Fever and Bacteremia

Fever in a child with sickle cell anemia is a medical emergency, requiring prompt medical evaluation and delivery of antibiotics due to the increased risk of bacterial infection and concomitant high fatality rate with infection. Several clinical management strategies have been developed for children with fever, ranging from admitting all patients with a fever for IV antimicrobial therapy to administering a 3rd-generation cephalosporin in an outpatient setting to patients without any of the previously established risk factors for occult bacteremia (Table 456-1). Given the observation that the average time for a positive blood culture with a bacterial pathogen is <20 hr in children with sickle cell anemia, admission for 24 hr is probably the most prudent strategy for children and families without a telephone or transportation, or with a history of inadequate follow-up. Outpatient management should be considered only for those with the lowest risk for bacteremia, and treatment choice should be considered carefully.

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

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

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

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