- Timothy L. McCavit, MD*
- *Division of Hematology-Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Center for Cancer and Blood Disorders, Children's Medical Center Dallas, Dallas, TX.
Dr McCavit has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.
- acute chest syndrome
- sickle hemoglobin
- hematopoietic stem cell transplantation
- invasive pneumococcal disease
- pulmonary artery hypertension
- pneumococcal conjugate vaccine
- Prophylactic Penicillin Study
- red blood cell
- sickle cell disease
- sickle cell anemia
- sickle β0 thalassemia
- transcranial Doppler
- tricuspid regurgitant jet velocity
- vaso-occlusive crises
In the United States, sickle cell trait is carried by 7% to 8% of people of African ancestry, and the sickle hemoglobinopathies are estimated to affect 90,000 to 100,000 people.
After completing this article, readers should be able to:
Understand how the sickle hemoglobin mutation leads to the various manifestations of sickle cell disease (SCD).
Identify common health maintenance needs for children with SCD.
Recognize the common acute complications of SCD and their treatment.
Assess the risks and benefits of the common treatment modalities for SCD.
Discuss the improved prognosis for children with SCD.
The World Health Organization estimates that 7% of the world's population carries a hemoglobin (Hgb) mutation and that 300,000 to 500,000 children are born each year with severe hemoglobinopathy. The sickle Hgb (HgbS) mutation occurred independently at least four times (three times in sub-Saharan Africa and once in India or the Arabian peninsula) in regions with endemic malaria. In the heterozygous state, the sickle mutation provides protection against infection by the falciparum species of malaria and likely confers a survival advantage, leading to its continued high prevalence in some populations of sub-Saharan Africa and the Middle East/India. In the United States, sickle cell trait is carried by 7% to 8% of people of African ancestry, and the sickle hemoglobinopathies are estimated to affect 90,000 to 100,000 people. (1) US newborn screening data suggest that 1 in 2,500 newborns is affected by a form of sickle cell disease (SCD).
SCD refers to a group of heterogeneous disorders that are unified by the presence of at least one β globin gene affected by the sickle mutation (position 6, β-globin gene; codon GAG changes to codon GTG, coding for glutamic acid instead of valine). Homozygotes for the sickle mutation have sickle cell anemia (SS) or Hgb SS disease, which accounts for ∼60% to 65% of SCD.
When inherited with the sickle mutation in a compound heterozygous state, other β-globin gene mutations lead to other distinct forms of SCD. The most common of these is HgbC, which, when coinherited with the sickle mutation, leads to sickle hemoglobin-C disease, accounting for 25% to 30% of all SCD. Coinheritance of a β thalassemia mutation with the sickle mutation leads to sickle β0 thalassemia (Sβ0) or sickle β+ thalassemia, which account for 5% to 10% of all SCD (β0 indicates no β globin production; β+ indicates diminished β globin production).
Other less common β-globin mutations that lead to SCD when coinherited with HgbS include Hgbs OArab, D, and E. When discussing patients with SCD, precise nomenclature is important because of the phenotypic variability between the various forms.
It should also be noted that the term “sickler” is viewed as a derogatory term by many in the SCD clinician and patient community and is inappropriate to use in communication among clinicians. More appropriate terminology would be “a patient with sickle cell disease.”
The sickle mutation leads to the replacement of hydrophilic glutamic acid by a hydrophobic valine. The presence of the hydrophobic valine residue allows HgbS to polymerize in the deoxygenated state. In addition to low oxygen tension, low pH and an increased concentration of HgbS within the red blood cell (RBC) encourage polymer formation. HgbS polymerization ultimately causes RBCs to take on the characteristic sickle shape in a reversible fashion. Repeated episodes of polymerization and “sickling” can cause an RBC to be irreversibly sickled. In the circulation, these stiff, nondeformable sickled cells can lead to vaso-occlusion, with resultant tissue ischemia. As a result of or in addition to HgbS polymerization, other pathophysiologic mechanisms in patients with SCD have been observed, including activation of the vascular endothelium, leukocytosis, leukocyte activation, platelet activation, and oxidative stress from tissue reperfusion. Additionally, reduced RBC deformability and injury of the RBC cytoskeleton caused by the presence of HgbS polymers ultimately result in both intravascular and extravascular hemolysis. In the past 10 years, it has been suggested that nitric oxide depletion secondary to intravascular hemolysis may contribute to certain complications of SCD, such as pulmonary artery hypertension (PAH), although this postulate is controversial. (2)(3)
Before newborn screening, the diagnosis of SCD was made only after a potentially devastating complication prompted medical attention. Justification of newborn screening for SCD was provided by the Prophylactic Penicillin Study (PROPS) in 1986 (see below), and since then, universal newborn screening with Hgb electrophoresis (Table 1) or other methods has become the standard in the United States. Certain states also provide confirmation of an SCD electrophoresis result by DNA sequencing. As with most genetic conditions, prenatal diagnosis of a fetus with SCD is possible in the first trimester through chorionic villus sampling or in the second trimester through amniocentesis.
Newborn Screen Results for Common Hemoglobinopathies
SCD is medically complex, affecting virtually any organ in the body, so children born with SCD benefit from well-coordinated, comprehensive, multidisciplinary care. This care occurs ideally through regular interactions with both a primary care provider and a pediatric hematologist. Psychologists, social workers, and expert nursing support play important roles as patients and families adjust to life with SCD and its complications. Additionally, other subspecialty expertise in SCD is important, including neurology, pulmonology, nephrology, radiology, ophthalmology, otorhinolaryngology, general surgery, and anesthesiology. In addition to the elements of routine health maintenance highlighted in Table 2, common chronic problems and activities discussed at routine visits include enuresis, sleep and sleep-disordered breathing, jaundice, mental health and adjustment to chronic disease, and sports participation. In the teenage years, fostering self-care, responsibility, and readiness for transition to adult care become the focus.
Health Maintenance Timeline for Children With SCD
Effects on Blood
A variety of hematologic abnormalities typify SCD. Anemia is the primary hematologic manifestation of SCD, with the severity determined by genotype (Table 3), in addition to the specific patient's rates of hemolysis, erythropoiesis, and plasma volume expansion. (4) After the transition to adult β globin expression occurs in the first year of life, children with SCD typically maintain stable baseline Hgb levels with significant fluctuations occurring usually during acute disease complications. Additionally, a leukocytosis with typical total white blood cell counts of 15,000 to 25,000/mm3 is observed. A mild thrombocytosis is also common among patients with SCD, with average platelet counts of 400,000 to 475,000/mm3.
Hematologic Parameters for the Common Forms of SCD
Pneumococcus and Prophylactic Penicillin
A predilection to infection by the encapsulated organism Streptococcus pneumoniae has long been recognized in children with SCD, particularly those with SS, due to functional asplenia. Before attempts at prophylaxis, the incidence of invasive pneumococcal disease (IPD) was six episodes/100 patient years, with a peak in the first 3 years of life. Beginning in the late 1970s and early 1980s, the pneumococcal polysaccharide vaccine became standard for children with SCD. In 1986, the landmark PROPS clinical trial revealed an 84% decrease in the risk of IPD in children receiving daily prophylactic penicillin, compared with those receiving placebo. (5)
The PROPS II study attempted to answer the question of whether prophylactic penicillin could be discontinued safely at 5 years of age. (6) The number of IPD events was unexpectedly low during the study period, so a difference in the rates of IPD between groups could not be demonstrated clearly. This finding has led to a variable practice among sickle cell centers with some recommending daily penicillin for life (or at least until age 18 years), whereas others recommend cessation of prophylaxis at age 5 years. Similarly, the role of penicillin in patients with Hgb SC and other mild genotypes is controversial.
The heptavalent pneumococcal conjugate vaccine, licensed in 2000, has led to a further 70% decrease in the incidence of IPD, now estimated to be 0.3 to 0.5/100 patient years. (7) After heptavalent pneumococcal conjugate vaccine licensure, nonvaccine serotypes emerged as the most common cause of IPD, particularly serotype 19A. Pneumococcal conjugate vaccine (PCV13), licensed in 2010, includes 19A and other currently prevailing serotypes. Current standard practice should include daily prophylactic penicillin beginning before 2 months of age, the PCV13 series as recommended for all children, and at least two doses of pneumococcal polysaccharide vaccine, with the first dose at 2 years of age.
Because of the risk of IPD, any fever (typically defined as ≥38.3°C) is treated as a medical emergency for children with SCD. Urgent evaluation of all febrile episodes, including physical examination, complete blood count, and blood culture, is of utmost importance. Although hospitalization for observation is sometimes necessary, patients with SCD evaluated for fever without a source who lack certain high risk features (white blood cell count >30,000/mm3 or <5,000/mm3, fever >40°C, “ill-appearing”) may be managed safely as an outpatient after intravenous administration of an empiric, antipneumococcal antibiotic (eg, ceftriaxone). Other factors that must be considered in deciding whether to discharge a patient from the emergency department include the age of the patient, the ability of the family to return promptly for recurrent fever or clinical deterioration, and the availability of close follow-up.
Infection by parvovirus B19 leads to a maturation arrest for RBC precursors in the bone marrow for ∼10 to 14 days. In hematologically normal children, this arrest in RBC production is not problematic because of the 120-day lifespan of normal RBCs. In SCD, however, the RBC lifespan is between 10 and 20 days, so cessation of RBC production for 10 to 14 days can lead to profound anemia. Signs and symptoms of profound anemia, including pallor, fatigue, decreased activity, altered mentation, and poor feeding, are typical of aplastic crises. Laboratory evaluation reveals severe anemia with reticulocytopenia and occasional thrombocytopenia. The management of an aplastic crisis includes transfusion support as needed until reticulocyte recovery has occurred. Family members of patients with SCD who are experiencing an aplastic crisis should be evaluated if they have SCD and no previous history of parvovirus infection.
Severe, episodic pain is the clinical hallmark of SCD. Commonly referred to as vaso-occlusive crises (VOC), these episodes can occur from infancy until old age, although they increase in frequency throughout childhood with a peak in the mid 20s. The pathophysiologic mechanism for most VOC is bone marrow ischemia with resultant infarction. Risk factors for more frequent VOC include severe genotype (SS or Sβ0), increasing age, and high baseline Hgb level. On the other hand, a high baseline fetal Hgb concentration is protective. VOCs are triggered commonly by infection, emotional stress, or exposure to cold, wind, or high altitude. The episodes may occur in many locations throughout the body, although the lower back, legs, and arms are most common. Using the frequency of interactions with the health-care system as a proxy for pain frequency and severity may vastly underestimate the problem of pain in SCD. It is, therefore, crucial that health-care providers specifically assess pain occurring at home during routine visits.
The severity and duration of VOCs vary from minor pain lasting minutes to excruciating pain lasting days. Examination of a patient having a VOC may reveal erythema, edema, joint effusions, or point tenderness, but none of these signs may be present and they are not required for the diagnosis. A minor decrease in Hgb concentration from baseline and an increased white blood cell count are common but nonspecific laboratory features.
The approach to treating severe acute pain, sadly, has not changed in decades. Opioid analgesics, anti-inflammatory medications, and intravenous fluids remain the mainstays of treatment. RBC transfusions, however, do not aid in the resolution of severe VOCs. Recognition and treatment of psychosocial contributors to acute and chronic pain are other key elements to VOC management. Many pain crises can be treated at home with distraction and other coping behaviors in addition to oral pain medications. Prevention of VOCs can be aided by the avoidance of precipitating factors, the use of hydroxyurea (HU, see below), and maintenance of intravascular volume through oral fluid intake.
Dactylitis is a specific type of VOC that occurs in infants and young children with SCD, especially SS. Dactylitis is defined by tender, erythematous, and edematous hands or feet (Fig 1). It occurs in 25% of infants by 1 year of age and 40% by 2 years of age, although significant variability in the prevalence has been noted among studies. Principles of dactylitis management do not differ from other VOCs; analgesics and intravenous fluids are key. Dactylitis before 1 year of age was identified as one of three prognostic factors used to predict severe outcome (frequent VOCs, frequent acute chest syndrome [ACS], acute stroke, or death) in a large cohort study of pediatric patients with SCD in the United States, although this finding could not be replicated in a large independent pediatric cohort study.
Dactylitis is characterized by tender, erythematous, and edematous hands or feet. Courtesy of Doernbecher Children's Hospital, Portland, Oregon.
Acute Chest Syndrome
The very term ACS suggests an incomplete understanding of this phenomenon. Clinically, ACS is defined by a new pulmonary infiltrate (Fig 2) on chest radiograph in addition to one or more of the following: fever, tachypnea, dyspnea, hypoxia, and chest pain. ACS is a common and potentially lethal complication of SCD. The incidence of ACS is highest (25 episodes/100 patient years) in children between 2 and 5 years of age. When the underlying cause of ACS was investigated in detail including bronchoscopy, 45% of patients had no identifiable cause, whereas infection caused 30% of cases. The most common infectious causes of ACS included Chlamydia pneumoniae (28% of infections), viral infection (22%), and Mycoplasma pneumoniae (20%). Pulmonary infarction and fat embolism caused 16% and 8% of all ACS cases, respectively. The pathogenesis of ACS likely varies, depending on the cause, but commonly includes inflammation, pulmonary vascular occlusion, ventilation/perfusion mismatch, airway hyper-reactivity, and pulmonary edema.
Chest radiograph of an 18-month-old infant with SS and severe ACS with diffuse bilateral infiltrates.
The treatment of ACS includes supplemental oxygen, empiric antibiotics (including a macrolide for coverage of atypical pathogens), bronchodilators, and careful management of analgesia and intravascular volume. Blood transfusion is another fundamental treatment for ACS. A decrease in Hgb level from baseline and an increasing supplemental oxygen requirement are common indications for transfusion in ACS. Simple transfusion may be adequate for mild to moderate ACS, but exchange transfusion should be considered early in the course of progressive or severe ACS.
In addition to transfusion, supportive respiratory care, up to and including mechanical ventilation and extracorporeal membrane oxygenation, may be necessary in severe cases. Finally, corticosteroids have been shown to reduce the severity of ACS hospitalizations. Unfortunately, corticosteroid use is complicated by a high rate of “rebound” VOC, so if used at all, corticosteroids should be reserved for the most severe cases.
Asthma is prevalent in children with SCD, as in the general population, affecting nearly 20% of patients. In SCD, a diagnosis of asthma is associated with higher rates of ACS, VOC, and early death. The mechanism by which asthma influences the severity of SCD is unclear but could relate to inflammation, ventilation-perfusion mismatching, or other mechanisms. Because of the strength of the SCD/asthma association, patients with SCD should be screened for asthma on an annual basis by history and physical examination beginning at 1 year of age. Additionally, some groups recommend screening with pulmonary function testing at least every 5 years, beginning at 6 years of age. Patients with SCD with persistent asthma also should be followed by a pulmonologist, regardless of severity.
Pulmonary Artery Hypertension
PAH is a severe complication of SCD that typically occurs in adulthood. Its pathogenesis may relate to nitric oxide depletion secondary to release of free Hgb into the plasma from chronic intravascular hemolysis. Symptoms of PAH may include exertional dyspnea, fatigue, and syncopal events. Right heart catheterization classically has been required for the diagnosis of PAH, although an elevated tricuspid regurgitant jet velocity (TRJV) on echocardiography is correlated with catheter-determined pulmonary artery pressures. Thus, echocardiography for TRJV is used commonly as a screening test for PAH in adults with SCD, and, although controversial, has been suggested as a screening test for children with SCD as well. Abnormal TRJVs have become synonymous with PAH in some segments of the literature, but right heart catheterization is still recommended for a definitive diagnosis and before treatment of PAH.
Children with SS and Sβ0 have long been recognized as being at risk for acute stroke. The risk of stroke is 10% in the first 20 years of life, with a peak incidence between 4 and 8 years of age. (8) Most strokes in SCD are ischemic in nature, with hemorrhagic stroke accounting for less than 10% of the total. The presenting symptoms of acute stroke in SCD include hemiparesis, facial droop, aphasia, and more generalized symptoms, including stupor and, rarely, seizure. Acute stroke symptoms may mimic a VOC in a young child reluctant to use a painful limb. The pathogenesis of acute stroke is incompletely understood but includes a vasculopathy marked by hypertrophy of the intima and media layers of the large arteries in the anterior cerebral circulation (primarily the middle cerebral arteries).
The evaluation of a patient suspected of experiencing acute stroke should include a careful history and neurologic examination; emergent radiographic evaluation by MRI or computed tomography followed by MRI when MRI is not immediately available; and a laboratory evaluation, including blood count, reticulocyte count, Hgb S percentage, and blood group and screen.
The principle underlying the treatment of acute stroke is the rapid reduction of the Hgb S percentage. This goal may be achieved through simple RBC transfusion or partial manual exchange, although automated exchange transfusion with erythrocytopheresis reduces the Hgb S percentage more efficiently and is widely regarded as standard practice. This treatment frequently leads to resolution or a marked dimunition in neurologic symptoms within 24 to 48 hours.
The long-term outcome of acute stroke is variable; many patients lack significant motor impairment but may demonstrate impaired executive functioning. A second stroke is very likely without the use of regular RBC transfusions to suppress the Hgb S percentage, and even with a chronic transfusion regimen (see below), ∼20% of acute stroke victims will experience a second acute stroke. For this reason, hematopoietic stem cell transplantation (HSCT) may be an optimal therapy for children who have a history of acute stroke when a suitable donor is available (see below).
Primary Stroke Prevention
The terrible burden of acute stroke in patients with SS and Sβ0 has driven research dedicated to primary stroke prevention. In the early 1990s, transcranial Doppler (TCD) ultrasonography was shown to predict risk of acute stroke in SS and Sβ0, with an abnormal TCD examination representing a 40% risk of stroke in the subsequent 3 years. In the landmark Stroke Prevention Trial in Sickle Cell Anemia, children identified to be at high risk by TCD were randomly assigned to monthly blood transfusions versus observation, with a 90% decrease in the rate of stroke observed in the transfusion group. (9) Hence, annual screening with TCD has become standard care for children with SS and Sβ0. The duration of transfusion is indefinite, although current studies are addressing whether patients may be transitioned safely to HU to prevent stroke.
In the past decade, silent stroke has been recognized as an important problem in children with SS and Sβ0. Silent stroke is defined by the presence of findings on MRI suggestive of old cerebral infarction, typically small areas of gliosis, without a corroborating clinical history of acute stroke symptoms. Silent strokes are associated strongly with neurocognitive deficits and are a risk factor for subsequent acute stroke. Most studies have revealed that silent strokes occur in ∼30% of children (10) with SS and Sβ0, leading to estimates of the cumulative prevalence of central nervous system infarct events (acute and silent stroke) of ∼40% in this population. Regular blood transfusions are under study to determine whether they may decrease the risk of acute stroke in patients who have experienced silent stroke.
Not surprisingly, patients with SCD with a history of acute stroke or silent stroke have high rates of neuropsychological dysfunction. Even the SCD population that has not been affected by acute or silent stroke has a high rate of a neuropsychological dysfunction that worsens with age, including deficits in general intelligence, attention and executive functioning, memory, language, and visual-motor performance compared with matched controls. The result may be difficulty at school and in other tasks requiring executive functioning. Early evaluation and intervention in school settings may improve outcomes for this at-risk population.
Other Clinical Sequelae
Rapid enlargement of the spleen with resultant trapping of the blood elements is known as acute splenic sequestration and occurs in ∼30% of children with SS by 5 years of age, with most first episodes occurring before 2 years of age. Children with SC disease tend to develop splenic sequestration at 10 years of age or older. Splenic sequestration was a common cause of mortality among children with SCD before the 1980s. Education of family members in daily spleen palpation is now standard care and has increased the detection of sequestration and markedly decreased mortality.
Evaluation of a child with splenic sequestration will reveal splenomegaly, a Hgb value below baseline, and thrombocytopenia, because all blood elements will be trapped in the enlarged spleen. The management of an initial splenic sequestration episode typically includes cautious transfusion to Hgb values between 7 and 9 gr/dL. A reduction in spleen size frequently occurs 1 to 3 days after initial presentation and may lead to 2 to 3 gr/dL increases in Hgb, a phenomenon known as “auto-transfusion.”
Approximately one-half of patients will experience recurrence of splenic sequestration. Splenectomy is performed commonly after a second or third sequestration episode, although some centers chronically transfuse affected infants until 2 years of age before undertaking splenectomy.
SCD is a chronic hemolytic anemia, and when Hgb is released from the RBC, bilirubin is produced, leading to jaundice. Ultimately, this increased bilirubin is stored in the gall bladder and can precipitate to form stones. Presenting signs and symptoms of cholelithiasis in SCD include right upper quadrant or epigastric abdominal pain, jaundice, and vomiting. Incidentally discovered, asymptomatic gallstones may be observed without requiring intervention. Symptomatic stones or stones obstructing the common bile duct commonly require cholecystectomy. A laparoscopic approach is now standard for cholecystectomy, which reduces the duration of postoperative pain and hospitalization. See below for additional notes on the surgical management of patients with SCD.
Priapism is a prolonged, painful erection of the penis with typical onset in the early morning hours. It can occur in two forms: prolonged, an episode of ≥4 hours duration, and stuttering, self-limited episodes that can occur in clusters. In SCD, priapism is thought to be caused by sickling of RBCs in the corpora cavernosa of the penis, leading to sludging and an increase in intrapenile pressure. (11) This effect, in turn, leads to local acidosis and worsening deoxygenation, which leads to further sickling in a vicious cycle that causes further outflow tract obstruction and severe pain.
Priapism can occur as young as 3 years of age, and ∼30% of boys will have an episode by age 15. If a prolonged episode is left untreated, fibrosis of the cavernosa may develop, leading to permanent erectile dysfunction. Treatment of an acute episode of priapism may include aggressive analgesia and pharmacologic efforts to decrease the vascular engorgement of the cavernosa through agents such as pseudoephredrine and etilefrine. Aspiration and irrigation of the cavernosa by a urologist may be necessary for prolonged episodes. Blood transfusions and oxygen are of unproven benefit for acute episodes of priapism.
Prevention of priapism is understudied, although nightly pseudoephedrine or etilefrine have been reported to achieve some success in case series or uncontrolled trials. Gonadotropin releasing hormone analogs also have been used to prevent recurrent priapism. The effects of HU and chronic blood transfusion for prevention of priapism are largely unreported.
Major surgery places a child with SCD at risk of complications, including ACS. To that end, perioperative transfusion to increase the Hgb concentration and decrease the Hgb S percentage is considered standard care for major surgeries. Additionally, measures such as incentive spirometry, carefully titrated analgesia, oxygen therapy, and close inpatient observation may help decrease the risk of postoperative SCD-related complications. The role of preoperative transfusion for minor surgery including tonsillectomy/adenoidectomy is controversial, but transfusion may be safely avoided for some patients undergoing such procedures.
HU is the only medication approved by the Food and Drug Administration for the treatment of SCD. HU use for children with SCD has been reviewed recently. (12) HU was developed originally as a chemotherapeutic agent for certain leukemias and myeloproliferative diseases, but in the early 1980s, HU was recognized to increase expression of fetal Hgb. Fetal Hgb was known to inhibit the polymerization of HgbS, the primary mechanism underlying the SCD pathogenesis. HU also may act through a relative myelosuppression with a decrease in circulating neutrophils, cells whose role in the pathogenesis of some SCD complications has recently been recognized.
In clinical trials for adults with SCD, HU was shown to markedly reduce the rate of VOCs, ACS, blood transfusions, and all-cause hospitalizations. In addition, long-term follow-up studies have revealed HU to confer a survival advantage for adults with SS and Sβ0. In children with SCD, the published experience with HU is less extensive, although clinical trials with HU have been conducted in children as young as 9 to 18 months of age.
A randomized clinical trial of HU for infants with SCD (BABY-HUG) was completed recently. (13) Although HU failed to improve the primary outcomes of kidney and spleen function, a decrease was observed in the rates of hospitalization, blood transfusion, ACS, dactylitis, and other VOCs for infants on HU compared with those on placebo. There is also some evidence that HU may reduce conditional and even abnormal TCD velocities.
The toxicity profile for HU has shown it to be tolerable with minimal toxicities other than the risk of mild myelosuppression. Thus, regular monitoring of blood counts is required while on HU. HU is theorized to be a teratogen as well and is contraindicated in pregnant women. Some concerns have existed in both the patient and clinician community that HU, as a chemotherapeutic agent, may induce genetic changes that could lead to myelodysplasia, leukemia, or other malignancy, yet these complications have never been attributed to HU in an actual patient with SCD. Importantly, recent analyses of peripheral blood mononuclear cells have not demonstrated impaired DNA repair mechanisms or increased mutations in children on HU compared with other patients with SCD.
In summary, HU is an important therapeutic option for children with SCD. Historically, HU was reserved only for children with severe or frequent complications of SCD, but as suggested by the authors of the recently published BABY-HUG study, consideration must now be given to offering HU to all children with SS or Sβ0. (13)
The suppression of endogenous RBC production by regular transfusion of donor RBCs is another means by which complications of SCD may be ameliorated. The clearest indications for chronic transfusions are for both primary and secondary stroke prevention. Short- and long-term chronic transfusions also have been used to treat complications such as frequent pain, severe or frequent ACS, and growth failure, among others. Simple transfusion is the most commonly used method for RBC delivery in chronic transfusions. This method carries with it the ubiquitous problem of iron overload, because each milliliter of transfused blood contains between 0.5 and 1 mg of elemental iron, which approximates normal daily absorption. Iron loading occurs primarily in the liver, heart, and endocrine glands in patients with SCD, and severe overload can result in morbidity and mortality.
The treatment of iron overload requires an exogenous iron chelator because humans lack a mechanism to increase excretion of the excess iron. Before 2007, the only available iron chelator (deferroxamine) in the United States required subcutaneous administration for 10 to 12 hours per day, 5 to 7 days per week. Adherence to such a medication regimen was understandably low, so severe iron overload developed in many chronically transfused patients with SCD. In 2007, an oral iron chelator (deferasirox) was licensed. Deferasirox appears to be as efficacious as deferroxamine in reducing iron burden.
In addition to iron overload, transfusion-related infection and alloantibody formation are other potential complications of chronic transfusions. Improved donor selection policies and careful nucleic acid based-testing have greatly reduced, but not eliminated, the likelihood of transfusion-related infection. The risk of alloantibody formation may be mitigated by extended RBC cross-matching and programs to match donors and recipients by race and ethnicity. Exchange transfusion, either by manual exchange or erythrocytopheresis, is an alternative to simple transfusion and appears to greatly decrease iron loading in patients on chronic transfusions.
Hematopoietic Bone Marrow Transplantation
HSCT remains the only curative option for children with SCD. Transplantation works by replacing sickle erythrocyte progenitors with normal erythrocyte progenitors in the bone marrow. HSCT typically is reserved for patients affected by severe or life-threatening complications of SCD, including stroke and ACS.
The most important risks of HSCT include peri-transplant mortality (frequently from infection), graft-versus-host disease, graft failure, and conditioning-induced infertility. Limitations to the use of HSCT include a paucity of matched siblings and poor representation of minorities in the bone marrow donor pool. Unrelated HSCT and reduced intensity conditioning regimens have been published recently but require further exploration in the clinical trial setting.
Recently, a variety of new therapies have been suggested for SCD. Most tantalizing is the potential of gene therapy via the insertion of a normal β globin or γ globin gene into a patient's own hematopoietic precursors. Bone marrow has been the traditional source of hematopoietic stem cells, although the recent recognition that pluripotent stem cells may be induced from skin cells may make the production of corrected hematopoietic precursors less invasive and painful. Other emerging therapeutics currently under development for patients with SCD include novel agents aimed at inducing HgF expression, novel anti-inflammatory or antithrombotic agents to treat or prevent sickle cell complications, inhaled nitric oxide, HSCT from unrelated donors, and reduced intensity conditioning for HSCT, among others.
Quality of Care
The provision of care to patients with SCD in the United States occurs within a complex tapestry of societal and personal interactions. The acute complications of SCD lead to frequent emergency department visits and hospitalizations for some patients. Unfortunately, studies of patient experiences and clinician attitudes in both the emergency department and inpatient settings have demonstrated frequent distrust between patients and providers. Patients describe both over- and undertreatment and lack of involvement in decision-making.
The quality-of-care provided varies depending on the rarity and severity of a given complication and the experience of the hospital and its personnel with SCD patients. Recently, the first set of rigorously developed quality-of-care indicators for children with SCD were published. (14) These indicators establish a benchmark that will allow providers and health-care organizations to measure their performance in SCD care, and as changes are made to improve performance, the SCD patient's experience of care also may begin to improve.
Prognosis and Survival
In spite of the many complications that may afflict children who have SCD, their prognosis has improved in past decades. Before routine newborn screening and pneumococcal prophylaxis, death from IPD, splenic sequestration, ACS or other severe complications of SCD was a common occurrence in childhood. Recent studies from cohorts in the United States and the United Kingdom suggest that death in childhood is becoming an infrequent event, with ∼95% of children with SCD surviving to age 18 years. (15) Unfortunately, the young adult years, following transition to adult care, appear to be a high-risk period for individuals with SCD, which has led to a recent emphasis on improving the transition process, with the long-term goals of improving quality of life, quality of medical care, and survival for patients with SCD.
Sickle cell disease (SCD) is a heterogeneous group of prevalent, potentially life-threatening, chronic disorders of hemoglobin (Hgb).
Hgb polymerization underlies the pathophysiology of SCD.
Children who have SCD benefit from regular health maintenance visits with a pediatric hematologist and a primary care pediatrician.
The high incidence of invasive pneumococcal disease (IPD) in SCD justifies newborn screening, daily prophylactic penicillin, and immunization with the pneumococcal conjugate and polysaccharide vaccines.
Vaso-occlusive pain crises are the clinical hallmark of SCD and occur with increasing frequency through childhood. These episodes warrant aggressive treatment with analgesics and hydration and may be prevented with hydroxyurea (HU) therapy.
Annual transcranial Doppler (TCD) screening for patients ages 2 to 16 years identifies those at high risk for acute stroke, and regular blood transfusions can reduce this risk greatly.
Common indications for initiating HU therapy have been severe or frequent vaso-occlusive crises or acute chest syndrome, but this therapy may be considered in younger and less symptomatic patients.
The prognosis for children with SCD has improved, with the vast majority surviving into adulthood, prompting a focus on improving the process of transition to adult care.
Sickle cell disease (SCD) usually manifests early in childhood. For the first 6 months of life, infants are protected largely by elevated levels of Hb F; soon thereafter, the condition becomes evident.
The most common clinical manifestation of SCD is vaso-occlusive crisis. A vaso-occlusive crisis occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and resultant pain. Pain crises constitute the most distinguishing clinical feature of sickle cell disease and are the leading cause of emergency department visits and hospitalizations for affected patients.
Approximately half the individuals with homozygous Hb S disease experience vaso-occlusive crisis. The frequency of crisis is extremely variable. Some have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or none at all. Each individual typically has a consistent pattern for crisis frequency.
Pain crises begin suddenly. The crisis may last several hours to several days and terminate as abruptly as it began.
The pain can affect any body part. It often involves the abdomen, bones, joints, and soft tissue, and it may present as dactylitis (bilateral painful and swollen hands and/or feet in children), acute joint necrosis or avascular necrosis, or acute abdomen.  With repeated episodes in the spleen, infarctions and autosplenectomy predisposing to life-threatening infection are usual. The liver also may infarct and progress to failure with time. Papillary necrosis is a common renal manifestation of vaso-occlusion, leading to isosthenuria (ie, inability to concentrate urine).
Severe deep pain is present in the extremities, involving long bones. Abdominal pain can be severe, resembling acute abdomen; it may result from referred pain from other sites or intra-abdominal solid organ or soft tissue infarction. Reactive ileus leads to intestinal distention and pain.
The face also may be involved. Pain may be accompanied by fever, malaise, and leukocytosis.
Bone pain is often due to bone marrow infarction. Certain patterns are predictable, since pain tends to involve bones with the most bone marrow activity and because marrow activity changes with age. During the first 18 months of life, the metatarsals and metacarpals can be involved, presenting as dactylitis or hand-foot syndrome.
As the child grows older, pain often involves the long bones of the extremities, sites that retain marrow activity during childhood. Proximity to the joints and occasional sympathetic effusions lead to the belief that the pain involves the joints. As marrow activity recedes further during adolescence, pain involves the vertebral bodies, especially in the lumbar region.
Although the above patterns describe commonly encountered presentations, any area with blood supply and sensory nerves can be affected.
Triggers of vaso-occlusive crisis
Often, no precipitating cause can be identified. However, because deoxygenated hemoglobin S (HbS) becomes semisolid, the most likely physiologic trigger of vaso-occlusive crises is hypoxemia. This may be due to acute chest syndrome or accompany respiratory complications.
Dehydration can precipitate pain, since acidosis results in a shift of the oxygen dissociation curve (Bohr effect), causing hemoglobin to desaturate more readily. Hemoconcentration also is a common mechanism.
Another common trigger is changes in body temperature—whether an increase due to fever or a decrease due to environmental temperature change. Lowered body temperature likely leads to crises as the result of peripheral vasoconstriction. Patients should wear proper clothing and avoid exposure to ensure normal core temperature.
Chronic pain in SCD
Many individuals with SCD experience chronic low-level pain, mainly in bones and joints. Intermittent vaso-occlusive crises may be superimposed, or chronic low-level pain may be the only expression of the disease.
Anemia is universally present. It is chronic and hemolytic in nature and usually very well tolerated. While patients with an Hb level of 6-7 g/dL who are able to participate in the activities of daily life in a normal fashion are not uncommon, their tolerance for exercise and exertion tends to be very limited.
Anemia may be complicated with megaloblastic changes secondary to folate deficiency. These result from increased RBC turnover and folate utilization. Periodic bouts of hyperhemolysis may occur.
Children exhibit few manifestations of anemia because they readily adjust by increasing heart rate and stroke volume; however, they have decreased stamina, which may be noted on the playground or when participating in physical education class.
A serious complication is the aplastic crisis. This is caused by infection with Parvovirus B-19 (B19V). This virus causes fifth disease, a normally benign childhood disorder associated with fever, malaise, and a mild rash. This virus infects RBC progenitors in bone marrow, resulting in impaired cell division for a few days. Healthy people experience, at most, a slight drop in hematocrit, since the half-life of normal erythrocytes in the circulation is 40-60 days. In people with SCD, however, the RBC lifespan is greatly shortened (usually 10-20 days), and a very rapid drop in Hb occurs. The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.
Splenic sequestration occurs with highest frequency during the first 5 years of life in children with sickle cell anemia. Splenic sequestration can occur at any age in individuals with other sickle syndromes. This complication is characterized by the onset of life-threatening anemia with rapid enlargement of the spleen and high reticulocyte count.
Splenic sequestration is a medical emergency that demands prompt and appropriate treatment. Parents should be familiar with the signs and symptoms of splenic sequestration crises. Children should be seen as rapidly as possible in the emergency room. Treatment of the acute episode requires early recognition, careful monitoring, and aggressive transfusion support. Because these episodes tend to recur, many advocate long-term transfusion in young children and splenectomy in older children.
As HbS replaces HbF in the early months of life, problems associated with sickling and red cell membrane damage begin. The resulting rigid cells progressively obstruct and damage the spleen, which leads to functional asplenia. This, along with other abnormalities, results in extreme susceptibility to infection.
Organisms that pose the greatest danger include encapsulated respiratory bacteria, particularly Streptococcus pneumoniae. The mortality rate of such infections has been reported to be as high as 10-30%. Consider osteomyelitis when dealing with a combination of persistent pain and fever. Bone that is involved with infarct-related vaso-occlusive pain is prone to infection. Staphylococcus and Salmonella are the 2 most likely organisms responsible for osteomyelitis.
During adult life, infections with gram-negative organisms, especially Salmonella, predominate. Of special concern is the frequent occurrence of Salmonella osteomyelitis in areas of bone weakened by infarction.
Effects on growth and maturation
During childhood and adolescence, SCD is associated with growth retardation, delayed sexual maturation, and being underweight. Rhodes et al demonstrated that growth delays during puberty in adolescents with SCD is independently associated with decreased Hb concentration and increased total energy expenditure. 
Rhodes et al found that children with SCD progressed more slowly through puberty than healthy control children. Affected pubertal males were shorter and had significantly slower height growth than their unaffected counterparts, with a decline in height over time; however, their annual weight increases did not differ. In addition, the mean fat free mass increments in affected males and females were significantly less than those of the control children. 
Infants with SCD may develop hand-foot syndrome, a dactylitis presenting as exquisite pain and soft tissue swelling of the dorsum of the hands and feet. The syndrome develops suddenly and lasts 1-2 weeks. Hand-foot syndrome occurs between age 6 months and 3 years; it is not seen after age 5 years because hematopoiesis in the small bones of the hands and feet ceases at this age. Osteomyelitis is the major differential diagnosis.
Cortical thinning and destruction of the metacarpal and metatarsal bones appear on radiographs 3-5 weeks after the swelling begins. Leukocytosis or erythema does not accompany the swelling.
Acute chest syndrome
In young children, the acute chest syndrome consists of chest pain, fever, cough, tachypnea, leukocytosis, and pulmonary infiltrates in the upper lobes. Adults are usually afebrile and dyspneic with severe chest pain and multilobar and lower lobe disease.
Acute chest syndrome is a medical emergency and must be treated immediately. Patients are otherwise at risk for developing acute respiratory distress syndrome.
Acute chest syndrome probably begins with infarction of ribs, leading to chest splinting and atelectasis. Because the appearance of radiographic changes may be delayed, the diagnosis may not be recognized immediately.
In children, acute chest syndrome is usually due to infection. Other etiologies include pulmonary infarction and fat embolism resulting from bone marrow infarction. Recognition of the specific cause is less critical than the ability to assess the management and pace of the lung injury.
Central nervous system involvement
Central nervous system involvement is one of the most devastating aspects of SCD. It is most prevalent in childhood and adolescence. The most severe manifestation is stroke, resulting in varying degrees of neurological deficit. Stroke affects 30% of children and 11% of patients by 20 years. It is usually ischemic in children and hemorrhagic in adults. 
Hemiparesis is the usual presentation. Other deficits may be found, depending on the location of the infarct.
Convulsions are frequently associated with stroke. Convulsions occur as an isolated event but also appear in the setting of evolving acute chest syndrome, pain crisis, aplastic crisis, and priapism. Rapid and excessive blood transfusion to a hemoglobin level of greater than 12 g/dL increases blood viscosity and can lead to stroke.
Children with sickle cell disease may have various anatomic and physiologic abnormalities that involve the CNS even if they appear to be neurologically healthy. These silent brain infarcts occur in 17% of patients and may be associated with deterioration in cognitive function, with effects on learning and behavior; these infarcts may increase the potential risk for clinical and subclinical damage to the CNS.
Hemorrhagic stroke is often caused by rupture of aneurysms that might be a result of vascular injury and tend to occur later in life. Moya moya, a proliferation of small fragile vessels found in patients with stenotic lesions, can also lead to cerebral hemorrhage. Hemorrhagic stroke is associated with a mortality rate of more than 29%.
The heart is involved due to chronic anemia and microinfarcts. Hemolysis and blood transfusion lead to hemosiderin deposition in the myocardium. Both ventricles and the left atrium are all dilated.
A study by Nicholson et al also indicated that coronary artery dilation is common in children with SCD. The prevalence of coronary artery ectasia in patients with SCD was 17.7%, compared with 2.3% for the general population.  Furthermore, a systolic murmur is usually present, with wide radiation over the precordium.
Cholelithiasis is common in children with SCD, as chronic hemolysis with hyperbilirubinemia is associated with the formation of bile stones. Cholelithiasis may be asymptomatic or result in acute cholecystitis, requiring surgical intervention. The liver may also become involved. Cholecystitis or common bile duct obstruction can occur.
Consider cholecystitis in a child who presents with right upper quadrant pain, especially if associated with fatty food. Consider common bile duct blockage when a child presents with right upper quadrant pain and dramatically elevated conjugated hyperbilirubinemia.
The kidneys lose concentrating capacity. Isosthenuria results in a large loss of water, further contributing to dehydration in these patients. Renal failure may ensue, usually preceded by proteinuria. Nephrotic syndrome is uncommon but may occur.
Paraorbital facial infarction may result in ptosis. Retinal vascular changes also occur. A proliferative retinitis is common in Hb SC disease and may lead to loss of vision. See Ophthalmic Manifestations of Sickle Cell Anemia for a complete discussion of this topic.
Leg ulcers are a chronic painful problem. They result from minor injury to the area around the malleoli. Because of relatively poor circulation, compounded by sickling and microinfarcts, healing is delayed and infection becomes established.
Priapism, defined as a sustained, painful, and unwanted erection, is a well-recognized complication of SCD. Priapism tends to occur repeatedly. When it is prolonged, it may lead to impotence.
According to one study, the mean age at which priapism occurs is 12 years, and, by age 20 years, as many as 89% of males with sickle cell disease have experienced one or more episodes of priapism. Priapism can be classified as prolonged if it lasts for more than 3 hours or as stuttering if it lasts for more than a few minutes but less than 3 hours and resolves spontaneously. Stuttering episodes may recur or develop into more prolonged events.
Prolonged priapism is an emergency that requires urologic consultation. Recurrent episodes of priapism can result in fibrosis and impotence, even when adequate treatment is attempted.
Vascular occlusion can result in avascular necrosis (AVN) of the femoral or humeral head and subsequent infarction and collapse at either site. AVN of the femoral head presents a greater problem because of weight bearing. Patients with high baseline hemoglobin levels are at increased risk. Approximately 30% of all patients with SCD have hip pathology by age 30 years.
The natural history of symptomatic hip disease in patients with sickle cell disease who are treated conservatively varies with the patient's age. In skeletally immature patients aged 12 years or younger, treatment with analgesics, NSAIDs, and protected weight bearing usually results in healing and remodeling of the involved capital epiphysis, similar to that observed in Legg-Calve-Perthes disease. This approach results in preservation of the joint despite the persistence of deformity, such as coxa magna and coxa plana.
In contrast, conservative management of osteonecrosis usually fails in older adolescents and adults. Progressive flattening and collapse of the femoral head results in painful secondary degenerative arthritis.
Blood in the pulmonary circulation is deoxygenated, resulting in a high degree of polymer formation. The lungs develop areas of microinfarction and microthrombi that hinder the flow of blood. The resulting areas that lack oxygenation aggravate the sickling process. Pulmonary hypertension may develop. This may be due in part to the depletion of nitric oxide. Various studies have found that more than 40% of adults with SCD have pulmonary hypertension that worsens with age.
This is increasingly recognized as a serious complication of sickle cell disease, with an incidence as high as 31.8%. [28, 29] Familial clustering has also been recognized. Hemolysis, chronic hypoxia caused by sickle cell disease, and pulmonary disease (eg, recurrent acute chest syndrome, asthma, obstructive sleep apnea) are contributing factors.
Pulmonary hypertension is characterized by a regurgitant pulmonary (tricuspid) jet velocity of more than 2.5 m/s by echocardiography. Recently, there has been a lot of debate about the positive predictive value of measuring tricuspid regurgitant jet velocity. A recent study found that in a population of sickle cell patients, 25% had a tricuspid regurgitant jet of more than 2.5 m/s, but only 6% had actual pulmonary hypertension on right-sided heart catheterization.  It is associated with a high mortality rate in adult patients. Children with pulmonary hypertension have lower mortality, but the disease is associated with high morbidity.