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Sickle cell disease (SCD) results
from the substitution of a valine residue for glutamic acid at position 6 in the
beta-subunit of
hemoglobin (Ingram,
1956). With a few minor exceptions, people with only one gene for hemoglobin
S (Hb S) are phenotypically normal (sickle
trait). People who inherit two Hb S genes from their parents have sickle
cell disease. Deoxygenated Hb S tends to polymerize non-covalently into long
strands that deform the erythrocyte, giving the characteristic "sickle cell"
morphology (Eaton and Hofrichter, 1990). Hb S with bound oxygen (e.g., in the
arterial circulation) does not polymerize.
Normal and Sickle Red Cells
The schematic diagram shows the changes that occur as sickle or normal red cells release oxygen in the microcirculation. The upper panel shows that normal red cells retain their biconcave shape and move through the microcirculation (capillaries) without problem. In contrast, the hemoglobin polymerizes in sickle red cells when they release oxygen, as shown in the lower panel. The polymerization of hemoglobin deforms the red cells. The problem, however, is not simply one of abnormal shape. The membranes of the cells are rigid due in part to repeated episodes of hemoglobin polymerization/depolymerization as the cells pick up and release oxygen in the circulation. These rigid cells fail to move through the microcirculation, blocking local blood flow to a microscopic region. Amplified many times, these episodes produce tissue hypoxia. The result is pain, and often damage to organs.
Recently, red cell adhesion to endothelial cells has been recognized as a major factor in the pathogenesis of sickle cell disease. Normal red cells do not adhere to endothelial cells. In contrast, sickle cells are quite "sticky". Even brief adherence to endothelium would increase the probabilty of the red cells sickling before they can get out of the capillaries into the endothelium. This enhances the chance of vaso-occlusion and local tissue hypoxia.
The mechanism by which these changes in the physical properties of the hemoglobin molecule produce the clinical manifestations of the disease is not unequivocally proven. The most widely accepted hypothesis is that erythrocytes deform as they release their oxygen in the capillaries and are trapped in the microcirculation (Eaton et al., 1976) (Kaul et al., 1989). The blockade of blood flow produces areas of tissue ischemia, leading to the myriad of clinical problems seen with sickle cell disease. Although a good deal of indirect evidence supports this theory, definitive proof that this is the pathophysiologic mechanism in sickle cell disease is lacking.
Recently, investigators have focused on other factors outside the red cell that could contribute to the manifestations of sickle cell disease. Hebbel and colleagues first showed that sickle erythrocytes adhere abnormally to vascular endothelial cells. Their observations were confirmed and extended by other workers. The endothelial cells may abnormally express adhesion receptors, perhaps in response to activators released from sickle red cells (e.g., reactive oxygen species). Other investigators have focused on leucocytes and platelets which might also contribute to disturbed blood flow in sickle cell disease. The involvement of multiple components of the blood in the manifestations of sickle cell disease makes understanding the pathophysiology more difficult. On the other hand, these additional modulators could be targeted by new therapies, with diminution in the severity of sickle cell symptoms.
Sickle cell disease is extremely
varied in its manifestations (Ballas, 1991) (Wethers, 1982). This includes
both the organ systems that are affected as well as the severity of the
affliction. A study of the natural history of sickle cell disease indicated that
about 5% of patients account for nearly one-third of hospital admissions (Platt
et al., 1991). A significant number of patients with the disease have few
admissions and live productive and relatively healthy lives. The average
life-span of people with sickle cell disease is shorter than normal, however,
reflecting increased mortality due to the complications of the disease.
Variations in the severity of sickle cell disease between individuals usually defy explanation. Some factors have been identified that ameliorate the severity of the condition, however. The most important of these is a high level of hemoglobin F (Hb F) in the erythrocytes (Platt et al., 1991). The first insight into the role of fetal hemoglobin in the clinical manifestations of SCD was made by a pediatrician, Janet Watson (Watson, et al., 1948). She and her colleagues at a New York hospital noted that babies with SCD rarely had manifestations of the condition in the first year of life. They proposed that the high level of fetal Hb in the red cells, which persists during the first year of life, somehow protects the infant. Fetal Hb levels decline to their routinely low steady-state level between the ages of one to two years. The childhood manifestations of SCD are seen thereafter.
Patients with sickle cell disease who also have hereditary persistence of fetal hemoglobin (HPFH) often have few if any symptoms (Stamatoyannopoulos et al., 1975). In these individuals, Hb F usually comprises greater than 20% of the hemoglobin in the erythrocytes. Patients may be partially protected from the ravages of sickle cell disease with even lower levels of Hb F. Unfortunately, few patients with SCD have Hb F levels of greater than 10 or 11% in the absence of HPFH.
Fetal Hb disrupts the polymerization of deoxy-Hb-S (Goldberg et al., 1977). Since polymerization of deoxy-Hb-S is the signal event in the pathogenesis of SCD, fetal Hb effectively prevents disease manifestation. The distribution of Hb F among RBCs is also important. In hereditary persistence of fetal hemoglobin (HPFH), Hb F exists at high levels in all red cells. All red cells are equally protected from sickling. In the absence of HPFH, patients with high levels of Hb F have a heterogeneous distribution of fetal hemoglobin between cells. An over simplified example is a patient in whom half the cells have 30% Hb F and half have 0%. The patient would have 15% Hb F overall. However, half the cells would sickle and occlude flow through the microcirculation. These deformed cells would block the flow of the normally shaped high Hb F cells. The patient would experience all the manifestations of sickle cell disease.
Relative to patients with straightforward sickle cell disease, the rate of hemolysis is lower in people who also have two-gene deletion alpha-thalassemia (Embury et al., 1982). The mechanism by which alpha-thalassemia ameliorates red cell destruction is unknown. Polymerization of sickle hemoglobin is exponentially related to its concentration in the cell. The red cell hemoglobin concentration in patients with two gene deletion alpha-thalassemia and sickle cell disease is no different from that of patients with ordinary sickle cell disease, however (Steinberg and Embury, 1986). The Hb F concentrations often is higher in the red cells of these patients and may contribute partially to the reduction in the rate of hemolysis.
The advent of therapies that can significantly ameliorate the clinical course of sickle cell disease opens the possibility of early intervention. If physicians could predict which children will fall victim to recurrent severe pain crises or bouts of acute chest syndrome, they could intervene before the clinical episodes thereby preventing the associated morbidity and possible mortality. This is particularly relevant for treatments such as bone marrow transplantation that can cure sickle cell disease but also carry the risk of significant morbidity and even mortality.
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Miller and colleagues (2000) examined the records of nearly 400 children followed at comprehensive sickle cell centers. Their multivariate analysis of the clinical courses of these children between infancy and 10 years of age uncovered several factors that augured severe complications, including recurrent severe pain episodes, stroke and acute chest syndrome. As seen in Table 1, the variables can be easily identified. Children who manifest these characteristics can be considered for aggressive early treatment of their sickle cell disease. A smaller study that tracked the course of adult and pediatric patients over a 7-year period found that adults with an elevated white count experienced more frequent hospital admissions for painful vaso-occlusive crises than did those with lower white counts (Olatunji, et al., 2000). Interestingly, none of the assessed variables correlated with severity in the children. The smaller size of the study and the the greater age range of the children evaluated likely account for the difference from the report by Miller and colleagues (2000). Together, these reports point to high white count as a significant risk factor of adverse events in patients with sickle cell disease.
The relationship of stroke risk to high blood velocity in the intracranial arteries is discussed below.
The beta-globin gene exists in a region of chromosome 11 called the "beta globin locus." Random mutations occur in the non-coding regions of the beta-globin locus which are neither selected for or against. When a gene mutation occurs in the coding region of the beta-globin gene (for instance, the conversion of glutamic acid to valine at postion 6 in sickle hemoglobin), the surrounding non-coding region is not affected. The genetic background of the surrounding region is called the "haplotype" of that particular mutation. The chance is extreme small that another radom mutation will occur in the non-coding region. Therefore, the haplotype of a particular gene mutation event is fixed. Analysis of the genomic structure of the beta-globin gene shows consistent patterns of base substitutions in the non-coding regions of the Hb S gene (Bouhassira et al., 1989). The structural regions of the Hb S genes are identical. The substitutions in the flanking regions of the gene (the haplotypes) show that Hb S arose separately at least four times in Africa, and once in Asia, probably in India (Nagel and Fleming, 1992). The four African haplotypes show broad trends in disease severity. The Central African Republic haplotype tends to have the least favorable clinical course, followed by the Benin and Senegal haplotypes (Powars and Hiti, 1993). The ranking of the more recently described fourth haplotype, Cameroon, is uncertain.
No clear explanation exists for the differences in average severity between the haplotypes. The mutations in the flanking region could secondarily affect severity by altering Hb F expression in the cells. This is only a hypothesis, however. The patterns of severity apply only to populations. Broad overlap in the clinical patterns prevents the use of haplotypes to predict the clinical course in a particular person. Usually, people with sickle cell disease outside Africa (e.g., blacks in the United States) or India have mixed haplotypes for their sickle cell genes. Analysis of haplotype in this setting is even less likely to provide clinically useful information.
Hb S is common in some areas of the Mediterranean basin, including regions of Italy, Greece, Albania and Turkey (Boletini et al., 1994) (Schiliro et al., 1990). Haplotype analysis shows that the Hb S in these areas originated in Africa. The genes probably moved along ancient trading routes between wealthy kingdoms in western Africa and the trade centers in the Mediterranean basin. The high levels of Hb S attained in some areas reflects partial protection against protection against malaria provided by sickle cell trait (see below).
The Hb S mutation arose independently a fifth time in southwest Asia (Miller et al., 1987). The area of the Middle East near the head of the Persian Gulf is very marshy. In the past the area was swampy and harbored malaria. Malaria remains endemic to much of the Indian subcontinent. The fact that the Hb S mutation apparently arose in response to malaria in southwest Asia supports the "malaria explanation" of the prevalence of the gene. The identity of the hemoglobin S haplotype in India and the Persian Gulf region suggests that it arose in one area and moved to the other with trade or migration (Ramasamy et al., 1994) (Kar et al., 1986). Although we cannot be certain of the origin of the Asian haplotype of the sickle cell gene, the very high prevalence of the gene in tribal peoples of India suggest that the subcontinent was the place of origin. This Asian variety of Hb S may on average produce fewer complications than its African counterparts (Perrine et al., 1978).
The high representation of the hemoglobin S gene in some populations reflects the protection it provides against malaria (Gendrel et al., 1991) (Carlson et al., 1994). The malaria parasite does not survive as well in the erythrocytes of people with sickle trait as it does in the cells of normals (Orjih et al., 1985). The basis of the toxicity of sickle hemoglobin for the parasite is unknown. One possibility is that the malarial parasite produces extreme hypoxia in the red cells of people with sickle trait. These cells then sickle and are cleared (along with the parasites they harbor) by the reticuloendotheila system (Roth, et al, 1978). Another possible mechanism is that low levels of hemichromes are formed in sickle trait erythrocytes. Hemichromes are complexes that contain heme moieties that have dissociated from the hemoglobin. Hemichromes catalize the formation of reactive oxygen species, such as the hydroxyl radical, which can injury or even kill the malarial parasites (Anastasi, 1984).
The malaria hypothesis maintains that during prehistory, on average, people without the sickle gene died of malaria at a high frequency. On the other hand, people with two genes for sickle hemoglobin died of sickle cell disease. In contrast, the heterozygotes (sickle trait) were more resistant to malaria than normals and yet suffered none of the ill-effects of sickle cell disease. This selection for heterozygotes is termed "balanced polymorphism". Support for this concept comes from epidemiological studies in malaria-endemic regions of Africa. The frequency of sickle cell trait is lower in people coming for treatment to malaria clinics than is seen in the general population (Wilcox, et al., 1983). The reasonable assumption is that relative protection form malaria is at work in this situation.
Although malaria remains a major health problem in many tropical regions of the world, the disease is not a significant threat to people in the temperate zones. Consequently, the protection afforded by sickle trait no longer has a survival advantage for many groups of people in whom the sickle cell gene is common. This has left sickle cell disease as the major health issue in these populations.
Vaso-occlusive pain episodes experienced by patients with sickle cell disease vary tremendously in frequency and severity. Some patients rarely have painful crises, while others spend the greater part of a given year in the hospital receiving analgesics. The cooperative study of the natural history of sickle cell disease showed that about 5% of patients accounted for one-third of hospital days devoted to pain control (Platt et al., 1991). To complicate matters further, the pattern of pain varies over time, so that a patient who has a particularly severe year may later have a prolonged period characterized by only minor pain. The frequency and severity of vaso-occlusive pain episodes often change as a person moves from childhood to being an adult. The "breakpoint" often occurs during the late teens or early 20's. Changes in hormonal status that occur during these years could contribute to the changes in severity of sickle cell disease. However, no causal relationship has been established, so the association remains only temporal.
The mode of onset of sickle cell pain crises likewise varies. Patients can develop agonizingly severe pain in as little as 15 minutes. In other instances, the pain gradually escalates over hours or even days. Patients manage most episodes of pain at home. Oral analgesics, combined with rest and fluids often allows a person to "ride out" the pain episode. Some patients report that warm baths or warm compresses applied to aching joints ameliorates the severity of the pain.
The sites affected in acute painful crises vary for each patient. Pain occurs commonly in the extremities, thorax, abdomen, and back (Ballas and Delengowski, 1993). Pain tends to recur at the same site for a particular person. For each person, the quality of the crisis pain is usually similar from one crisis to another. During the evaluation, the provider should question the patient as to whether the pain feels like "typical" sickle cell pain. Most patients can distinguish back pain due to pyelonephritis or abdominal pain due to cholecystitis, for instance, from their typical sickle cell pain. If the quality of the pain is not typical of their sickle cell disease, other causes should be investigated before ascribing it to vaso-occlusion.
No reliable objective index of pain exists. The provider depends solely on the patient's report. One of the most difficult problems that patients with sickle cell disease face is seeking treatment for pain in a setting in which they are unknown. The typical scenario is one in which a patient is brought to a busy emergeny room complaining of pain. Some patients writh with severe pain while others are stoic. The person who bears the pain with as much poise as possible runs the risk of not being believed by the staff. Some providers mistakenly believe that the number of deformed sickle cells on the peripheral blood smear reflects the degree of pain that a patient is experiencing. Other providers look to parameters such as blood pressure and heart rate. Although these measures provide more information than the peripheral smear, they do not reliably reflect pain severity. Trust in the patient report is key to the management of sickle cell pain crises.
The pain experienced with an acute painful crisis typically is quite severe. Most patients describe a full blown crisis as the most intense pain that they have ever experienced. The pain sometimes increases in severity slowly over a couple of days. At other times, a crescendo is reached in less than 15 minutes. Pain control often requires large quantities of opiod analgesics. The exact amount varies, and depends in part on the frequency with which the person requires opiods. For many patients, 4 to 8 mg of hydromorphone can be given as an intravenous bolus over 15 to 20 minutes followed by another 4 mg in 30 minutes if pain control is inadequate.
Patients often feel that one analgesic, such as hydromorphone for example, controls pain more effectively than others. Therefore, they should be questioned about the kind of medication that has worked best in the past. Also, some patients may experience reactions with one analgesic (e.g., itching with meperidine) but not with others (Pegelow, 1992).
Pain relief occurs more slowly with intramuscular injections, and the injections themselves can produce substantial discomfort. Consequently, intravenous administration of analgesics is usually preferable. As pain control improves, the analgesia should be maintained to prevent the patient from slipping back into a painful cycle. The "prn" administration of analgesics should be avoided, if possible (Robieux et al., 1992). Following stabilization in the emergency situation with intravenous boluses of opiods, the patient should be transferred to the floor and placed a maintenance regimen. "Patient-controlled analgesia" (PCA) often works well for pain relief (Holbrook, 1990) (McPherson et al., 1990). With these infusion devices, patients can administer small doses of additional medication over their continuous infusion (to a fixed maximum) to control flares of pain.
Patients can become drowsy as their pain is controlled. Often, this reflects the fatigue that comes with one or more sleepless nights with pain at home. The analgesics should not be discontinued automatically for somnolence as long as the patient is easily aroused. A common misconception is that if a person is sleeping, the analgesics are controlling the pain. Patients often sleep despite severe pain. The quantity of analgesia can be slowly reduced as the patient's symptoms improve. While the tapering of intravenous analgesics can require only two or three days, control of a full blown crisis often requires 10 to 14 days. Less commonly, bouts of sickle vaso-occlusive pain require several weeks to control.
Meperidine can present problems for pain control in patients with sickle cell disease. The half-life of the drug in the circulation is about 4 hours. The liver converts meperidine to normeperidine, a derivative that has analgesic activity but which also is toxic. Grand mal seizure is a particularly serious complication that occurs with the administration of large amounts of meperidine. Normeperidine likely is the primary culprit in this situation. Other opiod analgesics, therefore, are preferable to meperidine. The American Pain Society recommends that meperidine no longer be used for control of pain in people who require long-term analgesic treatment.
Eventually the patient should be switched to oral opiod analgesics, which may be necessary for a week or more after discharge (Friedman et al., 1986). The parenteral analgesics should be tapered after the oral medication is started. Abrupt termination of parenteral analgesics when oral medications are begun can cause a rebound in sickle cell crisis pain. Most patients with sickle cell disease manage their analgesics responsibly. If possible, they should have a supply of analgesics at home to control less severe episodes of pain. In addition to analgesia, patients with painful crises should also receive supplemental oxygen and intravenous fluids. Once the pain is under control, oral hydration can replace the intravenous fluids.
Epidural analgesia has been used for pain control in some patients with sickle cell disease (Tobias, 1993) (Yaster et al., 1994). This approach is most effective when the major discomfort is below the level of the chest. Although some patients receive good relief with epidural analgesia alone, others continue to require systemic analgesics, albeit at lower doses. Some patients have a psychological aversion to having needles introduced into their backs and balk at epidural analgesia, despite its superior pain relief relative to systemic analgesics.
Recently, NSAIDs have been added to the management algorithm of acute sickle
cell pain (Sanders et al., 1992). The drug that has been used most often in this
context is ketorolac tromethamine. The reports of the use of this agent to
control acute painful episodes in patients with sickle cell disease have been
largely anecdotal (Perlin et al., 1994). While some reports are positive, others
show no effect of ketorolac in the treatment of acute vaso-occlusive pain crises
(Wright et al., 1992). Ketorolac comes in a preparation that is designated for
intramuscular injection. However, the medication can be diluted into normal
saline and infused as an intravenous bolus. Ketorolac alone usually will not
control an episode of acute sickle cell pain. However, the medication appears to
operate synergistically with opiod analgesics. Patients often recover more
rapidly and require less opiods when ketorolac is added to the treatment
regimen. A single 30 mg intravenous bolus is usually administered for
supplemental pain control. Ketorolac can produce gastritis and bleeding. The
drug should be used cautiously in patients with peptic ulcer disease or a
history of gastrointestinal bleeding.
NSAIDs can impair kidney function and accelerate the renal injury produced by
sickle cell disease itself. For these reasons, many specialists avoid
NSAIDs in patients with sickle cell disease.
Transfusion therapy appears intuitively reasonable for a disorder that results from polymerization of deoxygenated hemoglobin in the red cells. The complex pathophysiology of sickle cell disease confounds the picture, however. Vaso-occlusive sickle cell crises are probably fueled, at least in part, by sluggish blood flow through the microcirculation (Clark et al., 1980). Slow blood flow promotes deoxygenation of hemoglobin and polymerization of the molecules. Although the oxygen carrying capacity of blood increases with hematocrit, so does viscosity. As the hematocrit rises beyond the range of the low-30's, increased viscosity may outweigh enhanced oxygen delivery and swing the dynamics of the situation toward sickling.
In areas where tissues are poorly perfused due to vaso-occlusion, the ability of additional red cells to reverse local hemoglobin S polymerization is questionable. Transfused erythrocytes will not improve blood flow through regions of the microcirculation that are occluded by deformed red cells. Although the transfused red cells do not sickle in the microcirculation even with slow flow, the overwhelming predominant sickle erythrocytes in the circulation is decisive in the development of local vaso-occlusion.
Simple transfusion is not an effective intervention for the management of acute painful episodes in patients with sickle cell disease. Exchange transfusion has been used in attempts to alleviate bouts of severe, intractable pain with better effect, overall (Davies and Brozovic, 1989). In addition, chronic transfusion therapy has been used to decrease the frequency of pain in patients with recurrent debilitating painful crises (Keidan et al., 1987). While sometimes effective, this approach as a number of problems, as detailed below.
A recent report described the use of corticosteroids in a cohort of children with severe sickle cell pain crises (Griffin et al., 1994). The patients received large doses of intravenous steroids on each of the first two days of their painful sickle crises. The treatment group required narcotic analgesics for approximately half as long as the control patients. The rate of pain relapse was significantly higher in patients who received the steroid treatment. This intriguing observation awaits confirmation, particularly in adults with sickle cell disease.
Acute chest syndrome (ACS) is difficult to diagnose because its etiology varies and its manifestations are variegate. Common characteristics include fever, dyspnea, cough, and pulmonary infiltrates (Haynes Jr and Kirkpatrick, 1993) (Poncz et al., 1985). The infiltrates can have a lobar distribution, but often are bilateral. Sometimes, the pulmonary picture is one of diffuse, hazy opacities that resemble adult respiratory distress syndrome. In other instances, ACS looks like a simple pneumonia. This problem in diagnosis is aggravated by the fact that infectious agents such as viruses, bacteria, and mycoplasma can trigger the syndrome (Charache et al., 1979) (Kirkpatrick et al., 1991) (Miller et al., 1991). Bone marrow infarction with secondary pulmonary fat emboli also can trigger the acute chest syndrome (Vichinsky et al., 1994) (Gelfand et al., 1993). In most instances, the etiology of ACS is a mystery.
The arterial blood oxygen saturation commonly falls with ACS to a greater degree than occurs with a simple pneumonia of the same magnitude. Patients with the acute chest syndrome often have progressive pulmonary infiltrates despite treatment with antibiotics (Koren et al., 1990). Infection may set off a wave of local ischemia that produces focal sickling, deoxygenation and additional sickling.
The microcirculatory vessels in the lung tend to constrict with hypoxia rather than dilate, as occurs with vessels in other parts of the body. Regions of vascular constriction could worsen the occlusion of the microcirculation. Unchecked, ACS can produce cardiovascular collapse and death. ACS occurs more commonly in children than adults (Sprinkle et al., 1986) (Gill et al., 1995). People who survive an episode of ACS are more likely than the general sickle cell population to have future attacks. Patients who suffer recurrent episodes of ACS are prone to develop chronic lung insufficiency.
Given the baseline anemia in SCD, pulmonary compromise is a serious complication. The most important step in the treatment of ACS is to recognize the disorder. Potential bacterial infections should be treated with appropriate antibiotics. When symptoms progress, particularly with a worsening of the chest roentgenogram, ACS must be considered. Sometimes, the pulmonary pattern mimics congestive heart failure. However, congestive heart failure is uncommon in patients with SCD who are in the 15 to 30 year age range, making the presumptive diagnosis of ACS more likely. A relentless decline in arterial oxygenation is often a harbinger of ACS, and demands prompt action.
Exchange transfusion is the treatment of choice for ACS (Lanzkowsky et al., 1978) (Emre et al., 1995). The procedure involves exchange of the total blood volume and is done most efficiently using an apheresis machine. When an apheresis machine is not available, sequential transfusion/phlebotomy can be performed. A hemoglobin electrophoresis should be sent prior to the exchange transfusion. A second should be sent after the procedure. The object is to ensure that the exchange has reduced the percentage of Hb S cells to under 30%. Patients often improve substantially within hours of an exchange. Rising arterial oxygenation and decreasing dyspnea usually augur recovery. The chest roentgenogram typically lags behind the clinical status. Since a bacterial pneumonia rarely can be excluded in these patients, most receive concomitant broad-spectrum antibiotics.
A serious potential problem with exchange transfusion is delayed transfusion reaction (Diamond et al., 1980). Most patients with SCD are of African ancestry. Most of the blood available for transfusion comes from people of European descent. A number of minor red cell antigens are expressed at different frequencies in these two groups. Repeated transfusion of any African-American can, therefore, induce antibodies directed against these minor antigens.
Should years pass between transfusions, the titers of antibody can fall to levels that are undetectable by routine cross matching. Transfusion with blood containing the offending antigen often rekindles antibody production to high levels in only a few days. In a person who has received exchange transfusion, a large fraction of the circulating red cells can be destroyed in a deadly delayed transfusion reaction.
The transfusion records of any exchange transfusion candidate should be searched thoroughly for any history of antibodies to minor red cell antigens. Antibody screening should be repeated three to four weeks after the exchange transfusion to look for new alloantibodies to minor antigens.
Patients with sickle cell disease are susceptible to overwhelming infection (Olopoenia et al., 1990) (Overturf et al., 1977) (Landesman et al., 1982). The most significant factor is splenic autoinfarction during childhood (Fernbach and Burdine Jr, 1970). Functional asplenia leaves patients vulnerable to infections with encapsulated organisms such as Streptococcus pneumoniae and Hemophilus influenzae. Further, some studies suggest that neutrophils do not function properly in patients with sickle cell disease (Humbert et al., 1990). How the mutation in sickle cell disease might lead to a defect in neutrophil function is unclear.
Patients with SCD and unexplained fever should be cultured thoroughly. If
the clinical condition suggests septicemia, the best action is to start broad
spectrum antibiotics after complete culturing. Signs of systemic infection
include fever, shaking chills, lethargy, malaise, and hypotension.
Patients with septicemia can expire in
only a few hours. Therefore, observation is not a good option
when sepsis is suspected.
Acute bone marrow necrosis is now recognized more often as a complication of sickle cell disease, in part due to improved methods of detection (Johnson et al., 1994) (Shapiro and Hayes, 1984). In the past, the diagnosis could only be made by bone marrow biopsy or inferred from the complications that resulted. If the necrosis occurred in regions of the marrow that were not easily biopsied, the diagnosis was almost impossible to confirm. This has changed with the introduction of magnetic resonance imaging (MRI) techniques (Mankad et al., 1990) (Rao et al., 1989). Bone marrow should have the density of other body tissues on MRI scans. With bone marrow necrosis, marrow liquefaction is easily detected on scan.
Patients with bone marrow necrosis often suffer excruciatingly severe pain. Some patients require drastic measures, such as epidural anesthesia for control of wrenchingly intense pain. Patients often describe acute bone marrow necrosis as producing "the worst pain I've ever experienced." The necrosis frequently occurs in the marrow of the ribs, femur or tibia.
Pulmonary fat emboli can complicate bone marrow necrosis (Johnson et al., 1994). Fat emboli can trigger respiratory insufficiency or even acute chest syndrome. Making the diagnosis of fat emboli to the lungs is difficult. In some cases, sputum samples stained with Oil Red O will show fat-laden macrophages. Exchange transfusion has been used with success in some patients with acute bone marrow necrosis. The experience is anecdotal, since the ability to document bone marrow necrosis in patients is a relatively recent development.
Strokes are much more common in children than in adults. The average age of stroke victims is about 4 years (Ohene-Frempong, 1991). Frequently, large arteries such as the internal carotid or the middle cerebral are occluded (Balkaran et al., 1992) (Earley, et al., 1998). The mechanism of occlusion of these vessels is not clear, despite necropsy examination of a number of children who succumbed to the condition. Imaging procedures such as angiography and the non-invasive magnetic resonance angiography (MRA) have provided information on the sequence of events that proceed a stroke (Adams et al., 1992) (DeBaun et al., 1995) (Wang et al., 1992). Narrowing of arteries near sharp turns often are seen. A common finding is narrowing at the separation of the middle cerebral and the internal corotid arteries. Paradoxically, the higher rate of blood flow produced by arterial narrowing is believed to contribute to the risk of complete arterial occlusion. A complete occlusion at this critical location produces massive strokes.
A key question is whether medical intervention can prevent a stroke in a child with an arterial lesion. The Stroke Prevention Trial in Sickle Cell Anemia (STOP), sponsored by the NHLBI, was conducted at several institutions (Adams, et al., 1998) to address this question.
Between February, 1995 and October, 1996, the trial, coordinated through the Medical College of Georgia (Dr. Robert Adams) and the New England Research Institutes (Dr. Donald Brambilla), enrolled 130 subjects, ages 2 to 16, who were at high risk for stroke on the basis of elevated cerebral blood flow measured by transcranial doppler (TCD) screening tests (greater than or equal to 200 cm/sec time averaged mean velocities). The patients, drawn from 13 US clinical centers and one in Canada, were randomized to receive either standard supportive care or periodic blood transfusions. The primary endpoint was the rate of stroke rates in the treated and control groups.
The primary data analysis in the STOP Trial compared stroke rates in 63 children randomized to receive repeated exchange or simple transfusions and 67 children who received standard supportive care. A stroke was defined as clinically significant neurologic impairment and physical findings, supported by an abnormal magnetic resonance imaging (MRI) study. The clinical records and MRI's were analyzed by a panel that was blinded to the treatment assignment of the study subjects.
The patients in the transfusion arm received simple or exchange transfusions every 3-to- 4 weeks in an effort to maintain the Hb S level below 30%. After one year, 10 of the children in the standard care group had suffered a cerebral infarction, compared with one child in the transfusion group. This difference represents a 90% relative decrease in the stroke rate in the transfused patients. These results were so compelling that the study's Data and Safety Monitoring Board, composed of independent, outside experts in the fields of pediatric hematology, neurology, radiology, statistics, and ethics recommended that the trial be terminated early so that the children who had been receiving standard supportive care could be offered an effective treatment to prevent first-time stroke. On September 2, 1997, the study was halted, and the investigators in the 14 participating centers were notified of the results and the efficacy of transfusion therapy.
The STOP Trial confirmed that TCD can identify children with sickle cell anemia at high risk for first-time stroke. Since the greatest risk of stroke occurs in early childhood, the NHLBI recommends that children ages 2-16 receive TCD screening. Screening should be conducted at a site where clinicians have been trained to provide TCDs of comparable quality and information content to those used in the STOP Trial. The clinicians should also be able to read them in a manner consistent with what was done in STOP. To apply the predictive and therapeutic information developed in the STOP Trial, two abnormal STOP-comparable TCDs are needed to identify patients at high risk of stroke (velocity greater than 200 cm/sec on two separate occasions).
During follow-up, some children in the large screening population, who initially had normal or ambiguous TCD readings developed frankly abnormal TCD readings. These data suggest that children with normal TCDs should be re-screened at an interval which depends on their age and the prior result of TCD. Although the optimal timing is not known, re-screening approximately every 6 months is a reasonable objective.
Stroke in SCD is a medical emergency. The deficits are often profound, although many children recover substantial function. Exchange transfusion followed by maintenance hypertransfusion is mandatory (Cohen et al., 1992) (Pegelow et al., 1995). This action improves recovery and reduces the risk of recurrent stroke. In the absence of this intervention, as many as two-thirds of children will suffer subsequent events (Wang et al., 1991). The optimal duration of therapy is unclear. Several studies have shown that as many of 50% of children on maintenance therapy for as long as 5 years suffer new strokes within months of stopping treatment.
A newly recognized area of concern in patients with sickle cell disease is "silent stroke" (White and DeBaun, 1998). Recent technological advances, including MRI, MRA, and PET scanning have been combined with neuropsychiatric testing to gain a new window into the effect of silent strokes in children with sickle cell disease. Analysis of 42 children followed as part of the Cooperative Study of Sickle Cell Disease showed that nearly 20% had suffered silent cerebral infarction, as detected by MRI (Kinney, et al., 1999). Multivariate analysis showed a number of associations, including a greater risk of silent infarctions with lower hematocrits. This association was found in another study of 50 patients (Steen, et al., 1999). One-third of the latter children showed evidence of mild intellectual impairment on cognitive testing. Positron emission scans and magnetic resonance angiography could be useful adjuncts in the effort to diagnose children with silent cerebral infarction (Powars, et al., 1999), (Gilliams, et al., 1998). Clearly this is an area of major concern that deserves much more investigation.
In adults, hemorrhagic stokes occur more frequently than arterial occlusive strokes (Van Hoff et al., 1985). Subarachnoid hemorrhages are most common. Bleeds that involve deep structures in the brain, such as the thalamus, also occur, however. In some instances, this reflects the development of "moya-moya" syndrome years after an earlier thrombotic stroke. A network of delicate capillaries can form, often in the area of the old infarction. Angiography reveals the complex filamentous structure of the moya-moya lesion (Peerless, 1997). Should these capillaries rupture, disastrous intracranial hemorrhage occurs. Easily accessible lesions are sometimes surgically excised. Thrombotic strokes in adults are as mysterious as those in children. Nonetheless, exchange transfusion followed by maintenance hypertransfusion is a prudent course of action.
Splenic sequestration crisis results from the acute entrapment of large amounts of blood in the spleen (Sears and Udden, 1985). The manifestations are left upper quadrant pain, exacerbated anemia and, often, hypotension. In children, a large fraction of the circulating blood volume is frequently sequestered. Splenic sequestion crisis is a medical emergency that demands prompt and appropriate treatment. Parents should be familiar with the signs and symptoms of splenic sequestion crisis. Children should be seen as speedily as possible in the emergency room.
Circulatory collapse and death can occur in less than thirty minutes. Splenic autoinfarction makes splenic sequestration crisis uncommon in adults with homozygous Hb S sickle cell disease. The condition can occur in adults with sickle beta-thalassemia or sickle-hemoglobin C (SC) disease since autoinfarction does not occur in these syndromes (Roshkow and Sanders, 1990) (Solanki et al., 1986). The most prominent symptom is left upper quadrant pain. The larger blood volumes of adults make hypotension and circulatory collapse much less common than in children.
The treatment of splenic sequestration crisis includes intravenous fluids and transfusion as necessary to maintain the intravascular volume. A child who suffers one episode of splenic sequestration crisis is at greater risk of a second attack (Kinney et al., 1990). Specialists debate whether children who survive an episode of splenic sequestration crisis should undergo prophylactic splenectomy after their recovery (Szwed et al., 1980). Less is known about the condition in adults. Given the lower morbidity and mortality in adults, splenectomy is rarely a consideration.
Aplastic crisis is a potentially deadly complication of sickle cell disease that develops when erythrocyte production temporarily drops. Infection with parvovirus B-19 frequently causes aplastic crises (Saarinen et al., 1986). This adeno-associated virus causes "Fifth Disease", a normally benign childhood disorder associated with fever, malaise, and a mild rash. The virus has a trophism for erythroid progenitor cells, and impairs cell division for a few days during the infection. Normal people experience, at most, a slight drop in hematocrit since the half-life of erythrocytes in the circulation is 40 to 60 days. The picture is different in patients with hemolytic anemias, who maintain reasonable hematocrits only through prodigious production of new red cells. A shut-down in erythroid production for a few days in these patients can lead to potentially deadly declines in hematocrit (Mallouh and Qudah, 1993). Often, but not always, aplastic crises coincide with a painful crises. The reticulocyte count should be checked on admission to the emergency room or to the hospital in patients with SCD. The treatment of aplastic crisis is purely supportive, with transfusions to maintain an acceptable hematocrit until marrow activity is restored.
Sickled cells can become lodged in the liver obstructing blood flow through the organ (Davies and Brozovic, 1989). The result is painful hepatic enlargement accompanied by an increase in the plasma levels of hepatic synthetic enzymes (e.g., ALT, AST). The serum bilirubin levels often skyrocket to levels in the range of 30 to 40 mg/dl. Acute hepatic failure can ensue. Fluids, oxygen and analgesia are the usual management interventions taken. The benefit of more aggressive measures such as exchange transfusion is unknown.
Priapism is a potentially serious problem for young men with sickle cell disease. The condition is believed to result from impaired blood egress from the corpus spongiosum of the penis, leading to prolonged erections (Fowler Jr et al., 1991). The affliction often occurs in association with spontaneous nocturnal erections. Episodes of priapism can last from several hours to several days. One group of investigators reported a ninety percent actuarial probability of at least one episode of priapism by age twenty-one years (Mantadakis, et al., 1999).
Stuttering priapism is common. Here, the (typically) young man develops erections lasting one to two hours, initially, that resolve spontaneously. The condition then progresses to a point where the erections are quite prolonged and painful. Priapism lasting more than three or four hours is a medical emergency since it can produce impotence (Mykulak and Glassberg, 1990) (Emond et al., 1980).
The most commonly used intervention in the past was irrigation of the ventral vein of the penis by a urologist in an attempt to remove the blockage to blood flow. Since the problem is one of microvascular occlusion, the results of this approach were generally poor. Not only does the surgery often fail to resolve the priapism, but the procedure itself risks inducing impotence (Yang et al., 1990). More recently, exchange transfusion has been used in some of these patients with mixed results (Seeler, 1973). Non-acute cases of priapism are sometimes treated with conjugated estrogens (Serjeant et al., 1985) or vasodilators (Baruchel et al., 1993). While there is some clinical data to support the short-term use of estrogens, the opinions of specialists in sickle cell disease remain divided.
Chronic pain is a major problem for many patients with sickle cell disease.
The etiology of chronic pain in sickle cell disease is uncertain. Organ injury
and necrosis produced by years of intermittent ischemia from vaso-occlusion
likely plays a large role. Radiographs of bones show characteristic deformities
of the ribs, for instance. The damage that produced the deformities likely
produces chronic pain. The severity of the pain varies greatly and can change
over time. Some patients control their pain by intermittently using mild
analgesics, such as non-steroidal anti-inflammatory agents. Others require
frequent doses of opiod analgesics. Consequently, no universally applicable
formula exists for management of chronic pain. The patients who frequently
present the greatest management challenges for physicians, are those with
persistent severe pain controlled by chronically administered opiod analgesics.
Non-steroidal anti-inflammatory drugs (NSAIDs) can control chronic pain in many patients with sickle cell disease (Sanders et al., 1992). The agents can be used alone or in conjunction with opiod analgesics. Most commonly, NSAIDs are used intermittently to control flairs of pain. One potential problem with these agents is renal damage. Patients with sickle cell disease are more susceptible than normal people to renal injury. Since renal damage can be compounded by NSAIDs, physicians must closely monitor renal function in patients on these drugs. Cox-2 inhibitors allegedly produce less nephrotoxicity than do standard NSAID's. Limited experience exists with the use of these agents to control chronic pain in people with sickle cell disease. They are nonetheless worth serious consideration in these patients.
Most patients who require large or frequent doses of opiods to control pain are not seeking drugs for recreational purposes. Often, these patients become tolerant to opiods. Consequently, the quantity of medication needed to control severe pain exceeds that of an individual with a severe but self-limited painful episode, such as torn knee ligaments. Most patients report accurately the quantity of analgesics needed to control their pain (Gil et al., 1994). In some instances, long-acting opiod analgesics can blunt the severity of the pain, allowing patients to use less of the shorter acting agents. Unfortunately, no objective measure of pain exists. Appropriate treatment of pain irrespective of the cause requires an on-going dialogue between the doctor and patient (Armstrong et al., 1992).
Whenever possible, patients should start taking their analgesics before the pain becomes extremely severe. Maintaining pain at a tolerable level is easier than reducing it from a high level of intensity. A typical episode of severe sickle pain can require a patient to consume 4 to 8 mg of oral hydromorphone every three hours to achieve relief. Many "severe" sickle crises can be managed at home with analgesics, fluids, and rest. If the pain progresses despite the use of reasonable quantities of medication, the patient should seek emergency medical care.
Pain due to sickle cell disease is typically viewed as episodic bouts secondary to occlusion of the microcirculation. Many health care providers do not realize that severe chronic pain is also a consequence of sickle cell disease. Chronic sickle cell pain occurs more commonly in adults than in children. Permanent damage to the microcirculation secondary to years of recurrent sickle injury likely is the basis of this syndrome. Bony abnormalities on x-ray, such as vertebral body compression, attest to the injury that occurs over the years. Other tissues, by inference, suffer similar problems.
One of the obstacles to control of chronic pain is the short duration of action common to many analgesics, such as hydromorphone and meperidine. A number of longer acting formulations are available. One of the most effective drugs for the control of chronic sickle cell pain is methadone. Although best know for its use in narcotic detoxification programs, methadone is a highly effective analgesic when given three times per day. Methadone for control of narcotic addiction can be dispensed only at certified detoxification centers. Methadone for pain control can be given at other facilities in accordance with the guidelines for use of any opiod.
Meperidine can present problems for pain control in patients with sickle cell disease. The half-life of the drug in the circulation is about 4 hours. The liver converts meperidine to normeperidine, a derivative that has analgesic activity but which also is toxic. Grand mal seizure is a particularly serious complication that occurs with the administration of large amounts of meperidine. Normeperidine likely is the primary culprit in this situation. Other opiod analgesics, therefore, are preferable to meperidine. The American Pain Society recommends that meperidine no longer be used for control of pain in people who require long-term analgesic treatment.
Addiction is a concern for for medical providers and patients alike when chronic pain require long-term use of opiods for control. The magnitude of the problem is less than is often imagined, however. Those who develop an addiction or drug-seeking behavior are seen frequently in emergency rooms and as hospital inpatients. This overrepresentation of a small number of patients in the health care system leads many providers to conclude that drug-seeking behavior is a problem for most patients with sickle cell disease. Opiods used for pain control, even when given in relatively high doses, usually do not lead to addiction. As with any other group of people, some patients with sickle cell disease have a propensity to develop addictive disorders. The "easier access" that these patients have to narcotics brings out a problem that might have developed in any event.
An important first step in managing this problem is to define drug-seeking behavior. The use of large quantities of oral opiods or frequent visits to the emergency room do not de facto signify drug-seeking behavior. Drug-seeking behavior is the use of opiods in the absence of pain sufficiently severe to justify these medications. Since no objective measure of pain exists, reaching this conclusion is difficult. Drug-seeking behavior can be established only by getting to know the patient and by observing the pattern of drug usage. This means that over a period of months, frequent and heavy use of opiods by the patient may need to be tolerated in order to establish the pattern of drug consumption. Only then can the medical care provider reasonably say on the basis of subtle signs such as facial expression, vocal inflexion, pulse rate, etc., that drug-seeking behavior is likely. At this point, the patient can be approached to discuss what appears to be unwarranted use of drugs.
These patients can respond positively. Drug-seeking behavior can be a very psychologically painful experience. Many patients are relieved when they are confronted and given an option of help. Counseling or sessions with a psychologist or social worker can be useful. In establishing drug-seeking behavior, allowing a few patients to succeed in taking extra medication for a while outweighs punishing patients who have a legitimate need by placing arbitrary limits on everyone.
A few patients demonstrate incorrigible and sometimes frankly sociopathic behavior. In these instances, the best approach is to limit opiod availability. The patient should be informed that a limit is being imposed and the reason for its implementation. Excuses for requesting additional medication fit a pattern that can be a clue to drug-seeking behavior. Common pretexts include, (a) forgetting to fill the prescription before expiration, (b) losing the drug after the prescription is filled, (c) being robbed of the prescription or the medication, (d) having a friend or relative abscond with the medication after having the prescription filled. The limit should be followed strictly. Tracking patterns of medication use is aided by keeping a log of all opiod prescriptions issued. Photocopys of prescriptions provide excellent documentation. If possible, a single provider at the institution should write the prescriptions and maintain the record. Covering staff and ER physicians should be alerted to the arrangement and should not supply additional prescriptions. The arrangement is not punitive. Rather it allows the staff to better assess and treat legitimate sickle cell pain. Health providers should document their efforts to monitor and control excess use of opiods by their patients. Scrupulous record-keeping also helps avoid entanglements with medical practice oversight agencies.
Patients with extreme drug seeking behavior or sociopathic personality disorders often acquire medication from other hospitals or medical facilities. Sometimes this is done under the cover of an alias. Health-care providers have limited ability to control such activity. The provider must be sure that the pattern of drug use at his or her institution is reasonable, but cannot police the entire region.
The psychosocial dynamics of sickle cell disease are complex. As with any other chronic, and often debilitating, illness, patients face a plethora of social problems that greatly influence their clinical condition (Whitten and Fischhoff, 1974). Loneliness, isolation, self-resentment, loss of self-esteem, and simple anger are common in patients with sickle cell disease. These factors can profoundly influence the patient's ability to cope with pain. Patient support groups and psychological counseling often are very useful. The positive results in studies in which children were taught psychological coping skills for pain, reinforce the importance of this component of patient care (Gil et al., 1991).
Patients with sickle cell disease, like other people with hemolytic anemias, require daily folic acid replacement. Folate is rapidly consumed by the proliferating erythroid precursors. The normal daily intake of this vitamin sometimes is insufficient to maintain a balance. One mg of supplemental folate per day is more than enough to satisfy the needs of the erythron. A patient with sickle cell disease whose hematocrit begins to fall unexpectedly should be checked for folate deficiency as a part of the general work-up.
Patients with sickle cell disease are anemic, by definition. The degree of the anemia varies. The hematocrit frequently is in the mid- 20's. Some patients have hematocrits in the low 30's while others have values in the high teens. The baseline hematocrit remains relatively stable in a given patient, however. Patients with Hemoglobin SC disease tend to run hematocrits in the low to mid 30's. Most patients are conditioned to tolerate their degree of anemia, and routine transfusion is not necessary. Raising the hematocrit provides no clinical benefit, unless the baseline value has fallen into the mid-teens, at which point oxygen carrying capacity can be compromised. Hematocrits in such a low range leave little leeway for further decline. On the other hand, transfusing patients with sickle cell disease to hematocrits in the mid- to upper-30's can be dangerous, since blood viscosity increases substantially at higher hematocrits (Kaul et al., 1983). The increase in viscosity can worsen the sickling propensity by increasing the time during which the cells remain in the low oxygen tension regions of the circulation.
The best established use of chronic transfusion therapy is in patients who have suffered strokes and have had initial exchange transfusions. Chronic transfusion therapy is less well established for the treatment of other complications of sickle cell disease. This modality has been advocated as a means of treating recurrent severe episodes of sickle pain, priapism, and as a prophylactic measure inpregnant patients. Variable improvement in these condition occurs. The utility of transfusion therapy is limited by complications, most notably alloimmunization and iron overload (Rosse et al., 1990) (Wang et al., 1986) . Clinically significant iron overload can occur after as few as 30 red cell transfusions. The only treatment for transfusional iron overload is chelation therapy with desferrioxamine (Cohen and Schwartz, 1979). Marginal iron mobilization with this drug is a frequent problem.
A major hurdle to the use of desferrioxamine is non-compliance. This is a particular problem for young people, and occurs in other disorders that require chelation therapy for transfusional iron overload, including beta-thalassemia and congenital sideroblastic anemia. Investigation of other chelators, including some orally active drugs, is ongoing. Approval is imminent for no agent, however.
Alloimmunization against minor red cell antigens is a major problem for patients with sickle cell disease who receive frequent transfusions (Rosse et al., 1990). The representation of minor antigens, such as Kell, Duffy, and Kidd, differs between African-Americans and European- Americans (Issitt, 1994). For patients who receive only a few transfusions, the problem is not serious. With repeated transfusion, however, antibodies develop against these minor determinants complicating typing and jeopardizing further transfusion.
Blacks are substantially underrepresented as blood donors, compounding the problem of alloimmunization for patients with sickle cell disease. In addition, patients with sickle cell disease appear to develop alloantibodies more rapidly than other black patients who are transfused (Vichinsky et al., 1990). Some institutions perform extended panel matching which includes the most clinically significant minor antigens in an effort to delay the development of alloantibodies. Some patients develop such severe problems with alloantibodies that transfusion becomes nearly impossible. A number of institutions have active programs to recruit blood donors from the black community to lessen the impact of alloimmunization.
Routine use of blood from black donors for black patients with sickle cell disease is not warranted. The likelihood of finding matched units for patients with sickle cell disease is greater when black people are in the donor pool. Matching is necessary nonetheless since antigen variation among black people, like all other humans, is great. An expanded donor pool substantially improves the chance of a match with antigen testing.
Sometimes, the severity of the anemia in patients with sickle cell disease gradually increases as they age. The reason for this marrow "burn-out" phenomenon is unknown. The clinical situation is complicated by the fact that many of the patients have end-organ damage, such as a dilated cardiomyopathy, that may limit their ability to tolerate such severe anemia. Data from the national cooperative study of sickle cell disease indicates that on average patients with sickle cell disease survive until the mid 5th decade of life. Bone marrow "burn-out" will be a greater issue as better general medical care and new therapies prolong the lives of patients with sickle cell disease.
Infection is a leading cause of death in patients with sickle cell disease. Hyposplenism, due to splenic autoinfarction, is a major contributor. Hyposplenism is not the sole cause of the defective host defense as evidenced by the fact that overwhelming sepsis is the leading cause of death of children under three years of age (Gill et al., 1995). Splenic autoinfarction is less common in these very young children.
A double-blind study of the use of penicillin prophylaxis for children between the ages of six months and three years was terminated before the expected time of completion (Gaston et al., 1986). The trend indicated clearly that penicillin protected patients from infection or death due to overwhelming infection by Streptococcus pneumoniae. The recommendation now is that all children be placed on prophylactic penicillin at a dose of 250 mg twice a day. Patients with allergies to penicillin should be treated with erythromycin. No recommended duration of treatment with prophylactic penicillin exists.
A second study looking at the role of prophylactic penicillin in older children was recently completed. No difference in the incidence of severe infection was found in this cohort of children between the ages of 5 and 12 years (Falletta, et al., 1995). The implication is that penicillin plays an important prophylactic role only in young children. One caveat to the interpretation of this study is that the incidence of pneumoccocal infection was strikingly low in both groups. This could have been a clinical fluke. As such, a true difference in infection rate between the two groups could possibly have been missed.
The role of prophylactic penicillin in adults with sickle cell disease is unclear. Adults develop overwhelming sepsis, but at a much lower frequency than do children. No controlled study to determine whether prophylactic antibiotics are useful in adults has been done. The recently completed trial in older children suggest that prophylactic antibiotics may not benefit adults. Nonetheless, many physicians still prescribe prophylactic antibiotics for adults.
Immunization with the pneumococcal vaccine is standard practice both in adults and children with sickle cell disease. Several studies suggest that immunization provides some protection, although incomplete, against pneumoccocal infection (Ammann et al., 1977) (Ammann, 1982) (Schwartz, 1982). The vaccine appears to be effective even in adults where splenic function has been lost (Wong et al., 1992). The more recently available 23-valent vaccine provides broader coverage than earlier versions. Although the duration of protection is unknown, most specialists re-innoculate patients once every 5 to 7 years. A noteworthy contrary voice comes from a broadbased review of pneumococcal vaccine efficacy that cast doubt on the role of the vaccine in patients with sickle cell disease (Butler, et al., 1993).
More recently, a vaccine against Hemophilus influenzae has entered the clinical arena (Rubin et al., 1989). The efficacy of this vaccine in sickle cell disease is unknown. Given the serious nature of H. influenzae infections in these patients, many specialists, particularly pediatricians, now routinely immunize their patients against this organism.
Immunization against viral influenza is common practice. Viral influenza per se is not a special threat for patients with sickle cell disease. Since influenza is often complicated by bacterial infection and other problems, prevention of the disease by immunization is a very practical intervention.
Recently, an effective vaccine against hepatitis B was developed. Since patients with sickle cell disease are likely to require one or more transfusions in their lifetime, immunization against hepatitis B is a reasonable precaution (Mok et al., 1989).
Avascular necrosis of bone is a common problem in patients with sickle cell disease. This process is distinctly different from the acute bone marrow necrosis discussed earlier. The areas most frequently affected are cortical bone of the acetabulum, the head of the femur, and the head of the humerus (Hernigou et al., 1993). The etiology of avascular necrosis of bone is unknown. One hypothesis posits marrow hyperplasia in the femoral head with tissue crowding and secondary reduced blood flow to the bone as the inciting factor. Avascular necrosis also occurs in patients with compound heterozygous conditions such as Hb SC disease, as well as in patients with homozygous SS disease.
Patients usually report that the quality of the pain associated with avascular bone necrosis differs substantially from their sickle cell pain. The articular cartilage thins and often disappears as the process progresses. The joints can deteriorate to a condition of bone-on-bone interface. Movement of the joint becomes wrenchingly painful. Early on, non-steroidal anti-inflammatory agents can be useful. With more severe situations, particularly those that involve the shoulder, injections of corticosteroids may help. Finally, decompression of the tissue in the head of the humerus or the head of the femur is used by some orthopedic surgeons with success. This invasive procedure should be reserved for patients with more advanced cases of avascular necrosis. The possible efficacy of femoral head core decompression is currently being investigated in a multicenter study coordinated by Dr. Elliot Vichinsky at the Children's Hospital of Oakland, California.
Even with these interventions, the process cannot be completely halted, leading to joint replacement in some instances. Since most of the patients are in their 20's or 30's when this becomes an issue, the decision to proceed with joint replacement is difficult. Artificial joints are not well-tolerated by some patients with sickle syndromes (Moran, 1995). As many as one-third of patients require a second surgery within four years of joint replacement. Also, these patients, for unclear reasons, are very vulnerable to infections of their orthopedic hardware. The unfortunate result sometimes is a destroyed articular interface and a flail joint which, in the case of the femur, can leave the patient confined to a wheelchair.
More research is needed to identify patients at risk early in the course of the degenerative process so that preventive measures can be instituted. One promising addition to the diagnostic armamentarium is MRI imaging. This technique can detect very early evidence of damage to the bone, and holds the hope of improved management of this very debilitating complication of sickle cell disease.
Osteomyelitis often occurs at the site of necrotic segments of bone. Nearly three-quarters of cases of osteomyelitis in patients with sickle cell disease are due to Salmonella species (Anand and Glatt, 1994). Local pain and fever are the most common indicators of chronic osteomyelitis (Epps Jr et al., 1991). In the early stages of the disorder, bone roentenograms and even bone scans frequently are unrevealing. Gallium scans can provide early evidence of the disorder. Recently, MRI has been added to the diagnostic arsenal, and appears to be a promising technique (Bonnerot et al., 1994). Definitive diagnosis often requires bone biopsy. This procedure sometimes is not an option, due to the location of the infection, however. Once the diagnosis is made, four to six weeks of intravenous antibiotic therapy are needed.
If a causative organism is not identified, broad- spectrum antibiotics that have good tissue penetration should be used. Evidence of effectiveness, in these instances, is an improvement in the pattern of fever and pain. The advent of home infusion services obviates the need for prolonged hospitalizations in many cases.
Skin ulcers are relatively infrequent in the United States in comparison to reports from Jamaica. In that country, about 30% of patients with sickle cell disease develop skin ulcers. This exceeds by far the incidence in the US, which is closer to 1% (Koshy et al., 1989). Nonetheless, when skin ulcers occur, the problems are very serious.
The most common site of skin ulcers is over the lateral malleoli. The ulcerations often have no clear-cut antecedent trauma and progress over a period of weeks to the point that the lesions extend into the dermis, and often into the underlying subcutaneous tissue. With the breakdown in the protection provided by the integument, patients are susceptible to infections and other complications.
Treatment of ankle ulcers should be conservative. Rest, elevation, and dry dressings with antimicrobial ointments are the best approaches to this problem. Attempts at skin grafting are frequently thwarted by the poor blood flow to the affected region. Healing usually takes weeks to months. The area should be protected against trauma when the patient is up and about (Wethers et al., 1994). Anecdotal reports exist of enhanced healing of ulcers in patients placed on chronic transfusion therapy. In some instances, patients were begun on chronic transfusion prior to skin grafting and maintained with monthly transfusions for two or three months thereafter. Socks or other clothing that cover the area should be avoided, to reduce friction injury. A simple dry dressing provides additional protection. At one time, a group of investigators advocated oral zinc supplementation as a means of speeding the healing of ankle ulcers (Prasad et al., 1977). The rationale was that patients with sickle cell disease are often deficient in zinc (which is the second most common metal ion in red cells and is lost during hemolysis). Zinc is important for wound healing. The evidence that zinc supplementation aids the healing of ankle ulcers is controversial. However, the benign nature of zinc supplementation makes it a reasonable option in patients with this terribly debilitating and often recalcitrant condition.
The most common defect in patients with sickle cell disease is impaired urine concentrating ability, or hyposthenuria (Kontessis, et al., 1992). Hyposthenuria often occurs by the age of 3 or 4 years. The condition should be considered in children with sickle cell disease who display bedwetting. Hyposthenuria is seen in patients with homozygous sickle cell disease as well as in compound heterozygotes (e.g., sickle-beta thalassemia). The extremely high osmolality in the distal tubule produces some sickling even of the cells in patients with sickle trait. As a consequence, hyposthenuria is the most common abnormality seen that results from sickle cell trait (Gupta, et al., 1991).
The risk of renal dysfunction or failure is substantial in patients with sickle cell disease (Flanagan et al., 1993). The high osmolality in the renal medulla increases cell propensity to sickling. As a result, medullary ischemia and papillary necrosis are common problems (Powars et al., 1991).
Sometimes, the necrotic papillae slough into the collecting system, obstructing the outflow tract. No specific intervention has been devised that is particularly effective in these patients. When the BUN and creatinine begin to rise, limiting protein consumption is reasonable, as is recommended for other patients with renal dysfunction. One report suggested that angiotensin converting enzyme inhibitors may also retard the progression of nephropathy in sickle cell disease (Falk et al., 1992). Further investigation of this promising lead is needed.
Patients with sickle cell disease usually have low serum creatinine and BUN levels. This is probably due to the high glomerular filtration rate along with a high rate of creatinine secretion in the distal tubule. BUN values of 7 and creatinine values of 0.5 are typical of those seen in patients with sickle cell disease. A formal evaluation of glomerular filtration rate should be considered in patients in whom the serum creatinine rises above the level of about 1.0..
Potentially nephrotoxic drugs should be used with extreme caution in patients with sickle cell disease. Antibiotics such as gentamicin should be avoided when other agents are available that are less toxic to the kidney. As noted previously, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used cautiously in patients with sickle cell disease. Heavy loads of radiographic contrast agents formerly were a significant problem for patients with sickle cell disease. The newer agents produce a much lower osmotic load, with less dehydration of the kidneys, as a result.
Limited experience exists on the efficacy of dialysis in patients with sickle cell disease (Falk et al., 1983). Reports that hemodialysis is problematic in patients with sickle cell disease are anecdotal. Every effort to prevent renal deterioration should be undertaken. Microscopic hematuria is a common problem in patients with sickle cell disease (as well as some patients with sickle cell trait). Hematuria per se requires no intervention unless blood loss is massive. Some patients with sickle cell disease and renal failure have received allografts (Gonzalez-Carrillo et al., 1982).
People with sickle cell trait sometimes develop massive hematuria (Sears, 1978). Interestingly, the bleeding often comes from the left kidney. Hydration and alkalization of the urine are commonly used interventions. Anecdotal reports of the use of DDAVP in this situation are encouraging (Baldree, et al., 1990). Episilon amino caproic acid (Amicar) has been used in some patients with refractory bleeding from the kidney (Black, et al., 1976). Bleeding can continue for weeks. Iron replacement may be necessary in some cases as treatment interventions continue.
Retinopathy is a significant problem for 10% to 20% of patients with sickle cell disease (Moriarty et al., 1988). The peak age of onset is in the 20's. For unknown reasons, the condition develops more frequently in patients with hemoglobin SC disease than in those with homozygous sickle cell disease (Clarkson, 1992). The retinopathy resembles that seen in people with diabetes.
The condition is believed to result from ischemia to the retina. The areas affected, at least initially, are in the periphery of the retina, so that direct ophthalmoscopy is rarely revealing (Kimmel et al., 1986). An ophthalmologist should evaluate the patient using pupillary dilation and indirect ophthalmoscopy. Patients should be seen at least once a year, and more frequently if abnormalities are noted. Ischemia can lead to retinal thinning as well as neovascularization. The fragile vessels formed by neovascularization are subject to rupture, often leading to disastrous intraorbital hemorrhages. This complication can produce sudden loss of vision (Pulido et al., 1988). Laser photocoagulation has been used in an effort to prevent retinal hemorrhage (Condon and Serjeant, 1980). Another common problem is retinal detachment, particularly as a sequel to retinal hemorrhage.
Cardiomegaly is common in patients with sickle cell disease. Usually this condition reflects sustained state of high cardiac output. While high output failure occurs in some patients with sickle cell disease, the heart is hyperdynamic in most (Gerry et al., 1978).
Pulmonary congestion due to fluid overload during hydration for painful crisis is not a common problem in young patients. The picture changes as patients age. A distinct minority of patients will develop problems with fluid balance with the fluid challenge that occurs with hydration (Haynes, Jr and Allison, 1986). For some patients, the problem is more one of left atrial dysfunction than impaired ventricular activity. Nonetheless, patients who develop a chest roentgenographic picture suggestive of "congestive heart failure" during treatment for painful crisis must be examined carefully to rule out other complications such as acute chest syndrome.
Women with sickle cell disease can carry pregnancies to term, but the process sometimes is complicated (Koshy et al., 1987) (Seoud et al., 1994). The frequency of painful crises sometimes increases. Physical activity should be limited, particularly after the mid-second trimester when the intravascular volume increases substantially. Fetal development is usually normal if the patient can be coaxed through the pregnancy (Powars et al., 1986). Some specialists in sickle cell disease advocate simple blood transfusion in these patients. Others have found no benefit to this intervention (Tuck et al., 1987). The object is to maintain a hematocrit that allows normal fetal development. Exchange transfusion has been used in some instances in which patients had particularly difficult problems during the pregnancy. These reports are anecdotal.
Women who have painful crises during pregnancy should be treated with analgesics as necessary, including narcotics. The newborns who have been exposed to opiods must be withdrawn by administering decreasing doses of these drugs in the neonatal period. Warned of this issue, neonatologists can easily manage the problem.
Hydroxyureainhibits
ribonucleotide reductase, blocking DNA synthesis and cell division. The drug
also enhances fetal hemoglobin by developing erythroid cells (Platt et al.,
1984) (Stamatoyannopoulos and Nienhuis, 1992). Since fetal hemoglobin blocks
sickling, hydroxyurea has been administered to patients with sickle cell disease
in an effort to enhance fetal hemoglobin production (Charache, 1991) (Rodgers et
al., 1990). Hydroxyurea induces fetal hemoglobin production, increases the red
cell mean corpuscular volume, and reduces the number of dense cells and
irreversibly sickled cells in the circulation (Goldberg et al., 1992).
On
January 31, 1995, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH)
was suspended by the NIH because patients on the hydroxyurea arm of the study
had significantly fewer painful crises than did the controls (Charache et al.,
1995). This made hydroxyurea the first (and only) drug proven to prevent sickle
cell crises. A second major observation was that 50% fewer episodes of acute
chest syndrome occurred in the patients treated with hydroxyurea. Hydroxyurea
does not cure sickle cell disease, nor is it effective in all patients. A
detailed study showed that hydroxyurea modifies the characteristics of red cells
in patients with homozygous HbS disease to resemble those of patients with HbSC
disease (Bridges, et al, 1996). The heterogeneous response seen in the MSH study
is consistent with people with sickle cell disease being "converted" to a HbSC
disease physiognomy. Patients should be carefully screened and meet certain
criteria:
Hydroxyurea is not reasonable therapy for many patients with sickle cell disease. Patients who have relatively few vaso-occlusive pain crises should not receive hydroxyurea therapy. Other contraindications for hydroxyurea include:
Although thrombocytopenia and/or neutropenia are relative contraindications, some patients can tolerate the medication despite these pre-existing factors with close monitoring. Bimonthly blood counts are required when patients are started on hydroxyurea. In some patients on hydroxyurea, the hematocrit rises to the high 30's or even low 40's. No evidence exists to support hydroxyurea as prophylaxis against stroke, chronic leg ulcers, priapism, or other complications of sickle cell disease.
The dose of hydroxyurea needed to prevent painful crises is unknown. In the MSH study, patients received the maximum tolerated dose (MTD). The dose administered was increased stepwise until signs of toxicity, such as mild neutropenia, developed. The dose of hydroxyurea was then reduced slightly. Whether such intense treatment is required is unknown. Lower doses of hydroxyurea (e.g., 25mg/Kg/day) are used by some specialists. Most patients treated with hydroxyurea develop macrocytosis (e.g., MCV=110). Macrocytosis is not a good treatment gauge, however.
The data on hydroxyurea applies only to patients with homozygous sickle cell disease (two hemoglobin S genes). Patients with compound heterozygous conditions (e.g., sickle-beta thalassemia, Hb SC disease) were excluded from the MSH study to eliminate if possible any response variability in the data. Future trials may address these issues.
Hydroxyurea is not approved for use in children. The MSH study was restricted to people 18 years of age or older. An NIH-sponsored trial of the drug in children is on-going. A number of issues have been raised regarding hydroxyurea in children, including neurocognitive development and bone maturation. The pediatric hydroxyurea study will address some of these issues.
Hydroxyurea is teratogenic in mice, but its toxicity to the human fetus is
unknown. The drug has not been associated with carcinogenesis. The carcinogenic
potential with very long-term use is unknown, however. The NIH-sponsored
Follow-up Study of Hydroxyurea in Sickle Cell Disease is designed to monitor
the 300 people in the original MSH study for long-term side effects.
Bone marrow transplantation can cure SCD. This intervention was first used in a patient with sickle cell disease who also had relapsed acute lymphocytic leukemia. The transplant was done to treat the leukemia, but cured the sickle cell disease as well. The largest experience with transplantation for sickle cell disease comes from Belgium and France, where about 80 patients have undergone bone marrow transplantation (Apperley, 1993). The results have been quite promising with cure of the sickle cell disease in every case in which engraftment occurred.
Concerns about problems such as graft versus host disease and interstitial pneumonia, two potentially fatal complications of bone marrow transplantation, have limited the use of this modality in the United States (Kalinyak et al., 1995) (Davies, 1993). A recently reported trial of bone marrow transplantation in children from centers in the US reaffirmed that the procedure can cure sickle cell (Walters et al., 1996). Ten percent of the children died from the procedure, and some suffered severe complications, such as graph rejection. A later report by this group includes thirty-four children under the age of 16 years who have received bone marrow transplants (Walters MC, et al., 1997). The incidence of complications as lower in the children who underwent transplant subsequent to the initial report.
The questions of when to perform a transplant and which patients should receive the therapy are difficult. The optimal time for transplantation is during childhood, since children fare better with transplantation than do adults. The variable clinical manifestation of sickle cell disease makes it impossible to predict in childhood which patients will have a more severe course. This issue is particularly pertinent considering that transplantation is best carried out prior to the development of end organ damage from the sickle cell disease.
Analysis of data from the Study of the Natural History of Sickle Cell Disease reported by Platt, et al, suggested that patients with fetal hemoglobin levels of less than 8.6% tend to have more severe disease over the long run (Platt et al., 1994). This would seem to provide a guide that could be used in the decision of which patients to transplant. However, the data are only statistical values. With rare exceptions, statistical data cannot be applied to a particular patient to predict the clinical course.
An unresolved ethical question surrounds bone marrow transplantation for children with sickle cell disease. Sickle cell disease is often a debilitating condition that makes life miserable for its victims. Although the Natural History Study indicates that patients with sickle cell disease die earlier than actuarial projections for other African-Americans, data collected in the 1980's showed a life span that extends into the 40's. With the nearly universal use of prophylactic penicillin in children to prevent overwhelming pneumococcal infections along with other advances in supportive treatment, this figure is likely to improve.
The question of who should decide to subject a child to this potentially fatal procedure likewise is complex. Should the decision be left to parents and physicians? In a study at the University of Chicago, parents were presented with hypothetical data on cure/mortality rates for their children with sickle cell disease, and asked to indicate when the risks of the procedure were acceptable relative to the gravity of the disease (Kodish et al., 1991). About one-third of the parents indicated that a transplant mortality rate of 15% along with a 15% incidence of graft-versus-host disease were acceptable odds. However, young adults older than 18 years were not allowed to participate in the decision process. Should the patients, the ones with the most to gain and the most to lose, be excluded from the decision-making loop? Should the courts appoint advocates for the children, to ensure that the parents and physicians indeed are acting in the "best interest" of the youngsters?
A program of bone marrow transplantation for beta-thalassemia major has been successfully initiated in Italy (Lucarelli et al., 1993). Although sickle cell disease and beta-thalassemia major are both hemoglobinopathies, clear differences between the diseases exist. The most important is the monotonous progression to disability and death that occurs with beta-thalassemia major. Bone marrow transplantation for sickle cell disease offers promise. The jury has not returned a final verdict, however.
Erythropoietin is a hormone produced by the kidneys that stimulates red cell production (Adamson and Eschbach, 1990). Usually, the hormone is made in response to hypoxemia (Kario et al., 1992). Erythropoietin also increases fetal hemoglobin levels in the red cells of many patients (Nagel et al., 1993). A number of investigators have examined the extent to which erythropoietin will raise fetal hemoglobin levels in sickle cell disease. The consensus is that the drug can significantly raise fetal hemoglobin levels, particularly when given in high doses.
In one report, the drug was used in a dose of over 1,000 U/kg three times per week (Rodgers et al., 1993). The treatment significantly elevated fetal hemoglobin levels. The quantity of erythropoietin required for this effect was enormous, particularly when compared to patients on hemodialysis where the typical dose is now about 150 U/kg three times per week. The cost of erythropoietin at the higher dose is prohibitive. Further, while erythropoietin can increase the fetal hemoglobin content of red cells, no controlled trial has shown that it alters the clinical course of sickle cell disease.
Arginine butyrate and similar compounds have been tested in patients with sickle cell disease (Perrine et al., 1989). The use of this agent stemmed from the observation that babies born to diabetic mothers with poor glucose control had sustained production of fetal hemoglobin after birth relative to infants born to normal women. Butyrate produced as a byproduct of the hyperglycemia produced the phenomenon. A group of investigators subsequently examined the use of butyrate as a means of inducing fetal hemoglobin synthesis in patients with sickle cells disease (Perrine et al., 1993).
Arginine butyrate can increase fetal hemoglobin levels, but the effect is variable (Sher et al., 1995). Unfortunately, the drug must be given intravenously and has a half-life of only about 5 minutes. Intermittent rather than continuous infusion of arginine butyrate may induce fetal hemoglobin synthesis more effectively. Side effects that have been seen in patients who have received arginine butyrate include anorexia, nausea, vomiting, and abnormal liver function tests (One patient had a seizure on the medication after inadvertently receiving 4 times the recommended dose.) For most patients, arginine butyrate is well-tolerated, however. The requirement for intravenous administration limits the use of the agent. However, many drugs now are administered intravenously to patients at home (e.g., desferrioxamine for iron overload). Creative strategies are being explored to make arginine butyrate a useful therapeutic option.
An effort is underway to identify orally active agents with longer half-lives. Several compounds have been identified, and a couple have been placed into early clinical trials. One of these is sodium phenylbutyrate, a drug that has been used for patients with urea cycle disorders (Dover et al., 1994). Unfortunately, patients tolerated the medication poorly, in part due to the fact up to 40 tablets per day are needed to obtain acceptable blood levels. The increase in Hb F levels produced by the oral agents studied thus far have been significantly less than that seen with arginine butyrate (Perrine et al., 1994). The butyrates have a number of hurtles to leap before they are accepted for more general use, including a demonstration that they consistently alter the red cell profile and, ultimately, improve the clinical picture in sickle cell disease.
Red cell dehydration contributes substantially to polymerization of sickle hemoglobin in patients with sickle cell disease. The cell membrane is damaged in part through repeated physical distortion by hemoglobin polymerization/depolymerization, and in part through oxidant damage from reactive oxygen species generated by hemichromes and other hemoglobin byproducts. K-CL co-transport increases, with K+ loss and associated water loss. Also, sickle cells accumulate Ca2+. As a consequence, the Gardos channel (Ca2+-activated K+ export) is activated, with further dehydration.
Clotrimazole and other imidazole antimycotics specifically inhibit the Ca2+-activated K+ channel pathway of normal and sickle erythrocytes. The original report of Alvarez and colleagues described the inhibition of the normal human red cell Gardos channel by clotrimazole (CLT) and other imidazole antimycotics. Dr. Carlo Brugnara showed in sickle erythrocytes that CLT blocks K+ transport via the Gardos channel, prevents the change in membrane potential observed when the Gardos channel is activated by internal Ca2+, and inhibits dehydration induced by either the Ca2+ ionophore A 23187 or cyclic oxygenation-deoxygenation.
Initial work by Dr. Brugnara and colleagues at Children's Hospital, Boston
showed that clotrimazole reduces the number of dense cells and the number of
irreversibly sickled cells in patients with sickle cell disease (Brugnara, et
al, 1996). A study of the agent at Children's Hospital and Brigham and Women's
Hospital evaluated the combined effects of clotrimazole and hydroxyuea in
patients with sickle cell disease. The hope was that the agents, which have
different mechanisms of action on sickle cells, would work at least
cooperatively, and perhaps synergistically, to reduce sickling. Clotrimazole
proved to have a number of side-effects that limited its success, including
severe dysuria in many men. A newer imidazole with fewer side-effects has
recently come available. Enrollment in the clotrimazole study has be suspended
in anticipation of this newer agent.
Nitric oxide is one of the newest agents to enter testing for possible treatment of patients with sickle cell disease. It is an inhaled gas that has been used in a variety of investigational conditions, including neonatal pulmonary hypertension and adult respiratory distress syndrome.
Nitric oxide is know primarily for its ability to relax smooth muscle relaxation. However, the compound also forms a covalent link with hemoglobin, particularly attaching as an S-nitroso group to the ß-93 cysteine (Gow and Stamler, 1998). This amino acid residue is near the "acceptor pocket" on the ß-subunit of hemoglobin where the ß-6 valine of Hb S forms a non-covalent interaction. The hydrophilic S-nitroso cysteine at the ß-93 residue could destabilize the interaction between deoxy-Hb S molecules in polymerized sickle hemoglobin.
Dr. C. Alvin Head, of Massachusetts General Hospital, and Dr. Carlo Brugnara,
of Children's Hospital, studied the interaction of nitric oxide both in vitro
and in vivo in normal volunteers and patients with sickle cell disease (Head, et
al., 1997). Their data suggested that nitric oxide breathed at a concentration
of 80 ppm reduces the polymerization tendency of sickle hemoglobin. Reduced
polymerization was inferred by a fall in the P50
of sickle hemoglobin (no effect occurred with Hb A). Nitric oxide for acute
painful vaso-occlusive crisis is being studied in an ongoing multicenter trial.
Other investigators were unable to reproduce the P50
effect (Gladwin, et al., 1999). Further work is needed to determine whether
nitric oxide has a role in the treatment of patients with sickle cell disease.
FluocorTM is a drug manufactured by the
CytRx Corporation of Norcross, Georgia. A phase III clinical trial of the drug
for patients with acute sickle cell pain crisis was recently completed. FluocorTM
is a more highly purified version of the drug, RheothRxTM
which went through phase II clinical studies several years ago. Fifty patients
were followed in a placebo-control pilot study designed to evaluate safety and
efficacy of the compound (Adams-Graves, et al., 1997). The investigators infused
the drug continuously for 48 hours at the beginning of a sickle cell crisis. The
treated patients required less narcotic analgesic and showed a net reduction in
hospital length-of-stay relative to placebo control patients. The multicenter
study of FluocorTM failed to confirm these
preliminary results. The future of the drug in the treatment of sickle cell
disease is unclear.
The beta-globin gene was cloned a number of years ago, fueling interest in the possibility of gene replacement therapy for sickle cell disease. While the idea of simply replacing the defective gene with a normal one is appealing, a number of major difficulties must be surmounted. The first is to engineer a construct in which the beta-globin gene is expressed at high levels. Our understanding of the factors that control globin gene expression has advanced significantly over the past few years, but many of the nuances are yet to be worked out. A large segment of DNA upstream of the beta-globin gene cluster, called the locus control region, is necessary for efficient transcription of beta-globin mRNA. Any attempt at gene therapy must include the large locus control region.
Another problem is that the inserted gene must be regulated in its expression so that it produces beta-globin chains at a level roughly equal to the production of endogenous alpha- globin chains. Failure to achieve such a balance would produce a thalassemia. Further, the endogenous sickle beta-globin gene likely would have to be silenced, so that it does not continue to produce sickle globin chains.
Finally, the cloned gene would have to be introduced into pluripotent stem
cells so that the patient would continue to make normal beta-globin in
perpetuity. The retroviral vectors that have been used to this point infect
dividing cells, while pluripotent stem cells divide very slowly. To overcome
this difficulty, a number of researchers have turned to adeno-associated viruses
(AAV) as vehicles for gene therapy since these viruses can infect resting cells.
Here a new barrier, namely immune response to the viral vector, has appeared. In
any event, gene therapy for sickle cell disease, the ultimate cure for the
disorder, is not imminent.
Without major breakthroughs in gene therapy or bone marrow transplantation
that make these treatments applicable to a large number of patients, drug
intervention will remain the major therapeutic option for sickle cell disease.
The likelihood is low of finding a "magic bullet" medication that substantially
improves sickle cell disease for all or even most patients. Treatment likely
will involve the use of different agents alone or in combination to produce
optimal results. Most chronic illnesses, in fact, require combination drug
therapy. Hypertension, for instance, cannot be managed solely with diuretics.
Physicians test combinations of diuretics, beta blockers, calcium channel
blockers, and angiotensin converting enzyme (ACE) inhibitors to acheive opitmal
control of hypertension while producing the fewest side-effects.
| Treatment Goal | Cure | Maintenance | Acute Pain Management |
| Bone Marrow Transplant | hydroxyurea | nitric oxide | |
| Gene Therapy | clotrimazole | FluocorTM | |
| magnesium pitolate | Inibitiors of endothelial cell adhesion | ||
| arginine butyrate | Antiinflammatory agents |
Combination therapy currently is not an option for sickle cell disease, since only hydroxyurea has been proven to alter the course of the condition. Many, if not most of the agents currently under investigation likely will fall short of investigators' hopes. If a few survive the rigors of testing and joint the clinical armamentarium, however, we could mix and match drugs for patients with sickle cell disease. Ideally, the treatment regimens would include drugs with differing modes of action. Hydroxyurea, for instance, combined with clotrimazole would team a drug that enhances fetal hemoglobin production (hydroxyurea) with one that reduces erythrocyte dehydration (clotrimazole). For a particular patient, sickle cell symptoms might be improved substantially by neither drug alone. The combination, however, might significantly ameliorate the condition.
Table 2 shows how therapies might be combined, using as examples some of the agents currently under investigation. We cannot say whether the therapeutic algorithm that eventually evolves will include these approaches or modalities not yet conceived. The only statement that can be made with confidence is that new vistas in the treatment of sickle cell disease will usher in better and more fulfilling lives for these patients.
A major goal of investigation should be development of interventions that can
be used in very young patients. Many of the problems experienced by adults and
adolescents with sickle cell disease reflect incremental organ damage by bouts
of hypoxia. The affected areas may initially be microscopic. With time, these
foci of injury colasce to form regions of macroscopic injury, such as avascular
necrosis of the femur. Prevention must be the watchword as we seek to improve
the management of patients with sickle cell disease.
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