Sickle Cell Disease (SCD)

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Practice Essentials

Sickle cell disease (SCD) and its variants are genetic disorders resulting from the presence of a mutated form of hemoglobin, hemoglobin S (HbS)[1, 2] (see the image below). The most common form of SCD in North America is homozygous HbS disease (HbSS), an autosomal recessive disorder most oftren found in people of African and Mediterranean ancestry (see Pathophysiology). SCD causes significant morbidity and mortality, although the severity, frequency of crisis, degree of anemia, and organ systems involved vary considerably from individual to individual.



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Signs and symptoms

Screening for HbS at birth is currently mandatory in the United States. For the first 6 months of life, infants are protected largely by elevated levels of fetal hemoglobin (HbF). SCD usually manifests early in childhood, in the following ways:

Approximately half the individuals with homozygous HbS disease experience vaso-occlusive crises. The frequency of crises is extremely variable. Some individuals have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or have none at all. Each individual typically has a consistent pattern for crisis frequency. Triggers of vaso-occlusive crisis include the following:

Many individuals with HbSS 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.

See Presentation for more detail.

Diagnosis

SCD is suggested by the typical clinical picture of chronic hemolytic anemia and vaso-occlusive crisis. Electrophoresis confirms the diagnosis with the presence of homozygous HbS and can also document other hemoglobinopathies (eg, HbSC, HbS-beta+ thalassemia).

Laboratory tests used in patients with SCD include the following:

Imaging studies

Imaging studies that aid in the diagnosis of sickle cell anemia in patients in whom the disease is suggested clinically include the following:

See Workup for more detail.

Management

The goals of treatment in SCD are symptom control and management of disease complications. Treatment strategies include the following 7 goals:

Pharmacotherapy

SCD may be treated with the following medications:

Gene therapy

The following two therapies involve editing of a patient's own hematopoietic stem cells:

Other therapy

Additional approaches to managing SCD include the following:

Combination pharmacotherapy and non-pharmacotherapy

See Treatment and Medication for more detail.

Background

Carriers of the sickle cell trait (ie, heterozygotes who carry one HbS allele and one normal adult hemoglobin [HbA] allele) have some resistance to the often-fatal malaria caused by Plasmodium falciparum. This property explains the distribution and persistence of this gene in the population in malaria-endemic areas.[4, 5, 6]

However, in areas such as the United States, where malaria is not a problem, the trait no longer provides a survival advantage. Instead, it poses the threat of SCD, which occurs in children of carriers who inherit the sickle cell gene from both parents (ie, HbSS).

Although carriers of sickle cell trait do not suffer from SCD, individuals with one copy of HbS and one copy of a gene that codes for another abnormal variant of hemoglobin, such as HbC or Hb beta-thalassemia, have a less severe form of the disease.

 

Genetics

SCD denotes all genotypes containing at least one sickle gene, in which HbS makes up at least half the hemoglobin present. Major sickle genotypes described so far include the following:

Sickle cell trait or the carrier state is the heterozygous form characterized by the presence of around 40% HbS, absence of anemia, inability to concentrate urine (isosthenuria), and hematuria. Under conditions leading to hypoxia, it may become a pathologic risk factor.

SCD is the most severe and most common form. Affected individuals present with a wide range of clinical problems that result from vascular obstruction and ischemia. Although the disease can be diagnosed at birth, clinical abnormalities usually do not occur before age 6 months, when functional asplenia develops. Functional asplenia results in susceptibility to overwhelming infection with encapsulated bacteria. Subsequently, other organs are damaged. Typical manifestations include recurrent pain and progressive incremental infarction.

Newborn screening for sickle hemoglobinopathies is mandated in 50 states. Therefore, most patients presenting to the emergency department have a known diagnosis.

Pathophysiology

HbS arises from a mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG. This causes coding of valine instead of glutamate in position 6 of the Hb beta chain. The resulting Hb has the physical property of forming polymers under deoxy conditions. It also exhibits changes in solubility and molecular stability. These properties are responsible for the profound clinical expressions of the sickling syndromes.

Under deoxy conditions, HbS undergoes marked decrease in solubility, increased viscosity, and polymer formation at concentrations exceeding 30 g/dL. It forms a gel-like substance containing Hb crystals called tactoids. The gel-like form of Hb is in equilibrium with its liquid-soluble form. A number of factors influence this equilibrium, including oxygen tension, concentration of Hb S, and the presence of other hemoglobins.

Oxygen tension is a factor in that polymer formation occurs only in the deoxy state. If oxygen is present, the liquid state prevails. Concentration of Hb S is a factor in that gelation of HbS occurs at concentrations greater than 20.8 g/dL (the normal cellular Hb concentration is 30 g/dL). The presence of other hemoglobins is a factor in that normal adult hemoglobin (HbA) and fetal hemoglobin (HbF) have an inhibitory effect on gelation.

These and other Hb interactions affect the severity of clinical syndromes. HbSS produces a more severe disease than sickle cell HbC (HbSC), HbSD, HbSO Arab, and Hb with one normal and one sickle allele (HbSA).

When red blood cells (RBCs) containing homozygous HbS are exposed to deoxy conditions, the sickling process begins. A slow and gradual polymer formation ensues. Electron microscopy reveals a parallel array of filaments. Repeated and prolonged sickling involves the membrane; the RBC assumes the characteristic sickled shape. (See image below.)



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After recurrent episodes of sickling, membrane damage occurs and the cells are no longer capable of resuming the biconcave shape upon reoxygenation. Thus, they become irreversibly sickled cells (ISCs). From 5-50% of RBCs permanently remain in the sickled shape.

When RBCs sickle, they gain Na+ and lose K+. Membrane permeability to Ca++ increases, possibly due, in part, to impairment in the Ca++ pump that depends on adenosine triphosphatase (ATPase). The intracellular Ca++ concentration rises to 4 times the reference level. The membrane becomes more rigid, possibly due to changes in cytoskeletal protein interactions; however, these changes are not found consistently. In addition, whether calcium is responsible for membrane rigidity is not clear.

Membrane vesicle formation occurs, and the lipid bilayer is perturbed. The outer leaflet has increased amounts of phosphatidyl ethanolamine and contains phosphatidylserine. The latter may play a role as a contributor to thrombosis, acting as a catalyst for plasma clotting factors. Membrane rigidity can be reversed in vitro by replacing HbS with HbA, suggesting that HbS interacts with the cell membrane.

Interactions with vascular endothelium

Complex multifactorial mechanisms involving endothelial dysfunction underlie the acute and chronic manifestations of SCD.[7] A current model proposes that vaso-occlusive crises in SCD result from adhesive interactions of sickle cell RBCs and leukocytes with the endothelium.[8]

In this model, the endothelium becomes activated by sickle cell RBCs, either directly, through adhesion molecules on the RBC surface, or indirectly through plasma proteins (eg, thrombospondin, von Willebrand factor) that act as a soluble bridge molecule. This leads, sequentiallly, to recruitment of adherent leukocytes, activation of recruited neutrophils and of other leukocytes (eg, monocytes or natural killer T cells), interactions of RBCs with adherent neutrophils, and clogging of the vessel by cell aggregates composed of RBCs, adherent leukocytes, and possibly platelets.[8]

Sickle cells express very late antigen–4 (VLA-4) on the surface. VLA-4 interacts with the endothelial cell adhesive molecule, vascular cell adhesive molecule–1 (VCAM-1). VCAM-1 is upregulated by hypoxia and inhibited by nitric oxide.

Hypoxia also decreases nitric oxide production, thereby adding to the adhesion of sickle cells to the vascular endothelium. Nitric oxide is a vasodilator. Free Hb is an avid scavenger of nitric oxide. Because of the continuing active hemolysis, there is free Hb in the plasma, and it scavenges nitric oxide, thus contributing to vasoconstriction.

In addition to leukocyte recruitment, inflammatory activation of endothelium may have an indispensable role in enhanced sickle RBC–endothelium interactions. Sickle RBC adhesion in postcapillary venules can cause increased microvascular transit times and initiate vaso-occlusion.

Several studies have shown involvement of an array of adhesion molecules expressed on sickle RBCs, including CD36, a-4-ß-1 integrin, intercellular cell adhesion molecule–4 (ICAM-4), and basal cell adhesion molecule (B-CAM).[9] Adhesion molecules (ie, P-selectin, VCAM-1, a-V-ß-3 integrin) are also expressed on activated endothelium. Finally, plasma factors and adhesive proteins (ie, thrombospondin [TSP], von Willebrand factor [vWf], laminin) play an important role in this interaction.

For example, the induction of VCAM-1 and P-selectin on activated endothelium is known to enhance sickle RBC interactions. In addition, a-V-ß-3 integrin is upregulated in activated endothelium in patients with sickle cell disease. a-V-ß-3 integrin binds to several adhesive proteins (TSP, vWf, red-cell ICAM-4, and, possibly, soluble laminin) involved in sickle RBC adhesion, and antibodies to this integrin dramatically inhibit sickle RBC adhesion.

In addition, under inflammatory conditions, increased leukocyte recruitment in combination with adhesion of sickle RBCs may further contribute to stasis.

Sickle RBCs adhere to endothelium because of increased stickiness. The endothelium participates in this process, as do neutrophils, which also express increased levels of adhesive molecules.

Deformable sickle cells express CD18 and adhere abnormally to endothelium up to 10 times more than normal cells, while ISCs do not. As paradoxical as it might seem, individuals who produce large numbers of ISCs have fewer vaso-occlusive crises than those with more deformable RBCs.

Other properties of sickle cells

Sickle RBCs also adhere to macrophages. This property may contribute to erythrophagocytosis and the hemolytic process.

The microvascular perfusion at the level of the pre-arterioles is influenced by RBCs containing Hb S polymers. This occurs at arterial oxygen saturation, before any morphologic change is apparent.

Hemolysis is a constant finding in sickle cell syndromes. Approximately one third of RBCs undergo intravascular hemolysis, possibly due to loss of membrane filaments during oxygenation and deoxygenation. The remainder hemolyze by erythrophagocytosis by macrophages. This process can be partially modified by Fc (crystallizable fragment) blockade, suggesting that the process can be mediated by immune mechanisms.

Sickle RBCs have increased immunoglobulin G (IgG) on the cell surface. Vaso-occlusive crisis is often triggered by infection. Levels of fibrinogen, fibronectin, and D-dimer are elevated in these patients. Plasma clotting factors likely participate in the microthrombi in the pre-arterioles.

Development of clinical disease

Although hematologic changes indicative of SCD are evident as early as the age of 10 weeks, symptoms usually do not develop until the age of 6-12 months because of high levels of circulating fetal hemoglobin. After infancy, erythrocytes of patients with SCD contain approximately 90% hemoglobin S (HbS), 2-10% hemoglobin F (HbF), and a normal amount of minor fraction of adult hemoglobin (HbA2). Adult hemoglobin (HbA), which usually gains prominence at the age of 3 months, is absent.

The physiologic changes in RBCs result in a disease with the following cardinal signs:

Silent cerebral infarcts are associated with cognitive impairment in SCD. These infarcts tend to be located in the deep white matter where cerebral blood flow is low.[10]  However, cognitive impairment, particularly slower processing speed, may occur independent of the presence of infarction and may worsen with age.[11]

Musculoskeletal manifestations

The skeletal manifestations of SCD result from changes in bone and bone marrow caused by chronic tissue hypoxia, which is exacerbated by episodic occlusion of the microcirculation by the abnormal sickle cells. The main processes that lead to bone and joint destruction in sickle cell disease are as follows:

When the rigid erythrocytes jam in the arterial and venous sinusoids of skeletal tissue, the result is intravascular thrombosis, which leads to infarction of bone and bone marrow. Repeated episodes of these crises eventually lead to irreversible bone infarcts and osteonecrosis, especially in weight-bearing areas. These areas of osteonecrosis (avascular necrosis/aseptic necrosis) become radiographically visible as sclerosis of bone with secondary reparative reaction and eventually result in degenerative bone and joint destruction.

Infarction tends to occur in the diaphyses of small tubular bones in children and in the metaphyses and subchondrium of long bones in adults. Because of the anatomic distribution of the blood vessels supplying the vertebrae, infarction affecting the central part of the vertebrae (fed by a spinal artery branch) results in the characteristic H vertebrae of SCD (steplike endplate depression; also known as the Reynold sign or codfish vertebrae). The outer portions of the plates are spared because of the numerous apophyseal arteries.

Osteonecrosis of the epiphysis of the femoral head is often bilateral and eventually progresses to collapse of the femoral heads. This same phenomenon is also seen in the humeral head, distal femur, and tibial condyles.

In summary, infarction of bone and bone marrow in patients with SCD can lead to the following changes (see images below):



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The shortened survival time of the erythrocytes in SCD (10-20 days) leads to a compensatory marrow hyperplasia throughout the skeleton. The bone marrow hyperplasia has the resultant effect of weakening the skeletal tissue by widening the medullary cavities, replacing trabecular bone and thinning cortices.

Deossification due to marrow hyperplasia can bring about the following changes in bone:

In SCD, the abnormal maturation of bone can result in a variety of growth effects, such as the following

Go to Skeletal Sickle Cell Anemia for complete information on this topic.

SCD can result in significant skeletal muscle remodeling and reduced muscle functional capacities, which contribute to exercise intolerance and poor quality of life.[12] In addition, changes in muscle and joints can result in altered posture and impaired balance control.[13]

Pulmonary hypertension

Blood entering 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.

 Additional factors contributing to pulmonary hypertension include the following:

Renal manifestations

Renal manifestations of SCD range from various functional abnormalities to gross anatomic alterations of the kidneys. See Renal Manifestations of Sickle Cell Disease for more information on this topic.

Splenic manifestations

The spleen enlarges in the latter part of the first year of life in children with SCD. Occasionally, the spleen undergoes a sudden very painful enlargement due to pooling of large numbers of sickled cells. This phenomenon is known as splenic sequestration crisis.

The spleen undergoes repeated infarction, aided by low pH and low oxygen tension in the sinusoids and splenic cords. Despite being enlarged, its function is impaired, as evidenced by its failure to take up technetium during nuclear scanning.

Over time, the spleen becomes fibrotic and shrinks. This is, in fact, an autosplenectomy. The nonfunctional spleen is a major contributor to the immune deficiency that exists in these individuals. Failure of opsonization and an inability to deal with infective encapsulated microorganisms, particularly Streptococcus pneumoniae, ensue, leading to an increased risk of sepsis in the future.

Chronic hemolytic anemiaand vasculopathy

The anemia in SCD is a form of hemolytic anemia, with red cell survival of around 10-20 days. Approximately one third of the hemolysis occurs intravascularly, releasing free hemoglobin (plasma free hemoglobin [PFH]) and arginase into plasma. PFH has been associated with endothelial injury including scavenging nitric oxide (NO), proinflammatory stress, and coagulopathy, resulting in vasomotor instability and proliferative vasculopathy.

A hallmark of this proliferative vasculopathy is the development of pulmonary hypertension in adulthood. Plasma arginase degrades arginine, the substrate for NO synthesis, thereby limiting the expected compensatory increase in NO production and resulting in generation of oxygen radicals. Plasma arginase is also associated with pulmonary hypertension and risk of early mortality.

Infection

Life-threatening bacterial infections are a major cause of morbidity and mortality in persons with SCD. Recurrent vaso-occlusion induces splenic infarctions and consequent autosplenectomy, predisposing to severe infections with encapsulated organisms (eg, Haemophilus influenzae, Streptococcus pneumoniae).

Lower serum immunoglobulin M (IgM) levels, impaired opsonization, and sluggish alternative complement pathway activation further increase susceptibility to other common infectious agents, including Mycoplasma pneumoniae, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli. Common infections include pneumonia, bronchitis, cholecystitis, pyelonephritis, cystitis, osteomyelitis, meningitis, and sepsis.

Pneumococcal sepsis continues to be a major cause of death in infants in some countries. Parvovirus B19 infection causes aplastic crises.

Etiology

SCD originated in West Africa, where it has the highest prevalence. It is also present to a lesser extent in India and the Mediterranean region. DNA polymorphism of the beta S gene suggests that it arose from five separate mutations: four in Africa and one in India and the Middle East. The most common of these is an allele found in Benin in West Africa. The other haplotypes are found in Senegal and Bantu, Africa, as well as in India and the Middle East.

The HbS gene, when present in homozygous form, is an undesirable mutation, so a selective advantage in the heterozygous form must account for its high prevalence and persistence. Malaria is possibly the selecting agent because a concordance exists between the prevalence of malaria and Hb S. Sickling might protect a person from malaria by either (1) accelerating sickling so that parasitized cells are removed or (2) making it more difficult for the parasite to metabolize or to enter the sickled cell. While children with sickle cell trait Hb SA seem to have a milder form of falciparum malaria, those with homozygous Hb S have a severe form that is associated with a very high mortality rate.

The sickling process that prompts a crisis may be precipitated by multiple factors. Local tissue hypoxia, dehydration secondary to a viral illness, or nausea and vomiting, all of which lead to hypertonicity of the plasma, may induce sickling. Any event that can lead to acidosis, such as infection or extreme dehydration, can cause sickling. More benign factors and environmental changes, such as fatigue, exposure to cold, and psychosocial stress, can elicit the sickling process. A specific cause is often not identified.

Vaso-occlusive crises are often precipitated by the following:

Data also suggest a role for exertional stress, particularly when compounded with heat and hypovolemia.

Aplastic crises are often preceded by the following:

Acute chest syndrome has been linked to the following:

Epidemiology

SCD is present mostly in people of sub-Saharan African descent. It also is found, with much less frequency, in eastern Mediterranean and Middle East populations. Individuals of Central African Republic descent are at an increased risk for overt kidney failure.

United States statistics

The sickle gene is present in approximately 8% of Black Americans. More than 2 million people in the United States, nearly all of them of African American ancestry, carry the sickle gene. The following statistics are available from the Centers for Disease Control and Prevention and the National Institutes of Health[15, 16] :

Risk of chronic kidney disease (CKD) is increased in SCD, with one study showing an almost 30% prevalence of baseline CKD in a cohort with mean age 31.6 years, increasing to 41.8% over 5 years. Among US sickle cell trait carriers of African or Hispanic ancestry, the risk of CKD is about 1.5-2–fold higher than in noncarriers.[17] The prevalence of sickle cell trait is twice as high in African Americans with end-stage kidney disease compared with the general African-American population (15% versus 7%, P < 0.001).[18]

Certain gene variants have been linked with increased risk of kidney disease in SCD. In particular, patients who carry APOL1 G1 and G2 risk variants (which confer protection against trypanosomiasis) have a 7-fold higher risk of CKD progression and a 7-30–fold greater risk of kidney failure.[19]

International statistics

In several parts of Africa, the prevalence of sickle cell trait (heterozygosity) is as high as 30%. Although the disease is most frequently found in sub-Saharan Africa, it is also found in some regions of Sicily, Greece, southern Turkey, and India, all of which have areas in which malaria is endemic.

The mutation that results in HbS is believed to have originated in several locations in Africa and India. Its prevalence varies but is high in these countries because of the survival advantage to heterozygotes in regions of endemic malaria. As a result of migration, both forced and voluntary, it is now found worldwide.

Sex distribution

The male-to-female ratio is 1:1. No sex predilection exists, since sickle cell anemia is not an X-linked disease.

Although no particular gender predilection has been shown in most series, analysis of the data from the US Renal Data System demonstrated marked male predominance of sickle cell nephropathy in affected patients.[20]

Clinical characteristics at different ages

Although hematologic changes indicative of the disorder are evident as early as the age of 10 weeks, clinical characteristics of SCD generally do not appear until the second half of the first year of life, when fetal Hb levels decline sufficiently for abnormalities caused by HbS to manifest. SCD then persists for the entire lifespan. After age 10 years, rates of painful crises decrease, but rates of complications increase. These include potentially fatal conditions such as kidney failure and pulmonary hypertension.[21, 22]

Prognosis

Therapeutic advances have markedly improved the prognosis for patients with SCD. In earlier reports, approximately 50% of patients did not survive beyond age 20 years, and most did not survive to age 50 years.[23] In the United States at present, nearly all children with SCD survive to adulthood; nevertheless, the average life expectancy in people with SCD remains 20 years below that of the general population.[2]

Morbidity is highly variable in patients with SCD, partly depending on the level of HbF. Nearly all individuals with the condition are affected to some degree and experience multiple organ system involvement. Patients with Hb SA are heterozygous carriers and essentially are asymptomatic.

Vaso-occlusive crisis and chronic pain are associated with considerable economic loss and disability. Repeated infarction of joints, bones, and growth plates leads to aseptic necrosis, especially in weightbearing areas such as the femur. This complication is associated with chronic pain and disability and may require changes in employment and lifestyle.

In addition, with longer survival comes an increased likelihood of other chronic complications. Pulmonary hypertension has emerging as an important complication and is one of the leading causes of morbidity and mortality in adults with SCD.[22]  The estimated glomerular filtration rate (eGFR) declines rapidly in over 30% of adults with SCD, and patients with SCD who develop kidney failure have higher mortality and are less likely to receive a kidney transplant, compared with patients without SCD.[21]

Prognostic factors

The following prognostic factors have been identified as predictors of an adverse outcome in SCD[24] :

Hand-foot syndrome, which affects children younger than 5 years, has proved a strong predictor of overall severity (ie, risk of stroke, high pain rate, recurrent acute chest syndrome, death). Children who have an episode before age 1 year are at high risk of a severe clinical course. The risk is further increased if the child's baseline hemoglobin level is less than 7 g/dL or the baseline white blood cell count is elevated.

Pregnancy

Pregnancy represents a special area of concern. The rate of fetal loss is high, due to spontaneous abortion. Placenta previa and abruption are common, due to hypoxia and placental infarction. Premature birth and low birth weight are common.

Mortality

Mortality in SCD is elevated, especially in the early childhood years. However, childhood deaths have decreased markedly since the introduction of widespread penicillin prophylaxis and pneumococcal vaccination. The leading cause of death is acute chest syndrome. Children have a higher incidence of acute chest syndrome but a lower mortality rate than adults; the overall death rate from acute chest syndrome is 1.8% and 4 times higher in adults than in children. Causes of death are pulmonary embolism and infection.

Older cohort studies examined the natural history of SCD. The Cooperative Study of Sickle Cell Disease (CSSCD), initiated in 1977, estimated that the median survival for individuals with HbSS was 48 years for women and 42 years for men.[25] In a United Kingdom study, published in 1994, of a neonatal cohort followed in a hospital- and community-based program that included modern therapy with transcranial Doppler ultrasonography screening, the estimated survival of HbSS children at 16 years was 99%.[25]  

In the Dallas Newborn Cohort, which was initiated in 1983, a 2010 report estimated that overall survival at 18 years of age was 93.9% in HbSS and HbSβ0 patients, and was 98.4% in HbSC and HbSβ+ patients. Acute chest syndrome and multiorgan failure syndrome had become the leading causes of death, surpassing bacterial sepsis.[23]

In Africa, available mortality data are sporadic and incomplete. Many children are not diagnosed, especially in rural areas, and death is often attributed to malaria or other comorbid conditions.

This significant increase in life expectancy and survival of patients with SCD has been achieved thanks to early detection and introduction of disease-modifying therapies. Neonatal screening; penicillin prophylaxis for children; pneumococcal immunization; red cell transfusion for selected patients (with chelation therapy); hydroxyurea therapy; parental and patient education; and, above all, treatment in comprehensive centers, have all likely contributed to this effect on longevity.

Patient Education

Patients must be educated about the nature of their disease. They must be able to recognize the earliest signs of a vaso-occlusive crisis and seek help, treat all febrile illness promptly, and identify environmental hazards that may precipitate a crisis. Reinforcement should occur incrementally during the course of ongoing care.

Patients or parents should be instructed on how to palpate the abdomen to detect splenic enlargement, and the importance of observation for pallor, jaundice, and fever. Teach the importance of seeking medical care in certain situations, including the following:

Patients should avoid the following:

Families should be educated on the importance of hydration, diet, outpatient medications, and immunization. Emphasize the importance of prophylactic penicillin. Patients on hydroxyurea must be educated on the importance of regular follow-up with blood counts.

Patients (including asymptomatic heterozygous carriers) should understand the genetic basis of the disease, be educated about prenatal diagnosis, and know that genetic counseling is available. Genetic testing can identify parents at risk for having a child with sickle cell disease.

If both parents have the sickle cell trait, the chance that a child will have sickle cell disease is 25%. If one parent is carrying the trait and the other has the disease, the odds increase to 50% that their child will inherit the disease. Screening and genetic counseling theoretically have the potential to drastically reduce the prevalence of SCD. This promise has not been realized. Some authors have recommended emergency department screening or referral for patients unaware of their status as a possible heterozygote.[26]

Families should be encouraged to contact community sickle cell agencies for follow-up information, new drug protocols, and psychosocial support. Families should also follow the advances of gene therapy, bone marrow transplantation, and the usage of cord blood stem cells.

For patient education information, see Sickle Cell Disease. In addition, the Centers for Disease Control and Prevention offers a range of patient-centered Communication Resources on Sickle Cell Disease.[27]

History

Sickle cell disease (SCD) usually manifests early in childhood. For the first 6 months of life, infants are protected largely by elevated levels of fetal hemoglobin (HbF); soon thereafter, the condition becomes evident.

The most common clinical manifestation of SCD is vaso-occlusive crisis, which occurs when the microcirculation is obstructed by sickled red blood cells (RBCs), causing ischemic injury to the organ supplied and resultant pain. Pain crises constitute the most distinguishing clinical feature of SCD and are the leading cause of emergency department visits and hospitalizations in this population.

Approximately half the individuals with homozygous hemoglobin S (HbS) disease experience vaso-occlusive crisis. The frequency of crisis is extremely variable. Some individuals have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or have 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.[28] With repeated episodes involving the spleen, the infarctions and resulting autosplenectomy predispose to life-threatening infection. 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).

Abdominal pain can be severe, resembling acute abdomen; it may be referred from other sites or reflect 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.

Severe deep pain in the extremities 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 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 decre ase due to environmental temperature change. Lowered body temperature likely leads to crises as the result of peripheral vasoconstriction. To ensure normal core temperature, patients should wear proper clothing and avoid exposure.

Chronic pain

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

Anemia is universally present. It is chronic and hemolytic in nature and usually very well tolerated. Not uncommonly, patients with an Hb level of 6-7 g/dL are able to participate in the activities of daily life in a normal fashion; however, their tolerance for exercise and exertion tends to be very limited. Although children exhibit few manifestations of anemia because they readily adjust by increasing heart rate and stroke volume, their decreased stamina may be noted on the playground or in physical education class.

Aplastic crisis

Aplastic crisis is a serious complication caused by infection with parvovirus B19 (B19V). This virus causes fifth disease, a normally benign childhood disorder involving fever, malaise, and a mild rash. B19V 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, because the half-life of normal erythrocytes in the circulation is 40-60 days. People with SCD, however, have a greatly shortened the RBC lifespan (usually 10-20 days), so a very rapid drop in hemoglobin occurs. The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.

Splenic sequestration

Splenic sequestration occurs with highest frequency during the first 5 years of life in children with HbSS, but 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 department. Treatment of the acute episode requires early recognition, careful monitoring, and aggressive transfusion support. Because these episodes tend to recur, many experts advocate long-term transfusion therapy in young children and splenectomy in older children.

Infection

As HbS replaces HbF in the early months of life, problems associated with sickling and RBC 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.[29]

Rhodes et al also 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 growth 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.[29]

Hand-foot syndrome

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, 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 neurologic deficit. Stroke affects 30% of children and 11% of patients by 20 years. It is usually ischemic in children and hemorrhagic in adults.[30]

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 SCD may have various anatomic and physiologic abnormalities that involve the CNS even if they appear to be neurologically healthy. 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%.

Cardiac involvement

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 become dilated.

A study by Nicholson et al also indicated that coronary artery dilatation 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.[31] Furthermore, a systolic murmur is usually present, with wide radiation over the precordium.

Cholelithiasis

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 it follows consumption of a high-fat meal. Consider common bile duct blockage when a child presents with right upper quadrant pain and dramatically elevated conjugated bilirubin.

Renal involvement

The kidneys lose concentrating capacity. Isosthenuria results in a large loss of water, further contributing to dehydration in these patients. Kidney failure may ensue, usually preceded by proteinuria. Nephrotic syndrome is uncommon but may occur.

Eye involvement

Paraorbital facial infarction may result in ptosis. Retinal vascular changes also occur. A proliferative retinitis is common in HbS–hemoglobin C disease and may lead to loss of vision. See Ophthalmic Manifestations of Sickle Cell Anemia for a complete discussion of this topic.

Leg ulcers

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 may become established.

Priapism

Priapism, defined as a sustained, painful, and unwanted erection, is a well-recognized complication of SCD. Priapism tends to occur repeatedly. 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 SCD have experienced one or more episodes of it. Almost three quarters of episodes in SCD are stuttering priapism, which lasts for more than a few minutes but less than 3 to 4 hours and resolves spontaneously. Stuttering episodes may recur or develop into more prolonged events.[32]

Major priapism (defined as an episode lasting more than 4 hours) is an emergency that requires urologic consultation, as it may lead to erectile dysfunction. Recurrent episodes of priapism can result in penile fibrosis and erectile dysfunction, even when adequate treatment is attempted.

Avascular necrosis

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. Progressive flattening and collapse of the femoral head results in painful secondary degenerative arthritis.

Pulmonary hypertension

Pulmonary hypertension is a serious complication of SCD, with an incidence as high as 31.8%, and the frequency increases with patient age.[33, 34] Familial clustering has also been recognized. Hemolysis, chronic hypoxia caused by SCD, and pulmonary disease (eg, recurrent acute chest syndrome, asthma, obstructive sleep apnea) are contributing factors.

Dyspnea on exertion and fatigue are the most common initial symptoms of pulmonary hypertension. As pulmonary hypertension progresses, patients may develop peripheral edema and exertional chest pain and syncope, due to right ventricular failure. Anorexia and/or abdominal pain and distention may also occur.

Physical Examination

Physical findings are not specific. Scleral icterus is present, and, upon ophthalmoscopic examination of the conjunctiva with the +40 lens, abnormal or corkscrew-shaped blood vessels may be seen. The mucous membranes are pale. A systolic murmur may be heard over the entire precordium.

Hypotension and tachycardia may be signs of septic shock or splenic sequestration crisis. With the severe anemia that accompanies aplastic crisis, patients may exhibit signs of high-output heart failure.

In one study of 38 asymptomatic children with SCD, investigators found that hypertension and abnormal blood pressure patterns were prevalent in children with SCD. They suggested using 24-hour ambulatory blood pressure monitoring (ABPM) to identify these conditions in young patients. In the study, 17 patients (43.6%) had ambulatory hypertension, whereas 4 (10.3%) had hypertension on the basis of their clinic blood pressure. Twenty-three patients (59%) had impaired systolic blood pressure dipping, 7 (18%) had impaired diastolic blood pressure dipping, and 5 (13%) had reversed dipping.[35]

Orthostasis suggests hypovolemia. Tachypnea suggests pneumonia, heart failure, or acute chest syndrome. Dyspnea suggests acute chest syndrome, pulmonary hypertension, and/or heart failure.

Fever suggests infection in children; however, it is less significant in adults unless it is a high-grade fever. Examine the head and neck for meningeal signs or possible source of infection (eg, otitis, sinusitis).

Auscultate the heart to search for signs of congestive heart failure. Auscultate the lungs for signs of pneumonia, heart failure, or acute chest syndrome (similar to pulmonary embolism). Palpate for tenderness (abdomen, extremities, back, chest, femoral head) and hepatosplenomegaly.

In childhood, splenomegaly may be present, although this is usually not present in adults due to autosplenectomy. Spleen size should be measured, and parents should be made aware of it. A tongue blade may be used as a "spleen stick" in a small child, with the upper end of the blade corresponding to the nipple in the midclavicular line and a marking made on the stick corresponding to the edge of the spleen.

Growth parameters show patients falling below the growth isobars. This usually occurs around the prepubertal age because of delayed puberty.

Observe for pallor, icterus, and erythema or edema of the extremities or joints. In adults, leg ulcers may be found over the malleoli. Perform a neurologic examination to search for focal neurologic deficits.

Ocular manifestations

Sickle cell vaso-occlusive events can affect every vascular bed in the eye, often with visually devastating consequences in advanced stages of the disease.

Anterior segment abnormalities include the following:

The abnormalities of the posterior segment can be divided into 6 categories, as follows[36, 37, 38, 39] :

Optic disc changes

Intravascular occlusions on the surface of the optic disc appear ophthalmoscopically as dark-red intravascular spots. These occlusions are transient and do not produce any clinical impairment.[40] These changes are most common in hemoglobin SS disease but can also occur in patients with hemoglobin SC and hemoglobin S.

Posterior retinal and macular vascular occlusions

Retinal artery occlusions are either central or branch. Peripapillary or macular arteriolar occlusions are rare. Retinal vein occlusions also are rare with SCD.

Chronic macular changes

Chronic macular vascular occlusions occur in SCD. These are manifested by microaneurysms resembling dots, hairpin-shaped vascular loops, and abnormal foveal avascular zone (FAZ).

Choroidal vascular occlusions

This is an extremely rare manifestation of SCD. Only 3 cases have been reported thus far in the literature.

Nonproliferative retinal changes

Nonproliferative or background sickle retinopathy includes the following manifestations:

Venous tortuosity probably is due to arteriovenous shunting from the retinal periphery. It can occur in many patients with hemoglobin SS and hemoglobin SC disease.

Salmon-patch hemorrhages are superficial intraretinal hemorrhages. They are usually seen in the mid periphery of the retina adjacent to a retinal arteriole.

The schisis cavity is a space caused by the disappearance of the intraretinal hemorrhage. Nonproliferative sickle retinopathy features iridescent spots and glistening refractive bodies in the schisis cavity.

The black sunburst consists of round chorioretinal scars usually located in the equatorial fundus. These lesions result from pigment accumulated around the vessels. They do not cause any visual symptoms.

Proliferative sickle retinopathy

Proliferative sickle retinopathy (PSR) is the most severe ocular change in SCD. This is a peripheral retinal change most frequent in patients with hemoglobin SC but also can be present in patients with hemoglobin S–thalassemia disease, homozygous hemoglobin SS, and hemoglobin AS and hemoglobin AC disease.[41, 42]

PSR is progressive. A desirable objective is to treat the neovascular tissue before a vitreous hemorrhage occurs.

Goldberg classified PSR into the following 5 stages:

  1. Peripheral arteriolar occlusions
  2. Arteriolar-venular anastomosis
  3. Neovascular proliferation
  4. Vitreous hemorrhage
  5. Retinal detachment

In stage I, the peripheral arteriolar vessels occlude, with anteriorly located avascular vessels evident. Early in the process, the occluded arterioles are dark-red lines, but eventually they turn into silver-wire–appearing vessels.

In stage II, peripheral arteriolar-venular anastomosis occurs as the eye adjusts to peripheral arteriolar occlusion, and blood is diverted from the occluded arterioles into the adjacent venules. Peripheral to these anastomoses, no perfusion is present.

In stage III, new vessel formation occurs at the junction of the vascular and avascular retina. These neovascular tufts resemble sea fans. Initially, the sea fans can be fed by a single arteriole and draining vessel.

Later, as the sea fan grows in size, it is difficult to distinguish the major feeding and draining vessels. The sea fans may acquire a glial and fibrotic tissue envelope. This envelope may pull on the vitreous. A full-thickness retinal break, which may lead to total rhegmatogenous retinal detachment, may occur.

For more information, see Ophthalmologic Manifestations of Sickle Cell Disease (SCD).

Meningitis

Meningitis is 200 times more common in children with HbSS than in the general population. Consider lumbar puncture in children with fever who appear toxic and in those with neurologic findings such as neck stiffness, positive Brudzinski or Kernig signs, or focal deficits. Meningeal signs are not reliable if the child is irritable and inconsolable.

Skeletal manifestations

The characteristic appearance in children with SCD includes frontal and parietal bossing and a prominent maxilla due to marrow hyperplasia expanding the bone. The extremities may appear proportionately longer than normal because there is often flattening of the vertebrae. Bone marrow expansion often causes maxillary hypertrophy with overbite; orthodontics consultations are recommended to prevent or correct this problem.

The physical findings of acute infarction include local effects from swelling of the affected bone, such as proptosis or ophthalmoplegia from orbital bone infarction. Also present is pain, swelling, and warmth of the involved extremity, such on the dorsa of the hands and feet in patients with dactylitis.

Sequelae of chronic infarction include structural and functional orthopedic abnormalities. Examples include an immobile or nonfunctional shoulder joint, abnormal hip growth and deformity, secondary osteoarthritis, shortened fingers and toes, and kyphoscoliosis.

Hand-foot syndrome

Hand-foot syndrome, or aseptic dactylitis, is a common presentation in children younger than 5 years. This condition is caused by infarction of bone marrow and cortical bone in the metacarpals, metatarsals, and proximal phalanges. Hand-foot syndrome is usually one of the earliest clinical manifestations of SCD.

Acute bone pain crisis

Acute bone pain crisis is caused by bone marrow ischemia or infarction. These crises usually start after age 2-3 years and occur as gnawing, progressive pain, most commonly in the humerus, tibia, and femur and less commonly in the facial bones. Periarticular pain and joint effusion, often associated with a sickle cell crisis, are considered a result of ischemia and infarction of the synovium and adjacent bone and bone marrow.

Patients with acute bone pain crisis usually present with fever, leukocytosis, and warmth and tenderness around the affected joints. This process tends to affect the knees and elbows, mimicking rheumatic fever and septic arthritis.

Osteonecrosis

In adolescence and adulthood, the most prominent complication is osteonecrosis of 1 or more epiphyses, usually of the femoral or humeral heads. Chronic pain is often associated with later stages of osteonecrosis, particularly in the femoral head. Pain due to avascular necrosis is most notable with weight bearing on the joint. Patients often have pain associated with functional limitation of the affected joint.

Osteomyelitis

Patients with sickle cell disease are prone to infection of the bone and bone marrow in areas of infarction and necrosis. Although Staphylococcus aureus is the most common cause of osteomyelitis in the general population, studies have shown that in patients with sickle cell disease, the relative incidence of Salmonella osteomyelitis is twice that of staphylococcal infection.

Nephrologic manifestations

See Nephrologic Manifestations of Sickle Cell Disease for more information on this topic.

Approach Considerations

Screening for hemoglobin S (HbS) at birth is currently mandatory in the United States. This allows institution of early treatment and control of sickle cell disease (SCD).

Prenatal diagnosis is also available. Prenatal testing must be accompanied with genetic and psychological counseling. Chorionic villus sampling can be performed at 8-12 weeks' gestation to obtain DNA. This procedure is low risk and sensitive. DNA from amniotic fluid cells can be examined at 16 weeks' gestation. Investigational attempts are ongoing to isolate cell-free fetal DNA from maternal blood for prenatal diagnosis.[43]

Children with SCD frequently have abnormal pulmonary function test (PFT) results. PFTs should be performed regularly in children with a history of recurrent acute chest episodes or low oxygen saturation. Because lung function declines with age, it is important to identify those who require close monitoring and treatment.

Noninvasive techniques can be used to identify asymptomatic brain disease in children with SCD. Transcranial near-infrared spectroscopy or cerebral oximetry is increasingly being used to screen for low cerebral venous oxygen saturation in these patients.

Measurement of cerebral blood flow velocity by transcranial Doppler ultrasound (TCD) has proved a good predictor of stroke risk. Although overall, children with SCD have a stroke risk of 1% per year, those with high cerebral blood flow velocities (time-averaged mean velocity > 200 cm/s) have stroke rates of greater than 10% a year. TCD surveillance remains the gold standard for stroke risk prediction in children with TCD; annual TCD screening from 2 to 16 years of age has been recommended.[44]

Consider lumbar puncture to exclude meningitis if the patient has altered mental status, meningeal signs, or fever. When focal neurologic signs are present or intracranial hemorrhage is suspected, consider computed tomography (CT) prior to lumbar puncture. Consider lumbar puncture if a subarachnoid hemorrhage is suspected and head CT is unrevealing.

Meningitis in children with SCD requires early recognition; aggressive diagnostic evaluation including complete blood cell count (CBC), urinalysis, chest radiographs, and blood cultures; prompt administration of intravenous antibiotics active against Streptococcus pneumoniae; and close observation.

In acute chest syndrome, arterial blood oxygen saturation commonly falls to a greater degree than that seen in simple pneumonia of the same magnitude. Patients with acute chest syndrome often have progressive pulmonary infiltrates despite treatment with antibiotics. Infection may set off a wave of local ischemia that produces focal sickling, deoxygenation, and additional sickling.

Newborn hemoglobinopathy screening

The introduction of newborn screening has been one of the greatest advances in the management of SCD. Currently, 50 states and the District of Columbia have mandatory universal programs for newborn screening for hemoglobin disorders. The United States Health Resources & Services Administration includes SCD as a core condition on its Recommended Uniform Screening Panel for newborns, along with sickle hemoglobin/hemoglobin C (HbSC) disease (a milder sickling disorder; see DDx/Diagnostic Considerations) and HbS/beta thalassemia.[45] If results are positive, a repeat hemoglobin electrophoresis should be performed for confirmation.

Hemoglobin electrophoresis

Fetal hemoglobin (HbF) is predominant in young infants. If eletrophoresis results show only HbF and HbS, the child has either SCD or HbS–β-0 thalassemia. If results show HbF, HbS, and HbC, the child has HbSC disease. If results show HbF, HbS, and adult hemoglobin (HbA), determine whether the child has received a transfusion. If the child has not received a transfusion and HbS is greater than HbA, HbS–beta+ thalassemia is most likely the diagnosis. If HbA is greater than HbS, the child is presumed to have the sickle trait. If HbA and HbS concentrations are close, conduct a study of the parents to determine if one of them has the thalassemia trait. Repeat Hb electrophoresis on the child after several months.

In children with normocytic hemolytic anemia, if results of electrophoresis show only HbS with an HbF concentration of less than 30%, the diagnosis is sickle cell anemia. If HbS and HbC are present in roughly equal amounts, the diagnosis is HbSC disease.

In children with microcytic hemolytic anemia, order quantitative HbA2 in addition to electrophoresis. HbA2 is found at low levels in normal human blood but tends to occur at higher levels in persons with beta thalassemia. If HbS is predominant, HbF is less than 30% and HbA2 is elevated, a diagnosis of HbS–beta-0 thalassemia can be inferred. If possible, perform a study of the parents. If their HbA2 levels are normal, consider the possibility of concomitant HbSS and iron deficiency in the child. If HbS is greater than HbA and HbA2 is elevated, a diagnosis of HbS–beta+ thalassemia can be inferred. If HbS and HbC are present in equal amounts, the diagnosis is HbSC disease.

Homozygous children will have 80-90% HbS, 2-20% HbF, and 2-4% HbA2. A carrier patient will have 35-40% HbS and 60-65% HbA). The test is not accurate in a patient who has recently received blood transfusions.

Baseline Blood Study Abnormalities

Typical baseline abnormalities in the patient with SCD are as follows:

Anemia may be complicated by megaloblastic changes secondary to folate deficiency. These result from increased RBC turnover and folate utilization. Periodic bouts of hyperhemolysis may occur.

Findings on peripheral blood smears are shown in the images below.



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Suggested Routine Clinical Laboratory Evaluations

Obtaining a series of baseline values on each patient to compare with results at times of acute illness is useful. The table below shows a typical schedule of routine clinical laboratory evaluations.

Table. Schedule of Laboratory Tests for Patients With Sickle Cell Disease



View Table

See Table

Laboratory Studies in the Ill Child

Standard laboratory tests cannot be used to distinguish pain crisis from the child's baseline condition. If laboratory tests are obtained, they should be interpreted in light of baseline values.

There is a near-ubiquitous recommendation to obtain "routine" CBC and reticulocyte counts in all SCD patients with an acute illness, including those presenting with apparently uncomplicated painful crisis. However, a meta-analysis found that "the routine use of complete blood count and reticulocyte count in sickle cell patients presenting with painful crisis does not alter management decisions. Selective use of these tests can be based on patient age, reported symptoms, vital signs, physical examination, and clinical judgment."[46]

Febrile children with SCD, especially those younger than 5 years, should have an aggressive investigation. The following are usually indicated:

Additional studies may be indicated, depending on the clinical presentation. Type and crossmatch blood in case transfusion is necessary.

On the CBC, anemia is often identified; however, a major drop in hemoglobin (ie, more than 2 g/dL) from previously recorded values indicates a hematologic crisis. Leukocytosis is expected in all patients with SCD, but a major elevation in the WBC count (ie, > 20,000/mm3) with a left shift raises suspicion for infection. Leukopenia is suggestive of parvovirus infection. The platelet count is typically elevated. If it is low, consider hypersplenism.

The reticulocyte percentage documents the briskness of the marrow response. If the reticulocyte count is normal, splenic sequestration is the probable cause. If the reticulocyte count is low, an aplastic crisis is the probable cause. If the reticulocyte count is high, hyperhemolytic crisis is the probable cause.

Additional Tests

Measurement of blood urea nitrogen (BUN), serum creatinine, and serum electrolytes can be useful. Assays of lactate dehydrogenase (LDH) and haptoglobin are useful but not required. Elevated levels of LDH support the diagnosis of hemolysis, with LDH being released from destroyed RBCs. Decreased levels of haptoglobin confirm the presence of hemolysis.

Arterial blood gases

Arterial blood gas measurements (ABGs) may be obtained in patients who are in respiratory distress, to supplement information provided by oxygen saturation monitoring. This will reflect the severity of pulmonary crisis. Serial ABGs are necessary to follow the response in pulmonary crisis.

Urinalysis

Perform urinalysis if the patient has fever or signs of urinary tract infection (UTI). Patients with SCD often have hematuria and isosthenuria. If signs of UTI are present, obtain a urine Gram stain and culture.

Sickling test

Because of mandated newborn screening for sickle hemoglobinopathies, the diagnosis of SCD is already established in most patients with the disease who present for emergency care. If the diagnosis of hemoglobinopathy is uncertain, a sickling test will establish the presence of the HbS gene. It will not, however, differentiate between individuals who are homozygous and those who are heterozygous.

Secretory phospholipase A2

Secretory phospholipase A2 (sPLA2), an enzyme that cleaves fatty acids from triglycerides, is an accurate marker for identifying present or incipient acute chest syndrome in young patients with sickle cell pain crisis. Its serum concentration increases before acute chest syndrome becomes clinically apparent, peaks at the clinical onset of acute chest syndrome, and declines during its resolution.

Radiography

Chest radiography should be performed in patients with respiratory symptoms. Radiographic findings may initially be normal in patients with acute chest syndrome, however.

Plain radiography of the extremities is useful in evaluating subacute and chronic infarction and in assessing the number and severity of prior episodes of infarction. Plain radiographs are also excellent for evaluating deformities and other complications of bone infarction. Osteonecrosis is visible on plain images only in the later stages, after the affected bone is substantially damaged.

In early dactylitis, plain radiographs will show only soft tissue swelling. Periosteal new-bone formation can be seen on radiographs 7-10 days later. Additionally, medullary expansion, cortical thinning, trabecular resorption, and resultant focal lucency may be seen 2-3 weeks after the onset of symptoms, but these findings usually resolve within weeks.

Radiography is not as sensitive as other studies for osteomyelitis in the first 1-2 weeks. However, plain images subsequently show cortical destruction, periosteal new bone, and (with time) sinus tracts and sequestra.

See Sickle Cell Anemia Skeletal Imaging for more information on imaging studies in SCD.

Magnetic Resonance Imaging

MRI can demonstrate avascular necrosis of the femoral and humeral heads and may distinguish between osteomyelitis and bony infarction in patients with bone pain. MRI is the best method for detecting early signs of osteonecrosis in patients with SCD and for identifying episodes of osteomyelitis.

MRI allows the early detection of changes in bone marrow due to acute and chronic bone marrow infarction, marrow hyperplasia, osteomyelitis, and osteonecrosis. Bone sequestra, sinus tracts, and subperiosteal abscesses are also clearly identified when present.

As with plain radiography, the sine qua non of diagnosing osteomyelitis on MRI is the identification of cortical destruction, for which MRI is exquisitely sensitive. MRI has a specificity of 98% and a sensitivity of 85-97% for identifying bone marrow infarcts.

Children with SCD who have "silent" cerebral infarcts revealed with MRI have a higher rate of abnormal neuropsychometric (NPM) findings and a higher risk of overt strokes. Stroke prevention strategies based on abnormal MRI results have not been tested, but children with abnormal MRI or NPM findings may be evaluated more frequently and carefully and considered for therapeutic measures.

According to the 2024 American Heart Association/American Stroke Association (AHA/ASA) primary stroke prevention guidelines, MRI and MRA findings for identifying children with SCD for primary stroke prevention have not been established. As such, these tests are not recommended in lieu of transcranial Doppler ultrasound for this purpose.[44]

Computed Tomography

Although CT is not an initial study in most patients, it may be useful to demonstrate subtle regions of osteonecrosis not apparent on plain radiographs in patients who are unable to have an MRI.[3]

CT scanning is performed to exclude renal medullary carcinoma in patients presenting with hematuria. CT is not the test of choice for evaluation of acute osteomyelitis.

Nuclear Medicine Scans

Nuclear medicine scanning can be used to detect early osteonecrosis. This modality also plays a role in detecting osteomyelitis.

Technetium-99m (99mTc) bone scanning can be used to detect early stages of osteonecrosis, and it is not as costly as MRI. Tc-99m bone marrow scans demonstrate areas of decreased activity in marrow infarction.[47]

Indium-111 (111In) white blood cell (WBC) scanning is useful for diagnosing osteomyelitis, which appears as an area of increased activity within bone. However, areas of marrow proliferation, which are common in patients with SCD, will also demonstrate increased activity on 111In WBC scans.

The combination of a bone scan and a bone marrow scan has been used to differentiate acute osteomyelitis from bone infarcts in patients with SCD, a useful capacity because the clinical presentation of these 2 conditions may be very similar. Acute osteomyelitis produces increased activity on the bone scan with normal activity on the bone marrow scan, while bone infarction produces decreased activity on the bone marrow scan with corresponding abnormal uptake on the bone scan.

Transcranial Doppler Ultrasonography

Transcranial Doppler ultrasonography (TCD) can identify children with SCD who are at high risk for stroke by documenting abnormally high blood flow velocity in the large arteries of the circle of Willis—the middle cerebral or internal carotid arteries. Velocity, which is usually increased by severe anemia, becomes elevated in a focal manner when stenosis reduces the arterial diameter. (MRI, with or without angiography, and NPM studies have also been used to detect these abnormalities.)

The upper limit of normal flow velocity varies with the method used. Values are lower for duplex Doppler (180 cm/s) than for non–duplex Doppler (200 cm/s).

Children with HbSS or HbS–β-0 thalassemia should be considered candidates for TCD screening. TCD screening should begin at age 2 years and continue to age 16 years.[44, 48] TCD is repeated annually if TCD results are normal or every 4 months if TCD results are marginal. Abnormal results should prompt a repeat TCD within 2-4 weeks.

According to the AHA/ASA primary prevention guidelines, while there is no established optimal screening interval, it is reasonable for younger children and those with borderline abnormal TCD velocities to be screened more often to detect incidence of high-risk TCD indications for intervention.[44]

The Stroke Prevention in Sickle Cell Anemia (STOP) trial demonstrated that a transfusion program in patients with abnormal TCD results normalizes the TCD results and reduces the risk of strokes.[49] A subsequent trial (STOPII) showed that when transfusions are discontinued, an unacceptably high percentage of patients show TCD reversion to high risk, and some suffer actual strokes.[50] On the other hand, TCD results normalize over time in some patients who do not receive transfusions.

Abdominal Ultrasonography

In patients with abdominal pain, abdominal ultrasonography can be used to rule out cholecystitis, cholelithiasis, or an ectopic pregnancy and to measure spleen and liver size. Abdominal ultrasonography can visualize biliary stones and detect signs of thickening gallbladder walls or ductal inflammation, indicating possible cholecystitis.

Ultrasonography of the kidneys is performed to exclude other causes of postrenal or obstructive uropathy (eg, nephrolithiasis) and may demonstrate papillary necrosis.

Echocardiography and Right Heart Catheterization

Echocardiography can be used to identify pulmonary hypertension, based on tricuspid regurgitant jet velocity, and should be performed in patients with SCD who have dyspnea on exertion or other suggestive symptoms. However, right heart catheterization is considered the gold standard for diagnosis of pulmonary hypertension and identification of its subtypes.[51]  A French study of 398 patients with SCD found that although 27% had tricuspid regurgitant jet velocity of at least 2.5 m/sec, right heart catheterization confirmed pulmonary hypertension in only 6%; echocardiography had a positive predictive value of 25% for identifying pulmonary hypertension.[52]

Patients with SCD may have an array of abnormalities of systolic and diastolic function. Left ventricular diastolic dysfunction (LVDD) is commonly reported in SCD patients and is linked to premature death. Echocardiography is the most widely used method to evaluate LV diastolic function, but the majority of patients with SCD-associated cardiomyopathy have high-output left heart failure, and the evaluation of diastolic function is more challenging in this setting.[53]

The diagnosis of high-output heart failure, especially when it is at an early stage, could be missed by echocardiography and/or right heart catheterization performed with the patient at rest. However, early-stage high-output heart failure can be identified on invasive low-level exercise testing that shows exercise-induced elevation of LV filling pressure despite a normal resting value. Consequently, Hammoudi et al recommend considering low-level invasive exercise testing in SCD patients with inconclusive measurements at rest when there is clinical suspicion of heart failure (specifically, symptoms with exercise and no history of congestion, or use of diuretics).[53]

Approach Considerations

The National Institutes of Health advises that optimal care for patients with sickle cell disease (SCD), including preventive care, is best achieved through treatment in clinics that specialize in the care of SCD. All patients with SCD should have a principal health care provider, who should either be a hematologist or be in frequent consultation with one.[54]

For sickle cell crisis, when the severity of the episode is assessable, self-treatment at home with bed rest, oral analgesia, and hydration is possible. Individuals with SCD often present to the emergency department (ED) after self-treatment fails.

Do not underestimate the patient's pain. United States and United Kingdom guidelines emphasize the need for prompt initiation of analgesia (eg, within 30 minutes of triage)  and rapid initiation of parenteral opioids for patients in severe pain.[55, 48] Early achievement of maximum analgesia has been shown to shorten hospital stays in pediatric patients with pain from SCD.[56]

Patients with SCD crisis who are being transported by emergency medical services (EMS) should receive supplemental oxygen and intravenous hydration en route to the hospital. Some areas have specialized facilities that offer emergency care of acute pain associated with SCD; many EDs have a standardized treatment plan in place. National Heart, Lung, and Blood Institute guidelines recommend using an individualized pain management plan (written by the patient’s SCD provider) or an SCD-specific plan whenever possible.[48]

Pain management should include four stages: assessment, treatment, reassessment, and adjustment. While considering the severity of pain and the patient's past response, follow consistent protocols to relieve the patient's pain.

Children younger than 12 months with a temperature of higher than 39°C who appear toxic, with an infiltrate on chest radiograph and an elevated white blood cell (WBC) count, should be admitted to the hospital. Consider outpatient treatment only if no high-risk features appear on history, physical examination, or laboratory evaluation; if the child is older than 12 months; and if outpatient follow-up care can be ensured.

The goals of treatment are symptom control and management of disease complications. Treatment strategies include the following seven goals:

An expert panel has released evidence-based guidelines for the treatment of SCD, including a strong recommendation that hydroxyurea and long-term, periodic blood transfusions should be used more often to treat patients. Other recommendations include the following[57] :

In 2017, the US Food & Drug Administration (FDA) approved L-glutamine oral powder (Endari) for patients age 5 years and older to reduce severe complications of SCD.[58]  L-glutamine increases the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes; this probably reduces oxidative stress, which contributes to the pathophysiology of SCD.[59]

Approval of L-glutamine was based on data from a randomized, placebo-controlled trial in which, over the course of 48 weeks, patients receiving L-glutamine had fewer hospital visits for pain crises that resulted in treatment with parenteral narcotics or ketorolac (median three vs four), fewer hospitalizations for sickle cell pain (median two vs three), and fewer days in hospital (median 6.5 vs 11). In addition, fewer patients taking L-glutamine had episodes of acute chest syndrome (8.6% vs 23.1%).[58]

Crizanlizumab, a P-selectin inhibitor, was approved by the FDA in 2019 to reduce the frequency of vaso-occlusive crisis (VOC) in adults with SCD. Binding P-selectin on the surface of activated endothelium and platelet cells blocks interactions between endothelial cells, platelets, red blood cells (RBCs), and leukocytes. Approval was based on the SUSTAIN clinical trial, in which crizanlizumab reduced the median annual rate of VOCs leading to health care visits by 45.3% compared with placebo (1.63 vs 2.98, P=0.010) in patients with or without hydroxyurea treatment.[60, 61]

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure SCD, but it has many risks, so the risk-to-benefit ratio must be assessed carefully. In addition, while HSCT from an HLA-matched sibling donor has a high success rate, especially in young recipients, only a minority of those with SCD have an HLA-matched sibling who does not have SCD, or a fully matched unrelated donor in the national pool.[62] Expansion of the donor pool to include partial-matched unrelated donors, half-matched (ie, haploidentical) donors, and partial-matched cord blood has ameliorated this shortage, however, and use of reduced-intensity or nonmyeloablative conditioning regimens in these cases has reduced the increased risk of graft-versus-host disease and graft failure otherwise seen with non–fully matched donors.[62, 63]

In 2023, the FDA approved the first 2 gene-editing therapies for severe SCD in patients aged 12 years and older.[64] One therapy, exagamglogene autotemcel (Casgevy), uses the gene-editing tool CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) to edit patient's hematopoietic stem cells to produce high levels of fetal hemoglobin (HbF) in RBCs. The other, lovotibeglogene autotemcel (Lyfgenia), uses a lentiviral vector to add functional copies of a modified form of the beta-globin gene, which codes for anti-sickling hemoglobin (HbAT87Q).

Hydroxyurea Therapy

Hydroxyurea (hydroxycarbamide) has an established role as a safe and effective treatment for SCD.[65] Hydroxyurea increases total and fetal hemoglobin in children with SCD.[66] The increase in fetal hemoglobin retards gelation and sickling of RBCs. Hydroxyurea also reduces levels of circulating leukocytes, which decreases the adherence of neutrophils to the vascular endothelium (see image below.) In turn, these effects reduce the incidence of pain episodes[66] and acute chest syndrome episodes.[54]



View Image

Hydroxyurea was first approved for use in adults with SCD, in 1998.[67] In 2008, a National Institutes of Health Consensus Development Conference concluded that “strong evidence supports the efficacy of hydroxyurea in adults to decrease severe painful episodes, hospitalizations, number of blood transfusions, and the acute chest syndrome.”[54]

Other studies demonstrated the benefit of hydroxyurea in children. In a meta-analysis of the literature through 2007, Strouse et al studied the efficacy, effectiveness, and toxicity of hydroxyurea in children with SCD and found that fetal hemoglobin levels increased from 5-10% to 15-20%; hemoglobin concentration increased modestly (approximately 1 g/L) but significantly; hospitalizations decreased by 56-87%; and the frequency of pain crisis decreased.[68]

A phase III multicenter international clinical trial in 38 children with SCD found that hydroxyurea treatment can lower elevated cerebral blood flow velocities, which have been linked to stroke risk. After a mean of 10.1 months, transcranial Doppler (TCD) ultrasound showed that mean velocity had decreased 15.5 cm/sec in patients receiving hydroxyurea but had increased 10.2 cm/sec in those receiving observation only (P=0.02). Post hoc analysis according to treatment received showed that after 15 months, conversion from conditional to abnormal cerebral blood flow velocities occurred in 50% of patients in the observation group but none of those in the hydroxyurea group.[69]  

In 2017, the FDA approved Siklos (hydroxyurea) to reduce the frequency of painful crises and the need for blood transfusions in children 2 years of age and older and adolescents with SCD who have recurrent moderate to severe painful crises. The approval was based on data from the ESCORT (European Sickle Cell Disease Cohort), an open-label single-arm trial in 405 pediatric patients. After 12 months of treatment, all patients had increased fetal hemoglobin levels and a reduced percentage of patients had experienced at least one vaso-occlusive episode, one episode of acute chest syndrome, one hospitalization due to SCD, or one blood transfusion.[70]  

An oral hydroxyurea solution (Xromi) was approved in 2024 for use in pediatric patients 6 months of age and older.[71]

Hydroxyurea is usually prescribed by a hematologist, using rigorous selection criteria. Indications for hydroxyurea include the following:

Patients receiving hydroxyurea require frequent blood testing and monitoring, with special attention to development of leukopenia and/or thrombocytopenia. A good continuous doctor-patient relationship and rapport must exist to ensure that potential toxicity is identified at its onset.

Hydroxyurea is a potentially leukemogenic and carcinogenic agent. Children studied by a cooperative group remained on hydroxyurea for more than a year with only minor adverse effects, but potential complications from long-term use are not yet known.

For patients who fail to respond to hydroxyurea, repeated transfusions for a limited period may be an option. Management of constant pain is extremely difficult, and expert advice should be obtained.

Transfusion

Blood transfusions are not needed for the usual anemia or episodes of pain associated with SCD. Urgent replacement of blood is often required for sudden, severe anemia due to acute splenic sequestration, parvovirus B19 infection, or hyperhemolytic crises. Transfusions are helpful in acute chest syndrome, perioperatively, and during pregnancy. Acute red cell exchange transfusion is indicated in the following situations:

Regular blood transfusions are used for primary and secondary stroke prevention in children with SCD. See Treatment/Stroke Prevention, below. In addition, Hilliard et al reported that in pediatric patients with frequent pain episodes despite being prescribed hydroxyurea, 1 year of red blood cell transfusion therapy significantly reduced the number of total emergency department visits for pain (6 vs 2.5 visits/year, P = 0.005), mean hospitalizations for pain (3.4 vs 0.9 pain admissions/year), and mean hospital days per year for pain crisis (23.5 vs 4.5, P = 0.0001).[72]

Transfusion-related complications include alloimmunization, infection, and iron overload. Treatment of iron overload is becoming easier with the new oral chelators.

Alloimmunization is a common problem that arises from the differences in certain minor red cell antigens in the predominantly Black patient population and the mostly White blood donors. Matching for C, E, Kell, JKB (Kidd), and Fya (Duffy) antigens can significantly reduce alloimmunization.

Transfusion and surgery

Intraoperative and postoperative complications may result from hypoxia, dehydration, or hypothermia that occurs during or after a surgical procedure. More complex procedures or longer duration of anesthesia are more likely to lead to acute chest syndrome or other complications. Providing preoperative transfusion may decrease the risk.

A Cochrane review found very low quality evidence that preoperative transfusions may prevent postoperative acute chest syndrome in HbSS patients. The reviewers found insufficient evidence to determine whether simple transfusions (increasing hemoglobin to 10 g/dL) or aggressive transfusions (decreasing sickle hemoglobin to less than 30%) were more effective.[73]

In general, raising the hemoglobin concentration to between 10 g/dL and 12 g/dL provides the patient with approximately 20-30% hemoglobin A. The presence of this fraction of normal hemoglobin may provide some protection from complications. Many anesthesiologists require a hemoglobin concentration of more than 10 g/dL prior to the procedure.[74]  However, a randomized trial that compared preoperative simple transfusion and no transfusion in 138 pediatric patients with SCD who underwent adenotonsillectomy concluded that patients whose hemoglobin level is above 7.5 g/dL do not need transfusions for this procedure.[75]

When the patient’ baseline hemoglobin level is above 10 g/dL, the approach is less certain. If the complexity of the surgical procedure or the duration and risk of anesthesia is considerable, exchange transfusion or erythrocytapheresis can reduce the hemoglobin S concentration to 30%, while keeping the total hemoglobin level below 12 g/dL.

Individualize all other situations based on the complexity of the procedure and underlying medical condition.

Treatment of iron overload

With continued transfusion, iron overload inevitably develops and can result in heart and liver failure and multiple other complications. Serum ferritin is inaccurate for estimating the iron burden; liver iron evaluation, or perhaps MRI, is a more accurate means of determining tissue iron concentration and the response to chelation.

Three agents are available for iron chelation: deferoxamine, deferasirox, and deferiprone.

Deferoxamine is an efficient iron chelator. However, its use requires prolonged intravenous or subcutaneous infusions for 5-7 days a week, and this demanding regimen . Although effective, there are significant challenges associated with its use that can result in noncompliance.[76]

Deferiprone and deferasirox, oral iron chelators, are effective for iron overload treatment and have differences (eg, different pharmacokinetics and adverse effect profiles). Deferasirox has a capacity similar to  deferoxamine in chelating iron, but it is administered orally. Renal toxicity might be a limiting factor in its use, but it is generally safe. Deferiprone does not seem to be as effective as the other 2 agents and is considered a second-line therapy. Unlike deferasirox and deferoxamine, it selectively removes cardiac iron; is most effective when used in combination with deferoxamine or deferasirox.

Erythrocytapheresis

Erythrocytapheresis is an automated red cell exchange procedure that removes blood that contains HbS from the patient while simultaneously replacing that same volume with packed red cells free of HbS.[77] Transfusion usually consists of sickle-negative, leuko-reduced, and phenotypically matched blood for red cell antigens C, E, K, Fy, and Jkb.

The procedure is performed on a blood cell processor (pheresis machine) with a continuous-flow system that maintains an isovolemic condition. RBCs are removed and simultaneously replaced, with normal saline followed by transfused packed RBCs along with the patient's plasma. The net RBC mass/kg is calculated for each procedure based on the measured hematocrit of the transfused and removed blood and the total RBC volume transfused.

Erythrocytapheresis thus has the advantage of controlling iron accumulation in patients with SCD who undergo long-term transfusion, as well as the ability to achieve adequate Hb and HbS concentrations without exceeding the normal concentration. This precision is achieved because, before the start of the transfusion, the computer in the pheresis machine calculates the expected amount of packed RBCs required to obtain a specific posttransfusion hemoglobin level, using various physiologic parameters (eg, height, weight, Hb level). Further, erythrocytapheresis requires less time than simple transfusion of similar blood volumes.

Although erythrocytapheresis is more expensive than simple transfusion, the additional costs associated with simple transfusions (ie, those of chelation and organ damage due to iron overload) make erythrocytapheresis more cost-effective than simple transfusion programs. Central venous access devices can safely be used for long-term erythrocytapheresis in patients with SCD, with a low rate of complications.

Management of Ophthalmic Manifestations

Ocular treatment is directed toward preventing vision loss from vitreous hemorrhage, retinal detachment, and epiretinal membranes. Medical ocular management may include topical medications; however, carbonic anhydrase inhibitors are contraindicated because they may cause further sickling and worsen the outflow obstruction. If the intraocular pressure remains elevated after a judicious trial of medical therapy, surgical intervention with an anterior chamber lavage is indicated.

The goal of treatment is to eliminate existing neovascularization and thus to eliminate the sequelae of proliferative sickle retinopathy (PSR). Modalities to treat PSR include diathermy, cryotherapy, xenon arc photocoagulation, and argon laser photocoagulation.

Diathermy is used infrequently because of the high incidence of complications accompanying this procedure. Cryotherapy, both single freeze-thaw and triple freeze-thaw, has been used to treat PSR. Triple freeze-thaw has a high complication rate. Single freeze-thaw is used to treat peripheral vitreous hemorrhage in the presence of vitreous hemorrhage. Xenon arc and argon laser photocoagulation have been used to treat either the peripheral neovascularization or the feeder vessels to the neovascularization.

Photocoagulation applied through various techniques (eg, feeder vessel, focal scatter, peripheral circumferential scatter) is effective for treating proliferative sickle retinopathy and reducing the risk of vision loss. Because of potential complications from photocoagulation and the tendency for regression, patients older than 40 years probably do not require treatment. Complications of photocoagulation include choroidal neovascularization, retinal breaks, and peripheral choroidal ischemia.

Surgical treatment

Surgical procedures may be performed to treat retinal detachments, nonclearing vitreous hemorrhage, and epiretinal membranes. Early studies reported a high incidence of anterior segment ischemia in patients who undergo scleral buckling surgery for PSR and recommended preoperative exchange transfusions or erythropheresis. However, a more recent review of vitreoretinal surgery for sickle cell retinopathy concluded that with modern surgical techniques, preoperative exchange transfusions appear to be unnecessary.[78]

Perioperative measures to reduce the incidence of anterior segment ischemia include the following:

Anterior segment ischemia after surgery is an emergency. Options for oxygenating the anterior segment include hyperbaric oxygen therapy, continuous supplemental oxygen therapy, and transcorneal oxygen with goggles, but the prognosis is notoriously poor.[79]

Elevated intraocular pressure

Blood in the anterior chamber in patients with SCD is a medical emergency. A sickle screen is warranted for every Black patient who has an unexplained hyphema.[80, 81] The environment of the anterior chamber promotes sickle hemoglobin polymerization, which can result in elevated intraocular pressure due to blockage of the trabecular meshwork.

Because patients with SCD are particularly prone to central retinal artery occlusion and optic atrophy, even with mildly elevated intraocular pressures, close monitoring of intraocular pressure is mandatory. The pressure should not be allowed to exceed 25 mm Hg for longer than 24 hours.

Vaso-Occlusive Crisis Management

Vaso-occlusive crisis is treated with vigorous intravenous hydration and analgesics. Intravenous fluids should be of sufficient quantity to correct dehydration and to replace continuing loss, both insensible and due to fever. Normal saline and 5% dextrose in saline may be used. Treatment must be in an inpatient setting.

A retrospective chart review from a tertiary center identified characteristics associated with admission and longer length of stay in children who presented to the ED in vaso-occlusive crisis.[82] Predictors of admission included the following:

Factors associated with longer length of hospital stay included the following:

The authors conclude that these characteristics can help healthcare providers predict and plan admission and management of children with SCD.

The randomized BABY HUG study demonstrated that hydroxyurea (hydroxycarbamide) significantly reduces the incidence of vaso-occlusive crisis and dactylitis in very young children.[83] The primary toxicity observed was neutropenia. Further study is needed to evaluate long-term treatment effects on growth and development as well as kidney, lung, and CNS function. A randomized, placebo-controlled trial in adults did not demonstrate a significant improvement in the time to resolution of vaso-occlusive crisis.[84]

Crizanlizumab, a P-selectin inhibitor, was approved by the FDA in 2019 to reduce frequency of vaso-occlusive crisis in adults with SCD. Binding P-selectin on the surface of activated endothelium and platelet cells blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes. Approval was based on the SUSTAIN clinical trial, which showed that crizanlizumab reduced the median annual rate of vaso-occlusive crises leading to health care visits by 45.3% compared with placebo (1.63 vs 2.98, P=0.010) in patients with or without hydroxyurea.[60, 61]  

Control of Acute Pain

Control of acute pain is best achieved with opioids. Morphine is the drug of choice.

The United Kingdom's National Institute for Health and Care Excellence (NICE) guidelines on sickle cell acute painful episodes include the following recommendations[55] :

In the United States, 2014 recommendations from an expert panel convened by the National Heart, Lung, and Blood Institute for treatment of pain in patients experiencing a vaso-occlusive crisis included the following[48] :

Morphine dosing has to be individualized. The drug should be given intravenously, hourly at first. Once the effective dose is established, it should be administered every 3 hours. After 24-48 hours, as pain is controlled, equivalent doses of sustained-release oral morphine should be given.

When marked improvement occurs, the patient may be discharged home on sustained-release oral morphine. The dose is then reduced gradually over several days. Morphine elixir can be used to control breakthrough pain.

Treatment of Acute Chest Syndrome

British Committee for Standards in Haematology (BCSH) 2015 guidelines for treatment of acute chest syndrome (ACS) recommend use of the following measures[85] :

Simple transfusion administered early may halt progressive respiratory deterioration, preventing complications such as increasing tachypnea and need for supplemental oxygen. If necessary, an exchange transfusion is performed by removing 1 unit of blood and transfusing 1 unit. The aim is to reduce the concentration of HbS to less than 30%. This can be achieved by repeating the exchange transfusion or by using continuous-flow pheresis. Adults, in general, need a higher rate of transfusions and longer hospitalization than children.

Empiric antibiotics should be initiated and given intravenously, after obtaining samples for appropriate cultures. The antibiotics chosen should be active against Streptococcus pneumoniae, Mycoplasma pneumoniae, and Chlamydia; for the latter two, a macrolide may be appropriate. Antibiotic changes are based on response to therapy and results of cultures and sensitivities.

Analgesics are required. Agents that do not suppress respiration, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), can be used. Narcotic agents may be used judiciously for more severe pain. Other supportive measures include careful hydration. Volume overload must be avoided, as it may contribute to pulmonary infiltrates and exacerbate hypoxia.

Elevated levels of serum phospholipase A2, an enzyme involved in the breakdown of phospholipids, have been found to be a promising biomarker for predicting ACS in patients with SCD. Although it has the potential to guide risk stratification and early intervention strategies, phospholipase A2 assay protocols have not yet been standardized and further research is warranted.[86]

For episodes of severe hypoxia, rapid progression, diffuse pulmonary involvement, and failure to improve, erythrocytapheresis is indicated. patients in severe hypoxia or respiratory distress require intensive care, as respiratory decompensation can rapidly require mechanical ventilation. Treatment should also include oxygen therapy, with close monitoring for hypoxemia with continuous pulse oximetry or frequent assessment of blood gases.

Administer oxygen if saturation is less than 94%. If that level cannot be maintained at a fraction of inspired oxygen (FiO2) of 0.4, provide simple transfusion (avoid raising the hematocrit above 36%). If no improvement is seen, reduce the HbS level to 30% with erythrocytapheresis or exchange transfusion. The process can rapidly progress to respiratory failure. Ventilatory assistance may be required.

The role of corticosteroids in nonasthmatic patients with ACS remains a topic of clinical research. Both significant benefits and serious adverse effects have been reported with their use.[87]

Some patients have repeated severe episodes of ACS. Regular transfusion reduces the recurrence and hydroxyurea reduces the rate of acute chest syndrome by about half.

Control of Chronic Pain

Chronic pain is managed with long-acting oral morphine preparations, acetaminophen, and NSAIDs. NSAIDs are particularly effective in reducing bone pain.

Many patients may require breakthrough oral opiates as well. The weak opiates (eg, codeine and hydrocodone) are commonly used first. Sustained-release long-acting oral morphine is reserved for more severe cases. Hydromorphone may also be used but is considerably more expensive than morphine. Meperidine is not recommended for pain treatment because of CNS toxicity related to its metabolite, normeperidone.

The addition of tricyclic antidepressants may permit dose reduction or withdrawal of opiates by interfering with pain perception. In addition, many patients with chronic pain are depressed, and lifting the depression has a salutary effect on the pain as it elevates the pain threshold.

Hydroxyurea may decrease the frequency and severity of pain episodes.[66] The safety of long-term hydroxyurea use in children remains uncertain, however (see Hydroxyurea Therapy, above).

Nonpharmacologic approaches to pain management may have a substantial impact. These include physical therapy, heat and cold application, acupuncture and acupressure, hypnosis, and transcutaneous electric nerve stimulation (TENS). Support groups are also useful.

Inform parents and children that recurring pain is expected. Assist them in developing an approach that allows continued normal activities even with pain. Instruct parents and family members to provide sympathy but to do so with encouragement and support, so as to help the child accept the pain rather than to submit to it.

Parents and family members are encouraged to provide local measures and over-the-counter drugs for mild pain. Physicians suggest keeping on hand a small supply of a mild narcotic analgesic for pain that does not respond to lesser measures.

Pain that does not respond to the above measures almost always requires hospitalization. In such cases, treat with morphine or other major narcotic analgesics in doses sufficient to provide a reasonable degree of relief. Continuous infused morphine is most effective. Attempting to resolve pain by providing 1-2 doses of parenteral narcotics in the emergency department is inadvisable, since moderately severe sickle cell pain is expected to persist for several days.

Choose a dosage to provide reasonable pain relief with precautions to avoid oversedation and respiratory depression. A starting dose of morphine (0.05-0.01 mg/kg/h) is suggested following a bolus dose to provide a reasonable degree of pain relief. Adjust according to patient response. Patient-controlled analgesia with self-administered bolus morphine and low-dose continuous intravenous infusion is effective and well accepted by patients.

Fentanyl and nalbuphine have also been used as continuous IV infusion. Ketorolac can be given along with opioid analgesics and typically reduces the opioid dose required to achieve the desired effect.

Opioid dependence may occur. It can result if a patient uses narcotics for euphoriant or stimulant effects rather than analgesia. Narcotic addiction in people with SCD is no more common than in the general population and may be minimized with a carefully designed analgesic regimen and maintenance of proper pain control.

When drug addiction with substance abuse is present, however, difficult management problems ensue. These require a team approach involving counselors, substance abuse specialists, hematologists, and pain management experts.

Chronic opioid therapy

Patients with SCD who have emerging and/or recently developed chronic pain that is refractory to multiple other treatment modalities may benefit from regularly scheduled administration of opioids; this strategy is termed chronic opioid therapy (COT). According to the American Society of Hematology, COT should be considered after risk stratification using a validated tool, based on the following[88] :

As the benefit of COT in SCD is largely unknown and the harms have been established via indirect evidence, ASH advises that shared decision-making is essential before initiating a trial of COT. The decision-making process should include discussion of failure criteria for the trial, along with development of a plan for opioid cessation and alternative treatments to try in the case of failure.

ASH remarks regarding COT include the following:

Adverse events that have been noted in non-SCD patient populations are dose dependent and include increased risk of the following:

Management of Chronic Anemia

Anemia is usually well tolerated. However, because of the high RBC turnover, folate stores are often depleted. Althogh no scientific evidence shows that patients develop folate deficiency, folic acid (1 mg/d) is commonly prescribed for adults to prevent development of megaloblastic anemia due to increased folate requirements caused by hemolysis. Folic acid supplementation may raise the Hb level and support a healthy reticulocyte response.

Usual folic acid doses are age based, as follows:

Women who are menstruating should be checked for coexisting iron deficiency and, if it is found, given iron supplements. An adequate overall diet is essential.

Blood transfusion is indicated only in specific situations. These include acute chest syndrome, stroke, abnormal findings on transcranial Doppler in children (for stroke prevention), pregnancy, and general anesthesia. The aim is to decrease the concentration of HbS to 30% or less. Transfusion may also be required during aplastic crisis.

For anemic crisis with splenic sequestration, give early red cell transfusions because the process can rapidly progress to shock. Do not allow hemoglobin levels to rise to more than 10 g/dL, since the spleen may disgorge trapped cells, which can create a relative polycythemia and increased blood viscosity.

Children who experience a single sequestration event frequently have recurrences. Surgical splenectomy or a short-term transfusion regimen has been suggested for this complication.

Transfusion is required in an aplastic crisis if the anemia is symptomatic (eg, dyspnea, signs of hypovolemia). Because aplastic crises are self-limited, transfusion may be avoided if the child is stable and can be adequately observed. If hospitalization is required, use precautions to prevent transmission of parvoviral infection to patients who are immunosuppressed or caretakers who are pregnant.

Voxelotor, a hemoglobin S (HbS) polymerization inhibitor that increases the affinity of Hb for oxygen, was approved by the FDA in 2019 for treatment of SCD. However, in September 2024 the manufacturer voluntarily withdrew voxelotor from all markets, citing an imbalance in vaso-occlusive crises and fatal events that outweighs the benefits of the drug for SCD.[89]

Prevention and Treatment of Infections

Neonatal screening, penicillin prophylaxis, appropriate immunizations (particularly against Streptococcus pneumoniae), and parental teaching have remarkably minimized infection-related morbidity and mortality. Prevention of infection also improves chances of survival in SCD. In the adult patient, all infections must be treated promptly with broad-spectrum antibiotics. Once a causative organism is identified, therapy is tailored according to its antibiotic sensitivity.

Antibiotics are indicated when an infection is suspected, when body temperature is higher than 38° C, or when a patient has localized bone tenderness. The 2003 BCSH guidelines also recommend the use of broad-spectrum antibiotics in the patient who is systemically ill or has chest involvement.[55] Fever in children is strongly suggestive of infection. Signs of infection have proved to be more accurate in children than in adults.

Recommended parenteral antibiotics include cephalosporins (eg, ceftriaxone, cefuroxime) and macrolides for acute chest syndrome. If the patient is discharged home, oral antibiotics (eg, amoxicillin-clavulanic acid, clarithromycin, cefixime) are useful in selected cases. If the patient has localized bone tenderness, the antibiotic selected should provide coverage for Salmonella typhimurium and Staphylococcus aureus.

Penicillin prophylaxis significantly reduces the incidence of infection with encapsulated organisms—in particular, S pneumoniae —and may decrease the mortality rate. Begin at age 2 months with 125 mg bid of penicillin V or G; at 3 years, increase the dose to 250 mg bid. Prophylaxis should continue until age 5 years or the early teens. Recent trials have shown that the susceptibility for septicemia with encapsulated organisms persists well into adulthood, and the benefit of continuing penicillin prophylaxis is now the subject of clinical research. If the patient is allergic to penicillin, erythromycin may be substituted.

As with all long-term medication regimens, maintaining compliance can be difficult. Therefore, remind parents of the importance of prophylaxis at each visit.

The Advisory Committee on Immunization Practices (ACIP) currently recommends the use of 20-valent pneumococcal conjugate vaccine (PCV20) for pediatric patients 2-18 years of age with SCD. For children who previously received the 13- or 15-valent pneumococcal vaccine the ACIP recommends either a dose of PCV20 or one or more doses of the 23-valent pneumococcal polysaccharide vaccine (PPSV23)[90]

In addition to receiving pneumococcal vaccination, pediatric patients with SCD should follow the immunization schedule currently recommended by the American Academy of Pediatrics, including meningococcal vaccination.[91] Patients with asplenia require a special series of meningococcal vaccinations, and revaccinations every 5 years as adults.

Treatment of Gallstones

Treatment of acute cholecystitis in patients with sickle cell disease does not differ from that for the general population. Patients receive antibiotics and general supportive care and may consider elective cholecystectomy several weeks after the acute episode subsides. Elective laparoscopic cholecystectomy in a well-prepared patient has become the standard approach for symptomatic disease. If patients present with right upper quadrant abdominal pain, evaluate the gallbladder with ultrasonography. Provide appropriate medical and supportive care for cholecystitis if stones are visualized, if gallbladder walls are thickening, or upon signs of ductal inflammation.

Elective cholecystectomy has been used for asymptomatic patients with cholelithiasis, to avoid the possible future need for an emergent procedure. This approach remains controversial.

A retrospective review of 191 cholecystectomies in pediatric sickle cell patients with cholelithiasis (51 elective, 110 symptomatic, and 30 emergent) found postoperative hospitalization time was longer with emergent cholecystectomy than with elective or symptomatic cholecystectomy. Goodwin et al concluded that although overall outcomes for symptomatic and elective patients are favorable, prospective studies are needed to identify clinical indicators that predict the need for emergent cholecystectomy.[92]

Treatment of Priapism

At the onset of priapism, patients should be advised to drink extra fluids, use oral analgesics, and attempt to urinate. A nightly dose of pseudoephedrine (30 mg orally) may prevent priapism in some cases.

For episodes that last more than 2 hours, patients should go to the emergency department to receive intravenous hydration and parenteral analgesia. According to one protocol, if detumescence does not occur within 1 hour after arrival in the emergency department, penile aspiration followed by irrigation of the corpora with a 1:1,000,000 solution of epinephrine in saline is initiated.[32] (The procedure should be performed within 4-6 h of priapism onset.)

The concomitant use of automated red cell exchange transfusions to reduce the HbS level to less than 30% may also be considered, especially if early intervention with irrigation fails. Should the condition recur despite aspiration and local instillation of vasoactive drugs, consider shunting. In this procedure, known as the Winter procedure, a shunt is created between the glans penis and the distal corpora cavernosa; this allows blood from the distended corpora cavernosa to drain into the uninvolved corpus spongiosa. A larger shunt may be created if this is not successful.

Complications of priapism and treatment include bleeding from the holes placed in the penis as part of the aspiration or shunting procedures, infections, skin necrosis, damage or strictures of the urethra, fistulas, and impotence. If impotence persists for 12 months, the patient may wish to consider implantation of a semirigid penile prosthesis.

New approaches to prevent recurrent priapism include off-label use of phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil). In a pilot study and a small randomized, controlled trial (n = 13), long-term treatment with these agents alleviated recurrent priapism in some patients with SCD.[93, 94] However, a systematic review of sidenafil, stilbestrol, etilefrine, or ephedrine to reduce the frequency of stuttering priapism in boys and men with SCD identified only three trials with 102 participants, and concluded that there is a lack of evidence for the benefits or risks of these drugs in this setting.[95]

Treatment of Leg Ulcers

Leg ulcers are treated with debridement and antibiotics. Zinc oxide occlusive dressing (Unna boot) and leg elevation are employed. Transfusion may accelerate healing. Skin grafting may be necessary in recalcitrant cases. Leg ulcers may result from venous stasis and chronic hypoxia and may become infected. Management is the same as with other stasis ulcers.

Stroke Prevention

Adults with SCD should be evaluated for known stroke risk factors and managed according to the 2014 AHA/ASA primary stroke prevention guidelines.[44]

The AHA and ASA also provided guidelines for the prevention of stroke in patients with stroke or transient ischemic attack. These secondary stroke prevention guidelines include recommendations for controlling risk factors and the use of antiplatelet agents. Other therapies to consider in preventing recurrent cerebral ischemic attacks in adults with SCD include regular blood transfusions (to reduce HbS to < 30%-50% total hemoglobin), hydroxyurea, or bypass surgery for advanced occlusive disease.[96]

Transfusion therapy, aimed at keeping the proportion of HbS below 30%, is now considered standard care for primary and secondary stroke prevention in children with SCD. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) showed that regular blood transfusions produced a marked (90%) reduction in first stroke in asymptomatic high-risk children who had 2 abnormal transcranial Doppler (TCD) studies with velocities of 200 cm/s or greater.[97] According to the 2014 AHA/ASA primary stroke prevention guidelines, this form of therapy has been proven effective for reducing stroke risk in those children at increased risk for stroke.[44]

During the transfusion period, most of the TCD studies reverted to or toward normal. Once the transfusion program was stopped, however, there was an unacceptably high rate of TCD reversion to high risk, as well as to actual strokes.[50]

Unless long-term transfusion therapy is provided, 70-90% of children who experience a single stroke have subsequent events. DeBaun et al reported that in children with SCD, regular blood transfusions significantly reduced the rate of cerebral infarct recurrence.[98]

As patients grow into adulthood, the transfusion frequency may be decreased, but whether it can be discontinued remains unclear. Many believe that lifelong transfusion therapy is necessary to completely eliminate recurrences in patients with SCD. The AHA/ASA primary stroke prevention guidelines endorse (pending further study) the continued use of transfusion, even in those with TCD velocities that return to normal.[44] Iron overload from repeated transfusions requires chelation therapy after 2-3 years.

Erythrocytapheresis is now increasingly used as an alternative to simple transfusion. This procedure allows rapid reduction of HbS concentrations to less than 30% without significantly increasing total hemoglobin concentration post transfusion (see Transfusion, above).

According to the AHA/ASA primary prevention guidelines, hydoxyurea or bone marrow transplantation might be an option for children at high risk for stroke in whom RBC transfusion is contraindicated.[99] For children with a human leukocyte antigen (HLA)–matched sibling, a consortium has demonstrated that the risk of recurrent stroke can be greatly reduced with allogeneic bone marrow transplantation. This offers an alternative to long-term transfusion and iron chelation.[100]

The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial documented no strokes in patients with SCD (n=66) who received monthly transfusions plus daily deferasirox iron chelation but seven strokes in patients (n=67) treated with hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose, followed by monthly phlebotomy. Although the stroke percentage with hydroxyurea/phlebotomy was within the noninferiority stroke margin, the National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content in the two groups, indicating futility for the composite primary end point. The SWiTCH investigators concluded that “transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload”.[101]

In the TCD With Transfusions Changing to Hydroxyurea (TWiTCH) trial, hydroxycarbamide treatment was found to be noninferior to transfusion therapy for maintaining TCD velocities and helping to prevent primary stroke. TWiTCH was conducted in high-risk children with sickle cell anemia and TCD velocities ≥200 cm/s who had received at least 1 year of transfusions and had no severe vasculopathy identified on magnetic resonance angiography.[102]

In TWiTCH, no strokes were identified in patients treated with either transfusions (n=61) hydroxycarbamide (n=60), but three transient ischemic attacks occurred in each group.  TCD velocities were 143 cm/s in children who received transfusions and 138 cm/s in those who received hydroxycarbamide.[102]

 

Treatment of Pulmonary Hypertension

Pulmonary hypertension, defined as a mean pulmonary artery pressure > 20 mm Hg measured by right heart catheterization, is an emergent complication seen in 32% of adult patients with SCD and is associated with a high mortality rate.

Even modestly increased pulmonary artery pressures are associated with severe reduction in exercise capacity, as assessed by both the 6-minute walk and cardiopulmonary exercise testing, and herald a poor prognosis. Both pulmonary hypertension and cardiac sequelae, such as diastolic dysfunction, have been associated with accelerated mortality in the SCD population.

For symptomatic patients, hydroxyurea and chronic transfusion have been used. Enothelin-1 receptor antagonists (eg, bosentan) and phosphodiesterase inhibitors (eg, sildenafil) have been used, but their role is limited by other complications. Cor pulmonale may ensue, and the management is that of patients with right-sided heart failure and chronic obstructive pulmonary disease.

Sickle Cell Nephropathy

See Nephrologic Manifestations of Sickle Cell Disease for more information on this topic.

Treatment of Other Complications

Avascular necrosis of the femoral and humeral heads is treated by not bearing weight at the site. The patient may need to make career and lifestyle adjustments. Occupational retraining and physical therapy may be needed. In many cases, surgical intervention with hip replacement or other orthopedic procedures are needed.

In skeletally immature patients aged 12 years or younger, conservative treatment with analgesics, nonsteroidal anti-inflammatory drugs, 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.

SCD can promote psychological problems, such as depression, anxiety, and chronic pain behavior. Counseling is crucial. Ensure an appropriate physician-patient relationship. Anxiolytics and amitriptyline may be used.

Gene Therapy

In December 2023 the FDA approved the first 2 gene-editing therapies for severe SCD) in patients aged 12 years and older. One therapy, exagamglogene autotemcel (Casgevy), is the first to use the gene-editing tool CRISPR. The other, lovotibeglogene autotemcel (Lyfgenia), uses a different gene-editing tool called a lentiviral vector. 

Exagamglogene autotemcel

Exagamglogene autotemcel is a non-viral cell therapy designed to reactivate fetal hemoglobin via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). It specifically acts at the erythroid-specific enhancer region of the BCL11A gene.[103]  

In the ongoing phase III CLIMB SCD-121 trial, 42 patients with severe SCD had received exagamglogene autotemcel as of February 2023. Of the patients evaluable for primary endpoint, 19 of 20 (95%) had experienced no vaso-occlusive crisis (VOC) for at least 12 consecutive months (P < 0.0001) and 20/20 (100%) had not been hospitalized for VOCs for at least 12 consecutive months (P < 0.0001); 29/30 (96.7%) had been free of VOCs for at least 9 consecutive months (P < 0.0001).[103]  

Lovotibeglogene autotemcel

Lovotibeglogene autotemcel is manufactured by modifying autologous stem cells, using lentiviral vectors to add normal globin genes, gene editing to correct the sickle cell disease mutation, and genetic silencing to enhance production of fetal hemoglobin.[104, 105] A pilot study by Esrick et al reported reduction or elimination of clinical manifestations of SCD in six patients who received autologous CD34+ cells transduced with a lentiviral vector that downregulates a gene responsible for repressing fetal hemoglobin production in adult red blood cells.[106]  

Approval was supported by the phase I/II HGB-206 and phase III HGB-210 studies. These showed that a one-time treatment resulted in sustained production of HbAT87Q (an anti-sickling hemoglobin) and nearly complete resolution of vaso-occlusive events (VOEs) and severe VOEs up to 18 months post treatment.[107, 108, 109]

Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure SCD. Most transplants are performed in younger patients, and results are better in that population: an international survey of human leukocyte antigen (HLA)–identical sibling HSCT found that median age at transplantation was 9 years, and the 5-year overall survival rate was 95% for children under age 16 and 81% for those age 16 and older; the 5-year graft-versus-host disease (GVHD)–free survival rate in those age groups was 86% and 77%, respectively.[62]

To date, HSCT has been considered indicated in SCD patients younger than 16 years with HbSS or HbS–β-0 thalassemia who have severe disease, as evidenced by one or more of the following[110] :

HSCT for SCD has historically been limited to patients with an HLA-identical sibling donor. However, only 18% of patients with SCD have an HLA-matched sibling who does not have SCD. This has spurred the exploration of other donor options. Only 16% to 18% of African Americans have a full HLA-matched unrelated donor option in the national donor pool, but partial-matched unrelated donors, half-matched (ie, haploidentical) donors, and partial-matched cord blood have all been used.[111, 63]

Unrelated donor transplants are associated with a higher rate of GVHD than HLA-matched sibling donor transplants, but use of reduced-intensity or nonmyeloablative conditioning regimens in these cases has reduced the risk of GVHD and graft failure otherwise seen with non–fully matched donors.[62, 63] A reduced-intensity conditioning regimen was also used in a successful pilot study of HSCT in adolescents and young adults (age 17-36 years).[112]

Diet and Activity Restrictions

A general well-balanced diet is required. No restrictions are necessary.

Although activity is unrestricted, patients may not be able to tolerate vigorous exercise or exertion. Patients with avascular necrosis of the femur may not be able to tolerate weightbearing and may be restricted to bed rest. Patients with chronic leg ulcers may need to restrict activity that involves raising the legs.

Encourage children to participate in physical activities. Because of anemia, they have less stamina than their hematologically healthy playmates. Advise supervising adults of this limitation, particularly teachers and coaches who may otherwise require children to run designated distances. Arrange for children to have ready access to liquids and a place to rest and cool off.

Investigational Treatments

Investigational treatments include nitric oxide inhalation, topical granulocyte-macrophage colony-stimulating factor (GM-CSF), butyrate, and arginine, as follows:

Consultations

Consultation with a hematologist may be necessary. Each of the protean manifestations of SCD may require assistance from an expert in the involved area. Consultations with pain management experts, social workers, psychiatrists, physical therapists, substance abuse counselors, and vocational rehabilitation workers may be required. Consultation with infectious disease specialists is recommended during febrile illness.

If avascular necrosis of the hip is suspected in a patient with hip pain and difficulty in walking, consult an orthopedist for possible hip joint replacement. Orthopedic consultation is also appropriate if osteomyelitis is suspected. Interventional radiologists may play a role in obtaining a sample to identify the infecting organism in osteomyelitis. Imaging guidance may also allow the drainage of subperiosteal and soft tissue abscesses with the patient under light sedation, thereby avoiding surgery and general anesthesia.

If retinopathy or hyphema is suspected and visual symptoms are present, consultation with an ophthalmologist is warranted. In cases of priapism that does not resolve after 6 hours of hydration and analgesia, consult a urologist for corpus cavernosum aspiration or shunting.

A retina specialist should follow patients to monitor for retinal disease. Uncontrolled secondary glaucoma may require consultation with a glaucoma specialist.

Long-Term Monitoring

Lifelong follow-up is required for patients with SCD. The frequency of outpatient visits depends on the patient's clinical status. For patients with minimal symptoms, a visit with blood work every 3-4 months is reasonable. Others may need much more frequent observation.

Educate all patients to recognize signs of infection, increasing anemia, and organ failure. Treat all infections, even trivial ones, very promptly and vigorously. Institute pain medication at the earliest symptoms of a vaso-occlusive crisis. Patients on a chronic transfusion program must adhere to iron chelation therapy. Social services, occupational therapy, and counseling are essential elements in the long-term management of patients with SCD.

Follow-up care in patients with proliferative sickle retinopathy (PSR) depends on involvement; once stabilized, visits every 3-6 months may be adequate. When intraocular pressures are stabilized, the patient can be monitored every 6 months

Fluid intake and output should be closely monitored in kidney transplant recipients. In comparison with the general population, these patients have an increased propensity toward intravascular volume depletion, especially secondary to volume losses (through, for example, diarrhea, vomiting, and insensible losses), thereby increasing the risk of an acute sickle cell crisis.

Patients who have undergone a splenectomy as part of their SCD treatment regimen have an increased risk of infection with encapsulated organisms, such as Streptococcus pneumoniae.[113] Pneumococcal and influenza vaccination is safe in patients with functioning kidney transplants.[114, 115, 116] However, the use of live vaccines is contraindicated due to the immunosuppressive therapy that these patients require.

For infants with SCD, provide a suggested schedule for well-child visits to ensure that immunizations and other aspects of routine pediatric care are followed. For children aged 1-3 years with hemoglobin (Hb)SS and HbS–β-0 thalassemia, consider visits every 3 months, to be certain that parents have sufficient penicillin for prophylaxis and to encourage compliance.

Guidelines Summary

The American Society of Hematology (ASH) has published evidence-based guidelines on the screening, diagnosis, and management of cardiopulmonary, renal, and cerebrovascular complications of sickle cell disease (SCD), as well as on management of SCD-related pain and transfusion support in SCD. (Note that conditional recommendations—actions for which there is very low certainty in the evidence about effects—are listed as suggestions.)[117, 118, 88, 119]  In 2021, ASH issued guidelines on hematopoietic stem cell transplantation (HSCT) in SCD.[120]  

The United Kingdom's National Institute for Health and Care Excellence (NICE) has published guidelines on managing acute painful episodes of SCD in hospital. The guidelines were most recently updated in 2012.[55]

Pulmonary Hypertension

Given the risk for cardiopulmonary disease in individuals with SCD, it is good practice to routinely take a targeted history for signs and symptoms that might indicate a need for further evaluation, including consideration for a diagnostic echocardiogram.[117] In asymptomatic children and adults with SCD, the ASH guideline panel suggests against performing a routine screening echocardiogram to identify pulmonary hypertension (PH). However, the following findings may warrant a consultation with a PH expert or a diagnostic echocardiogram to evaluate for PH:

In addition, a diagnostic echocardiogram should be considered for patients with SCD who also have comorbid conditions (eg, connective tissue disease) or disease complications (eg, leg ulcers, priapism) known to be associated with PH, when signs or symptoms of PH are present.

The ASH panel considers it good practice to obtain echocardiograms at steady state and not during acute illness, such as hospitalization for pain or acute chest syndrome, when the results will be used as the basis for decisions about the need for right-heart catheterization.

Recommendations for patients with an abnormal echocardiogram are as follows:

Treatment of PAH is as follows:

End points for monitoring the benefits of PAH-specific therapy in these patients include the following:

Pulmonary function testing

For asymptomatic children and adults with SCD, the ASH guideline panel suggests against routine screening pulmonary function testing (PFT).

The following signs, symptoms, or diagnoses may warrant diagnostic PFT to evaluate for abnormal lung function:

Comprehensive PFT should include full spirometry as well as complete evaluation of diffusion capacity and lung volumes.

Sleep-Disordered Breathing

For asymptomatic children and adults with SCD, the ASH guideline panel suggests against screening with formal polysomnography (sleep study) for sleep-disordered breathing.[117]

When appropriate, validated tools (eg, Epworth Sleepiness Scale or Pittsburgh Sleep Quality Index) should be used to further identify patients who should be considered for formal sleep testing. The following signs or symptoms may warrant a diagnostic sleep study for otherwise healthy patients to evaluate for sleep-disordered breathing:

For patients in whom a sleep study is warranted, the ASH panel notes that American Academy of Sleep Medicine guidelines currently recommend in-laboratory, “attended” sleep studies for children and for adults with chronic disease and known comorbidities, specifically cardiopulmonary. Additionally, it is important for formal sleep studies to be conducted in a certified sleep center that meets standards as required by accreditation groups.

Kidney Disease

Albuminuria

The ASH guideline panel did not assess the evidence to inform decisions about albuminuria screening, but notes that Kidney Disease Improving Global Outcomes (KDIGO) guidelines state that albuminuria should be confirmed by either a first morning urine sample or 2 consecutive untimed urine samples. The National Heart, Lung, and Blood Institute (NHLBI) 2014 expert panel report states that screening for albuminuria should occur annually beginning at 10 years of age for patients with SCD. However, more recent evidence suggests a potential benefit of earlier screening.

For children and adults with SCD and albuminuria, the ASH guideline panel suggests the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs).

The initiation of ACEIs and ARBs for patients with SCD requires adequate follow-up and monitoring of side effects (eg, hyperkalemia, cough, hypotension).

As recommended by the KDIGO guidelines for the general population, the following attention to baseline and changes in renal function are appropriate when prescribing ACEIs or ARBs for patients with SCD:

Chronic kidney disease

In children and adults with SCD and worsening anemia associated with chronic kidney disease (CKD), the ASH guideline panel suggests combination therapy with hydroxyurea and erythropoiesis-stimulating agents. This recommendation is based on evidence available only from patients with hemoglobin SS or S/β0 thalassemia, for whom erythropoiesis-stimulating-agent dosing in the studies reviewed was higher than that typically used in the general population.

For patients with SCD and CKD who are already on steady-state hydroxyurea, starting erythropoiesis-stimulating agents is appropriate when a simultaneous drop occurs in the hemoglobin concentration and absolute reticulocyte count. Optimizing adherence to hydroxyurea therapy while on erythropoiesis-stimulating agents may help maximize fetal hemoglobin responses for patients treated with combination therapy.

For patients with SCD undergoing treatment with erythropoiesis-stimulating agents, a conservative hemoglobin threshold is advised above which treatment should be decreased or held. The ASH guideline panel advises not exceeding a hemoglobin threshold of 10 g/dL (hematocrit of 30%) to reduce the risk of vaso-occlusion–related complications, stroke, and venous thromboembolism.

For children and adults with SCD and advanced CKD or end-stage renal disease, the ASH guideline panel suggests referral for renal transplantation. Judicious use of corticosteroids as part of the posttransplant immunosuppression regimen is advised given the potential relationship between steroid exposure and vaso-occlusive pain for patients with SCD.

Cardiovascular Disease

Management of blood pressure

For adults with SCD, the ASH guideline panel recommends a blood pressure goal of ≤130/80 mm Hg over a goal of ≤140/90 mm Hg.90 There is a lack of evidence to suggest that blood pressure goals should differ for individuals with and without SCD. The impact of hypertension on patient-important outcomes is significant for African Americans and therefore requires adherence to guidelines developed for the general population independent of having SCD.

Management of venous thromboembolism

The ASH panel considers SCD to be a chronic underlying risk factor for initial and recurrent venous thromboembolism (VTE). Consequently, for adults with SCD and first unprovoked VTE, the ASH guideline panel suggests indefinite anticoagulation over shorter, defined periods of anticoagulation.

For adults with SCD and first provoked VTE (whether surgically or nonsurgically provoked), the ASH guideline panel suggests defined periods of anticoagulation (3-6 months) over indefinite anticoagulation. Anticoagulation should continue as long as any provoking risk factor (eg, a central venous line) continues to be present.

In adults with SCD and recurrent provoked VTE, the ASH guideline panel suggests indefinite anticoagulation. However, the type, strength, and duration of the provoking events are important to take into account when considering indefinite anticoagulation for those patients.

Whether to continue anticoagulation should be re-evaluated regularly, and should involve shared decision-making based on patient values and preferences. Discussions of the benefits vs harms of anticoagulation, as well as duration of therapy, should take into consideration bleeding risk, including from existing use of other medications that could further increase risk of bleeding (eg, nonsteroidal anti-inflammatory drugs).

Anticoagulant selection for patients with SCD should account for comorbidities such as renal impairment that may affect drug clearance. For example, because of the potential for decreased efficacy of edoxaban in the setting of increased creatinine clearance (CrCl), alternative anticoagulants should be considered for SCD patients with CrCl of > 95 mL/min.

Cerebrovascular Complications

The ASH guidelines on prevention, diagnosis, and treatment of the most common neurological morbidities in SCD include recommendations stratified by income setting (low-middle or high).[118] Strong recommendations are summarized below.

Stroke prevention and treatment

Primary stroke prevention in children:

Management of suspected or confirmed ischemic stroke or transient ischemic attack (all income settings):

Prompt blood transfusion is recommended for children or adults with SCD who have acute neurologic deficits, including transient ischemic attack (TIA). The transfusion should not be delayed beyond 2 hours of acute neurologic symptom presentation. Individual patient factors and local transfusion resources determine the type of transfusion provided (simple, modified exchange, or apheresis).

Secondary prevention of ischemic strokes:

Cognitive impairment

Screening for developmental delay or cognitive impairment in children and adults with SCD:

Rehabilitation for children and adults with cognitive impairments

The following are recommended for children with SCD and abnormal developmental or cognitive status screens:

The following are recommended for adults with SCD and abnormal cognitive status screens:

Cerebral infarcts

Screening for silent cerebral infarcts in children and adults with HbSS or HbSβ0 thalassemia:

Pain

ASH 2020 guidelines for management of acute and chronic pain in patients with sickle cell disease (SCD) include the recommendations and suggestions (ie, conditional recommendations based on very low certainty in the evidence) summarized below. Unless otherwise specified, these apply to both adults and children.[88]

Acute pain

For patients with SCD presenting to an acute care setting with acute pain related to SCD, ASH strongly recommends rapid (within 1 hour of emergency department [ED] arrival) assessment and administration of analgesia with frequent reassessments (every 30 to 60 minutes) to optimize pain control. The panel notes that non-intravenous (IV) routes of administration (eg, subcutaneous and intranasal) can facilitate rapid analgesic treatment.

When opioid therapy is indicated for acute pain in the acute care setting, ASH suggests using tailored opioid dosing, based on consideration of baseline opioid therapy and prior effective therapy. The panel notes that individualized care plans that include medications and doses that are effective for a given patient can be embedded in the electronic medical record and used to guide opioid dosing.

For patients with acute pain related to SCD, ASH guideline panel suggests a short course (5 to 7 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to opioids, in the absence of significant risk factors for NSAID use.

ASH suggests against corticosteroids for management of SCD-related acute pain.

For hospitalized patients with SCD-related acute pain that is refractory or not effectively treated with opioids alone, ASH suggests a subanesthetic (analgesic) ketamine infusion as adjunctive treatment, in centers with the appropriate expertise to administer the drug. The recommended dose in this setting starts at 0.1 to 0.3 mg/kg per hour with a maximum of 1 mg/kg per hour.

For patients with SCD-related acute localized pain that is refractory or not effectively treated with opioids alone, ASH suggests regional anesthesia treatment approaches (ie, epidural or peripheral nerve catheter-delivered analgesia for abdominal, hip, or leg pain).

ASH does not offer a recommendation for or against IV fluids in addition to standard pharmacological management for the treatment of acute pain.

ASH suggests massage, yoga, transcutaneous electrical nerve stimulation (TENS), virtual reality (VR), and guided audiovisual (AV) relaxation in addition to standard pharmacological management for acute pain.

ASH chooses not to offer a recommendation for or against acupuncture or biofeedback for the treatment of acute pain in addition to standard pharmacological management.

For patients who develop acute pain episodes requiring hospital care, ASH suggests using SCD-specific hospital-based acute care facilities (ie, day hospitals and infusion centers, that have appropriate expertise to evaluate, diagnose, and treat pain and other SCD complications).

Chronic pain

For adults with chronic (as opposed to episodic) pain from the SCD-related identifiable cause of avascular necrosis of bone, ASH suggests use of duloxetine (and other serotonin and norepinephrine reuptake inhibitors [SNRIs], because there is evidence of a class effect) and NSAIDs as options for management, in the context of a comprehensive disease and pain management plan. ASH offers no recommendation for or against the use of SNRIs and/or NSAIDs for children in this setting.

For patients with SCD who have chronic (as opposed to episodic) pain from the SCD-related identifiable cause of leg ulcers, ASH does not offer a recommendation for or against any specific nonopioid pharmacological management strategy.

For adults who have SCD-related chronic pain with no identifiable cause beyond SCD, ASH suggests SNRIs (eg, duloxetine and milnacipran), tricyclic antidepressants (eg, amitriptyline), or gabapentinoids (eg, pregabalin) as options for pain management.

For patients with SCD and emerging and/or recently developed chronic pain that is refractory to multiple other treatment modalities, ASH suggests consideration of long-term opioid therapy, after risk stratification using a validated tool.

For patients who have chronic pain related to SCD, ASH suggests cognitive and behavioral pain management strategies in the context of a comprehensive disease and pain management plan.

For adults who have chronic pain related to SCD, ASH suggests other provider-delivered integrative approaches (eg, massage therapy and acupuncture) as available, as tolerated, and conditional upon individual patient preference and response. These approaches should be delivered in the context of a comprehensive disease and pain management plan.

For patients who have chronic pain related to SCD, ASH chooses not to offer a recommendation for or against a number of physical activities, exercise, or combined meditation/movement programs (including aerobic exercise, yoga, and Pilates) to improve pain and disability. ASH notes that if such interventions are considered, it requires shared decision-making that addresses feasibility, tolerability, acceptability, and patient experience and preference.

Transfusions

For patients with SCD and recurrent acute pain, ASH suggests against long-term monthly transfusion therapy as a first-line strategy to prevent or reduce recurrent acute pain episodes. However, the ASH guidelines note that in unique circumstances when all other measures to control recurrent pain episodes have failed (eg, hydroxyurea, other disease modifying therapies) and when shared decision making can be fully applied, a trial of monthly transfusions may be reasonable.

For patients with chronic pain from SCD, ASH chooses not to offer a recommendation for or against long-term monthly transfusion therapy as an option for pain management.

Transfusion Support

ASH 2020 guidelines for transfusion support in patients with SCD recommend prophylactic red cell antigen matching for Rh (C, E or C/c, E/e) and K antigens over only ABO/RhD matching for patients with SCD (all genotypes) receiving transfusions.[119] The guidelines also include the following suggestions (ie, conditional recommendations based on very low certainty in the evidence):

Hematopoietic Stem Cell Transplantation (HSCT)

ASH 2021 guidelines for HSCT in SCD include the following conditional recommendations[120] : 

Medication Summary

The goals of pharmacotherapy are to reduce and prevent complications. The drugs used in treatment of sickle cell disease (SCD) include antimetabolites, analgesics, antibiotics, vaccines, and nutritional agents.

Hydroxyurea (Droxia, Hydrea, Hydroxycarbamide)

Clinical Context:  Indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in children aged ≥6 months with sickle cell anemia with recurrent moderate-to-severe painful crises. Droxia capsules (and generics) are approved for adults, Siklos tablets for adults and children aged older than 2 years, and Xromi oral solution for children aged 6 months and older. 

Class Summary

Hydroxyurea inhibits deoxynucleotide synthesis. Its myelosuppressive effects last a few days to a week and are easier to control than those of alkylating agents.  

Crizanlizumab (Adakveo, Crizanlizumab-tmca)

Clinical Context:  P-selectin inhibitor indicated to reduce frequency of vasoocclusive crises in adults with sickle cell disease.

Class Summary

Binding P-selectin on the surface of the activated endothelium and platelet cells blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes; thereby, decreasing vaso-occlusive crises.

Exagamglogene autotemcel (Casgevy)

Clinical Context:  Indicated for sickle cell disease in patients aged ≥12 years with recurrent vaso-occlusive events.

Lovotibeglogene autotemcel (Lyfgenia)

Clinical Context:  Indicated for treatment of sickle cell disease in patients aged ≥12 years with a history of vaso-occlusive events. 

Class Summary

In December 2023, the FDA approved the first 2 gene-editing therapies for severe sickle cell disease in patients aged 12 years and older. One therapy, exagamglogene autotemcel (Casgevy), uses the gene-editing tool CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats). The other, lovotibeglogene autotemcel (Lyfgenia), uses a different gene-editing tool called a lentiviral vector.

Amitriptyline (Elavil, Levate)

Clinical Context:  Amitriptyline inhibits presynaptic reuptake of serotonin and norepinephrine and blocks cholinergic, adrenergic, histaminergic, and sodium channels.

Nortriptyline (Aventyl, Pamelor)

Clinical Context:  Nortriptyline may increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by reuptake inhibition via the presynaptic neuronal membrane; inhibits the activity of histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine.

Class Summary

Tricyclic antidepressants (TCAs) increase the levels of certain brain chemicals which improve mood and regulate pain signals. Low doses of TCAs relieve pain, although its mechanism is still unknown.

Glutamine (Endari, NutreStore (DSC))

Clinical Context:  Glutamine is an amino acid oral powder for acute complications associated with SCD. The precise mechanism of action is unknown. Sickle RBCs are more susceptible to oxidative damage than normal RBCs, which may contribute to chronic hemolysis and vaso-occlusive events associated with SCD. Pyridine nucleotides, NAD+ and its reduced form NADH, regulates and prevents oxidative damage in RBCs. Glutamine is believed to improve the NAD redox potential in sickle RBCs by increasing reduced glutathione’s availability.

Class Summary

Severe anemia and vaso-occlusive processes results in incapacitating complications. Glutamine reduces acute complications (eg acute chest syndrome) associated with SCD.

Pseudoephedrine (Nexafed, Sudafed, Zephrex-D)

Clinical Context:  Pseudoephedrine promotes vasoconstriction by directly stimulating alpha-adrenergic receptors.

Class Summary

These agents have been used successfully for priapism, possibly due to their sympathomimetic vasopressor activity.

Pneumococcal vaccine 20-valent (Prevnar 20)

Clinical Context:  The pneumococcal 20-valent vaccine contains capsular antigens extracted from Streptococcus pneumoniae and is used to stimulate active immunity to pneumococcal infection.

Pneumococcal vaccine polyvalent (Pneumovax 23)

Clinical Context:  Pneumococcal polysaccharide polyvalent is an inactive bacterial vaccine that induces active immunization to the 23 pneumococcal serotypes contained in the vaccine.

Haemophilus influenzae type b vaccine (ActHIB, Hiberix, Liquid PedvaxHIB)

Clinical Context:  The vaccine consists of Haemophilus influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP). IgG acts as an anti-capsular PRP antibody, demonstrating bactericidal activity against H influenzae type b.

Meningococcal A C Y and W-135 diphtheria conjugate vaccine (Menactra, Menveo)

Clinical Context:  The vaccine induces bactericidal antibody production specific to the capsular polysaccharides (eg, serogroups A, C, Y and W-135). The presence of anti-capsular meningococcal antibodies are associated with protecting against invasive meningococcal diseases.

Class Summary

It is recommended to maintain an up-to-date immunization schedule for pneumococcal, haemophilus influenzae and meningococcal vaccine

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cell trait (SCT)?What are the early manifestations of sickle cell disease (SCD)?Is universal screening for sickle cell disease (SCD) mandated in the US?What is the role of hemoglobin S (HbS) in the pathogenesis of sickle cell disease (SCD)?What happens to hemoglobin S (HbS) under deoxy conditions?What is the role of oxygen tension in the pathogenesis of sickle cell disease (SCD)?What is the pathophysiology of the sickling process in sickle cell disease (SCD)?What is the result of recurrent episodes of sickling in sickle cell disease (SCD)?What happens when red blood cells (RBCs) sickle?What is the roles of endothelial dysfunction in the pathophysiology of sickle cell disease (SCD)?What is the role of very late antigen-4 (VLA-4) in the pathogenesis of sickle cell disease (SCD)?What is the role of nitric oxide in the pathogenesis of sickle cell disease (SCD)?What is the role of inflammatory activation of the endothelium in the pathogenesis of sickle cell disease (SCD)?What is the role of adhesion molecules in the pathogenesis of sickle cell disease (SCD)?What causes sickle red blood cells (RBCs) to adhere to endothelium?What causes sickle red blood cells (RBCs) to adhere to macrophages?What is hemolysis and what is its role in the pathophysiology of sickle cell disease (SCD)?When do the symptoms of sickle cell disease (SCD) develop?Which physiological changes in red blood cells (RBCs) suggest sickle cell disease (SCD)?Which processes result in bone and joint destruction in sickle cell disease (SCD)?What causes osteonecrosis in sickle cell disease (SCD)?Where does bone infarction typically occur in sickle cell disease (SCD)?What is the presentation of osteonecrosis in sickle cell disease (SCD)?Which skeletal manifestations of sickle cell disease (SCD) are caused by infarction of bone and bone marrow?What is the role of bone marrow hyperplasia in sickle cell disease (SCD)?Which skeletal manifestations of sickle cell disease (SCD) are caused by bone marrow hyperplasia?Which growth defects may occur in patients with sickle cell disease (SCD)?What are the renal manifestations of sickle cell disease (SCD)?What are the manifestations of sickle cell disease (SCD) in the spleen?What is the pathogenesis of chronic hemolytic anemia in sickle cell disease (SCD)?What is the pathogenesis of pulmonary hypertension in sickle cell disease (SCD)?What is the major cause of morbidity and mortality in sickle cell disease (SCD)?Why are patients with sickle cell disease (SCD) at higher risk of infection from common bacteria?Where did sickle cell disease (SCD) originate?How do variants of the hemoglobin S (HbS) gene affect the severity of malaria?Which factors can precipitate the sickling process that prompts a crisis in sickle cell disease (SCD)?Which factors increase the risk of vaso-occlusive crises in sickle cell disease (SCD)?Which factors often precede aplastic crises in sickle cell disease (SCD)?What populations are most likely to develop sickle cell disease (SCD)?What is the prevalence of the sickle gene in the US?What is the prevalence of sickle cell disease (SCD) in the US?What is the global prevalence of sickle cell disease (SCD)?Is sickle cell disease (SCD) more common in males or females?Does the clinical presentation of sickle cell disease (SCD) vary among age groups?What is the prognosis of sickle cell disease (SCD)?What is the socioeconomic impact of sickle cell disease (SCD)?Which prognostic factors predict an adverse outcome in sickle cell disease (SCD)?How does sickle cell disease (SCD) affect pregnancy?What is the mortality rate of sickle cell disease (SCD)?What is the survival rate for children with sickle cell disease (SCD)?Has the mortality rate of sickle cell disease (SCD) improved over the past 30 years?What is the life expectancy of patients with sickle cell disease (SCD) and end-stage renal disease (ESRD)?What is the life expectancy of patients with homozygous HbS (HbSS) sickle cell disease (SCD)?Which factors have contributed to an increase in life expectancy in sickle cell disease (SCD)?What are the possible complications for aging patients with sickle cell disease (SCD)?What education should patients with sickle cell disease (SCD) receive?When should medical care be sought by patients with sickle cell disease (SCD)?What should be avoided by patients with sickle cell disease (SCD)?How should families be educated about sickle cell disease (SCD)?What genetic information should be given to patients with sickle cell disease (SCD) or sickle cell trait (SCT)?What is the likelihood that a child will have sickle cell disease (SCD) if both parents have the sickle cell trait (SCT)?What encouragement can be given to families of patients with sickle cell disease (SCD)?What is the presentation of cholelithiasis (gallstones) in sickle cell disease (SCD)?At what age do the symptoms of sickle cell disease (SCD) typically develop?What is the most common clinical manifestation of sickle cell disease (SCD)?How common is vaso-occlusive crisis in patients with homozygous HbS (HbSS) sickle cell disease (SCD)?How do pain crises develop in sickle cell disease (SCD)?Which patterns of bone pain suggest sickle cell disease (SCD)?What triggers vaso-occlusive crises in sickle cell disease (SCD)?Can dehydration precipitate pain in vaso-occlusive crises in sickle cell disease (SCD)?Can changes in body temperature trigger vaso-occlusive crises in sickle cell disease (SCD)?Do patients with sickle cell disease (SCD) experience chronic pain?When is anemia present in sickle cell disease (SCD)?What are the symptoms of anemia in children with sickle cell disease (SCD)?What causes aplastic crisis in sickle cell disease (SCD)?When is splenic sequestration most likely to occur in patients with sickle cell disease (SCD)?How is splenic sequestration managed in sickle cell disease (SCD)?What causes extreme susceptibility to infection in sickle cell disease (SCD)?Which organisms pose the greatest risk for infection in sickle cell disease (SCD)?What are the effects of sickle cell disease (SCD) on growth and maturation?What is the hand-foot syndrome in sickle cell disease (SCD)?What is the disease course of hand-foot syndrome in sickle cell disease (SCD)?How does acute chest syndrome present in children and adults with sickle cell disease (SCD)?Should acute chest syndrome in sickle cell disease (SCD) be treated as a medical emergency?How does acute chest syndrome in sickle cell disease (SCD) begin?What are the central nervous system (CNS) manifestations of sickle cell disease (SCD)?When are patients with sickle cell disease (SCD) at risk for convulsions?What are the potential central nervous system (CNS) manifestations of sickle cell disease (SCD) in children?Are patients with sickle cell disease (SCD) at increased risk for hemorrhagic stroke?Which cardiac complications may be present in sickle cell disease (SCD)?What findings suggest cholecystitis in patients with sickle cell disease (SCD)?How is the renal system involved in sickle cell disease (SCD)?What are the possible ocular (ophthalmic) complications of sickle cell disease (SCD)?What causes leg ulcers in sickle cell disease (SCD)?How common is priapism in sickle cell disease (SCD)?Which patients with sickle cell disease (SCD) are at an increased risk for avascular necrosis (AVN)?How is hip disease managed in patients with sickle cell disease (SCD)?How does pulmonary hypertension develop in sickle cell disease (SCD)?What is the incidence of pulmonary hypertension in patients with sickle cell disease (SCD)?How is pulmonary hypertension characterized in sickle cell disease (SCD)?What causes acute bone pain crisis in patients with sickle cell disease (SCD) and what are the symptoms?What are the physical findings in sickle cell disease (SCD)?What does hypotension and tachycardia indicate in sickle cell disease (SCD)?Which symptoms suggest cardiovascular complications in sickle cell disease (SCD)?What does a fever suggest in children with sickle cell disease (SCD)?What is the role of auscultation in the physical exam in patients with sickle cell disease (SCD)?How is spleen size measured in children with sickle cell disease (SCD)?When do growth parameters typically fall in children with sickle cell disease (SCD)?What physical exam should be performed in patients with sickle cell disease (SCD)?What are ocular (ophthalmic) manifestations in sickle cell disease (SCD)?When should meningitis be suspected in patients with sickle cell disease (SCD)?Which skeletal findings are typical in children with sickle cell disease (SCD)?Which physical findings suggest acute bone infarction in patients with sickle cell disease (SCD)?What are the possible sequelae of chronic bone infarction in patients with sickle cell disease (SCD)?What is hand-food syndrome in patients with sickle cell disease (SCD)?What are the symptoms of osteonecrosis in patients with sickle cell disease (SCD)?What causes osteomyelitis in patients with sickle cell disease (SCD)?How is HbS-beta 0 thalassemia diagnosed?How is the diagnosis of sickle cell disease (SCD) confirmed?Which sickle cell variants must be distinguished from hemoglobin S (HbS) disease in sickle cell disease (SCD)?What is the presentation of hemoglobin C (HbSC) disease?How is hemoglobin C (HbSC) disease diagnosed?What is the sickle cell trait (SCT)?How do hemoglobin S (HbS) variants in sickle cell disease (SCD) occur?How are Gaucher disease and sickle cell disease (SCD) differentiated?Which conditions should be included in the differential diagnoses of sickle cell disease (SCD)?What are the differential diagnoses for Sickle Cell Disease (SCD)?When is screening for hemoglobin S (HbS) done in the US?Which test is performed for the prenatal diagnosis of sickle cell disease (SCD)?How often should pulmonary function tests (PFTs) be performed in children with sickle cell disease (SCD)?What are the roles of transcranial near-infrared spectroscopy and cerebral oximetry in the workup of sickle cell disease (SCD) in children?What is the role of transcranial Doppler (TCD) ultrasonography in the workup of sickle cell disease (SCD)?What is the role of lumbar puncture in the management of children with sickle cell disease (SCD)?Which high-risk features of sickle cell disease (SCD) require hospitalization?What are the BCSH treatment guidelines for patients with sickle cell disease (SCD) admitted to the hospital?What is the presentation of acute chest syndrome in patients with sickle cell disease (SCD)?What are the newborn screening guidelines for hemoglobin disorders in the US?Which hemoglobin screening results suggest sickle cell disease (SCD)?What is the role of hemoglobin electrophoresis a in the diagnosis of sickle cell disease (SCD)?Which hemoglobin electrophoresis findings suggest sickle cell disease (SCD)?What are the typical baseline blood study abnormalities in patients with sickle cell disease (SCD)?Which peripheral blood smear findings suggest sickle cell disease (SCD)?What is the suggested schedule for routine lab testing for sickle cell disease (SCD)?Can lab tests be used to distinguish pain crisis from the baseline condition of sickle cell disease (SCD)?Are routine CBC counts and reticulocyte counts necessary in all patients with sickle cell disease (SCD) who have an acute illness?Which tests should be performed in febrile children with sickle cell disease (SCD)?Which CBC count findings suggest hematologic crisis in sickle cell disease (SCD)?What is the role of reticulocyte percentage testing in sickle cell disease (SCD)?What additional tests may be useful for a diagnosis of hemolysis in sickle cell disease (SCD)?When are ABG measurements indicated in patients with sickle cell disease (SCD)?When should a urinalysis be performed in patients with sickle cell disease (SCD)?When is a sickling test indicated in patients with sickle cell disease (SCD)?Is secretory phospholipase A2 a biomarker for acute chest syndrome in patients with sickle cell disease (SCD)?When is chest radiography indicated in patients with sickle cell disease (SCD)?What is the role of radiography of the extremities in patients with sickle cell disease (SCD)?How sensitive is radiography compared to other studies for osteomyelitis in sickle cell disease (SCD)?What is the role of MR) in the workup of sickle cell disease (SCD)?What is the sensitivity and specificity of MRI for identifying bone marrow infarction in patients with sickle cell disease (SCD)?What do abnormal MRI or neuropsychometric (NPM) findings in patients with sickle cell disease (SCD) indicate?Are MRI and MRA important screening tools for sickle cell disease (SCD) in the prevention of primary stroke?What is the role of CT scanning in the management of sickle cell disease (SCD)?What is the role of nuclear medicine scanning in the management of sickle cell disease (SCD)?What is the role of 99m Tc bone scanning in the management of sickle cell disease (SCD)?What is the role of indium-111 (111In) WBC scanning in the management of sickle cell disease (SCD)?How is acute osteomyelitis differentiated from bone infarction in patient with sickle cell disease (SCD)?What is the role of transcranial Doppler (TCD) ultrasonography in the management of sickle cell disease (SCD)?What are the indications for transcranial Doppler (TCD) screening in sickle cell disease (SCD) and how often should it be done?Should transfusions be administered to patients with abnormal transcranial Doppler (TCD) results and sickle cell disease (SCD)?What is the role of abdominal ultrasonography in the management of sickle cell disease (SCD)?What is the role of ultrasonography of the kidneys in the management of sickle cell disease (SCD)?What is the role of ECG in the management of sickle cell disease (SCD)?According to the NIH, how is optimal care for sickle cell disease (SCD) achieved?What is self-treatment for sickle cell disease (SCD)?How should patients with sickle cell disease (SCD) crisis be managed during transport by emergency medical services (EMS)?What should be included in pain management for sickle cell disease (SCD)?What are the goals of treatment for sickle cell disease (SCD)?Is there a cure for sickle cell disease (SCD)?What are the guidelines for the treatment of sickle cell disease (SCD)?What new drugs are approved for use in the treatment of sickle cell disease (SCD)?What is the role of allogenic hematopoietic stem cell transplantation (HSCT) in the treatment of sickle cell anemia (SCA)?What is the role of gene therapy in the treatment of sickle cell anemia (SCA)?What are the effects of hydroxyurea in patients with sickle cell disease (SCD)?Is hydroxyurea an effective treatment for adults with sickle cell disease (SCD)?Is hydroxyurea an effective treatment for children with sickle cell disease (SCD)?What are the indications for hydroxyurea in patients with sickle cell disease (SCD)?What monitoring is required for patients with sickle cell disease (SCD) receiving hydroxyurea?What are the possible adverse effects of hydroxyurea in patients with sickle cell disease (SCD)?What are the treatment options after failed hydroxyurea therapy for sickle cell disease (SCD)?When are transfusions indicated in the treatment of sickle cell disease (SCD)?What are possible transfusion-related complications in sickle cell disease (SCD)?Which intraoperative and postoperative complications are possible in patients with sickle cell disease (SCD)?Does raising hemoglobin concentration prior to surgery protect patients with sickle cell disease (SCD) from complications?Should hemoglobin concentrations be reduced in patients undergoing retinal surgery for sickle cell disease (SCD)?Which test provides an accurate measure of tissue iron concentration in patients with sickle cell disease (SCD)?Which agents are used for iron chelation in patients with sickle cell disease (SCD)?What is the role of erythrocytapheresis in the treatment of sickle cell disease (SCD)?How is an erythrocytapheresis performed in the treatment of sickle cell disease (SCD)?What are the advantages of erythrocytapheresis over simple transfusion in the treatment of sickle cell disease (SCD)?How are ophthalmic manifestations of sickle cell disease managed?What is the role of surgery in the treatment of the ocular manifestations of sickle cell anemia (SCA)?How is elevated intraocular pressure treated in patients with sickle cell anemia (SCA)?How are vaso-occlusive crises treated in patients with sickle cell disease (SCD)?Which risk factors are associated with hospital admission for patients with sickle cell disease (SCD) in vaso-occlusive crisis?Which risk factors are associated with longer length of hospital stay for vaso-occlusive crisis in patients with sickle cell disease (SCD)?How can the incidence of vaso-occlusive crisis in patients with sickle cell disease (SCD) be reduced?What are the NICE guidelines for pain control in sickle cell disease (SCD)?What are the NHLB recommendations for pain management in the treatment of sickle cell disease (SCD)?How should morphine be administered in patients with sickle cell disease (SCD)?What are the BCSH guidelines for treatment of acute chest syndrome (ACS) in patients with sickle cell disease (SCD)?How can acute chest syndrome (ACS) complications in patients with sickle cell disease (SCD) be prevented?How is acute chest syndrome (ACS) treated in patients with sickle cell disease (SCD)?Which medications can be administered to treat acute chest syndrome (ACS) in patients with sickle cell disease (SCD)?Does an elevated level of serum phospholipase A2 predict acute chest syndrome (ACS) in patients with sickle cell disease (SCD)?How is severe hypoxia treated in patients with acute chest syndrome (ACS) and sickle cell disease (SCD)?What role do corticosteroids play in nonasthmatic patients with acute chest syndrome (ACS) and sickle cell disease (SCD)?Which treatment may reduce the recurrence of acute chest syndrome (ACS) in patients with sickle cell disease (SCD)?How is chronic pain treated in patients with sickle cell disease (SCD)?What is the role of tricyclic antidepressants in the treatment of chronic pain in patients with sickle cell disease (SCD)?Is hydroxyurea used to treat chronic pain in patients with sickle cell disease (SCD)?What are the nonpharmacological approaches to pain management in sickle cell disease (SCD)?What can family members and patients do to manage recurring pain of sickle cell disease (SCD)?When is hospitalization indicated for the management of pain in sickle cell disease (SCD)?Which dosage regimen is used to treat chronic pain in patients with sickle cell disease (SCD)?Which opioids are used to treat chronic pain in sickle cell disease (SCD) and when is opioid dependence a concern?When is chronic opioid therapy (COT) indicated in the treatment of sickle cell disease (SCD)?What are the ASH guidelines on the use of chronic opioid therapy (COT) in the treatment of sickle cell disease (SCD)?What are the possible adverse effects of chronic opioid therapy (COT) for the treatment of sickle cell disease (SCD)?How is megaloblastic anemia prevented in patients with sickle cell disease (SCD)?What is the role of folic acid therapy in the treatment of chronic anemia in sickle cell disease (SCD)?Does menstruation cause iron deficiency (chronic anemia) in women with sickle cell disease (SCD)?When is blood transfusion indicated for treatment of chronic anemia in patients with sickle cell disease (SCD)?What is the role of voxelotor in the treatment of sickle cell anemia (SCA)?How is anemic crisis with splenic sequestration treated in patients with sickle cell disease (SCD)?When is a transfusion required for the treatment of anemia in patients with sickle cell disease (SCD)?How is infection-related morbidity and mortality minimized and prevented in sickle cell disease (SCD)?When is antibiotic therapy indicated in the treatment of sickle cell disease (SCD), and which antibiotics are used?Which prophylaxis antibiotic is effective in reducing the incidence of infection in patients with sickle cell disease (SCD)?Are pneumococcal vaccines (PCVs) effective in preventing invasive infection in children with sickle cell disease (SCD)?What is the role of immunization in preventing infection in children with sickle cell disease (SCD)?How is acute cholecystitis treated in patients with sickle cell disease (SCD)?What is the role of cholecystectomy in asymptomatic patients with cholelithiasis (gallstones) and sickle cell disease (SCD)?What is the initial treatment for priapism in patients with sickle cell disease (SCD)?When is emergency department (ED) treatment indicated for priapism in patients with sickle cell disease (SCD)?What are the complications of priapism in patients with sickle cell disease (SCD)?How is recurrent priapism prevented in patients with sickle cell disease (SCD)?How are leg ulcers treated in patients with sickle cell disease (SCD)?What are the AHA/ASA guidelines for prevention of primary stroke in patients with sickle cell disease (SCD)?What is the standard care for stroke prevention in children with sickle cell disease (SCD)?How many children with sickle cell disease (SCD) and stroke experience subsequent events if long-term transfusion therapy is not provided?What is an alternative to simple transfusion in the treatment of sickle cell disease (SCD)?What are the AHA/ASA treatment guidelines for children with sickle cell disease at high risk for stroke if RBC transfusion is contraindicated?What is the efficacy of transfusions or hydroxycarbamide for the prevention of stroke in patients with sickle cell disease (SCD)?What is the significance of pulmonary hypertension in patients with sickle cell disease (SCD), and what factors contribute to pulmonary hypertension?What is associated with severe reduction in exercise capacity, in addition to pulmonary hypertension, and what is associated with accelerated mortality in sickle cell disease?How is symptomatic pulmonary hypertension managed in patients with sickle cell disease (SCD)?How are hip complications of sickle cell disease (SCD) (avascular necrosis) treated?Which psychiatric disorders can be caused by sickle cell disease (SCD) and how can they be treated?What is the efficacy of stem cell transplantation (SCT) for the treatment of sickle cell disease (SCD)?What are the restrictions to stem cell transplantation (SCT) for sickle cell disease (SCD)?Are there dietary restrictions for patients with sickle cell disease (SCD)?Are there activity restrictions for patients with sickle cell disease (SCD)?Which activities should be encouraged in children with sickle cell disease (SCD)?Are there investigational treatments for sickle cell disease (SCD)?Which specialist consultations may be required in the treatment of sickle cell disease (SCD)?Which specialist consultations may be required for complications of sickle cell disease (SCD)?When is consultation with an ophthalmologist or urologist indicated in the treatment of sickle cell disease (SCD)?When is consultation with a retina or glaucoma specialist indicated in the treatment of sickle cell disease (SCD)?How often is follow-up required in the treatment of sickle cell disease (SCD)?What education should patients receive about long-term management of sickle cell disease (SCD)?What follow-up care is required for patients with proliferative sickle retinopathy (PSR)?Should fluid intake and output be monitored in the treatment of sickle cell disease (SCD)?What are the increased risks for patients with sickle cell disease (SCD) who have undergone a splenectomy?What is recommended long-term monitoring for infants and children with sickle cell disease (SCD)?What guidelines have been published for the diagnosis and management of of sickle cell disease (SCD)?What are the ASH guidelines on pulmonary hypertenstion (PH) screening and diagnosis in patients with sickle cell disease (SCD)?What are the ASH guidelines on treatment of pulmonary hypertenstion (PH) in patients with sickle cell disease (SCD)?According to the ASH guidelines, when is pulmonary function testing (PFT) indicated in the management of sickle cell disease (SCD)?According to the ASH guidelines, how should patients with sickle cell disease (SCD) be screened for sleep-disordered breathing?According to the ASH guidelines, when is albuminuria screening indicated in the management of sickle cell disease (SCD)?What are the ASH guidelines on the treatment of chronic kidney disease in patients with sickle cell disease (SCD)?What are the ASH guidelines on the management of blood pressure in patients with sickle cell disease (SCD)?What are the ASH guidelines on the management of venous thromboembolism in patients with sickle cell disease (SCD)?How are the ASH guidelines on management of neurological morbidities in sickle cell disease (SCD) stratified?What does ASH recommend for the prevention of stroke in patients with sickle cell disease (SCD)?What are the ASH guidelines for the screening and management of cognitive impairment in patients with sickle cell disorder (SCD)?According to the ASH guidelines, what are the indications for silent cerebral infarcts screening in patients with sickle cell disorder (SCD)?What are the ASH guidelines on the treatment of acute pain in patients with sickle cell disease (SCD)?What are the ASH guidelines on the treatment of chronic pain in patients with sickle cell disease (SCD)?What are the ASH guidelines on long-term monthly transfusion therapy for patients with sickle cell disease (SCD)?What are the ASH guidelines on transfusion support for patients with sickle cell disease (SCD)?What drugs are used in treatment of sickle cell disease (SCD)?Which medications in the drug class Antimetabolites are used in the treatment of Sickle Cell Disease (SCD)?Which medications in the drug class P-Selectin Inhibitor are used in the treatment of Sickle Cell Disease (SCD)?Which medications in the drug class Gene Therapies, Hematologics are used in the treatment of Sickle Cell Disease (SCD)?Which medications in the drug class Tricyclic Antidepressants are used in the treatment of Sickle Cell Disease (SCD)?Which medications in the drug class Nutritionals are used in the treatment of Sickle Cell Disease (SCD)?

Author

Joseph E Maakaron, MD, Research Fellow, Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Coauthor(s)

Ali T Taher, MD, PhD, FRCP, Professor of Medicine, Associate Chair of Research, Department of Internal Medicine, Division of Hematology/Oncology, Director of Research, NK Basile Cancer Center, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Additional Contributors

Mark Ventocilla, OD, FAAO, Chief Executive Officer, Elder Eye Care Group, PLC; Chief Executive Officer, Mark Ventocilla, OD, Inc; President, California Eye Wear, Oakwood Optical

Disclosure: Nothing to disclose.

Acknowledgements

Roy Alson, MD, PhD, FACEP, FAAEM Associate Professor, Department of Emergency Medicine, Wake Forest University School of Medicine; Medical Director, Forsyth County EMS; Deputy Medical Advisor, North Carolina Office of EMS; Associate Medical Director, North Carolina Baptist AirCare

Roy Alson, MD, PhD, FACEP, FAAEM is a member of the following medical societies: Air Medical Physician Association, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, North Carolina Medical Society, Society for Academic Emergency Medicine, and World Association for Disaster and Emergency Medicine

Disclosure: Nothing to disclose.

Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians

Disclosure: Nothing to disclose.

Robert J Arceci, MD, PhD King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Wadie F Bahou, MD Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook

Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Dvorah Balsam, MD Chief, Division of Pediatric Radiology, Nassau University Medical Center; Professor, Department of Clinical Radiology, State University of New York at Stony Brook

Disclosure: Nothing to disclose.

Salvatore Bertolone, MD Director, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Kosair Children's Hospital; Professor, University of Louisville School of Medicine

Salvatore Bertolone, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Education, American Association of Blood Banks, American Cancer Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Kentucky Medical Association

Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences,and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Nedra R Dodds, MD Medical Director, Opulence Aesthetic Medicine

Nedra R Dodds, MD is a member of the following medical societies: American Academy of Anti-Aging Medicine, American Academy of Cosmetic Surgery, American College of Emergency Physicians, American Medical Association, National Medical Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society

Disclosure: Nothing to disclose.

Adlette Inati, MD Head, Division of Pediatric Hematology-Oncology, Medical Director, Children's Center for Cancer and Blood Diseases, Rafik Hariri University Hospital; Research Associate, Balamand University; Head of Post Bone Marrow Transplant Clinic and Consultant Hematologist, Chronic Care Center; Founding Faculty, Lebanese American University School of Medicine, Lebanon

Adlette Inati, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Hematology, European Hematology Association, and International Society of Hematology

Disclosure: Nothing to disclose.

Ziad N Kazzi, MD Assistant Professor, Department of Emergency Medicine, Emory University; Medical Toxicologist, Georgia Poison Center

Ziad N Kazzi, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, and American College of Medical Toxicology

Disclosure: Nothing to disclose.

Richard S Krause, MD Senior Clinical Faculty/Clinical Assistant Professor, Department of Emergency Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Richard S Krause, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Ashok B Raj, MD Associate Professor, Section of Pediatric Hematology and Oncology, Department of Pediatrics, Kosair Children's Hospital, University of Louisville School of Medicine

Ashok B Raj, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and Kentucky Medical Association

Disclosure: Nothing to disclose.

Sharada A Sarnaik, MBBS Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Hosseinali Shahidi, MD, MPH Assistant Professor, Departments of Emergency Medicine and Pediatrics, State University of New York and Health Science Center at Brooklyn

Hosseinali Shahidi, MD, MPH is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, and American Public Health Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Garry Wilkes MBBS, FACEM, Director of Emergency Medicine, Calvary Hospital, Canberra, ACT; Adjunct Associate Professor, Edith Cowan University; Clinical Associate Professor, Rural Clinical School, University of Western Australia

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Ulrich Josef Woermann, MD Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland

Disclosure: Nothing to disclose.

Grace M Young, MD Associate Professor, Department of Pediatrics, University of Maryland Medical Center

Grace M Young, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Emergency Physicians

Disclosure: Nothing to disclose.

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Tests Age Frequency
CBC count with WBC differential,



reticulocyte count



3-24 mo



> 24 mo



Every 3 mo



Every 6 mo



Percent Hb F6-24 mo



> 24 mo



Every 6 mo



Annually



Kidney function (creatinine, BUN, urinalysis)≥ 12 moAnnually
Hepatobiliary function (ALT, fractionated bilirubin)≥ 12 moAnnually
Pulmonary function (transcutaneous O2 saturation)≥ 12 moEvery 6 mo