetal hemoglobin switch (Hb M Saskatoon, Hb M Hyde Park, Hb M Milwaukee). The abnormal hemoglobins are autosomal dominant and are diagnosed by hemoglobin analysis using special techniques and HPLC. There is no specific treatment. Children with the β form should avoid oxidant drugs.

Low-affinity hemoglobins have less cyanosis than the M hemoglobins. The amino acid substitutions destabilize the oxyhemoglobin and lead to decreased oxygen saturation. The best characterized are Hb Kansas and Hb Beth Israel.

456.7 Hereditary Methemoglobinemia

Michael R. DeBaun, Melissa Frei-Jones, Elliott Vichinsky

The iron molecule in hemoglobin is normally in the ferrous state (Fe²⁺), which is essential for its oxygen-transporting function. Under physiologic conditions there is a slow, constant loss of electrons to released oxygen, and the ferric (Fe³⁺) form combines with water, producing methemoglobin (MetHb). The predominant intracellular mechanism for the reduction of MetHb is cytochrome 5b. This mechanism is >100-fold more efficient than the production of MetHb, and only 1% of hemoglobin is in the ferric state normally.

MetHb may be increased in the red cell owing to exposure to toxic substances or to absence of reductive pathways, such as NADH-cytochrome b5 reductase deficiency. Toxic methemoglobinemia is much more common than hereditary methemoglobinemia (Table 456-7). Infants are particularly vulnerable to hemoglobin oxidation because their RBCs have half the amount of cytochrome b5 reductase seen in adults; fetal hemoglobin is more susceptible to oxidation than hemoglobin A; and the more alkaline infant gastrointestinal tract promotes the growth of nitrite-producing gram-negative bacteria. When MetHb levels are >1.5 g/24 hr, cyanosis is visible (15% MetHb); a level of 70% MetHb is lethal. The level is usually reported as a percentage of normal hemoglobin, and the toxic level is lower at a lower hemoglobin level. Methemoglobinemia has been described in infants who ingested foods and water high in nitrates, who were exposed to aniline teething gels or other chemicals, and in some infants with severe gastroenteritis and acidosis. Methemoglobin can color the blood brown (Fig. 456-6).

Table 456-7 KNOWN ETIOLOGIES OF ACQUIRED METHEMOGLOBINEMIA

MEDICATIONS

Benzocaine

Chloroquine

Dapsone

EMLA (eutectic mixture of local anesthetics) topical anesthetic (lidocaine 2.5% and prilocaine 2.5%)

MEDICAL CONDITIONS

Pediatric gastrointestinal infection, sepsis

Recreational drug overdose with amyl nitrate (“poppers”)

Sickle cell disease-related painful episode

MISCELLANEOUS

Aniline dyes

Fume inhalation (automobile exhaust, burning of wood and plastics)

Herbicides

Industrial chemicals: nitrobenzene, nitroethane (found in nail polish, resins, rubber adhesives)

Pesticides

Gasoline octane booster

From Ash-Bernal R, Wise R, Wright SM: Acquired methemoglobinemia, Medicine 83:265–273, 2004.

Figure 456-6 Normal arterial blood vs methemoglobulinemia. Arterial whole blood with 1% methemoglobin (left) vs arterial whole blood with 72% methemoglobin (right). Note the characteristic chocolate-brown color of the sample with an elevated methemoglobin level. Both samples were briefly exposed to 100% oxygen and shaken. This quick analysis is a good bedside test for methemoglobulinemia. The sample on the left turned bright red, whereas the sample on the right remained chocolate-brown. Methods: Whole blood samples were drawn at the same time from the same person. The measured hemoglobin concentration was 11.7 g/dL. Calculated concentration of methemoglobin: 11.7 g/dL × 0.01 = 0.117 g/dL (left) and 11.7 g/dL × 0.72 = 8.42 g/dL (right). An elevated methemoglobin level was made in vitro by adding 0.1 mL of a 0.144 molar solution of sodium nitrate (right), and 0.1 mL of normal saline was added as a control (left). Co-oximetry measurements were taken on both samples shortly after the blood was drawn and 20 min after the addition of sodium nitrate solution. Both blood samples were exposed to 100% oxygen before the 2nd measurement.

(Protocol based on personal communication with Dr. Ali Mansouri, December 2002.)

Hereditary Methemoglobinemia with Deficiency of NADH Cytochrome B5 Reductase

Hereditary methemoglobinemia with deficiency of NADH cytochrome b5 reductase is a group of rare disorders classified into 4 types. In type I, the most common form, the deficiency of NADH cytochrome b5 activity is found only in RBCs. In type II, the enzyme deficiency is present in all tissues and therefore has more significant symptoms beginning in infancy with encephalopathy, mental retardation, spasticity, microcephaly, and growth retardation. In type III, the deficiency occurs in leukocytes, platelets, and RBCs. In type IV, deficiency is localized to only RBC cytochrome b5.

Clinically, cyanosis varies in intensity with season and diet. Methemoglobin can color the blood brown (see Fig. 456-6). The time at onset of cyanosis also varies; in some patients it appears at birth, in others as late as adolescence. Although as much as 50% of the total circulating hemoglobin may be in the form of nonfunctional methemoglobin, little or no cardiorespiratory distress occurs in these patients, except on exertion.

Daily oral treatment with ascorbic acid (200-500 mg/day in divided doses) gradually reduces the methemoglobin to about 10% of the total pigment and alleviates the cyanosis as long as therapy is continued. Chronic high doses of ascorbic acid have been associated with hyperoxaluria and renal stone formation. Ascorbic acid should not be used to treat toxic methemoglobinemia. When immediately available, poison control should be contacted to verify the most up-to-date therapeutic strategies. Methylene blue given IV (1-2 mg/kg initially) is used to treat toxic methemoglobinemia. An oral dose can be administered (100-300 mg PO per day) as maintenance therapy.

Methylene blue should not be used in patients with G6PD deficiency. This treatment is ineffective and can cause severe oxidative hemolysis. In the event that methylene blue is given to a patient that has G6PD deficiency, there will be no change in the clinical status of the patient. Given the observation that G6PD deficiency status is rarely available at the time of treatment, a careful history should be elicited. When the history is negative for symptoms of G6PD deficiency, treatment should be initiated judiciously, and the patient should be evaluated for improvement shortly afterward.

Bibliography

Rehman HU. Methemoglobinemia. West J Med. 2001;175:193-196.

Sanchez-Echaniz J, Benito-Fernandez J, Mintegui-Raso S. Methemoglobinemia and consumption of vegetables in infants. Pediatrics. 2001;107:1024-1028.

456.8 Syndromes of Hereditary Persistence of Fetal Hemoglobin

Michael R. DeBaun, Melissa Frei-Jones, and Elliott Vichinsky

HPFH syndromes are a form of thalassemia; mutations are associated with a decrease in the production of either or both β- and δ-globins. There is an imbalance in the α : non-α synthetic ratio (Chapter 456.9) characteristic of thalassemia. More than 20 variants of HPFH have been described. They are deletional, δβ⁰ (Black, Ghanaian, Italian), nondeletional (Tunisian, Japanese, Australian), linked to the β-globin-gene cluster (British, Italian-Chinese, Black), or unlinked to the β-globin-gene cluster (Atlanta, Czech, Seattle). The δβ⁰ forms have deletions of the entire δ- and β-gene sequences, and the most common form in the United States is the Black (HPFH 1) variant. As a result of the δ and β gene deletions, there is production only of γ-globin and formation of Hb F. In the homozygous form, no manifestations of thalassemia are present. There is only Hb F with very mild anemia and slight microcytosis. When inherited with other variant hemoglobins, Hb F is elevated into the 20-30% range; when inherited with Hb S, there is an amelioration of sickle cell disease with fewer complications.

456.9 Thalassemia Syndromes

Michael R. DeBaun, Melissa Frei-Jones, Elliott Vichinsky

Thalassemia refers to genetic disorders in globin chain production. In individuals with beta thalassemia, there is either a complete absence of β globin production (β-thalassemia major) or a partial reduction in β globin production (β thalassemia minor). In alpha thalassemia, there is an absence of or partial reduction in α globin production. The primary pathology in thalassemia stems from the quantity of globin production, whereas the primary pathology in sickle cell disease is related to the quality of globin produced.

Epidemiology

There are >200 mutations for β-thalassemia, although most are rare. About 20 common alleles constitute 80% of the known thalassemias worldwide; 3% of the world’s population carry genes for β-thalassemia, and in Southeast Asia 5-10% of the population carry genes for α-thalassemia. In a particular region, there are fewer common alleles. In the United States, an estimated 2,000 persons have β-thalassemia.

Pathophysiology

Two related features contribute to the sequelae of β-thalassemia: inadequate β-globin gene production leading to decreased levels of normal hemoglobin (Hb A) and unbalanced α- and β-globin chain production. Selected features of thalassemia can be seen in Table 456-8. In the bone marrow, thalassemia mutations disrupt the maturation of erythrocytes, resulting in ineffective erythropoiesis; the marrow is hyperactive, but there are relatively few reticulocytes and severe anemia exists. In β-thalassemia, there is an excess of α-globin chains relative to β- and γ-globin chains, and α-globin tetramers (α₄) are formed. These inclusions interact with the red cell membrane and shorten red cell survival, leading to anemia and increased erythroid production. The γ-globin chains are produced in increased amounts, leading to an elevated Hb F (α₂γ₂). The δ-globin chains are also produced in increased amounts, leading to an elevated Hb A₂ (α₂δ₂) in β-thalassemia.

Table 456-8 THE THALASSEMIAS

In α-thalassemia there are relatively fewer α-globin chains and an excess of β- and γ-globin chains. These excess chains form Bart’s hemoglobin (γ₄) in fetal life and Hb H (β₄) after birth. These abnormal tetramers are not lethal but lead to extravascular hemolysis. Prenatally a fetus with α-thalassemia can become symptomatic because Hb F requires sufficient of α-globin gene production, whereas postnatally infants with β-thalassemia become symptomatic because Hb A requires sufficient production of β-globin genes.

Homozygous β-Thalassemia (Thalassemia Major, Cooley Anemia)

Clinical Manifestations

If not treated, children with β-thalassemia usually become symptomatic from progressive hemolytic anemia, with profound weakness and cardiac decompensation during the 2nd 6 mo of life. Depending on the mutation and degree of fetal hemoglobin production, transfusions in β-thalassemia major are necessary beginning in the 2nd mo to 2nd yr of life, but rarely later. The decision to transfuse depends on the child’s ability to compensate for the degree of anemia.

Most infants and children have cardiac decompensation at hemoglobins of 4 g/dL or less. Generally, fatigue, poor appetite, and lethargy are late findings of severe anemia in an infant or child and were more common before transfusions were standard therapy. The classic presentation of children with severe disease includes thalassemic facies (maxilla hyperplasia, flat nasal bridge, frontal bossing), pathologic bone fractures, marked hepatosplenomegaly, and cachexia and is now primarily seen in developing countries. The spleen can become so enlarged that it causes mechanical discomfort and secondary hypersplenism. The features of ineffective erythropoiesis include expanded medullary spaces (with massive expansion of the marrow of the face and skull producing the characteristic thalassemic facies), extramedullary hematopoiesis, and higher metabolic needs (Fig. 456-7). The hepatosplenomegaly can interfere with nutritional support. Pallor, hemosiderosis, and jaundice can combine to produce a greenish brown complexion.

Figure 456-7 Ineffective erythropoiesis in a 3 yr old patient who has thalassemia major and has not received a transfusion. A, Massive widening of the diploic spaces of the skull as seen on MRI. B, Radiographic appearance of the trabeculae as seen on plain radiograph. C, Obliteration of the maxillary sinuses with hematopoietic tissue as seen on CT scan.

The chronic anemia produces an increase in iron absorption from the gastrointestinal tract, with toxicity leading to further complications. Many of these features become less severe and infrequent with transfusion therapy, but excessive iron stores associated with transfusional iron overload is a major concern in patients with β-thalassemia. Many of the complications of thalassemia seen in developed countries today are the result of increased iron deposition. Most of these complications can be avoided by the consistent use of an iron chelator. However, chelation therapy also has associated complications, including hearing loss, peripheral neuropathy, and poor growth.

Endocrine and cardiac pathology are often associated with excessive iron stores in patients with β-thalassemia major who are chronically transfused. Endocrine dysfunction can include hypothyroidism, hypogonadotrophic gonadism, growth hormone deficiency, hypoparathyroidism, and diabetes mellitus. Congestive heart failure and cardiac arrhythmias are potentially lethal complications of excessive iron stores in children with thalassemia.

Laboratory Findings

The infant is born only with Hb F or, in some cases, Hb F and Hb E (heterozygosity for β-thalassemia zero). Eventually, there is severe anemia, reticulocytopenia, numerous nucleated erythrocytes, and microcytosis with almost no normal-appearing erythrocytes on the peripheral smear (see Fig. 456-5E). The hemoglobin level falls progressively to <5 g/dL unless transfusions are given. The reticulocyte count is commonly <8% and is inappropriately low when compared to the degree of anemia due to ineffective erythropoiesis. The unconjugated serum bilirubin level is usually elevated, but other chemistries may be normal at an early stage. Even if the child does not receive transfusions, eventually there is iron accumulation with elevated serum ferritin and transferrin saturation. Bone marrow hyperplasia can be seen on radiographs (see Fig. 456-7).

Treatment

Before initiating chronic transfusions, the diagnosis of β-thalassemia major should be confirmed and the parents counseled concerning this life-long therapy. Beginning transfusion and chelation therapy are difficult challenges for parents to face early in their child’s life. Before beginning transfusion therapy, a red-cell phenotype is obtained; blood products that are leukoreduced and phenotypically matched for the Rh and Kell antigens are required for transfusion. If a bone marrow transplant is a possibility, the blood for transfusion should be negative for cytomegalovirus unless the child has had a previous cytomegalovirus infection. Transfusion therapy promotes general health and well-being and avoids the consequences of ineffective erythropoiesis. A transfusion program generally requires monthly transfusions, with the pretransfusion hemoglobin level between 9.5 and 10.5 g/dL. In patients with cardiac disease, higher pretransfusion hemoglobin levels may be beneficial. Some blood centers have donor programs, pairing donors and recipients, which decreases the exposure to multiple red cell antigens.

Excessive iron stores from transfusion cause many of the complications of β-thalassemia major. Accurate assessment of excessive iron stores is essential to optimal therapy. The serum ferritin is useful in assessing iron balance trends but does not accurately predict quantitative iron stores. Undertreatment or overtreatment of presumed excessive iron stores can occur in managing a patient based on serum ferritin alone. Quantitative iron by liver biopsy is the standard method for accurately determining iron store for patients. T2* MRI software is now being used to estimate iron stores in the liver and heart among patients with β-thalassemia major. One reason for the preference of T2* MRI over liver biopsy is that liver iron stores might not accurately reflect cumulative changes in cardiac iron. Patients can have cardiac iron overload at the time of a safe liver iron measurement. Many thalassemia centers now monitor cardiac iron with T2* MRI imaging.

Excessive iron stores can be prevented by the use of deferoxamine (Desferal) or deferasirox (Exjade). Deferoxamine chelates iron and some other divalent cations, allowing their excretion in the urine and the stool. Deferoxamine is given subcutaneously over 10-12 hr, 5-6 days a week. The side effects include ototoxicity with high-frequency hearing loss, retinal changes, and bone dysplasia with truncal shortening. The number of hours that deferoxamine is used daily is more important than the daily dosage. High dose, short-term infusions increase toxicity with little efficacy. Plasma non–transferrin bound iron (NTBI) is most likely responsible for serious iron injury. When deferoxamine is infusing, it binds NTBI. When deferoxamine is stopped, there are rebound increases in NTBI levels and risk for injury. In patients with excessive iron stores in the heart resulting in symptomatic congestive heart failure, 24-hr deferoxamine has been shown to reverse cardiomyopathy.

The oral iron chelator deferasirox (Exjade) is commercially available in the United States. For many patients and families, deferasirox has replaced deferoxamine because the latter must be given subcutaneously for 10 hr a night, typically 5 of 7 nights a week. Although the optimal dose of deferasirox is well defined, some patients have a less-than-expected response to the maximum approved doses (30 mg/kg/day). The optimal dose beyond 30 mg/kg/day is not known, but it should be evaluated carefully if evidence of a positive iron balance continues to occur while the patient is adherent to the medication.

Hematopoietic stem cell transplantation has cured >1,000 patients who have β-thalassemia major. Most success has been in children younger than 15 yr of age without excessive iron stores and hepatomegaly who undergo sibling HLA-matched allogeneic transplantation. All children who have an HLA-matched sibling should be offered the option of bone marrow transplantation.

Other β-Thalassemia Syndromes

The β-thalassemia syndromes are broken into six groups: β-thalassemia, δβ-thalassemias, γ-thalassemias, δ-thalassemias, εγδβ-thalassemias, and the HPFH syndrome. Most of these thalassemias are relatively rare, some being found only in family groups. The β-thalassemias can also be classified clinically as thalassemia trait, minima, minor, intermedia, and major, reflecting the degree of anemia. The genetic classification does not necessarily define the phenotype, and the degree of anemia does not always predict the genetic classification.

Thalassemia intermedia can be any combination of β-thalassemia mutations (β⁰/β⁺, β⁰/β^variant, E/β⁰), which will lead to a phenotype of microcytic anemia with hemoglobin of about 7 g/dL. There is controversy about whether these children should receive transfusions. They will certainly develop a degree of medullary hyperplasia, nutritional hemosiderosis perhaps requiring chelation, splenomegaly, and other complications of β-thalassemia associated with excessive iron stores. Extramedullary hematopoiesis can occur in the vertebral canal, compressing the spinal cord and causing neurologic symptoms; the latter is a medical emergency requiring immediate local radiation therapy to halt erythropoiesis. Transfusion alleviates the thalassemic manifestations; the decision to transfuse must be balanced against the future need for chelation therapy.

Splenectomy may be indicated for patients with thalassemia intermedia who have a falling steady-state hemoglobin and for transfused patients with rising transfusion requirements. However, splenectomy can have serious consequences, including infection, pulmonary hypertension, and thrombosis. All patients should be fully immunized against encapsulated bacteria before splenectomy and subsequently should be on long-term penicillin prophylaxis with appropriate instructions regarding fever management.

The thalassemias classified as minima and minor are usually heterozygotes (β⁰/β, β⁺/β⁺), having a phenotype more severe than trait but not as severe as intermedia. These children should be investigated for their genotype and monitored for iron accumulation. The β-thalassemias are influenced by the presence of α-thalassemia: α-thalassemia trait leading to less severe anemia and duplicated α genes (ααα/αα) leading to a more severe thalassemia. Often, patients who are in these groups require transfusions in adolescence or adulthood; some may be candidates for chemotherapy such as hydroxyurea.

Thalassemia trait is often misdiagnosed as iron deficiency in children because the 2 produce similar hematologic abnormalities on CBC, and iron deficiency is much more prevalent. A short course of iron and re-evaluation is all that is required to identify children who will need further evaluation. Children who have β-thalassemia trait have a persistently normal red cell distribution width and low mean corpuscular volume (MCV). On hemoglobin analysis, they have an elevated Hb F and diagnostically elevated Hb A₂. There are “silent” forms of β-thalassemia trait, and if the family history is suggestive, further studies may be indicated.

α-Thalassemia

The same evolutionary pressures that produced β-thalassemia and sickle cell disease produced α-thalassemia. Infants are identified in the newborn period by the increased production of Bart’s hemoglobin (γ₄) during fetal life and its presence at birth. The α-thalassemias occur most commonly in Southeast Asia. Deletion mutations are common in α-thalassemia. In addition to deletional mutations, there are nondeletional α-globin gene mutations, the most common being Constant Spring (α^CSα); these mutations cause a more severe anemia and clinical course than the deletional mutations. There are four α-globin genes and four deletional α-thalassemia phenotypes.

The deletion of one α-globin gene (silent trait) is not identifiable hematologically. Specifically, no alterations are noted in the mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Persons with this deletion are usually diagnosed after the birth of a child with a 2-gene deletion or Hb H (β₄). During the newborn period, <3% Hb Bart’s is observed. The deletion of one α-globin gene is common in African-Americans.

The deletion of 2 α-globin genes results in α-thalassemia trait. The α-globin genes can be lost in a trans-(−α/−α) or cis– (α,α/^-SEA) configuration. The trans or cis mutations can combine with other mutations and lead to Hb H or α-thalassemia major. In persons from Africa or of African descent the most common α-globin gene deletion is in the trans configuration, whereas in persons from Asia or the Mediterranean region the cis deletion is most common.

The α-thalassemia traits manifest as a microcytic anemia that can be mistaken for iron-deficiency anemia (see Fig. 456-5F). The hemoglobin analysis is normal, except during the newborn period, when Hb Bart’s is commonly <8% but >3%. Children with a deletion of 2 α-globin genes are commonly thought to have iron deficiency, given the presence of both low MCV and MCH. The simplest approach to distinguish between iron deficiency and α-thalassemia trait is with a good dietary history. Children with iron-deficiency anemia often have a diet that is low in iron. Alternatively, a brief course of iron supplementation along with monitoring of erythrocyte parameters might confirm the diagnosis of iron deficiency, or α-globin gene deletion analysis may be necessary.

The deletion of three α-globin genes leads to the diagnosis of Hb H disease. In California, where a large population of Asians resides, ~1 : 15,000 newborns have Hb H disease. The simplest manner of diagnosing Hb H disease is during the newborn period, when excess in γ-tetramers are present and Hb Bart’s is commonly >25%. Obtaining supporting evidence from the parents is also necessary. Later in childhood, there is an excess in β-globin chain tetramers that results in Hb H. A definitive diagnosis of Hb H disease requires DNA analysis with supporting evidence. Brilliant cresyl blue can stain Hb H, but it is rarely used for diagnosis. Patients with Hb H disease have a marked microcytosis, anemia, mild splenomegaly, and, occasionally, scleral icterus or cholelithiasis. Transfusion is not commonly used for therapy because the range of hemoglobin is 7-11 g/dL, with MCV 51-73 fl.

The deletion of all four α-globin genes causes profound anemia during fetal life, resulting in hydrops fetalis; the ζ-globin gene must be present for fetal survival. There are no normal hemoglobins present at birth (primarily Hb Bart’s, with Hb Gower 1, Gower 2, and Portland). If the fetus survives, immediate exchange transfusion is indicated. These infants with α-thalassemia major are transfusion dependent, and hematopoietic stem cell transplant is the only cure.

The presence of a nondeletional α-globin mutation with a 2-gene deletion results in a more severe anemia, increased hepatosplenomegaly, increased jaundice, and a much more severe clinical course than Hb H disease. Hb H Constant Spring is the most common form (−α/α,α^CS).

Treatment of the α-thalassemia deletion syndromes consists of folate supplementation, possible splenectomy (with the attendant risks), intermittent transfusion during severe anemia for the nondeletional Hb H diseases, and chronic transfusion therapy or bone marrow transplant for survivors of hydrops fetalis. These children also should not be exposed to oxidative medications.

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