The term sickle cell crisis was introduced to describe a recurring attack of pain involving the skeleton, chest, abdomen, or all three. Using the term in a broader sense, vaso-occlusive “crises” comprise a variety of syndromes that are typically recurrent and potentially catastrophic. Clinical manifestations are sudden in onset and are directly attributable to obstruction of the
microcirculation by intravascular sickling. Modest exacerbation of anemia and increased leukocytosis are common. Infections often precede vaso-occlusive episodes in children, suggesting that fever, dehydration, and acidosis may be contributing factors. In adults, a triggering event is not often identified, however.

The initial vaso-occlusive episode in infants, named hand-foot syndrome or dactylitis, often involves the small bones of the hands and feet. By 2 years of age, nearly 50% of Jamaican children and 25% of American children with SCA have experienced at least one episode of dactylitis.¹⁷³, ¹⁸¹ Typically, the dorsa of the hands and/or feet are swollen, nonerythematous, and exquisitely painful. Fever and leukocytosis are common. Radiographic changes are limited initially to soft-tissue swelling; cortical thinning and destruction of metacarpals, metatarsals, and phalanges appear 2 to 3 weeks after the onset of symptoms. Dactylitis is sudden in onset and may last 1 or 2 weeks. It may recur on one or more occasions until the patient is ˜3 years of age.¹⁸¹

Usually, after the first few years of life, interruption of blood flow occurs in the larger bones of the extremities, spine, rib cage, and periarticular structures, producing painful crises of the bones and joints.¹⁸², ¹⁸³ The sinusoidal circulation of the bone marrow provides an ideal vascular bed for the sickling phenomenon.

In the CSSCD, epidemiologic features of pain crises were analyzed in a large group of patients with sickle cell disease.¹⁸⁴ The average rate of pain was 0.8 episode/patient-year in Hb SS, 1.0 episode/patient-year in Hb S β⁰-thalassemia, and 0.4 episode/patient-year in Hb SC disease and Hb S β⁺-thalassemia. However, the rate varied widely from patient to patient: 39% of patients with SCA had no episodes of pain, but 1% had more than six episodes per year. With Hb SS patients 5% accounted for almost one third of all the episodes. The pain rate increased moderately from childhood to the third decade of life. A higher rate of pain events has been associated with low nocturnal oxygen saturation detected by continuous monitoring during sleep.¹⁸⁵ When children with a history of asthma experience an episode of pain, antecedent or concurrent respiratory symptoms (cough, wheeze, tachypnea, retractions, or grunting) occur more frequently than in children without a history of asthma, suggesting that involvement of the respiratory system is a risk factor for these events.¹⁸⁶

Pain resulting from ischemia of the bone marrow is gnawing and progressive in severity. Although pain can affect any bone in the body, the most frequent sites are the humerus, tibia, and femur. Involvement of facial bones is less common but is well documented. The swelling associated with infarction of the orbital bone may be sufficient to produce proptosis and ophthalmoplegia.¹⁸⁷ Swelling of the elbows or knees may mimic rheumatic fever or septic arthritis.¹⁸⁸ Infarcts involving deep bones are usually not associated with detectable swelling, erythema, or surface temperature change. Laboratory findings, too, are inconstant and nonspecific. The radiographic features of bone infarction and periostitis usually do not appear until after the resolution of symptoms. Increased signal with T2-weighted images is seen by magnetic resonance imaging (MRI) in approximately one third of pain crises.¹⁸⁹ Discrete areas of decreased localization of ⁹⁹Tc-sulfur colloid identify areas of decreased marrow blood flow, and ⁸⁵Sr or ⁹⁹Tc-phosphate localizes the increased osteoblastic activity that occurs with healing.¹⁹⁰ Although radionuclide bone and bone marrow scans theoretically enable differentiation of bone infarcts from osteomyelitis, in practice they are of limited value.¹⁸² Unlike osteomyelitis, bone infarcts are associated with no more than a low-grade fever, little or no left shift in the leukocyte differential, and only occasional edema. As a cause of bone pain, infarction is >50 times as common as osteomyelitis.¹⁸²

An abdominal pain crisis, a diagnosis of exclusion, is attributed to small infarcts of the mesentery and abdominal viscera. An abdominal pain crisis is characterized by severe abdominal pain and signs of peritoneal irritation; however, the differential diagnosis of other causes of abdominal pain (e.g., cholecystitis, pancreatitis, constipation) should always be considered. The persistence of bowel sounds differentiates pain crises from acute intra-abdominal disorders requiring surgical intervention. Diagnosis is facilitated by prior experience with the patient, because the pattern of pain tends to repeat itself from crisis to crisis. Atypical clinical or laboratory features should suggest one of several complications to which patients with SCA are especially susceptible, such as ACS, urinary tract infection, or cholecystitis.

On average, painful crises persist for 4 or 5 days, although protracted episodes may last for weeks, especially among adults. Data from the CSSCD indicate that an increased frequency of painful events is associated with a high hematocrit and a low Hb F level.¹⁸⁴ Adults with high rates of pain episodes tend to die earlier than those with low rates.¹⁸⁴ Of therapeutic significance, it was noted in the CSSCD that even when the Hb F level was low, a small increase was associated with an ameliorating effect on the pain rate and potentially improved survival.

No specific form of therapy has proven effective for acute vaso-occlusive crises. None of the many medications and manipulations that have been touted as beneficial have withstood critical scrutiny. Low-molecular-weight dextran, phenothiazines, fibrinogenolytic agents, bicarbonate and other alkalis, and urea solutions, when evaluated in controlled clinical studies, were found to be without apparent effect.¹⁹¹, ¹⁹², ¹⁹³, ¹⁹⁴, ¹⁹⁵, ¹⁹⁶ Other therapeutic strategies, although not subjected to randomized clinical trials, have enjoyed only fleeting popularity. These strategies have included carbonic anhydrase inhibitors,¹⁹⁷ vasodilators, anticoagulants, progesterone,¹⁹⁸ testosterone,¹⁹⁹ papaverine,²⁰⁰ antithyroid drugs,²⁰¹ and hyperbaric oxygen.²⁰² Studies of pentoxifylline, an agent that increases red blood cell deformability and inhibits platelet aggregation,²⁰³ and cetiedil, a smooth muscle relaxant that inhibits sickling and cell dehydration,²⁰⁴ suggested a reduction in duration of painful crises, but results have not been substantiated by further trials. Poloxamer-188, a nonionic surfactant compound, reduced total analgesic use, but a Phase III trial demonstrated only a slight shortening of the duration of pain crises.²⁰⁵ Phase II and III randomized, placebo-controlled, double-blind studies investigating the Gardos channel blocker Senicapoc (ICA-17043), showed improvement of anemia and reduction of dense erythrocytes and reticulocytes when compared to placebo; however, they
failed to demonstrate reduction of painful crises.²⁰⁶, ²⁰⁷ Despite encouraging results in Phase II trials, a prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled NO gas failed to demonstrate benefit in reducing duration of pain crisis or amount of narcotic use.²⁰⁸ Vitamin D levels are reported low in the majority of individuals with sickle cell disease, and there are reports linking chronic pain with vitamin D insufficiency and deficiency.²⁰⁹, ²¹⁰, ²¹¹, ²¹² Replacement of vitamin D has been reported in a few patients to improve symptoms of chronic pain.²¹³, ²¹⁴ The duration and severity of pain crises are notoriously variable, and the natural course is one of spontaneous improvement. Consequently, uncontrolled reports of effective therapies must be viewed with skepticism, especially if the proposed treatment entails an element of risk.

The cornerstones of present-day therapy are fluids and analgesics. The volume of fluids administered should be sufficient to abolish any deficit, correct hypertonicity, and fully compensate for ongoing losses imposed by fever, hyposthenuria, vomiting, or diarrhea. Typically 150% maintenance intravenous hypotonic fluids are used in the first 12 to 24 hours of the pain event, and subsequently reduced gradually. Precipitants of the crisis should be sought and eliminated. Infection, a common precipitating cause in children, may require antibiotic therapy. Acidosis is corrected readily with intravenous administration of sodium bicarbonate, but its etiology should be investigated and treated. Oxygen therapy in the absence of documented hypoxemia is without benefit and triggers an increase in the number of ISCs when discontinued.²¹⁵ Red blood cell transfusions are not indicated in the treatment of the acute pain crisis, unless there is associated accentuated anemia (e.g., parovirus B19 induced “aplastic crisis”). Furthermore, because fever and back pain are common features of pain crises, transfusion reactions may escape early recognition.²¹⁶

Control of pain requires the liberal use of analgesics,²¹⁷ but narcotic addiction is unlikely as long as analgesics are closely monitored. Nonsteroidal inflammatory drugs (NSAIDs) used in association with opioids offer benefit, but should be used with caution in patients with renal dysfunction. Regardless of the use of opioids and/or NSAIDs, pain should be treated promptly (within 60 minutes from initial assessment) and re-evaluated within 30 minutes from first dose of analgesic, according to published quality of care indicators.²¹⁸ The use of patient-controlled analgesia enables patients to administer opioids to themselves as needed and provides an element of self-control in pain management.²¹⁹, ²²⁰ Patient-to-patient variability in the response to pain treatment is common, and there has been great interest in developing individualized pain therapy to improve the efficacy of treatment, as well as patient experience and satisfaction.²²¹ Some of this individual variation may be explained by polymorphic enzyme cytochrome P450 (CYP) 2D6 variant alleles that are commonly observed among African Americans and may lead to impaired codeine conversion to morphine.²²² Nonpharmacologic management of pain, such as with self-hypnosis, has been used successfully for pain control in selected subjects.²²³ Local use of warm packs may be beneficial in some. Prophylactic approaches to pain management are discussed later in this chapter.

Stroke is a catastrophic complication of SCA that affects 6% to 17% of children and young adults.²²⁴, ²²⁵ Data from the CSSCD, in which ˜4,000 patients were followed for an average of 5 years, indicated that infarctive stroke was most frequent in children and older adults with Hb SS, whereas hemorrhagic stroke had the highest incidence in patients 20 to 29 years of age.²²⁴ The mortality rate was 26% after hemorrhagic stroke, but 0% after infarctive stroke. Severe anemia, a history of recent or recurrent acute chest syndrome, previous transient ischemic attack (TIA), and hypertension were independent risk factors for ischemic stroke; anemia and leukocytosis were independent risk factors for hemorrhagic stroke.²²⁴ The risk of stroke is increased in patients with Hb F levels <8%²²⁶ and in patients with siblings who have had strokes. Data from the CSSCD also revealed that silent cerebral infarcts (SCI, areas of increased signal intensity, primarily in deep white matter or watershed areas of the cerebral cortex, not attributed to an overt neurologic event or finding) on MRI were a strong independent risk factor for stroke.²²⁷, ²²⁸ In addition, nocturnal hypoxemia is a risk factor for acute neurologic events (stroke, TIA, or seizures).²²⁹ By far the best predictor of stroke risk at this time, however, is transcranial Doppler (TCD) velocity.²³⁰

The pathogenesis of cerebral vascular disease is incompletely understood (Fig. 33.6). Pathologically, vascular narrowing (stenosis) results from segmental proliferation and fragmentation of the intima. The internal elastic lamina may show degenerative changes, and the tunica media may be disrupted by fibrosis and hemorrhage. Occlusion is the result of progressive proliferation of vascular smooth muscle, superimposed thrombosis, or embolus.²³¹, ²³² Increased adherence of sickle red cells to the endothelium of vessel walls and decreased cerebral vessel CO₂ responsiveness (reflecting diminished reserve capacity for vasodilatation), may be additional mechanisms.²³³, ²³⁴ Aneurysms can be demonstrated in some patients who have sustained intracranial hemorrhage and may be observed as an incidental finding in children with cerebral vaso-occlusive disease.²³³

The distal internal carotid and proximal middle and anterior cerebral arteries are stenotic or occluded in sickle cell patients who have experienced a stroke.²³⁵ In response to chronic anemia and hypoxemia, cerebral blood flow is markedly increased.²³⁶ TCD velocities in the major cerebral arteries are influenced by both of these factors and are abnormally elevated in patients at high risk for stroke.²³⁰, ²³⁷ There are several factors that appear to modulate TCD velocities and stroke risk. Hb desaturation is linked to elevated TCD velocities and stroke,²³⁸, ²³⁹ whereas G6PD deficiency and elevated markers of hemolysis increase the risk of elevated TCD velocities.²⁴⁰ The most common sites of ischemic stroke are the parenchymal areas supplied by the anterior and middle cerebral arteries and the border zones between their distal circulations.²⁴¹, ²⁴² When acute or chronic conditions arise leading to diminished oxygen availability (e.g., an episode of ACS, an aplastic crisis, nocturnal hypoxemia), the increased hypoxic stress coupled with the inability of the cerebrovasculature to undergo further dilatation leads to ischemia.²²⁹

Increasing evidence for genetic modifiers of stroke has accumulated. In a clinical epidemiology study, 42 sibships of patients with SCA in which one sibling had had a stroke revealed a greater than expected number of families having two or more children with a stroke.²⁴³ In another study, children with SCA were far more likely to have an abnormally elevated flow velocity on TCD if they had a sibling with an abnormal TCD.²⁴⁴ Specific β-S-globin gene haplotypes have been associated with increased stroke risk, but findings have been inconsistent.²⁴⁵, ²⁴⁶ Certain HLA alleles and the presence of alpha thalassemia are recognized protective factors for cerebrovascular disease.²⁴⁰, ²⁴⁷, ²⁴⁸ Genes regulating immune function and inflammation, including Fcγ receptor and tumor necrosis factor-α (TNF-α), have not contributed to an increased risk of stroke, whereas single nucleotide polymorphisms (SNPs) within the vascular cell adhesion molecule (VCAM)-1 gene may influence this risk.²⁴⁹, ²⁵⁰ Other SNPs shown to be associated with increased stroke risk are ANXA2, TGFBR3, and TEK, whereas SNPs in the ADCY9 gene were linked to decreased stroke risk.²⁴⁸

A novel approach to “disentangling the web of interactions among genes, environment, and phenotype” has been the use of a Bayesian network, a multivariate dependency model that accounts for simultaneous associations and interactions among multiple genes and their interplay with clinical and physiologic factors.²⁵¹ Using data and stored samples from the CSSCD, 108 SNPs in 39 candidate genes from almost 1,400 individuals were analyzed. Candidate genes were involved in vasoregulation, inflammation,
cell adhesion, coagulation, hemostasis, cell proliferation, oxidative biology, and other functions. In 92 patients who had had an overt stroke, the network was used to determine 11 genes whose variants had a direct effect modulated by hemoglobin F levels and 9 genes whose variants were indirectly associated with stroke.

Clinically, strokes are characterized by the abrupt onset of hemiparesis, aphasia, seizures, sensory deficits, and altered consciousness, occurring singly or together. The patient may make a full recovery, but incomplete resolution of neurologic deficits may happen. Diffusion weighted imaging (DWI) MRI permits noninvasive and early visualization of focal ischemia. Emergent treatment of stroke includes vigorous hydration, simple transfusion, patient stabilization, followed by exchange transfusion once Hb concentration is at least 8 g/dl.

Strokes tend to be repetitive because of the progressive nature of cerebral vascular disease. Patients with moyamoya are more than twice as likely to incur subsequent stroke or transient ischemic attack despite transfusion treatment.²⁵² In general, unless patients begin a long-term transfusion program, they are at risk for recurrent cerebral infarctions with progressive neurologic deterioration. Chronic transfusion therapy designed to maintain the level of Hb S at <30% reduces the risk of recurrent strokes (within 36 months) from approximately 70% to 90% to 10% to 20%.²³³ Interruption or termination of treatment, even after 8 years of chronic transfusion, is associated with a stroke recurrence rate similar to that of untransfused patients,²⁵³, ²⁵⁴ suggesting that transfusion therapy for secondary stroke prophylaxis should be continued indefinitely. However, reduction of the intensity of chronic transfusion to allow pretransfusion Hb S levels to reach 50% appears safe after the first few years of prophylaxis²⁵⁵, ²⁵⁶ and is routinely utilized by many sickle cell centers.²⁵⁷ Many chronically transfused children have transfusions
discontinued when they reach adulthood. In one series of nine adult patients who stopped transfusion after a median of 6 years, none suffered recurrent stroke.²⁵⁸ In an initial report, long-term treatment with hydroxyurea appeared to prevent stroke recurrence in children who were treated with relatively high doses (30 to 40 mg/kg/day).²⁵⁹, ²⁶⁰ In a larger prospective trial, 35 children with SCA and stroke had transfusions discontinued and hydroxyurea started.²⁶¹ Initially, transfusion was stopped before hydroxyurea therapy was started, but later, transfusion was overlapped until full-dose hydroxyurea therapy was tolerated. Overall, stroke reoccurred at a rate of 5.7 events per 100 patient-years, but children receiving overlapping therapy had only 3.6 events per 100 patient-years. In a cohort from Jamaica, where blood supply is limited, hydroxyurea therapy was the only reliable treatment option and was shown to prevent stroke recurrence in children with prior stroke events.²⁶² These findings led to the Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) study, a phase III randomized, multicenter clinical trial, which compared standard treatment (transfusions with iron chelation) to alternative treatment (hydroxyurea with phlebotomy) for stroke prophylaxis in children who had experienced prior stroke.²⁶³, ²⁶⁴, ²⁶⁵ SWiTCH was a noninferiority trial with a composite primary endpoint of stroke and hepatic iron overload. This study was interrupted early because more strokes were observed in the hydroxyurea/phlebotomy arm and only equivalence in liver iron content was seen in the two arms. Chronic transfusion therapy and iron chelation remains the standard treatment for secondary prevention of stroke in children with SCA. Unfortunately, chronic blood transfusion does not prevent progression of brain vasculopathy or silent cerebral infarcts in children receiving this therapy for secondary stroke prevention, which makes blood transfusion an imperfect choice for this indication.²⁶³, ²⁶⁴

In a series of studies led by Robert Adams, an abnormal transcranial Doppler ultrasound examination (defined by a timeaveraged mean maximum velocity ≥200 cm/s in the distal internal carotid or proximal middle cerebral artery) was predictive of a 40% stroke risk in HbSS patients.²³⁰ In the Stroke Prevention in Sickle Cell Anemia (STOP) trial, 130 patients with abnormal TCD velocities were prospectively randomized to receive chronic transfusion or standard observation.²⁶⁶ A 92% reduction in the risk of stroke occurred in the patients receiving chronic transfusion. The appropriate length of time for transfusion for primary stroke prevention in patients with abnormal TCD velocities was addressed by the STOP II Trial.²⁶⁷ Patients enrolled in STOP II had had an initial abnormal TCD velocity and transfusion for at least 30 months, during which time the TCD velocity became normal (<170 cm/s). Patients were then randomly assigned to continue or stop transfusion, and the primary endpoint was stroke or a reversion to an abnormal TCD exam. Among the 41 children enrolled in the discontinuation-of-transfusion group, abnormal TCD results developed in 14 and stroke in 2 others within a mean of 4.5 months (range 2.1 to 10.1 months) of the last transfusion. None of these endpoint events occurred in the 38 children who continued to receive transfusions. A recent analysis of the participants of the STOP II trial demonstrated that among children who discontinued transfusions there was significant progression of SCI in comparison with those who continued transfusions.²⁶⁸, ²⁶⁸ In a separate cohort of children who were receiving chronic transfusion therapy for primary stroke prevention after having had abnormal TCD velocities, transfusions were successful in preventing progression of vasculopathy.²⁶⁹ As discussed earlier, the same protection does not seem to be conferred by transfusions to children with prior overt strokes.

Overall, among 209 total patients who underwent randomization in STOP and STOP II, 20 strokes occurred. In all cases, the last TCD examination before the stroke showed an abnormal velocity.²⁷⁰ The estimated stroke risk for untreated patients was 10% per year for an abnormal TCD and 2% to 5% per year for a conditional TCD. Extrapolation from these data has led to recommendations for the frequency of TCD screening in children with HbSS/Sβ⁰ thalassemia between the ages of 2 and 16 years (Table 33.2).²⁷¹ Information regarding utility of TCD examination in adults is extremely limited, although velocities are probably intermediate between those found in children with sickle cell disease and normal adult controls.²⁷²

Since the results of the STOP trials, TCD programs have led to a dramatic reduction of stroke incidence in some centers.²⁷¹, ²⁷³, ²⁷⁴ However, despite the well-publicized results of the STOP Trials, performance of TCD screening has been variable. Preliminary data from the C-Data Registry of the Comprehensive Sickle Cell Centers indicate that a TCD exam was performed in the past year in only 42% of 2- to 12-year-old children with HbSS and Hb Sβ⁰ thalassemia, the genotypes at greatest risk for stroke.²⁷⁵ The greatest perceived barrier to TCD screening in children with sickle cell disease was poor patient adherence to TCD appointments, which in part was attributable to the second most common obstacle: distance to a “vascular laboratory.”²⁷⁶ There also has been concern about complications of chronic transfusion, particularly the risk of iron overload. The availability of oral iron chelators, may partially alleviate that concern.

The use of hydroxyurea for primary stroke prevention is currently under investigation. In a French study, 6 of 10 patients with abnormal TCD whose velocities normalized on transfusion were switched successfully to treatment with hydroxyurea.²⁷⁷ In a Belgian study, patients with abnormal TCD were treated with hydroxyurea and observed for a total of 96 patient-years.²⁷⁸ Only a single neurologic event, a seizure, was observed. In two different cohorts of children with SCA, hydroxyurea treatment resulted in significant decrease in TCD velocities.²⁷⁹, ²⁸⁰ In addition, hydroxyurea treatment of adult patients with sickle cell disease resulted in improved, but not normalized, cerebral oxygen levels.²⁸¹ The ongoing phase III multicenter randomized TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial aims at maintaining or lowering TCD velocities in children who have received blood transfusions for abnormal TCD velocities for at least 12 months. In the TWiTCH trial, children with abnormal TCD velocities are randomized to continue transfusions, or to discontinue transfusions and begin hydroxyurea after a period of overlap between the two treatment arms (clinicaltrials.gov # NCT01425307).

Although the relative risk of primary stroke is lower among patients with conditional TCD velocities (time-averaged mean maximum velocity 170 to 199 cm/sec) than those with abnormal velocities (risk 2 to 5 vs. 9% per year), more children have conditional TCD velocities (17% vs. 9% prevalence), so the absolute number at risk for stroke without therapy is comparable. The risk of conversion from a conditional to abnormal TCD velocity is
highest in children under 10 years of age.²⁸², ²⁸³ Currently, conditional TCD velocity is not an indication for treatment, but the ongoing phase III multicenter Sparing Conversion to Abnormal TCD elevation (SCATE) study is investigating whether hydroxyurea therapy in children under age 11 years with conditional TCD will be less likely to develop abnormal TCD velocities than those who are observed (clinicaltrials.gov # NCT01531387).

SCI occurs in 27% of children with SCA under 6 years of age,²⁸⁴ and 37% by their 14th birthday.²⁸⁵ Data from the CSSCD have shown that children with SCI had an increased incidence of new stroke and new or more extensive SCI ²²⁷ and that SCIs were the strongest independent predictor of stroke.²²⁸ Data from the STOP trial indicated that those who had SCI as well as abnormal velocities were at higher risk for developing a new SCI or stroke than those whose MRI showed no abnormality.²⁸⁶ However, a comparison of patients who were in both the CSSCD and STOP studies indicated that those who had abnormal TCDs did not have an unusually high frequency of MRI abnormality; conversely, those who had SCI did not have an unusually high frequency of abnormal TCD velocities, suggesting that those findings represent different aspects of the pathophysiology of the brain in children with sickle cell disease.²⁸⁷ The ongoing Silent Cerebral Infarct Transfusion (SIT) trial is a phase III multicenter randomized study aiming at determining whether blood transfusion therapy will limit overt clinical strokes or new or progressive SCI in children with SCA and SCI identified by MRI screening in comparison with children randomized to observation (clinicaltrials.gov # NCT00072761).²⁸⁸ Baseline results of the SIT trial showed that lower Hb concentration and higher systolic blood pressure were associated with SCI in children with SCA.²⁸⁹

Acute chest syndrome (ACS) is an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray.²⁹⁰ ACS remains one of the most common causes for hospitalization, critical care utilization, and mortality in children and adults with sickle cell disease.²⁹¹, ²⁹² The term acute chest syndrome was coined because it is not usually possible to determine the relative importance of vascular occlusion and infection in the acute pulmonary process in any given patient. Infection tends to predominate in children and infarction in adults, but the two processes are often interrelated and concurrent.²⁹³ Impaired access of oxygen to infected segments of the lung likely enhances local sickling, with resulting focal microvascular thrombotic disease. Data from the CSSCD indicate that patients with Hb SS have an incidence of ACS of ˜13/100 patient-years; the rate is highest in children 2 to 4 years of age (25/100 patient-years) and decreases gradually with increasing age to that seen in adults (9/100 patient-years).²⁹⁴ A higher ACS rate is associated with a higher rate of mortality from all causes. The risk of ACS is associated with a lower fetal Hb level and a higher steady-state hematocrit and leukocyte count.²⁹⁵

Before the availability of pneumococcal vaccines and the widespread use of penicillin prophylaxis, pulmonary events in children typically were the result of bacterial infection.²⁷⁶, ²⁹⁶ Streptococcus pneumoniae was the most common causative organism. Infiltrates often affected multiple lobes, and resolution was slower than in the general population.²⁹⁷ Identified infectious agents have included Mycoplasma pneumonia,²⁹⁸ Chlamydia pneumonia,²⁹⁹ parvovirus B19,³⁰⁰ and respiratory viruses. The National Acute Chest Syndrome Study Group reported causes and outcomes based on analysis of 671 episodes of ACS.³⁰¹ Nearly half of the patients were initially admitted for another reason, primarily pain. The mean length of hospitalization was 10.5 days; 13% required mechanical ventilation, and 3% died. Patients who were 20 years of age or older had a more severe course. A specific cause of ACS was identified in 38% of all episodes and in 70% of episodes with complete data (Table 33.3).³⁰¹ The most common specific causes were pulmonary fat embolism, chlamydia, mycoplasma, miscellaneous viruses, and bacterial infections resulting from coagulase-positive Staphylococcus aureus and Streptococcus pneumoniae. Recently, influenza, especially H1N1, was shown to be associated with increased risk and severity of ACS, and therefore should be prevented whenever an outbreak or epidemic is detected.³⁰² In adults, an infectious basis for lobar consolidation is established less often than in children, and antibiotic therapy is without apparent effect on the duration or severity of symptoms.³⁰³ In situ vaso-occlusion owing to erythrocyte stasis appears to be the more common primary event. Interestingly, an association between smoking and increased rate of ACS and pain events has been observed among adults with sickle cell disease.³⁰⁴

The relationship of asthma/reactive airway disease to ACS has been examined. In children with Hb SS, asthma is associated with an increased incidence of sickle-cell-related morbidity,
including ACS and pain episodes, and mortality.³⁰⁵, ³⁰⁶ A similar relationship was observed between asthma and the incidence of ACS in pediatric patients with Hb SC.³⁰⁷ Sickle cell patients with a history of asthma were four times more likely to develop ACS during a hospital admission for pain and had a substantially longer duration of hospitalization.³⁰⁸ Similarly, children with pulmonary function test (PFT)-documented lower airway obstruction had a greater risk for pain and ACS hospitalization (risk ratio 2.0, CI: 1.3 to 3.3).³⁰⁹ In Jamaican children with sickle cell disease, asthma and bronchiolar hyperreactivity were more common than in ethnic-matched controls and were associated with recurrent ACS.³¹⁰ Much less information is available for adult patients, but a high prevalence of airway hyperresponsiveness to methacholine challenge was noted in those with a history of reactive airway disease.³¹¹ Hematologically, ACS is characterized by a sudden drop in Hb concentration and an increase in the number of platelets and leukocytes.³¹² Rib infarcts are a primary trigger of ACS when bone pain is followed by soft-tissue reaction, pleuritis, splinting, hypoventilation, atelectasis, and the typical radiologic picture.³¹³ Incentive spirometry with the use of maximal inspirations every 2 hours has been shown to prevent ACS in patients with sickle cell disease who were hospitalized with chest or back pain.³¹⁴ Lung crises may result from embolization of fat from infarcted bone marrow (pulmonary fat emboli)³¹⁵ or deep-vein thrombi. Occlusion of major pulmonary vessels is a recognized cause of sudden death. Pulmonary fat emboli are found more commonly than previously appreciated when a diagnosis is sought by fat staining of pulmonary macrophages obtained by bronchoalveolar lavage.³¹⁵ Fat emboli are associated with bone pain, chest pain, neurologic symptoms, acute decreases in Hb level and platelet count, and prolonged hospitalization. Secretory phospholipase A₂ (sPLA2), an inflammatory mediator that liberates free fatty acids and lysophospholipids and may be responsible for acute lung injury, is markedly elevated in sickle cell patients 24 to 48 hours before the diagnosis of ACS in patients presenting with a pain event³¹⁶, ³¹⁷ and in most patients at the time of diagnosis of ACS.³¹⁸ A clinical trial involved patients hospitalized for pain who developed fever and elevated sPLA2 and were randomized to receive transfusion or observation.¹⁵⁸ Because of slow accrual, conclusions could not be reached regarding the effect of transfusion to pre-emptively avert an ACS event, but information regarding the sensitivity of this test was provided; a threshold level of sPLA2 ≥ 48 ng/ml offered 73% sensitivity and 71% specificity.

A comprehensive review of the management of ACS in children has been recently published and is a useful guideline for treatment of this complication.³¹⁹ Because the relative importance of infection and infarction is difficult to ascertain, broad-spectrum parenteral antibiotics, such as a third- or fourth-generation cephalosporin, should be provided for children with ACS. A macrolide antibiotic is indicated to cover Mycoplasma and Chlamydia. Of utmost importance is the correction of hypoxemia. If the arterial PO₂ value is <75 mm Hg or the O₂ saturation by pulse oximetry is significantly below baseline, the clinician should consider prompt simple or partial exchange transfusion.³²⁰

Intravenous dexamethasone was shown to result in a shorter hospital stay and reduced need for blood transfusion and oxygen when compared to placebo in children with ACS.³²¹ Because there appeared to be a high risk of recurrent symptoms and readmission to the hospital after dexamethasone was abruptly discontinued, a recent randomized study investigated the use of tapered oral dexamethasone for ACS treatment.³²² Despite a very small number of participants, this trial showed a reduction in hospitalization duration in the dexamethasone arm, but higher rates of rebound pain. sL-selectin was found elevated among patients with rebound pain and could be a useful biomarker during ACS. Nitric oxide inhalation has been utilized in the regulation of hypoxic pulmonary vasoconstriction,³²³ but definitive trials have not yet substantiated its therapeutic role.

Priapism is an unwanted, painful, and persistent erection of the penis. Useful reviews of this topic have been published.³²⁴, ³²⁵ The incidence of priapism in patients with sickle cell disease has been reported to be between 3% and 45%³²⁶, ³²⁷; it has a bimodal distribution of age of onset, with peaks at 5 to 13 years of age and at 21 to 29 years of age.³²⁸ Most priapism episodes begin during sleep³²⁹ or early in the morning; they may be associated with physiologic dehydration and hypoventilation, which results in metabolic acidosis followed by increases in sickling and stagnation of blood within the penile sinusoids or the corpora cavernosa. In data from the CSSCD, subjects with priapism had significantly lower levels of hemoglobin and higher levels of bilirubin, reticulocytes, white blood cells, and platelets, suggesting an association of priapism with increased hemolysis, perhaps related to a diminished availability of circulating NO, which plays an important role in erectile function.³³⁰ Although priapism is usually self-limited and of relatively short duration, it is often recurrent and may become chronic. “Stuttering” priapism refers to multiple episodes, each <4 hours in duration, which may occur several times a week and may herald a prolonged event. Usually, these do not require medical intervention. Typically, priapism results from engorgement of the paired cavernosal bodies with sparing of the glans and corpus spongiosum and is maintained by the partial obstruction of venous drainage. However, tricorporal priapism may occur, especially in postpubertal patients, and is associated with a poor prognosis.³³¹ Although it occurs with approximately equal frequency in prepubertal and postpubertal males, priapism is more difficult to manage in the latter group.³³², ³³³ Numerous ISCs and clots are found in the distended sinuses when needle aspiration or incisional drainage is performed.³³⁴ The repetitive trapping of cells in the corpora cavernosa, with or without surgical intervention, may lead to fibrosis of the septa and impotence.

Penile blood gas measurements and technetium-99 penile scintigraphy scans have been used to define intracorporeal hemodynamics and to guide therapy. However, these modalities are not readily available, and a more conventional approach to treatment is necessary. Of particular concern is an increased rate of impotence reported in sickle cell patients whose attacks lasted >24 hours³³⁵, ³³⁶ As with other complications resulting from the sludging of sickled erythrocytes, aggressive hydration and adequate analgesia are of primary importance and should be pursued within the first few hours of symptoms. If no response is seen within 12 to 24 hours, partial exchange transfusion to lower the Hb S level to <30% may be performed; this is occasionally sufficient.³³⁷ However, an association of sickle cell disease, priapism, exchange transfusion, and neurologic events, including seizures and obtundation, referred to as ASPEN syndrome, is of concern.³³⁸, ³³⁹ If no resolution occurs within another 12 to 24 hours, corporal aspiration and irrigation with saline may be indicated through such means as a Winter procedure,³⁴⁰ in which a fistula between the glans penis and the corpora cavernosa is created using a biopsy needle. The Dallas program reported rapid complete detumescence in 35 of 37 consecutive episodes of prolonged priapism in pediatric patients treated with aspiration and irrigation with a dilute epinephrine solution.³⁴¹ If penile aspiration is unsuccessful, creation of a cavernosa spongiosum shunt³⁴² or a venous bypass may be considered.

Prevention of recurrent priapism has been accomplished in some patients with chronic transfusion, particularly through exchange transfusion. α-Adrenergic agonists increase contraction of the smooth muscle of the trabecular arteries of the cavernosa and facilitate venous outflow from the corpora, promoting detumescence. α-Adrenergic agents including etilefrine, pseudoephedrine, and phenylephrine may be administered either orally or by intracavernous injection.³⁴³, ³⁴⁴ Other approaches have been the administration of diethylstilbestrol,³⁴⁵
the gonadotropin-releasing hormone analog leuprolide acetate,³⁴⁶ low-dose antiandrogens,³⁴⁷ finasteride,³⁴⁸ and oral phosphodiesterase S inhibitor.³⁴⁹ Sildenafil is reported to improve priapism, but can trigger pain as a side effect.³⁵⁰ A polyethylene glycolmodified adenosine deaminase (PEG-ADA) has been used in transgenic sickle mice to reduce adenosine levels and promoted increased cavernosal relaxation, suggesting a possible new avenue of treatment for priapism.³⁵¹ Despite either conservative or aggressive treatment, >25% of patients have some degree of impotence³⁵² and may be candidates for a penile prosthesis after 6 to 12 months.³⁵³

Hematologic “crises,” characterized by sudden exaggeration of anemia, are pathogenetically and temporally unrelated to vaso-occlusive crises. If they are unrecognized or untreated, the decrease in Hb concentration may be so precipitous and severe as to cause heart failure and death within hours.

Aplastic Crises. Aplastic crises are the most common of the hematologic complications. The pathogenesis and course of aplastic crises in SCA are similar to those of other chronic hemolytic states. Several characteristics are indicative of an infectious basis: the crises are characteristically preceded by or associated with febrile illnesses; several members of families with congenital hemolytic anemia may have concurrent aplasia;³⁵⁴ recurrence of crisis within the same individual is not observed;³⁵⁵ and most aplastic episodes occur during childhood.³⁵⁶ Epidemiologic studies clearly implicate human parvovirus B19 as the cause for almost all aplastic crises.³⁵⁵, ³⁵⁶ Aplasia is the result of direct cytotoxicity of the parvovirus to erythroid precursors, especially colony-forming units, erythroid (CFU-E).³⁵⁷ However, not all parvovirus infections result in problems; serologic evidence of previous infection was found in 71% of subjects with SCA who reached adulthood, but only 27% had a previous clinically recognized aplastic crisis.³⁵⁸

In the early phase of an aplastic crisis, peripheral blood reticulocytes and bone marrow normoblasts disappear or are greatly reduced in number. Because red cell survival in Hb SS is no more than 10 to 20 days, cessation of erythropoiesis is followed by a rapid decrease in Hb concentration. The process is self-limited, however; within 10 days, red cell production resumes spontaneously, and large numbers of reticulocytes and nucleated erythrocytes appear in the peripheral blood. Thereafter, the Hb concentration returns to its precrisis level. Often, the patient is first seen early in the recovery phase, when differentiation from a hemolytic crisis may be difficult. Although leukocytes and platelets are usually normal, all marrow elements may be affected.³⁵⁹ Treatment consists of supportive care with red cell transfusion when necessary.

Susceptible hospital workers exposed to patients with aplastic crises are at high risk of contracting nosocomial erythema infectiosum.³⁶⁰ Because infection during the midtrimester of pregnancy may result in hydrops fetalis and stillbirth, respiratory isolation precautions are a necessity if an aplastic crisis is suspected.³⁶¹

In addition to causing aplastic crisis, an acute parvovirus event not infrequently will lead to a prolonged vaso-occlusive pain crisis or it may trigger acute splenic sequestration.³⁶², ³⁶³, ³⁶⁴ Less frequently, it is associated with long-term problems, such as glomerulonephritis, which may cause end-stage renal failure, cardiac dysfunction, and stroke.³⁶⁵, ³⁶⁶

Splenic Sequestration. Splenic sequestration is characterized by sudden trapping of blood in the spleen. A splenic sequestration crisis is defined by a decrease in the steady-state Hb concentration of at least 2 g/dl, evidence of compensatory marrow erythropoiesis, and an acutely enlarging spleen.³⁶⁷ This complication occurs in infants and young children whose spleens are chronically enlarged before autoinfarction and fibrosis. Although splenic sequestration has been documented in infants as young as 3 to 4 months of age,³⁶⁸ it is observed most commonly during the second 6 months of life and is a less frequent finding after 2 years of age; however, it has been reported in adults.³⁶⁷, ³⁶⁹ In a large pediatric French cohort study, the risk of recurrence decreased with age: when the first episode occurred after 2 years, the risk was lower than when it occurred before 1 year of age (hazard ratio, 0.60).³⁷⁰

Children experiencing splenic sequestration may have an earlier onset of splenomegaly and a lower level of Hb F at 6 months of age.³⁷¹ Crises often are associated with respiratory tract infections or with parvovirus B19, usually in conjunction with an aplastic crisis.³⁷², ³⁷³ The already enlarged spleen rapidly increases in size at the expense of blood volume; hypovolemic shock and death may occur within hours.³⁷⁴ The sole pertinent postmortem finding is engorgement of splenic sinusoids with sickled cells. Individuals who survive have a tendency for recurrent episodes until 5 or 6 years of age, by which time sufficient fibrosis of the spleen has occurred to limit its expansion. There has been wide variability in the long-term management of patients with splenic sequestration, and currently, no consensus exists. Chronic transfusion and surgical splenectomy have both been used in an effort to avoid recurrence. Due to concerns with invasive encapsulated organisms, often monthly erythrocyte transfusions are used and total splenectomy is delayed until an age after which the risk of sepsis is lower. Partial splenectomy has also been used in an attempt to preserve immunologic function in children with SCA and severe splenic sequestration,³⁷⁵ but the indications for this procedure and long-term outcomes are still under investigation. Although it is encountered much less frequently, sudden trapping of blood in the liver (hepatic sequestration crisis) also occurs.³⁷⁶

Hemolytic Crises (Hyperhemolytic Crises). Hemolytic (hyperhemolytic) crises result from a sudden acceleration of the hemolytic process. They have been described in association with co-inherited hereditary spherocytosis³⁷⁷ and concurrent mycoplasma infection.²⁹⁸ Other causes of hyperhemolytic crisis include acute or delayed hemolytic transfusion reactions (usually Coombs test positive),³⁷⁸ and drug-induced hemolysis.³⁷⁹ Although ˜10% of black male patients with SCA have the unstable A variant of glucose 6-phosphate dehydrogenase (G6PD),³⁸⁰ they have no more severe anemia and no greater frequency of acute hemolytic episodes than those with normal levels of G6PD, even when challenged with oxidant drugs and infections, because of the young mean age of sickle red blood cells.³⁸¹

Megaloblastic Crises. Megaloblastic crises result from the sudden arrest of erythropoiesis by folate depletion.³⁸² Chronic erythroid hyperplasia imposes a drain on folate reserves, and biochemical evidence of mild folate deficiency has been demonstrated with high frequency in subjects with SCA.³⁸³ Megaloblastic crises likely occur when food consumption is interrupted by illness or alcoholism or when the folate requirement is augmented by rapid growth or pregnancy. The inverse relationship between plasma homocysteine concentration and folate status has led to a series of reports describing homocysteine levels and the possible need for folate supplementation. However, both elevated homocysteine levels³⁸⁴ and normal homocysteine levels have been reported.³⁸⁵ Currently, folic acid deficiency, as a cause of exaggerated anemia in sickle cell disease, appears to be extremely rare in the United States. Nevertheless, it is common practice to prescribe prophylactic folic acid (1 mg/day) to patients with sickle cell disease in areas of the world where folate is not routinely added to grainderived products.

Overwhelming infection may be the presenting manifestation of SCA in early childhood. Acute infection has been one of the most
common causes of hospitalization and previously was the most frequent cause of death, particularly during the first 3 years of life. S. pneumoniae is the usual infecting organism; the blood and spinal fluid are the major sites of infection.³⁸⁶, ³⁸⁷ Previously, the incidence of invasive infection with S. pneumoniae was ˜7/100 patient-years in children with SCA who were <5 years of age; this rate was 30 to 100 times that which would be expected in a healthy population of this age.³⁸⁷, ³⁸⁸ More than 70% of meningitis in children with SCA also resulted from S. pneumoniae.³⁸⁹ The mortality rate of pneumococcal sepsis was as high as 35%, but widespread improvement in parental education and aggressive management of the febrile child have greatly improved the likelihood of surviving a septic event.³⁹⁰ Furthermore, penicillin prophylaxis and pneumococcal vaccines have dramatically lowered the risk of invasive pneumococcal infection. Despite the dramatic decline in the rate of pneumococcal sepsis in recent decades (secondary to widespread use of pneumococcal immunization and penicillin prophylaxis), invasive pneumococcal infection still exists and may be life threatening.³⁹¹, ³⁹² A major threat to continued success in prevention and management of S. pneumoniae invasive infection has been the emergence of antibiotic-resistant pneumococcal organisms over the past two decades.³⁹¹, ³⁹²

Beyond 5 years of age, Gram-negative bacteria replace S. pneumoniae as the major infectious agents.²⁹⁵, ³⁸⁷ In contrast to infections in young children, those in older children and adults generally have an identifiable source or focus (e.g., Escherichia coli associated with urinary tract infection).³⁸⁷, ³⁹³ Osteomyelitis, sometimes involving multiple sites, occurs with increased frequency at all ages. The increased risk of osteomyelitis may stem from tissue ischemia and infarction associated with pain crises; these provide a potential nidus for infection in the long bones. Although >80% of hematogenous osteomyelitis in the general population is caused by Staphylococcus, most cases of osteomyelitis occurring in individuals with SCA are caused by Salmonella.³⁹⁴, ³⁹⁵ Serum antibody levels against Salmonella antigens are normal, but microinfarcts of the intestinal mucosa may predispose to invasive infections.³⁹⁶ A positive blood culture for Salmonella in a patient with SCA strongly suggests the diagnosis of osteomyelitis. Staphylococcal bone infection, clinically indistinguishable from Salmonella infection, also occurs with increased frequency in sickle cell disease.³⁹⁷

Bloodstream infections in hospitalized adults with sickle cell disease have been increasingly recognized. In one series,³⁹⁸ 28% were caused by Staphylococcus aureus, the majority of which were methicillin-resistant. Gram-negative organisms, anaerobes, and yeast were also found and >80% of the infections were considered to be catheter-related. Bloodstream infections frequently are associated with bone and joint infection.³⁹⁹

The pathophysiologic basis for increased susceptibility to aggressive infection relates in large part to the loss of spleen function.⁴⁰⁰ During the first few years of life, recurrent perivascular hemorrhage and infarction reduce the spleen to a small siderofibrotic vestige.⁴⁰¹ Despite the frequent occurrence of splenomegaly in the first few years, spleen function often is impaired by 6 to 12 months of age.¹⁷⁶ Howell-Jolly bodies and “pits” (depressions in the red blood cell membrane) are seen in peripheral blood erythrocytes,⁴⁰² and radiolabeled sulfur colloid is not cleared by the spleen.⁴⁰³ Spleen function is temporarily restored by transfusion therapy in early life, suggesting that functional asplenia is a consequence of altered perfusion imposed by intrasplenic sickling.⁴⁰⁴ In the absence of spleen function, bloodborne particulate antigens fail to elicit an expected antigenic response.⁴⁰⁵ Spleen function is necessary for effective host response to S. pneumoniae in the absence of preformed antibodies; in the presence of antibody, organisms are trapped effectively at extrasplenic sites. Because the acquisition of pneumococcal antibodies occurs with advancing age, young children without spleen function fare less well than older children and adults. However, responses to conjugated Haemophilus influenzae vaccine in young infants with SCA were appropriate.⁴⁰⁶ Other mechanisms may contribute to the vulnerability of children with sickle cell disease to infectious crises. Serum IgM levels are decreased.⁴⁰⁷ The alternative pathway for complement activation may be defective.⁴⁰⁸ Alterations of B- and T-lymphocyte number and function and of the function of neutrophils and monocytes are of uncertain significance.⁴⁰⁹, ⁴¹⁰

Prevention of Infection. The use of penicillin prophylaxis has been a major advance in the management of sickle cell disease. Two controlled trials, one in Jamaica and the other organized by the National Institutes of Health, led to the widespread acceptance of penicillin prophylaxis as standard therapy.⁴¹¹, ⁴¹² In the latter trial (PROPS), twice-daily oral penicillin V resulted in an 84% reduction in the incidence of pneumococcal bacteremia in infants <36 months of age. Current recommendations are to initiate penicillin prophylaxis by 3 months of age and to continue it at least until 5 years of age in children with Hb SS or Hb Sβ⁰-thalassemia (or longer if there was a history of surgical splenectomy, incomplete pneumococcal immunization, or invasive pneumococcal infection). A multi-institutional controlled trial found no further advantage of penicillin in the prevention of invasive pneumococcal infection in children >5 years of age.⁴¹³ The use of prophylaxis in young children with Hb SC disease or Hb Sβ⁺-thalassemia is controversial,⁴¹⁴ but many centers maintain all children with sickle cell disease on penicillin until 5 years of age. Of concern has been the question of whether prophylaxis might increase the risk of penicillin-resistant pneumococcal organisms. Its usage reduces nasopharyngeal colonization with S. pneumoniae, but the effect on the development of antibiotic resistance has been equivocal.⁴¹⁵, ⁴¹⁶, ⁴¹⁷

Unfortunately, the pneumococcal serotypes that are most prevalent in the community and most highly virulent (types 6A, 14, 19, and 23F) are least immunogenic.⁴¹⁸, ⁴¹⁹ Although the immunologic response of children 2 years of age and older to polysaccharide-conjugated pneumococcal vaccine is comparable to that of the general population,⁴²⁰ antibody titers fall more rapidly than in adults. Children with sickle cell disease should receive a primary immunization with the 23-valent polysaccharide vaccine at 2 years of age and a booster immunization 3 to 5 years later⁴²¹; the vaccine is ineffective in children <2 years of age. Administration of booster doses of this vaccine to older children and adults with sickle cell disease is controversial, but a booster is administered to teenagers and adults once every 10 years in many centers.

In contrast, the seven-valent protein-conjugated pneumococcal vaccine (PCV-7 ) is immunogenic in the first few months of life and is routinely administered to infants in the United States. This vaccine (which includes serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) is administered at 2, 4, 6, and 12 months of age (same immunization schedule as in the general pediatric population) and produces adequate antibody concentrations in the same range as those achieved among infants without sickle cell disease.⁴²², ⁴²³ In addition, significant rises are seen in antibody concentration to all seven protein-conjugated pneumococcal vaccine serotypes after the administration of polysaccharide-conjugated pneumococcal vaccine at 24 months of age. Recently, the protein-conjugated vaccine has been reported to lower the incidence of invasive pneumococcal disease between 65% and to >90% in children with sickle cell disease,⁴²⁴, ⁴²⁵ but it has not completely eliminated invasive pneumococcal infection.³⁹¹ In 2010 the 13-valent pneumococcal conjugate (PCV13) vaccine replaced PCV-7 in the United States and the United Kingdom; PCV13 has the additional serotypes 1, 3, 5, 6A, 7F, and 19A.⁴²⁶ It is unclear whether addition of the serotypes included in the PCV13 vaccine will significantly improve protection as replacement colonization has been with predominantly non-PCV13 serotypes, and a resurgence of invasive disease has been seen in some areas with predominantly non-PCV13 serotypes.³⁹¹

The conjugated H. influenzae type B vaccine induces protective antibody levels in young infants with SCA³⁹⁰, ⁴⁰⁶ and has virtually eliminated invasive H. influenzae infection in this population. Yearly influenza virus vaccine (including H1N1 strains) and the complete series with 3 doses of hepatitis B vaccine offers further protection. Meningococcal polysaccharide diphtheria toxoidconjugated vaccine offers protection against groups A, C, Y, and W-135 meningococcus and is recommended in children with sickle cell disease at age 2 with a booster at 5 years of age. It is unclear if adults should receive a booster of the meningococcus vaccination, but some centers offer boosters every 5 years. For updated information regarding the recommended schedule of immunization in children and adults in the United States, the Centers of Disease Control website (www.CDC.gov) should be consulted. The high frequency of parvovirus B19 infections in children with sickle cell disease, their life-threatening nature, and the associated risk of complications indicate the need for a vaccine that would confer lifelong immunity. A vaccine for parvovirus B19 (viral particles 1 and 2 proteins expressed in a baculovirus system with adjuvant MF-59) has been developed and undergone pilot testing, but side effects have stalled further studies.⁴²⁷

Management of Fever. Any fever ≥38.5°C in a child with SCA must be considered a medical emergency because of the potential risk of overwhelming pneumococcal sepsis, especially during the high-risk period between 6 months and 3 years of age. Previously, routine hospitalization of every febrile patient with SCA was standard management, to deliver intravenous antibiotic coverage until blood cultures were demonstrated to be negative. More recently, the majority of febrile patients have been managed in the emergency department and the outpatient setting if they do not have high-risk characteristics (e.g., toxic appearance, very high fever, serious localized infection, exceptionally high or low white blood cell count, a history of invasive infection, or inadequate capacity for close follow-up).³⁹⁰, ⁴²⁸, ⁴²⁹, ⁴³⁰ These children may be managed with prompt assessment, rapid administration of ceftriaxone, observation for at least 2 hours, and close outpatient follow-up.