SICKLE CELL DISEASE

SICKLE CELL DISEASE

Current Diagnosis

• Sickle cell disease (SCD) is diagnosed by neonatal screening in the United States

• Persons with congenital hemolytic anemia should be tested for SCD by hemoglobin electrophoresis regardless of their ethnic background.

• Infection with parvovirus B19 should be suspected in children presenting with acute anemia and reticulocytopenia.

• Human leukocyte antigen (HLA) class I and II testing should be performed in all patients with SCD and unaffected siblings to identify candidates for hematopoietic stem-cell transplant.

• Transcranial Doppler screening for primary prevention of stroke is indicated in children with SCD.

• Acute chest syndrome is diagnosed in patients presenting with fever, hypoxemia, and a radiographic pulmonary infiltrate.

• Screening for iron overload by ferritin, quantitative liver MRI, cardiac MRI, or liver biopsy is indicated in all patients who have received more than 10 lifetime transfusions.

• Pulmonary hypertension screening by transthoracic echocardiogram is indicated in all patients with homozygous SCD.

Current Therapy

• All children with sickle cell disease (SCD) should receive penicillin prophylaxis.

•   High fever should be treated empirically with coverage for Streptococcus pneumoniae pending results of blood cultures.

• Children with high transcranial Doppler velocity need to be placed on a chronic transfusion regimen to keep the hemoglobin (Hb) S <30%, indefinitely.

• Painful vaso-occlusive episodes warrant prompt treatment with an individualized intravenous opiate regimen, as well as supportive care and incentive spirometry.

• Preoperative transfusion should aim at a target hemoglobin level of 10 g/dL regardless of the HbS percentage and is indicated in all patients with SCD undergoing major surgery.

• Therapy with hydroxyurea is indicated in all patients at all ages with HbSS disease and HbSβ-thalassemia, and in patients with HbSC with a severe phenotype on a case-by-case basis.

• Erythropoietin-stimulating agents can be used in conjunction with hydroxyurea to prevent or ameliorate reticulocytopenia and in patients with underlying renal insufficiency.

• Iron chelation is indicated in all patients with findings of iron overload.

• Treatment of acute chest syndrome includes parenteral antibiotics to cover atypical microorganisms and transfusion, with exchange transfusion reserved for the most severe cases.

• Patients with pulmonary hypertension should receive optimal hematologic care (maximal hydroxyurea and/or chronic transfusion therapy) and specific therapy for pulmonary hypertension in severe cases, with coordination and referral to a pulmonary hypertension specialist.

• Bone marrow transplantation should be offered to all patients who have a matched donor and display a severe phenotype.

Epidemiology

Sickle cell disease (SCD) affects 70,000 to 100,000 persons in the United States and millions worldwide. The hemoglobin (Hb) S mutation

arose from four geographic areas in Africa and Asia approximately 10,000 years ago and then propagated to vast tropical and subtropical areas due to the selective pressure of malaria infection. It is predominantly found in persons of African, Mediterranean, Arab, or Indian ancestry. In the United States, approximately 1 in 15 African Americans harbors the HbS (sickle hemoglobin) mutation and 1 in 400 is affected by the disease. Most patients with SCD in the United States are homozygous for HbS (SS), with heterozygous HbSC being the second most common abnormality. Conversely, in Mediterranean countries, HbS/β-thalassemia is the most common SCD syndrome, and in the Arab peninsula HbSS in combination with hereditary persistence of fetal hemoglobin (HPFH) is particularly prevalent.

Pathophysiology

SCD consists of a group of inherited hemoglobinopathies characterized by a qualitatively abnormal hemoglobin molecule that affects the structure and integrity of the red blood cells (RBCs). SCD is an autosomal recessive disease due to homozygosity for HbS, characterized by a single base substitution in the β-globin gene of the hemoglobin tetramer, leading to an amino acid substitution (valine to glutamic acid), or coinheritance of HbS with other abnormal hemoglobins such as hemoglobin C or β-thalassemia.

HbS is less soluble than normal hemoglobin (HbA) in the deoxygenated state and polymerizes when sickle RBCs are exposed to hypoxic conditions in the microcirculation. In the classic pathophysiologic explanation of SCD, sickled RBCs containing HbS polymers are less deformable and remain trapped in the microcirculation, causing end-organ ischemia and necrosis.

Compounding this mechanism, more recent literature has emphasized the role of cellular adhesion, abnormal cytokine levels, ischemia- reperfusion injury, oxidative damage and an abnormal endothelial milieu. HbS polymers also lead to deformity and fragility of the RBC membrane, with resulting intra- and extravascular hemolysis.

Patients with SCD suffer from severe chronic hemolytic anemia and acute episodes of RBC trapping and destruction in the microvasculature (vaso-occlusive episodes). Vaso-occlusive episodes are the hallmark of SCD and are characterized by more intense episodic vaso-occlusion, often with increasing hemolysis, and are due to exogenous or endogenous factors that acutely alter the rheologic properties of the RBCs. The main determinants of RBC sickling and vaso-occlusion are hypoxemia, RBC dehydration, RBC concentration, high HbS relative to fetal hemoglobin (HbF), and blood viscosity; these can occur in a multitude of clinical settings. Most common clinical inciting events leading to vaso-occlusive episodes are dehydration due to inadequate replacement of fluid losses, thermal changes, surgical stress, exposure to low oxygen tension, infections, and psychological stressors.

Epidemiologic studies indicate that the risk of vaso-occlusive episodes and acute chest syndrome is related to high steady-state hemoglobin levels, leukocytosis, and low HbF levels. These findings are consistent with pathogenic mechanisms of altered red cell rheology, higher viscosity, HbS polymerization, and inflammatory cellular adhesion. Interestingly, the epidemiologic risk factors associated with chronic vascular complications such as pulmonary hypertension, cutaneous leg ulceration, priapism, systemic systolic hypertension, renal failure with proteinuria, and possibly stroke are different and include a low steady-state hemoglobin level, increased hemolytic intensity, iron overload, and markers of low nitric oxide bioavailability. One hypothesis is that SCD is driven by two overlapping but different mechanisms of disease: on one hand, vaso- occlusion causes vaso-occlusive episodes and acute chest syndrome, and on the other hand, hemolytic anemia leads to endothelial dysfunction and chronic vasculopathy. Both are caused fundamentally by HbS polymerization.

Prevention

“Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014” at http://www.nhlbi.nih.gov/health- pro/guidelines/sickle-cell-disease-guidelines for detailed, consensus guidelines on prevention and treatment.

Bacterial Infections

Before the antibiotic era, most patients with SCD succumbed to bacterial sepsis from encapsulated organisms. A landmark multicenter, randomized, double-blind, placebo-controlled clinical trial of prophylaxis with oral penicillin in children with sickle cell anemia published in 1986 showed that bacterial prophylaxis started at birth reduced by about 80% the incidence of infection in the penicillin group, as compared with the group given placebo. This study became the foundation for universal screening of SCD. Results of the Penicillin Prophylaxis in Sickle Cell Study II (PROPS 2) trial show that prophylaxis can be safely discontinued at age 5 years as long as there is no history of prior serious pneumococcal infection or surgical splenectomy and in the setting of appropriate comprehensive care. All children should also receive both the 13-valent pneumococcal conjugate (Prevnar 13) and 23-valent pneumococcal polysaccharide (Pneumovax) vaccines, and adults should receive Pneumovax.

Vaccinations for H. influenzae and N. meningitidis are also indicated.

Neurologic Events

Stroke is a devastating complication of SCD and affects predominantly children with HbSS and abnormal transcranial Doppler (TCD) results. Silent cerebral infarcts are asymptomatic MRI- detectable abnormalities that also carry a high risk of morbidity, including overt stroke and cognitive impairment. There is conclusive evidence that chronic transfusions are effective in the primary and secondary prevention of both overt and silent strokes in SCD. A first landmark trial (STOP) published in 1995 showed that the first stroke can be prevented by placing children with abnormal TCD on prophylactic monthly transfusions with a target HbS of <30%.

Transfusions were later found to also have a beneficial effect on reducing the incidence of the recurrence of silent cerebral infarcts, as shown by the SIT trial. The importance of continuing transfusions for more than 30 months was underscored by the STOP2 trial, where TCD abnormalities recurred and the incidence of silent cerebral infarctions on MRI was higher in the transfusion-halted group. Thus, the enthusiasm over the beneficial effects of transfusions was tempered by the concerns about the obvious side effects of long term, possibly indefinite use of this therapeutic strategy. There has been, therefore, an interest in exploring whether hydroxyurea could be an alternative to transfusion in high risk children. Specifically, the SWiTCH trial explored the hypothesis that hydroxyurea and phlebotomy could maintain an acceptable stroke recurrence rate and significantly reduce the hepatic iron burden as compared to a prophylactic chronic transfusion regimen, but was terminated early because of a significantly higher stroke recurrence rate in the hydroxyurea arm compared to the transfusion arm, with equivalent hepatic iron burden in both groups. Thus the issue of when, if ever, it is safe to discontinue transfusions for the secondary prevention of stroke is still unknown.

Conversely, as shown by the results of the TWiTCH trial, another study halted prematurely by the NIH, hydroxyurea is not inferior to chronic transfusions in lowering TCD velocities in children at high risk but without a history of stroke, thereby suggesting that this drug may be equally effective in the primary prevention of neurologic complications.

Clinical Manifestations

Multiple genetic and epigenetic factors affect the SCD phenotype. Patients homozygous for HbS (SS) or compound heterozygous for HbS and a nonfunctional β0-thalassemia allele tend to display the most severe manifestations. On the other end of the spectrum, hereditary persistence of HbF (HPFH), particularly common in Saudi Arabia, or coinheritance of β-thalassemia mitigates the phenotype.

Although the net effect of high HbF levels on the phenotype of SCD is beneficial, coinheritance of one or two α-thalassemia alleles has a more complex effect. α-Thalassemia is present in approximately 30% of patients with SCD and is associated with higher hemoglobin, lower mean corpuscular volume (MCV), and decreased rate of hemolysis.

These effects are protective toward cerebrovascular accident (CVA) and leg ulcers, but lead to increased rates of vaso-occlusive episodes, osteonecrosis, and acute chest syndrome because of increased blood viscosity related to the higher hemoglobin level. Patients with HbSC and HbS/β+-thalassemia have an intermediate severity phenotype (Table 1). Haplotypes of polymorphic sites in the β-globin gene cluster in chromosome 11, which correspond and are linked to defined geographic regions of origin of the HbS gene, have been associated with different disease severity and rates of complications. Other yet unidentified genetic factors predispose certain patients to develop a particularly severe hemolysis with brisk reticulocytosis and a high rate of specific complications that include leg ulcers, priapism, and pulmonary hypertension.

Table 1

Severity of the Main Sickle Cell Syndromes

Genotype                                                                  Clinical Severity                                              Hemoglobin (g/dL)
HbSS Usually marked 6–10
HbS-β0-thalassemia Moderate to marked 6–10
HbS-β+-thalassemia Mild to moderate 9–12
HbSC Mild to moderate 10–15
HbSS-HPFH Mild

Abbreviations: HbSC = heterozygous phenotype; HbSS = homozygous phenotype; HPFH = hereditary persistence of fetal hemoglobin.

Hematology

This section describes the main clinical manifestations of SCD in each organ system (Figure 1 and Table 2).

FIGURE 1    Acute and chronic complications of sickle cell  disease.

Table 2

Landmark Randomized Clinical Trials in Sickle Cell Disease

Year of                   Publication Title                                            Main Findings
1986 Prophylaxis with oral penicillin in children with sickle cell anemia: A randomized trial 84% reduction in incidence of infection and no deaths from pneumococcal septicemia in the penicillin group
1995 Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Reduced incidence of painful crises, ACS, and transfusion in the hydroxyurea group

Survival benefit in follow-up study

1995 Preoperative Transfusion in Sickle Cell Disease Study A conservative transfusion regimen was as effective as an aggressive regimen in preventing perioperative complications in patients with sickle cell anemia
1996 Multicenter investigation of bone marrow transplantation for sickle cell disease HCT is safe in SCD with survival and event-free survival at 4 y of 91% and 73% and can lead to cure
1998 Stroke Prevention Trial in Sickle Cell Anemia (STOP) Transfusion reduces the risk of a first stroke by 92% in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography
2005 Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Discontinuation of transfusion for the prevention of stroke in children with sickle cell disease results in a high rate of reversion to abnormal blood-flow velocities on Doppler studies and stroke
2009 Improving the Results of Bone Marrow Transplantation for Patients with Severe Congenital Anemias Nine of 10 adults who received nonmyeloablative allogeneic hematopoietic stem- cell transplantation for severe sickle cell disease achieved stable, mixed donor– recipient chimerism and reversal of the sickle cell phenotype, without acute or chronic GVHD.
2011 Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). Children ages 9–18 mo randomized to receive hydroxyurea irrespective of disease severity for 2 y had decreased pain episodes, dactylitis, ACS, hospitalization, leukocyte count, and transfusion and increased hemoglobin as compared to children receiving placebo.
2014 Silent Infarct Trial (SIT). Children with silent cerebral infarcts and normal TCD velocity who were randomized to chronic transfusion therapy had a 58% relative risk reduction in the recurrence of silent cerebral infarct or stroke as compared to those in the observation arm.

Abbreviations: ACS = acute chest syndrome; GVHD = graft-versus-host disease; HCT = hematopoietic cell transplantation; SCD = sickle cell disease; VOE = vaso-occlusive   crisis.

Baseline or Steady-State Hematologic Abnormalities

Chronic intravascular and extravascular hemolysis causes a chronic anemia of moderate to severe intensity in HbSS and HbS/β0- thalassemia, with a hemoglobin range of 6 to 9 g/dL. In HbSC and HbS/β+-thalassemia, the anemia may be mild or absent. The anemia of SCD is usually normocytic in HbSS, with anisocytosis and poikilocytosis and a population of small dehydrated dense cells, irreversibly sickled cells, numerous reticulocytes, and schistocytes.

Reticulocytosis is common but not compensatory, and nucleated RBCs are seen in acute exacerbations of the anemia such as in splenic or hepatic sequestration. Baseline leukocytosis with neutrophilia is also common and is a poor prognostic sign associated with acute chest syndrome in adults and frequent vaso-occlusive episodes in children.

Preclinical studies have shown that leukocytes are not simply a marker of disease activity and acute phase but also have a direct pathogenic role in cellular adhesion and vaso-occlusion. The platelet count is commonly elevated in SCD, particularly in patients who are autosplenectomized as a result of repeated splenic infarction, and platelet activation is increased. In the subset of patients with HbSC and and HbS/β+-thalassemia who retain a functional spleen and develop splenomegaly, features of hypersplenism may instead be observed with resulting mild pancytopenia.

Hematologic Indices during Vaso-occlusive Episodes

In acute vaso-occlusive episodes the Hb decreases as a result of hemolysis (by 1.6 g/dL in acute chest syndrome) and sickle cells are observed in the peripheral smear. The lactate dehydrogenase (LDH), reticulocyte count, and other markers of hemolysis such as aspartate transaminase (AST) and indirect bilirubin are elevated in steady state, and in many—but not all—patients are further increased during vaso- occlusive episodes. Haptoglobin levels are chronically depressed in SCD and typically not measurable, even in steady state, in patients with HbS homozygosity. In patients with HbSC, vaso-occlusive episodes may be due to increased blood viscosity and RBC sickling, and worsening hemolysis might not be readily appreciated.

Splenic sequestration crises occur mostly in childhood and are characterized by anemia disproportionate to the degree of hemolysis, reticulocytosis, and acute splenomegaly. Splenic sequestration and repeated episodes of splenic infarction eventually lead to autosplenectomy, although some patients develop splenomegaly.

Splenic infarction usually manifests with left upper-quadrant pain and may be massive, involving more than 50% of the splenic tissue.

In severe vaso-occlusive episodes, massive bone marrow infarction can also occur. In these instances, the peripheral blood smear reveals a leukoerythroblastic picture with immature neutrophilic forms, nucleated RBCs, and teardrop cells. Fat emboli syndrome, a life- threatening complication of vaso-occlusive episodes, can then develop as bone marrow fat embolizes to peripheral capillary beds, leading to multiorgan failure.

Red Blood Cell Alloimmunization

RBC alloimmunization is a common complication of transfusional therapy in SCD and occurs in approximately 30% of patients. It is primarily due to the disparate expression of RBC antigens in African Americans as compared to the donor pool, which is mostly composed of Caucasians. Alloimmunization complicates RBC matching and leads to delayed hemolytic transfusion reactions. Alloantigens that become undetectable by indirect Coombs test 2 months after exposure to mismatched blood have the potential to result in future false-negative cross-matching results. A subset of heavily alloimmunized patients with SCD undergoes life-threatening hemolytic reactions upon exposure to mismatched RBC units. In these hyperhemolytic crises, there is intense hemolysis of transfused and nontransfused RBCs and acute anemia. Treatment of hyperhemolytic crises is empirical and includes erythropoietin-stimulating agents (ESA), parenteral steroids, and intravenous immunoglobulins (Gammagard).1

Iron Overload

Hemosiderosis is the other major complication of transfusional therapy in SCD and is characterized by iron deposition in the heart, liver, and endocrine glands, leading to organ failure and significant morbidity and mortality. It commonly occurs in patients who have received more than 10 lifetime transfusions or more than 20 packed RBC units. Liver biopsy is the gold standard for diagnosis but it is an invasive and uncomfortable procedure. Noninvasive imaging methods such as quantitative liver and myocardial MRI and superconducting quantum interference device (SQUID) are not always available, and therefore diagnosis often rests on the finding of an elevated ferritin and transferrin saturation in the appropriate clinical setting.

Hemostatic Activation and Thrombosis

Numerous studies have shown that arterial and venous thrombosis are common in SCD and include pulmonary embolism, in situ pulmonary thrombosis, and stroke. In SCD, alterations at all levels of the hemostatic system have been described: patients with sickle cell disease exhibit increased basal and stimulated platelet activation, increased markers of thrombin generation and fibrinolysis, increased tissue factor activity, and increased von Willebrand factor (vWF) antigen and thrombogenic ultralarge vWF multimers. Interestingly, hemostatic activation is amplified during vaso-occlusive episodes, as shown by increases in multiple markers of thrombosis as compared to steady state, suggesting a link between hemolysis and thrombosis.

Neurology

Ischemic stroke is common in SCD, with the highest incidence between 2 and 5 years of age. Patients may develop overt CVAs from large vessel occlusion (5%–8% of patients with HbSS) or silent infarcts from focal ischemia detectable by MRI without symptoms (20%–35% of patients with HbSS). The pathophysiology of stroke in SCD is unclear, although genetic factors and an unbalance between oxygen demand and supply have been postulated. Multiple epidemiological studies have shown that the risk factors for ischemic stroke in adult patients include HbSS genotype, severity of anemia, systolic hypertension, male gender, and increasing age. Patients with repeated strokes are at risk for development of anatomic abnormalities and Moyamoya pattern of vascularization, which predisposes to cerebral hemorrhages later in life. The highest incidence of intracerebral hemorrhages occurs in patients older than 20 years.

Both overt and silent strokes have a negative impact on IQ and cause cognitive impairment measurable by psychometric testing. Children and adults with SCD can develop cognitive impairment and subtle signs of accelerated brain aging and vascular dementia even in the absence of focal ischemia by MRI, with a low hematocrit being a predictor of neuropsychological dysfunction. These abnormalities are probably due to chronic and diffuse, as opposed to focal, cerebral anoxia and may be unmasked by psychometric testing. In patients who do have MRI abnormalities without a history of CVA, the gray matter is predominantly affected.

Ophthalmology

Retinal abnormalities are common in SCD and are often asymptomatic until the occurrence of ophthalmologic emergencies. Retinal disease is due to arteriolar occlusion, with subsequent vascular proliferation, neovascularization, retinal hemorrhage (stage IV) and detachment (stage V). Patients with HbSC are more prone to retinal complications, possibly as a result of increased blood viscosity.

Nephrology

Renal abnormalities are common in SCD and manifest primarily as hematuria, proteinuria, and renal tubular acidosis. Hematuria is usually due to papillary necrosis and is an acute finding that requires supportive care and carries a good prognosis. Rarely, gross hematuria requires urologic consultation. Tubular functional defects include inability to concentrate the urine (hyposthenuria) and renal tubular acidosis. Hyposthenuria often manifests with enuresis in childhood, and it is clinically relevant because it predisposes patients to an increased risk of dehydration. Renal tubular acidosis similar to type IV renal tubular acidosis is a common finding in SCD and may lead to hyperkalemia, an important consideration in patients already predisposed to hyperkalemia with intravascular hemolysis and whenever therapy with angiotensin-converting enzyme inhibitors is entertained.

Hyperphosphatemia and hyperuricemia are also often observed in SCD. Microalbuminuria may be detected in early adulthood and tends to progress to nephrotic range proteinuria. Focal segmental glomerulosclerosis is the most common glomerular abnormality and it is probably due to glomerular sickling and infarction. There are currently no approved therapies to prevent progression to end-stage renal disease, which occurs in up to 20% of patients and at a median age of 37 years. Renal replacement therapy is therefore often needed in older adults with SCD. Serum creatinine and 24-hour creatinine clearance are not adequate for screening and monitoring of progression of kidney disease, because tubular secretion of creatinine is preserved and glomerular hyperfiltration is common in SCD, leading to a relatively low creatinine and a high glomerular filtration rate even in patients with underlying kidney impairment. The albumin or protein-to-creatinine ratio and plasma cystatin C levels may instead be used as a screening tool of glomerulopathy in SCD, as they can predict development of chronic kidney disease.

Leg Ulcers

Leg ulcers occur in 10% to 20% of patients with HbSS and have been associated with a chronically high hemolytic rate. They are usually located over the malleolar areas and are exquisitely painful, debilitating, disfiguring, and nonhealing. Vascular and plastic surgery consultation are recommended and aim at excluding local vascular problems that can complicate management of the ulcers and at providing prompt débridement and skin grafting. Although hydroxyurea is associated with development of leg ulcers in patients with myeloproliferative disorders, a review of the literature has failed to show an association with leg ulcers in SCD. Whereas wound healing may be impaired with hydroxyurea use, patients who develop an increase in fetal hemoglobin and have reduced sickling as a result of hydroxyurea therapy might have a net benefit in terms of tissue oxygenation and perfusion. Transfusional therapy, including exchange transfusional therapy, topical nitrates,1 and nutritional zinc7 or L-arginine supplementation,7 have shown benefit in anecdotal reports, but the evidence is inconclusive.

Gastroenterology

Nausea, vomiting, and dyspepsia in SCD are related to delayed gastric emptying and gastrointestinal motility disorders, autonomic neuropathy, or medical therapy. Opiates are often responsible for acute nausea and vomiting, whereas other medications such as hydroxyurea and deferasirox (Exjade) are occasionally responsible for chronic symptoms. Gastroparesis may be due to damage of the microvasculature of autonomic nerves (vasa vasorum) from repeated episodes of sickling.

The liver may be episodically affected by hepatic sequestration crises, heralded by direct hyperbilirubinemia, right upper quadrant pain from distention of the hepatic capsule, acute anemia, and reticulocytosis. Supportive therapy and exchange transfusion, rather than simple transfusion, are indicated for this vaso-occlusive complication. Elevation of liver injury tests may be drug-induced (hydroxyurea, deferasirox), but also related to hepatic sickling, particularly if it occurs during a vaso-occlusive episode. Hepatitis C has a higher prevalence than in the general population and may compound the hepatic manifestations of SCD.

Diarrhea is a common side effect of therapy with deferasirox, particularly in lactose-intolerant patients, and where it is usually self- limited.

Infectious Disease

Patients homozygous for HbSS develop functional asplenia during childhood. This is due to repeated episodes of splenic infarction leading to fibrosis and autosplenectomy. As a result, children are susceptible to overwhelming bacterial sepsis from encapsulated organisms such as S. pneumoniae, H. influenzae, and N. meningitidis. High pediatric mortality from sepsis was therefore common before a landmark study published in 1986 demonstrated the benefit of penicillin prophylaxis instituted at birth. Vaccination for encapsulated organisms is also standard of care in children and adults. In spite of preventive measures, the incidence of life-threatening bacterial infections is increased in SCD, and high fever should be treated empirically as in splenectomized patients, with coverage for penicillin-resistant S. pneumoniae pending blood culture results. Patients with indwelling venous catheters are at risk of catheter- related bacteremia.

Viral infections with bone marrow–tropic viruses such as Epstein– Barr virus, citomegalovirus, and predominantly parvovirus B19 place patients at risk for bone marrow suppression, which can further worsen chronic anemia. In children, infections with parvovirus B19 are responsible for transient red cell aplasia and severe aplastic crises, characterized by acute anemia and reticulocytopenia due to intra marrow destruction of erythroid precursors. Treatment of these episodes includes transfusion and intravenous immunoglobulins,1 besides supportive measures.

Pulmonology

A subset of patients with vaso-occlusive episodes develop acute chest syndrome, the major pulmonary complication of SCD. Acute chest syndrome is a lung injury syndrome defined by fever, pleuritic chest pain, oxygen desaturation, and multilobar radiographic infiltrates associated with severe vaso-occlusive episodes, infection, and bone marrow fat embolization (Figure 2). It usually develops a few days after hospitalization for vaso-occlusive episodes and is often misdiagnosed as nosocomial pneumonia or aspiration pneumonia, particularly because it displays a predilection for the lower lobe of the lungs. Although pneumonia often accompanies acute chest syndrome, proper diagnosis is important because acute chest syndrome warrants simple or exchange transfusion in addition to antibiotic therapy and supportive measures. Common infectious pathogens identified in cases of acute chest syndrome include Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophyla, thus dictating inclusion of a macrolide in the antibiotic cocktail. Pulmonary embolism with resulting infarct is also in the differential diagnosis of acute chest syndrome and may occur concurrently in 17% of patients according to a recent French study. If not recognized and treated promptly, acute chest syndrome leads to pulmonary failure and carries a high mortality.

FIGURE 2    Vicious cycle of acute chest syndrome (ACS).  Vaso- occlusive crises are characterized by increased intraerythrocytic polymerization of deoxygenated hemoglobin S, leading to red blood cell sickling, cellular hyperadhesion, hemolysis, and vaso-occlusion in the microvasculature. These processes are responsible for acute  pain (pain crisis) and bone marrow necrosis. ACS typically occurs in a subset of patients 2-3 days after hospitalization for a vaso-occlusive episode, and radiographically may present as new multilobar, basilar infiltrates on a chest x-ray. Fat embolization from the necrotic marrow is a recognized cause of ACS and is diagnosed by identifying lipid-laden macrophages in the bronchoalveolar lavage. Pulmonary infection is, however, the most common trigger of ACS and may be superimposed over existing pulmonary infarction. Hypoventilation and molecular pathogens such as reactive oxygen species from ischemia-reperfusion injury and by-products of hemolysis may also play a role in inducing or exacerbating lung injury. Finally, in situ pulmonary thrombosis  has been frequently identified as a co-morbid condition in patients with ACS and may be caused by endothelial and hemostatic activation. As a result of lung injury, ventilation-perfusion mismatches and shunting ensues, with subsequent hemoglobin desaturation and  hypoxemia.

Tissue hypoxia in turn triggers further hemoglobin S polymerization and sickling in a vicious cycle.

Reactive airways disease is common in children with SCD and needs to be actively diagnosed and aggressively treated. Children with chronic respiratory symptoms need to be tested for bronchial hyperresponsiveness.

Chronic complications of SCD include pulmonary fibrosis and pulmonary hypertension. Pulmonary hypertension (PH) is an emergent complication of SCD, and is associated with a high morbidity and mortality. Multiple epidemiologic studies have shown that a high baseline hemolysis rate, low hemoglobin, increasing age, a history of leg ulcers, liver dysfunction, iron overload, and kidney failure are risk factors for the development of pulmonary hypertension. Noninvasive transthoracic Doppler echocardiography is recommended as a screening test in this population due to its safety, low cost, and availability to identify patients at high risk for having PH and at high risk for early death. The definitive diagnosis of PH requires a confirmatory right heart catheterization (RHC). Three epidemiologic studies and a randomized clinical trial have shown that an elevated tricuspid regurgitant jet velocity (TRV) measured by Doppler-echocardiography is a common occurrence in SCD, with 30% of the patients having a TRV of 2.5 m/sec (2 SD above the normal mean) or higher, and 10% of the patients having a TRV of 3.0 m/sec (3 SD above the normal mean) or higher. These have proved to be valuable cut-off values, as a TRV of less than 2.5 m/sec, when combined with an N-terminal pro B-type natriuretic peptide (NT- proBNP) value less than 160 has a high negative predictive value for PH. A TRV of 3.0 m/sec or higher confers a positive predictive value for having PH by RHC of 60% to 75% and a relative risk for death of 10.6. Controversy exists on the significance of an intermediate TRV value of 2.5 to 2.9 m/sec, as it is unclear how accurately it predicts RHC-diagnosed PH. In three recently published studies, patients with intermediate or high TRV values had a prevalence of PH by RHC ranging from 25% to 65% depending on what specific cutoff value was used as criteria to perform a RHC (2.5 vs. 2.8) and on whether patients with evidence of end-organ damage were included or excluded. It is, however, worrisome that regardless of the prevalence of PH, patients with an intermediate TRV are as a whole at increased risk of death (RR 4.4). One screening approach is to consider RHC in all patients with TRV of 3.0 or higher and in patients with intermediate TRV values of 2.5 to 2.9 m/sec if the NT-proBNP is greater than 160 pg/mL or the 6 minute walk is less than 333 meters or there is a high clinical pretest probability of having PH (mosaic perfusion pattern on CT scan, low DLCO, significant dyspnea on exertion, etc.). It is likely that intermediate TRV values will need to be combined with other measures of right ventricular function and functional capacity such as NT-proBNP, and 6 minute walk to derive a highly predictive composite biomarker of PH. All studies have been concordant on the high risk of death conferred by PH in SCD whether measured by echocardiography, NT-proBNP, or RHC.

Right heart catheterization studies of patients with SCD and pulmonary hypertension reveal a hyperdynamic state similar to the hemodynamics characteristic of portopulmonary hypertension. It is increasingly clear that pulmonary pressures rise acutely in vaso- occlusive episodes and even more during acute chest syndrome. This suggests that acute pulmonary hypertension and right heart dysfunction represent a major comorbidity during acute chest syndrome, and right heart failure should be considered in patients presenting with acute chest syndrome.

Cardiology

Similarly to other conditions with chronic anemia, SCD is associated with a hyperdynamic state, low peripheral vascular resistance, and normal blood pressure or hypotension. In this setting, even mild elevation of the blood pressure can indicate relative hypertension and represent a risk factor for stroke. Because there are no studies on the treatment of hypertension in SCD, general guidelines on antihypertensive therapy are applied.

Coronary artery disease is rarely observed in SCD, although many patients complain of chest pain during vaso-occlusive episodes. In these instances, the usual work-up for acute coronary syndrome is recommended. It is possible that myocardial microvascular occlusions are the predominant ischemic event in SCD.

Left-sided heart disease in SCD is primarily due to diastolic dysfunction (present in approximately 13% of patients), although systolic dysfunction and mitral or aortic valvular disease (2% of patients) can also occur. The presence of diastolic dysfunction alone in SCD patients is an independent risk factor for mortality. Patients with both pulmonary vascular disease and echocardiographic evidence of diastolic dysfunction are at a particularly high risk for death (OR, 12.0; 95% CI, 3.8-38.1; P <0.001).

Cardiac dysfunction is a late complication and the major cause of death in patients with iron overload. Heart failure and conduction defects are the most common abnormalities and warrant emergent iron chelation treatment. Both deferoxamine (Desferal) and deferasirox reduce cardiac iron content and may be used in combination in severe cases.

Methadone (Dolophine) is associated with a risk of QTc prolongation, which carries a risk of arrhythmias and sudden death, particularly in the setting of pulmonary hypertension and iron overload. Frequent electrocardiographic (ECG) monitoring, as well as dosage reduction or discontinuation, are warranted in this group, particularly if the QTc is greater than 500 msec.

Endocrinology

Iron overload is a common cause of endocrinopathy in SCD and thalassemia, with the hypophysis, gonads, and thyroid glands being particularly affected. Patients with iron overload should therefore undergo screening for endocrine dysfunction as it is routinely mandated in thalassemia.

Patients with SCD are, however, at risk for specific endocrine problems regardless of their iron status. Delayed growth and puberty are relatively common, presenting in females with delayed age of menarche by 2 to 3 years and in males with small testicular size and hypospermia. Likely pathogenic factors include increased catabolism, chronic hpoxemia, hospitalizations with prolonged immobility, ischemic insults during vasooclusive episodes, and chronic use of opiates.

Priapism

Priapism is the most common urogenital complication in patients with the HbSS genotype. It is a sustained, painful erection in the absence of sexual stimulation from occlusion of the penile blood return. It is defined as stuttering if it lasts from minutes to less than 3 hours, and as prolonged if it lasts more than 3 hours. The latter is considered a urologic emergency because of the risk of permanent fibrosis and impotence, and requires a urologic consultation. Pseudoephedrine (Sudafed)1 may lead to detumescence in nonemergency settings, whereas aspiration of the corpus cavernosum is required in the emergency setting and is performed under conscious sedation and local anesthesia. This is usually accompanied by installation of epinephrine.1 Other supportive measures, such as intravenous fluids and parenteral opiates, are usually indicated.

A rare neurologic syndrome known as ASPEN syndrome (association of sickle cell disease, priapism, exchange transfusion, and neurologic events) has been described in patients with priapism who have undergone exchange transfusion. It is characterized by headache and seizures occasionally progressing to obtundation requiring mechanical ventilation, and may be caused by high postexchange hematocrits.

Penile shunts are employed as a last resort to prevent further episodes of priapism by increasing the cavernous blood flow using native vessels or by creating an arteriovenous shunt. They invariably result in impotence, which can be ameliorated by implantation of an inflatable penile prosthesis. An ongoing clinical trial is assessing whether sildenafil (Viagra)1 therapy can prevent priapism by altering vascular smooth muscle tone through inhibition of phosphodiesterase 2 activity.

Diagnosis

The diagnosis of SCD rests on the hemoglobin electrophoresis or high- performance liquid chromatography (HPLC), which allow detection of most hemoglobin variants. In patients with microcytosis α-globin gene sequencing may reveal coinheritance of an α-thalassemia trait.

Neonatal Screening

Children with SCD have an increased susceptibility to bacteremia due to S. pneumoniae, which can occur as early as 4 months of age and carries a case fatality rate as high as 30%. Acute splenic sequestration crises also contribute to mortality in infancy. Diagnosis by newborn screening and immediate entry into programs of comprehensive care, including the provision of effective pneumococcal prophylaxis, can reach infants who might otherwise be lost to the health care system and has been demonstrated to decrease morbidity and improve survival. Currently, newborn screening and follow-up of SCD are carried out in all 50 states in the United States as well as in most developed countries.

Late Diagnoses and Misdiagnoses

Rarely, patients who were born before universal screening was introduced or who were lost at the time of follow-up of positive neonatal screening are only diagnosed late in life. This is particularly the case of patients with HbSC, who might have normal hemoglobin and hematocrit and a mild disease phenotype. Occasionally, the disease is misdiagnosed as iron deficiency in patients with HbS/β+- thalassemia on account of their microcytosis, and they undergo futile and potentially harmful prolonged trials of iron supplementation.

Patients who have a low HbS level (<40%) due to recent transfusion or who have only mildly decreased hemoglobin (HbSC or HbS/β+- thalassemia) may receive an erroneous diagnosis of sickle cell trait (carrier state).

Treatment

From the original description of SCD in 1910 to the 1970s, there was no efficacious therapy for SCD, and most patients died within the first 2 decades of life, with infectious complications being responsible for the majority of pediatric fatalities. Several preventive and pharmacologic milestones since then, and the realization that care has to occur in a multidisciplinary setting, have profoundly affected the natural history of the disease (Table 3). Median age at death in resource-rich countries was 42 years in male patients and 48 years in female patients with HbSS, according to data from the Cooperative Study of Sickle Cell Disease in the 1980s (a pre-hydroxyurea setting), thereby still lagging approximately 2 to 3 decades behind that of the general African American population. The following sections summarize the therapeutic approach to the most important complications of SCD.

Table 3

Manifestations of Sickle Cell Disease with Key Prevention and Treatment Strategies

Manifestation                                                                  Prevention                                                                                    Treatment
Pneumococcal sepsis Penicillin,  Prevnar/Pneumovax vaccination Antibiotic therapy for  penicillin-resistant

Streptococcus pneumoniae

Splenic or liver sequestration Exchange transfusion
Painful vaso- occlusive episode Hydroxyurea (Droxia), prevention of exposure to triggers Intravenous fluids, parenteral opiates, supplemental oxygen
Acute chest syndrome Incentive spirometry during VOE, hydroxyurea Transfusion, broad-spectrum antibiotics with atypical coverage
Iron overload Optimization of transfusion therapy Iron chelation with deferasirox (Exjade) or deferoxamine (Desferal)
RBC

alloimmunization

Transfusion with leukoreduced RBCs
CVA Chronic transfusion in children with high transcranial Doppler velocity Exchange transfusion and thrombolytics in selected cases
Pulmonary hypertension Hydroxyurea?, treatment of predisposing conditions such as obstructive sleep apnea, hypoxemia, thromboembolism Hydroxyurea, chronic transfusion therapy, specific therapy
Kidney disease Antihypertensive therapy?, hydroxyurea?, ACE   inhibitors? ACE inhibitors?, renal replacement therapy, kidney transplant
Priapism Hydroxyurea? Pseudoephedrine (Sudafed),1 aspiration of corpus cavernosum, sildenafil (Viagra)1
Leg ulcers Hydroxyurea?,  chronic transfusion? Surgical débridement, surgical grafting

Abbreviations: ACE = angiotensin-converting enzyme; CVA = cerebrovascular accident;   RBC

= red blood cells; TCD = transcranial Doppler; VOE = vaso-occlusive  crisis.

1  Not FDA approved for this indication.

Vaso-Occlusive Episodes

Acute pain from vaso-occlusive episodes in SCD is extremely intense, affects both children and adults, and is due to ischemia or necrosis of the vascular beds. Most patients report severe pain in the bones and joints of the extremities, as well as lower back, although acute ischemia and pain can affect unusual sites such as the mandibular area. Occasionally, an affected limb displays the typical signs of inflammation, such as edema, warmth, and erythema, but a paucity of signs is the norm. Imaging studies such as MRI and bone scan can reveal signs of acute bone marrow infarction in a painful bony area, but they are not routinely employed in the work-up of a pain episode.

High-dose IV opiates, as well as nonsteroidal antiinflammatory drugs (NSAIDs), are the mainstay of treatment of a pain episode. Even in opiate-naive patients with SCD, opioid dosages often exceed those required for other indications. For instance, doses of intravenous hydromorphone (Dilaudid) of 1 to 2 mg are typical in adult patients.

Most patients, however, are on an oral pain regimen at home and have a history of multiple admissions for vaso-occlusive episodes, thereby dictating individualized care based on what has been effective in the past and the patient’s own perception of the intensity of pain.

After an attempt at controlling the pain with three or four closely spaced narcotic boluses is made, patients who are in persistent discomfort or have evidence of underlying complications triggering the vaso-occlusive episode should be admitted and placed on patient- controlled analgesia. The American Pain Society has published guidelines for the treatment of acute and chronic pain in SCD, followed by other institutions in the past decade.

Common obstacles to prompt and effective care in SCD are the health professional’s fear of overdosing the patient, as well as misconceptions about addiction and pseudoaddiction. In general, health care professionals tend to overestimate the prevalence of opioid abuse and addiction in SCD, and tend to undertreat patients significantly, leading to patients’ frustration and anger when their pain demands are not met (pseudoaddiction).

Nonpharmacologic therapies such as biofeedback, relaxation, localized heat, and acupuncture may be effective and should be incorporated in the management of pain episodes whenever possible. Care for vaso-occlusive episodes should also include management of possible precipitating factors: dehydration and hypovolemia should be corrected with hypotonic crystalloids, and an infection work-up should be initiated in patients with fever, hypoxemia, or leukocytosis above baseline. Antiemetics and antipruritus therapy are also usually needed.

Prior experiences such as that of the Bronx Comprehensive Sickle Cell Center have shown that a dedicated facility for effective and rapid management of uncomplicated vaso-occlusive episodes reduces hospitalizations and length of stay and facilitates integration of care— psychological, socioeconomic, and nutritional—in a multidisciplinary approach. This experience is at the basis of the concept of day hospital in SCD and relies on the need to provide prompt assessment and treatment of pain, safe dose titration to relief, monitoring of adverse effects, and adequate disposition (emergency department, inpatient admission, home) in a clinical environment familiar with SCD and the individual patient.

Chronic Pain

Chronic pain is common, and recent literature based on pain diaries compiled by patients shows that most patients with SCD experience pain on an almost daily basis (PiSCES study). Patients who have successfully transitioned from pediatric to adult care, have a good support system, and are distracted by their work or school schedules tend to cope better and require less pharmacologic support. In most cases, though, short-acting and long-acting opiates are required to empower the patient to manage pain at home and minimize use of the emergency department. Drugs for neuropathic pain, such as gabapentin (Neurontin),1  may also be used in combination with opiates.

Because analgesic care is life-long, consultation with pain specialists is often valuable, particularly in patients for whom more-sophisticated pain regimens are needed. For instance, the mu-opioid receptor partial agonist buprenorphine (Buprenex, Butrans), opioid rotation, and methadone used as analgesic can help reduce the total opiate requirements. Urine toxicology screens are indicated and should be scheduled at regular intervals both to document adherence with the therapy and to screen for use of illicit substances.

Transfusional Therapy

In SCD, the benefits of transfusion in terms of improved hemodynamics and oxygenation need to be balanced with the risks of iron overload, alloimmunization, transfusion reactions, and viral transmission of infectious agents. Leukoreduced, sickle-negative RBCs with extended phenotypic matching for Rh Cc, Ee, and Kell, which account for 80% of detected antibodies, are required. By employing extended phenotypic matching, the rate of alloimmunization decreased from 3% to 0.5% per unit, and the rate of delayed hemolytic transfusion reactions decreased by 90% in the STOP study. In previously immunized patients, a full RBC match also inclusive of matching for the Duffy, Kidd, and S antigens is recommended.

Indications for transfusion include hemoglobin less than 5 g/dL or less than 6 g/dL with symptoms and any severe complication such as stroke, aplastic anemia, splenic or hepatic sequestration, or acute chest syndrome.

Prophylactic transfusions have been considered standard of care before surgery (with the exclusion of minor procedures such as intravenous port placement). The benefit of preoperative transfusions in preventing SCD-related complications in HbSS patients has been recently confirmed in a small randomized clinical trial (the TAPS study). As to the type of transfusion strategy to be used, a clinical trial published in 1995 showed that a conservative prophylactic transfusion regimen to achieve a target hemoglobin of 10 g/dL and any HbS value was as effective as an aggressive regimen to achieve a hemoglobin of 10 g/dL and a target HbS value of <30% in preventing postsurgical complications such as acute chest syndrome.

Exchange transfusion (erythrocytapheresis with RBC exchange) is usually reserved for the most severe complications, which include acute chest syndrome with impending pulmonary failure, acute stroke and its prevention in children, multiorgan failure and sepsis. Box 1 summarizes the main indications for simple and exchange transfusion in SCD as well as the areas of uncertainty.

Box 1
Indications for Transfusion
No Indication

Chronic steady-state anemia

Uncomplicated painful episode

Infections

Minor surgery without general anesthesia

Aseptic necrosis of hip or shoulder

Uncomplicated pregnancy

Unclear Indication

Intractable or frequent painful episodes

Leg ulcers

Before receiving IV contrast dye

Complicated pregnancy

Cerebrovascular accident in adults

Chronic organ failure

Simple Transfusion

Symptomatic anemia

•   High output cardiac failure

•   Dyspnea

•   Angina

•  Central nervous system dysfunction

Sudden decrease in hemoglobin

•   Aplastic crisis

•   Acute splenic sequestration

Severe anemia (Hb ~5 g/dL) with fatigue or dyspnea Preparation for surgery with general anesthesia

Exchange Transfusion

Acute cerebrovascular accident

Multiple organ system failure

Acute chest syndrome

Hepatic sequestration

Retinal surgery

Iron Chelation

Patients who have received more than 10 transfusions or 20 units of packed RBCs should be screened for iron overload. Most authorities recommend initiation of iron chelation based on a ferritin level consistently greater than 1000 ng/mL, based on data from the thalassemia literature, although liver iron quantitation by MRI or biopsy should be obtained, when available, prior to therapy and to monitor its effectiveness. In the United States, the oral chelating agents deferasirox and deferiprone (Ferriprox) and the parenteral deferoxamine are available and should be administered until the ferritin level is less than 500 ng/mL for three consecutive measurements. Patients on iron chelation with deferasirox and defereoxamine need to be monitored for hepatic, renal, auditory, and visual toxicity, and particular caution has to be exercised in the setting of renal disease, because transient, reversible increases in serum creatinine as well as rare instances of irreversible acute kidney injury have been reported in patients with underlying renal insufficiency. In most patients, however, deferasirox is well tolerated, and dyspepsia and diarrhea are the most common side effects. Deferiprone (Ferriprox) was approved for the treatment of transfusional iron overload in thalassemia and may have a role as a third iron chelator in SCD. Deferiprone has been associated with agranulocytosis and neutropenia, mandating close monitoring of the absolute neutrophil count during therapy.

Erythropoietic Stimulating Agents

Whereas a brisk reticulocytic response is common in SCD, patients who develop renal failure or aplastic crises or who receive therapy with hydroxyurea may experience a relative or absolute reticulocytopenia (<100,000 reticulocytes/mL) and a worsening of their baseline anemia. In these situations, therapy with erythropoietic stimulating agents (ESAs) is indicated. Occasionally, ESAs are used to allow upward titration of hydroxyurea and are used in combination with this medication. A review of the literature and of the experience at the NIH shows that ESAs are safe in patients with SCD, particularly when used in combination with hydroxyurea and when the target hemoglobin is no more than 10 g/dL.

Because of bone marrow expansion in patients with HbSS, higher starting doses of erythropoietin (Epogen, Procrit)1 than in patients without SCD and on the order of 300 U/kg three times per week (or alternatively as a single dose of 900 U/kg once weekly) may be considered. For darbepoetin (Aranesp),1 a reasonable starting dose is 100 to 200 µg/weekly or every 2 weeks. ESAs can be titrated by 20% to 25% increases in dose per week in patients who do not respond adequately. Weekly monitoring of hematocrit is essential to avoid overdosage and relative erythrocytosis, which can lead to hyperviscosity and vaso-occlusive episodes.

Nutritional Considerations

Malnutrition, growth retardation, and stunting with findings of low lean and fat body mass have a high prevalence in children and adolescents with SCD due to their increased caloric demands and a hypermetabolic state. Macronutrient and micronutrient deficiencies are common, and nutritional counseling is therefore warranted.

Hypovitaminosis D and low bone mineral density are also prevalent in children and adults. Folic acid1 is indicated at the dose of 1 mg daily as in other hemolytic diseases. Strategies aimed at decreasing iron intake and absorption should be implemented early. There is also growing interest in antioxidant nutrients, although there are no clear guidelines at present. The small subset of patients who are overweight or obese is at risk for exacerbating or precipitating common orthopaedic problems in SCD such as avascular necrosis of the femoral heads and their resulting disability. These patients should also receive targeted nutritional counseling.

Hydroxyurea

Since the pediatric hematologist Janet Watson suggested in 1948 that the paucity of sickle cells in the peripheral blood of newborns was due to the presence of increased HbF, there has been interest in developing therapies to modulate the hemoglobin switch from fetal to newborn life. Several antineoplastic agents, including 5-azacytidine (Vidaza)1 and hydroxurea, became the focus of attention after they were found to increase HbF levels in nonhuman primates and individuals with SCD.

The landmark Multicenter Study of Hydoxyurea in Sickle Cell Disease (MSH) showed that the incidence of painful crises was reduced from a median of 4.5 per year to 2.5 per year in hydroxyurea- treated patients with SCD. The rates of acute chest syndrome and blood transfusion were also reduced significantly. A follow-up for up to 9 years of 233 of the original 299 subjects showed a 40% reduction in mortality among those who received hydroxyurea. This study led to the approval of hydroxyurea (Droxia) as the only disease- modifying therapy in adults with SCD. More recent studies showed that hydroxyurea is safe and effective in children with adults with SCD. The recently concluded Baby-HUG study showed that children 9–18 months with HbSS disease randomized to receive 2 years of hydroxyurea therapy, irrespective of the disease severity, had less dactilytis and fewer pain episodes, hospitalizations, and transfusions than children receiving placebo.

On a molecular and cellular level, the benefits of hydroxyurea are mostly related to increased intracellular HbF, which prevents the formation of HbS polymers and sickling. In addition to this mechanism, some patients on hydroxyurea who do not adequately increase their HbF levels also display clinical benefits, suggesting that hydroxyurea might have other beneficial rheologic properties.

Although the MSH study only included patients with HbSS, its findings traditionally have been extrapolated to other sickle cell syndromes such as HbSC and HbS/β-thalassemia. A report from Greece, where S/β-thalassemia is highly prevalent, has confirmed that hydroxyurea similarly reduces complications and mortality in patients with HbS/β0-thalassemia, with a nonsignificant benefit also observed in HbS/β+thalassemia. Although the NIH guidelines on SCD do recommend hydroxyurea in patients with HbSC disease, there is still no direct published evidence of benefit in this population, and some authorities contend it should not be used in HbSC disease because the main pathophysiologic alteration in this subset of patients is increased viscosity rather than hemolysis and sickling.

Hydroxyurea has been indicated at a dosage of 15 mg/kg (7.5 mg/kg in patients with renal disease) in patients with frequent pain episodes, history of acute chest syndrome, other severe vaso-occlusive episodes, or severe symptomatic anemia, although a newer approach is to prescribe it to all patients with HbSS regardless of their phenotype.

Endpoints are less pain, increase in HbF to 15% to 20%, increased hemoglobin level to 7 to 9 g/dL in severely anemic patients, improved well-being, and acceptable myelotoxicity. The dosage can be increased by 500 mg every other day every 8 weeks to a maximum of 35 mg/kg if no toxicity is encountered. Considering the potential myelotoxicity, hepatotoxicity, and nephrotoxicity of this medication, laboratory monitoring needs to be performed every 2 weeks at the time of initiation or escalation and monthly during maintenance therapy.

Laboratory studies should include a complete blood cell count (CBC), differential and reticulocyte count, and serum chemistries.

Measurements of HbF can be performed every 3 months. An elevated MCV is a marker of adherence to the therapy.

Criteria for holding hydroyurea are listed in Figure 3. Patients need to be counseled on the teratogenic potential, as demonstrated in animal studies, as well as the risks of infertility and leukemogenesis, although to date no increase in baseline risk of leukemia in patients with SCD on hydroxyurea has been reported.

FIGURE 3    Protocol for hydroxyurea treatment.

Other side effects that can affect compliance include, but are not limited to, weight gain, alopecia, skin and nail hyperpigmentation (melanonychia), nausea and vomiting, and mucosal ulcerations.

Because of the toxicity concerns as well as factors intrinsic to long-term preventive therapy, hydroxyurea therapy has had low effectiveness in spite of high efficacy, with underprescribing by health care professionals and poor patient compliance being major obstacles to its widespread adoption.

Therapy of Pulmonary Hypertension

Because evidence-based guidelines for managing pulmonary hypertension in patients with SCD are not available, recommendations are based upon the pulmonary arterial hypertension literature, case reports, small open-label studies, and expert opinion. For patients with mild pulmonary hypertension (tricuspid regurgitant velocity [TRV], 2.5-2.9 m/sec), it is important to identify and treat risk factors associated with pulmonary hypertension such as rest, exercise or nocturnal hypoxemia, sleep apnea, pulmonary thromboembolic disease, restrictive lung disease or fibrosis, left ventricular systolic and diastolic dysfunction, severe anemia, and iron overload. These patients may benefit from aggressive SCD management, including optimization of hydroxyurea dosage and initiation of a chronic transfusion program in those who do not tolerate or respond poorly to hydroxyurea. Consultation with a pulmonologist or cardiologist experienced in pulmonary hypertension is also recommended.

For patients with TRV 3 m/sec or more, we recommend following the guidelines for TRV 2.5 to 2.9 m/sec. In addition, right heart catheterization is necessary to confirm diagnosis and to directly assess left ventricular diastolic and systolic function. We would consider specific therapy with selective pulmonary vasodilator and remodeling drugs if the patient has pulmonary arterial hypertension defined by right heart catheterization and exercise limitation defined by a low 6- minute walk distance.

FDA-approved drugs for primary pulmonary arterial hypertension include the endothelin receptor antagonists (bosentan [Tracleer] and ambrisentan [Letairis]), prostaglandin-based therapy (epoprostenol [Flolan], treprostinil [Remodulin, Tyvaso, Orenitram], and iloprost [Ventavis]), the phosphodiesterase-5 inhibitors (sildenafil [Revatio]), and riociguat [Adempas], the first member of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators. No published randomized studies in the SCD population exist for any of these agents, although a multicenter placebo-controlled trial of sildenafil for pulmonary hypertension of SCD was stopped early because of an unexpected increase in hospitalizations for vaso-occlusive crisis in the treatment group receiving sildenafil.

Anticoagulation is indicated in patients who have evidence of pulmonary thromboembolic complications and is supported by evidence of benefit in other populations with pulmonary hypertension.

Hematopoietic Stem Cell Transplantation

Despite improvement of supportive care in SCD, life expectancy remains lower than for those not affected. In addition, quality of life for patients with SCD is usually significantly impaired. Although hydroxyurea can decrease acute complications of SCD such as vaso- occlusive episodes and acute chest syndrome, no satisfactory measures exist to prevent the development of irreversible organ damage in adults. Further, therapy with hydroxyurea is lifelong, and only 20% to 30% of eligible patients are prescribed or actually take the drug.

Currently, allogeneic hematopoietic stem cell transplantation (HCT) remains the only curative treatment. Indications for HCT have been empirically determined from prognostic factors derived from studies of the natural history of SCD. The most common indications for which patients with SCD have undergone HCT are a history of stroke, recurrent acute chest syndrome, or frequent vaso-occlusive episodes.

Allogeneic HCT after myeloablative therapy has been performed in hundreds of pediatric and numerous adult patients with SCD. The backbone of the preparative regimens have consisted of busulfan (Busulfex)1  14 to 16 mg/kg and cyclophosphamide (Cytoxan)1200 mg/kg. Additional immunosuppressive agents used have included antithymocyte globulin (Atgam),1 rabbit antithymocyte globulin (Thymoglobulin),1 antilymphocyte globulin, or total lymphoid irradiation (Figure 4). Cyclosporine A (Neoral),1 alone or with mercaptopurine (Purinethol)1 or methotrexate,1 has been used for post-transplant graft-versus-host disease prophylaxis.

FIGURE 4    Spectrum of immunosuppression and myelosuppression  in preparative regimens in hematopoietic stem cell transplantation (HCT) in sickle cell disease (SCD). Most preparative regimens for HCT  in SCD have employed a backbone of busulfan (BU) (Busulfex)1 and cyclophosphamide (CY) (Cytoxan).1 Additional immunosuppressive agents include equine antithymocyte globulin (Atgam) or leporine antithymocyte globulin (Thymoglobulin) (ATG), antilymphocyte globulin, total lymphoid or total body irradiation (TLI or TBI), fludarabine (Flu) (Fludara),1 and alemtuzumab (Campath).1 Attempts to reduce the intensity of preparative regimens for patients with SCD have been based on one of two approaches. The first is the use of reduced- intensity conditioning regimens to produce less myeloablation. These require donor marrow infusion for hematopoietic recovery. The second is the use of nonmyeloablative regimens, which do not eradicate host hematopoiesis and allow hematopoietic recovery even without  donor stem cell infusion. (Adapted with permission from Krishnamurti L: Hematopoietic cell transplantation: A curative option for sickle cell disease. Pediatr Hematol Oncol 2007;24:569–575.)

The outcome of HCT for patients with SCD from matched siblings is excellent. Of one thousand recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the

European Blood and Marrow Transplant, Eurocord and the Center for International Blood and Marrow Transplant Research the 5-year event-free and overall survival was 91.4% (95% CI 89.6%–93.3%) and 92.9% (95% CI 91.1%–94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR] 1.09; p<0.001) and higher for transplantations performed after 2006 (HR 0.95, p=0.013). Twenty-three patients experienced graft failure; 70 patients (7%) died, the most common cause of death being infection. Stabilization or reversal of organ damage from SCD has been documented after HCT. In patients who have stable donor engraftment, complications related to SCD resolve, and there are no further episodes of pain, stroke, or acute chest syndrome. Patients who successfully receive allografts do not experience sickle-related central nervous system complications and have evidence of stabilization of central nervous system disease by cerebral MRI. However, the impact of successful HCT on reversal of cerebral vasculopathy has been variable. Current research is focused on improving the applicability of HCT to a greater proportion of patients with SCD by the development of novel conditioning regimens minimizing myeloablation (see Figure 4), the use of novel sources of hematopoietic stem cells such as umbilical cord blood, extending HCT to adult recipients and alternate donors such as matched unrelated donors and haploidentical donors. The aim of these studies is to develop safe and effective alternatives for patients without matched sibling donors, thus increasing the applicability of curative therapy for SCD.

Experimental Therapies

The recent decade has witnessed a flourishing of new therapeutic approaches for sickle cell disease. New potential therapies, such as treatment with pharmacologic doses of L-glutamine7 to reduce oxidant stress in the sickle red blood cells, have shown promising results in clinical trials and are at advanced stages of development. Other approaches are outlined in the following paragraphs.

Modulation of Cellular Dehydration

Cellular dehydration plays a key role in HbS polymerization and sickling and is caused by water loss through the Ca2+-activated K+ channel (IK1 or Gardos channel) and the K-Cl cotransport (KCC). The Gardos channel inhibitor senicapoc was tested in phase II and phase III clinical trials, where it led to increased hemoglobin and decreased hemolysis but did not result in a reduction in the rate of pain episodes. There is hope that strategies aiming at reducing cellular dehydration may be used in combination with other therapies to prevent vaso-occlusive episodes.

Modulation of Nitric Oxide

Nitric oxide (NO) is an active biogas and a free radical species that mediates arterial relaxation, cellular adhesion to endothelium, hemostasis, and blood viscosity. In SCD, NO bioactivity is reduced as a result of decreased production due to endothelial perturbation and NO scavenging by cell-free hemoglobin generated during intravascular hemolysis. Dietary supplementation with L-arginine,7 a precursor of NO, and delivery of exogenous NO or NO bioactivity to the microvasculature in SCD, should promote dilatation of the terminal arterioles where obstruction to flow and tissue damage occurs, improvement of lung ventilation and perfusion matching, decrease in pulmonary artery pressures, and inhibition of platelet aggregation and cellular adhesion. Although two recent clinical trials on L-arginine supplementation and inhaled NO (DeNOVO trial) for vaso-occlusive episodes failed to show a clinical benefit, optimization of timing and dosing, and novel strategies to target the NO pathway, might lead to valuable NO therapeutics in the future.

Modulation of cellular adhesion

Adhesive interactions between red blood cells, white blood cells and platelets and between cells and endothelium are implicated in the pathogenesis of vaso-occlusive episodes. Recently, several compounds have been developed to target specific adhesion molecules such as E- selectin and P-selectin. A small molecule inhibitor of E-selectin and a monoclonal antibody against P-selectin are being investigated in Phase 1 and 2 clinical trials and single-stranded oligonucleotides (aptamers) against selectins have shown promise in pre-clinical models.

Gene therapy

The ultimate cure for sickle cell disease, gene therapy, is finally on the horizon. A French group has reported that a patient has been successfully treated with lentiviral-mediated insertion of an anti- sickling beta globin gene into autologous stem cells. The transduced cells were then transplanted into the patient who is free from the hallmarks of sickle cell disease fifteen months post transplant.

Surgical Issues

Preoperative patient optimization includes prophylactic transfusion, close monitoring of pulse oximetry, adequate analgesia based on the patient’s opiate tolerance, and monitoring for sickle cell–related complications.

Avascular necrosis (AVN) of the femoral heads, and more rarely of the humeral heads, is the most common orthopaedic problem in SCD. Surgery is usually deferred until the pain and disability from AVN become intolerable and usually involves total hip or shoulder arthroplasty. This is usually a more involved procedure than in the general population on account of the altered bone anatomy in SCD. Patients with bone marrow expansion may experience thinning of the cortical bone and prosthetic instability, whereas some may suffer from the opposite problem of obliteration of the medullary shaft by sclerotic bone in response to multiple necrotic events.

Patients with SCD tend to develop pigmented gallstones and cholelithiasis. Cholecystectomy is performed in patients with SCD with cholelithiasis, right upper quadrant pain, and a positive hepatobiliary iminodiacetic acid (HIDA) scan. In SCD, the rate of intraoperative complications is higher and so is the rate of reversion from laparoscopic to open cholecystectomy.

Splenectomy has been reserved for patients with massive splenic infarction (>50% of the spleen volume); intractable, recurrent splenic pain; and splenic abscess in the setting of splenic infarction. It is important to limit splenectomy to these few specific circumstances, because overwhelming sepsis and acute pulmonary hypertension have been reported in the postsplenectomy period in SCD.

Kidney transplantation has been successfully performed in patients with SCD on chronic renal replacement therapy, although survival at 7 years is lower than in African Americans without SCD (67% vs.83%). This difference is mostly due to vaso-occlusive complications in the transplanted kidney, possibly exacerbated by the higher hematocrit in the postoperative period from resumption of endogenous erythropoietin production and increased blood viscosity. It is therefore critical to closely monitor ESA therapy in the post- transplantation period to prevent overdosing and relative erythrocytosis. A chronic transfusion program to prevent intrarenal sickling and maximization of hydroxyurea therapy should also be entertained, although its benefits need to be balanced against the risk of HLA alloimmunization and rejection. Combined solid organ and HCT protocols are being developed to overcome these complications. Recently, lung transplantation has been successfully performed in a SCD patient with severe pulmonary arterial hypertension and pulmonary veno-occlusive disease.

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1  Not FDA approved for this  indication.

7  Available as dietary supplement.

1  Not FDA approved for this  indication

1 Not FDA approved for this indication.

1  Not FDA approved for this  indication

1  Not FDA approved for this  indication

1  Not FDA approved for this  indication

1  Not FDA approved for this  indication

1  Not FDA approved for this  indication

1 Not FDA approved for this indication.

7  Available as dietary supplement.

7  Available as dietary supplement.

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