Sickle Cell Disease (SCD)

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.[5, 6, 7]

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.

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:

• HbSS disease or sickle cell anemia (the most common form) - Homozygote for the S globin with usually a severe or moderately severe phenotype and with the shortest survival

• HbS/b-0 thalassemia - Double heterozygote for HbS and b-0 thalassemia; clinically indistinguishable from sickle cell anemia (SCA)

• HbS/b+ thalassemia - Mild-to-moderate severity with variability in different ethnicities

• HbSC disease - Double heterozygote for HbS and HbC characterized by moderate clinical severity

• HbS/hereditary persistence of fetal Hb (S/HPHP) - Very mild or asymptomatic phenotype

• HbS/HbE syndrome - Very rare with a phenotype usually similar to HbS/b+ thalassemia

• Rare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia, HbO Arab, and others

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 ED have a known diagnosis.

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 properties 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.)

Molecular and cellular changes of hemoglobin S.

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.[8] A current model proposes that vaso-occlusive crises in SCD result from adhesive interactions of sickle cell RBCs and leukocytes with the endothelium.[9]

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.[9]

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).[10] 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 sickle cell anemia 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 physiological changes in RBCs result in a disease with the following cardinal signs:

1. Hemolytic anemia
2. Painful vaso-occlusive crisis
3. Multiple organ damage from microinfarcts, including heart, skeleton, spleen, and central nervous system

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.[11]  However, cognitive impairment, particularly slower processing speed, may occur independent of the presence of infarction and may worsen with age.[12]

Musculoskeletal manifestations

The skeletal manifestations of sickle cell disease 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:

• Infarction of bone and bone marrow
• Compensatory bone marrow hyperplasia
• Secondary osteomyelitis
• Secondary growth defects

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 sickle cell disease. 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.

Infarction of bone and bone marrow in patients with sickle cell disease can lead to the following changes (see images below):

• Osteolysis (in acute infarction)
• Osteonecrosis (avascular necrosis/aseptic necrosis)
• Articular disintegration
• Myelosclerosis
• Periosteal reaction (unusual in the adult)
• H vertebrae (steplike endplate depression; also known as the Reynold sign or codfish vertebrae)
• Dystrophic medullary calcification
• Bone-within-bone appearance
• Skeletal sickle cell anemia. H vertebrae. Lateral view of the spine shows angular depression of the central portion of each upper and lower endplate.

  Skeletal sickle cell anemia. Bone-within-bone appearance. Following multiple infarctions of the long bones, sclerosis may assume the appearance of a bone within a bone, reflecting the old cortex within the new cortex.

The shortened survival time of the erythrocytes in sickle cell anemia (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:

• Decreased density of the skull
• Decreased thickness of outer tble of skull due to widening of diploe
• Hair on-end striations of the calvaria
• Osteoporosis sometimes leading to biconcave vertebrae, coarsening of trabeculae in long and flat bones, and pathologic fractures

Patients with sickle cell disease can have a variety of growth defects due to the abnormal maturation of bone. The following growth defects are often seen in sickle cell disease:

• Bone shortening (premature epiphyseal fusion)
• Epiphyseal deformity with cupped metaphysis
• Peg-in-hole defect of distal femur
• Decreased height of vertebrae (short stature and kyphoscoliosis)

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.[13] In addition, changes in muscle and joints can result in altered posture and impaired balance control.[14]

Renal manifestations

Renal manifestations of SCD range from various functional abnormalities to gross anatomic alterations of the kidneys. See Nephrologic 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 anemia

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 patients 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.

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:

• Cold weather (due to vasospasm)
• Hypoxia (eg, flying in unpressurized aircraft)
• Infection
• Dehydration (especially from exertion or during warm weather)
• Acidosis
• Alcohol intoxication
• Emotional stress
• Pregnancy

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

Aplastic crises are often preceded by the following:

• Infection with parvovirus B19
• Folic acid deficiency
• Ingestion of bone marrow toxins (eg, phenylbutazone)

Acute chest syndrome has been linked to the following:

• Fat embolism
• Infections
• Pain episodes
• Asthma. ^[15]

SCD is present mostly in blacks. 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 renal failure.

United States statistics

The sickle gene is present in approximately 8% of black Americans. The expected prevalence of sickle cell anemia in the United States is 1 in 625 persons at birth. The actual prevalence is less because of early mortality. More than 2 million people in the United States, nearly all of them of African American ancestry, carry the sickle gene. More than 30,000 patients have homozygous HbS disease.

The following statistics are available from the Centers for Disease Control and Prevention and the National Institutes of Health[16, 17] :

• Sickle cell anemia is the most common inherited blood disorder in the United States
• In the United States, approximately 100,000 people have SCD
• SCD occurs in about 1 of every 16,300 Hispanic-American births
• Approximately 1 in 13 black or African Americans has sickle cell trait

In the United States, SCD accounts for less than 1% of all new cases of end-stage renal disease (ESRD).[18] The following factors are known to portend a greater likelihood of progression to overt renal failure: hypertension, nephrotic-range proteinuria, hematuria, severe anemia, and a Central African Republic heritage.[19, 20, 21] In patients with SCD, 5-18% develop renal failure.[22] In one study cohort, the median age at the time of renal failure in patients with SCD was 23.1 years.

International statistics

In several sections 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 parts 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.[23]

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.

The median age at the time of renal failure in patients with SCD is 23.1 years, the median survival time after the diagnosis of ESRD is about 4 years, and the median age of death is 27 years, despite dialysis treatment.[24]

Because SCD is a lifelong disease, prognosis is guarded. The goal is to achieve a normal life span with minimal morbidity. As therapy improves, the prognosis also improves. 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.

Prognostic factors in SCD

The following prognostic factors have been identified as predictors of an adverse outcome[25] :

• Hand-foot syndrome (dactylitis) in infants younger than 1 year
• Hb level of less than 7 g/dL
• Leukocytosis in the absence of infection

Hand-foot syndrome, which affects children younger than 5 years, has proved a strong predictor of overall severity (ie, death, risk of stroke, high pain rate, recurrent acute chest syndrome). Those that 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 WBC count is elevated.

Pregnancy in SCD

Pregnancy represents a special area of concern. The high rate of fetal loss is due to spontaneous abortion. Placenta previa and abruption are common due to hypoxia and placental infarction. At birth, the infant often is premature or has low birth weight.

Mortality in SCD

Mortality is high, especially in the early childhood years. Since the introduction of widespread penicillin prophylaxis and pneumococcal vaccination, a marked reduction has been observed in childhood deaths. 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.

In the Dallas newborn cohort, estimated survival at 18 years was 94%. In a recent neonatal United Kingdom cohort followed in a hospital and community-based program including modern therapy with transcranial Doppler ultrasonography (TCD) screening, the estimated survival of HbSS children at 16 years was 99%. Data from the 1995 cooperative study of SCD (CSSCD) suggested that the median survival for individuals with SCD was 48 years for women and 42 years for men.[26] This life expectancy was considerably lower than that for African Americans who do not have SCD.

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.

Data from Quinn et al in 2004 suggest that mortality from SCD has improved over the past 30 years.[27] In earlier reports, approximately 50% of patients did not survive beyond age 20 years, and most did not survive to age 50 years.

In one study, the median survival time in patients with SCD after the diagnosis of ESRD was about 4 years, and the median age of death after diagnosis was 27 years, despite dialysis treatment.[24]

The cooperative study of SCD (CSSCD) estimated that the median survival for individuals with SS was 48 years for women and 42 years for men.[26] In the Dallas newborn cohort, estimated survival at 18 years was 94%. In a recent neonatal United Kingdom cohort followed in a hospital and community-based program including modern therapy with TCD screening, the estimated survival of HbSS children at 16 years was 99%.

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 and chelation therapy, hydroxyurea therapy, parental and patient education and, above all, treatment in comprehensive centers have all likely contributed to this effect on longevity.

However, as the population of patients with SCD grows older, new chronic complications are appearing. Pulmonary hypertension is emerging as a relatively common complication and is one of the leading causes of morbidity and mortality in adults with SCD.[28]

A study of 398 outpatients with SCD in France found that the prevalence of pulmonary hypertension confirmed by right heart catheterization was 6%; echocardiography alone had a low positive predictive value for pulmonary hypertension.[29]

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 patients to seek medical care in certain situations, including the following:

• Persistent fever (>38.3°C)
• Chest pain, shortness of breath, nausea, and vomiting
• Abdominal pain with nausea and vomiting
• Persistent headache not experienced previously

Patients should avoid the following:

• Alcohol
• Nonprescribed prescription drugs
• Cigarettes, marijuana, and cocaine
• Seeking care in multiple institutions

Families should be educated on the importance of hydration, diet, outpatient medications, and immunization protocol. 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 actually has 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.[30]

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 the Sickle Cell Disease Directory.

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

The most common clinical manifestation of SCD is vaso-occlusive crisis. A vaso-occlusive crisis occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and resultant pain. Pain crises constitute the most distinguishing clinical feature of sickle cell disease and are the leading cause of emergency department visits and hospitalizations for affected patients.

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

Pain crises begin suddenly. The crisis may last several hours to several days and terminate as abruptly as it began.

The pain can affect any body part. It often involves the abdomen, bones, joints, and soft tissue, and it may present as dactylitis (bilateral painful and swollen hands and/or feet in children), acute joint necrosis or avascular necrosis, or acute abdomen.[31] With repeated episodes in the spleen, infarctions and autosplenectomy predisposing to life-threatening infection are usual. The liver also may infarct and progress to failure with time. Papillary necrosis is a common renal manifestation of vaso-occlusion, leading to isosthenuria (ie, inability to concentrate urine).

Severe deep pain is present in the extremities, involving long bones. Abdominal pain can be severe, resembling acute abdomen; it may result from referred pain from other sites or intra-abdominal solid organ or soft tissue infarction. Reactive ileus leads to intestinal distention and pain.

The face also may be involved. Pain may be accompanied by fever, malaise, and leukocytosis.

Bone pain is often due to bone marrow infarction. Certain patterns are predictable, since pain tends to involve bones with the most bone marrow activity and because marrow activity changes with age. During the first 18 months of life, the metatarsals and metacarpals can be involved, presenting as dactylitis or hand-foot syndrome.

As the child grows older, pain often involves the long bones of the extremities, sites that retain marrow activity during childhood. Proximity to the joints and occasional sympathetic effusions lead to the belief that the pain involves the joints. As marrow activity recedes further during adolescence, pain involves the vertebral bodies, especially in the lumbar region.

Although the above patterns describe commonly encountered presentations, any area with blood supply and sensory nerves can be affected.

Triggers of vaso-occlusive crisis

Often, no precipitating cause can be identified. However, because deoxygenated hemoglobin S (HbS) becomes semisolid, the most likely physiologic trigger of vaso-occlusive crises is hypoxemia. This may be due to acute chest syndrome or accompany respiratory complications.

Dehydration can precipitate pain, since acidosis results in a shift of the oxygen dissociation curve (Bohr effect), causing hemoglobin to desaturate more readily. Hemoconcentration also is a common mechanism.

Another common trigger is changes in body temperature—whether an increase due to fever or a decrease due to environmental temperature change. Lowered body temperature likely leads to crises as the result of peripheral vasoconstriction. Patients should wear proper clothing and avoid exposure to ensure normal core temperature.

Chronic pain in SCD

Many individuals with SCD experience chronic low-level pain, mainly in bones and joints. Intermittent vaso-occlusive crises may be superimposed, or chronic low-level pain may be the only expression of the disease.

Anemia

Anemia is universally present. It is chronic and hemolytic in nature and usually very well tolerated. While patients with an Hb level of 6-7 g/dL who are able to participate in the activities of daily life in a normal fashion are not uncommon, their tolerance for exercise and exertion tends to be very limited.

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

Children exhibit few manifestations of anemia because they readily adjust by increasing heart rate and stroke volume; however, they have decreased stamina, which may be noted on the playground or when participating in physical education class.

Aplastic crisis

A serious complication is the aplastic crisis. This is caused by infection with Parvovirus B-19 (B19V). This virus causes fifth disease, a normally benign childhood disorder associated with fever, malaise, and a mild rash. This virus infects RBC progenitors in bone marrow, resulting in impaired cell division for a few days. Healthy people experience, at most, a slight drop in hematocrit, since the half-life of normal erythrocytes in the circulation is 40-60 days. In people with SCD, however, the RBC lifespan is greatly shortened (usually 10-20 days), and a very rapid drop in Hb occurs. The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.

Splenic sequestration

Splenic sequestration occurs with highest frequency during the first 5 years of life in children with sickle cell anemia. Splenic sequestration can occur at any age in individuals with other sickle syndromes. This complication is characterized by the onset of life-threatening anemia with rapid enlargement of the spleen and high reticulocyte count.

Splenic sequestration is a medical emergency that demands prompt and appropriate treatment. Parents should be familiar with the signs and symptoms of splenic sequestration crises. Children should be seen as rapidly as possible in the emergency room. Treatment of the acute episode requires early recognition, careful monitoring, and aggressive transfusion support. Because these episodes tend to recur, many advocate long-term transfusion in young children and splenectomy in older children.

Infection

As HbS replaces HbF in the early months of life, problems associated with sickling and red cell membrane damage begin. The resulting rigid cells progressively obstruct and damage the spleen, which leads to functional asplenia. This, along with other abnormalities, results in extreme susceptibility to infection.

Organisms that pose the greatest danger include encapsulated respiratory bacteria, particularly Streptococcus pneumoniae. The mortality rate of such infections has been reported to be as high as 10-30%. Consider osteomyelitis when dealing with a combination of persistent pain and fever. Bone that is involved with infarct-related vaso-occlusive pain is prone to infection. Staphylococcus and Salmonella are the 2 most likely organisms responsible for osteomyelitis.

During adult life, infections with gram-negative organisms, especially Salmonella, predominate. Of special concern is the frequent occurrence of Salmonella osteomyelitis in areas of bone weakened by infarction.

Effects on growth and maturation

During childhood and adolescence, SCD is associated with growth retardation, delayed sexual maturation, and being underweight. Rhodes et al demonstrated that growth delays during puberty in adolescents with SCD is independently associated with decreased Hb concentration and increased total energy expenditure.[32]

Rhodes et al found that children with SCD progressed more slowly through puberty than healthy control children. Affected pubertal males were shorter and had significantly slower height growth than their unaffected counterparts, with a decline in height over time; however, their annual weight increases did not differ. In addition, the mean fat free mass increments in affected males and females were significantly less than those of the control children.[32]

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, the acute chest syndrome consists of chest pain, fever, cough, tachypnea, leukocytosis, and pulmonary infiltrates in the upper lobes. Adults are usually afebrile and dyspneic with severe chest pain and multilobar and lower lobe disease.

Acute chest syndrome is a medical emergency and must be treated immediately. Patients are otherwise at risk for developing acute respiratory distress syndrome.

Acute chest syndrome probably begins with infarction of ribs, leading to chest splinting and atelectasis. Because the appearance of radiographic changes may be delayed, the diagnosis may not be recognized immediately.

In children, acute chest syndrome is usually due to infection. Other etiologies include pulmonary infarction and fat embolism resulting from bone marrow infarction. Recognition of the specific cause is less critical than the ability to assess the management and pace of the lung injury.

Central nervous system involvement

Central nervous system involvement is one of the most devastating aspects of SCD. It is most prevalent in childhood and adolescence. The most severe manifestation is stroke, resulting in varying degrees of neurological deficit. Stroke affects 30% of children and 11% of patients by 20 years. It is usually ischemic in children and hemorrhagic in adults.[33]

Hemiparesis is the usual presentation. Other deficits may be found, depending on the location of the infarct.

Convulsions are frequently associated with stroke. Convulsions occur as an isolated event but also appear in the setting of evolving acute chest syndrome, pain crisis, aplastic crisis, and priapism. Rapid and excessive blood transfusion to a hemoglobin level of greater than 12 g/dL increases blood viscosity and can lead to stroke.

Children with sickle cell disease may have various anatomic and physiologic abnormalities that involve the CNS even if they appear to be neurologically healthy. These silent brain infarcts occur in 17% of patients and may be associated with deterioration in cognitive function, with effects on learning and behavior; these infarcts may increase the potential risk for clinical and subclinical damage to the CNS.

Hemorrhagic stroke is often caused by rupture of aneurysms that might be a result of vascular injury and tend to occur later in life. Moya moya, a proliferation of small fragile vessels found in patients with stenotic lesions, can also lead to cerebral hemorrhage. Hemorrhagic stroke is associated with a mortality rate of more than 29%.

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 are all dilated.

A study by Nicholson et al also indicated that coronary artery dilation is common in children with SCD. The prevalence of coronary artery ectasia in patients with SCD was 17.7%, compared with 2.3% for the general population.[34] 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 associated with fatty food. Consider common bile duct blockage when a child presents with right upper quadrant pain and dramatically elevated conjugated hyperbilirubinemia.

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 Hb SC disease and may lead to loss of vision. See Ophthalmic Manifestations of Sickle Cell Anemia for a complete discussion of this topic.

Leg ulcers

Leg ulcers are a chronic painful problem. They result from minor injury to the area around the malleoli. Because of relatively poor circulation, compounded by sickling and microinfarcts, healing is delayed and infection becomes established.

Priapism

Priapism, defined as a sustained, painful, and unwanted erection, is a well-recognized complication of SCD. Priapism tends to occur repeatedly. When it is prolonged, it may lead to impotence.

According to one study, the mean age at which priapism occurs is 12 years, and, by age 20 years, as many as 89% of males with sickle cell disease have experienced one or more episodes of priapism. Priapism can be classified as prolonged if it lasts for more than 3 hours or as stuttering if it lasts for more than a few minutes but less than 3 hours and resolves spontaneously. Stuttering episodes may recur or develop into more prolonged events.

Prolonged priapism is an emergency that requires urologic consultation. Recurrent episodes of priapism can result in fibrosis and impotence, even when adequate treatment is attempted.

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.

The natural history of symptomatic hip disease in patients with sickle cell disease who are treated conservatively varies with the patient's age. In skeletally immature patients aged 12 years or younger, treatment with analgesics, NSAIDs, and protected weight bearing usually results in healing and remodeling of the involved capital epiphysis, similar to that observed in Legg-Calve-Perthes disease. This approach results in preservation of the joint despite the persistence of deformity, such as coxa magna and coxa plana.

In contrast, conservative management of osteonecrosis usually fails in older adolescents and adults. Progressive flattening and collapse of the femoral head results in painful secondary degenerative arthritis.

Pulmonary hypertension

Blood in the pulmonary circulation is deoxygenated, resulting in a high degree of polymer formation. The lungs develop areas of microinfarction and microthrombi that hinder the flow of blood. The resulting areas that lack oxygenation aggravate the sickling process. Pulmonary hypertension may develop. This may be due in part to the depletion of nitric oxide. Various studies have found that more than 40% of adults with SCD have pulmonary hypertension that worsens with age.

This is increasingly recognized as a serious complication of sickle cell disease, with an incidence as high as 31.8%.[35, 36] Familial clustering has also been recognized. Hemolysis, chronic hypoxia caused by sickle cell disease, and pulmonary disease (eg, recurrent acute chest syndrome, asthma, obstructive sleep apnea) are contributing factors.

Pulmonary hypertension is characterized by a regurgitant pulmonary (tricuspid) jet velocity of more than 2.5 m/s by echocardiography. Recently, there has been a lot of debate about the positive predictive value of measuring tricuspid regurgitant jet velocity. A recent study found that in a population of sickle cell patients, 25% had a tricuspid regurgitant jet of more than 2.5 m/s, but only 6% had actual pulmonary hypertension on right-sided heart catheterization.[37] It is associated with a high mortality rate in adult patients. Children with pulmonary hypertension have lower mortality, but the disease is associated with high morbidity.

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.

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 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 neurological examination to search for focal neurological deficits.

Ocular manifestations

Sickle cell vasoocclusive 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:

• Segmentation "corkscrew" conjunctival vessel, more commonly seen in the inferior bulbar conjunctiva
• Iris infarct and atrophy
• Cataracts
• Phthisis bulbi
• Hyphema

The abnormalities of the posterior segment can be divided into 6 categories, as follows[38, 39, 40, 41] :

• Optic disc changes
• Posterior retinal and macular vascular occlusionChronic macular changes (sickling maculopathy)
• Choroidal vascular occlusions
• Nonproliferative retinal changes
• Proliferative retinal changes

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.[42] 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
• Salmon-patch hemorrhage
• Schisis cavity
• The black sunburst

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.[43, 44]

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. 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 children are irritable and inconsolable.

Skeletal manifestations

The characteristic appearance in children with sickle cell disease includes frontal and parietal bossing and 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 of sickle cell disease. 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 manifestations of the disease.

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.

Screening for hemoglobin S (HbS) at birth is currently mandatory in the United States. This method of case finding allows institution of early treatment and control.

Prenatal diagnosis is also available. The laboratory procedures employed in prenatal testing are sensitive and rapid. 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 low-risk procedure is safe. DNA from amniotic fluid cells can be examined at 16 weeks' gestation. Investigational attempts are ongoing to isolate fetal cells from maternal blood for DNA assay.

Children with sickle cell disease (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.

Newer techniques for noninvasive assessment of the brain have also been used to identify children with asymptomatic brain disease. Transcranial near-infrared spectroscopy or cerebral oximetry is increasingly being used as a screening tool for low cerebral venous oxygen saturation in children with sickle cell disease.

Measurement of 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.[45]

Consider lumbar puncture to exclude meningitis if there is altered mental status, meningeal signs, or fever. When focal neurologic signs are present or intracranial hemorrhage is suspected, consider 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 CBC count, urinalysis, chest radiographs, and blood cultures; prompt administration of intravenous antibiotics active against S pneumoniae; and close observation.

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 WBC count, should be admitted to the hospital. Consider only outpatient treatment 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.

According to the 2003 BCSH guidelines, a full blood count is required for all patients who are admitted to the hospital, with other investigations performed as necessitated by the clinical situation. Intravenous fluids are not routinely indicated, but should be given if the patient is unable to drink, has diarrhea or is vomiting. Nasogastric fluids are an appropriate alternative to IV fluids.[46]

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.

The 2003 BCSH guidelines strongly advocate the use of incentive spirometry for patients with chest or back pain.[46]

Newborn hemoglobinopathy screening

The introduction of newborn screening has been one of the greatest advances in the management of sickle cell disease. Currently, 50 states and the District of Columbia have mandatory universal programs for newborn screening for hemoglobin disorders. Guidelines for screening for sickle cell disease in newborns have been established.[47] If results are positive, a repeat hemoglobin electrophoresis should be performed for confirmation.

Fetal hemoglobin is predominant in young infants. If results show only hemoglobin (Hb) F and S, the child has either sickle cell anemia or HbS–β-0 thalassemia. If results show HbF, S, and C, the child has HbSC disease. If results show HbF, S, and A, determine whether the child has received a transfusion.

If the child has not received a transfusion and S is greater than A, HbS–beta+ thalassemia is most likely the diagnosis. If A is greater than S, the child is presumed to have the sickle trait. If A and S 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.

Hemoglobin electrophoresis

Hemoglobin electrophoresis differentiates individuals who are homozygous for HbS from those who are heterozygous. It establishes the diagnosis of SCD by demonstrating a single band of HbS (in HbSS) or HbS with another mutant hemoglobin in compound heterozygotes.

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 Hb A2 in addition to electrophoresis. If HbS is predominant, Hb F is less than 30% and Hb A2 is elevated, a diagnosis of HbS–beta-0 thalassemia can be inferred. If possible, perform a study of the parents. If the HbA2 level is normal, consider the possibility of concomitant HbSS and iron deficiency. If HbS is greater than A 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.

A homozygous patient will have hemoglobin SS (HbSS, 80-90%), hemoglobin F (HbF, 2-20%), and hemoglobin A2 (HbA2, 2-4%). A carrier patient will have HbSS (35-40%) and hemoglobin A (HbA, 60-65%). The test is not accurate in a patient who has recently received blood transfusions.

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

• Hemoglobin level is 5-9 g/dL

• Hematocrit is decreased to 17-29%

• Total leukocyte count is elevated to 12,000-20,000 cells/mm3 (12-20 X 109/L), with a predominance of neutrophils

• Platelet count is increased

• Erythrocyte sedimentation rate is low

• The reticulocyte count is usually elevated, but it may vary depending on the extent of baseline hemolysis

• Peripheral blood smears demonstrate target cells, elongated cells, and characteristic sickle erythrocytes

• Presence of RBCs containing nuclear remnants (Howell-Jolly bodies) indicates that the patient is asplenic

• Results of hemoglobin solubility testing are positive, but they do not distinguish between sickle cell disease and sickle cell trait

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

Peripheral blood with sickled cells at 400X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Peripheral blood smear with sickled cells at 1000X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Obtaining a series of baseline values on each patient to compare with those 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 (Open Table in a new window)

Standard laboratory tests cannot be used to distinguish pain crisis from the 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 sickle cell 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."[48]

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

• CBC with differential and reticulocyte count

• Liver function tests (LFTs)

• Urinalysis

• Blood cultures

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 sickle cell anemia, 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.

Measurement of blood urea nitrogen (BUN), serum creatinine, and serum electrolytes can be useful. Assays of lactic dehydrogenase and haptoglobin are useful but not required. Elevated levels of lactic dehydrogenase support the diagnosis of hemolysis 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 sickle cell anemia 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 sickle cell anemia is uncertain, a sickling test will establish the presence of 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.

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

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 sickle cell disease 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 2014 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 TCD for this purpose.[45]

Computed Tomography

Although CT is not an initial study in most patients, CT may be useful to demonstrate subtle regions of osteonecrosis not apparent on plain radiographs in patients who are unable to have an MRI.[4]

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

Technetium-99m (99m Tc) 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.[49]

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, would also demonstrate increased activity on111 In WBC scans.

The combination of a bone scan and a bone marrow scan has been used to differentiate acute osteomyelitis from bone infarcts in patient with SCD, since 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 (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.[45, 50] 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.[45]

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.[51] 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.[52] On the other hand, TCD results normalize over time in some patients who do not receive transfusions.

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. Assess liver and spleen size. Abdominal ultrasonography can be used to visualize stones and to detect signs of thickening gallbladder walls or ductal inflammation, indicating possible cholecystitis. Abdominal ultrasound is useful to document spleen size and the presence of biliary stones.

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

Echocardiography is used to identify patients with pulmonary hypertension based on tricuspid regurgitant jet velocity. Patients with sickle cell disease may have an array of abnormalities of systolic and diastolic function. Adults should be tested for evidence of pulmonary hypertension with Doppler echocardiography. Cardiac echocardiography should be performed for patients with dyspnea.

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]

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.[46, 50] Early achievement of maximum analgesia has been shown to shorten hospital stays in pediatric patients with pain from SCD.[55]

If patients with SCD crisis are being transported by emergency medical services (EMS), they 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.[50]

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.

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

• Management of vaso-occlusive crisis
• Management of chronic pain syndromes
• Management of chronic hemolytic anemia
• Prevention and treatment of infections
• Management of the complications and the various organ damage syndromes associated with the disease
• Prevention of stroke
• Detection and treatment of pulmonary hypertension

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[56, 57] :

• Use of daily oral prophylactic penicillin up to age 5
• Annual transcranial Doppler examinations between the ages of 2 and 16 years in patients with sickle cell anemia
• Long-term transfusion therapy to prevent stroke in children with abnormal transcranial Doppler velocity (≥200 cm/s)
• In patients with sickle cell anemia, preoperative transfusion therapy should be used to increase hemoglobin levels to 10 g/dL
• Rapid initiation of opioids for the treatment of severe pain associated with a vasoocclusive crisis
• Use of analgesics and physical therapy for the treatment of avascular necrosis

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, 59]  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.[60]

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, 59]

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.[61, 62]

Voxelotor was also approved by the FDA in 2019. It is indicated for treatment of SCD in adults and adolescents aged 12 years or older. Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to RBCs. By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. Results showed 51% patients on the higher dose of voxelotor achieved a hemoglobin response compared with 6% with placebo.[63]

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.[64] 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.[64, 65]

Gene therapy is emerging as a possible cure for severe SCD. Experimental approaches include modification of autologous stem cells with 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.[66, 67, 68] For example, 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.[69]

Hydroxyurea has an established role as a safe and effective treatment for SCD.[70] Hydroxyurea increases total and fetal hemoglobin in children with SCD.[71] 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[71] and acute chest syndrome episodes.[54]

Effects of therapy with hydroxyurea.

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. Although the evidence for efficacy of hydroxyurea treatment for children is not as strong, the emerging data are encouraging.”[54]

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.[72]

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.[73]  

In December 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 sickle cell anemia who have recurrent moderate to severe painful crises. Siklos is the first hydroxyurea formulation to be FDA-approved for pediatric SCD. The approval was based on data from the ESCORT (European Sickle Cell Disease Cohort), an open-label single-arm trial that enrolled 405 pediatric patients with sickle cell disease from 2-18 years of age (274 children, ages 2-11 y; 108 adolescents, ages 12-16 y). The median change in fetal hemoglobin levels was 0.5 g/dL in 63 patients at 6 months and 0.7 g/dL in 83 patients at12 months after initiation of  treatment. After 12 months of treatment, the drug exhibited an ability to increase fetal hemoglobin in all patients, and decrease the percentage of patients who experienced at least on vaso-occlusive episode, one episode of acute chest syndrome, one hospitalization due to SCD, or one blood transfusion.[74]

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

• Frequent painful episodes (six or more per year) ^[54]
• History of acute chest syndrome
• History of other severe vaso-occlusive events
• Severe symptomatic anemia
• Severe unremitting chronic pain that cannot be controlled with conservative measures
• History of stroke or a high risk for stroke

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.

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:

• Acute infarctive stroke
• Severe acute chest syndrome
• Multiorgan failure syndromes
• Right upper quadrant syndrome
• Priapism that does not resolve after adequate hydration and analgesia

Regular blood transfusions are used for primary and secondary stroke prevention in children with SCD. See 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 pain 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).[75]

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 found 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 times are more likely to lead to acute chest syndrome or other complications. Providing preoperative transfusion may decrease the risk.

Although one study demonstrated no overall difference in the complication rate among subjects who received either preoperative exchange or simple transfusion, it provided little guidance for what type of transfusion would be best in individual situations.

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.[76]

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.

In patients undergoing retinal surgery, the HbS concentration or combined concentration of HbS and HbC needs to be reduced to less than 30% (increase the hemoglobin A concentration to 70%).

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 an inaccurate means of 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. It is administered as a prolonged infusion intravenously or subcutaneously for 5-7 days a week. Although effective, there are significant challenges associated with its use that can result in non-compliance.[77]

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. 

A novel new iron chelator is being developed but is still in the clinical testing phase.[78]

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.[79] Transfusion usually consists of sickle-negative, leuco-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.

Ocular treatment is directed toward preventing vision loss from vitreous hemorrhage, retinal detachment, and epiretinal membranes. Medical ocular management may include topical medications; however, avoid carbonic anhydrase inhibitors, 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 proliferative sickle retinopathy 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. Based on a 71% incidence of anterior segment ischemia in patients with PSR who are undergoing scleral buckling surgery, prophylactic preoperative exchange transfusions or erythropheresis is recommended. Risks associated with exchange transfusions and improvement in vitreoretinal surgical techniques warrant a careful reevaluation of prophylactic exchange transfusions.

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

• Nonsympathomimetic local anesthesia
• Minimization of topical sympathomimetics
• Supplemental oxygen for 48 hours after surgery
• Avoiding wide encircling scleral buckling elements, expansile concentrations of intraocular gases, and carbonic anhydrase inhibitors
• Closely monitoring and treating elevated intraocular pressure

Anterior segment ischemia after surgery is an emergency. Although the prognosis is notoriously poor, make all attempts to oxygenate the anterior segment. Options include hyperbaric oxygen therapy, continuous supplemental oxygen therapy, and transcorneal oxygen with goggles.[80]

Elevated intraocular pressure

Blood in the anterior chamber in patients with sickle cell disease is a medical emergency. A sickle screen is warranted for every black patient who has an unexplained hyphema.[81, 82] 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 sickle cell disease are particularly prone to central retinal artery occlusion and optic atrophy, even with mildly elevated intraocular pressures, closely monitor the intraocular pressure. Do not allow it to exceed 25 mm Hg for longer than 24 hours.

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 patients who presented to the ED in vaso-occlusive crisis.[83] Predictors of admission included the following:

• Higher pain score at triage
• Older age
• Increased systolic blood pressure

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

• Higher pain score at triage
• Older age
• Increased polymorphonuclear count
• Homozygous SCD type

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

The randomized BABY HUG study has demonstrated that hydroxyurea (hydroxycarbamide) significantly reduces the incidence of vaso-occlusive crisis and dactylitis in very young children.[84] The primary toxicity observed was neutropenia. Further study is needed to evaluate long-term treatment effects on growth and development as well as renal, 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.[85]

Crizanlizumab, a P-selectin inhibitor, was approved by the FDA in November 2019 to reduce frequency of vaso-occlusive crisis (VOC) in adults with sickle cell disease. 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 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.[61, 62]  

Pain control 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 (published in in 2012 and confirmed in 2014) include the following recommendations[46] :

• Tailor the analgesic drug, dose, and administration route to the severity of the pain, the age of the patient, and any other pain medications the patient is concurrently taking for the current episode
• Offer a bolus of a strong opioid (eg, morphine) to all patients with severe pain and all patients with moderate pain who have already taken an analgesic
• Consider a weak opioid (eg, acetaminophen and codeine) for patients with moderate pain who have not yet had any analgesia
• Offer all patients regular acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) by a suitable administration route, in addition to an opioid, unless contraindicated
• Do not give meperidine for pain relief
• Chronic opiod use may cause adverse reactions (eg, constipation, dizziness, and itching), offer laxatives, antiemetics and antipruritics as needed

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[50] :

• Initiate analgesic therapy within 30 minutes of triage, or 60 minutes of registration
• Whenever possible, use an individualized prescribing and monitoring protocol (written by the patient’s SCD provider) or an SCD-specific protocol
• In patients with mild to moderate pain, continue treatment with NSAIDs in those who report relief with these agents, unless contraindicated
•  In patients with severe pain, rapidly initiate treatment with parenteral opioids
• Calculate the opioid dose on the basis of the patient’s current short-acting opioid dose being taken at home
• Administer opioids subcutaneously if intravenous access is not obtainable
• Reassess pain every 15-30 minutes until the patient reports that pain is under control; readminister opioids if necessary for continued severe pain
• Reassess for pain relief and monitor for adverse effects after each dose
• Maintain the opioid dose or consider escalation by 25% until pain is controlled
• Administer opioids by around-the-clock patient-controlled analgesia (PCA) or frequently scheduled doses rather than on an as-requested (prn) basis
• In patients receiving PCA, continue long-acting oral opioids unless these agents need to be withheld to prevent oversedation
• At discharge, titrate off the parenteral opioids before conversion to oral opioids, and adjust the home dose of long- and short-acting opioids to prevent opioid withdrawal
• Do not use meperidine unless it is the only effective opioid for that patient
• Use oral NSAIDs as an adjuvant analgesic, unless contraindicated
• Prescribe oral antihistamines for patients who require these agents for itching from opioids; give repeat doses every 4-6 hours, if needed, rather than with each dose of opioid

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, and the dose is reduced gradually over several days. Morphine elixir can be used to control breakthrough pain.

British Committee for Standards in Haematology (BCSH) 2015 guidelines for treatment of acute chest syndrome (ACS) recommend use of the following measures[86] :

• Prompt and adequate pain relief
• Incentive spirometry – In patients with chest or rib pain, to prevent ACS; should be considered in all patients with ACS
• Antibiotics, with cover for atypical organisms, even if blood cultures and sputum cultures are negative
• Anti-viral agents– If there is a clinical suspicion of H1N1 infection
• Early simple transfusion should be considered early in patients with hypoxia; however, exchange transfusion is necessary in patients with severe clinical features or evidence of progression despite initial simple transfusion
• Transfused blood should be sickle-negative and fully matched for Rh (C, D, and E type) and Kell antigens; a history of previous red cell antibodies should be sought and appropriate antigen-negative blood given
• Bronchodilators should be provided in patients with symptoms suggesting a history of asthma or evidence of acute bronchospasm

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 a 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 levels have been found to be associated with ACS and might predict its occurrence. In pilot studies, transfusion of patients who had pain, fever, and increased serum phospholipase A2 levels have apparently thwarted development of ACS.[87]

For episodes of severe hypoxia, rapid progression, diffuse pulmonary involvement, and failure to improve, erythrocytapheresis is indicated. Intensive care is indicated for patients in severe hypoxia or respiratory distress, 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 hematocrit to more than 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.[88]

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.

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 reduce the dose and need for 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.[71] The safety of long-term hydroxyurea use in children remains uncertain, however (see Hydroxyurea Therapy, above).

Nonpharmacological 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[89] :

• How well the patient’s SCD is managed
• Comprehensive assessment of behavioral risks (eg, risk factors for opioid misuse)
• Implications of opioid tolerance on the management of acute pain episodes
• Other known adverse effects of opioids

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:

• The profile of each opioid drug under consideration for use in a given patient should be reviewed, as individual opioid drugs have different specific toxicity profiles and interactions with end-organ injury.
• Prescribe the lowest effective opioid dose.
• Patients on COT should avoid the use of benzodiazepines, sedating medications, and alcohol.
• Providers should be aware that patients may inadvertently end up on COT if episodic pain is frequent enough that patients are receiving frequent opioid treatment of recurrent pain. Therefore, providers should make efforts to reduce or eliminate scheduled opioid doses between acute episodic pain events, which may reduce the likelihood of unintentional COT.
• Acute pain events may still be treated with opioid analgesia if this serves the overall pain treatment plan, but this should be done in conjunction with the primary outpatient management team. Furthermore, nonopioid medications and integrative therapies should also be offered; strategies for these can be developed through collaboration with a pain specialist.
• Patients on COT require careful monitoring with regard to functional status and risk assessment for the development of aberrant opioid use and medical, social, behavioral, or psychological complications, as a precursor to opioid dose reduction or weaning.
• Weaning and/or withdrawal from COTpotentially poses higher risk in patients with SCD (ie, it may trigger vasoocclusive events or other medical complications) and should be done carefully.
• The risk of adverse events related to COT rises as the total dose increases. Therefore, patients on high doses of opioids need close monitoring for complications and adverse effects.

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

• Poor surgical outcomes
• Motor vehicle collisions
• Myocardial infarction
• Bone fracture
• Mortality
• Hormonal alterations, which can lead to sexual dysfunction, with doses of >120 mg morphine milligram equivalents (MME)
• Overdose – Risk of overdose is ninefold higher with doses >100 mg MME, compared with doses < 20 mg MME in general non-SCD pain populations

.

Anemia is usually well tolerated. 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 doses for folic acid therapy are age based, as follows:

• Younger than 6 months: 0.1 mg/day
• Ages 6 months to 1 year: 0.25 mg/day
• Ages 1-2 years: 0.5 mg/day
• Older than 2 years: 1 mg/day

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.

Voxelotor, which was approved by the FDA in November 2019, is the first drug approved by the FDA for sickle cell disease based solely on data showing an increase in hemoglobin. It is indicated for treatment of sickle cell disease in adults and adolescents aged 12 years or older. Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to RBCs. By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. 

Approval of voxelotor was based on results from a clinical trial that enrolled 274 patients with sickle cell disease and treated them with either 1500 mg or 900 mg PO once daily of voxelotor or placebo. Results showed 51% patients on the higher dose of voxelotor achieved a hemoglobin response, defined as an increase in hemoglobin of at least 1 g/dL after 24 weeks. Just over 6% of the placebo patients had the same hemoglobin response. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group.[63]

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 (Hb) 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.

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.[46] 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.

Protein-conjugated pneumococcal vaccines (PCVs) that effectively protect children against invasive infections are now extensively used. The 7-serotype PCV (PCV7) in combination with penicillin prophylaxis and PPV23 booster vaccination offers the best hope for improved prevention against S pneumoniae infection. The vaccine is given at age 2 years, with a booster dose at age 5 years.

In one study, more than two thirds of S pneumoniae isolates stereotyped were PCV7 serotypes and included most penicillin-nonsusceptible strains. Most nonvaccine-serotype isolates were penicillin-sensitive.

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. Meningococcal prophylaxis is administered as a single quadrivalent vaccine when the child is older than 2 years.

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.[90]

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.[91] (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 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.[92, 93] 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.[94]

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.

Adults with SCD should be evaluated for known stroke risk factors and managed according to the 2014 AHA/ASA primary stroke prevention guidelines.[45]

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.[95]

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.[96] 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.[45]

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.[52]

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.[97]

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.[45] 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.[98] 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.[99]

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”.[100]

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.[101]

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.[101]

Pulmonary hypertension, defined as a tricuspid regurgitant jet velocity (TRJV) greater than 2.5 m/s on echocardiography, is an emergent complication seen in 32% of adult patients with SCD and is associated with a high mortality rate. Pulmonary hypertension is a complication of chronic intravascular hemolysis. Additional factors contributing to pulmonary hypertension include older age, renal insufficiency, cardiovascular disease, cholestatic hepatopathy, systolic hypertension, high hemolytic markers, iron overload, and a history of priapism.

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 sickle cell disease 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.

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

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. Avascular osteonecrosis may result from chronic hypoxia in weight-bearing joints, commonly the femoral head. Joint replacement is often necessary.

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.

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-vs-host disease (GVHD)–free survival rate in those age groups was 86% and 77%, respectively.[64]

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[102] :

• Stroke (or central nervous system event lasting longer than 24 hours)
• Recurrent acute chest syndrome
• Recurrent severe crisis pain (>2 episodes/y for several years)
• Recurrent priapism
• Impaired neuropsychological function with evidence of cerebral infarction on imaging studies
• Sickle cell nephropathy (glomerular filtration rate 30–50% of predicted normal)
• Stage I or II sickle lung disease
• Bilateral proliferative retinopathy and major visual impairment in at least one eye
• Osteonecrosis of multiple joints
• Red cell alloimmunization with more than 2 antibodies during long-term transfusion therapy

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.[103, 65]

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.[64, 65] A reduced-intensity conditioning regimen was also used in a successful pilot study of HSCT in adolescents and young adults (age 17-36 years).[104]

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

• Nitric oxide inhalation has been investigated in the treatment of pulmonary hypertension.
• Topical GM-CSF has been reported to hasten the healing of leg ulcers.
• Butyrate was studied to decrease vaso-occlusive crisis.
• Arginine has been proposed to use as a precursor of nitric oxide production.

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 and 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 follow-up is required for patients with SCD. This is a lifelong disorder. 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 depends on involvement with proliferative sickle retinopathy (PSR); 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 in patients with SCD.

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.[105] Pneumococcal and influenza vaccination is safe in patients with functioning kidney transplants.[106, 107, 108] However, the use of live vaccines is contraindicated due to the immunosuppressive therapy that these patients require.

For infants with sickle cell disease, 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.

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.)[109, 110, 89, 111]  In 2021, ASH issued guidelines on hematopoietic stem cell transplantation (HSCT) in SCD.[112]

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.[109] 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:

• Dyspnea, hypoxemia, or chest pain, at rest or with exertion, that is out of proportion to known condition, increased compared with baseline, or unexplained
• Increase in exercise limitation compared with baseline that is unexplained by other factors
• History of recurrent hypoxemia at rest or with exertion
• Evidence for sleep-disordered breathing with or without hypoxemia
• History of syncope or presyncope
• Loud P2 component of second heart sound or unexpected or new murmur on examination
• Signs of heart failure and/or fluid overload on examination
• History of pulmonary embolism

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:

• For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of 2.5 to 2.9 m/sec, the ASH guideline panel suggests against right-heart catheterization.
• For patients with peak TRJV of ≥2.5 m/sec who are asymptomatic, measurement of N-terminal pro-B-type natriuretic peptide (NT-BNP) levels and 6-minute walk distance (6MWD) may help to improve the diagnostic accuracy for PH. Cutoff values for abnormal NT-BNP and 6MWD have not been firmly determined for patients with SCD. However, NT-BNP values of ≥160 pg/mL and 6MWD values of < 333 m represent reasonable thresholds for adults with SCD, based on published studies in this population. Referrals for right-heart catheterization should also account for clinical judgment and discussion with a PH expert.
• For children and adults with SCD and a peak TRJV of ≥2.5 m/sec who also have a reduced 6MWD and/or elevated NT-BNP, the ASH guideline panel suggests right-heart catheterization.
• Patients whose echocardiograms demonstrate elevated peak TRJV should undergo repeat echocardiography prior to referral for right-heart catheterization under the guidance of a PH expert, because reproducibility of TRJV measurements may vary due to technical factors, severity of anemia, or increased cardiac output.
• For patients with peak TRJV of ≥2.5 m/sec who have normal 6MWD and NT-BNP, serial noninvasive monitoring with echocardiograms should be considered if clinically indicated.
• Consultation with a PH expert regarding the need for a right-heart catheterization should be considered for patients with TRJV of >2.9 m/sec who have normal 6MWD and NT-BNP or other echocardiographic findings, in addition to elevated peak TRJV, that could suggest significant PH (eg, right atrial enlargement, pericardial effusion, right ventricular failure, or septal flattening).
• PH is defined hemodynamically by right-heart catheterization using a mean pulmonary artery pressure threshold of > 20 mm Hg (recently reduced from ≥25 mm Hg). However, the mean pulmonary artery pressure alone does not distinguish pulmonary artery hypertension (PAH) from other forms of PH. Additional criteria for the diagnosis of PAH include a pulmonary artery wedge pressure of ≤15 mm Hg and a pulmonary vascular resistance of ≥3 Wood units (240 dyn × seconds × cm ⁻⁵).

Treatment of PAH is as follows:

• For children and adults with SCD who do not have PAH confirmed by right-heart catheterization, the ASH guideline panel strongly recommends against the use of PAH-specific therapies. 
• For children and adults with SCD and a diagnosis of PAH confirmed by right-heart catheterization, the ASH guideline panel recommends considering initiation and/or optimization of disease-modifying therapy such as hydroxyurea or chronic transfusions.
• For children and adults with SCD and a diagnosis of PAH confirmed by right-heart catheterization, the ASH guideline panel suggests the use of PAH-specific therapies under the care of a PH specialist, given the lack of alternative treatment options, associated high morbidity and mortality, and the possibility of increased adverse effects (eg, pain) with PAH-specific therapy such as sildenafil.
• Consider potential differences in the pathophysiologic basis of PAH (eg, contribution of chronic anemia and high-output cardiac states) and differences in adverse-effect profiles (eg, pain) when determining treatment options for PAH confirmed by right-heart catheterization in SCD.
• The recommendation for PAH-specific therapy in SCD applies to patients with SCD who have no other clear reason for their PAH confirmed by right-heart catheterization (eg, obstructive sleep apnea, significant lung disease, left-heart failure).

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

• Improvements in cardiopulmonary hemodynamics, as determined by right-heart catheterization
• Improvements in clinical status, such as a change in PAH symptoms or functional status, initiation of other PAH drugs, or diuretic requirements (eg, in the setting of right-heart failure)

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:

• Wheezing or increased cough at rest, with exertion, or during episodes of acute upper respiratory infection
• Dyspnea at rest or with exertion that is increased compared with baseline or that is unexplained
• Chest pain at rest or with exertion that is out of proportion to a known condition, that is increased compared with baseline, or that is unexplained
• Increase in exercise limitation compared with baseline or that is unexplained (eg, not resulting from sickle cell pain or musculoskeletal disease)
• Abnormal 6MWD defined by either reduced 6MWD or oxygen desaturation during test
• History of recurrent hypoxemia at rest or with exertion
• History of syncope or presyncope
• History of recurrent acute chest syndrome
• History of pulmonary embolism

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

For asymptomatic children and adults with SCD, the ASH guideline panel suggests against screening with formal polysomnography (sleep study) for sleep-disordered breathing.[109]

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:

• Snoring
• Witnessed apneas or respiratory pauses
• Nonrestorative sleep and/or excessive daytime sleepiness
• Obesity
• Early morning headaches
• Unexplained desaturation or hypoxemia during sleep, while awake, or with exertion
• Carbon dioxide retention on arterial blood gas
• History of poorly controlled hypertension or congestive heart failure
• History of nocturnal enuresis in an older child (eg, ≥10 years old)
• History of recurrent priapism or frequent daytime or nocturnal vaso-occlusive pain
• History of PH confirmed by right-heart catheterization
• History of ischemic stroke without evidence for vasculopathy
• History of memory loss, difficulty with concentration, or unexplained episodes of mental confusion
• Symptoms of attention deficit–hyperactivity disorder, poor academic achievement, and performance or behavior problems in children

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.

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:

• Start medication at a lower dose in individuals with a glomerular filtration rate (GFR) of < 45 mL/min/1.73 m ²
• Assess GFR and measure serum potassium within 1 week of starting medication or following any dose escalation
• Temporarily suspend medication during interval illness, planned IV radiocontrast administration, or bowel preparation for colonoscopy or prior to major surgery. 

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.

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.

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).[110] Strong recommendations are summarized below.

Stroke prevention and treatment

Primary stroke prevention in children:

• Annual transcranial Doppler (TCD) screening for children aged 2-16 years with hemoglobin SS (HbSS) or HbSβ0 thalassemia (all income settings)
• Regular blood transfusions for a minimum of 1 year for children aged 2-16 years with HbSS or HbSβ0 thalassemia who have abnormal TCD velocities and live in a high-income setting; this refers to a setting that permits regular blood transfusion therapy, typically every 3-4 weeks, to maintain the maximum HbS level below 30% and the hemoglobin level above 9.0 g/dL, to reduce stroke risk.

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:

• For children with HbSS or HbSβ ⁰ thalassemia and a history of prior ischemic stroke, blood transfusion goals for secondary stroke prevention are to increase the hemoglobin level above 9 g/dL at all times and maintain the HbS level at < 30% of total hemoglobin until the time of the next transfusion.

Cognitive impairment

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

• Conduct surveillance, using simplified signaling questions, for concerns about developmental delays in preschool-age children and concerns about neurodevelopmental disorders in school-age children, such as academic or behavioral problems or symptoms of inattention, hyperactivity, or impulsivity.

• For children who have abnormal surveillance results suggesting increased risk for developmental delay or cognitive impairment, screen or referl for formal screening by a psychologist or a pediatrician able to perform screening with the available validated tools

• For adults, conduct surveillance for cognitive impairment using simplified signaling questions; in those with abnormal results suggesting cognitive impairment, provide formal referral to a psychologist or a primary care physician able to perform more in-depth cognitive evaluation.

Rehabilitation for children and adults with cognitive impairments

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

• Developmental, cognitive, and medical assessment to diagnose any related disorders and to identify any modifiable risk factors for developmental delays or cognitive impairments
• Delivery of appropriate interventions by following the cognitive domain–specific, evidence-based guidelines for these disorders

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

• Cognitive and medical assessment to diagnose any related disorders and to identify any modifiable risk factors for cognitive impairments
• Delivery of appropriate interventions by following the cognitive domain–specific, evidence-based guidelines for these disorders

Cerebral infarcts

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

• At least a one-time magnetic resonance imaging (MRI) screening, without sedation, is recommended to detect silent cerebral infarcts in early school-aged children. This recommendation is made in view of the fact that silent cerebral infarcts are highly prevalent in children with HbSS or HbSβ0 thalassemia (1 in 3) and are associated with cognitive impairment, poor school performance, and future cerebral infarcts.

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.[89]

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.

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.[111] The guidelines also include the following suggestions (ie, conditional recommendations based on very low certainty in the evidence):

• Obtaining an extended red cell antigen profile by genotype (preferred) or serology in all patients with SCD (all genotypes) at the earliest opportunity (optimally before first transfusion). An extended red cell antigen profile includes C/c, E/e, K, Jk ^a/Jk ^b, Fy ^a/Fy ^b, M/N, S/s at a minimum.
• In patients with SCD (all genotypes) who are having a delayed hemolytic transfusion reaction and ongoing hyperhemolysis, provide immunosuppressive therapy (IVIg, steroids, rituximab, and/or eculizumab).
• Automated red cell exchange (RCE) is preferred over simple transfusion or manual RCE in patients with SCD (all genotypes) receiving chronic transfusions.
• Automated RCE or manual RCE is preferred over simple transfusions in patients with SCD and severe acute chest syndrome.
• Automated RCE, manual RCE, or simple transfusions may be used in patients with SCD and moderate acute chest syndrome.
• Use either red cell exchange with isovolemic hemodilution (IHD-RCE) or conventional RCE in patients with SCD (all genotypes) receiving chronic transfusions. (In IHD-RCE, which is available on some automated apheresis devices, the patient undergoes a red cell depletion with concurrent volume replacement before the RCE, with the intent of decreasing the number of red cell units needed for the RCE.) IHD-RCE is not advised for acute indications for RCE or when induction of further anemia during the IHD phase may be generally detrimental (eg, recent history of stroke or transient ischemic attack, severe vasculopathy, or severe cardiopulmonary disease).
• In pregnant patients with SCD (all genotypes) who have a history of severe SCD-related complications or other high-risk features, prophylactic transfusion at regular intervals may be considered; in other cases, standard care (transfusion when clinically indicated for a complication or hemoglobin lower than baseline) may be provided.
• Provide preoperative transfusion for patients with SCD undergoing surgeries that require general anesthesia and last longer than 1 hour. The goal for preoperative total hemoglobin levels is > 9 g/dL; RCE transfusion should be used for patients who require preoperative transfusion but have a high hemoglobin level (> 9-10 g/dL) that precludes administration of simple transfusion.
• To assess liver iron content, iron overload screening by MRI (R2, T2*, or R2*) every 1 to 2 years is preferred over serial monitoring of ferritin levels alone in patients with SCD (all genotypes) receiving chronic transfusion therapy.
• To assess for cardiac iron content, serial monitoring of ferritin levels alone is preferred over routine iron overload screening by T2* MRI in patients with SCD (all genotypes) receiving chronic transfusion therapy. However, cardiac T2*MRI screening may be considered for the subgroup of patients with SCD with a high iron burden (liver iron content > 15 mg/g [dw]) for 2 years or more, evidence of end organ damage resulting from transfusional iron overload, or evidence of cardiac dysfunction.

ASH 2021 guidelines for HSCT in SCD include the following conditional recommendations[112] : 

• Consider HLA-matched related HSCT rather than standard of care (ie, hydroxyurea [HU]/transfusion) in patients with SCD who have experienced an overt stroke or have an abnormal transcranial Doppler ultrasound (TCD).
• Consider related matched allogeneic HSCT for patients with frequent pain despite standard of care.
• Consider matched related allogeneic HSCT for patients with recurrent episodes of acute coronary syndrome despite optimal standard of care.
• For patients with SCD with an indication for HSCT who lack a matched sibling donor (MSD), consider using transplants from alternative donors in the context of a clinical trial.
• For allogeneic HSCT, consider using either total-body irradiation (TBI) ≤400 cGy or chemotherapy-based conditioning regimens.
• For children with SCD who have an indication for allogeneic HSCT and an MSD, consider using myeloablative conditioning rather than reduced-intensity conditioning (RIC) that contains melphalan/fludarabine regimens. 
• For adults with SCD who have an indication for allogeneic HSCT and an MSD, consider using nonmyeloablative conditioning rather than RIC that contains melphalan/fludarabine regimens.
• In patients with SCD who have an indication for HSCT and who are eligible for it, consider using allogeneic transplantation at an earlier age rather than an older age.
• Consider using HLA-identical sibling cord blood when available (and if there is an adequate cord blood cell dose with good viability) rather than bone marrow.

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.

Class Summary

Hydroxyurea affects DNA, resulting in increased production of Hb F, which inhibits sickling. Considerable effort is being expended to identify agents whose ultimate effect interferes with the sickling process and prevents the many complications of sickle cell disease.

Hydroxyurea (Siklos)

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

Class Summary

Opioid analgesics are used to control acute crisis and chronic pain.

Oxycodone and aspirin (Percodan)

This drug combination is indicated for the relief of moderate to severe pain. Oxycodone binds to opiate receptors in the CNS inhibiting the ascending pain pathways, altering pain response and perception. Aspirin inhibits platelet aggregation; has analgesic and anti-inflammatory properties.

Methadone (Dolophine, Methadose)

Methadone is used in the management of severe pain. It inhibits ascending pain pathways, diminishing the perception of and response to pain.

Morphine sulfate (Duramorph, Infumorph, MorphaBond ER, MS Contin, Kadian)

An opioid analgesic, morphine interacts with endorphin receptors in the CNS, inhibiting the pain pathways, altering pain response and perception.

Oxycodone and acetaminophen (Percocet, Endocet, Primlev)

This drug combination is indicated for the relief of moderate to severe pain. It is the drug of choice for patients who are hypersensitive to aspirin.

Fentanyl (Sublimaze PF, Duragesic, Abstral, Actiq, Fentora)

A synthetic opioid analgesic that is primarily a mu receptor agonist, fentanyl is 50-100 times more potent than morphine. Unlike morphine, fentanyl is not commonly associated with histamine release.

Nalbuphine

An opioid agonist/antagonist, nalbuphine stimulates kappa opioid receptor in the CNS, which causes inhibition of ascending pain pathways. An antagonist at the opioid mu receptors, it is useful for moderate-to-severe pain in sickle cell disease.

Codeine

Codeine binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering perception and response to pain.

Codeine/acetaminophen (Tylenol with Codeine #3,Tylenol with Codeine #4 )

This combination is a mild narcotic analgesic. Acetaminophen believed to inhibit the synthesis of prostaglandins in the CNS, and peripherally block pain impulse generation. Codeine binds to in the CNS; causing inhibition of ascending pain pathways, altering pain perception and response.

Class Summary

Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) add to the effects of opioids during painful crisis. This allows use of lower doses of narcotics.

Ketorolac

Ketorolac is an intravenously administered NSAID and a very powerful analgesic. It inhibits prostaglandin synthesis by decreasing activity of the enzyme cyclooxygenase, which results in decreased formation of prostaglandin precursors. In turn, this results in reduced inflammation.

Aspirin (Ecotrin, Ascriptin, Bayer Aspirin, St. Joseph Adult Aspirin, Durlaza)

Aspirin treats mild to moderate pain. It inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Acetaminophen (Tylenol, Aspirin-Free Anacin, Acephen, Cetafen Extra, Ofirmev)

Acetaminophen is the drug of choice for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants. Acetaminophen is believed to work peripherally to block pain impulse generation.

Ibuprofen (Advil, Genpril, I-Prin, Motrin IB, Addaprin)

Ibuprofen is usually the drug of choice for treatment of mild to moderate pain, if no contraindications exist. It inhibits inflammatory reactions and pain by decreasing the activity of the enzyme cyclo-oxygenase, resulting in inhibition of prostaglandin synthesis.

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.

Amitriptyline (Elavil)

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

Nortriptyline (Pamelor)

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

Supplemental folic acid replenishes the depleted folate stores necessary for erythropoiesis.

Folic acid (FA-8)

Folic acid is necessary for proper nucleotide metabolism. It is an important cofactor for enzymes used in production of RBCs.

Class Summary

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

Glutamine (Endari)

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

Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to RBCs. By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization.

Voxelotor (Oxbryta)

Indicated for treatment of sickle cell disease in adults and adolescents aged 12 years or older.

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.

Crizanlizumab (Adakveo, crizanlizumab-tmca)

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

Class Summary

The absence of a spleen inhibits immunological functions of clearing bacteria from the blood and synthesizing antibodies leading to an increased frequency of infetion. These agents are used for treatment of suspected or confirmed infections.

Cefuroxime (Ceftin, Zinacef)

Cefuroxime is a second-generation cephalosporin that maintains the gram-positive activity of first-generation cephalosporins and adds activity against Proteus mirabilis, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Moraxella catarrhalis. The condition of the patient, severity of infection, and susceptibility of the microorganism should determine proper dose and route of administration.

Amoxicillin and clavulanate (Augmentin, Augmentin XR, Augmentin ES-600)

This drug combination extends the antibiotic spectrum of this penicillin to include bacteria normally resistant to beta-lactam antibiotics. It is indicated for skin and skin structure infections caused by beta-lactamase-producing strains of Staphylococcus aureus.

Penicillin VK

Penicillin inhibits the biosynthesis of cell wall mucopeptide.

Cefixime (Suprax)

Cefixime inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs); thus inhibiting cell wall biosynthesis. Bacteria lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Ceftriaxone

A third-generation cephalosporin, inhibits bacterial cell wall synthesis by binding to one or more PBPs; downstream inhibits cell wall biosynthesis via inhibition the final steps of peptidoglycan synthesis along the bacterial cell walls.

Azithromycin (Zithromax, Zmax)

Azithromycin is a macrolide antibiotic that is useful for treatment of community-acquired pneumonia in sickle cell disease, as an adjunct to a cephalosporin to cover Chlamydia or Mycoplasma infections.

Cefaclor

A second-generation cephalosporin, cefaclor is indicated for infections caused by susceptible gram-positive cocci and gram-negative rods.

Clarithromycin (Biaxin, Biaxin XL)

Clarithromycin exerts its antibacterial action by binding to 50S ribosomal subunit resulting in inhibition of protein synthesis. The 14-OH clarithromycin metabolite is twice as active as the parent compound against certain organisms.

Class Summary

Phosphodiesterase type 5 (PDE5) inhibitors are used to treat pulmonary hypertension associated with sickle cell disease. These agents are also used to prevent priapism associated with sickle cell disease.

Sildenafil (Revatio)

Sildenafil promotes selective smooth muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.

Tadalafil (Adcirca)

Inhibits PDE-5 in smooth muscle of pulmonary vasculature where PDE-5 is responsible for the degradation of cyclic guanosine monophosphate (cGMP). Increased cGMP concentration results in pulmonary vasculature relaxation; vasodilation in the pulmonary bed and the systemic circulation may occur.

Class Summary

These agents are used for pulmonary hypertension associated with sickle cell disease.

Bosentan (Tracleer)

Bosentan improves pulmonary arterial hemodynamics by competitively binding to ET-1 receptors endothelin-A and endothelin-B in pulmonary vascular endothelium and pulmonary vascular smooth muscle. This leads to a significant increase in cardiac index associated with a significant reduction in pulmonary artery pressure, pulmonary vascular resistance, and mean right atrial pressure.

Class Summary

Iron overload is a consequence of the numerous transfusions required and may lead to complications such as heart or liver failure. Iron chelators help maintain hemoglobin levels within the desired range.

Deferoxamine mesylate (Desferal)

Deferoxamine helps prevent damage to the liver and bone marrow from iron deposition by promoting renal and hepatic excretion in urine and bile in feces. It readily chelates iron from ferritin and hemosiderin but not from transferrin. It does not affect iron in the cytochromes or hemoglobin. This agent is most effective when administered by continuous infusion. It gives urine a red discoloration.

Deferasirox (Exjade, Jadenu)

Deferasirox is an orally administered iron chelation agent that has been shown to reduce the liver iron concentration in adults and children who receive repeated RBC transfusions. It binds iron with high affinity in a 2:1 ratio.

Deferiprone (Ferriprox)

Deferiprone (1,2 dimethyl-3-hydroxypyridine-4-one) is a member of a family of hydroxypyridine-4-one (HPO) chelators that requires 3 molecules to fully bind iron (III), each molecule providing 2 coordination sites (bidentate chelation). It is indicated for adults and children aged 3 years and older with iron overload caused by transfusions for sickle cell disease, thalassemia syndromes, or other anemias. It is available as tablets and oral solution. 

Class Summary

These agents are useful in the treatment of symptomatic nausea.

Promethazine (Phenadoz, Phenergan)

Phenergan is used for symptomatic treatment of nausea in vestibular dysfunction. Antidopaminergic agent effective in the treatment of emesis. It blocks postsynaptic mesolimbic dopaminergic receptors in the brain and reduces stimuli to the brainstem reticular system.

Class Summary

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

Pseudoephedrine (Nexafed, Sudafed, Zephrex-D, Genaphed, SudoGest)

Pseudoephedrine promotes vasoconstriction by directly stimulating alpha-adrenergic receptors.

Class Summary

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

Pneumococcal vaccine 13-valent (Prevnar 13)

The pneumococcal 13-valent vaccine contains capsular antigens extracted from Streptococcus pneumoniae and are used to stimulate active immunity to pneumococcal infection.

Pneumococcal vaccine polyvalent (Pneumovax 23)

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, PedvaxHIB)

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)

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.