Contents

1. Background


1. Nature of the Problem


2. Modulators of SCD Severity


3. Origin of the Sickle Mutation
2. Management of Acute Problems


1. Pain


2. Acute chest syndrome


3. Infection


4. Bone marrow necrosis


5. Stroke


6. Splenic sequestration crisis


7. Aplastic crisis


8. Hepatic sequestration crisis


9. Priapism


3. Management of Chronic Problems


1. Pain


2. Anemia


3. infection prophylaxis


4. Avascular bone necrosis


5. Osteomyelitis


6. skin ulcers


7. Renal dysfunction


8. Retinopathy


9. Heart


10. Pregnancy


4. Newer Therapies


1. Hydroxyurea


2. Erythropoietin


3. Butyrate


4. Clotrimazole


5. Nitric Oxide


6. Fluocor^TM


7. Bone marrow transplantation


8. Gene replacement therapy

Background

Nature of the Problem

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.

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.

Modulators of SCD Severity

Fetal Hemoglobin

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 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 the molecule 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.

Alpha-thalassemia

Origin of the Sickle Mutation

Beta-globin haplotypes

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) 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 may, in part have resulted from protection against malaria (see below).

The Hb S mutation arose independently a fifth time in the region of Mesopotamia (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. The fact that the Hb S mutation apparently arose in response to malaria on the Arabian peninsula supports the "malaria explanation" of the prevalence of the gene. The Arabian haplotype is also found in regions of India (Ramasamy et al., 1994) (Kar et al., 1986). The pockets of Hb S in India probably resulted from migration of people from the Middle East along trade routes. This Near East variety of Hb S may on average produce fewer complications than its African counterparts (Perrine et al., 1978).

The Sickle Gene and Malaria

Although malaria remains a major health problem in some tropical regions, 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.

Management of Acute Problems

Pain

The sites affected in acute painful crises vary for each patient. Commonly affected areas are the extremities, thorax, abdomen, and back (Ballas and Delengowski, 1993). Pain tends to recur at the same site for a particular person. For a given patient, the quality of the crisis pain is usually similar as well. During the evaluation, the patient should be asked whether the pain feels like "typical" sickle cell pain. Most can distinguish back pain due to pyelonephritis or abdominal pain due to cholecystitis, for instance, from their typical sickle cell pain.

Opiods

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 could be 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.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Transfusion

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.

Corticosteroids

Acute Chest Syndrome

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 are treated concomitantly with 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 a 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.

Infection

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

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.

Stroke

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

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

Hepatic Sequestration Crisis

Priapism

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.

Management of Chronic Problems

Pain

Non-steroidal anti-inflammatory drugs

Opiod analgesics

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 many of the commonly used 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 can be given for pain control at other facilities in accordance with the guidelines for use of any opiod.

Drug-seeking behavior

An important first step in managing this problem is to define drug-seeking behavior. The use of large amounts of oral opiods or frequent visits to the emergency room do not de facto define 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 will demonstrate incorrigible and sometimes 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.

Support Groups/Psychiatric Support

Anemia

Vitamin Supplementation

Sporadic Transfusion

Chronic Transfusion Therapy

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

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.

Age and severity of anemia

Infection Prophylaxis

Antibiotics

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

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

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

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

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.

Renal Dysfunction

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 creatinine clearance evaluation 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 right 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). Bleeding can continue for weeks. Iron replacement may be necessary in some cases as treatment interventions continue.

Retinopathy

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.

Heart

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.

Pregnancy

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.

Newer Therapies

Therapies of Proven Benefit

Hydroxyurea

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:

1. Age - 18 years or older.
2. Frequent painful vaso-occlusive crises. "Frequent" can reasonably be defined as three or more crises per year that require hospitalization.
3. Use of accepted modes of contraception to prevent conception while on the drug.

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:

1. Pregnancy
2. Allergy to the drug
3. Thrombocytopenia or neutropenia

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

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.

Experimental Therapies

Erythropoietin

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.

Butyrate

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.

Clotrimazole

Clotrimazole and other imidazole antimycotics are potent and specific inhibitors of the Ca²⁺-activated K⁺ channel pathway of normal and sickle erythrocytes. The original report of Alvarez et al. 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 is currently underway at Children's Hospital and Brigham and Women's Hospital evaluating the combined effects of clotrimazole and hydroxyuea in patients with sickle cell disease. The hope is that the agents, which have different mechanisms of action on sickle cells, will work at least cooperatively, and perhaps synergistically, to reduce sickling.

Nitric Oxide

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.

Fluocor^TM

Gene Replacement Therapy

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.

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