Sickle cell disease

Table I.

Name	Beta Globin Genotype	Abbreviation	Average Clinical Severity
Sickle cell anemia	βSβS	Hb SS	4+
Sickle-hemoglobin C disease	βSβC	Hb SC	2+
Sickle-β+-thalassemia	βSβ+	Hb Sβ+	1-2+
Sickle-β0-thalassemia	βSβ0	Hb Sβ0	4+

On average, patients with Hb SS and Hb Sβ⁰ are more severely affected than those with Hb SC and Hb Sβ⁺, having more severe anemia and more frequent complications. However, even patients with “milder” forms of SCD (Hb SC and Hb Sβ⁺) can develop all the severe and life-threatening complications of SCD that are more frequently seen in Hb SS and Hb Sβ⁰.

Less common forms of sickle cell disease

There are several other, infrequent forms of SCD, including sickle-Hb D ^Punjab disease and sickle-Hb O ^Arab. Mild or asymptomatic forms of SCD may occur when β^S is co-inherited with another β-globin mutation that produces high levels of fetal Hb (Hb F); this compound heterozygous state is called sickle-hereditary persistence of fetal Hgb (Hb S-HPFH).

Diagnostic confusion and other considerations

No other diseases cause sickling and vaso-occlusion, which are features only of SCD.

The following diseases are also hemoglobinopathies (like SCD) and may be confused with SCD, perhaps because of unfamiliarity with the terminology of hemoglobinopathies, but they are not forms of SCD.

• Homozygous Hb C disease (Hb CC) causes a mild, chronic anemia. Splenomegaly is often present in older children and adults. The peripheral blood smear shows many target cells and Hb C crystals, but no irreversibly sickled cells. Sickling and vaso-occlusion do not occur, and patients with Hb CC disease do not have SCD or experience any of the “crises” or complications of SCD (beyond anemia, jaundice, splenomegaly, and risk of aplastic crisis). Hb CC disease is not the same as sickle-hemoglobin C disease (Hb SC), which is a form of SCD.

• Thalassemia refers to a group of anemias caused by ineffective erythropoiesis and hemolysis due to a defect in the production of a sufficient amount of globin (alpha or beta). The peripheral blood smear shows hypochromia, microcytosis, and target cells but no irreversibly sickled cells. Patients with symptomatic thalassemia (thalassemia intermedia or major) have anemia, jaundice, splenomegaly, and risk of aplastic crisis, but they do not have SCD or experience any of the “crises” or complications of SCD. Thalassemia intermedia and major are not the same as sickle-β⁺ -thalassemia or sickle-β⁰ -thalassemia, which are forms of SCD.

Sickle cell trait

Individuals with sickle trait are almost always healthy. They do not have a disease. Sickle trait does not cause anemia, microcytosis, splenomegaly, or pain. Further, people with sickle trait can donate blood.

It is important for individuals to know that they have the trait because of the risk to their offspring. Sickle cell anemia (Hb SS) is an autosomal recessive disease, so if both parents have sickle trait, then each of their offspring will have a one-quarter or 25% chance of having sickle cell anemia. Genetic counseling should be offered, and pre-implantation and prenatal diagnosis are also available.

Uncommon and rare complications of sickle cell trait

Sickle cell trait on very rare occasions is associated with increased morbidity and mortality. The following rare associations have been reported:

• Splenic infarction at high altitude, with extreme exercise, or with hypoxemia

• Isothenuria with loss of maximal renal concentrating ability

• Hematuria and renal papillary necrosis

• Fatal exertional heat illness with exercise (rhabdomyolysis)

• Sudden idiopathic death with exercise (cardiac arrest)

• Glaucoma or recurrent hyphema following a first episode of hyphema

• Renal medullary carcinoma in adolescents and young adults

• Early onset of end-stage renal disease from autosomal dominant polycystic kidney disease

The deaths associated with sickle trait occurred under extreme conditions of exertion, heat, and dehydration. Exercise and sports are safe for individuals with sickle trait as long as over-exertion, over-heating, and dehydration are avoided. These should be avoided in children without sickle trait, too.

What caused this disease to develop at this time?

• Sickle cell disease is a genetic disease, so it is present from birth. However, during the first several months of life, patients with SCD are asymptomatic because of the presence of significant amounts of fetal hemoglobin (Hb F). As Hb F normally declines after birth, there is a proportionate rise in sickle hemoglobin (Hb S). As Hb S rises (instead of the normal Hb A), SCD begins to manifest itself. Splenic dysfunction (hyposplenism) occurs as early as 3 months of age (so prophylactic penicillin should be started by this age). Anemia occurs by about 6 months of age, and it progresses with age. Dactylitis can occur in the first year of life, but most other complications begin to occur after 1 year of age.

• A variety of acute and chronic complications can also occur sporadically and often unpredictably. Often, no trigger is appreciated for common complications like vaso-occlusive pain or acute splenic sequestration. The acute and chronic complications are discussed individually throughout this chapter.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of sickle cell disease (SCD) is now most commonly made by newborn screening (in developed countries). When newborn screening has not been performed or the results are not available, some combination of blood counts, peripheral blood morphology, hemoglobin separation techniques, genetic testing, and family studies are performed to make the diagnosis of SCD.

• Complete Blood Count and Reticulocyte Count. The different forms of SCD have different characteristic blood counts (see Table II). Laboratory Findings in Common Forms of SCD). The usual, baseline Hb concentration is 6-9 g/dL in patients with Hb SS and HbSβ⁰, with a corresponding reticulocyte count of 10%-25%. The baseline Hb concentration is higher in the milder forms of SCD (Hb SC and Hb Sβ⁺), usually in the 9-12 g/dL range, with a corresponding reticulocyte count of 3%-10%. Patients with Hb SS and Hb SC have a normocytic anemia, unless they have coinherited α-thalassemia. Patients with Hb Sβ⁺ and Hb Sβ⁰ have a microcytic anemia.

  Table II.

  Laboratory Findings in Common Forms of SCD

  Name	Main Hemoglobins Present (and Proportion)	Usual Hgb (g/dL)	Usual MCV	Usual Retic (%)
  Sickle cell anemia	S	6-9	normal	10-25
  Sickle-hemoglobin C disease	S ≈ C	9-12	normal	5-10
  Sickle-β+-thalassemia	S > A	10-12	low	3-10
  Sickle-β0-thalassemia	S	6-9	low	10-25

• Peripheral Blood Morphology. The presence of irreversibly sickled cells is pathognomonic for SCD. If these cells are present on a standard blood smear (film), the patient has a form of SCD (but it does not inform about the specific type of SCD). The absence of irreversibly sickled cells, on the other hand, does not exclude SCD, because these cells may be rare or absent in Hb SC or Hb Sβ⁺.

• Newborn Screening. SCD is most commonly diagnosed as part of universal newborn screening for hemoglobinopathies, which is now performed in all 50 states in the United States. Canada and many other developed countries in Europe and elsewhere also perform newborn screening for hemoglobinopathies. Newborn screening programs use high-throughput Hb separation techniques and sometimes include genetic testing.

• Hemoglobin Separation Techniques. The mainstay of the diagnosis of the different forms of SCD is a hemoglobin separation technique. Either isoelectric focusing (a form of electrophoresis) or high-performance liquid chromatography (HPLC) is used to determine which different types of Hb, normal and abnormal, are present in the blood specimen. The proportions of the different Hbs is also determined, which is important in making a specific diagnosis (see Table II: Laboratory Findings in Common Forms of SCD).

• Genetic Diagnosis. Increasingly, genetic methods are being used to establish a diagnosis of SCD. Some forms of sickle cell disease (e.g., Hb SS and Hb Sβ⁰) can be challenging to differentiate using Hb separation techniques alone, so genetic testing may be particularly useful for this purpose.

• Family Studies. Parents can be tested to determine the presence of abnormal Hbs (e.g., Hb S or Hb C) or thalassemic mutations so that a clear picture of inheritance can be determined for a particular family.

Caution: The “sickle prep” (SickleDex®, sickle test, or Hb S test) cannot be used to make a diagnosis of SCD in isolation. This test only establishes the presence of Hb S. It does not differentiate the heterozygous or trait state (sickle trait) from the disease state (any form of SCD). The presence of Hb S does not, by itself, indicate a form of SCD. Other forms of testing (discussed above) need to be performed instead.

A note on sickle trait: Individuals with Hb S trait (Hb AS) will have both Hb A and Hb S present on Hb electrophoresis (or any Hb separation technique), but the amount of Hb A will be greater than Hb S (A>S). Individuals with sickle-β⁺ -thalassemia (Hb Sβ⁺) will also have both Hb A and Hb S present on Hb electrophoresis (or any Hb separation technique), but the amount of Hb A will be less than Hb S (S>A). This distinction is critically important and serves as the main way to distinguish sickle trait from certain forms of SCD (specifically, Hb Sβ⁺).

Common complications of sickle cell disease

SCD produces a number of characteristic acute and chronic complications. Traditionally, the acute complications were referred to as “crises,” although this terminology is now out of favor. The following are the mainly acute complications that clinicians should be familiar with. Chronic complications are discussed elsewhere in this chapter.

• Fever and Sepsis. Because of functional hyposplenism from splenic auto-infarction, all high fevers (e.g., ≥ 101 – 101.5 F) need to be considered, at least initially, as the first sign of invasive bacterial infection. Of course, patients will also develop fevers from other, often transient and benign causes (e.g., viral respiratory or gastrointestinal infections), but this is often not clear at the onset of fever.

• Painful Episodes (vaso-occlusive, “VOC”). SCD causes intermittent and often unpredictable episodes of pain, mild to severe, that may last for hours or days. The pain is usually bony or adjacent to bones, but it can also occur in the abdomen. Pain may be multifocal, regional, and/or bilaterally symmetric. Sometimes (about 20% of episodes) erythema or induration can be seen over a bony site of pain. However, it is important to remember that patients usually have severe pain without any correlating signs. So, it is important to trust the patient’s report of pain.

• Acute chest syndrome (ACS). This is a pneumonia-like illness that can occasionally be rapidly progressive and life-threatening. It is characterized by some combination of chest pain, tachypnea, dyspnea, cough, and hypoxemia. ACS has many causes or precipitants, such as infection, hypoventilation, atelectasis, bronchospasm, fat embolism, thromboembolism, pulmonary edema, and infarction.

• Dactylitis is a characteristic form of a painful episode seen in very young children with Hb SS (usually 6m – 3y of age). It is caused by sterile bony infarction of the metacarpals and phalanges. The inflammatory response produces painful swelling of the hands and feet. This is sometimes called the hand-foot syndrome.

• Osteomyelitis. Individuals with SCD are susceptible to osteomyelitis. The most common organisms are Pseudomonas and Staphylococcus. Osteomyelits can be challenging to differentiate from VOC, but the clinical scenario most consistent with osteomyelitis is a single focus of pain with fever and a positive blood culture.

• Avascular necrosis. Sterile osteonecrosis most commonly affects the hips (femoral heads), but shoulders and other bones may also be affected. It can be asymptomatic or cause chronic pain. AVN of the hips causes knee and/or hip pain with walking or climbing. This chronic pain syndrome needs to be differentiated from the acute pain of VOC. Patients can sometimes present with both AVN and superimposed acute VOC.

• Acute splenic sequestration. This classical complication of childhood SCD is caused by the sudden entrapment of blood within the spleen. Blood enters the spleen, but it cannot exit. This results in progressive splenomegaly, hypovolemia, and anemia. It can vary in severity, but it can be rapidly progressive and result in fatal hypovolemic shock. Acute splenic sequestration generally occurs in young children (<5 years of age) with Hb SS or Hb Sβ⁰, because splenic involution is usually complete after 5 years of age. On the other hand, individuals with Hb SC or Hb Sβ⁺, because of the course of slower splenic involution, may experience splenic sequestration as adolescents and young adults. Splenic sequestration tends to be a recurrent problem.

• Aplastic crisis. Human parvovirus infection can cause a sub-acute moderate to severe anemia in patients with SCD (and other hemolytic anemias) called the transient aplastic crisis. This in not the same as aplastic anemia. Parvovirus infects erythroid progenitors in the bone marrow, causing transient erythroid hypoplasia and reticulocytopenia. Because of the very short RBC lifespan in SCD, the Hb concentration can fall over the course of several days to dangerously low levels. The degree of anemia depends on the RBC lifespan, which varies among individuals. Once neutralizing antibodies are formed, there is spontaneous recovery heralded by an outpouring of nucleated RBCs (NRBCs) and reticulocytes from the bone marrow. Recovery is associated with the development of lifelong immunity, so this is not a recurrent phenomenon.

• Stroke and cerebral vasculopathy. Patients with SCD, especially those with Hb SS, are at high risk of stroke. Stroke may be ischemic or, less commonly in children, hemorrhagic. Stroke may be overt, causing classical signs and symptoms like hemiparesis and aphasia, or clinically covert (“silent”). Silent strokes are usually discovered incidentally on imaging, but can cause neurocognitive and school problems. Silent stroke is experienced by 30%-40% of patients with SCD. Overt stroke is often preceded by progressive stenosis of the large intracranial arteries at the base of the brain (sickle cerebral vasculopathy). Historically, 11% of children with Hb SS suffered an overt stroke by 18 years of age. Primary prevention strategies have since reduced the frequency of overt stroke.

• Priapism is a painful, unintended erection of the penis. It may be transient and recurrent (“stuttering”) or prolonged. The cause is some combination of dysregulated vasomotor tone and vaso-occlusion. It can occur in young, pre-pubertal boys. It increases in frequency with age, sometimes becoming problematic during puberty.

• Cholelithiasis and cholecystitis. The chronic hemolytic anemia of SCD results in an increased bilirubin load (from the breakdown of heme) that must be processed by the hepatobiliary system. This predisposes to bilirubinate (pigment) gallstones. These stones can appear in the first few years of life. They are often asymptomatic, but they can produce the classical signs and symptoms of cholecystitis. Symptomatic gallstones are more common with increasing age.

A note on clinical acumen: Patients with SCD can also experience complications or illnesses unrelated to SCD. It is important to bear this in mind when formulating a diagnosis. However, this possibility should not lead to an exhaustive work-up including unnecessary laboratory studies and radiation exposure for all patients who present with typical SCD-related findings. Indeed, some complications of SCD are diagnosed on clinical grounds alone, like the painful vaso-occlusive episode (“VOC”) where in-depth laboratory or radiographic testing cannot definitively include or exclude the condition.

Laboratory studies for the assessment of complications of sickle cell disease

The following are recommendations for appropriate laboratory testing and interpretation when assessing a patient with SCD.

• Complete blood count. A CBC should be obtained to assess almost all complications of SCD, including fever and co-morbid illnesses. The CBC is most useful in determining how much lower the patient’s Hb concentration is from its usual, baseline state (the steady-state). See Table II: Laboratory Findings in Common Forms of SCD. The Hb concentration in combination with the clinical status of the patient determines the need for transfusion therapy.

  Hgb and Hct: It is important to interpret the degree of anemia with respect to the patient’s baseline value. A Hgb of 6.5 g/dL might be “normal” for one patient (e.g., with Hb SS) but markedly decreased for another (e.g., Hb SC). See Table II: Laboratory Findings in Common Forms of SCD. Anemia may be exacerbated mildly during painful episodes and especially by ACS. The Hb can fall drastically during splenic sequestration and aplastic crisis.

  Total leukocyte count (WBC): The baseline or steady-state WBC count is often elevated in patients with SCD. In the apparently well state, patients may have a WBC in the 10 – 20,000/mm³ range. By itself, this moderate degree of leukocytosis does not necessarily indicate infection. Marked leukocytosis, especially in combination with an increase in the number of bands, warrants further investigation.

  Platelet count: Patients may have a baseline or steady-state platelet count that is high-normal or elevated (e.g., 350-750,000/mm³). The platelet counts needs to be interpreted with this in mind. A platelet count in the low-normal to mildly reduced range (e.g., 100-175,000/mm³) might be significant. The platelet count may be decreased due hypersplenism in the acute splenic sequestration crisis or from decreased production in the aplastic crisis.

• Reticulocyte count. A reticulocyte count should be obtained when ordering a CBC. The reticulocyte count allows one to determine the mechanism of any worsening anemia (e.g., decreased reticulocyte count with aplastic crisis or increased reticulocyte count with acute splenic sequestration). This knowledge also helps determine whether a transfusion might be needed sooner or later. Nucleated red blood cells (NRBCs) can also be seen with intense erythroid stress, as with splenic sequestration.

• Blood culture. A blood culture needs to be obtained for any high fever (e.g., >100 – 101.5 F) or persistent, unexplained fever. The culture should be obtained before antibiotics are given.

• Liver and pancreatic enzymes. Patients with SCD are at increased risk of cholelithiasis (pigment or bilirubinate gallstones), so these labs should be considered in patients with consistent clinical features.

• Renal function studies. Patients with SCD are at increased risk of renal failure, especially adolescents and adults. These studies should be checked whenever a potentially nephrotoxic medication is administered (e.g., ketorolac).

• Urinalysis. Dark urine is common in SCD, due to the presence of pyrroles (breakdown products of heme), but hematuria and hemoglobinuria can also occur. A urinalysis with microscopic evaluation can differentiate these three conditions when necessary (pyrroles: blood negative, RBCs negative; hemoglobinuria: blood positive, RBCs negative; hematuria: blood positive; RBCs positive). Urinary protein should be quantified in patients with edema. Urobilinogen is usually present because of the hyperbilirubinemia from chronic hemolysis.

• Type and crossmatch. These tests are necessary when a transfusion is anticipated. Also request sickle-negative blood. When possible, the blood bank should supply phenotype compatible (extended crossmatched) PRBCs (e.g., matched to C, D, E, and Kell) to minimize alloimmunization.

• Quantitative Hb S determination. When exchange transfusion is performed, it is necessary to know the pre-exchange value of Hb S in the blood. If exchange transfusion is anticipated, order this study along with a type and crossmatch.

• Quantitative Hb S determination. This is useful to monitor the therapeutic response to hydroxyurea. It is generally not necessary to measure this in the acute or ill setting.

• Serum ferritin. This is helpful to monitor the degree of iron loading in chronically transfused patients. It is not helpful to measure this in an acutely ill patient.

A number of commonly ordered tests are often not useful or confounded by hemolysis:

• ESR and CRP. The ESR may be abnormally low in SCD. The CRP may be elevated in patients with SCD. These tests do not distinguish infection from “crisis” or “crisis” from “non-crisis.”

• LDH. All patients with SCD have hemolysis, so the LDH is often elevated from RBC breakdown. The LDH correlates with the degree of hemolysis, which differs among patients. It is not able to distinguish “crisis” from “non-crisis.”

• Bilirubin. All patients with SCD have hemolysis, so the indirect bilirubin will be elevated from RBC breakdown. This is not useful to measure unless there is a marked changed in the patient’s degree of jaundice, or when hepatobiliary disease is suspected (e.g., cholecystitis).

• AST. This is also an RBC enzyme, so the chronic hemolysis will often raise the AST in the blood (out of proportion to the ALT). An increased AST does not necessarily indicate hepatic or other disease, unless there is marked elevation and especially when the ALT is greater than the AST.

There is no laboratory test that can tell you whether or not a patient is experiencing a painful, vaso-occlusive crisis. One should trust the patient’s report of pain.

Would imaging studies be helpful? If so, which ones?

No imaging studies are needed to make a diagnosis of SCD itself. However, imaging studies may be used to diagnose and manage different complications of SCD. Patients with SCD may also have characteristic bony changes and other findings on radiographs that may be confused with other conditions.

• Imaging Studies for Complications of SCD

  Fever. Imaging is generally not needed for children with SCD who have fever without an apparent source. Some hematologists do recommend a chest radiograph for all SCD patients with fever, but others do not believe this is necessary in the absence of chest wall pain, hypoxemia, or respiratory signs or symptoms.

  Acute chest syndrome (ACS). ACS is a general term for an acute pulmonary illness in a patient with SCD. ACS has many causes or precipitants, such as infection, hypoventilation, atelectasis, bronchospasm, fat embolism, thromboembolism, pulmonary edema, and infarction. The common criterion for the diagnosis of ACS is a radiographic pulmonary infiltrate, so a chest radiograph is required for a diagnosis of ACS. Any patient with respiratory signs or symptoms, chest wall pain, and/or hypoxemia, especially in combination with fever, needs to have a chest radiograph. The radiographic appearance of ACS is essentially indistinguishable from pneumonia in a patient without SCD.

  Painful Episodes (Bony Pain). Radiographs of the painful part are usually not needed because a painful episode (a “vaso-occlusive crisis” or “VOC”) is a clinical diagnosis, and misinterpretation of SCD-related bony changes often leads to inappropriate and invasive diagnostic or therapeutic interventions. The affected (painful) bone may appear normal radiographically, or the bone may have lytic lesions from bony infarction. There may also be a sympathetic (sterile) joint effusion if the bony infarction is near a joint. Bone scans (radionuclide scintigraphy) may show normal, increased or decreased uptake. So, neither radiographs nor bone scans can readily differentiate sterile bony infarction (sickle cell pain) from osteomyelitis. It is best to avoid radiation exposure as much as possible for children with uncomplicated painful episodes. MRI also cannot easily differentiate infarction from infection, unless pus is visualized, a late finding.

  Dactylitis or hand-foot syndrome, is a characteristic form of an acute painful episode experienced by very young children (the first 1-3 years of life) with SCD. Sterile infarction of the metacarpals and phalanges of the hands and/or feet causes painful fusiform swelling of the digits. Like most painful episodes, imaging is not needed, despite the impressive swelling, erythema, and tenderness.

  Osteomyelitis. Patients with SCD are at increased risk of osteomyelitis, especially from Pseudomonas and Staphylococcus. Osteomyelitis can cause bone pain, like SCD-related painful episodes (“VOC”). As described above, it is very difficult to differentiate sterile bony infarction from osteomyelitis by imaging, because they both produce similar findings on radiographs, bone scans, and MRI. Therefore, routine imaging of all painful areas is not indicated. Clinical features that increase clinical suspicion for a diagnosis of osteomyelitis over an uncomplicated painful episode are a single focus of pain, fever, and bacteremia. The only definitive ways to differentiate infarction from infection by imaging are a bone marrow scan (not a bone scan), which is not available clinically in most institutions, and the presence of pus visualized by MRI, which is a late finding. Imaging should be reserved for select patients in whom there is high clinical suspicion of osteomyelitis, with the understanding that imaging is often problematic in this scenario.

  Avascular necrosis occurs in SCD, especially in the femoral heads, and to a lesser frequency in the humeral heads and sometimes other bones. Hip or knee pain should prompt consideration of avascular necrosis. Plain radiographs (antero-posterior and frog-legs lateral views) are often sufficient, but MRI of the hips may be needed to show early disease or plan surgical interventions.

  Stroke. Patients with SCD, especially those with sickle cell anemia (Hb SS) are at high risk of stroke, both ischemic and hemorrhagic. Imaging of the brain is needed to evaluate any patient with severe headache, seizure, altered mental status, or signs and symptoms of stroke, such as weakness, paralysis, speech problems, and visual changes. A CT scan of the brain can usually be performed quickly, and can quickly differentiate hemorrhagic from ischemic stroke. However, an MRI of the brain is generally preferred, because it can better define the location and extent of the lesion(s), determine whether the infarction is (sub-)acute or remote, and be paired with an MR angiogram. MRI can also differentiate hemorrhagic from ischemic stroke using the proper sequences.

  Cerebral vasculopathy. Stroke is often preceded by progressive stenosis of the large intracranial arteries at the base of the brain (sickle cerebral vasculopathy). This narrowing, or occlusion, can be visualized by angiography, such as MR angiography. CT or conventional angiography can also be performed in select cases, but care must be taken with the administration of hypertonic contrast agents. Stenosis will increase cerebral arterial blood flow velocity (or decrease it when the stenosis is severe), and this can be detected by transcranial Doppler ultransonography (TCD).

  Cholelithiasis. SCD and other chronic hemolytic anemias increase the risk of cholelithiasis with bilrubinate or pigment gallstones. This should be considered in the differential diagnosis of all patients with SCD who have RUQ pain, especially post-prandial and associated with vomiting. Bilirubinate gallstones and cholecystitis are readily visualized by ultrasonography.

• Characteristic radiographic findings in SCD (not to be confused with acute complications)

  Cardiomegaly. The body compensates physiologically for a chronic moderate to severe anemia by increasing cardiac output. As such, compensatory cardiomegaly is a common finding in patients with SCD, even in their normal baseline or steady-state. Likewise, a systolic ejection murmur (a “flow” murmur) is a frequent finding on physical examination. The degree of cardiomegaly may increase during acute exacerbations of anemia. The presence of mild-to-moderate cardiomegaly alone, even in conjunction with a systolic ejection murmur, is generally not a cause for worry unless there are signs or symptoms of cardiac failure, which would be uncommon.

  Vertebrae. The vertebrae may have a biconcave appearance or step-like depressions of the vertebral surfaces. These radiographic features of SCD should not necessarily be interpreted as evidence of compression fractures.

  Ribs. Lateral chest radiographs may show cupping of the sternal segments of the ribs.

  Skull. The marrow cavity of the skull bones may be expanded by erythropoiesis, giving rise to the hair-on-end appearance. This is a rare radiographic feature caused by widening of the diploic cavity. Similar changes may be seen in other skull bones, like the maxilla and mandible.

If you are able to confirm that the patient has sickle cell disease, what treatment should be initiated?

There are three main disease-modifying treatments that can reduce the overall severity of SCD or cure it: hydroxyurea, chronic transfusions, and hematopoietic stem cell transplantation. Not all patients qualify for or require one of these treatments, but the use of all three is increasing.

• Hydroxyurea is a cytostatic chemotherapeutic agent that has multiple beneficial effects in patients with SCD. Hydroxyurea increases the concentration of fetal Hb (Hb F), decreases the leukocyte count, decreases the platelet count, and improves blood rheology. Clinically, hydroxyurea reduces the frequency of painful crises, acute chest syndrome, and transfusions by about 50% in adults. Smaller studies in children have shown similar effects. Common indications for hydroxyurea include frequent episodes of pain or acute chest syndrome, although the drug is being used increasingly for a variety of indications.

• Chronic transfusion programs entail regular, usually monthly, transfusions of packed RBCs with the aim to maintain the percentage of Hb S in the blood less than 30%. Chronic transfusions are effective at preventing most complications of SCD, but the most common indications are primary and secondary stroke prophylaxis. Complications of transfusions include iron overload (and the consequent need for chelation therapy), alloimmunization, and transfusion-transmitted infections.

• Stem cell (or bone marrow) transplantation is currently the only cure for SCD. About 500 stem cell transplants for SCD have been reported to international registries. Widespread use of transplantation is limited by the lack of a suitable donor and the toxicities and complications of the procedure. Transplantation is safest when hematopoietic stem cells are obtained from an HLA-matched sibling (without SCD), but only 10% of patients actually have a sibling donor. The use of alternative donors is an area of ongoing study. In North America, the most common indication has been stroke or cerebrovascular disease, but transplantation is also offered for other, especially recurrent and severe, vaso-occlusive complications.

Common acute and chronic complications of SCD, which can occur despite the use of hydroxyurea or chronic transfusions, require specific management.

• Fever is a medical emergency in all patients with hyposplenism. Fever can be the first sign of invasive bacterial infection. Patients need to present promptly to medical attention for any high fever (e.g., > 101 – 101.5 F). Rapid evaluation with a focused physical examination should be followed by empiric treatment with a broad-spectrum parenteral antibiotic (e.g., ceftriaxone) after obtaining a blood culture and complete blood count. Most patients with SCD and fever can be managed as an outpatient. Inpatient management is needed for toxic-appearing children and should be strongly considered for those who are very young (<1 year of age), have concomitant acute chest syndrome, have blood counts significantly different from baseline, who have missed doses of prophylactic penicillin, or who have uncertain follow-up.

• Painful Episodes (vaso-occlusive, “VOC”)is treated according to its severity and primarily includes hydration and analgesics. Mild episodes of pain may be treated by scheduled oral ibuprofen (or other NSAID) alone. Moderately severe pain requires the addition of opiates to the NSAID “backbone”, such as hydrocodone, or oxycodone. Severe episodes of pain can be treated with parenteral opiates, such as morphine or hydromorphone. Meperedine should be avoided because of the risk of seizures. Generally, a scheduled regimen of an NSAID (e.g., ibuprofen or ketorolac) should be given along with a scheduled, long-acting opiate with an additional, rapid-acting opiate for breakthrough pain. This can be achieved with or without a PCA (patient-controlled analgesia) pump. Maintenance of normal hydration (avoiding over-hydration) and adequate treatment of pain (avoiding over-treatment) are key supportive measures. Transfusion is generally not indicated for an uncomplicated painful episode. Frequent incentive spirometry (e.g., q2h) should be prescribed and encouraged to prevent acute chest syndrome.

• Acute chest syndrome (ACS) is treated empirically with a combination of antibacterials (including a macrolide) such as ceftriaxone or cefuroxime combined with azithromycin or erythromycin. Supplemental oxygen is needed only for hypoxemia. Simple transfusion should be considered, especially for patients with hypoxemia, acute exacerbation of anemia, or any respiratory distress. Exchange transfusion should be considered for those with widespread pulmonary infiltrates, rapid clinical deterioration, or hypoxemia despite oxygen supplementation. Mechanical ventilation may be needed for severe episodes. Maintenance of normal hydration (avoiding over-hydration) and adequate treatment of pain (avoiding over-treatment) are key supportive measures. Bronchodilators should be administered for wheezing or symptoms and signs of asthma. Steroids may be useful for moderate to severe episodes of ACS, but should be used judiciously to prevent rebound toxicity (pain).

• Dactylitisis treated like other painful episodes are treated (see above).

• Osteomyelitis. Once the diagnosis is established, which may be challenging, osteomyelitis should be treated as it would in a patient without SCD. The most common causative organisms in SCD are Pseudomonas and Staphylococcus, so empiric therapy should be directed against these organisms. Specific therapy can be given once an organism is identified.

• Avascular necrosis(AVN) can be symptomatic or asymptomatic. No therapy is needed for asymptomatic AVN. Symptomatic AVN is usually treated conservatively with physical therapy and long-acting NSAIDs (e.g., naproxen). Surgical therapy (e.g., core decompression) may be performed for some patients.

• Acute splenic sequestration. Sequestration can occur quickly, and the patient will be hypovolemic (a significant fraction of the patient’s blood volume may be trapped within the spleen). Sudden moderate to severe symptomatic anemia is managed by transfusion of PRBCs. Consideration should be given to rapid transfusion for severe hypovolemia. Avoid over-transfusion, however, because transfusion can produce splenic unloading and “auto-transfusion”, which in combination with the transfused PRBCs can cause polycythemia and hyperviscosity. Generally, one should transfuse to a minimally “safe” Hb concentration (e.g., to the patient’s baseline Hb or to around 8 g/dL).

• Aplastic crisis. The anemia in aplastic crisis does not develop suddenly, as it does in acute splenic sequestration, so there is a compensatory increase in blood volume. As such, patients with aplastic crisis may be normovolemic or mildly hypervolemic despite severe anemia. Rapid transfusion of PRBCs of intravenous fluid boluses may precipitate heart failure. Strong consideration should be given to slow transfusion of PRBCs in small, sequentially administered aliquots (each over 4 hours). Thus, it is important to distinguish acute splenic sequestration from aplastic crisis, because the transfusion management differs significantly.

• Stroke. Oxygen supplementation and exchange transfusion to lower the proportion of Hb S to less than 30% and to raise the total Hb concentration to ~10 g/dL are the most important acute interventions to limit the extent of stroke and improve outcomes. Supportive care, similar to all other stroke patients, is also key, including the avoidance of over-hydration (and judicious use of relatively hypotonic fluids). Over-transfusion should also be avoided to prevent hyperviscosity (i.e., total Hb concentration > ~11 g/dL) and exacerbation of the stroke.

  When stroke is suspected, transfusion therapy should be instituted as quickly as possible, avoiding delays caused by confirmatory imaging. Sometimes a simple transfusion can be given as a temporizing measure while awaiting exchange transfusion (again, with the avoidance of over-transfusion and hyperviscosity). Generally, anticoagulation and thrombolysis are not used for acute stroke in SCD.

• Priapism. At the first sign of priapism, patients should be encouraged to urinate and take fluids by mouth. A warm shower may also help. Rapid-acting pseudoephedrine taken orally can also help terminate priapism. Pain should be treated like any other SCD-related pain with opiates. For prolonged episodes of priapism (4 or more hours) aspiration and irrigation of the corpora cavernosa, which can be performed bedside with appropriate analgesia and sedation, can produce rapid detumescence. Intravenous hydration should also be given for prolonged priapism and pseudoephedrine administered if not taken already. Transfusion therapy for priapism is controversial and may be associated with stroke, so it should not be considered a routine treatment for this complication. Surgical shunts should be avoided as much as possible to preserve erectile function.

• Cholelithiasis and cholecystitis. Asymptomatic cholelithiasis is common and should be followed clinically. Prophylactic cholecystectomy is generally not recommended. However, patients with symptomatic cholelithiasis and cholecystitis need intervention. These conditions should be managed similar to a patient without SCD. Endoscopic retrograde cholangiopancreatography (ERCP) may be performed. Cholecystectomy may be needed.

A caution about surgery

Patients with SCD may need surgery for a number of reasons.

It is critical to know that general anesthesia and surgery are high-risk procedures in SCD. These are associated with a high risk of post-operative complications, such as acute chest syndrome, which can be life-threatening.

Patients need to be adequately prepared for surgery (e.g., IV hydration and often transfusion). Special care is needed intra-operatively (e.g., minimizing or avoiding acidosis, hypovolemia, hypotension, hypothermia, hypoxemia, and the use of tourniquets). Post-operative care includes careful maintenance of normal hydration (avoiding over- and under-hydration), adequate treatment of pain (avoiding over- and under-treatment), aggressive incentive spirometry, and vigilance for early signs of acute chest syndrome. Intensive care support may be needed.

So, surgery should be performed by a team of surgeons, anesthesiologists, hematologists, and, when necessary, intensivists who have the experience and resources to manage this high-risk population.

When to transfuse or not (acute transfusion therapy)

Acute (episodic) transfusion therapy for the treatment of SCD-related complications bears special mention. It is important to know which complications of SCD should be treated with (or consideration given to) transfusion of packed red blood cells, such as moderate to severe acute chest syndrome, overt stroke, and symptomatic acute splenic sequestration and aplastic crisis (see also the discussion of these complications elsewhere in this chapter). Transfusion is generally not warranted for baseline (steady-state) anemia, uncomplicated painful episodes, dactylitis, fever without concomitant severe anemia, avascular necrosis, or osteomyelitis because it does not help these conditions. There is debate about the use of transfusion for priapism because exchange transfusion for priapism can be associated with stroke; therefore, careful deliberation is required.

Over-transfusion is a real concern in SCD. Clinicians may be tempted to raise the Hb concentration to the “normal” range, but this can be harmful in SCD. Whenever a significant fraction of Hb S is present in the body (especially when greater than 30%), raising the total Hb concentration above ~11 g/dL can produce hyperviscosity, decreased oxygen delivery to tissues, and ischemia or infarction. Indeed, over-transfusion can cause stroke, so it should always be anticipated and avoided.

What are the adverse effects associated with each treatment option?

Each disease-modifying treatment is associated with unique toxicities.

• Hydroxyurea is quite safe for patients with SCD of any age. The main toxicity is transient, often mild, dose-related cytopenias (e.g., thrombocytopenia or neutropenia). It is important to monitor blood counts serially while the patient is on therapy, especially during intercurrent illnesses. The drug may have to be temporarily withheld, or the dose reduced, for significant cytopenias (e.g., platelets < 100,000 /mm³ or absolute neutrophil count < 1,000/mm³). Some patients have GI symptoms when starting hydroxyurea therapy, but these tend to abate with time. A minority of patients report thinning of the hair or changes in nailbed pigmentation. Hydroxyurea does not appear to increase the risk of malignancy or impair growth and development.

• Chronic transfusions are associated with three main adverse effects: iron overload, alloimmunization, and transfusion-transmitted infections. Iron overload (transfusional hemochromatosis) occurs because the body has no mechanism to increase the “excretion” of the large amount of added iron provided by the transfused PRBCs. Untreated, iron overload can lead to hepatic, cardiac, and endocrinologic toxicity and early death. Iron chelation therapy is needed after 1 to 1.5 years of monthly transfusions. Alloimmunization is reduced by leukofiltration and extended antigen matching, but it may still occur and lead to the inability to find sufficient compatible blood in as many as 10% of patients. Fortunately, transfusion-transmitted infections are now rare given contemporary donor selection and product testing.

• Stem cell (or bone marrow) transplantation is associated with a mortality rate of about 2%-5%, a graft rejection rate of about 5%, and the occurrence of significant graft-versus-host disease in about 5%. Therefore, the chances of a successful, curative transplant without major morbidity are around 85 –90%.

What are the possible outcomes of sickle cell disease?

The prognosis for children with sickle cell disease has greatly improved over the past several decades. In North America and Europe, most children with SCD (>95%) can expect to live to adulthood if cared for in an experienced sickle cell center. Improvement in survival has occurred as a result of universal newborn screening, prophylactic penicillin, immunizations, advances in supportive care, and increased use of disease-modifying treatments (hydroxyurea, chronic transfusions, and stem cell transplantation). Primary prevention strategies have also greatly reduced the frequency of severe complications, such as overt stroke.

Transition to adult medical care is a high-risk period associated with an increased risk of mortality. Adolescents and young adults need to seek medical care in a clearly identified center with expertise in SCD.

Long-term survival estimates (beyond young adulthood) are less accurately known for individuals with Hb SS. Median survival is probably into the fifth or sixth decade of life. Individuals with Hb SC have survival estimates that approximate the overall (general) population.

What causes this disease and how frequent is it?

• Genetics. Sickle cell disease is caused by two mutations the HBB gene, one on each chromosome 11, that encodes the β-globin subunit of hemoglobin (Hb). At least one of these mutations must be the sickle Hb mutation (β^S) that replaces the normal glutamic acid in the sixth position of the β-globin chain with a valine. The result is an abnormal hemoglobin molecule called sickle hemoglobin or hemoglobin S (Hb S). Hb S is problematic because it will polymerize (gel or “sickle”) upon deoxygenation, rather than remaining free in solution. So, as Hb S-containing RBCs transit the circulation, repeated cycles of oxygenation and deoxygenation, with attendant sickling and un-sickling, damage the RBC membrane and produce rigid, dense, poorly deformable, and adhesive cells that have a shortened lifespan–hence, a hemolytic anemia–that may also occlude the microcirculation–hence, vaso-occlusive episodes.

• Epidemiology. Sickle cell trait, the heterozygous or carrier state for the Hb S mutation (β^S), protects against severe malarial infections, so it arose and became a balanced polymorphism in currently and historically malarious regions of the world. As such, SCD occurs most commonly among individuals of African, Mediterranean, Middle Eastern, or Asian-Indian ancestry. SCD is now found throughout the world in diverse populations, and it can occur in people of any skin color. In the United States, approximately 1 in 2,500 newborns and 1 in 400 African-American newborns has SCD. It is estimated that there are 70,000 to 100,000 individuals with SCD in the United States.

What complications might you expect from the disease or treatment of the disease?

In addition to acute complications, SCD can also cause of number of chronic complications or chronic organ injury.

• Retinopathy. SCD can cause a proliferative retinopathy characterized by abnormal arteriovenous communications in retinal vasculature. It is the one complication of SCD that clearly occurs more commonly in Hb SC than in Hb SS. Retinopathy can lead to visual loss if untreated. Photocoagulation of feeder vessels can control the disease and prevent visual loss, if performed early.

• Nephropathy. SCD affects the kidneys in several ways:

  Urinary concentrating defect. This begins in very young children and persists throughout life. Individuals with SCD cannot maximally concentrate their urine, which predisposes to dehydration and often causes nocturnal enuresis.

  Impaired excretion of potassium. Care should be taken to avoid indiscriminate use of potassium supplements in IV fluids, and vigilance is needed when treating patients with medications that can cause hyperkalemia, such as ACE inhibitors and angiotensin receptor blockers.

  Microalbuminuria and proteinuria. The natural history is unclear, but asymptomatic microalbuminuria may progress to proteinuria with age, and occasionally nephrotic-range proteinuria occurs. The progression of proteinuria may presage chronic renal failure.

  Hematuria. Microscopic hematuria is common, probably resulting from microscopic infarctions in the renal medulla. Occasionally, gross hematuria can occur due to larger infarctions. Renal papillary necrosis can cause gross hematuria and painful urinary obstruction (the necrotic papilla separates and becomes lodged in the ureter).

• Chronic pulmonary disease. Asthma or asthma-like signs and symptoms are common in SCD. Asthma should be treated aggressively to help prevent acute chest syndrome. Recurrent episodes of acute chest syndrome may lead to a chronic restrictive and/or obstructive pulmonary disease in adulthood. Pulmonary hypertension is an increasingly recognized complication of SCD (see below for further discussion of pulmonary hypertension).

• Delayed growth and sexual maturation. Children with Hb SS are commonly thinner and shorter than their peers. The onset of puberty may also be delayed by a year or two. With the onset of puberty, there is usually “catch-up” growth so that adults with Hb SS may approach normal, expected height. Nutritional support and/or hormonal therapy may be needed for children with significant growth delay or markedly delayed puberty.

• Neurocognitive complications. The brain is frequently affected by SCD, especially in Hb SS. Overt stroke still occurs, although with decreasing frequency thanks to primary prevention strategies using transcranial Doppler (TCD) ultrasound. Unfortunately, silent cerebral infarction (SCI) is present in 30%-40%. In some patients, SCI and chronic anemia may lead to intellectual deficits, learning difficulties, behavioral challenges, and school problems. A multidisciplinary team including school intervention specialists, psychologists, and neuropsychologists is a key feature of comprehensive SCD care.

How can sickle cell disease be prevented?

• Invasive bacterial infections. Chiefly because of hyposplenism due to autoinfarction, children with SCD are at very high risk of invasive and life-threatening bacterial infections, especially with encapsulated organisms, like Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Therefore, a multi-pronged approach is necessary to prevent infections and save lives.

  Universal newborn screening identifies at-risk but asymptomatic neonates who would benefit from a life-saving intervention (specifically, prophylactic penicillin).

  Prophylactic penicillin (PCN) should be started no later than 3 months of age (it can be started at the time of diagnosis) for children with HbSS and HbSβ⁰. The usual regimen is penicillin V potassium 125 mg p.o. twice daily. The dose should be increased to 250 mg p.o. twice daily at 3 years of age. Prophylactic penicillin is usually given until 5 years of age and then stopped, unless there is a history of pneumococcal bacteremia, a surgical splenectomy, or the family wishes to continue it. The risk of invasive bacterial infections continues life-long, but its frequency decreases at 5 years of age. On average, hyposplenism is less severe and later in onset in children with HbSC and HbSβ⁺. So, prophylactic PCN may not be prescribed for these genotypes of SCD, but practice varies in this respect.

  Immunization against the pneumococcus, Hib, and the meningococcus, especially with the newer protein-conjugate vaccines (e.g., Prevnar 13® and Menactra®). Hib disease has been eradicated in SCD by vaccination. Pneumococcal disease has declined significantly but remains a problem. Doses of the polysaccharide pneumococcal vaccine are recommended at ages 2 and 5 years (following immunization with the usual childhood series of pneumococcal protein-conjugate vaccine).

  Parental education about the significance of fever and what to do in the event of fever is critical. Caretakers need to know to seek immediate medical attention for any high fever (e.g., ≥101.5ºF).

• Acute painful
  episodescan often be prevented by avoiding known precipitating factors or “triggers,” such as exposure to cold, dehydration, infection, excessive physical exertion, and physical or psychological stress. However, some of these factors may not be easy to avoid, and sometimes no trigger of a painful episode is apparent. Medical therapy with hydroxyurea has been shown to decrease the frequency of painful episodes in controlled and uncontrolled clinical trials, especially in adults, and to a lesser degree of certainty in children. Chronic transfusion therapy can also prevent acute painful episodes.

• Acute splenic sequestration. Parents should be taught to palpate their young child’s spleen twice daily. This is especially important in the first 5 years of life, before splenic involution is usually complete. Parents should seek immediate medical attention if they notice any significant increase in the size of the spleen, especially if the child is pale, lethargic, or otherwise not well. This education and plan has decreased the frequency of severe, life-threatening acute splenic sequestration. Recurrent episodes of splenic sequestration can be prevented by surgical splenectomy or a chronic transfusion program.

• Acute chest syndrome (ACS). For individuals with asthma, which is common in SCD, excellent control of asthma will help prevent episodes of ACS that are triggered by asthma exacerbations. Hydroxyurea has been shown to decrease the frequency of ACS in controlled and uncontrolled clinical trials, especially in adults, and to a lesser degree of certainty in children. Chronic transfusion therapy can also prevent ACS.

• Stroke can be prevented before it happens the first time (primary prevention) or subsequent strokes can be prevented following a first stroke (secondary prevention).

  Primary prevention
  . Young children with Hb SS and Hb Sβ⁰ should be screened at least yearly with transcranial Doppler (TCD) ultrasonography to identify those at highest risk of overt stroke. Children with abnormally elevated TCD velocities (i.e., ≥200 cm/s by a non-imaging technique), who have a risk of stroke of 10% per year over the subsequent 3 years, should be offered chronic red blood cell transfusions to prevent first stroke. Once started, chronic transfusions (given approximately monthly) must continue indefinitely, as no effective alternative to transfusion has yet been established in randomized clinical trials.

  Secondary prevention. After a first stroke, the risk of recurrent stroke is 50%-90%. So, chronic transfusions are considered a standard of care for secondary stroke prophylaxis. Transfusions decrease the risk of stroke to 10%-20% (from 50%-90%).

• Retinopathy can occur in any form of SCD, but is more common in Hb SC. If left untreated, proliferative retinopathy can lead to visual loss. Yearly ophthalmologic screening for sickle retinopathy, beginning at 10 years of age, can identify early lesions that can be treated to prevent blindness.

• Cholecystitis. Some clinicians recommend screening abdominal ultrasonography to detect asymptomatic gallstones to possibly prevent cholecystitis. However, cholecystectomy should probably be reserved for those with symptomatic cholelithiais or acute cholecystitis.

• Priapism. Recurrent priapism can be prevented with long-acting pseudoephedrine preparations (e.g., nightly dosing) or leuprolide therapy. Surgical shunts should be avoided to maintain erectile function.

SCD is a genetic disease, so the only way to reliably prevent it, if desired, is by preconception genetic counseling coupled with reproductive decisions made by prospective parents.

• For a child to have sickle cell disease, both parents must have sickle trait (or, perhaps, sickle cell disease) or one parent can have sickle cell trait (or disease) and the other carries a different abnormal hemoglobin, such as Hb C or β-thalassemia. If both parents have the sickle cell trait (or one has sickle trait and the other has the trait for Hb C or β-thalassemia), then offspring have a 25% chance of having sickle cell disease.

• It is important to remember that only one parent must carry the β^S mutation, not both, for a child to have sickle cell disease. However, both parents must carry the β^S mutation for the child to have sickle cell anemia (HbSS).

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